Abstract
Background
Although combination formulas containing antihistamines, decongestants, and/or analgesics are sold over‐the‐counter in large quantities for the common cold, the evidence for their effectiveness is limited. This is an update of a review first published in 2012.
Objectives
To assess the effectiveness of antihistamine‐decongestant‐analgesic combinations compared with placebo or other active controls (excluding antibiotics) in reducing the duration of symptoms and alleviating symptoms (general feeling of illness, nasal congestion, rhinorrhoea, sneezing, and cough) in children and adults with the common cold.
Search methods
We searched CENTRAL, MEDLINE via EBSCOhost, Embase, CINAHL via EBSCOhost, LILACS, and Web of Science to 10 June 2021. We searched the WHO ICTRP and ClinicalTrials.gov on 10 June 2021.
Selection criteria
Randomised controlled trials investigating the effectiveness of antihistamine‐decongestant‐analgesic combinations compared with placebo, other active treatment (excluding antibiotics), or no treatment in children and adults with the common cold.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. We categorised the included trials according to the active ingredients.
Main results
We identified 30 studies (6304 participants) including 31 treatment comparisons. The control intervention was placebo in 26 trials and an active substance (paracetamol, chlorphenindione + phenylpropanolamine + belladonna, diphenhydramine) in six trials (two trials had placebo as well as active treatment arms). Reporting of methods was generally poor, and there were large differences in study design, participants, interventions, and outcomes. Most of the included trials involved adult participants. Children were included in nine trials. Three trials included very young children (from six months to five years), and five trials included children aged 2 to 16. One trial included adults and children aged 12 years or older. The trials took place in different settings: university clinics, paediatric departments, family medicine departments, and general practice surgeries.
Antihistamine‐decongestant: 14 trials (1298 participants). Eight trials reported on global effectiveness, of which six studies were pooled (281 participants on active treatment and 284 participants on placebo). The odds ratio (OR) of treatment failure was 0.31 (95% confidence interval (CI) 0.20 to 0.48; moderate certainty evidence); number needed to treat for an additional beneficial outcome (NNTB) 3.9 (95% CI 3.03 to 5.2). On the final evaluation day (follow‐up: 3 to 10 days), 55% of participants in the placebo group had a favourable response compared to 70% on active treatment. Of the two trials not pooled, one showed some global effect, whilst the other showed no effect.
Adverse effects: the antihistamine‐decongestant group experienced more adverse effects than the control group: 128/419 (31%) versus 100/423 (13%) participants suffered one or more adverse effects (OR 1.58, 95%CI 0.78 to 3.21; moderate certainty of evidence).
Antihistamine‐analgesic: four trials (1608 participants). Two trials reported on global effectiveness; data from one trial were presented (290 participants on active treatment and 292 participants on ascorbic acid). The OR of treatment failure was 0.33 (95% CI 0.23 to 0.46; moderate certainty evidence); NNTB 6.67 (95% CI 4.76 to 12.5). Forty‐three per cent of participants in the control group and 70% in the active treatment group were cured after six days of treatment. The second trial also showed an effect in favour of the active treatment.
Adverse effects: there were not significantly more adverse effects in the active treatment group compared to placebo (drowsiness, hypersomnia, sleepiness 10/152 versus 4/120; OR 1.64 (95 % CI 0.48 to 5.59; low certainty evidence).
Analgesic‐decongestant: seven trials (2575 participants). One trial reported on global effectiveness: 73% of participants in the analgesic‐decongestant group reported a benefit compared with 52% in the control group (paracetamol) (OR of treatment failure 0.28, 95% CI 0.15 to 0.52; moderate certainty evidence; NNTB 4.7).
Adverse effects: the decongestant‐analgesic group experienced significantly more adverse effects than the control group (199/1122 versus 75/675; OR 1.62 95% CI 1.18 to 2.23; high certainty evidence; number needed to treat for an additional harmful outcome (NNTH 17).
Antihistamine‐analgesic‐decongestant: six trials (1014 participants). Five trials reported on global effectiveness, of which two studies in adults could be pooled: global effect reported with active treatment (52%) and placebo (34%) was equivalent to a difference of less than one point on a four‐ or five‐point scale; the OR of treatment failure was 0.47 (95% CI 0.33 to 0.67; low certainty evidence); NNTB 5.6 (95% CI 3.8 to 10.2). One trial in children aged 2 to 12 years, and two trials in adults found no beneficial effect.
Adverse effects: in one trial 5/224 (2%) suffered adverse effects with the active treatment versus 9/208 (4%) with placebo. Two other trials reported no differences between treatment groups.
Authors' conclusions
We found a lack of data on the effectiveness of antihistamine‐analgesic‐decongestant combinations for the common cold. Based on these scarce data, the effect on individual symptoms is probably too small to be clinically relevant. The current evidence suggests that antihistamine‐analgesic‐decongestant combinations have some general benefit in adults and older children. These benefits must be weighed against the risk of adverse effects. There is no evidence of effectiveness in young children. In 2005, the US Food and Drug Administration issued a warning about adverse effects associated with the use of over‐the‐counter nasal preparations containing phenylpropanolamine.
Plain language summary
Oral antihistamine‐decongestant‐analgesic combinations for the common cold
Review question
Are combination formulas containing antihistamines (AH), decongestants (DC), and/or analgesics (AN), sold over‐the‐counter, effective in treating the symptoms of the common cold?
Background
On average, young children have six to eight colds per year, and adults have two to four. The common cold is caused by viruses, and symptoms include sore throat, nasal stuffiness and discharge, sneezing, and cough. The common cold usually resolves by itself within one to two weeks; however, it has a large impact on time off work or school.
As there is no cure for the common cold, only symptomatic treatment is available. Several treatments are needed to tackle the variety of symptoms, therefore different products are combined in one pill: antihistamines against sneezing, cough, and nasal discharge; decongestants against nasal stuffiness; and analgesics against sore throat.
Search date
The evidence is current to 10 June 2021.
Study characteristics
Study participants were adults or children with the common cold. The effects of four combinations (AH + DC; AH + AN; AN + DC; AH + AN + DC) were compared to those of placebo (dummy treatment) (24 trials) or an active substance (6 trials). A beneficial effect was defined as a decrease in severity or duration of overall symptoms or of specific symptoms such as stuffy nose, runny nose, cough, or sneezing. We also investigated whether side effects were more common with the combination treatments than with placebo.
Study funding sources
Only three studies reported independent financing.
Key results
We identified three new three new trials (1038 participants) in this 2021 update, bringing the total number of included trials to 30 (6304 participants). The evidence suggests that all combinations have some beneficial effect on overall symptoms of the common cold in adults and older children. There was no effect in younger children. The AH + DC and DC + AN combinations result in more side effects than placebo; however, there was no difference between groups in side effects for the other combinations. In 2005, the US Food and Drug Administration issued a warning about adverse effects associated with the use of over‐the‐counter nasal preparations containing phenylpropanolamine.
Certainty of the evidence
The 30 included studies differed in the way they were conducted, the included participants, the treatments used, and in the way the effect was measured. There was frequently not enough information in the trials to judge the certainty of the evidence.
Summary of findings
Summary of findings 1. Antihistamine‐decongestant compared to placebo for the common cold.
| Antihistamine‐decongestant compared to placebo for the common cold | ||||||
| Patient or population: otherwise healthy adults and children with common cold symptoms Setting: multicentre, university hospital, general practice. Studies were performed in the UK, Peru, Spain, Belgium, Austria, and Finland. Intervention: antihistamine‐decongestant Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo | Risk with antihistamine‐decongestant | |||||
| Global evaluation | Study population | OR 0.31 (0.20 to 0.48) | 565 (6 RCTs) | ⊕⊕⊕⊝ MODERATEa | Participants or physicians evaluated the overall response to the treatment at end of follow‐up. Treatment failure means participants or physicians did not evaluate the treatment as beneficial. On the final evaluation day (follow‐up: 3 to 10 days), 41% of participants in the placebo group had a favourable response, compared to 66% of participants in the active treatment group. It should be noted that 1 trial reported number of colds as the unit of analysis (Bye 1980). |
|
| 553 per 1000 | 298 per 1000 (223 to 363) | |||||
| Adverse effects: all | Study population | OR 1.58 (0.78 to 3.21) | 842 (7 RCTs) | ⊕⊕⊕⊝ MODERATEb | ||
| 236 per 1000 | 328 per 1000 (195 to 498) | |||||
| Adverse effects: drowsiness, hypersomnia, and excessive sleepiness | Study population | OR 1.38 (0.63 to 3.00) | 692 (5 RCTs) | ⊕⊕⊝⊝ LOWc | In 2 of the 5 studies reporting this adverse effect, it was less frequent with active treatment, whilst in the other 3 studies it was less frequent with placebo. | |
| 55 per 1000 | 74 per 1000 (35 to 148) | |||||
| Adverse effects: dry mouth | Study population | OR 3.75 (1.74 to 8.10) | 640 (4 RCTs) | ⊕⊕⊕⊕ HIGH | ||
| 28 per 1000 | 98 per 1000 (48 to 190) | |||||
| Adverse effects: insomnia | Study population | OR 2.89 (0.88 to 9.56) | 344 (2 RCTs) | ⊕⊕⊕⊝ MODERATEb | ||
| 30 per 1000 | 81 per 1000 (26 to 227) | |||||
| Adverse effects: gastrointestinal upset | Study population | OR 2.81 (0.64 to 12.33) | 296 (2 RCTs) | ⊕⊕⊕⊝ MODERATEb | ||
| 13 per 1000 | 36 per 1000 (8 to 141) | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aDowngraded one level because most trials are at risk of bias due to lack of reporting on blinding, randomisation, and allocation method; two trials are also at risk of reporting bias. bDowngraded one level due to imprecision: wide confidence interval includes 1. cDowngraded two levels due to serious inconsistency.
Summary of findings 2. Antihistamine‐analgesic compared to placebo for the common cold.
| Antihistamine‐analgesic compared to placebo for the common cold | ||||||
| Patient or population: otherwise healthy adults and children with common cold symptoms Setting: general practice, or setting not mentioned. Studies performed in the USA and the UK. Intervention: antihistamine‐analgesic Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | ||
| Risk with placebo | Risk with antihistamine‐analgesic | |||||
| Global evaluation | Study population | OR 0.33 (0.23 to 0.46) | 582 (1 RCT) | ⊕⊕⊕⊝ MODERATEa | The active treatment also contained caffeine and ascorbic acid; control was ascorbic acid. Outcome based on results of Koytchev 2003, reported on day 6. In Koytchev 2003, the proportion of participants who were completely cured at the end of the trial was 70% with Grippostad and 43% with control (ascorbic acid). |
|
| 568 per 1000 | 303 per 1000 (233 to 377) | |||||
| Adverse effects: drowsiness, hypersomnia, and excessive sleepiness | Study population | OR 1.64 (0.48 to 5.59) | 272 (2 RCTs) | ⊕⊕⊝⊝ LOWa,b | The active treatment also contained caffeine, which also may have adverse effects; wide confidence interval including 1: uncertain whether adverse effects are more frequent with treatment. | |
| 33 per 1000 | 54 per 1000 (16 to 162) | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aDowngraded one level due to risk of bias (random sequence generation and allocation concealment unclear, inadequate blinding). bDowngraded one level due to imprecision: limited number of participants; broad confidence interval including 1.
Summary of findings 3. Analgesic‐decongestant compared to placebo for the common cold.
| Analgesic‐decongestant compared to placebo for the common cold | ||||||
| Patient or population: otherwise healthy adults and children with common cold symptoms Setting: university hospital, general practice, or setting not mentioned. Studies performed in the UK, Germany, and the USA. Intervention: analgesic‐decongestant Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo | Risk with analgesic‐decongestant | |||||
| Global evaluation | Study population | OR 0.28 (0.15 to 0.52) | 181 (1 RCT) | ⊕⊕⊕⊝ MODERATEa | Only Middleton 1981 assessed this outcome. On day 5, overall subjective effectiveness at the end of the study was assessed by asking "on the whole do you think the tablets have helped you?". | |
| 578 per 1000 | 277 per 1000 (170 to 416) | |||||
| Adverse effects: all | Study population | OR 1.62 (1.18 to 2.23) | 1797 (6 RCTs) | ⊕⊕⊕⊕ HIGH | ||
| 111 per 1000 | 168 per 1000 (129 to 218) | |||||
| Adverse effects: drowsiness, hypersomnia, lethargy, excessive sleepiness, and other central nervous system adverse effects | Study population | OR 1.34 (0.76 to 2.37) | 1644 (5 RCTs) | ⊕⊕⊕⊝ MODERATEb | ||
| 32 per 1000 | 42 per 1000 (24 to 72) | |||||
| Adverse effects: dry mouth | Study population | OR 1.43 (0.53 to 3.83) | 764 (3 RCTs) | ⊕⊕⊝⊝ LOW b,c | ||
| 18 per 1000 | 26 per 1000 (10 to 67) | |||||
| Adverse effects: gastrointestinal | Study population | RR 1.71 (0.97 to 3.01) | 1644 (5 RCTs) | ⊕⊕⊕⊕ HIGH | ||
| 27 per 1000 | 46 per 1000 (26 to 81) | |||||
| Adverse effects: dizziness, lightheadedness | Study population | OR 2.86 (1.02 to 8.01) | 1287 (4 RCTs) | ⊕⊕⊕⊕ HIGH | ||
| 8 per 1000 | 24 per 1000 (9 to 64) | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aDowngraded one level due to lack of reporting on blinding, randomisation, and allocation concealment. One study was also at risk of randomisation and allocation bias, and one study was at risk of reporting bias. bDowngraded one level due to imprecision: wide confidence interval includes 1. cDowngraded one level due to inconsistency between trial results.
Summary of findings 4. Antihistamine‐analgesic‐decongestant compared to placebo for the common cold.
| Antihistamine‐analgesic‐decongestant compared to placebo for the common cold | ||||||
| Patient or population: otherwise healthy adults or children with common cold symptoms Setting: paediatric clinic (1 study), setting not mentioned (2 studies). Studies performed in Turkey, the USA, and the UK. Intervention: antihistamine‐analgesic‐decongestant Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo | Risk with antihistamine‐analgesic‐decongestant | |||||
| Global evaluation: after 3 days of treatment (included children 2 to 12 years old only) | Study population | OR 0.34 (0.09 to 1.31) | 109 (1 RCT) | ⊕⊕⊝⊝ LOWa,b | Outcome reported as clinical recovery. | |
| 938 per 1000 | 836 per 1000 (574 to 952) | |||||
| Global evaluation: after 5 days of treatment (included children 2 to 12 years old only) | Study population | OR 1.17 (0.49 to 2.77) | 83 (1 RCT) | ⊕⊕⊝⊝ LOWa,b | Outcome reported as clinical recovery. | |
| 450 per 1000 | 489 per 1000 (286 to 694) | |||||
| Global evaluation: on the morning after evening dosing (included adults only) | Study population | OR 0.47 (0.33 to 0.67) | 548 (2 RCTs) | ⊕⊕⊝⊝ LOWa,b | In Thackray 1978, participants rated their general feeling (useless, almost useless, not very good, good, very good, excellent) in the morning. In Mizoguchi 2007, overall relief was measured on a 5‐point severity scale the morning following the nighttime intake of medication. |
|
| 658 per 1000 | 475 per 1000 (388 to 563) | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aDowngraded one level due to lack of reporting on random sequence generation, allocation concealment, and blinding. One study was at risk of attrition bias. bDowngraded one level due to imprecision: confidence interval includes 1.
Background
Description of the condition
The common cold is probably the most common illness known. It is a recurrent, acute respiratory tract infection which affects the whole population. On average, young children have six to eight colds per year, and adults have two to four (Gwaltney 2002a; Heikkinnen 2003). The occurrence of the common cold is clearly related to the seasons. In temperate regions of the Northern Hemisphere, the frequency of respiratory infections increases rapidly in the autumn, remains fairly high throughout the winter, and decreases in the spring. In tropical areas, most colds occur during the rainy season (Heikkinnen 2003).
Although the common cold is not a serious condition, it has a substantial impact on time off from work and school, general practitioner consultations, and money spent on both prescription and over‐the counter (OTC) medications. In the USA there is a loss of approximately 22 million school days and 20 million work days, as well as 25 million visits to the family physician annually due to the common cold (Heikkinnen 2003; NIAID 2007).
More than 200 different viruses are known to cause the common cold. Rhinovirus is by far the most frequent cause of the common cold (30% to 50%), although a substantial number of colds are caused by coronaviruses (10% to 15%). Respiratory syncytial virus, influenza, parainfluenza, and adenovirus have also been implicated (Wat 2004). The relative proportion of the different virus types depends on several factors such as age, season, virus sampling and detection methods. In 20% to 30% of cases no cause can be found.
Most studies of common colds are based on rhinovirus due to its prevalence (Wat 2004). The infection is transmitted to the nasal epithelium by airborne droplets, and by hand from fomites. The initial accumulation of rhinovirus in the eyes and nose leads to attachment of the virus to intercellular receptors at the back of the throat. The detailed mechanisms by which viral infection causes changes in the nasal mucosa are still not fully understood. The absence of epithelial destruction during rhinovirus infections has led to the hypothesis that the clinical symptoms of the common cold might not be caused by a direct cytopathic effect of the viruses, but instead are primarily caused by the inflammatory response of the host. There is evidence of increased concentrations of several mediators which affect the vascular tissues of the nasal epithelium causing engorgement and vascular permeability (Gwaltney 2002a; Gwaltney 2002b; Heikkinnen 2003; Jacobs 2013; Wat 2004).
The symptoms of the common cold arise after an incubation period that can vary considerably between different viruses. The incubation period for a rhinovirus infection is 8 to 12 hours (Gwaltney 2002a). Generally symptom severity increases rapidly, peaking within two to three days after infection, and decreasing soon after. The mean duration of the common cold is 7 to 10 days, but in a proportion of people some symptoms may still be present after three weeks. Rhinovirus infections typically start with a 'scratchy' throat, which is soon accompanied by nasal stuffiness and discharge, sneezing, and cough. The soreness of the throat usually disappears quickly, whereas the initial watery rhinorrhoea turns thicker and more purulent. The purulence of the nasal discharge is not associated with changes in the nasopharyngeal bacterial flora. Fever is an infrequent finding during rhinovirus infections in adults, but is fairly common in children (Heikkinnen 2003).
Description of the intervention
Since there is no widely available cure or vaccination for the common cold, treatment is focused on alleviating the symptoms. There is a small amount of evidence that first‐generation antihistamines have a limited effect on rhinorrhoea and sneezing (De Sutter 2015). Decongestants can reduce nasal blockage and secretion through vasoconstriction of the nasal vessels (Deckx 2016). Analgesics can relieve headache, muscle ache, sore throat, or mild fever, and non‐steroidal anti‐inflammatory drugs (NSAIDs) may suppress the inflammatory response caused by the viral infection. There is some evidence that NSAIDs relieve discomfort caused by a cold (Kim 2015).
How the intervention might work
Combinations of antihistamines, decongestants, and analgesics are used to relieve the broad spectrum of common cold symptoms. The evidence of the effectiveness of these combinations in relieving cold symptoms is summarised in this review.
Why it is important to do this review
Although combination formulas containing antihistamines, decongestants, and/or analgesics are prescribed or sold OTC in large quantities for the common cold, their effectiveness is not clear. A previous Cochrane Review reviewed the evidence for the effectiveness of antihistamines in monotherapy in treating the common cold (De Sutter 2015). Our review complements that work by summarising the evidence on the effectiveness of a broader range of therapies containing antihistamines in combination with other active agents such as analgesics or decongestants, or both.
Objectives
To assess the effectiveness of antihistamine‐decongestant‐analgesic combinations compared with placebo or other active controls (excluding antibiotics) in reducing the duration of symptoms and alleviating symptoms (general feeling of illness, nasal congestion, rhinorrhoea, sneezing, and cough) in children and adults with the common cold.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials comparing treatment of the common cold with a combination of antihistamine and/or decongestant and/or analgesic versus placebo or other active treatments (excluding antibiotics) in adults and children.
Types of participants
We included otherwise healthy adults and children with common cold symptoms, who met the case definition for inclusion in the review. The case definition of the common cold comprises symptoms of runny and/or stuffy nose and sneezing, with or without symptoms of headache and cough. We excluded participants if they suffered from allergic rhinitis, had concurrent respiratory infections or other chronic diseases, atopic eczema, asthma, fever (> 38 °C), sinusitis, exudative pharyngitis, or had had symptoms for more than a week. Participants were volunteers recruited from the community, hospital, or community outpatients. We assessed additional evidence from studies of healthy volunteers challenged with rhinovirus in experimental conditions.
Types of interventions
We included combination therapies containing analgesics and/or decongestants and/or antihistamines administered orally. We permitted other active ingredients with the exception of antibiotics. This treatment was compared with a control. The control was either active, placebo, or no treatment.
Types of outcome measures
Primary outcomes
Global evaluation of effectiveness (expressed as complete relief, marked, moderate, slight/no relief at all; or the proportion of participants with treatment failure).
Adverse effects of treatment.
Secondary outcomes
Decrease in the amount, or duration, of individual common cold symptoms (sneezing, nasal congestion, rhinorrhoea, or cough). These symptoms can be assessed by means of severity scales (absent, mild, moderate, severe) or by global evaluation of effectiveness (complete relief, marked, moderate, slight or no relief at all).
Objective assessments such as rhinometry to assess mean nasal airflow, rhinoscopy to assess redness and swelling of nasal mucosa, nasal secretions and nasal obstruction, counts of number of sneezes and weight of nasal secretions.
Search methods for identification of studies
Electronic searches
For the 2021 search update we searched additional databases. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library; 2021, Issue 5) (www.cochranelibrary.com/) (accessed 10 June 2021), MEDLINE via (EBSCOhost) (2012 to 10 June 2021), Embase (2012 to 10 June 2021), CINAHL via EBSCOhost (Cumulative Index to Nursing and Allied Health Literature) (10 June 2021), LILACS (Latin American and Caribbean Health Science Information database) (10 June 2021), and Web of Science, Clarivate (10 June 2021).
The search terms we used for MEDLINE and CENTRAL are provided in Appendix 1. We adapted the search for Embase (Appendix 2), CINAHL (Appendix 3), LILACS (Appendix 4), and Web of Science (Appendix 5).
Details of the previous search are provided in Appendix 6.
Searching other resources
We searched two trials registries: the World Health Organization International Clinical Trials Registry Platform (www.who.int/clinical-trials-registry-platform) and ClinicalTrials.gov (clinicaltrials.gov/) (latest search 10 June 2021). We searched the reference lists of the retrieved articles and contacted experts and pharmaceutical companies to locate any potentially relevant studies. We imposed no language or publication restrictions.
Data collection and analysis
Selection of studies
Two review authors (ADS, AS) independently screened the titles and abstracts of studies identified by the search of the original review. One review author (LE) performed the searches for this review update. We excluded trials that failed to meet the inclusion criteria. We retrieved and assessed the full papers of studies identified by the search for which there was no abstract.
Data extraction and management
Two review authors (ADS, AS) independently extracted data from the trials identified in the original review. One review author (ADS) extracted data from the three new trials included in this update. Any disagreements were resolved by discussion between two review authors (ADS, MVD). It was not necessary to include a third review author as arbiter. We attempted to contact trial authors for additional data where necessary, but were unsuccessful. We analysed trials including young children, and trials in older children and adults independently, where applicable. We divided the included trials into four categories:
combination 1: antihistamine and decongestant;
combination 2: antihistamine and analgesic;
combination 3: analgesic and decongestant; and
combination 4: antihistamine and analgesic and decongestant.
We extracted data on the amount, or duration, of individual common cold symptoms (sneezing, nasal congestion, rhinorrhoea, or cough) and on objective assessments such as rhinometry to assess mean nasal airflow, rhinoscopy to assess redness and swelling of nasal mucosa, nasal secretions and nasal obstruction, counts of number of sneezes and weight of nasal secretions.
Assessment of risk of bias in included studies
We assessed risk of bias of the included trials using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). In the first publication of this review, two review authors (AK, OL with supervision from MVD) independently assessed risk of bias based on the following risk of bias domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential sources of bias. Any disagreements were discussed with the supervisor and resolved by consensus. The results of the risk of bias assessment are reported in the risk of bias tables in the Characteristics of included studies section.
Measures of treatment effect
The ways in which outcome measures were presented varied widely across trials. In most studies the outcome measures were a global evaluation of effectiveness (e.g. complete relief, marked, moderate, slight or no relief at all) or a decrease in the severity of individual common cold symptoms assessed by severity scales or by global evaluation of effectiveness. We did not extract data where individual severity scores were added up and effectiveness was evaluated by comparing these sum scores, because the clinical meaning of sum scores is unclear. We compared the proportion of participants with treatment failure at the end of treatment to evaluate the global effectiveness. We used odds ratio (OR) of treatment failure with 95% confidence interval (CI) to report the effect estimate for dichotomous data. We used mean difference (MD) or standardised mean difference (SMD) with standard deviation (SD) for continuous variables (Review Manager 2020).
Unit of analysis issues
We used the individual participant as the unit of analysis for meta‐analysis. If the unit of randomisation was not the same as the unit of analysis, such as in cluster‐randomised trials, we would apply the correction for clustering using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If studies included separate arms with different drugs from the same class (e.g. one arm with paracetamol and another arm with acetylsalicylic acid), these groups were combined. We included one cross‐over trial in the review (Thackray 1978).
Dealing with missing data
We attempted to contact the trial authors to obtain missing data where required. If this information was not available or could not be obtained, we used intention‐to‐treat (ITT) analysis when pooling the available data. ITT analysis assumes that all missing data represent unsuccessful outcomes.
Assessment of heterogeneity
We assessed the presence of heterogeneity using a two‐step approach. Firstly, we assessed heterogeneity between trials at face value (e.g. obviously different populations, settings, treatment regimens). We did not pool data if clinical heterogeneity was clearly present. Secondly, we assessed statistical heterogeneity using the Chi2 test and the I2 statistic as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This evaluates whether variations in the results of different trials are attributable to chance alone or are the result of differences in trial design. We considered a Chi2 test result with a P < 0.10 and an I2 statistical result of 50% or higher as indicative of substantial heterogeneity.
Assessment of reporting biases
We aimed to assess risk of publication bias by using funnel plots if 10 or more studies were available for a given outcome. In the presence of asymmetry, we intended to use the 'trim and fill' method to assess the effect of this asymmetry on the conclusions (Higgins 2011).
Data synthesis
We included in the meta‐analysis the results from included studies that reported any of the prespecified outcomes. We pooled data only if they were available, sufficiently similar, and of sufficient quality as described in Measures of treatment effect. We used a random‐effects model for meta‐analysis (Higgins 2011).
Subgroup analysis and investigation of heterogeneity
We explored the effects of treatments in children versus adults in a subgroup analysis.
Sensitivity analysis
We did not perform sensitivity analyses, as insufficient data were available for the pooling of treatment effects.
Summary of findings and assessment of the certainty of the evidence
We created four summary of findings tables (Table 1; Table 2; Table 3; Table 4) using the following outcomes for each comparison: global effectiveness and adverse effects. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies which contributed data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We used the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), employing GRADEpro GDT software (GRADEpro GDT). We justified all decisions to down‐ or upgrade the certainty of the evidence using footnotes and made comments to aid the reader's understanding of the review where necessary.
Results
Description of studies
See Characteristics of included studies and Characteristics of excluded studies tables and the PRISMA flow chart (Figure 1).
1.
Study flow diagram of searches after 2012.
Results of the search
We performed searches in 2012 and 2021. We identified 5642 references in the searches since 2012, of which 4781 remained after duplicates were removed. Of these, 4712 studies were excluded on the basis of title or abstract, or both. In total, we retrieved 69 papers for more detailed evaluation. We included 27 trials in the 2012 publication of this review (De Sutter 2012), and three new trials in the 2021 update (Eccles 2014; Montijo‐Barrios 2011; Zhang 2018). This review is based on 30 studies (31 comparisons). We excluded 37 trials. We identified one ongoing study, NCT02904304, and one study awaiting classification (NCT02246166).
Included studies
The included trials showed important differences in participants, interventions, outcomes, and study designs. In most trials there was inadequate information to allow pooling of data, and our requests to trial authors for additional data remained unanswered. Pooling of data was therefore very limited, and consequently we analysed four different treatment combinations in the review. Available numerical outcomes of the different trials are summarised in Additional tables.
Details of included population, setting, inclusion and exclusion criteria, intervention and dosage, outcome measures, and main methodological shortcomings (risk of bias assessment) for the individual studies are presented in the Characteristics of included studies table.
We included 30 randomised controlled trials involving a total of 6304 participants suffering from the common cold. The interventions consisted of combinations of antihistamines (azatadine, pyrilamine, diphenylpyraline, clemastine, diphenhydramine, dexchlorpheniramine, doxylamine, brompheniramine, chlorpheniramine, pheniramine, triprolidine, promethazine, loratadine, dexbrompheniramine, carbinoxamine) with decongestants (ephedrine, pseudoephedrine, phenylpropanolamine, 1,2,3,4‐tetrahydro‐1‐naphtyl imidazoline) and/or analgesics (paracetamol; NSAIDs (acetylsalicylic acid, ibuprofen, ketoprofen, naproxen) or aminophenazone).
We divided the trials into four treatment comparison groups. The first group consisted of 14 trials evaluating antihistamine‐decongestant combinations; in three of these trials active treatment also contained an antitussive. The second group consisted of three trials that evaluated antihistamine‐analgesic combinations. The third group comprised six trials examining analgesic‐decongestant combinations. Finally, the fourth group of six studies investigated a combination of the three agents. In this comparison also three trials active treatment also contained an antitussive. In one study two different combinations were used: analgesic + antihistamine for nighttime and analgesic + decongestant for daytime. We included the daytime combination in the analgesic‐decongestant group and the nighttime combination in the antihistamine‐analgesic group.
Twenty‐one trials compared active treatment with placebo. One trial had a cross‐over design. Four trials had more than one active treatment arm (one of the components of the combination, a different dosage of the same combination, or a different combination). In five trials the control group received an active treatment: paracetamol (three trials), chlorphenindione + phenylpropanolamine + belladonna (one trial), and diphenhydramine (one trial).
Most of the included trials involved adult participants. Children were included in nine trials: three trials included very young children (from six months to five years; Clemens 1997; Hutton 1991; Montijo‐Barrios 2011); one trial included children aged 2 to 16 years (Martinez 1994), in one trial children were at least four years old (Weippl 1984), in two trials at least six years old (Galvez 1985; Scavino 1985), and in one trial two to 12 years (Unuvar 2007). One trial included adults and children aged 12 years or older (Schrooten 1993).
The trials took place in a variety of settings, including university clinics, paediatric departments, family medicine departments, and general practice surgeries. Eight trials were multicentre trials. Participants in two trials were experimentally infected with cold viruses, whilst participants in the remaining 28 trials had community‐acquired colds. In most studies the recruitment of the participants was not clearly defined.
In the vast majority of trials the inclusion criterion was the presence of common cold symptoms. There was significant diversity amongst trials. In general a minimal score on a symptom severity scale was required. This score was calculated by adding the individual severity scores of a number of typical common cold symptoms such as headache, sneezing, chills, sore throat, nasal discharge, nasal obstruction, cough, and malaise. In two trials the inclusion criterion was the serum neutralising antibody titre (1:2) to the challenge rhinovirus. In one trial the inclusion criterion was the presence of cough attributed to an upper respiratory tract infection. In another study the inclusion criterion was nasal obstruction assessed by rhinomanometry. In yet another trial the inclusion criterion was the presence of congestive rhinitis.
In 18 trials respiratory allergy was an explicit exclusion criterion. One trial was conducted outside the pollen season, and another trial excluded participants with recent hay fever. In 10 trials it was unclear whether patients with allergies were excluded.
In the majority of trials the duration of symptoms before inclusion was less than 48 hours. In three trials this was up to three days, in two trials up to five days, and in two (paediatric) trials up to seven days. In one paediatric trial this was unclear. In the trials in which participants were experimentally infected with cold viruses, the therapy started 24 and 30 hours after virus challenge. The majority of trials lasted five days, but this varied from single administration to eight days of treatment. Diaries were usually kept for the duration of treatment. The longest follow‐up period was 14 days.
Only three trials reported independent financial support. All others were fully or partly supported by pharmaceutical companies by means of grants, supply of study drugs, or other forms of assistance. In 10 trials the source of financial support was not clear.
Excluded studies
We excluded 34 trials after detailed assessment, as follows:
the inclusion criteria were not in agreement with our protocol (10 trials) (Axelsson 1971; Connell 1967; Ghorayeb 2006; Kaminszczik 1983; McLaurin 1966; Mora 1993; Nelson 1970; Picon 2013; Taborelli 1975; Todd 1984);
other interventions were studied (15 trials) (Bachert 2005; Bhattacharya 2013; Bonifaci 1977; Carta 1967; Cohen 2017; Hosseini 2016; Krishnaprasad 2012; Kuspert 1965; Lea 1984; Mariano 2011; Paul 2004; Peter 1972; Sakchainanont 1990; Schuetz 2014; Septimus 2017);
outcome measures were different (four trials) (Cantekin 1980; Randall 1979; Schachtel 2010; Virtanen 1982); and
the study design was not in agreement with the protocol (five trials) (Chung 1991; Lu 1993; Lu 2010; Pasotti 1966; Yong 1991).
Five studies were registered as ongoing, but we could not find published data: three studies were withdrawn by the sponsor and have been excluded (NCT01938144; NCT02678234; NCT02730364); one study has been completed and we are awaiting the publication of findings (NCT02246166); and one study was registered in 2016 but is planning to start recruitment in 2020 and has been assessed as an ongoing study (NCT02904304). We will enter the data in the review as soon as they are available. There was complete agreement amongst the review authors assessing the trials.
Risk of bias in included studies
A summary of the risk of bias assessment is illustrated in Figure 2 and Figure 3.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
The method of sequence generation was not described in the majority of the included trials. Only seven trials described the sequence generation, such as the use of a computerised random number generator or envelopes (Berkowitz 1989; Curley 1988; Eccles 2014; Loose 2004; Montijo‐Barrios 2011; Schrooten 1993; Unuvar 2007).
There was insufficient information regarding allocation concealment in almost all of the included trials, with either no description of the method of concealment or insufficient detail provided to permit a definitive judgement on how concealment was achieved.
Blinding
Blinding was poorly reported in most trials. There was insufficient information documented to permit a judgement as to whether blinding was successful. Blinding of study participants and assessors was seldom reported, with only a few trials stating that they were double‐blinded. Only half of the trials reported that the placebo and active drugs were identical in nature.
Incomplete outcome data
Attrition and exclusion were adequately addressed across most trials. However, the impact of incomplete data is seldom discussed, thereby making interpretation of the results and assessment of their generalisability difficult. Most trials did not carry out ITT analysis for the clinical outcomes, but reported ITT analysis for adverse events.
Selective reporting
Seventeen trials documented their study protocol and reported on their prespecified outcomes. Adverse effects were reported in only a small proportion of the trials, some of which failed to clarify if the adverse reactions were seen in the placebo or treatment group(s).
Other potential sources of bias
It was noted that 12 of the trials were either funded by pharmaceutical companies or that the authors of the trial were employed by a pharmaceutical company with interests in the trial drug. The majority of trials also failed to document the methods used to recruit participants, which could introduce selection bias.
Effects of interventions
See: Table 1; Table 2; Table 3; Table 4
We included 30 trials involving a total of 6304 participants with the common cold including 31 treatment comparisons. The control intervention was placebo in 26 trials and an active substance (paracetamol, chlorphenindione + phenylpropanolamine + belladonna, diphenhydramine) in six trials (two trials had placebo as well as active treatment arms). Fourteen trials studied antihistamine and decongestant combinations (antihistamine‐decongestant); three studied antihistamine and analgesic combinations (antihistamine‐analgesic); six studied analgesic and decongestant combinations (antihistamine‐decongestant); and six studied antihistamine, analgesic, and decongestant combinations (antihistamine‐analgesic‐decongestant). In one trial two different combinations were used: analgesic + antihistamine for nighttime and analgesic + decongestant for daytime. We included the daytime combination in the analgesic‐decongestant group, and the nighttime combination in the antihistamine‐analgesic group. The reporting of methods used was poor in most trials, and there were large differences in trial design, participants, interventions, control conditions, and outcomes.
Overall, most combinations had a significant effect on general recovery in adults and older children. Antihistamine‐decongestant odds ratio (OR) of treatment failure was 0.27 (95% confidence interval (CI) 0.15 to 0.50). We could not pool data for the other outcomes. The combinations containing a decongestant also had some effect on nasal obstruction. Rhinorrhoea and cough improved with antihistamine‐decongestant‐analgesic, whilst antihistamine‐decongestant combinations may have some effect on severity of sneezing, but not on the first day of treatment. The size of the effect on specific symptoms, when reported, was less than one severity point on a four‐ or five‐point scale. The combinations containing antihistamine‐decongestant and analgesic‐decongestant had significantly more adverse effects than placebo. Many different adverse effects are mentioned. There is insufficient evidence for the effectiveness (global recovery) in young children.
Combination 1: oral antihistamine‐decongestant
Fourteen trials evaluated the effectiveness of oral antihistamine‐decongestant in combination: 12 in adults, and two in children.
Short description of the studies
Aschan 1974 studied the effect of promethazine + ephedrine and clemastine + phenylpropanolamine compared to placebo in 60 adults with nasal blockage due to acute rhinitis. Repeated rhinometric recordings at 30‐ to 50‐minute intervals were performed after one dose of the medication. The recordings took place over a nine‐hour period. The effect was evaluated as a positive or negative rhinometric response.
Berkowitz 1989 treated 261 participants with cold‐like symptoms with loratadine + pseudoephedrine or placebo. Participants kept a diary during the five days of treatment, and scored the overall response and the severity of different symptoms (nasal stuffiness, nasal discharge, sneezing, and cough) daily. The overall response and severity score of the different symptoms were evaluated by the physician on days three and five of treatment.
Bye 1980 studied the effect of triprolidine + pseudoephedrine in 199 cold episodes in adults. Some participants were entered several times, having had several cold episodes during the course of the trial. Participants marked the severity of 12 symptoms (e.g. runny nose, sneezing, blocked nose, cough) and seven signs (four of which were possible unwanted adverse effects) on a daily diary card. Treatment was provided for as long as required. An overall assessment was made by the participants 8 to 10 days after the start of treatment.
Curley 1988 studied the effect of dexbrompheniramine maleate + pseudoephedrine in comparison with placebo in 86 adults with symptoms of the common cold. Treatment lasted one week. Symptom severity was scored daily on a five‐point scale in a 14‐day diary.
Debelic 1973 studied the effect of clemastine + phenylpropanolamine in comparison with belladonna + chlorphenamine + phenylpropanolamine in 40 adults. There was no placebo or 'no treatment' group. The medication was administrated twice daily for eight days. Severity of nasal obstruction, rhinorrhoea (counts of used tissues), and sneezing were assessed daily. Global effectiveness was rated by participants and physicians separately on the last day of treatment.
Galvez 1985 included 60 participants aged six years or older. Almost a quarter of participants were lost to follow‐up. The active treatment consisted of azatadine + dextromethorphan + pseudoephedrine for five days. Effectiveness was evaluated using a sum score of different symptoms including rhinorrhoea, nasal congestion, cough, and sneezing. Individual scores were not provided. Overall therapeutic response was evaluated on days three and five using a five‐point scale (exacerbated/poor/fair/good/excellent).
Lebacq 1994 included 36 participants (18 adults and 18 children aged 6 to 12 years) with acute congestive rhinitis and compared the effect of phenylpropanolamine + carbinoxamine and phenylpropanolamine + pheniramine maleate + mepyramine maleate with placebo on bilateral rhinometry results, the subjective evaluation of nasal congestion, and the aspect of the nasal mucosa. Participants were kept under standardised circumstances for one day, and measurements were performed at different time points after one dose of medication (0.5, 1, 2, 4, 6.5, 11 hours (adults), or 10 hours (children) after medication administration). In children, the treatment was continued over four days, and effectiveness of the combination was assessed by the parents. This trial had methodological problems: the aetiology of congestive rhinitis and duration of symptoms before the start of treatment were unclear; investigators were not blinded; and one of the treatment groups was not masked (combination 2).
Robert 2004 studied the effect of the combination of ebastine + pseudoephedrine compared with placebo in 204 participants with the common cold. The medication was administrated once daily for three days. On the last day, a physician evaluated the overall effectiveness, the evolution of the symptoms (runny nose, blocked nose, sneezing), determined nasal peak flow, and estimated the likelihood of the participant to take the medication again.
Scavino 1985 (in a trial identical to the trial by Galvez 1985) included 58 participants aged six years or older. Ten participants were lost to follow‐up. The active treatment consisted of azatadine + dextromethorphan + pseudoephedrine. Effectiveness was evaluated in the same way as in the Galvez trial.
Schrooten 1993 evaluated the effect of a combination of astemizole + pseudoephedrine in comparison with placebo in 83 participants aged 12 to 65 years. During seven days of treatment the total nasal symptom severity score (nasal discharge, nasal obstruction, sneezing, postnasal drip), total symptom severity score (nasal symptoms plus coughing, sore throat, headache, myalgia, and general discomfort), and adverse effects were recorded daily by a pharmacist co‐investigator. Used nasal tissues were collected and weighed.
Virtanen 1983 studied the effectiveness of dexchlorpheniramine maleate + pseudoephedrine in comparison with placebo in 92 adults with acute rhinitis. Participants registered the mean severity score of nasal obstruction, secretion, itching, and sneezing on a four‐point severity scale (absent, mild, moderate, severe) daily for 10 days.
Hutton 1991 studied brompheniramine + phenylephrine + phenylpropanolamine in comparison with placebo in 54 children aged six months to five years. Evaluation took place 48 hours after the start of treatment. Congested or runny nose was assessed by the parents by means of a four‐point severity scale.
Clemens 1997 included 59 children aged six months to five years in a study comparing brompheniramine + phenylpropanolamine with placebo. Parents were asked to evaluate the cold symptoms two hours after the child taking the medication. In total, 175 responses were registered in the 59 children.
Finally, the Weippl 1984 trial included 60 children aged four years and older. Overall therapeutic response of the combination of azatadine maleate + pseudoephedrine + dextromethorphan was compared with an expectorant containing diphenhydramine. The overall therapeutic response and the change in severity score for symptoms of common cold, including rhinorrhoea, nasal congestion, sneezing, and cough, were rated by a physician on days three and five of treatment. The time of onset of symptomatic relief was noted.
Primary outcomes
1. Global evaluation of effectiveness
Adults
Eight trials evaluating cold episodes assessed the global effectiveness of an oral combination of antihistamine and decongestant on the course of the common cold (Berkowitz 1989; Bye 1980; Debelic 1973; Galvez 1985; Robert 2004; Scavino 1985; Schrooten 1993; Weippl 1984). Six trials showed some effect.
In Bye 1980, active treatment was significantly more effective on cold symptoms compared to placebo at final evaluation, that is 8 to 10 days after the start of therapy (P < 0.01). In Berkowitz 1989, physicians' scores of overall effectiveness favoured active treatment at both evaluation time points (P = 0.01 and P = 0.02), but participant diary scores favoured active treatment only on day three (P = 0.02). In Robert 2004, the proportion of participants for whom the investigator scored the effectiveness of the treatment received as good or excellent after three days of therapy was significantly higher in the active treatment group (75.8%) compared to the placebo group (57.6%; P < 0.001). In Schrooten 1993, the global impression expressed by the participants on day seven favoured the combination, with 55% of participants reporting good to excellent results on astemizole‐pseudoephedrine versus 35% on placebo (P = 0.013). In Galvez 1985, there was a significant difference in the total number of participants evaluated by the physician as having a favourable response (fair to excellent) between the active treatment group and the placebo group (P = 0.014 and P = 0.024) at both evaluation times. In Scavino 1985, the response was better (fair to excellent) with active treatment compared to placebo (P = 0.010 and P = 0.012) at both evaluation times. The Debelic 1973 trial compared two active combinations, finding no difference between the two treatment groups in the number of participants reporting treatment as good or excellent. In Weippl 1984, the overall response was rated at day three and on the final visit (day five) by the physician on a four‐point scale. On day three, physicians evaluated the response as good or excellent in 83% of participants in the active treatment group and 7% of participants in the control group (P < 0.001). At day five this was 86% and 30%, respectively (P < 0.001).
Six trials reported adequate data to include in a meta‐analysis (Bye 1980; Galvez 1985; Robert 2004; Scavino 1985; Schrooten 1993; Weippl 1984). The pooled odds ratio of therapy failure at final evaluation was 0.31 (odds ratio (OR) 0.31, confidence interval (CI) 0.20 to 0.48; 6 trials, 565 adults; moderate certainty evidence; Analysis 1.1), and the number needed to treat for an additional beneficial outcome (NNTB) was 3.9. We downgraded the certainty of the evidence one level to moderate due to a serious risk of bias. We could not include Berkowitz 1989 and Debelic 1973 in the meta‐analysis because numerical data were not reported; however, the results of Berkowitz 1989 were in line with the other trials, whilst Debelic 1973 showed no effect.
1.1. Analysis.
Comparison 1: Antihistamine‐decongestant, Outcome 1: Global evaluation
We therefore concluded that antihistamine‐decongestant combinations have some effect on general recovery compared to placebo.
Children
In Hutton 1991, there was no difference between treatment groups in the number of parents reporting overall improvement (P = 0.74).
In Clemens 1997, child overall improvement was not an outcome. However, children were more likely to fall asleep within two hours after administration with active treatment, which was considered as a favourable outcome (P = 0.01).
2. Adverse effects of treatment
Adults
Adverse effects were evaluated in eight trials including 1997 cold episodes (Berkowitz 1989; Bye 1980; Debelic 1973; Galvez 1985; Robert 2004; Scavino 1985; Schrooten 1993; Virtanen 1983). Many different adverse effects were described, such as drowsiness, excessive sleepiness, dry mouth, insomnia, dizziness, palpitations, nervousness, headache, and gastrointestinal upset.
The number of trials reporting specific adverse effects is presented in Table 5. We pooled data from different trials where possible. Other data are summarised in Table 6.
1. Combination 1: number of trials reporting specific adverse effects.
| Adverse effect | Number |
| All | 8 |
| Drowsiness | 7 |
| Dry mouth | 6 |
| Gastrointestinal upset | 5 |
| Insomnia | 4 |
| Dizziness | 3 |
| Nervousness | 1 |
| Headache | 1 |
| Palpitations | 2 |
| Rash | 1 |
| Gingival swelling | 1 |
| Somnolence | 1 |
2. Combination 1: adverse effects data not meta‐analysed.
| Adverse effect | Study ID | Result |
| Nervousness | Berkowitz 1989 | Active treatment 5/133, placebo 3/128; P = 0.51 |
| Dizziness | Berkowitz 1989 | Active treatment 5/133, placebo 2/128; P = 0.45 |
| Dizziness | Curley 1988 | Active treatment: 13/38, placebo 10/35; P = 0.06 |
| Rash | Curley 1988 | Active treatment 1/38, placebo 0/35; P = 0.33 |
| Palpitations | Virtanen 1983 | Active treatment 1/44, placebo 0/48; P = 0.29 |
| Headache | Virtanen 1983 | Active treatment 8/44, placebo 11/48; P = 0.25 |
| Debelic 1973 (comparison of 2 active treatments) | Clemastine + phenylpropanolamine (= treatment) Adverse effects: Insomnia 4 Sleepiness 0 Dry mouth 4 Dizziness 3 Palpitations 0 Nausea 0 | Belladonna, chlorpheniramine, phenylpropanolamine (= control) Adverse effects: Insomnia 3 Sleepiness 5 Dry mouth 7 Dizziness 2 Palpitations 4 Nausea 1 |
Total number of participants suffering adverse effects
In seven trials, the total number of participants with one or more adverse effects was provided (Berkowitz 1989; Bye 1980; Galvez 1985; Robert 2004; Scavino 1985; Schrooten 1993; Virtanen 1983). A total of 842 participants were evaluated for adverse effects: 419 in the active treatment group, of which 128 (31%) experienced adverse effects, and 423 in the placebo group, of which 100 (24%) experienced adverse effects (OR 1.58, 95% CI 0.78 to 3.21; 7 trials, 842 adults; moderate certainty evidence due to imprecision) (Analysis 1.2). Whilst in six trials adverse effects were more frequent in the active treatment group, in Bye 1980, adverse effects were remarkably more frequent in the placebo group, causing significant heterogeneity. In Debelic 1973, which compared two active treatments, 19 of 40 participants experienced adverse effects.
1.2. Analysis.
Comparison 1: Antihistamine‐decongestant, Outcome 2: Adverse effects: all
Participants experiencing sedation
In five trials, 692 participants were evaluated for sedation (drowsiness, hypersomnia, excessive sleepiness, asthenia): 345 in the active treatment group, of which 26 (8%) suffered from sedation, and 347 in the placebo group, of which 19 (5%) suffered from sedation (OR 1.38, 95% CI 0.63 to 3.00; 5 studies, 692 adults; Analysis 1.3; low certainty evidence due to imprecision and inconsistency) (Berkowitz 1989; Galvez 1985; Robert 2004; Schrooten 1993; Virtanen 1983). There was significant heterogeneity between the trials. In Debelic 1973, five participants treated with the combination containing belladonna experienced sleepiness.
1.3. Analysis.
Comparison 1: Antihistamine‐decongestant, Outcome 3: Adverse effects: drowsiness, hypersomnia, and excessive sleepiness
Participants experiencing dry mouth
In four trials, 713 participants were evaluated for dry mouth: 358 in the active treatment group, of which 63 (18%) experienced dry mouth, and 355 in the placebo group, of which 28 (8%) had dry mouth (OR 3.75, 95% CI 1.74 to 8.10; 4 trials, 640 adults; Analysis 1.4; high certainty evidence) (Berkowitz 1989; Robert 2004; Schrooten 1993; Virtanen 1983). Likewise, in Curley 1988, an increase in dry mouth on days two to nine in the active treatment group was reported. In Debelic 1973, 11 of 40 participants experienced dry mouth.
1.4. Analysis.
Comparison 1: Antihistamine‐decongestant, Outcome 4: Adverse effects: dry mouth
Participants experiencing insomnia
In two trials, 344 participants were evaluated for insomnia (Berkowitz 1989; Schrooten 1993). Fifteen of 176 participants in the active treatment group (8.5%) and 5 of 168 participants in the placebo group (3%) experienced insomnia (OR 2.89, 95% CI 0.88 to 9.56; 2 trials, 344 adults; Analysis 1.5; moderate certainty evidence due to imprecision). In Debelic 1973, 7 of 40 participants experienced insomnia.
1.5. Analysis.
Comparison 1: Antihistamine‐decongestant, Outcome 5: Adverse effects: insomnia
Participants experiencing gastrointestinal upset
In two trials, 296 participants were evaluated for gastrointestinal upset (Robert 2004; Virtanen 1983). Six of 144 participants in the active treatment group and two of 152 participants in the placebo group suffered this adverse effect (OR 2.81, 95% CI 0.64 to 12.33; 2 studies, 296 adults; Analysis 1.6; moderate certainty evidence due to imprecision). In Debelic 1973, one participant experienced nausea, and in Curley 1988 there was no increase in gastrointestinal upset in the active treatment group.
1.6. Analysis.
Comparison 1: Antihistamine‐decongestant, Outcome 6: Adverse effects: gastrointestinal upset
Participants experiencing dizziness
In Berkowitz 1989, dizziness was evaluated in 261 participants. Five of 133 participants in the active treatment group (3.8%) and 2 of 128 participants in the placebo group (1.6%) experienced dizziness (P = 0.29). In Curley 1988, an increase in dizziness in the active treatment group was recorded on days five to seven. In Debelic 1973, 5 of 40 participants felt dizzy.
In conclusion, although the total number of adverse effects was not significantly different between antihistamine‐decongestant combinations and placebo, dry mouth and possibly insomnia occurred more frequently with the active treatment.
Children
In Hutton 1991, the adverse effects sleep disturbance, excessive sleepiness, and vomiting were evaluated, but there was no difference between groups (P > 0.2).
Secondary outcomes
1. Decrease in the amount, or duration, of individual common cold symptoms
Nasal symptoms and cough
Adults
Subjective severity assessment of nasal obstruction
Seven trials including a total of 677 participants assessed the effect of antihistamine‐decongestant combinations on the subjective severity of nasal obstruction (Berkowitz 1989; Bye 1980; Curley 1988; Debelic 1973; Lebacq 1994; Virtanen 1983; Weippl 1984).
In Lebacq 1994, parents assessed severity of nasal congestion in their children. There was no significant difference between groups (P values not mentioned) on any of the four treatment days, nor was there any significant difference in nasal congestion between groups in two trials (P values not mentioned) (Debelic 1973; Virtanen 1982).
On the other hand, Bye 1980 found significantly less nasal obstruction with active treatment, but only on day one (P value not mentioned).
In Berkowitz 1989, the severity scores for nasal obstruction were significantly lower in the active treatment group from day one to day five (exact P value not provided). This was also the case in the Curley 1988 study on days two and three (P < 0.01), four (exact P value not provided), and five (P < 0.01).
Weippl 1984 showed a significant effect on nasal congestion with active treatment compared with control at both evaluation times (P < 0.001).
We could not pool data from these trials because of differences in outcome measures and a lack of adequate data. We summarised the results in Table 7. The trials showing no effect had methodological problems (Lebacq 1994); had a small sample size (Virtanen 1982); or compared two active treatments (Debelic 1973). The trials demonstrating some positive effect were larger and of higher methodological quality. Only the size of the effect is reported in Berkowitz 1989 (the difference in mean severity score of nasal congestion between groups being at most 0.3 severity points on a four‐point scale). We can conclude that antihistamine + decongestant combinations may have a limited effect on subjective severity of nasal obstruction, but it is not clear whether this is clinically significant.
3. Combination 1: results antihistamine‐decongestant.
| Study ID | Results |
| Aschan 1974 | a. Objective nasal obstruction Promethazine + ephedrine: pmr 15/15; placebo: pmr 0/15. P < 0.001 Clemastine + phenylpropanolamine: pmr 14/15; placebo: pmr 0/15. P < 0.001 |
| Berkowitz 1989 | a. Global efficacy
1. Overall response evaluated by physicians on a 4‐point scale: day 3, P = 0.01; day 5, P = 0.02 in favour of active treatment
2. Overall response evaluated by participants on a 4‐point scale: day 3, P = 0.02 in favour of active treatment
No further data available.
b. Subjective severity assessment of nasal obstruction
Mean scores: active treatment/placebo
Day 1: 1.8/2.1
Day 3: 1.7/1.9
Day 3: 1.4/1.7
Day 4: 1.3/1.6
Day 5: 1.2/1.5
P ≤0.05 for all presented days*
c. Rhinorrhoea
Mean scores: active treatment/placebo
Day 1: 1.8/1.9
Day 2: 1.5/1.9, P < 0.05*
Day 3: 1.4/1.5
Day 4: 1.2/1.4, P < 0.05*
Day 5: 1.1/1.3
d. Sneezing
Mean scores: active treatment/placebo
Day 1: 0.9/1
Day 2: 0.6/0.9, P < 0.05*
Day 3: 0.5/0.7, P < 0.05*
Day 4: 0.3/0.6, P < 0.05*
Day 5: 0.3/0.5, P < 0.05*
e. Cough
Mean scores: active treatment/placebo
Day 1: 1.2/1.3
Day 2: 1.2/1.2
Day 3: 1.0/1.1
Day 4: 0.8/1.0
Day 5: 0.8/0.9
No statistically significant difference *Exact P values not provided. |
| Bye 1980 | a. Subjective severity assessment of nasal obstruction Severity score significantly reduced on day 1. b. Rhinorrhoea Severity score not significantly reduced with active treatment compared with placebo. c. Sneezing Severity score of sneezing significantly reduced on days 2, 3, and 4 in the active group in comparison with the placebo group. d. Cough Severity score not significantly reduced with active treatment compared with placebo. |
| Clemens 1997 | a. Subjective severity assessment of nasal obstruction Proportion of participants with improvement of nasal congestion 2 hours after intake of: active treatment 41/84 (48.8%); placebo 40/79 (50.6%); P = 0.94 b. Rhinorrhoea Proportion of participants with improvement of nasal congestion 2 hours after intake of: active treatment 42/83 (50.6%); placebo 46/80 (57.5%); P = 0.48 Comparison between scores made on 7‐point Likert scale: active treatment 4.69; placebo 4.76; P = 0.56 c. Cough Proportion of participants with improvement of nasal congestion 2 hours after intake of: active treatment 24/49 (49.0%); placebo 28/65 (43.1%); P = 0.66 Comparison between scores made on 7‐point Likert scale: active treatment 4.67; placebo 4.57; P = 0.53 |
| Curley 1988 | a. Subjective severity assessment of nasal obstruction (1) Graphical display of mean severity score shows a significant difference on: Day 1: P = 0.01 Day 2: P = 0.05 Day 3: P = 0.01 Day 4: P = 0.01 Day 5: P = 0.01 No further data available. (2) Prevalence of nasal obstruction after 14 days of treatment: active treatment 6/38, placebo 20/35. P < 0.001 b. Rhinorrhoea (1) Graphical display of mean severity score shows a significant difference on: Day 2: P = 0.05 Day 3: P = 0.01 No further data available. (2) Prevalence of nasal obstruction after 14 days of treatment: active group: 14/38; placebo group: 12/35; P = 0.82 c. Cough (1) Graphical display of mean severity score shows a significant difference on: Day 3: P = 0.05 Day 4: P = 0.05 Day 5: P = 0.05 No further data available. |
| Hutton 1991 | a. Subjective severity assessment of nasal obstruction (1) Effect is expressed as "severity score changes" and presented as z‐score: negative z‐score means "less than average improvement", positive z‐score means "more than average improvement". z‐score on "congested and runny nose": active treatment −0.166, placebo +0.194; difference not significant (2) Number of parents reporting "improvement" of runny or congested nose: active treatment: 16/30; placebo 19/24; P = 0.05 b. Rhinorrhoea (1) Effect is expressed as "severity score changes" and presented as z‐score: negative z‐score means "less than average improvement", positive z‐score means "more than average improvement". z‐score on "congested and runny nose": active treatment −0.166, placebo +0.194; difference not significant (2) Number of parents reporting "improvement" of runny or congested nose: active treatment: 16/30; placebo 19/24; P = 0.05 c. Cough (1) Effect is expressed as "severity score changes" and presented as z‐score: negative z‐score means "less than average improvement", positive z‐score means "more than average improvement". z‐score on "cough": active treatment +0.024, placebo −0.058; difference not significant (2) Number of parents reporting "improvement" of cough: active treatment 20/30; placebo 14/24; not statistically significant |
| Lebacq 1994 | a. Objective nasal obstruction Nasal resistance as percentage of pre‐value P (placebo) (n = 6), A1 (combination 1) (n = 6), A2 (combination 2) (n = 6) Adult: 0.5 h postdose: P 116%; A1 61% (P < 0.05)*; A2 106% 1 h postdose: P 96%; A1 52% (P < 0.05)*; A2 96% 2 h postdose: P 100%; A1 58% (P < 0.05)*; A2 81% 4 h postdose: P 103%; A3 77%; A2 83% 6.5 h postdose: P 100%; A1 72%; A2 77% 11 h postdose: P 96%; A1 69%; A2 76% *Significantly different from placebo Children: 0.5 h postdose: P 96%; A1 63%; A2 115% 1 h postdose: P 68%; A1 70%; A2 99% 2 h postdose P 60%; A1 75%; A2 112% 4 h postdose: P 103%; A3 77%; A2 83% 6.5 h postdose: P 64%, A1 78%; A2 97% 11 h postdose: P 65%; A1 72%; A2 99% No significant difference b. Subjective severity assessment of nasal obstruction Severity assessment is presented in 6 scores on a 3‐point scale. There was no difference between treatment groups. We show (as an example) results of 1 evaluation point (2 hours after intake of medication). Median score 1. adults, 2. children Placebo (n = 6) 2; placebo (n = 6) 2 A1 (n = 6) 2; A1 (n = 6) 1.5 A2 (n = 6) 2; A5 (n = 6) 2 A1 = combination 1, A2 = combination 2 c. Effects assessed by anterior rhinoscopia Rhinoscopia results are presented as median of 6 scores on a 3‐point scale. There was no difference between treatment groups. We show (as an example) results of 1 evaluation point (2 hours after intake of medication). Median score 1. adults 2. children Placebo (n = 6) 2; placebo (n = 6) 1.5 A1 (n = 6) 2; A1 (n = 6) 1 A2 (n = 6) 2; A5 (n = 6) 1.5 A1 = combination 1, A2 = combination * Exact P‐value not provided. |
| Robert 2004 | a. Global efficacy
Evaluation of overall efficacy was made by the investigators on a 4‐point scale. Percentage of participants rating "good" or "excellent" was 75.8% (n = 100) for the treatment group and 57.6% (n = 104) for the control group (P < 0.001)*.
b. Objective nasal obstruction
In the "Results" chapter of the paper it is reported that no differences were observed between treatment and placebo groups regarding an increase of mean values for nasal peak flow carried out before and after 3 days of treatment.
* Exact P‐value not provided. |
| Virtanen 1983 | a. Subjective severity assessment of nasal obstruction
Graphical presentation of mean severity scores of nasal obstruction register during 10 days (treatment on first 5 days) shows no significant difference between treatment groups. No further data available.
b. Rhinorrhoea
Graphical presentation of mean severity scores of nasal obstruction register during 10 days (treatment on first 5 days) shows no significant difference between treatment groups, except for day 3 (P < 0.05)*.
No further data presented.
c. Sneezing
Graphical presentation of mean severity scores of nasal obstruction register during 10 days (treatment on first 5 days) shows a significant difference between treatment groups on:
Day 2, P < 0.05*
Day 3, P < 0.001
Day 4, P < 0.01*
Day 5, P < 0.001
Day 6, P < 0.01*
Day 7, P < 0.01*
Day 8, P < 0.05* * Exact P‐value not provided. |
| Weippl 1984 | a. Global efficacy
Overall therapeutic response was rated by the physician on a 5‐point scale (excellent, good, fair, poor, exacerbated) on days 3 and 5:
Day 3: percentage of "good" or "excellent" responses: therapeutic group 83% (24/29), placebo group 7% (2/27) (P < 0.01)*
Day 5: percentage of "good" or "excellent" responses: therapeutic group 86% (25/29), placebo group 30% (8/27) (P < 0.01)*
b. Cough
Statistically significant improvement (P = 0.05) at the interim visit c. Significantly greater improvement at both visits (P < 0.001)* in rhinorrhoea, nasal congestion, and sneezing. No further data presented. * Exact P‐value not provided. |
| Galvez 1985 | a. Global efficacy
Physician's evaluation of overall therapeutic response on a 6‐point scale (difference given by the percentage of participants responding "good" or "excellent" on the medication):
Day 3: treatment group 60%, placebo group 8%, P < 0.01*
Day 5: treatment group 77%, placebo group 21%, P < 0.01*
* Exact P‐value not provided. |
| Scavino 1985 | a. Global efficacy
Overall therapeutic response evaluated by a physician on a 4‐point scale (excellent, good, fair, poor, exacerbated) on days 3 and 5:
Day 3: percentage of participants responding "good" or "excellent": therapeutic group 76%, placebo group 17% (P < 0.01)*
Day 5: percentage of participants responding "good" or "excellent": therapeutic group 88%, placebo group 48% (P < 0.01)*
b. Cough
Evaluation of the percentage of improvement from the baseline score on days 3 and 5:
Day 3: active treatment 54%, placebo 24%
Day 5: active treatment 90%, placebo 60%
* Exact P‐value not provided. |
P: placebo pmr: positive manometric result
Rhinorrhoea
Seven trials including a total of 877 cold episodes assessed the effect of an antihistamine‐decongestant combination on rhinorrhoea (Berkowitz 1989; Bye 1980; Curley 1988; Debelic 1973; Schrooten 1993; Virtanen 1983; Weippl 1984).
Two trials evaluated rhinorrhoea objectively by counting used tissues, Debelic 1973, or by weighing the used tissues (Schrooten 1993). No difference between groups was found.
Five other trials evaluated rhinorrhoea using a subjective severity score. In Bye 1980, no effect of active treatment was noted. In Berkowitz 1989, severity scores for rhinorrhoea were significantly lower in the active treatment group on day two (exact P value not provided) and four (exact P value not provided), but not on days one, three, and five. In Curley 1988, severity scores for rhinorrhoea were significantly lower in the active treatment group on day two (exact P value not provided) and three (P < 0.01), but not on days one, four and five. In Virtanen 1983, severity scores for rhinorrhoea were significantly lower in the active treatment group on day three (exact P value not provided), but not on the other nine observation days. Finally, in Weippl 1984, there was a significant effect on rhinorrhoea with active treatment compared with control at both evaluation times (P < 0.001).
Pooling was not possible. The available results are summarised in Table 7. The size of the effect on nasal discharge was reported in only one of the trials with a positive result: in Berkowitz 1989 the difference in mean severity score between groups is at most 0.3 severity point on a four‐point scale. We can conclude that although we cannot exclude a small effect on rhinorrhoea on some days of treatment with a combination of antihistamine + decongestant, a clinically relevant effect is unlikely.
Sneezing
Sneezing was investigated in five trials including a total of 718 cold episodes (Berkowitz 1989; Bye 1980; Debelic 1973; Virtanen 1983; Weippl 1984). There was some effect in four trials (Berkowitz 1989; Bye 1980; Virtanen 1983; Weippl 1984). In Berkowitz 1989, severity scores for sneezing were significantly lower with active treatment from day two until day five (exact P value not provided). In Bye 1980, severity scores for sneezing were significantly lower with active treatment on days two, three, and four (no P values mentioned). In Virtanen 1983, severity scores for sneezing were significantly lower with active treatment on days two to eight (day two: exact P value not provided; day three: P < 0.001; day four P < 0.01; days six and seven: P < 0.01; and day eight: exact P value not provided). Weippl 1984 mentions a significant effect on sneezing with active treatment compared with control at both evaluation times (P < 0.001). Debelic 1973 compared two active combinations and found no difference between groups.
Pooling of results was not possible. All available data are presented in Table 7. All trials in which this symptom was evaluated found some effect of the active treatment in comparison with placebo. However, the size of the effect was reported in only one trial: in Berkowitz 1989, the difference in mean severity score between groups is at most 0.3 severity point on a four‐point scale. We can tentatively conclude that a combination of antihistamine‐decongestant has some effect on sneezing, but the effect is small and probably not clinically relevant.
Cough
Four trials including a total of 672 cold episodes evaluated the effect of an antihistamine‐decongestant combination on the severity of cough (Berkowitz 1989; Bye 1980; Curley 1988; Weippl 1984). Neither Berkowitz 1989 nor Bye 1980 found any significant difference in severity of cough between the active treatment group and the control group. In Curley 1988, the mean severity score for cough was significantly less on days three, four, and five (exact P value not provided). In the paediatric trial by Weippl 1984, there was an improvement of cough at the interim visit in comparison to control (P = 0.03); however, the active treatment also contained dextromethorphan. Pooling was not possible. All available data are represented in Table 7. Results from these four trials are conflicting, precluding the drawing of any conclusions about the effectiveness of antihistamine‐decongestant combinations on cough.
Children
In Hutton 1991, there was no difference between groups in the improvement of symptoms (P = 0.51). In Clemens 1997, there was no difference between groups in the proportion of responses reporting an improvement in runny nose or nasal congestion (P = 0.54 and P = 0.94, respectively).
2. Objective assessments (rhinomanometry, rhinoscopy)
Aschan 1974 recorded positive rhinomanometric changes in nasal patency in 24 of 30 participants after a single dose of the active treatment. There were no positive changes with placebo (P < 0.001). In Lebacq 1994, phenylpropanolamine + carbinoxamine had some effect on nasal resistance in adult participants 30 minutes to two hours after intake of medication (exact P value not mentioned), but there was no effect in children. The combination of phenylpropanolamine + pheniramine maleate + mepyramine maleate was ineffective. In Robert 2004, participants' peak nasal flow was evaluated before and after three days of treatment. No clear difference was seen between the active treatment and placebo. Pooling of results was not possible because different outcome measures were used. Results are presented in Table 7. Two trials showed positive results in objective nasal patency (Aschan 1974; Lebacq 1994); these trials had small sample sizes and took place in an experimental setting. One study had serious methodological problems (Lebacq 1994). The third trial took place in a clinical setting and had a much larger sample size (Robert 2004). This trial showed no effect. We can therefore conclude that antihistamine + decongestant combinations probably have no effect on objectively measured nasal patency in clinical circumstances, although there may be some effect in experimental settings.
Effect on results on anterior rhinoscopy: in Lebacq 1994, the condition of the nasal mucosa was assessed at different time points using a four‐point scale (normal, red, violet, blue). There was no difference in the aspect of the nasal mucosa between groups (Table 7). In Berkowitz 1989, physicians assessed severity of swelling and hyperaemia on days three and five of treatment, and found no significant differences between groups.
Combination 2: oral antihistamine‐analgesic combinations
Short description of the studies
Gwaltney 2002 studied the effects of chlorpheniramine + ibuprofen + intranasal interferon and chlorpheniramine + ibuprofen in comparison with placebo in 150 adult participants with experimental rhinovirus infection. Participants received treatment for 4.5 days, and effectiveness was evaluated by recording daily subjective severity of nasal symptoms. We considered the comparison chlorpheniramine + ibuprofen versus placebo in the review.
Koytchev 2003 included 1167 adult cold participants and assessed the effect of Grippostad, a combined formulation of acetaminophen + caffeine + chlorpheniramine + ascorbic acid in comparison with two references (chlorpheniramine + ascorbic acid and acetaminophen + caffeine + ascorbic acid) and ascorbic acid. Treatment was administered for six days. Participants assessed the severity of their cold symptoms daily, and sum scores were calculated. Data for individual symptoms were not provided. At the end of the treatment period a final global evaluation of effectiveness was made by the participant and the investigator. The proportion of the participants cured was also assessed. We considered the comparison between Grippostad and ascorbic acid (582 participants) in the review.
Middleton 1981 included 191 participants and assessed the effectiveness of Benylin Day and Night, a combined formulation consisting of two different combinations of active substances: Benylin Day (paracetamol + phenylpropanolamine) and Benylin Night (paracetamol + diphenhydramine hydrochloride) in comparison to paracetamol. During the five days of treatment, participants reported severity scores for cold symptoms daily including runny nose, nasal congestion, and cough. On day five a final global evaluation was made by physicians and participants (for day and night separately).
Montijo‐Barrios 2011 included 100 children aged 6 to 24 months and compared a combination of buphenine, aminophenazone, and diphenylpyraline (n = 57) to placebo (n = 43). Both groups also received paracetamol. As an outcome they compared the proportion of children at day three, five, and seven with rhinorrhoea, sneezing more than six times per day, moderate to severe irritability, difficulty with eating, noisy breathing, breathing through the mouth, significant tearing, and fever episodes. The amount of milk consumption and the number of hours of sleep during daytime and nighttime were also compared.
Primary outcomes
1. Global evaluation of effectiveness
Two trials including a total of 773 participants assessed the global effectiveness of antihistamine + analgesic in the common cold (Koytchev 2003; Middleton 1981).
In Koytchev 2003, the proportion of participants who were completely cured at the end of the trial was 70% with Grippostad and 43% with the control (ascorbic acid). This difference was significant (OR 0.33, 95% CI 0.23 to 0.46; 582 adults; moderate certainty evidence due to risk of bias). In Middleton 1981, overall subjective assessment was measured at the end of the study by asking "on the whole do you think the tablets have helped you?". Significantly more participants receiving the active nighttime medication compared with the control group (paracetamol) responded affirmatively to the question: 73% versus 52% (OR 0.35, 95% CI 0.18 to 0.70; 191 adults; moderate certainty evidence).
We did not pool these data because one of the trials used an active control (Koytchev 2003). As both trials had a favourable result, we can conclude that antihistamine‐analgesic combinations may have a positive effect on subjective general recovery.
2. Adverse effects of treatment
All trials reported adverse effects (Gwaltney 2002; Koytchev 2003; Middleton 1981; Montijo‐Barrios 2011). Many different adverse effects were described: nasal dryness, nasal irritation, blood‐stained nasal mucus, drowsiness, dry mouth, gastrointestinal upset, loss of appetite, headache, depression, and dizziness. Most of the adverse effects were rare and mentioned in only one trial (Table 8; Table 9).
4. Combination 2: number of trials reporting a specific adverse effect.
| Adverse effect | Number |
| All | 2 |
| Drowsiness | 1 |
| Dizziness | 1 |
| Gastrointestinal upset | 1 |
| Dry mouth | 1 |
5. Combination 2: adverse effects data not meta‐analysed.
| Adverse effect | ID | Result |
| Dry mouth | Middleton 1981 | Active treatment 2/91, placebo 2/90 |
| Gastrointestinal upset | Middleton 1981 | Active treatment 6/91, placebo 5/90 |
| Dizziness | Middleton 1981 | Active treatment 1/91, placebo 1/90 |
| All participants reporting | Koytchev 2003 | In all trial groups (n = 1167), 39 participants reported an adverse effects. |
Total number of participants suffering adverse effects
In Koytchev 2003, 39 of 1167 participants reported an adverse effect. There were no differences between groups. In Middleton 1981, both combinations (day and night) were evaluated together: 11 of 79 participants receiving paracetamol and nine of 82 participants receiving the active treatment mentioned adverse effects (P = 0.57). Montijo‐Barrios 2011 did not report adverse effects.
Participants suffering drowsiness
In Gwaltney 2002, five of 61 participants receiving the active treatment and 0 of 30 participants receiving placebo experienced drowsiness (P = 0.03). In Middleton 1981, drowsiness was mentioned by five participants receiving paracetamol and four participants receiving the combination therapy (P = 0.68). After pooling, 7% of participants receiving the combination therapy and 3% of participants receiving placebo or paracetamol suffered from drowsiness (OR 1.64, 95% CI 0.48 to 5.59; 2 studies, 272 adults; low certainty evidence; Analysis 2.1).
2.1. Analysis.
Comparison 2: Antihistamine‐analgesic, Outcome 1: Adverse effects: drowsiness, hypersomnia, and excessive sleepiness
Other adverse effects were very rare, and there were no differences between treatment groups (Table 9). We can conclude that the combination of antihistamine with analgesics is generally well tolerated.
Secondary outcomes
1. Decrease in the amount, or duration, of individual common cold symptoms
Three trials assessed the effect of an antihistamine‐analgesic combination on the subjective severity of nasal obstruction, rhinorrhoea, and cough (Gwaltney 2002; Middleton 1981; Montijo‐Barrios 2011). The symptoms were evaluated daily for five days in two trials (Gwaltney 2002; Middleton 1981). Both trials failed to show a significant effect of the active treatment compared with placebo or paracetamol on mean severity scores for nasal obstruction, rhinorrhoea, and cough. Montijo‐Barrios 2011 evaluated rhinorrhoea, noisy breathing, and mouth breathing on days three, five, and seven, and found a significant difference in the proportion of children experiencing these symptoms between groups (Table 10).
6. Combination 2: results antihistamine‐analgesic.
| Study ID | Results |
| Gwaltney 2002 | a. Subjective severity assessment of nasal obstruction
Comparisons between baseline ‐ adjusted mean daily symptom scores on days 2 to 5 mentioned in a table. Treatment with oral chlorpheniramine and ibuprofen showed no significant effect on nasal congestion scores on any day during treatment. Day 2: 1.0 Day 3: 1.0 Day 4: 1.6 Day 5: 1.7 b. Rhinorrhoea Comparisons between baseline ‐ adjusted mean daily symptom scores on days 2 to 5 mentioned in a table. Treatment with oral chlorpheniramine and ibuprofen showed no significant effect on rhinorrhoea scores on any day during treatment. Day 2: 1.9 Day 3: 1.1 Day 4: 1.7 Day 5: 1.15 c. Sneezing Comparisons between baseline ‐ adjusted mean daily symptom scores on days 2 to 5 mentioned in a table. Treatment with oral chlorpheniramine and ibuprofen showed a significant effect on sneezing scores only on day 5 of treatment. Day 2: 2.0 Day 3: 3.2 Day 4: 2.3 Day 5: 6.2; statistically significant (P < 0.05*) d. Cough Comparisons between baseline ‐ adjusted mean daily symptom scores on days 2 to 5 mentioned in a table. Treatment with oral chlorpheniramine and ibuprofen showed no significant effect on cough scores on any day during treatment. Day 2: 3.0 Day 3: 1.8 Day 4: 2.1 Day 5: 1.8 *Exact P values not provided. |
| Koytchev 2003 | a. Global efficacy
The proportion of participants who were completely cured at the end of the trial:
treatment group: 70%;
control group and reference 1 group: 43% to 45%.
b. Subjective severity assessment of nasal obstruction
Comparison of the subscore referring to blocked nose, cough, and disturbance of sleep quality was performed between the group of participants receiving the active treatment and the group receiving the reference 2. The difference was statistically significant (P < 0.05*). No further data available.
c. Cough
Comparison of the subscore referring to blocked nose, cough, and disturbance of sleep quality was performed between the group of participants receiving the active treatment and the group receiving the reference 2. The difference was statistically significant (P < 0.05*). No further data available. *Exact P values not provided. |
| Middleton 1981 | a. Global efficacy
Overall subjective assessment was made after asking the participant the question: "On the whole do you think the tablets have helped you?".
Daytime: Response Control Treatment Yes 47 66 No 52 25 Compared with the control group, a statistically significantly larger number of participants receiving the active medication responded affirmative to the question (P < 0.01*). b. Subjective severity assessment of nasal obstruction No significant difference reported between the active substance and placebo in treating nasal congestion. The results are mentioned in the "Results" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. c. Rhinorrhoea No significant difference reported between the active substance and placebo in treating rhinorrhoea. The results are mentioned in the "Results" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. d. Sneezing No significant difference reported between the active substance and placebo in treating sneezing. The results are mentioned in the "Results" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. e. Cough No significant difference reported between the active substance and placebo in treating cough. The results are mentioned in the "Results" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. *Exact P values not provided. |
| Montijo‐Barrios 2011 | DAY 3 Active (%) placebo (%) Moderate to severe rhinorrhoea………………….48…………….43 P < 0.05* At least 6/day sneezing…………….……………28………….….28 Moderate to severe irritability……………………23……….…….17 Difficulty eating…………………………………..32…………..…..37 Noisy breathing……………………………………48……….…….41 Breathing through mouth……………………….39……………….24 P < 0.01* Significant tearing…………………………………27……………..11 P < 0.01* Fever………………………………………………9…………….…..6 Milk consumption (ounces)……………………..18 +/−11…..……18+/−12 Number of hours of sleep (daytime)……....….3+/−2…….….....2+/−2 Number of hours of sleep (nighttime)…..........9+/−2………...…9+/−2 DAY 5 Moderate to severe rhinorrhoea………………….48……………….11 P < 0.01* Moderate to severe irritability……………………17…………………9 P < 0.05* Breathing through mouth….…………….………26…………....….16 P < 0.05* Significant tearing……….….……………………27………………..11 P < 0.05* (other symptoms: no significant difference) DAY 7 Moderate to severe rhinorrhoea………………….22……………….4 P < 0.01* Difficulty eating……………………….…………..11………………..5 P < 0.05* Breathing through mouth………….…………….16……………….7 P< 0.05* (other symptoms: no significant difference) *Exact P values not provided. |
Severity of sneezing was studied in Gwaltney 2002. The baseline adjusted mean severity score was significantly lower in the active treatment group, but only on the fifth day of therapy. Montijo‐Barrios 2011 did not find a difference between groups for sneezing (Table 10).
Pooling of data was not possible. Results are summarised in Table 10. Based on these results we can conclude that a combination of antihistamines and analgesic probably has no effect on nasal symptoms or cough in adults. We have very weak evidence that there is some effect on nasal symptoms in small children.
2. Objective assessments
Not evaluated.
Combination 3: oral decongestant‐analgesic combinations
Short description of the studies
Eccles 2006a examined the effectiveness of a combination of pseudoephedrine + paracetamol in comparison to placebo, pseudoephedrine, or paracetamol in monotherapy (four study arms). The study included a total of 305 participants with a natural cold. Participants had symptomatic upper respiratory tract infection with pain of at least moderate intensity and nasal obstruction measurable by rhinomanometry. Effectiveness of treatment on nasal obstruction was assessed during the first four hours after administration of one dose by rhinomanometry, during the next three days of treatment by subjective assessment of nasal congestion, and finally by a global assessment of nasal congestion relief at the follow‐up visit after three days of therapy.
Eccles 2014 examined the effectiveness of a combination of pseudoephedrine + acetylsalicylic acid in comparison to placebo, pseudoephedrine, acetylsalicylic acid in monotherapy (four study arms). The study included a total of 883 participants with a natural cold. Inclusion criteria and methodology were similar to Eccles 2006a.
Loose 2004 studied the effect of a single‐dose acetylsalicylic acid + pseudoephedrine and pseudoephedrine + paracetamol compared to placebo in 643 adults with a cold and nasal congestion for five days. Outcomes were the change in nasal congestion score (on an 11‐point scale for severity of nasal congestion) and change in the subjective severity of nasal congestion two, four, and six hours after the ingestion of the study medication.
Martinez 1994 investigated the effectiveness of naproxen + pseudoephedrine compared to pseudoephedrine and placebo in 65 paediatric participants aged 2 to 16 years. Treatment was administrated three times daily for five days in different concentrations, depending on the age of the child. The duration of nasal symptoms (nasal oedema and nasal congestion) was evaluated at the end of the study.
Middleton 1981 included 191 participants and studied the effectiveness of Benylin Day and Night, a combined formulation consisting of two different combinations of active substances: Benylin Day (paracetamol + phenylpropanolamine) and Benylin Night (paracetamol + diphenhydramine hydrochloride) compared to paracetamol. This trial was described in the previous section; we considered the day combination here.
In Sperber 1989, 58 participants developed a cold after experimental virus inoculation. They were kept under observation until six days after inoculation and treated with a combination of pseudoephedrine + ibuprofen, or pseudoephedrine or placebo. Subjective severity of cold symptoms (runny nose, nasal obstruction, sneezing, cough) were evaluated daily. Rhinorrhoea was further evaluated by weighing used tissues. Nasal congestion was measured by anterior rhinometry. We considered the comparison between pseudoephedrine + ibuprofen and placebo in the review.
In Sperber 2000, the effectiveness of two doses (the second dose administered six hours after the first) of pseudoephedrine + paracetamol was compared with placebo in 430 adult participants with a natural cold. Participants were evaluated two hours after each administration. The effectiveness of the treatment was measured against the subjective severity of common cold symptoms (nasal obstruction, sneezing, cough, rhinorrhoea) and was assessed using a five‐point severity scale.
Primary outcomes
1. Global evaluation of effectiveness
Only one trial assessed overall subjective effectiveness at the end of the study by asking "on the whole do you think the tablets have helped you?" (Middleton 1981). Significantly more participants receiving the active daytime medication compared with the control group (paracetamol) responded affirmatively to the question: 73% versus 52% (OR 0.28, 95% CI 0.15 to 0.52; 181 participants; moderate certainty evidence) (Analysis 3.1).
3.1. Analysis.
Comparison 3: Analgesic‐decongestant, Outcome 1: Global evaluation
2. Adverse effects of treatment
Six trials evaluated the adverse effects of analgesic‐decongestive combinations (Eccles 2006a; Eccles 2014; Loose 2004; Middleton 1981; Sperber 1989; Sperber 2000).
Many different adverse effects were noted, including drowsiness, difficulty sleeping, lethargy, indigestion, nervousness, palpitations, lightheadedness, nausea, vomiting, dizziness, dry mouth, headache, somnolence, fever, abdominal pain, pharyngitis, loss of appetite, depression, giddiness, general gastrointestinal system adverse effects, central nervous system adverse effects, and diarrhoea.
The number of trials reporting a specific adverse effect is presented in Table 11. We pooled data from different trials where possible (see Analysis 3.2; Analysis 3.3; Analysis 3.4; Analysis 3.5; Analysis 3.6). Other data are summarised in Table 12.
7. Combination 3: number of trials reporting a specific adverse effect.
| Adverse effect | Number |
| All | 6 |
| Gastrointestinal upset | 5 |
| Dizziness | 4 |
| Drowsiness | 4 |
| Dry mouth | 4 |
| Headache | 1 |
| Difficulty sleeping | 1 |
| Fever | 1 |
| Pharyngitis | 1 |
| Nervous system disorder | 1 |
3.2. Analysis.
Comparison 3: Analgesic‐decongestant, Outcome 2: Adverse effects: all
3.3. Analysis.
Comparison 3: Analgesic‐decongestant, Outcome 3: Adverse effects: drowsiness, hypersomnia, lethargy, excessive sleepiness and other central nervous system adverse effects
3.4. Analysis.
Comparison 3: Analgesic‐decongestant, Outcome 4: Adverse effects: dry mouth
3.5. Analysis.
Comparison 3: Analgesic‐decongestant, Outcome 5: Adverse effects: gastrointestinal
3.6. Analysis.
Comparison 3: Analgesic‐decongestant, Outcome 6: Adverse effects: dizziness, lightheadedness
8. Combination 3: adverse effects data not meta‐analysed.
| Adverse effect | Study ID | Result |
| Dry mouth | Middleton 1981 | Active treatment 2/91, paracetamol 2/90 |
| Gastrointestinal upset | Middleton 1981 | Active treatment 6/91, paracetamol 5/90 |
| Gastrointestinal system | Eccles 2014 | ASA + PSE 18/236, ASA 18/239, PSE 12/237, placebo 5/121 |
| Dizziness | Middleton 1981 | Active treatment 1/91, paracetamol 1/90 |
| Drowsiness and sleepiness | Middleton 1981 | Active treatment 5/91, paracetamol 4/90 |
| Loss of appetite | Middleton 1981 | Active treatment 0/91, paracetamol 1/90 |
| Depression headache | Middleton 1981 | Active treatment 0/91, paracetamol 1/90 |
| Giddy, dizzy | Middleton 1981 | Active treatment 1/91, paracetamol 1/90 |
| Abdominal pains, diarrhoea | Middleton 1981 | Active treatment 1/91, paracetamol 0/90 |
| Headache | Loose 2004 | Active treatment 17/481, placebo 9/162 |
| Fever | Loose 2004 | Active treatment 8/481, placebo 2/162 |
| Pharyngitis | Loose 2004 | Active treatment 4/481, placebo 2/162 |
| Nervousness | Sperber 2000 | Active treatment 8/216, placebo 0/214 |
| Difficulty sleeping | Sperber 1989 | Active treatment 1/23, placebo 1/10 |
| Central nervous system | Eccles 2006a | Active treatment 4/76, placebo 0/76 |
| Dry mouth | Eccles 2006a | active treatment 1/76, placebo 1/76 |
| Central nervous system | Eccles 2014 | ASA + PSE 10/236, ASA 2/239, PSE 4/237, placebo 6/121 |
ASA: acetylsalicylic acid PSE: pseudoephedrine
Total number of participants experiencing adverse effects
In six trials (2510 participants) the total number of participants with one or more adverse effects was registered (Eccles 2006a; Eccles 2014; Loose 2004; Middleton 1981; Sperber 1989; Sperber 2000). A total of 1644 participants were evaluated: 199/1122 in the active treatment group (17.7%) and 75/675 in the placebo group (11.1%) experienced adverse effects. The OR of an adverse effect with active treatment is 1.62 (95% CI 1.18 to 2.23; 6 studies; 1797 participants; high certainty evidence; Analysis 3.2). The number needed to treat for an additional harmful outcome (NNTH) is 18 (95% CI 9 to 59).
Participants experiencing drowsiness, hypersomnia, lethargy, excessive sleepiness, or other central nervous system adverse effects
This adverse effect was reported in five trials (Eccles 2014; Loose 2004; Middleton 1981; Sperber 1989; Sperber 2000). In the five trials, 4.4% of participants suffered from sedation with active treatment and 3.2% with control (OR 1.34, 95% CI 0.76 to 2.37; 5 studies, 1644 adults; moderate certainty evidence; Analysis 3.3). We downgraded the certainty of the evidence by one level to moderate due to imprecision.
Dry mouth
In three trials dry mouth was noted as an adverse effect (Eccles 2006a; Middleton 1981; Sperber 2000), occurring in 2.6% of participants in the active treatment group and 1.8% of participants in the control group (OR 1.43, 95% CI 0.53 to 3.83; 3 studies, 764 adults; low certainty evidence due to imprecision and inconsistency; Analysis 3.4).
Participants experiencing gastrointestinal upset or other gastrointestinal adverse effects
In the same five trials, 5.8% of participants suffered from some gastrointestinal upset in the active treatment group and 2.7% in the control group (OR 1.71, 95% CI 0.97 to 3.01; 5 trials, 1644 adults; high certainty evidence; Analysis 3.5).
Participants experiencing dizziness
In four trials, 3.8% of participants in the active treatment group and 0.8% of participants in the control group suffered from dizziness (Loose 2004; Middleton 1981; Sperber 1989; Sperber 2000). This difference was significant: P = 0.009. The OR of dizziness in the active treatment group was 2.86 (95% CI 1.02 to 8.01; 4 trials, 1287 adults; high certainty evidence; Analysis 3.6).
In conclusion, adverse effects are overall more frequent with a decongestant + analgesic combination than with control treatment. Specifically, dizziness is more frequent.
Secondary outcomes
1. Decrease in the amount, or duration, of individual common cold symptoms
Subjective severity assessment of nasal obstruction
This symptom was assessed in six trials.
In Middleton 1981, the severity of nasal obstruction was not significantly different between treatment and placebo groups. Conversely, in Martinez 1994, the active treatment significantly reduced the duration of nasal congestion.
In Loose 2004, the differences from baseline of nasal congestion scores and nasal relief scores were statistically larger (exact P value not provided) for all active treatments and at all observation intervals compared to placebo. The peak difference was noted at 120 minutes after dosing. There was no clear difference between the different active combinations.
Sperber 1989 evaluated nasal congestion during five days of therapy on a four‐point scale. There was a difference in the sum of the day scores between the active treatment (4 +/− 3) and the placebo (7 +/− 2; exact P value not provided).
In the other trial by Sperber 2000, the mean difference in nasal congestion score at the beginning of the trial and after the first and second dose of active medication was evaluated on a five‐point scale. Two hours after the first dose there was a clear decrease (P = 0.002) in favour of active treatment. After the second administration the difference was still significant, but smaller (P = 0.03).
In Eccles 2006a, the sum of nasal congestion differences over three days of treatment was significantly higher with active treatment than with placebo (P = 0.004) or paracetamol (P = 0.02). Global nasal congestion relief was also greater with active treatment compared to paracetamol or placebo (P = 0.004). This was not the case when the combination was compared to pseudoephedrine in monotherapy.
In Eccles 2014, the sum of nasal congestion differences over three days was significantly higher with the combination therapy (pseudoephedrine + acetylsalicylic acid) than with placebo (P = 0.048). This was also the case when compared to acetylsalicylic acid (P = 0.016). When compared to pseudoephedrine there was no significant difference (P = 0.371).
We could not pool the results of these trials because of differences in outcome measures or lack of adequate data. Results are summarised in Table 13.
9. Combination 3: results analgesic‐decongestant.
| Study ID | Results |
| Martinez 1994 | a. Subjective severity assessment of nasal obstruction The duration of the symptom of nasal congestion was significantly reduced on treatment days 3 and 5. Result mentioned in the "Results" chapter of the text. No further data available. d. Objective nasal obstruction The duration of the symptom of mucosal oedema was significantly reduced on treatment days 3 and 5 as compared to placebo. Result mentioned in the "Results" chapter of the text. No further data available. |
| Loose 2004 | a. Subjective severity assessment of nasal obstruction (1) Nasal congestion score The nasal congestion score was statistically significantly different (P < 0.05) for all active treatments and at all observation intervals (2, 4, and 6 hours after intake) compared with placebo. (2) Relief of nasal congestion Relief in nasal congestion was statistically significantly better compared to treatment with placebo for all active treatments and at all observation intervals (2, 4, and 6 hours after intake). Data provided in tables, but it is not clear what the tables represent. |
| Middleton 1981 | a. Global efficacy
Overall subjective assessment was made after asking the participant the question: "On the whole do you think the tablets have helped you?".
Nighttime: Response, Control, Treatment Yes, 56, 75 No, 34, 26 Compared with the control group, a statistically significantly larger number of participants receiving the active medication responded affirmative to the question (P < 0.01). b. Subjective severity assessment of nasal obstruction No significant difference reported between the active substance and placebo in treating nasal congestion. The results are only reported in the "Results" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. c. Rhinorrhoea No significant difference reported between the active substance and placebo in treating rhinorrhoea. The results are only reported in the "Result" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. d. Sneezing No significant difference reported between the active substance and placebo in treating sneezing. The results are only reported in the "Result" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. e. Cough No significant difference reported between the active substance and placebo in treating cough. The results are only reported in the "Result" chapter of the article. There are no tables or graphics showing the data from which the conclusions were drawn. |
| Sperber 1989 | a. Objective nasal obstruction
Overall and daily nasal patency was greater in the treatment group. The days when this difference was most noticeable were day 4 (P = 0.08) and day 5 (P = 0.06). Analysis of the mean values was confounded by high variability between participants.
b. Subjective severity assessment of nasal obstruction
Reduction of nasal congestion rated on a 4‐point scale:
Treatment group 4 ± 3; placebo group 7 ± 2, P < 0.05* (significant difference)
c. Rhinorrhoea
Reduction of nasal congestion rated on a 4‐point scale:
Treatment group 2 ± 2; placebo group 4 ± 3, P < 0.05* (not a significant difference) *Exact P values not provided. |
| Sperber 2000 | a. Subjective severity assessment of nasal obstruction Mean difference between the nasal congestion scores at the beginning of the study and after the first and second administration of active medication or placebo (nasal congestion evaluated on 5‐point scale): Dose 1: active group −1.06; placebo group −0.67, P = 0.002 (statistically significant) Dose 2: active group −1.26; placebo group −0.98, P = 0.03 (not statistically significant) b. Rhinorrhoea Mean difference between the rhinorrhoea score at the beginning of the study and after the first and second administration of active medication or placebo (rhinorrhoea evaluated on 5‐point scale): Dose 1: active group −0.80; placebo group −0.71, P = 0.12 (not statistically significant) Dose 2: active group −1.15; placebo group −0.86, P = 0.09 (not statistically significant) c. Sneezing Mean difference between the sneezing score at the beginning of the study and after the first and second administration of active medication or placebo (sneezing evaluated on 5‐point scale): Dose 1: active group −0.84; placebo group −0.79, P = 0.71 (not statistically significant) Dose 2: active group −0.98; placebo group −0.85, P = 0.15 (not statistically significant) d. Cough Mean difference between the cough score at the beginning of the study and after the first and second administration of active medication or placebo (cough evaluated on 5‐point scale): Dose 1: active group −0.61; placebo group −0.51, P = 0.27 (not statistically significant) Dose 2: active group −0.78; placebo group −0.58, P = 0.06 (not statistically significant) Trend suggestive of greater reduction in cough score. |
| Eccles 2006a | Nasal congestion Area under nasal airflow conductance curve 0 to 4 h (rhinomanometry) Mean difference 120.3, 95% CI 66.18 to 174.37, P < 0.0001 Sum of nasal congestion differences 0 to 3 days (4‐point scale) Mean difference 0.69, 95% CI 0.219 to 1.162, P = 0.004 Global nasal congestion relief (5‐point scale) Paracetamol + pseudoephedrine: 1.7 +/− 1.2 P < 0.001 Placebo: 1.0 +/− 0.9 |
| Eccles 2014 | Nasal congestion Area under nasal airflow conductance curve 0 to 4 h (rhinomanometry): ASA/PSE vs ASA P < 0.001 at each evaluation time (0 to 1 h, 1 to 2 h, 2 to 3 h, 3 to 4 h) ASA/PSE vs PSE P > 0.5 at each evaluation time (0 to 1 h, 1 to 2 h, 2 to 3 h, 3 to 4 h) ASA/PSE vs placebo P < 0.001 at each evaluation time (0 to 1 h, 1 to 2 h, 2 to 3 h, 3 to 4 h) Sum of subjective nasal congestion intensity difference ASA/PSE vs ASA at 0 to 4 h, P = 0.144; day 3, P = 0.969 ASA/PSE vs PSE at 0 to 4 h, P = 0.647; day 3, P = 0.037 ASA/PSE vs placebo at 0 to 4 h, P < 0.008; day 3, P = 0.048 Total subjective nasal congestion relief ASA/PSE vs ASA at 0 to 4 h, P < 0.001; day 3, P = 0.016 ASA/PSE vs PSE at 0 to 4 h, P = 0.890; day 3, P = 0.873 ASA/PSE vs placebo at 0 to 4 h, P < 0.001; day 3, P < 0.001 Global nasal congestion relief ASA/PSE vs ASA day 3, P = 0.040 ASA/PSE vs PSE day 3, P = 0.207 ASA/PSE vs placebo day 3, P < 0.001 |
ASA: acetylsalicylic acid CI: confidence interval PSE: pseudoephedrine
We can conclude that decongestant‐analgesic combinations are probably effective in alleviating nasal obstruction. There were some data on the size of the effect in three trials: in Sperber 1989, the difference in the sum of the severity scores over five days was three points on a four‐point scale; in the second trial of Sperber 2000, the difference was at most 1.06 severity points on a five‐point scale; and in Eccles 2006a, the mean sum of nasal congestion differences over three days was 0.69 (on a four‐point scale), and the difference in global nasal congestion relief was 0.7 (on a five‐point scale).
Rhinorrhoea
Three trials assessed the effect on the subjective severity of rhinorrhoea (Middleton 1981; Sperber 1989; Sperber 2000). None of these trials showed a favourable treatment effect. However, in Sperber 1989 there was a reduction of 30% in nasal mucus weight with the active treatment compared with the placebo (P = 0.04).
Pooling was not possible. The available data are presented in Table 13. We can conclude that decongestant‐analgesic combinations are ineffective in subjectively alleviating rhinorrhoea, although there may be an objectively measurable decrease in mucus secretion.
Sneezing
Middleton 1981 and Sperber 2000 also assessed the effect of an analgesic‐decongestive combination on the subjective severity of sneezing. There was no significant effect. The available data are presented in Table 13.
Cough
The same two trials also evaluated the effect on cough, finding no effect (Middleton 1981; Sperber 2000).
2. Objective assessments (rhinomanometry, nasal airflow conductance)
In Sperber 1989, recipients of the active treatment showed improved nasal patency on rhinomanometry from the pre‐treatment baseline flow rates on days four (P = 0.08) and five (P = 0.06) of treatment. The overall and daily patency tended to be greater in the recipients of pseudoephedrine + ibuprofen compared to placebo. In Eccles 2006a, the combination treatment was more effective than placebo in increasing nasal airflow conductance (P < 0.001).
In Martinez 1994, the combination significantly reduced the duration of mucosal oedema on anterior rhinoscopia.
Combination 4: oral antihistamine‐decongestant‐analgesic combinations
Short description of the studies
Blanco 2000 studied a combination of loratadine + pseudoephedrine + paracetamol in 40 adults with a common cold over a five‐day period. Participants were kept under observation during the first five hours after the first dose of treatment. Global assessment of their cold, somnolence, and general malaise were observed every 20 minutes. During the next five days the feeling of general malaise and common cold symptoms (nasal congestion, rhinorrhoea) were evaluated daily in a diary by participants and on days three and five by a physician.
Mizoguchi 2007 included 485 adults and investigated the effectiveness of a single dose of a syrup containing dextromethorphan 15 mg, paracetamol 500 mg, doxylamine 7.5 mg, and ephedrine 8 mg, which was administered in the evening. Follow‐up data were available for 470 participants. Effectiveness was evaluated by comparing the sum score of different symptoms (nasal congestion, runny nose, cough, and pain) and the severity scores of individual symptoms three hours after dosing and within one hour of rising the following morning.
Sachsenroder 1972 studied the effect of 2‐(5,6,7,8‐tetrahydro‐1‐naphtylamino)‐2‐ imidazoline‐HCl (a decongestant) + chlorthenoxazin (an anti‐inflammatory medication) + chlorphenamine (Cimporhin) compared with chlorthenoxazin and placebo in 165 adult participants suffering from rhinorrhoea and flu‐like symptoms. The effect on rhinorrhoea was evaluated as 'good' or 'bad' on days one, two, and three of treatment. We considered the comparison between Cimporhin and placebo in the review.
Thackray 1978 studied the effect of a combination of doxylamine + ephedrine + paracetamol + dextromethorphan on night symptoms of the common cold in 70 adult participants. A cross‐over design was used. Participants were randomly divided into two groups: the first night one group received the placebo, and the other group received the active treatment; the second night this was reversed. At the end of the study, effectiveness was assessed by rating the severity of common cold symptoms including nasal congestion, nasal discharge, sneezing, and cough on a six‐point scale and by assessing the relief of global cold symptoms. The numbers of positive ratings after one dose of active or placebo syrup were compared.
Unuvar 2007 included 201 children between 2 and 12 years of age with an acute respiratory infection and compared the effect of paracetamol versus diphenhydramine + paracetamol + pseudoephedrine. Outcome measures were the frequency of runny nose, stuffy nose, and cough; the sum of severity scores (on a four‐point scale) of different symptoms; and the clinical recovery ratios on the third and fifth days.
Zhang 2018 included 53 adults with symptoms of cold or flu. The intervention consisted of a single dose of a combination of paracetamol, pseudoephedrine, dextromethorphan, and chlorpheniramine. The study compared the difference in the total symptom score (sum of scores of individual cold symptoms on a four‐point severity score) and severity scores of cough and nasal symptoms after 15, 30, 60, 120, 180, and 240 minutes. Furthermore, they evaluated global assessment on a five‐point scale at 240 min and compared the frequency of adverse effects in both treatment groups.
Primary outcome
1. Global evaluation of effectiveness
Five trials including a total of 896 participants assessed the global effectiveness of oral combinations of antihistamine‐decongestant‐analgesic on the course of the common cold (Blanco 2000; Mizoguchi 2007; Thackray 1978; Unuvar 2007; Zhang 2018). The combination showed some effect in two trials (Mizoguchi 2007; Thackray 1978).
In Thackray 1978, participants received one dose before bedtime and rated their general feeling (useless, almost useless, not very good, good, very good, excellent) in the morning. More participants receiving the active treatment scored the active syrup as 'good' to 'excellent' compared with those receiving the placebo syrup (exact P value not provided).
In Mizoguchi 2007, overall relief was measured on a five‐point severity scale the morning following the nighttime intake of medication. The severity rating with active treatment was significantly lower than with placebo (P < 0.001); more participants receiving the active treatment rated their overall symptom relief during the night as 'good' or 'very good' on rising the following morning (50.2% versus 31.9%).
Three trials showed no effect of the treatment. In Blanco 2000, no significant difference was found between groups in the general evolution of the common cold. In Unuvar 2007, of 201 included children, 109 were evaluated for clinical recovery on day three, and 83 on day five. There was no meaningful difference in recovery rate. Zhang 2018 found no difference in total symptom score on any of the evaluation times, nor at the global evaluation point.
We pooled data from two trials (Analysis 4.1) (Mizoguchi 2007; Thackray 1978). Measured in the morning after an evening dose, significantly more participants evaluated the active evening dose treatment as beneficial (OR 0.47, 95% CI 0.33 to 0.67; 2 studies, 548 adults; low certainty evidence due to risk of bias and imprecision; Analysis 4.1). Other results are shown in Analysis 4.2; Analysis 4.3; Table 14.
4.1. Analysis.
Comparison 4: Antihistamine‐analgesic‐decongestant, Outcome 1: Global evaluation: on the morning after evening dosing
4.2. Analysis.
Comparison 4: Antihistamine‐analgesic‐decongestant, Outcome 2: Global evaluation: after 3 days of treatment
4.3. Analysis.
Comparison 4: Antihistamine‐analgesic‐decongestant, Outcome 3: Global evaluation: after 5 days of treatment
10. Combination 4: results antihistamine‐decongestant‐analgesic.
| Study ID | Results |
| Blanco 2000 | a. Global efficacy Comparison of severity ratings on the third day of treatment between treatment groups: results are graphically displayed and summarised in a table. It is not clear what is presented in the table. On the graphs, P values are mentioned when there is a statistically significant difference: for general unwell feeling, there is no significant difference. b. Subjective severity assessment of nasal obstruction Comparison of severity ratings on the third and fifth day of treatment between treatment groups: results are graphically displayed and summarised in a table. It is not clear what is presented in the table. In the graphs, P values are mentioned when there is a statistically significant difference: for nasal congestion, P = 0.041. c. Effect on results on anterior rhinoscopy Comparison of severity ratings on the third and fifth day of treatment between treatment groups: results are graphically displayed and summarised in a table. It is not clear what is presented in the table. In the graphs, P values are mentioned when there is a statistically significant difference: for anterior rhinoscopy, P = 0.045 on the third day. d. Rhinorrhoea Comparison of severity ratings on the third day of treatment between treatment groups: results are graphically displayed and summarised in a table. It is not clear what is presented in the table. In the graphs, P values are mentioned when there is a statistically significant difference: for anterior rhinorrhoea, P = 0.012. |
| Sachsenroder 1972 | a. Rhinorrhoea Number of participants rating the efficacy of the product "good" or "bad" in treating the symptom of rhinrrhoea on days 1, 2, and 3 of taking medications. Ap 67 (n = 52), Z 95‐Rhi (n = 52), placebo (n = 55). Difference: Day 1: good 18, 27, 9; bad 34, 25, 46 (significant) Day 2: good 30, 34, 18; bad 22, 18, 37 (not significant) Day 3: good 36, 40, 20; bad 16, 10, 35 (not significant) |
| Mizoguchi 2007 | a. Overall relief (scale: 0 = very poor, 1 = poor, 2 = fair, 3 = good, 4 = very good)
Day 2 morning: T 2.4 +/− 1.01, P 1.98 +/− 1.11, P < 0.001
b. Nasal congestion (0 = much worse, 1 = somewhat worse, 2 = about the same, 3 = somewhat better, 4 = much better)
Hour 3, day 1: T 2.59 +/− 0.72, P 2.43 +/− 0.68, P = 0.012
Day 2 morning: T 2.29 +/− 0.98, P 2.00 +/− 1.10, P = 0.002
c. Runny nose (0 = much worse, 1 = somewhat worse, 2 = about the same, 3 = somewhat better, 4 = much better)
Hour 3, day 1: T 2.73 +/− 0.78, P 2.56 +/− 0.75, P = 0.017
Day 2 morning: T 2.49 +/− 0.97, P 2.16 +/− 1.12, P = 0.001
d. Cough (0 = much worse, 1 = somewhat worse, 2 = about the same, 3 = somewhat better, 4 = much better)
Hour 3, day 1: T 2.72 +/− 0.77, P 2.46 +/− 0.82, P = 0.012
Day 2 morning: T 2.50 +/− 0.97, P 2.08 +/− 1.11, P = 0.002
Percentage (%) of participants improved (no P values provided)
1) Hour 3, day 1:
Nasal congestion: T 55.4, P 44.7
Runny nose: T 58.9, P 51
Cough: T 56.7, P 43.3
2) Day 2 morning: Nasal congestion: T 45.2, P 36.2 Runny nose: T 54.3, P 40.6 Cough: T 52.3, P 38 |
| Thackray 1978 | a. Global efficacy
Number of participants rating the formulation as "good, very good or excellent" on the morning after the previous night's dose:
n = 58
Active treatment: 35/58 Placebo: 25/58 P < 0.05* b. Subjective severity assessment of nasal obstruction Number of participants rating the formulation as "good, very good, excellent" on the morning after the previous night's dose: n = 58 Active treatment: 35/58 Placebo 25/58 P < 0.05* c. Rhinorrhoea Number of participants rating the formulation as "good, very good, excellent" on the morning after the previous night's dose: n = 55 Active treatment: 35/55 Placebo 21/55 P < 0.05* d. Sneezing Number of participants rating the formulation as "good, very good, excellent" on the morning after the previous night's dose: n = 30 Active treatment: 25/30 Placebo 20/30 P = 0.14 e. Cough Number of participants rating the formulation as "good, very good, excellent" on the morning after the previous night's dose: Active treatment: 57.6% Placebo 32.2% P < 0.01 *Exact P value not provided. |
| Unuvar 2007 | Clinical score Day 3: Treatment: 4.0 +/− 2.8 Paracetamol: 4.1 +/− 2.6 P = 0.81 Day 5: Treatment: 1.7 +/− 1.4 Paracetamol: 2.0 +/− 1.6 P =0.39 Nasal stuffiness Day 3: Treatment: 27/86 Paracetamol: 21/62 P = 0.75 Day 5: Treatment: 0/86 Paracetamol: 4/62 P = 0.016 Runny nose Day 3: Treatment: 28/86 Paracetamol: 25/62 P = 0.33 Day 5: Treatment: 7/86 Paracetamol: 8/62 P = 0.49 Cough Day 3: Treatment: 13/86 Paracetamol: 14/62 P = 0.24 Day 5: Treatment: 2/86 Paracetamol: 4/62 P = 0.29 Note: treatment = paracetamol + diphenhydramine + pseudoephedrine |
| Zhang 2018 | a. Total symptom score: active treatment (A) n = 25; placebo (P) n = 27. Only graphical data available. No significant difference between groups during the 4 hours follow‐up after a single administration. (P values at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h were 0.95, 0.72, 0.74, 0.77, 0.52, 0.90, respectively). Global assessment of response to treatment (P = 0.95) b. Nasal congestion (adjusted mean (SE)) baseline: A 1.2 (0.93) P 1.2 (0.92) 15 min: A −0.32 (0.086) P −0.31 (0.084) P = 0.9337 30 min: A −0.59 (0.119) P −0.6 (0.115) P = 0.96 1 hour: A −0.61 (0.127) P −0.68 (0.124) P = 0.6521 2 hours: A −0.91 (0.138) P −1.02 (0.134) P = 0.5384 3 hours: A −1.04 (0.156) P −1.14 (0.152) P = 0.6409 4 hours: A −1.19 (0.162) P −1.28 (0.157) P = 0.9618 c. Runny nose (adjusted mean (SE)) baseline: A 2 (0.35) P 1.9 (0.55) 15 min: A −0.20 (0.081) P −0.18 (0.080) P = 0.8711 30 min: A −0.48 (0.116) P −0.32 (0.114) P = 0.2919 1 hour: A −0.54 (0.145) P −0.61 (0.143) P = 0.6940 2 hours: A −0.78 (0.148) P −0.65 (0.146) P = 0.5132 3 hours: A −0.89 (0.161) P −0.98 (0.159) P = 0.6751 4 hours: A −1.12 (0.149) P −0.97 (0.147) P = 0.4692 d. Sneezing (adjusted mean (SE)) baseline: A 1.7 (0.79) P 1.6 (0.75) 15 min: A −0.10 (0.089) P −0.24 (0.088) P = 0.2279 30 min: A −0.25 (0.103) P −0.42 (0.10215) P = 0.2203 1 hour: A −0.50 (0.126) P −0.80 (0.124) P = 0.0785 2 hours: A −0.67 (0.138) P −0.86 (0.136) P = 0.3117 3 hours: A −0.83 (0.138) P −1.03 (0.136) P = 0.2938 4 hours: A −0.88 (0.135) P −1.11 (0.133) P = 0.2064 e. Cough (adjusted mean (SE)) baseline: A 1.6 (1.04) P 1.3 (0.94) 15 min: A −0.11 (0.071) P −0.06 (0.078) P = 0.5969 30 min: A −0.28 (0.077) P −0.25 (0.084) P = 0.7506 1 hour: A −0.49 (0.116) P −0.33 (0.12) P = 0.3222 2 hours: A −0.51 (0.109) P −0.45 (0.119) P = 0.6759 3 hours: A −0.53 (0.116) P −0.53 (0.127) P = 0.9838 4 hours: A −0.72 (0.131) P −0.59 (0.143) P = 0.4599 *Exact P value not provided. |
P: placebo SE: standard error T: active treatment
2. Adverse effects of treatment
Adverse effects were reported in five trials and included drowsiness, somnolence, gingival swelling, hypersomnia, insomnia, dizziness, palpitations, giddiness, diarrhoea, headache, abdominal pain, and vomiting (Blanco 2000; Mizoguchi 2007; Thackray 1978; Unuvar 2007; Zhang 2018). Data are summarised in Table 15.
11. Combination 4: adverse effects data not meta‐analysed.
| Adverse effect | Study ID | Result |
| Adverse effects: all | Thackray 1978 | Cross‐over design: all participants took active formulation. 19 adverse effects occurred, equally distributed between active and control formulation. No further numbers reported. |
| Adverse effects: all | Mizoguchi 2007 | 5 participants with active treatment reported 9 adverse effects. 9 participants with control treatment reported 10 adverse effects. |
| Adverse effects: all | Zhang 2018 | 1 participant with active treatment reported 1 adverse effect. 3 participants with control treatment reported 1 adverse effect. |
| Drowsy or sleepy |
Blanco 2000 Zhang 2018 |
Not more frequent with active treatment; numbers not mentioned T 1/25, P 0/25 |
| Giddiness/drowsiness | Thackray 1978 | Cross‐over design: adverse effects reported by 7 participants when taking active treatment and 4 participants when taking placebo |
| Diarrhoea | Mizoguchi 2007 | T 2/224, P 1/208 |
| Headache | Mizoguchi 2007 | T 2/224, P 1/208 |
| Abdominal pain | Mizoguchi 2007 | T 1/224, P 0/208 |
| Dizziness |
Mizoguchi 2007 Zhang 2018 |
T 1/224, P 1/208 T 0/25, P 1/27 |
| Vomiting | Mizoguchi 2007 | T 1/224, P 1/208 |
P: placebo T: active treatment
Total number of participants experiencing adverse effects
In three trials, the total number of participants with one or more adverse effects was registered (Mizoguchi 2007; Thackray 1978; Unuvar 2007; Zhang 2018). A total of 673 participants were evaluated in these trials, 356 with active treatment and 317 with control. In Thackray 1978, all participants (70) received the active treatment and placebo due to the cross‐over design. In one trial, no adverse effects occurred (Unuvar 2007). In Thackray 1978, 19 adverse effects occurred, of which 11 (16%) could be attributed to the formulations; these were equally distributed between the active and control groups. In Mizoguchi 2007, five (2%) participants receiving the active medication experienced nine adverse effects, and nine (4%) participants receiving the placebo experienced 10 adverse effects. Zhang 2018 reported three participants with adverse effects in the control group and one participant with an adverse effect in the treatment group.
Participants experiencing suffering drowsiness or somnolence
Three trials evaluated the incidence of drowsiness or somnolence (Blanco 2000; Mizoguchi 2007; Thackray 1978). A total of 542 participants were included in these three trials: 379 in the active treatment group, 337 in the placebo group, and 70 who received both the placebo and the active treatment in a cross‐over design. In Thackray 1978, seven participants with the active treatment and four with the placebo felt giddy or drowsy. In Blanco 2000, no more participants felt sleepy with the active treatment than with the placebo. In Mizoguchi 2007, two participants in the active treatment group and one participant in the placebo group experienced somnolence. In Zhang 2018, one participant experienced somnolence.
Secondary outcomes
1. Decrease in the amount, or duration, of individual common cold symptoms
Subjective severity assessment of nasal obstruction
Five trials assessed the effect of the antihistamine‐decongestant‐analgesic combination on the subjective severity of nasal obstruction, all of which showed some effect.
In Blanco 2000, participants were evaluated on the third and fifth day of treatment using a five‐point severity score. In participants who received active treatment, some decrease in nasal congestion was observed on the third day of treatment (P = 0.041).
In Thackray 1978, participants rated the effect of the medication on nasal obstruction (useless, almost useless, not very good, good, very good, excellent) in the morning. More participants with active treatment scored the active syrup as good to excellent than those with the placebo syrup (exact P value not provided).
In Unuvar 2007, there was a significant difference in frequency of nasal stuffiness on the fifth day (P = 0.016), but not on the third day of therapy. In Mizoguchi 2007, severity of nasal congestion was evaluated on a five‐point scale three hours after receiving the medication and the following morning. Severity scores were significantly lower with active treatment at both evaluation times (P = 0.012, and P = 0.002). Zhang 2018 found no significant difference between groups in decrease of severity of nasal obstruction on a five‐point severity score at any of the evaluation times.
Pooling of results was not possible. The results are summarised in Table 14. We can conclude that a combination of decongestant‐antihistamine‐analgesic may have some favourable effect on nasal obstruction. However, the size of this effect and its clinical relevance are not clear. The effect size was evaluated in one trial, and the difference in severity score was at most 0.29 on a five‐point severity scale (Mizoguchi 2007).
Rhinorrhoea
Six trials assessed the effect of an antihistamine‐decongestant‐analgesic combination on the subjective severity of rhinorrhoea, of which four showed some effect.
Blanco 2000 found a significantly greater reduction of rhinorrhoea compared with placebo on the third treatment day. In Thackray 1978, more participants evaluated the active syrup as beneficial for rhinorrhoea compared with placebo (exact P value not provided). In Sachsenroder 1972, significantly more participants receiving the active treatment rated the effect on rhinorrhoea as 'good' compared with placebo treatment (P < 0.001) on each of the three treatment days. Finally, in Mizoguchi 2007, severity of runny nose was evaluated on a five‐point scale three hours after intake of medication and the following morning. At both evaluation times, severity scores were significantly lower with active treatment (P = 0.017 and P = 0.001).
In contrast, in Unuvar 2007, there were not significantly more children without rhinorrhoea on days three or five with the combination therapy in comparison with paracetamol. Zhang 2018 found no significant difference in the decrease of severity of rhinorrhoea on a five‐point severity score at any of the evaluation times.
Due to differences in outcome measures and lack of adequate data, pooling was not possible. The available results are summarised in Table 14. We can conclude that a combination containing decongestant‐antihistamine‐analgesic may have some favourable effect on rhinorrhoea in adults. The effect size could be evaluated in one trial (Mizoguchi 2007): the difference in severity score was at most 0.33 severity points on a five‐point severity scale. However, the results in children were equivocal.
Sneezing
Thackray 1978 assessed the effect of an antihistamine‐decongestive‐analgesic combination on the subjective severity of sneezing. The trial showed no beneficial effect compared with placebo (P = 0.14). Zhang 2018 found no significant difference in decrease of severity of sneezing on a five‐point severity score at any of the evaluation times.
Cough
Four trials evaluated the action of an antihistamine‐decongestant‐analgesic combination on the symptom of cough in the common cold (Mizoguchi 2007; Thackray 1978; Unuvar 2007; Zhang 2018). Two trials showed some effect (Mizoguchi 2007; Thackray 1978). The active treatment in both trials contained dextromethorphan. In Thackray 1978, there was a clear difference between the number of participants rating the formulation as 'good, very good or excellent' on the morning after the dose received the night before (P < 0.01). In Mizoguchi 2007, at both evaluation times, severity scores were significantly lower with the active treatment (P = 0.0004 and P < 0.001). Zhang 2018 found no significant difference in decrease of severity of cough on a four‐point severity score at any of the evaluation times, despite the presence of dextromethorphan in the active treatment.
In contrast, the paediatric trial by Unuvar 2007 failed to show any effect on cough.
It was not possible to draw any conclusions on the effectiveness of a combination of antihistamine‐decongestant‐analgesic for cough in adults since in both trials where some effect was seen, it may have been due to the presence of dextromethorphan. This effect size could be evaluated in one trial (Mizoguchi 2007): change in severity score was at most 0.42 severity points on a five‐point severity scale. In children there was no effect.
2. Objective assessments (rhinoscopy)
On anterior rhinoscopy in Blanco 2000, a favourable effect on oedema of the nasal mucosa was seen on the third treatment day (P = 0.056) (Table 14).
Discussion
Summary of main results
In this review we evaluated the effectiveness of four different combinations of over‐the‐counter (OTC) treatments for the common cold. All four combinations showed a general benefit in adults and children aged over six years. Where pooling of results was possible, we found an NNTB of four for the combination of antihistamine‐decongestant. The combination of antihistamine‐analgesic was beneficial in the two trials, and the combination of analgesic‐decongestant was beneficial in the one trial providing data on this outcome. The combination of antihistamine‐analgesic‐decongestant was more effective than control in two of the five trials, one of which was large and of high methodological quality (Mizoguchi 2007). General improvement is a significant outcome since the literature shows that people experiencing a common cold find their generalised symptoms and functional impairment more important than specific symptoms (Barret 2005).
Most combinations containing decongestants reduced nasal obstruction, and there may be some effect on rhinorrhoea. It is unclear whether antihistamine‐analgesic‐decongestant combinations have some additional effect on cough, since in the trials with some effect, the active treatment also contained an antitussive. Antihistamine‐decongestant combinations may have some effect on the subjective severity of sneezing, but not on the first day of treatment. However, when the size of the effect was reported (which was rarely the case), it was invariably small (less that one point on a four‐ or five‐point severity scale).
Adverse effects were not always clearly reported, but based on the available data we found that adverse effects were usually more frequent with the active treatment than with control. Dry mouth and insomnia were more frequent with antihistamine‐decongestant, and dizziness was more frequent with analgesic‐decongestant combinations. The combinations antihistamine‐analgesic‐decongestant and antihistamine‐analgesic were well tolerated, which is rather remarkable as they contain similar products as the other two combinations. It is unclear whether the treatment benefits justify this cost of adverse effects. In a study on severity reduction in the common cold, Barret 2007 found that a sufficiently important difference meaning "the smallest amount of patient‐valued benefit that an intervention would require in order to justify associated costs, risk and other harms" was about 25% for a cheap treatment without adverse effects. The effect found on severity of specific symptoms is much lower than this.
Overall completeness and applicability of evidence
Although the number of included studies was small, most studies included participants suffering from a community‐acquired common cold, investigated current combinations of cold medications, and evaluated clinically relevant outcomes (subjective symptom assessment by the participants). The results of this systematic review therefore seem generalisable.
Quality of the evidence
The most striking finding is that despite the large number of combination products and formulations on the market, and the vast amounts sold, there are only a limited number of studies evaluating their effectiveness, especially in young children. The most studied combination was antihistamines combined with decongestants (eight trials in adults (1091 participants), two trials in young children (113 participants), and four trials including older children (214 participants)). The least studied combination was antihistamines with analgesics (three trials in adults (1508 participants) and one trial in young children (100 participants)). For analgesics with decongestants, we found six trials in adults and one trial in children (2525 participants), and for the combination of antihistamines with analgesics and decongestants, we found five trials in adults and one trial in children (1014 participants). The identified trials differed from each other in every possible aspect: definitions of the common cold, inclusion and exclusion criteria, settings, method of infection (natural (N = 28) or experimental (N = 2)), interventions, control, and outcome measures. Pooling of results was rarely possible, and our conclusions are based on a global assessment of the results of each trial (effective or not effective) rather than on numerical data. The overall quality of the included trials was acceptable, although often a clear description of the methods used was missing. In some of the (often older) trials, data required to judge the methodological rigour were not reported, that is mostly information related to the randomisation process. However, the results of these older studies were in line with the more recent, higher‐quality studies, therefore we believe this does not pose a threat to the validity of the meta‐analysis. Reporting of methods was generally poor, and there were large differences in design, participants, interventions, and outcomes. The certainty of evidence was mostly moderate to low due to imprecision or risk of bias.
Potential biases in the review process
Despite our extensive searches, it is possible that we did not identify all relevant trials, as it seems unlikely that so few trials have been performed in view of the vast market for an active preparation. Our results might be over‐optimistic, and publication bias cannot be excluded.
In most trials it was unclear how the participants were recruited, that is it is not clear if the included participants were actively seeking care for their symptoms of the common cold. This may jeopardise the generalisability of the findings. This also raises some ethical issues, as treatments with possible adverse effects may have been given to participants with minor self‐limiting illnesses.
We excluded illnesses with a possible bacterial cause or potentially non‐self‐limiting course, or conditions that might interfere with the natural course of the common cold (such as allergies). We excluded allergies because antihistamines are an effective treatment for them.
We included studies using active controls because we felt that this made the review more comprehensive, as a comparison with an active control allowed us to assess the added value of the combination versus a single substance or a current treatment.
One trial reported cold episodes as unit of analysis (Bye 1980). This trial has been included in the meta‐analysis (Table 1). Since the common cold is a short, acute, benign condition, and the vast majority of participants were included only once (199 participants had 1 cold, 36 had 2 colds, and 7 had 3 colds), we do not think that this introduces meaningful bias.
As not all trials reported on the occurrence of adverse effects, it is possible that the number of adverse effects is underestimated. Some trials evaluated the immediate effect of one dose of active medication, whilst other trials looked at the effectiveness over the duration of the cold. Although these are very different outcomes, both were relevant in view of the goals of this review.
Agreements and disagreements with other studies or reviews
Our results are in line with the results of similar reviews. Smith 1993 extensively reviewed the effectiveness of OTC cold medications and concluded that there was very little evidence of their effectiveness in young children, but that some medications and combinations were effective in adolescents and adults, which is confirmed by our findings. Smith 2014 found that there was no good evidence of effectiveness of OTC medication for acute cough, but that results of trials were conflicting. In our review we found some evidence of the effectiveness in cough in adults with the combination of antihistamine‐analgesic‐decongestant, which was mainly due to the results of one trial not included in the review by Smith (Mizoguchi 2007). However, the active treatment in this trial also contained dextromethorphan. Deckx 2016 concluded that a single oral dose of nasal decongestant is modestly effective for short‐term relief of congestion in adults, and that these medications also provide benefit after regular use over three to five days. This is in accordance with our findings that combinations with decongestants decrease nasal obstruction. A review by Eccles 2006b on the efficacy and safety of OTC analgesics in the treatment of common cold and flu found that there is little information on the use of analgesics in treating colds. Safety and efficacy data must be related to other pain and fever models. Eccles 2006b concluded that these medications were effective, which confirms our findings that most combinations showed some general benefit. De Sutter 2015 concluded that antihistamines have a limited short‐term beneficial effect on severity of overall symptoms, which may explain some of the effect we found in the combinations with antihistamines.
Regarding the possible risks, it must be noted that in 2005 the US Food and Drug Administration (FDA) issued a warning for OTC nasal preparations containing phenylpropanolamine because of the increased risk of intracranial bleeding (FDA 2005). Moreover, the Annual Report of the American Association of Poison Control Centers' Naional Poison Data System places analgesics, antihistamines, and cold/cough medication in the top 25 drug categories most frequently involved in human exposures, both in children and adults (Gummin 2018). A report from the US Centers for Disease Control and Prevention identified more than 1500 emergency room visits in 2004 and 2005 for children under two years of age who had been given cough or cold products, and a review by the FDA identified 123 deaths related to the use of such products in children under six years of age over the past few decades (Sharfstein 2007).
Authors' conclusions
Implications for practice.
The scarce data on the effectiveness of antihistamine‐analgesic‐decongestant combinations for the common cold show that there is some general benefit in adults and older children, which must be weighed against the risk of adverse events. The effect on individual symptoms is probably too small to be clinically relevant. Combinations containing phenylpropanolamine must be avoided. In young children these combinations should not be used given that evidence of their effectiveness is lacking and their potentially associated dangers.
Implications for research.
We found evidence to support the effectiveness of combinations with antihistamines, analgesics, and decongestants compared to placebo. However, it is unclear if the effect is due to one of the components alone or the combination product. Further trials are needed to explore the added value of combining these individual components in comparison with each in monotherapy. Analgesics, decongestants, and antihistamines have some effect in monotherapy (Deckx 2016; De Sutter 2015; Eccles 2006b). Further trials comparing the effectiveness of a single component with a combination may show that the single component is equally effective. Attention should be given to investigating the balance between increased risk of adverse events and clinical benefit. Future trials should report on participant recruitment and randomisation procedures, and include information on the participants' expectations. All trials should report participant well‐being as the primary outcome, as the benign course of the common cold makes laboratory outcomes or quantification of mucus, etc., irrelevant for clinical practice. We do not recommend new trials in small children, given the potentially dangerous adverse effects in children and the benign course of the common cold.
What's new
| Date | Event | Description |
|---|---|---|
| 10 June 2021 | New citation required but conclusions have not changed | Our conclusions remain unchanged. |
| 10 June 2021 | New search has been performed | We included three new trials, Eccles 2014; Montijo‐Barrios 2011; Zhang 2018, and excluded 11 new trials (Bhattacharya 2013; Cohen 2017; Hosseini 2016; Krishnaprasad 2012; NCT01938144; NCT02678234; NCT02730364; Picon 2013; Schachtel 2010; Schuetz 2014; Septimus 2017). We identified one ongoing trial (NCT02904304), and one trial awaiting classification (NCT02246166). |
History
Protocol first published: Issue 4, 2004 Review first published: Issue 2, 2012
| Date | Event | Description |
|---|---|---|
| 14 March 2008 | Amended | Converted to new review format |
Acknowledgements
We thank Louise Kenyon for the initial search and her efforts in tracing copies of old papers; without her help some studies would not have been found. We thank Sarah Thorning for her assistance with the searches in the first publication, and Liz Dooley for her support with the review process. We thank Alja Skrt, Olivia Lesslar and Anna Kumar for their contribution to the first version of the review. We also wish to thank the following people for commenting on the draft of the first review: Margarita Corry, Emin Unuvar, Mark Jones, and Peter Morris. We thank Katherine Jones for her assistance with the final edits in this update, and to Susan Smith for signing off on the final draft.
Appendices
Appendix 1. MEDLINE (EBSCOhost) search strategy
S35 S13 AND S34
S34 S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33
S33 analgesic* or acetaminophen* or aspirin* or ibuprofen* or ketoprofen* or naproxen*
S32 (MH "Naproxen")
S31 (MH "Ketoprofen")
S30 (MH "Ibuprofen")
S29 acetylsalicylic acid
S28 (MH "Aspirin")
S27 paracetamol*
S26 (MH "Acetaminophen")
S25 (MH "Analgesics+")
S24 ephedrine* or pseudoephedrine* or phenylephrine* or naphazoline* or oxymetazoline* or tramazoline* or xylometazoline* or phenylpropanolamine*
S23 (MH "Ephedrine")
S22 (MH "Pseudoephedrine")
S21 decongestant*
S20 (MH "Nasal Decongestants")
S19 antazoline* or methapyrilene* or pyrilamine* or tripelennamine* or clemastine* or dimenhydrinate* or diphenhydramine* or doxylamine* or brompheniramine* or chlorpheniramine* or dimethindene* or pheniramine* or triprolidine* or promethazine* or cetrizine* ormeclizine* or hydroxyzine* or astemizole* or cyproheptadine* or loratadine* or terfenadine* or acrivastine* or fexofenadine* or dexbrompheniramine* or carbinoxamine*
S18 anti‐allerg*
S17 histamine‐h1‐antagonist*
S16 (MH "Anti‐Allergic Agents")
S15 (MH "Histamine H1 Antagonists, Non‐Sedating")
S14 (MH "Histamine H1 Antagonists+")
S13 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12
S12 rhinovirus infection*
S11 (MH "Rhinovirus")
S10 sneez*
S9 (MH "Sneezing")
S8 nasal obstruction*
S7 (MH "Nasal Obstruction")
S6 cough*
S5 (MH "Cough")
S4 respiratory tract infection*
S3 (MH "Respiratory Tract Infections+")
S2 common cold*
S1 (MH "Common Cold")
Appendix 2. Embase (Elsevier) search strategy
#31 #29 AND #30 #30 'crossover procedure':de OR 'double‐blind procedure':de OR 'randomized controlled trial':de OR 'single‐blind procedure':de OR (random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR doubl* NEAR/1 blind* OR singl* NEAR/1 blind* OR assign* OR allocat* OR volunteer*):de,ab,ti NOT ('animal'/exp NOT ('animal'/exp AND 'human'/exp)) #29 #14 AND #28 #28 #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 #27 analgesic*:ab,ti OR paracetamol*:ab,ti OR acetaminophen*:ab,ti OR aspirin*:ab,ti OR 'acetylsalicylic acid':ab,ti OR ibuprofen:ab,ti OR ketoprofen:ab,ti OR naproxen*:ab,ti #26 'paracetamol'/de OR 'acetylsalicylic acid'/de OR 'ibuprofen'/de OR 'ketoprofen'/de OR 'naproxen'/de #25 'analgesic agent'/exp #24 ephedrine*:ab,ti OR pseudoephedrine*:ab,ti OR phenylephrine*:ab,ti OR naphazoline*:ab,ti OR oxymetazoline*:ab,ti OR tramazoline*:ab,ti OR xylometazoline*:ab,ti OR phenylpropanolamine*:ab,ti #23 'pseudoephedrine'/de AND [embase]/lim3763 #22 'ephedrine'/de AND [embase]/lim9946 #21 decongestant*:ab,ti OR decongestive*:ab,ti #20 'decongestive agent'/exp #19 antazoline*:ab,ti OR methapyrilene*:ab,ti OR pyrilamine*:ab,ti OR tripelennamine*:ab,ti OR clemastine*:ab,ti OR dimenhydrinate*:ab,ti OR diphenhydramine*:ab,ti OR doxylamine*:ab,ti OR brompheniramine*:ab,ti OR chlorpheniramine*:ab,ti OR dimethindene*:ab,ti OR pheniramine*:ab,ti OR triprolidine*:ab,ti OR promethazine*:ab,ti OR cetrizine*:ab,ti OR meclizine*:ab,ti OR hydroxyzine*:ab,ti OR astemizole*:ab,ti OR cyproheptadine*:ab,ti OR loratadine*:ab,ti OR terfenadine*:ab,ti OR acrivastine*:ab,ti OR fexofenadine*:ab,ti OR dexbrompheniramine*:ab,ti OR carbinoxamine*:ab,ti #18 antihistamin*:ab,ti OR 'anti‐histamine':ab,ti OR 'anti‐histamines':ab,ti #17 'histamine h1 antagonist':ab,ti OR 'histamine h1 antagonists':ab,ti OR 'histamine h1 receptor antagonist':ab,ti OR 'histamine h1 receptor antagonists':ab,ti #16 'antiallergic agent'/de #15 'antihistaminic agent'/de OR 'histamine h1 receptor antagonist'/exp #14 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 #13 ((coronavir* OR rhinovir*) NEXT/1 infect*):ab,ti #12 'rhinovirus infection'/de OR 'coronavirus infection'/de #11 sneez*:ab,ti OR cough*:ab,ti OR 'sore throat':ab,ti OR 'sore throats':ab,ti #10 'sore throat'/de #9 'coughing'/de #8 'sneezing'/de #7 (acute NEXT/1 (rhinit* OR rhinorrh*)):ab,ti #6 ((nasal OR nose) NEAR/2 (obstruction OR blocked OR congestion OR congested OR stuffy OR stuffiness OR runny OR discharge)):ab,ti #5 rhinopharyngit*:ab,ti OR nasopharyngit*:ab,ti AND [embase]/lim889 #4 'upper respiratory infection':ab,ti OR 'upper respiratory infections':ab,ti OR 'upper respiratory tract infection':ab,ti OR 'upper respiratory tract infections':ab,ti OR urti:ab,ti #3 'upper respiratory tract infection'/de OR 'viral upper respiratory tract infection'/de #2 'common cold':ab,ti OR 'common colds':ab,ti OR coryza:ab,ti #1 'common cold'/exp OR 'common cold symptom'/de
Appendix 3. CINAHL (EBSCOhost) search strategy
S45 S34 AND S44 S44 S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 S43 (MH "Quantitative Studies") S42 TI placebo* OR AB placebo* S41 (MH "Placebos") S40 (MH "Random Assignment") S39 TI random* OR AB random* S38 TI ((singl* or doubl* or tripl* or trebl*) W1 (blind* or mask*)) OR AB ((singl* or doubl* or tripl* or trebl*) W1 (blind* or mask*)) S37 TI clinic* trial* OR AB clinic* trial* S36 PT clinical trial S35 (MH "Clinical Trials+") S34 S18 AND S33 S33 S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 S32 TI (analgesic* or acetaminophen* or aspirin* or ibuprofen* or ketoprofen* or naproxen*) OR AB (analgesic* or acetaminophen* or aspirin* or ibuprofen* or ketoprofen* or naproxen*) S31 (MH "Naproxen") S30 (MH "Ibuprofen") S29 (MH "Aspirin") S28 (MH "Acetaminophen") S27 (MH "Analgesics") S26 TI (ephedrine* or pseudoephedrine* or phenylephrine* or naphazoline* or oxymetazoline* or tramazoline* or xylometazoline* or phenylpropanolamine*) OR AB (ephedrine* or pseudoephedrine* or phenylephrine* or naphazoline* or oxymetazoline* or tramazoline* or xylometazoline* or phenylpropanolamine*) S25 (MH "Ephedrine") S24 TI decongestant* OR AB decongestant* S23 (MH "Vasoconstrictor Agents, Nasal+") S22 TI (antazoline* or methapyrilene* or pyrilamine* or tripelennamine* or clemastine* or dimenhydrinate* or diphenhydramine* or doxylamine* or brompheniramine* or chlorpheniramine* or dimethindene* or pheniramine* or triprolidine* or promethazine* or cetrizine* or meclizine* or hydroxyzine* or astemizole* or cyproheptadine* or loratadine* or terfenadine* or acrivastine* or fexofenadine* or dexbrompheniramine* or carbinoxamine*) OR AB (antazoline* or methapyrilene* or pyrilamine* or tripelennamine* or clemastine* or dimenhydrinate* or diphenhydramine* or doxylamine* or brompheniramine* or chlorpheniramine* or dimethindene* or pheniramine* or triprolidine* or promethazine* or cetrizine* or meclizine* or hydroxyzine* or astemizole* or cyproheptadine* or loratadine* or terfenadine* or acrivastine* or fexofenadine* or dexbrompheniramine* or carbinoxamine*) S21 TI (antihistamin* or anti‐histamin* or antiallerg* or anti‐allerg*) OR AB (antihistamin* or anti‐histamin* or antiallerg* or anti‐allerg*) S20 TI Histamine H1 Antagonist* OR AB Histamine H1 Antagonist* S19 (MH "Histamine Antagonists") OR (MH "Histamine H1 Antagonists+") S18 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 S17 TI ((rhinovir* or coronavir*) N2 infect*) OR AB ((rhinovir* or coronavir*) N2 infect*) S16 (MH "Coronavirus Infections") S15 (MH "Coronavirus") S14 TI (sneez* or cough* or sore throat*) OR AB (sneez* or cough* or sore throat*) S13 (MH "Cough") S12 (MH "Sneezing") S11 TI (rhinopharyngit* or nasopharyngit*) OR AB (rhinopharyngit* or nasopharyngit*) S10 TI (acute N2 (rhinitis or rhinorrh*)) OR AB (acute N2 (rhinitis or rhinorrh*)) S9 (MH "Rhinitis") S8 TI ((nasal or nose) N2 (obstruction* or blocked or congest* or runny or stuffy or stuffiness or discharge)) OR AB ((nasal or nose) N2 (obstruction* or blocked or congest* or runny or stuffy or stuffiness or discharge)) S7 (MH "Nasal Obstruction") S6 TI (arti or ari or urti) OR AB (arti or ari or urti) S5 TI (respiratory tract infection* or upper respiratory infection*) OR AB (respiratory tract infection* or upper respiratory infection) S4 (MH "Respiratory Tract Infections") S3 TI coryza OR AB coryza S2 TI common cold* OR AB common cold* S1 (MH "Common Cold")
Appendix 4. LILACS (BIREME) search strategy
((mh:"Histamine H1 Antagonists" OR "Antagonistas de los Receptores Histamínicos H1" OR "Antagonistas dos Receptores Histamínicos H1" OR antihistamin* OR "anti‐histamine" OR "anti‐allergic" OR antazoline* OR methapyrilene* OR pyrilamine* OR tripelennamine* OR clemastine* OR dimenhydrinate* OR diphenhydramine* OR doxylamine* OR brompheniramine* OR chlorpheniramine* OR dimethindene* OR pheniramine* OR riprolidine* OR promethazine* OR cetrizine* OR meclizine* OR hydroxyzine* OR astemizole* OR cyproheptadine* OR loratadine* OR terfenadine* OR acrivastine* OR fexofenadine* OR dexbrompheniramine* OR carbinoxamine* OR mh:"Nasal Decongestants" OR decongestant* OR "Descongestionantes Nasales" OR "Descongestionantes Nasais" OR mh:ephedrine OR ephedrine OR efedrina OR mh:pseudoephedrine OR seudoefedrina OR pseudoefedrina OR ephedrine* OR pseudoephedrine* OR phenylephrine* OR naphazoline* OR oxymetazoline* OR tramazoline* OR xylometazoline* OR phenylpropanolamine* OR mh:analgesics OR analgésicos OR analgésicos OR mh:d27.505.696.663.850.014* OR mh:d27.505.954.427.040* OR mh:acetaminophen OR acetaminofén OR acetaminofen OR paracetamol* OR acetaminofeno OR hidroxiacetanilida OR paracetamol OR acetamidofenol OR mh:aspirin OR aspirin* OR "Acetylsalicylic Acid" OR "Ácido Acetilsalicílico" OR mh:ibuprofen OR ibuprofen* OR mh:ketoprofen OR ketoprofen OR cetoprofeno OR mh:naproxen OR naproxen* OR analgesic* OR acetaminophen*) AND (mh:"Common Cold" OR "common cold" OR "common colds" OR coryza OR "Resfriado Común" OR "Resfriado Comum" OR mh:"Respiratory Tract Infections" OR "Infecciones del Sistema Respiratorio" OR "Infecções Respiratórias" OR "respiratory tract infection" OR "upper respiratory infection" OR "upper respiratory infections" OR "Infecciones de las Vías Respiratorias" OR "Infecciones del Tracto Respiratorio Superior" OR "Infecciones del Aparato Respiratorio" OR "Infecciones de las Vías Respiratorias Superiores" OR "Infecciones del Tracto Respiratorio" OR "Infecciones Respiratorias" OR "Infecções das Vias Respiratórias" OR "Infecções do Trato Respiratório Superior" OR "Infecções do Aparelho Respiratório" OR "Infecções das Vias Respiratórias Superiores" OR "Infecções das Vias Aéreas Superiores" OR "Infecções do Sistema Respiratório" OR "Infecções do Sistema Respiratório Superior" OR "Infecções do Trato Respiratório" OR mh:nasopharyngitis OR nasopharyngitis OR rhinopharyngitis OR nasofaringit* OR mh:rhinitis OR rhinitis OR rinit* OR mh:sneezing OR sneez* OR estornudo OR espirro OR mh:cough OR cough* OR tos OR tosse OR "sore throat" OR "sore throats" OR mh:rhinovirus OR rhinovir* OR mh:"Coronavirus Infections" OR coronavir*) ) AND db:("LILACS") AND type_of_study:("clinical_trials")
Appendix 5. Web of Science (Clarivate) search strategy
# 8 #6 AND #7
# 7 TS=((random* or placebo* or allocat* or crossover* or "cross over" or (doubl* or singl*) (NEXT/1 blind*) )) OR TI=((trial))
# 6 #1 AND #5
# 5 #4 OR #3 OR #2
# 4 TS=((analgesic* or acetaminophen* or paracetamol* or aspirin* or "acetylsalicylic acid" or ibuprofen* or ketoprofen* or naproxen*)) # 3 TS=((decongestant* or ephedrine* or pseudoephedrine* or phenylephrine* or naphazoline* or oxymetazoline* or tramazoline* or xylometazoline* or phenylpropanolamine*))
# 2 TS=((antihistamin* or anti‐histamin* or antiallerg* or anti‐allerg* or "histamine h1 antagonist*" or antazoline* or methapyrilene* or pyrilamine* or tripelennamine* or clemastine* or dimenhydrinate* or diphenhydramine* or doxylamine* or brompheniramine* or chlorpheniramine* or dimethindene* or pheniramine* or triprolidine* or promethazine* or cetrizine* or meclizine* or hydroxyzine* or astemizole* or cyproheptadine* or loratadine* or terfenadine* or acrivastine* or fexofenadine* or dexbrompheniramine* or carbinoxamine*))
# 1 TS=(("common cold*" or coryza or "respiratory tract infection*" or "upper respiratory infection*" or nasopharyngit* or rhinopharyngit* or "acute rhinitis" or "acute rhinorrh*" or sneez* or cough* or "sore throat*" or ((rhinovir* or coronavir*) NEAR/1 infect*))) OR TS=(((nasal or nose) NEAR/2 (obstruction or blocked or congested or congestion or runny or stuffy or stuffiness or discharge) ))
Appendix 6. Details of previous search
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4) www.thecochranelibrary.com (accessed 16 December 2011) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, OLDMEDLINE (1953 to 1965), MEDLINE (1966 to November Week 3, 2011) and EMBASE (1990 to December 2011).
We used the following terms to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐ maximising version (2008 revision); Ovid format (Lefebvre 2011). We adapted the search for EMBASE.
MEDLINE (Ovid)
1 Common Cold/ 2 common cold*.tw. 3 Respiratory Tract Infections/ 4 respiratory tract infection*.tw. 5 Cough/ 6 cough*.tw. 7 Nasal Obstruction/ 8 nasal obstruction*.tw. 9 Sneezing/ 10 sneez*.tw. 11 Rhinovirus/ 12 rhinovirus infection*.tw. 13 or/1‐12 14 exp Histamine H1 Antagonists/ 15 exp Histamine H1 Antagonists, Non‐Sedating/ 16 exp Anti‐Allergic Agents/ 17 histamine‐h1‐antagonist*.tw. 18 anti‐allerg*.tw. 19 (antazoline* or methapyrilene* or pyrilamine* or tripelennamine* or clemastine* or dimenhydrinate* or diphenhydramine* or doxylamine* or brompheniramine* or chlorpheniramine* or dimethindene* or pheniramine* or triprolidine* or promethazine* or cetrizine* or meclizine* or hydroxyzine* or astemizole* or cyproheptadine* or loratadine* or terfenadine* or acrivastine* or fexofenadine* or dexbrompheniramine* or carbinoxamine*).tw,nm. 20 exp Nasal Decongestants/ 21 decongestant*.tw. 22 Ephedrine/ 23 Pseudoephedrine/ 24 (ephedrine* or pseudoephedrine* or phenylephrine* or naphazoline* or oxymetazoline* or tramazoline* or xylometazoline* or phenylpropanolamine*).tw,nm. 25 exp Analgesics/ 26 Acetaminophen/ 27 paracetamol*.tw. 28 Aspirin/ 29 acetylsalicylic acid.tw,nm. 30 Ibuprofen/ 31 Ketoprofen/ 32 Naproxen/ 33 (analgesic* or acetaminophen* or aspirin* or ibuprofen* or ketoprofen* or naproxen*).tw,nm. 34 or/14‐33 35 13 and 34
EMBASE (Ovid)
1 Common Cold/ 2 common cold*.tw. 3 Respiratory Tract Infection/ 4 respiratory tract infection*.tw. 5 Coughing/ 6 cough*.tw. 7 Nose Obstruction/ 8 nasal obstruction*.tw. 9 sneezing/ 10 sneez*.tw. 11 rhinovirus/ 12 rhinovirus infection*.tw. 13 or/1‐12 14 exp Histamine H1 Receptor Antagonist/ 15 exp Antiallergic Agent/ 16 (acrivastine* or fexofenadine* or dexbrompheniramine* or carbinoxamine* or antazoline* or methapyrilene* or pyrilamine* or tripelennamine* or clemastine* or dimenydrinate* or diphenhydramine* or doxylamine* or brompheniramine* or chlorpheniramine* or dimethindene* or pheniramine* or triprolidine* or promethzine* or cetrizine* or meclizine* or hydroxyzine* or astemizole* or cyproheptadine* or loratadine*).tw. 17 histamine‐h1‐antagonist*.tw. 18 anti‐allerg*.tw. 19 exp Decongestive Agent/ 20 (decongestant* or decongestive*).tw. 21 Ephedrine/ 22 Pseudoephedrine/ 23 (ephedrine* or pseudoephedrine* or phenylephrine* or naphazoline* or oxymetazoline* or tramazoline* or xylometazoline* or phenylpropanolamine*).tw. 24 exp Analgesic Agent/ 25 Paracetamol/ 26 (acetaminophen* or paracetamol*).tw. 27 Acetylsalicylic Acid/ 28 (aspirin* or acetylsalicylic acid).tw. 29 Ibuprofen/ 30 Ketoprofen/ 31 Naproxen/ 32 (analgesic* or ibuprofen* or ketoprofen* or naproxen*).tw. 33 or/14‐32 34 33 and 13 35 random.tw. or placebo.mp. or double‐blind.tw. 36 35 and 34
Data and analyses
Comparison 1. Antihistamine‐decongestant.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Global evaluation | 6 | 565 | Risk Difference (M‐H, Random, 95% CI) | ‐0.26 [‐0.33, ‐0.19] |
| 1.2 Adverse effects: all | 7 | 842 | Odds Ratio (M‐H, Random, 95% CI) | 1.58 [0.78, 3.21] |
| 1.3 Adverse effects: drowsiness, hypersomnia, and excessive sleepiness | 5 | 692 | Odds Ratio (M‐H, Random, 95% CI) | 1.38 [0.63, 3.00] |
| 1.4 Adverse effects: dry mouth | 4 | 640 | Odds Ratio (M‐H, Random, 95% CI) | 3.75 [1.74, 8.10] |
| 1.5 Adverse effects: insomnia | 2 | 344 | Odds Ratio (M‐H, Random, 95% CI) | 2.89 [0.88, 9.56] |
| 1.6 Adverse effects: gastrointestinal upset | 2 | 296 | Odds Ratio (M‐H, Random, 95% CI) | 2.81 [0.64, 12.33] |
Comparison 2. Antihistamine‐analgesic.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2.1 Adverse effects: drowsiness, hypersomnia, and excessive sleepiness | 2 | 272 | Odds Ratio (M‐H, Random, 95% CI) | 1.64 [0.48, 5.59] |
Comparison 3. Analgesic‐decongestant.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 3.1 Global evaluation | 1 | 181 | Odds Ratio (M‐H, Random, 95% CI) | 0.28 [0.15, 0.52] |
| 3.2 Adverse effects: all | 6 | 1797 | Odds Ratio (M‐H, Random, 95% CI) | 1.62 [1.18, 2.23] |
| 3.3 Adverse effects: drowsiness, hypersomnia, lethargy, excessive sleepiness and other central nervous system adverse effects | 5 | 1644 | Odds Ratio (M‐H, Random, 95% CI) | 1.34 [0.76, 2.37] |
| 3.4 Adverse effects: dry mouth | 3 | 764 | Odds Ratio (M‐H, Random, 95% CI) | 1.43 [0.53, 3.83] |
| 3.5 Adverse effects: gastrointestinal | 5 | 1644 | Risk Ratio (M‐H, Random, 95% CI) | 1.71 [0.97, 3.01] |
| 3.6 Adverse effects: dizziness, lightheadedness | 4 | 1287 | Odds Ratio (M‐H, Random, 95% CI) | 2.86 [1.02, 8.01] |
Comparison 4. Antihistamine‐analgesic‐decongestant.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 4.1 Global evaluation: on the morning after evening dosing | 2 | 548 | Odds Ratio (M‐H, Random, 95% CI) | 0.47 [0.33, 0.67] |
| 4.2 Global evaluation: after 3 days of treatment | 1 | 109 | Odds Ratio (M‐H, Random, 95% CI) | 0.34 [0.09, 1.31] |
| 4.3 Global evaluation: after 5 days of treatment | 1 | 83 | Odds Ratio (M‐H, Random, 95% CI) | 1.17 [0.49, 2.77] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Aschan 1974.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 60 participants included 100% follow‐up | |
| Participants | Adult volunteers Settings: university department; recruitment: not clear Inclusion: nasal blocking due to acute rhinitis Exclusion: complications (patient with history of pollen allergy not excluded, tests were performed in season without pollen) Duration of symptoms before inclusion: 2 to 3 days | |
| Interventions | 1. Promethazine chloride 15 mg + ephedrine 10 mg 2. Clemastine 1 mg + phenylpropanolamine 50 mg 3. Clemastine 1 mg + phenylpropanolamine 30 mg 4. Clemastine 1 mg + phenylpropanolamine 50 mg slow release Control: placebo Duration: 1 administration | |
| Outcomes | Rhinomanometric changes in nasal patency (positive or negative changes) | |
| Notes | Funding source: not reported | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | "...the key to each randomisation list was opened and correlated to the rhinomanometric findings only after all had been evaluated" |
| Blinding (performance bias and detection bias) All outcomes | Low risk | "Double‐blind investigations were carried out for all drugs tested..." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All outcome data addressed. |
| Selective reporting (reporting bias) | Low risk | All prespecified outcomes have been adequately reported. |
| Other bias | Unclear risk | Funding source and conflict of interest not reported. |
Berkowitz 1989.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 283 participants included 92% follow‐up | |
| Participants | Adult volunteers Setting: multicentre Recruitment: not clear Inclusion: moderate rhinorrhoea and stuffiness and a minimum sum score (measured on a 4‐point scale for each symptom) of at least 5 for subjective symptoms (nasal discharge, nasal congestion, sneezing, postnasal drip, cough, earache, sore throat, eye watering/tearing) and also at least 5 for physical signs (also measured on a 4‐point scale for each physical sign: nasal airway patency, eye redness, nasal hyperaemia, rhinorrhoea, mucosal swelling); negative streptococcal screening and pregnancy test Exclusion: presence of fever, exudative tonsillitis, symptoms of allergy, asthma, eczema, and sinusitis; use of concomitant medications including steroids, cromoglicic acid, antibiotics, or other cold preparations Duration of symptoms before inclusion: at most 48 hours | |
| Interventions | Loratadine 5 mg/pseudoephedrine 120 mg, 2 x/d Control: placebo Duration: 5 days | |
| Outcomes | 1. Overall response according to physician on day 3 and 5 2. Severity score of different signs on day 3 and 5 evaluated by physicians (rhinorrhoea, patency, swelling, cough) 3. Daily overall response score by participants 4. Daily severity score of different symptoms by participants (nasal stuffiness, nasal discharge, sneezing, cough, etc.) 5. Side effects | |
| Notes | Funding source: not reported, but Claritin‐D supplied by Schering‐Plough Corporation | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were assigned according to a computer‐generated randomised schedule..." |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | "This was a double‐blind, placebo‐controlled, parallel group study..." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Of the total of 283 participants entered into the study, 281 were evaluated for safety (2 participants dropped out of the study within hours of beginning the study (reason given)) and 261 for efficacy. 20 participants were not analysed in the final data due to protocol violations or lost to follow‐up (tables show differences between enrolled population and efficacy population). |
| Selective reporting (reporting bias) | Low risk | All prespecified outcomes were adequately reported. |
| Other bias | Unclear risk | Loratadine 5 mg plus pseudoephedrine 120 mg combination used was Claritin‐D supplied by Schering‐Plough Corporation. |
Blanco 2000.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 40 participants included 100% follow‐up | |
| Participants | Age: 18 to 45 years Setting: hospital research centre in Mexico Inclusion: at least 12 on the sum of symptom scores (0 to 3) for rhinorrhoea, nasal congestion, nasal itch, general malaise, odynophagia, headache, conjunctival hyperaemia, lacrimation + at least 5 on the sum of symptom score (0 to 3) for nasal mucosal oedema, retronasal discharge, conjunctival hyperaemia, obstruction of right and left nostrils Exclusion: preceding of present evidence or suffering allergies and/or bacterial infections Duration symptoms before inclusion: 48 hours | |
| Interventions | Loratadine 2.5 mg + pseudoephedrine 60 mg + paracetamol 500 mg 2 x 2/d for 5 days Control: placebo | |
| Outcomes | 1. During 5 hours after the first administration: global assessment of cold, general malaise* 2. Severity assessment by the investigators on a 5‐point scale of nasal congestion, rhinorrhoea, and general malaise on day 3 and 5 of treatment 3. General evaluation: feeling better or worse 4. Participant's self evaluation of symptoms (anterior rhinorrhoea, nasal congestion, nasal mucosal oedema, obstruction) 5. Evaluation of drowsiness | |
| Notes | Funding source: not reported | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | No information |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | The placebo tablets were similar in appearance size and taste to the active tablets and were given with the same timetable. No information on assessor blinding |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No numbers reported, so it is unclear if all participants were accounted for. |
| Selective reporting (reporting bias) | Unclear risk | Not reported |
| Other bias | Unclear risk | No information on COI or funding |
Bye 1980.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 243 cold episodes 97% follow‐up | |
| Participants | Adults Setting: multicentre; recruitment: volunteers of staff of 4 divisions of a pharmaceutical company Inclusion: healthy adults enrolled before symptoms, developing cold symptoms during study period Exclusion: other medications with possible interference in study, allergic disorders Duration of symptoms before start therapy: on average 20 hours | |
| Interventions | Triprolidine 2.5 mg + pseudoephedrine 60 mg 3 x/day Control: Tripolidine 2.5 mg 3 x/day Placebo Duration of treatment: as long as necessary (maximum 20 tablets or 7 days) | |
| Outcomes | 1. Daily scores (4‐point scale) of runny nose, sneezing, blocked nose, cough 2. Daily score of 7 possible adverse effects 3. Overall assessment 8 to 10 days after start of treatment | |
| Notes | Funding source: not reported Unit of analysis is number of colds, not participants (some participants have more than 1 cold entered). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Low risk | "drugs were allocated from separate randomisation lists for men and women aged below and above 40 years and at each centre (16 lists in all). Balance in numbers was arranged after every eighth person in each list" |
| Blinding (performance bias and detection bias) All outcomes | Low risk | "...the study is double‐blind and the subjects cannot recognise the active drugs from the perception of other, unwanted effects. Table I clearly shows that they did not; more people attributed unwanted effects to placebo than to any of the active drugs." "Drugs were issued to patients in coded bottles containing 20 tablets... All tablets were identical in appearance. All were specially made and differed in appearance from marketed preparations" |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | "Three stopped taking tablets (and completing the diary) because of unwanted effects; two because of excessive drowsiness while taking triprolidine; and 1 because urticaria developed during treatment with pseudoephedrine. No reasons were obtained from the other volunteers who did not complete diaries" |
| Selective reporting (reporting bias) | Unclear risk | Not clear from methods section |
| Other bias | High risk | 5 of the 7 authors worked for Wellcome (a former pharmaceutical company that only separated itself from the pharmaceutical industry in 1995 as a charitable foundation) |
Clemens 1997.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 175 "responses" in 59 children Follow‐up: unclear | |
| Participants | Age: 6 months to 5 years Setting: 4 private paediatric practices; recruitment: children presenting at these clinics Inclusion: diagnosis of URTI Exclusion: history of asthma or allergies, currently or subsequently taking any prescribed medication Duration of symptoms before therapy: < 7 days | |
| Interventions | Brompheniramine maleate 2 mg/5 mL + phenylpropanolamine hydrochloride 12.5 mg/5 mL (Antihistamine‐Decongestant Combination, ADC) Dose: 6 months to 2 years: half a teaspoon; 2 to 5 years: 1 teaspoon (as needed, max every 4 hours) Control: placebo | |
| Outcomes | During 48 hours to 2 hours after each intake of medication, registration of:
|
|
| Notes | Funding source: not reported Unit of analysis is "response", not treated child. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Low risk | "The child was then randomly assigned in a double‐blinded fashion, to receive either the ADC or placebo." |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "The placebo was formulated to be essentially identical in colour, taste and texture to the ADC." No information on blinding of physicians or assessors |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 175 responses recorded for 59 participants: 28 participants (90 responses) received ADC; 31 participants (85 responses) received placebo Attrition/exclusion were not discussed. |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes were adequately reported. No adverse effects reported. |
| Other bias | High risk | "...parents were instructed to give the study medication whenever they thought it was necessary" "With the exception of acetaminophen, not other medication was to be given during the study period." This would introduce the possibility of performance bias. |
Curley 1988.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 86 participants included 85% follow‐up | |
| Participants | Adults > 18 years Setting: university hospital, recruitment: unclear ‐ patients kept under observation Inclusion: symptoms and physical signs of nasal passages (e.g. rhinorrhoea, sneezing, nasal obstruction) Exclusion: pregnancy; intake of aspirin, analgesics, antihistamine, decongestants, antibiotics in prior 48 hours; known allergy or vasomotor rhinitis, asthma, eczema, or chronic sinusitis or obstructive pulmonary disease; oral temperature > 38 °C; suggestion of allergic or vasomotor rhinitis, sinusitis, pneumonia, acute non‐respiratory illness, positive throat culture for BHSGA, broncho‐provocation consistent with symptomatic asthma Duration of symptoms before inclusion: 12 to 72 hours | |
| Interventions | Dexbrompheniramine maleate 6 mg + pseudoephedrine sulphate 120 mg 2 x/day Control: placebo Duration of treatment: 1 week | |
| Outcomes | 1. Daily subjective severity scores of different symptoms (nasal obstruction, nasal discharge, sneezing, cough*) 2. Prevalence of different symptoms 14 days after start of treatment (nasal obstruction, nasal discharge, sneezing, cough*) | |
| Notes | Funding source: funding information not reported | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "With the aid of a computer‐generated random number sequence, eligible volunteers were randomised in a double‐blind fashion into two treatment groups" |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "...identical‐appearing placebo..."; double‐blinded? |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition/exclusion discussed. |
| Selective reporting (reporting bias) | Low risk | All prespecified outcomes were adequately reported. |
| Other bias | Unclear risk | Information on the authors not fully disclosed. |
Debelic 1973.
| Study characteristics | ||
| Methods | RCT, double‐blind, controlled Natural colds 40 participants included (20 in each group) 90% follow‐up | |
| Participants | Adults Setting: hospital, recruitment: unclear Inclusion: symptoms of common cold in early stage Exclusion: vasomotor or allergic rhinitis, rhinitis for more that 48 hours, pathological laboratory results, re‐convalescent patients, hypertension, post‐myocardial infarction, illnesses requiring chronic treatment Duration of symptoms before inclusion: at most 48 hours | |
| Interventions | Clemastine 1 mg + phenylpropanolamine 50 mg 2 x/day Control: belladonna 0.2 mg, chlorphenamine 4 mg, phenylpropanolamine 50 mg 2 x/day Duration of treatment: 8 days | |
| Outcomes | Daily assessment by the participant of severity of nasal obstruction Daily counts of used tissues Daily assessment by the participant of sneezing Global assessment of efficacy by the participant and physician at end of treatment Side effects | |
| Notes | Funding source: not reported No ITT analysis (only for adverse events) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Described as double‐blinded study; drugs looked alike and were administered 2 x per day for 5 to 8 days; blinding of outcome assessors not mentioned |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 4 participants excluded from the analysis, 3 because of aggravating symptoms and 1 (control (belladonna/chlorphenamine/phenylpropanolamine) group) due to severe adverse effect. |
| Selective reporting (reporting bias) | Low risk | All outcomes reported. |
| Other bias | Unclear risk | No funding source reported. Recruitment of participants: from clinic in Davos (Switzerland), but unclear how recruited |
Eccles 2006a.
| Study characteristics | ||
| Methods | RCT, double‐blinded Natural colds "patients with symptomatic URTI of up to 3 days duration" 384 patients screened; 305 randomised Duration of trial: 3 days Outcomes measured after single dose and after multiple doses on day 3. | |
| Participants | 305 randomised participants Inclusion criteria: nasal congestion (i.e. total nasal airflow resistance of > 0.25 Pa cm3 as determined by posterior rhinomanometry) and pain of at least moderate intensity at baseline; in general good health and at least 18 years old Exclusion criteria: "history of allergic rhinitis, chronic respiratory disease, anatomical nasal obstruction or deformity, nasal polyps, or a disease which contra‐indicated the use of either paracetamol or pseudoephedrine, or patients who had taken certain medications within a given time scale of study entry" | |
| Interventions | Group 1 (combination): n = 76 Group 2 (paracetamol): n = 76 Group 3 (pseudoephedrine): n = 76 Placebo: n = 77 Initially a single dose administered at the clinic, then as needed at home | |
| Outcomes | Primary:
Secondary:
|
|
| Notes | Funding source: study funded by GlaxoSmithKline (GSK), and 4 authors are employees of GSK Participants were recruited using non‐specific advertising campaign for people suffering from "cold and flu". | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Not described |
| Allocation concealment (selection bias) | High risk | Not reported ("...in equal ratio, according to parallel group randomisation schedule") |
| Blinding (performance bias and detection bias) All outcomes | Low risk | "blinded using double‐dummy method"; not described how this was implemented |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 305 randomised participants No attrition during single‐dose phase; 2 participants discontinued multiple‐dose phase due to adverse effects (1 each from combination treatment and placebo) and were not included in the analysis (impact on conclusions are not discussed); high follow‐up (only 2/305 not accounted for) |
| Selective reporting (reporting bias) | Low risk | All prespecified outcomes were adequately reported. |
| Other bias | Unclear risk | Study funded by GSK, and 1 author is employee of GSK. |
Eccles 2014.
| Study characteristics | ||
| Methods | RCT, double‐blind, Natural colds, patients with nasal congestion and pain associated with URTI of up to 3 days of duration 833 randomised Duration of the trial: 3 days Outcome measured after single dose and after multiple doses on day 3. |
|
| Participants | 833 randomised, 4 participants withdrew consent. ITT population: 829 Inclusion criteria: nasal congestion (i.e. total nasal airflow resistance of > 0.25 Pa cm3 as determined by posterior rhinomanometry) and pain (composite score for sore throat or headache, or both) of at least moderate intensity at baseline. Exclusion criteria: normal range of nasal resistance at baseline (Pa <= 0.25 cm3). Allergic rhinitis, chronic respiratory disease, hyperthyroidism, cardiovascular disease, severe hypertension, peptic ulcer, hypersensitivity to acetylsalicylic acid (ASA) or pseudoephedrine (PSE). Some medications were not allowed: monoamine‐oxidase inhibitors (30 days), antihistamines and antibiotics (7 days), analgesics and antipyretics (24 hours), nasal decongestants (12 hours), lozenges and throat sprays (6 hours), menthol‐containing products (6 hours). Patients under anticoagulation therapy and pregnant or lactating females were also excluded from the study. |
|
| Interventions | Each dose consisted of the following. Group 1 (n = 236): 2 sachets of 500 mg ASA + 30 mg PSE (dissolved in water and taken orally) Group 2 (n = 239): 2 sachets of 500 mg ASA Group 3 (n = 237): 2 sachets of 30 mg PSE Group 4 (n = 121): 2 sachets of placebo Initially a single dose at the clinic, then as needed at home |
|
| Outcomes | Primary: (1) Reduction of nasal congestion, as measured by the area under the nasal airflow conduction curve 0 to 4 hours post‐first dose comparing ASA + PSE versus PSE (2) Relief of pain as measured by the total pain relief score 0 to 4 hours post‐first dose Secondary: (1) Nasal airflow conductance from baseline to 1, 2, and 3 hours, sum of subjective nasal congestion intensity differences for the time period 0 to 4 hours and 0 to 3 days, total subjective nasal congestion relief for the time period 0 to 4 hours and 0 to 3 days, and global assessment of nasal congestion relief at the evening of day 3 (2) "Secondary endpoints pain were sum of pain intensity differences (SPID) for the time period 0–4 hours (SPID0–4h) and 0–3 days (SPID0–3D), total pain relief (TOTPAR) for the time period 0‐3 days (TOTPAR0–3D), and global assessment of pain relief at the evening of day 3." Adverse events: during the study and at follow‐up visit (within 7 days after start of study) |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Method of randomisation not mentioned. |
| Allocation concealment (selection bias) | Unclear risk | Method of allocation not mentioned. |
| Blinding (performance bias and detection bias) All outcomes | Low risk | All sachets had the same appearance, taste, and no noticeable smell. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Only 4 participants were lost to follow‐up. |
| Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported. |
| Other bias | Unclear risk | Number of participants per intervention group not mentioned. |
Galvez 1985.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 60 participants included 76.6% follow‐up on efficacy, 86% for safety evaluation | |
| Participants | 6 years of age or older Setting: not clear, recruitment: not clear Inclusion criteria: a minimum total symptom score of 8 for rhinorrhoea, nasal congestion, cough, sneezing, postnasal drip, lacrimation (scored on 4‐point scale); at least mildly severe nasal congestion, rhinorrhoea, and cough (score 1 or more for each symptom); and a minimum total sign score of 4 (swelling and hyperaemia of nasopharyngeal mucosa, nasal secretion, and obstruction of the left and right nostril, scored on 4‐point scale). Exclusion criteria: pregnancy and lactation; known hypersensitivity to the study drugs or their respective drug classes; renal, hepatic, or serious cardiovascular disease, hypertension, arrhythmias, hyperthyroidism, peptic ulcer, pyloroduodenal obstruction, glaucoma, predisposition for urinary retention, prostatic hypertrophy asthma or a history of asthma, allergic respiratory disease or other serious illness, concomitant pulmonary, nasopharyngeal, or sinus bacterial infection, including exudative pharyngitis; purulent nasal secretion, severe sore throat (score > 3), or temperature above 37.8 °C; use of oral corticosteroids within the past 5 days, parenteral corticosteroids within the past 3 weeks, or intranasal corticosteroids within 2 weeks of the trial; use of MAO inhibitors; 12‐hour wash‐out of cold medication, aspirin, and antibiotics. Duration of symptoms before entry: 24 to 48 hours | |
| Interventions | Intervention: SCH399 syrup (1 mg azatadine maleate, 60 mg pseudoephedrine sulphate, 20 mg dextromethorphan hydrobromide/5 mL) 1 teaspoon 3 x/day Control: placebo Duration of treatment: 5 days | |
| Outcomes | Sum score at day 3 and 5 of the following. 1. Overall therapeutic response (proportion of participants with excellent or good response) 2. Symptoms sum scores 3. Side effects | |
| Notes | Funding source: not reported | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not discussed |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "...in this randomised, double‐blind, parallel group study." Method of blinding not discussed. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | "[Patients] lost to the study because of adverse effects, serious illness or concomitant therapy prohibited by the protocol or lost to follow‐up, were considered study drop‐outs." (i.e. no ITT analysis). These participants were not discussed further. |
| Selective reporting (reporting bias) | High risk | "Patients in whom signs and symptoms remained unchanged or were exacerbated by therapy were removed from the study and designated as treatment failures" |
| Other bias | Unclear risk | The drug studied was SCH 399 (Idulafrin, Schering, USA). |
Gwaltney 2002.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Experimental colds 150 participants included 100% follow‐up | |
| Participants | 18 to 51 years of age Setting: not clear, recruitment: not clear Inclusion criteria: screening serum neutralising antibody titre of <= 2 to type 39 rhinovirus and normal nasal examination results, negative urine pregnancy test in woman Exclusion criteria: cold symptoms 2 weeks before virus challenge; history of allergic rhinitis, bronchial asthma, chronic sinusitis, or chronic lung disease; and allergy to the study medications Treatment started 24 hours after virus challenge. | |
| Interventions | lntranasal treatment consisted of lFN (interferon) alpha2b powder (INTRON A) (Schering) dissolved in PBS containing 0.2% potassium sorbate, 2% glycerin, and 1% human albumin. lntranasal placebo was PBS containing the same ingredients but without IFN. Oral medications were commercial ibuprofen (400 mg) and chlorpheniramine maleate (12 mg sustained‐release tablets). Chlorpheniramine 12 mg extended release + ibuprofen 400 mg 2 x/day Control: placebo Duration of treatment: 4.5 days |
|
| Outcomes | Daily severity scores (5‐point scale) of sneezing, runny nose, nasal obstruction, cough* Nasal tissue count Nasal mucus weight Side effects | |
| Notes | Funding source: not reported Declared conflict of interest of authors in the combined treatment used | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | "Three groups were randomised in a 2:2:1 ratio to the following drugs or placebo: intranasal IFN plus oral chlorpheniramine and ibuprofen, intranasal placebo plus oral chlorpheniramine and ibuprofen or intranasal placebo plus oral placebo." No information on concealment |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Oral placebo and active treatment were placed in identical capsules, and intranasal treatment and placebo were administered in coarse drops at 0.2 mL per nostril and contained the same ingredients except for IFN in the placebo group. Intranasal IFN and placebo were given at 12‐hour intervals for 3 treatments. Oral medication and placebo were given every 12 hours for 4.5 days. No information is provided on blinding of physicians or outcome assessors. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Study conducted in 2 trials (first trial = 80 participants, second trial = 70 participants) Total of 150 randomised participants challenged with type 39 rhinovirus (full treatment = 59; partial treatment = 61; placebo = 30) Attrition: "1 subject who missed the second oral dose because of malaise and 7 who missed the last oral dose (6 because of drowsiness, 1 because of malaise)" |
| Selective reporting (reporting bias) | Low risk | Nature of adverse effects and the groups in which they occurred were reported. All prespecified outcomes were adequately reported. |
| Other bias | Unclear risk | Information regarding recruitment of participants (possible selection bias) or setting in which trial was conducted was not eluded to. |
Hutton 1991.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 54 children included 87% follow‐up | |
| Participants | Age: children 6 months to 5 years Setting: paediatric walk‐in clinic and paediatric primary care clinic Inclusion criteria: symptoms of cold and signs of URTI (i.e. nasal congestion and rhinorrhoea) Exclusion criteria: signs or symptoms of a more serious or treatable disease (i.e. temperature > 38.9 °C, vomiting, > 3 loose stools in 24 hours, stridor, wheezing, chest retractions, laboratory tests ordered, antibiotics prescribed); contraindication to medication (e.g. history of seizures or other neurologic problem) Study carried out in winter period to avoid allergic episodes. Duration of symptoms before enrolment: not mentioned | |
| Interventions | Intervention: brompheniramine maleate 4 mg/5 mL + phenylephrine hydrochloride 4 mg/5 mL + propanolamine hydrochloride 5 mg/5 mL Dose: calculated by weight to achieve 0.5 to 0.75 mg/kg brompheniramine/day in 3 doses Control: placebo Duration of treatment: 2 days | |
| Outcomes | 1. Symptoms severity score change (congested or runny nose, cough*) 2. Number of children (as reported by parents) with overall improvement after 2 days 3. Number of children (as reported by parents) with improvement of congested or runny nose and cough | |
| Notes | Funding source: not reported Duration of symptoms before inclusion not mentioned. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | "...assign the child randomly to one of three groups: drug, placebo, or no medication." Not discussed |
| Blinding (performance bias and detection bias) All outcomes | Low risk | "Children randomly assigned to the placebo group received bottles with identical labelling containing placebo prepared by the John Hopkins Hospital Pharmacy" Information regarding blinding of physicians or assessors is not provided. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition/exclusion reported. |
| Selective reporting (reporting bias) | Low risk | "Approximately 20% of the patients in each group reported inappropriately high medicine levels remaining in the bottles, indicating that less than the prescribed amount was given" |
| Other bias | Unclear risk | There was discussion about children in the no treatment group receiving other medicines. "The outcome measure used was not objective but, rather, depended on parental report of symptoms." |
Koytchev 2003.
| Study characteristics | ||
| Methods | RCT, double‐blind, controlled trial (4 arms) Natural colds 1167 participants tested 97% follow‐up | |
| Participants | Age: adults (18 to 70 years) Setting: multicentre; recruitment: unclear Inclusion criteria: presence of symptoms of common cold and minimum score of symptoms of 6 points (with a maximum of 12) rated on a 4‐point scale before the beginning of treatment. Symptoms rated: headache, throat pain, extremities and joint pain, blocked nose, cough, sleep disturbances. Exclusion criteria: diagnosis of any other infectious disease that produces symptoms of common cold but needs specific treatment with antibacterial or antiviral drugs (e.g. bronchitis, pneumonia, etc.); hypersensitivity to paracetamol, caffeine, chlorpheniramine hydrogen maleate, ascorbic acid; lactose intolerance; changes in existing concomitant therapy with corticosteroids; or another drug with influence on the immune system; any other drug for symptoms of common cold; treatment with any investigational drug within 3 months; legal incapacity and/or other circumstances rendering the participant unable to understand the nature, scope, and possible consequences of the study; and evidence of an uncooperative attitude. Duration of symptoms before treatment: not mentioned | |
| Interventions | Grippostad‐C (paracetamol 200 mg, caffeine 25 mg + chlorpheniramine 2.5 mg + ascorbic acid 150 mg) 3 x 2/day Reference 1: paracetamol 200 mg + ascorbic acid 150 mg 3 x 2/day Reference 2: chlorpheniramine 2.5 mg + ascorbic acid 150 mg 3 x 2/day Control: ascorbic acid 150 mg 3 x 2/day Duration of treatment: 6 days | |
| Outcomes | 1. Total score of symptoms rated by the participant on each of the treatment days and a sum of days 2. Subscore referring to the ratings of headache, throat pain, extremities and joint pain 3. Subscore referring to the ratings of blocked nose, cough, and sleep disturbance 4. Percentage of participants cured at the end of treatment 5. Adverse effects | |
| Notes | Funding source: not reported | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | "The patients enrolled were randomly assigned to treatment with 1 or 4 medications at a dose of 3 x 2 capsules a day for 6 days." No further information provided. |
| Blinding (performance bias and detection bias) All outcomes | High risk | The study does not address this other than stating that "All capsules were identical"; active treatment contained caffeine. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT = 1167 participants (Germany = 182; Poland = 480; Bulgaria = 505) who were allocated into the following groups: active group = 290; placebo/control = 292; reference 1 = 294; reference 2 = 291. 1134 participants completed the trial (attrition = 33). 33 participants who did not complete the trial according to protocol, with premature termination from the trial due to adverse events (n = 17), were reported as "deterioration of the disease leading to acute bronchitis or other complications" and withdrawn from the study on participant's request (n = 15), presence of exclusion criteria (n = 1) Impact of premature termination not discussed in study. |
| Selective reporting (reporting bias) | Low risk | "Adverse events in the current trial n = 39...analysis of adverse events provided no indication of any difference between the 4 treatments administered" All prespecified primary and secondary outcomes were adequately reported. |
| Other bias | Unclear risk | No information provided as to how participants were recruited to the trial. |
Lebacq 1994.
| Study characteristics | ||
| Methods | RCT, single‐blind, placebo‐controlled trial (3 arms) Natural colds 36 participants tested 100% follow‐up | |
| Participants | Age: adults (25 to 39 years) and children (6 to 12 years) Setting: hospital, recruitment: unclear; patients are closely followed up during 1 day under standardised circumstances Inclusion criteria: impaired nasal respiration due to acute congestive rhinitis Exclusion criteria: any current disease other than acute congestive rhinitis; insufficiency of any aetiology; drug treatment undertaken within 15 days before the study; participation in other clinical trial in the previous 3 months Duration of symptoms before treatment: not mentioned | |
| Interventions | 1. Rhinopront (24 mg carbinoxamine + 300 mg phenylpropanolamine/100 g syrup) Adults: 15 g (1 x); children 1 g/year of age 2 x/day 2. Traminic (tablets: 50 mg phenylpropanolamine hydrochloride, 25 mg pheniramine maleate, 25 mg mepyramine maleate, 10 mg caffeine monohydrate (1 x); drops: 10 mg phenylpropanolamine hydrochloride, 10 mg pheniramine maleate, 10 mg mepyramine maleate/mL 3 drops/year of age 3 x/day) Control: placebo Duration: adults: 1 single dose; children: 4 days | |
| Outcomes | 1. Nasal resistance at several moments after administration of 1 single dose 2. Clinical score at several moments after administration of 1 dose (nasal congestion, aspect of nasal mucosa) 3. Children: daily nasal congestion severity score during 4 days of treatment 4. Side effects | |
| Notes | Funding source: Pfizer Duration of symptoms before inclusion not mentioned. Possible inclusion of allergic patients | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | "...each subject was randomly assigned...to receive Rhinopront or placebo...or Triaminic" |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "..conducted as a single blind trial with three parallel groups of six patients" "Blinding was imposed to the clinical investigator performing the nasal resistance measurements and the clinical observations" "...measurements and clinical observation were performed by another investigator who was kept unaware of the randomisation scheme" Information on blinding of participants or outcome assessors is not reported. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 36 participants: 18 adults and 18 children (3 parallel groups of: 6 = Rhinopront; 6 = placebo; 6 = Triaminic for adults) "All the patients enrolled in the study completed the treatment" |
| Selective reporting (reporting bias) | Low risk | "The tolerance was good in each treatment group and no significant adverse events were recorded" The nature of non‐significant adverse events was not documented. Treatment compliance reported as "100% on day 1 and, 90% on days 2 to 5 in children". All prespecified outcomes were adequately reported. |
| Other bias | Unclear risk | 1 of the authors is employed by Pfizer GmbH, who sponsored the study. It was unclear how participants were recruited (selection bias). |
Loose 2004.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 643 participants included 99.5% follow‐up | |
| Participants | Age: adult Setting: bi‐central, health centres at university; recruitment: not clear Inclusion criteria: baseline severity score of nasal congestion of at least 6, without spontaneous improvement; the presence of a URTI confirmed by the history of complaints and physical examination Exclusion criteria: use of menthol‐containing products in the 2 hours before enrolment; use of local or systemic nasal decongestants, acetylsalicylic acid, paracetamol, ibuprofen, or antihistaminic drugs in the 6 hours before enrolment; use of long‐acting nasal decongestants or NSAIDs in the 12 hours before enrolment; use of MAO inhibitors in the 2 weeks before enrolment; use of any other medications or presence of any other medical condition that might have interfered with the determination of nasal congestion or have compromised the patient's safety Duration of symptoms before inclusion: 5 days | |
| Interventions | Acetylsalicylic acid 1000 mg + pseudoephedrine 60 mg 1 x Acetylsalicylic acid 500 mg + pseudoephedrine 30 mg 1 x Paracetamol 1000 mg + pseudoephedrine 60 mg 1 x Control: placebo Duration: 1 administration | |
| Outcomes | 1. Time course of the difference of nasal congestion score from baseline 2. Relief of nasal congestion 3. Adverse effects | |
| Notes | Funding source: not reported, but first author is an employee of Bayer | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were assigned to two different severity groups according to their baseline score...four separate computer generated randomisation lists...one for each centre and severity. Study medication was assigned to each patient by giving the patient the next free randomisation number in ascending order" |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "All patients were given once the content of four sachets and additionally two capsules", which included 1 of the 3 treatments or placebo. No information on blinding of the researchers |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 645 participants enrolled; ITT population = 643 (ASA 100 mg + PSE 60 mg, N = 161; ASA 500 mg + PSE 30 mg, N = 161, paracetamol 1000 mg + PSE 60 mg, N = 159; placebo, N = 162) Per‐protocol population = 609 (3 participants from placebo excluded due to nasal polyps; 3 participants had no data at 0‐ to 4‐hour and 0‐ to 6‐hour interval (group not specified); 8 participants excluded from 0 to 4 h and 20 participants from 0 to 6 h, "as they took rescue mediation in these intervals" (exact numbers from each group not stated)) |
| Selective reporting (reporting bias) | Low risk | Adverse effects were clearly detailed. Both primary and secondary objectives were analysed and reported on. An outcome (muscle ache) was reported that was not prespecified. |
| Other bias | Unclear risk | Demographic characteristics of participants is not representative of the general populace, being young university students (selection bias). Author is an employee of Bayer. |
Martinez 1994.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 65 participants included Follow‐up 100% | |
| Participants | 2 to 16 years of age Setting: unclear; recruitment: not clear Inclusion criteria: not mentioned Exclusion: bacterial infection or systemic disease Duration of symptoms before inclusion: not mentioned | |
| Interventions | Naproxen sodium + pseudoephedrine 2 to 5 years age group: 50 mg naproxen + 15 mg pseudoephedrine every 8 hours 6 to 9 years age group: 100 mg naproxen + 30 mg pseudoephedrine every 8 hours 10 to 12 years age group: 150 mg naproxen + 45 mg pseudoephedrine every 8 hours Different concentrations, dependent on participant age Control: pseudoephedrine syrup (15, 30, or 45 mg)+ placebo Duration of treatment: 5 days | |
| Outcomes | 1. Number and duration of the symptoms of common cold 2. Adverse effects | |
| Notes | Funding source: not reported Follow‐up not mentioned. Inclusion criteria not clear. Duration of symptoms before inclusion not mentioned. Possible inclusion of allergic participants | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "...double‐blind clinical trial" Information regarding blinding of participants, physicians, or assessors not stipulated (possibility of performance bias). |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 65 paediatric participants (combination treatment = 20; pseudoephedrine = 15; placebo‐combination = 16; placebo‐pseudoephedrine = 14) No attrition or exclusions reported. 2 to 5 years age group: 5 participants given combination; 1 participant given pseudoephedrine 6 to 9 years age group: 5 participants given combination; 8 participants given pseudoephedrine 10 to 12 years age group: 7 participants given combination; 4 participants given pseudoephedrine 13 to 16 years age group: 3 participants given combination; 3 participants given pseudoephedrine |
| Selective reporting (reporting bias) | High risk | Not all prespecified outcomes in trial protocol were reported (reporting bias). "No side effects were reported" |
| Other bias | High risk | Participant recruitment was not documented (possibility of selection bias). |
Middleton 1981.
| Study characteristics | ||
| Methods | RCT, double‐blind, controlled Natural colds 191 participants included 92% follow‐up | |
| Participants | Age: 18 to 75 years Setting: general practice, recruitment: not mentioned Inclusion: symptoms of the common cold or related URTIs Exclusion: pregnancy, hyperthyroidism, hypertension, cardiac dysfunction, diabetes mellitus, hepatic disease, hypersensitivity to any of the trial medications, treatment with MAO inhibitors within 2 weeks Duration of symptoms before inclusion: not specified | |
| Interventions | 1. Benylin Day (paracetamol 500 mg + phenylpropanolamine 25 mg) 3 x/day 2. Benylin Night (paracetamol 500 mg + diphenhydramine hydrochloride 25 mg) 1 x/day before sleeping Control: paracetamol 500 mg Duration: 5 days | |
| Outcomes | 1. Overall response according to physician on day 5 2. Daily severity score of runny nose, nasal congestion, and cough* 3. Assessment of overall response by participant on day 5 4. Side effects | |
| Notes | Funding source: not reported, but support from Warner‐Lambert Ltd mentioned | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | No information provided on allocation concealment. |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | All medication was administered 4 times daily over 5 days. No reporting of blinding of participants, physicians, or outcome assessors |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 191 participants admitted to the trial, 95 paracetamol and 96 Benylin Day and Night. 10 participants did not return their diary cards and were excluded from the analysis of the participants with completed cards: 90 paracetamol and 91 Benylin Day and Night. 6 participants withdrew from the study, 1 stopping treatment for no stated reason, 1 complaining that "the tablets did not help". Remaining 4 participants experienced adverse effects; 3 of these participants received paracetamol. Impact not discussed in results. |
| Selective reporting (reporting bias) | Low risk | Primary outcome well reported. Adverse effects were reported for each group. |
| Other bias | Unclear risk | It was not clear how participants were recruited (selection bias). |
Mizoguchi 2007.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 485 participants included 97% follow‐up | |
| Participants | Age: 18 to 65 years Setting: multicentre across USA ‐ type of centre not specified Inclusion criteria: BMI 30 or less, symptoms of the common cold (present at some point during 24 h before inclusion): moderate or severe nasal congestion, moderate or severe runny nose, at least mild cough, at least mild pain from 1 or more of the following pain symptoms: sore throat, sore chest, headache or body aches/pains; sleep disturbance due to symptoms Exclusion criteria: known or suspected allergy to any of the study medications, acute symptoms of respiratory allergies, history of chronic aches/pains, chronic fatigue, or mood disorders, chronic respiratory illness, or had a significant coexisting illness or medical condition that would compromise their ability to swallow, absorb, metabolise, or excrete the study medication. Intake of any medications/supplements within the previous 24 hours for cold symptoms or pain relief or that could produce drowsiness or promote alertness, intake of any antihistamines within the previous 72 hours, any sedatives within the previous week, any antidepressants within the previous 3 weeks Duration of symptoms before inclusion: 1 to 5 days | |
| Interventions | Intervention: 1 evening dose of 30 mL containing 15 mg dextromethorphan hydrobromide, 7.5 mg of doxylamine succinate, 600 mg of paracetamol, 8 mg of ephedrine sulphate Control: placebo | |
| Outcomes | Change of severity of nasal congestion, runny nose, cough, and pain* rated on a 4‐point Likert scale at 3 hours postdosing and within 1 hour after rising the following morning | |
| Notes | Funding source: Procter & Gamble ITT described as all participants who dosed and provided at least 1 postdosing evaluation (inconsistent with standard definition of ITT). | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "Subjects...were stratified by sex and overall symptom severity at screening and randomised with equal probability (using a block size of 6) to 1 of 2 study product groups". No information on sequence generation |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | No reporting of blinding of participants, researchers, or assessors. However, the treatment and placebo were reported to be "identical in appearance". |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 485 participants (248 test group; 237 placebo group). 15 participants lost to follow‐up (no information available). ITT population = 470 (242 test group; 228 placebo group) Per‐protocol population = 432 (224 test group; 208 placebo group), as 38 participants were identified as having major protocol deviations Impact not discussed in results. |
| Selective reporting (reporting bias) | Low risk | Primary outcome well reported. Adverse effects reported for each group. |
| Other bias | Unclear risk | The majority of participants were Caucasian (understood to be white) (about 80%). All authors but 1 are employed by Procter & Gamble; study supported by funds from Procter & Gamble. |
Montijo‐Barrios 2011.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 100 children aged 6 to 24 months Follow‐up: unclear | |
| Participants | Inclusion criteria: children younger than 24 months with symptoms of common cold: sudden onset, sneezing, transparent rhinorrhoea, tears, possibly fever Exclusion criteria: antecedents of allergic or atypical symptoms; hypersensitivity to 1 of the products in the drug; malformations or surgical antecedents at the respiratory tract; indication for antibiotics; history of febrile convulsions or epilepsy; congenital cardiopathy; recent use of antihistamine or decongestants for more than 24 hours Duration of symptoms before inclusion: not clear | |
| Interventions | Intervention: buphenine, aminophenazone, diphenylpyraline; exact dose not mentioned Control: placebo Both groups also received paracetamol. | |
| Outcomes | Comparison of the frequency of presence of symptoms at days 3, 5, and 7 (rhinorrhoea, sneezing > 6 times/day, moderate to severe irritability, difficulty eating, noisy breathing, breathing through mouth, significant tearing, fever episode) Comparison of the amount of milk consumption, number of hours of sleep during daytime, during nighttime | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Allocation occurred centrally by a computerised system with block randomisation (4 per block). |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | No information provided. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No information on attrition rate provided. |
| Selective reporting (reporting bias) | Low risk | Predefined outcomes reported. |
| Other bias | High risk | Statistical method is not optimal to evaluate evolution of symptoms. |
Robert 2004.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 204 participants included 96% follow‐up | |
| Participants | Age: 18 to 65 years Setting: multicentre (general practice centres), recruitment: not mentioned Inclusion criteria: diagnosis of common cold; minimum score of 5 and maximum score of 9 for nasal and ocular symptoms (runny nose, blocked nose, tears/itchy eyes, and sneezing/itchy nose); symptoms of runny nose and blocked nose mandatory Exclusion criteria: allergic rhinitis (seasonal or perennial), atopic eczema or asthma; non‐allergic rhinitis (vasomotor, drug‐related), influenza, sinusitis, exudative tonsillitis bronchitis, or otitis media; fever; nasal polyps or deviation of the nasal bone; severe chronic illness of any nature; hepatic, renal, cardiac, or respiratory impairment; hypersensitivity to the compounds used; fertile woman not using a safe contraceptive method, pregnant or breastfeeding women; previous history of medicine, drug, or alcohol abuse; use of compound that could interfere with the study; patients in whom the administration of pseudoephedrine is not advised or is contraindicated (hyperthyroidism, diabetes mellitus, coronary illness, arterial hypertension, or prostatic hypertrophy); treatment with other sympathomimetic agents or MAO inhibitors; smokers (> 10 cigarettes/day) Duration of symptoms before inclusion: max 36 hours | |
| Interventions | Intervention: ebastine 10 mg (immediate release) + pseudoephedrine 120 mg (sustained release)/day Control: placebo Duration: 3 days | |
| Outcomes | 1. Evaluation of overall efficacy after 3 days of treatment by a physician 2. Evolution of symptoms (runny nose, blocked nose, sneezing*) 4. Disposition of the participant to take the medicine again 5. Variation of nasal peak flow 6. Adverse events | |
| Notes | Funding source: Almirall Prodesfarma, S.A. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "The patients were randomly assigned to one of the two possible treatment groups" |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "Both treatments were administered orally as microgranules as hard gelatin capsules" All medication taken once daily for 3 days. No information on blinding of physicians or outcome assessors |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 204 participants randomised; 8 participants withdrawn (5 in placebo group and 3 in active treatment group). Reasons for withdrawal in placebo group: 3 lack of efficacy; 1 violation of protocol; 1 adverse events Reasons for withdrawal in active treatment group: 2 violation of protocol; 1 adverse events Impact not discussed in results, but high follow‐up proportion. |
| Selective reporting (reporting bias) | High risk | Primary outcome well reported. Secondary outcomes: no numbers provided for nasal peak flow No reporting of the nature of the adverse events |
| Other bias | Unclear risk | It was not clear how participants were recruited (selection bias). |
Sachsenroder 1972.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 165 participants included | |
| Participants | Age: adults Setting: unclear Inclusion: rhinorrhoea, cough, and signs of flu‐like infection Exclusion criteria not mentioned. Duration of symptoms before enrolment: 48 hours | |
| Interventions | Z 95 ‐ Rhi (2 mg imidazoline hydrochloride + 6 mg chlorpheniramine maleate + 200 mg chlorthenoxazine) 1 x/day Control: chlorthenoxazine 200 mg Control: placebo Duration: 3 days | |
| Outcomes | Number of participants estimating the effect of the composition as good or bad, on days 1, 2, and 3 | |
| Notes | Funding source: unclear, but very likely to have been carried out by manufacturer of the studied products Age of participants described as 'from under 20 to over 40 years' Flu‐like illness = common cold? Setting unclear No exclusion criteria mentioned. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described, but referred to as "randomised" |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Stated as double‐blinded, but method of blinding not described |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Intended outcomes not separately described. |
| Selective reporting (reporting bias) | Unclear risk | Very unclear reporting, no totals reported |
| Other bias | Unclear risk | Clear explanation of the pharmacological characteristics of the studied drugs and very limited information on the actual trials; report on adverse effects No information on participant recruitment |
Scavino 1985.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 58 participants included 83% follow‐up | |
| Participants | Age: 6 years or older Setting: university, recruitment: unclear Inclusion criteria: sum of scores on rhinorrhoea, nasal congestion, cough, sneezing, postnasal drip, lacrimation (scale 0 to 3) is minimal 8; rhinorrhoea or nasal obstruction and cough score minimal 2, or rhinorrhoea, cough, and nasal obstruction all at least 1 Exclusion criteria: < 6 years of age; pregnancy, lactation, hypersensitivity to study medication; renal, hepatic, cardiovascular disease; hypertension, arrhythmias, hyperthyroidism, peptic ulcers, pyloroduodenal obstruction, glaucoma, predisposition to urinary retention, prostatic hypertrophy, asthma or a history of asthma, allergic respiratory disease or other serious illnesses; concomitant pulmonary, nasopharyngeal, or sinus bacterial infection; severe sore throat; exudative pharyngitis, temperature > 37.8 °C; therapy with oral corticosteroids within 5 days, parenteral corticosteroids within 3 weeks, intranasal corticosteroids within 2 weeks of empanelment; treatment with MAO inhibitors or other medication that might affect the action of study agents Duration of symptoms before inclusion: max 48 hours | |
| Interventions | SCH 339 syrup = azatadine maleate 1 mg, pseudoephedrine sulphate 60 mg, dextromethorphan hydrobromide 20 mg/5 cm3 3 x/day Control: placebo Duration of therapy: 5 days | |
| Outcomes | Evaluation on days 3 or 4 and 5 or 6 of sum of severity scores for 5 symptoms (rhinorrhoea, nasal congestion, cough, sneezing, postnasal drip, lacrimation, headache, tiredness/drowsiness, and general achiness) Global evaluation by physician Side effects | |
| Notes | Funding source: not reported | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "...randomised...study" Method not discussed. |
| Allocation concealment (selection bias) | Unclear risk | Not discussed |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "...double‐blind investigation of SCH 399 syrup and placebo was conducted..." Information regarding blinding of participants, physicians, or assessors not stipulated (possibility of performance bias). |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Participants who violated the protocol were not followed up. |
| Selective reporting (reporting bias) | Low risk | Attrition/exclusions, failures, and participants who received concomitant therapy were reported. |
| Other bias | Unclear risk | No discussion of how participants were recruited (possible recruitment bias) |
Schrooten 1993.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 83 participants included 57% follow‐up | |
| Participants | Age: 12 to 65 years Setting: community pharmacists. Recruitment: people in the environment of the participating pharmacist Inclusion criteria: symptoms of cold, at least 1 nasal symptom Exclusion criteria: temperature > 39 °C, allergic rhinitis, pregnant or nursing, women without adequate contraception, concomitant treatment with analgesics, antipyretics, corticoids, sympathomimetics, anticholinergics Duration of symptoms before inclusion: 24 hours or less | |
| Interventions | Astemizole 10 mg + pseudoephedrine 240 mg (controlled release) 1 x/day Control: placebo Duration of treatment: 7 days | |
| Outcomes | Symptom severity score (4‐point scale): nasal discharge, nasal obstruction, sneezing, cough, general discomfort Weight of nasal secretions: weight of used paper tissues General impression Adverse effect | |
| Notes | Funding source: not reported, but ethics approval from Janssen Research Foundation | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "The trial was designed as a double‐blind comparison in parallel groups between astemizole‐D and placebo. Patients admitted to the study were assigned to one of the two treatment groups according to a computer derived randomisation list" |
| Allocation concealment (selection bias) | Unclear risk | Not discussed |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "The placebo tablets looked identical and had the same taste." Blinding of others not described. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | "Sixteen patients were on some kind of concomitant treatment when they were included and during the trial 20 patients committed a protocol violation by taking analgesics, other cough‐and‐cold preparations or antibiotics". Despite this, these participants were included in the final findings. |
| Selective reporting (reporting bias) | Unclear risk | Although participants who violated the protocol were not considered failures, they were equally spread over both treatment groups. All prespecified outcomes were reported. |
| Other bias | Low risk | "Authorisation for this trial was obtained from the central ethics committee of the Janssen Research Foundation" However, method used to recruit participants to study not discussed, possible recruitment bias. |
Sperber 1989.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Experimental colds 58 volunteers included 95% follow‐up | |
| Participants | Healthy adults Setting: not mentioned; recruitment: not mentioned Inclusion criteria: serum neutralising antibody titre of > 1:2 to the challenge rhinovirus Exclusion criteria: upper respiratory symptoms or fever within week prior to initiation of the study; history of active or chronic sinusitis, asthma or recent hay fever; patients that require use of antihistamines, systemic or topical nasal decongestants, aspirin or other NSAIDs, MAO inhibitors or phenothiazines; patients who had a history of hypersensitivity to aspirin or other anti‐inflammatory drugs, pseudoephedrine or other sympathomimetics; pregnant or lactating women; would be smoking during the study period Treatment initiated 30 hours after virus inoculation. | |
| Interventions | Pseudoephedrine hydrochloride 60 mg + ibuprofen 200 mg 1 day: 2 doses; remaining days: 4 x/day Control: placebo Duration: 5 days | |
| Outcomes | 1. Daily evaluation of symptoms severity score (total score, nasal score, etc.) 2. Objective measures including mucus and tissues weight, nasal patency measurements 3. Duration of illness 4. Adverse effects | |
| Notes | Funding source: all medication and placebo supplied by Vicks Research Center, Shelton, CT | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "...[patients] were randomly assigned..." Method not discussed. |
| Allocation concealment (selection bias) | Unclear risk | Not discussed |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Placebo not described. No information on blinding of physicians or assessors "The subjects were isolated in motel rooms for five days beginning 24 hours after rhinovirus challenge..." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition/exclusion discussed. |
| Selective reporting (reporting bias) | Unclear risk | "The need for concomitant medications dispensed for cold symptoms was also recorded." This was not discussed further. |
| Other bias | Unclear risk | Method of recruiting participants not discussed. |
Sperber 2000.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 430 participants included 96% follow‐up | |
| Participants | Age: 18 to 65 years Setting: multicentre (university clinics), recruitment: not mentioned Inclusion criteria: otherwise healthy with cold symptoms; reported at least moderate symptom severity in response to the question: "Overall, how would you rate the severity of your sinus symptoms?" Absent, mild, moderate, moderately severe, severe Exclusion criteria: pregnancy; diastolic pressure > 90 mmHg; underlying illnesses that could be exacerbated by sympathomimetic drugs that might affect the assessment of common cold symptoms; receiving drugs that could interact with sympathomimetic drugs Duration of symptoms before inclusion: maximum 48 hours | |
| Interventions | Pseudoephedrine 60 mg + paracetamol 1000 mg, 2 doses (second dose administered 6 hours after the first dose) Control: placebo Duration: 8 hours | |
| Outcomes | Evaluation 2 hours after the first dose and 2 hours after the second dose 1. Rating on 5‐point scale of efficacy on: nasal obstruction, rhinorrhoea, sneezing, cough* 2. Adverse effects | |
| Notes | Funding source: Novartis Consumer Health | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "...study was a randomised, double‐blinded, placebo‐controlled clinical trial" Method used to generate allocation sequence not described. |
| Allocation concealment (selection bias) | Unclear risk | No information provided. |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "...study subjects were randomly assigned to receive bottles containing either 60 mg of pseudoephedrine plus 100mg of acetaminophen or identically appearing placebo tablets" Blinding of physicians or outcome assessors was not reported. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 430 participants (260 pseudoephedrine and paracetamol; 214 placebo) 18 participants (10 pseudoephedrine and paracetamol; 8 placebo) did not complete the study. Active treatment group: 2 withdrew due to adverse effects; 1 was withdrawn due to comorbidity; 7 were non‐compliant with study protocol Placebo group: 8 were non‐compliant with study protocol Impact not discussed in results. |
| Selective reporting (reporting bias) | Low risk | 51 participants in the active treatment group and 25 participants in the placebo group reported adverse effects. Adverse effects were related to the treatment in 41/51 active treatment group participants and 17/25 placebo group participants. Nature of the adverse effects described. |
| Other bias | Unclear risk | Participants were recruited across the sites; however, it is not stated how this was achieved. |
Thackray 1978.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled (cross‐over) Natural colds 70 participants included 100% follow‐up | |
| Participants | Age: 18 to 60 years Setting: doctor's surgeries (general practice?), recruitment: patients seeking help for their cold Inclusion criteria: common cold Exclusion criteria: not mentioned Duration of symptoms before inclusion: not mentioned | |
| Interventions | Active syrup containing: paracetamol 600 mg, dextromethorphan hydrobromide 15 mg, ephedrine sulphate 8 mg, doxylamine succinate 7.5 mg per 30 mL Control: placebo syrup Duration: 1 single dose of 30 mL before bed, evaluation the next morning | |
| Outcomes | 1. Rating on 6‐point scale of efficacy of medication on: nasal congestion, nasal discharge, sneezing, cough, and generally feeling unwell during the night* 2. Comparison of number of positive ratings after 1 dose of active syrup or placebo syrup 3. Side effects | |
| Notes | Funding source: Vick International Division of Richardson‐Merrell Ltd | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Low risk | "Patients were allotted by a random number code to a Treatment Group A or B" "Each (treatment group) was given two bottles... indistinguishable except for the labelling 'First Night Medicine' and 'Second Night Medicine'" |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "'Control' formula was identical but without the active, matched for colour, odour, appearance and taste." Blinding of doctor or outcome assessor not reported. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | No attrition or exclusions, and all participants followed up, as this was a short 2‐day trial |
| Selective reporting (reporting bias) | Unclear risk | "Only those subjects who had a symptom present on both nights were included in the evaluation of response to therapy for that symptom" |
| Other bias | High risk | Paper written by the Medical Director of Vick International Division of Richardson‐Merrell Ltd. (pharmaceutical company). Inclusion and exclusion criteria not discussed. |
Unuvar 2007.
| Study characteristics | ||
| Methods | RCT, single‐blind at inclusion, double‐blind at assessment Natural colds 201 participants included 74% follow‐up | |
| Participants | Age: 2 to 12 years Setting: university hospital, paediatric outpatients department Inclusion criteria: acute respiratory infection with symptoms such as running or stuffy nose, fever, and myalgia Exclusion criteria: symptoms for more than 7 days, known chronic disease, use of drugs of the same type as the study drug in the past week, allergy to the medicine, epilepsy, respiratory allergy, cardiac rhythm problem, hypertension, need for hospitalisation Duration of symptoms before inclusion: max 7 days | |
| Interventions | Solution of paracetamol (acetominophen) 120 mg/5 ml + diphenhydramine 1 mg/5 ml + pseudoephedrine 15 mg/5 ml.
Control: paracetamol syrup 120 mg/5 ml. Dose: based on 40‐60 mg/kg paracetamol dose given 4 x/day |
|
| Outcomes | Frequency of running nose, cough, nasal stuffiness at days 3 and 5 Clinical recovery ratio at days 3 and 5 Clinical sum scores at days 3 and 5 Complications and adverse effects | |
| Notes | Funding source: University of Istanbul, Turkey | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Randomisation list was acquired from a software and the sequence of the randomisation was prosecuted by using closed envelopes" |
| Allocation concealment (selection bias) | Low risk | "The case number was shown on the outside of these closed envelopes, and the group number was shown inside...the main researcher was blinded about the group that the next case would belong to" |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | No information regarding the appearance of the 2 treatments administered by the physician; however, the assessors were blinded to the group to which each participant belonged or the treatment administered. Insufficient information regarding blinding of participants |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 16/102 did not return during randomisation in Group 1, and 37/99 did not return during randomisation in Group 2. Further loss to follow‐up of 13 (3 discontinued intervention) in Group 1 and 31 (6 discontinued intervention) in Group 2. Reasons for discontinuation not discussed. |
| Selective reporting (reporting bias) | High risk | No clinical scores were reported for the last day of the trial (day 10). |
| Other bias | Low risk | No problems apparent |
Virtanen 1983.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled Natural colds 92 participants included 87% follow‐up | |
| Participants | Age: adults, volunteers Setting: university hospital, recruitment: from university population Inclusion criteria: acute rhinitis with common cold Exclusion criteria: fever, allergic manifestations, sinusitis or other disease, use of other cold preparations, steroids, antibiotic during study Duration of cold before enrolment: max 48 hours | |
| Interventions | Slow‐release dexchlorpheniramine maleate 6 mg, pseudoephedrine sulphate 120 mg 2 x/day Control: placebo Duration of treatment: 5 days | |
| Outcomes | 1. Daily score of nose obstruction, secretion, sneezing* 2. Adverse effects | |
| Notes | Funding source: Medipolar Ltd provided drugs | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "...patients were randomly allocated to one of two groups" Method not discussed. |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding (performance bias and detection bias) All outcomes | Low risk | "The 10 tablets needed for five days treatment were in a numbered package and were identical in appearance." "...and the other, a matching placebo" Although nothing more is written specifically about blinding of participants, researchers, and assessors, later in the article it reads: "After analysing the results, it was found that 39 patients had received the drug and 41 patients placebo", implying that there was blinding. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 12 dropouts were reported on. |
| Selective reporting (reporting bias) | Low risk | All prespecified outcomes and adverse reactions discussed. |
| Other bias | Unclear risk | Medipolar Ltd was thanked for supplying the drug and placebo. Medipolar is part of the Farmos Group, which is a Finnish pharmaceutical company. |
Weippl 1984.
| Study characteristics | ||
| Methods | RCT, double‐blind, controlled Natural colds 60 children included 93% follow‐up | |
| Participants | Children older than 4 years Setting: university hospital, recruitment: not mentioned Inclusion criteria: upper respiratory symptoms of the common cold and associated cough; at least moderate degree of nasal congestion and/or rhinorrhoea and cough (a rating of 2 or more on each symptom on a 5‐point severity scale); ratings of subjective symptoms (all except headache, aching, tiredness/drowsiness, and sore throat pain) totaling at least 8; rating for objective signs totaling at least 4; rating of sore throat pain no greater than 3 Exclusion criteria: exudative pharyngitis; allergic respiratory disease; asthma or a history of asthma, pulmonary or nasopharyngeal infection; bacterial sinusitis; renal, hepatic, or serious cardiovascular disease; arrhythmias; hyperthyroidism; peptic ulcer; pyloroduodenal obstruction; predisposition for urinary retention; glaucoma, other serious illness; temperature > 37.7 °C; sensitivity to the study drugs or the classes of drugs contained in the study products; patients receiving MAO inhibitors or other medications that might affect the course of study or the action of the test medication; oral corticosteroids within 5 days of the start of the study, or parenteral corticosteroids within 3 weeks, or intranasal corticosteroids within 2 weeks of the start of the study Duration of symptoms before inclusion: at least 24 hours, but not more than 48 hours | |
| Interventions | 1 teaspoon of SCH 399 syrup (azatadine maleate 1 mg, pseudoephedrine sulphate 60 mg, dextromethorphan hydrobromide 20 mg) Control: expectorant containing diphenhydramine Dose: 0.5 teaspoon 3 to 4 x/day Duration: 5 days | |
| Outcomes | 1. Overall therapeutic response on days 3 and 5 2. Time of onset of symptomatic relief 3. Adverse effects | |
| Notes | Funding source: not reported | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "A randomised, double‐blind design was selected..." Method not discussed. |
| Allocation concealment (selection bias) | Unclear risk | Not discussed |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "A randomised, double‐blind design was selected..." Blinding of participants, researchers, assessors not discussed. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Participants who completed the study but who violated protocol in some way were excluded from the efficacy analysis. Protocol violations were discussed. |
| Selective reporting (reporting bias) | Low risk | All prespecified outcomes were adequately reported. |
| Other bias | Unclear risk | Method of recruiting participants not discussed. |
Zhang 2018.
| Study characteristics | ||
| Methods | RCT, double‐blind, placebo‐controlled, single dose Common cold or flu 53 adults included 98% follow‐up | |
| Participants | Adults 18 to 64 Inclusion criteria: diagnosis of common cold or flu with at least moderate (≥ 2) intensity of: sore throat, headache, and/or pain in extremities; nasal congestion (mandatory); runny nose and/or sneezing Exclusion criteria: history of seasonal or perennial allergic rhinitis or acute, subacute, or chronic cough due to another condition. Concurrent illness or medical history that is contraindicated or cautioned about in the drug label; anatomical factors causing nasal congestion; body temperature > 38 °C; use of any medication or herbal remedy in the week prior to screening (antibiotic within 7 days, antihistamines within 72 hours, decongestants within 12 hours, medicated lozenges or throat spray within 8 hours); history of substance abuse or a smoking history of > 10 pack years; breastfeeding; pregnancy or trying to get pregnant for 6 months. Duration of symptoms before inclusion: less then 48 hours | |
| Interventions | Active treatment: paracetamol 500 mg, pseudoephedrine hydrochloride 30 mg, dextromethorphan hydrobromide 15 mg, chlorpheniramine maleate 2 mg Control: placebo Duration of treatment: single dose | |
| Outcomes | 1. Self‐assessment of severity at 15 and 30 minutes and at 1, 2, 3, and 4 hours after intake of medication of sore throat, headache, extremity pain, nasal congestion, sneezing, runny nose, cough using a 4‐point categorical scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) 2. Global response assessment after 4 hours using a 5‐point categorical scale (0 = ineffective, 1 = poor, 2 = fair, 3 = good, 4 = excellent) 3. Safety assessment: recording of adverse events: untoward medical occurrence in a participant temporally associated with the use of the investigational product, whether or not considered related to the investigational product and serious adverse events: untoward medical occurrence that results in death, a life‐threatening condition, or hospitalisation or prolongation of existing hospitalisation from time of informed consent until 5 days after administration of study drug |
|
| Notes | Pilot study mainly intended to monitor time‐to‐onset. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Enrolled participants were assigned randomisation numbers in ascending numerical order, with treatment assignment based on a randomisation schedule provided by the study sponsor. |
| Allocation concealment (selection bias) | Unclear risk | Not clear whether consecutive patients were included |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Active and placebo tablets were packaged in the same manner and were identical in appearance and taste. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up for 52 of 53 included participants |
| Selective reporting (reporting bias) | Low risk | Outcome of 52 participants on all outcome measures |
| Other bias | Unclear risk | Financing by pharmaceutical company |
*: In this study more effects on more symptoms were evaluated. The table only mentions outcomes used in the review. ADC: antihistamine‐decongestant combination ASA: acetylsalicylic acid BHSGA: beta‐haemolytic Streptococcus group A BMI: body mass index COI: conflict of interest IFN: interferon ITT: intention‐to‐treat max: maximum MAO: mono‐amine oxidase NSAID: non‐steroidal anti‐inflammatory drug Pa cm3: Pascal per cubic centimetre PBS: phosphate buffer saline PSE: pseudoephedrine RCT: randomised controlled trial URTI: upper respiratory tract infection x/d: times per day
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Axelsson 1971 | Population of participants with vasomotor rhinitis |
| Bachert 2005 | Interventions studied not eligible. |
| Bhattacharya 2013 | Outcome is cough, combination is antihistamine with dextromethorphan. |
| Bonifaci 1977 | A combination of an analgesic with an NSAID |
| Cantekin 1980 | Only Eustachian tube function evaluated. |
| Carta 1967 | Topical medicine used. |
| Chung 1991 | Not an RCT |
| Cohen 2017 | Other intervention studied. |
| Connell 1967 | Population of participants with allergic rhinitis |
| Ghorayeb 2006 | Did not meet inclusion criteria |
| Hosseini 2016 | Other intervention studied. |
| Kaminszczik 1983 | Mixed population of patients with different kinds of rhinitis (common cold, allergy, perennial rhinitis) |
| Krishnaprasad 2012 | Not an RCT; amantadine was part of the fixed combination |
| Kuspert 1965 | Other interventions studied. |
| Lea 1984 | Decongestant is phenylpropanolamine, not an antihistamine. |
| Lu 1993 | Design does not meet inclusion criteria. |
| Lu 2010 | Single‐blinded |
| Mariano 2011 | Combination with expectorant, does not meet inclusion criteria |
| McLaurin 1966 | Effects on nasal obstruction Aetiology of nasal obstruction is not clear. Common cold not mentioned. |
| Mora 1993 | Mixed population of patients with different kinds of rhinitis (common cold, allergy, perennial rhinitis) |
| NCT01938144 | Recruitment withdrawn in 2015. |
| NCT02678234 | Study withdrawn by sponsor in 2018. |
| NCT02730364 | Study withdrawn by sponsor in 2018. |
| Nelson 1970 | Population of patients with perennial rhinitis |
| Pasotti 1966 | Design does not meet inclusion criteria. |
| Paul 2004 | Only mono‐therapeutic effects of dextromethorphan and diphenhydramine evaluated. |
| Peter 1972 | Topical medicine used. |
| Picon 2013 | Mixed population of adults with cold symptoms and flu‐like symptoms with fever > 38.1 °C. The latter are excluded from this review. Data for cold patients and flu patients could not be separated. |
| Randall 1979 | Did not evaluate symptomatic relief |
| Sakchainanont 1990 | Compared antihistamines only |
| Schachtel 2010 | Outcome was pain, not common cold symptoms. |
| Schuetz 2014 | Other intervention studied. |
| Septimus 2017 | Other intervention studied/other outcome. |
| Taborelli 1975 | Mixed population of patients with different kinds of rhinitis |
| Todd 1984 | Patients have purulent nasopharyngitis, not common cold. |
| Virtanen 1982 | Only Eustachian tube function evaluated. |
| Yong 1991 | Not an RCT |
NSAID: non‐steroidal anti‐inflammatory drug RCT: randomised controlled trial
Characteristics of studies awaiting classification [ordered by study ID]
NCT02246166.
| Methods | RCT, double‐blind, randomised, placebo‐controlled, parallel‐group, single‐dose study |
| Participants | 18 to 65 years of age with common cold or influenza |
| Interventions | Paracetamol, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate tablets compared to placebo |
| Outcomes | Symptom severity over a 4‐hour period |
| Notes |
RCT: randomised controlled trial
Characteristics of ongoing studies [ordered by study ID]
NCT02904304.
| Study name | National clinical trial, phase III, multicenter, randomised, prospective, double‐blind, parallel, placebo‐controlled, to evaluate the efficacy, safety and superiority of Decongex Gripe in the treatment of symptoms associated with common cold |
| Methods | RCT |
| Participants | 18 to 65 years of age |
| Interventions | Desloratadine + phenylephrine + ibuprofen versus placebo |
| Outcomes | To evaluate the association of the superiority fixed dose of desloratadine 2.5 mg, 20 mg phenylephrine hydrochloride, and ibuprofen 400 mg compared to placebo in the treatment of symptoms related to the common cold/flu syndrome by varying the intensity total score of symptoms, 3 hours after the first dose of investigational product |
| Starting date | December 2020 |
| Contact information | clinicaltrials.gov/show/nct02904304 |
| Notes | Recruitment suspended, and viability of the study is being analysed; estimated start date December 2020. |
RCT: randomised controlled trial
Differences between protocol and review
No differences to report.
Contributions of authors
An IM De Sutter (ADS) contributed to the data extraction and performed the data analyses, and wrote the first draft based on the protocol for antihistamines. Mieke van Driel (MVD) contributed to risk of bias assessment, commented on the draft, and contributed to the final version of the review. Lars Eriksson (LE) conducted the searches for the 2021 update and contributed to the final version of the review.
Sources of support
Internal sources
Department of Family and Primary Health Care, Belgium
External sources
No sources of support provided
Declarations of interest
An IM De Sutter has declared that they have no conflict of interest. Lars Eriksson has declared that they have no conflict of interest. Mieke L van Driel has declared that they have no conflict of interest. Anna Gomez has declared that they have no conflict of interest.
New search for studies and content updated (no change to conclusions)
References
References to studies included in this review
Aschan 1974 {published data only}
- Aschan G.Decongestion of nasal mucous membranes by oral medication in acute rhinitis. A rhinomanometric study to demonstrate synergism between antihistamines and adrenergic substance. Acta Otolaryngologica 1974;77(6):433-8. [DOI] [PubMed] [Google Scholar]
Berkowitz 1989 {published data only}
- Berkowitz RB, Connell JT, Dietz AJ, Greenstein SM, Tinkelman DG.The effectiveness of the non sedating antihistamine loratadine plus pseudoephedrine in the symptomatic management of the common cold. Annals of Allergy 1989;63(4):336-9. [PubMed] [Google Scholar]
Blanco 2000 {published data only}
- Blanco de la Mora E, Cardillo L, De la Barrera, Marky B.Efficacy and safety of loratadine, pseudoephedrine and acetaminophen in the non-sedating symptomatic treatment of the common cold. Investigacion Medica Internacional 2000;24:14-25. [Google Scholar]
Bye 1980 {published data only}
- Bye CE, Cooper J, Empey DW, Fowle AS, Hughes DT, Letley E, et al.Effects of pseudoephedrine and triprolidine, alone and in combination, on symptoms of the common cold. British Medical Journal 1980;281(6234):189-90. [DOI] [PMC free article] [PubMed] [Google Scholar]
Clemens 1997 {published data only}
- Clemens CJ, Taylor JA, Almquist JR, Quinn HC, Mehta A, Naylor GS.Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children? Journal of Pediatrics 1997;130(3):463-6. [DOI] [PubMed] [Google Scholar]
Curley 1988 {published data only}
- Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV, Vernaglia PA, et al.Cough and the common cold. American Review of Respiratory Disease 1988;138(2):305-11. [DOI] [PubMed] [Google Scholar]
Debelic 1973 {published data only}
- Debelic M, Radielovic P.Therapy of banal rhinitis. Double-blind controlled clinical study. Schweizerische Rundschau fur Medizin Praxis 1973;62(35):1074-7. [PubMed] [Google Scholar]
Eccles 2006a {published data only}
- Eccles R, Jawad M, Jawad S, Ridge D, North M, Jones E, et al.Efficacy of a paracetamol-pseudoephedrine combination for treatment of nasal congestion and pain-related symptoms in upper respiratory tract infection. Current Medical Research 2006;22(12):2411-8. [DOI] [PubMed] [Google Scholar]
Eccles 2014 {published data only}
- Eccles R, Voelker M.Analgesic and decongestant efficacy of the combination of aspirin with pseudoephedrine in patients with symptoms of upper respiratory tract infection. Clinical Pharmacology in Drug Development 2014;3(2):118-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
Galvez 1985 {published data only}
- Galvez J.Symptomatic treatment of patients with the common cold. Clinical Trials Journal 1985;22(6):489-97. [Google Scholar]
Gwaltney 2002 {published data only}
- Gwaltney JM Jr, Winther B, Patrie JT, Hendley JO.Combined antiviral-antimediator treatment for the common cold. Journal of Infectious Diseases 2002;186(2):147-54. [DOI] [PMC free article] [PubMed] [Google Scholar]
Hutton 1991 {published data only}
- Hutton N, Wilson MH, Mellits ED, Baumgardner R, Wissow LS, Bonuccelli C, et al.Effectiveness of an antihistamine-decongestant combination for young children with the common cold: a randomized, controlled clinical trial. Journal of Pediatrics 1991;118(1):125-30. [DOI] [PubMed] [Google Scholar]
Koytchev 2003 {published data only}
- Koytchev R, Vlahov V, Bacratcheva N, Giesel B, Gawronska-Szklarz B, Wojcicki J, et al.Evaluation of the efficacy of a combined formulation (Grippostad-C) in the therapy of symptoms of common cold: a randomized, double-blind, multicenter trial. International Journal of Clinical Pharmacology and Therapeutics 2003;41(3):114-25. [DOI] [PubMed] [Google Scholar]
Lebacq 1994 {published data only}
- Lebacq E Jr, Gline JP, Joue P, Stockis A, Calderon P, Van Schoor O, et al.Exploratory study of the decongestive effect of Rhinopront syrup in adults and in children with acute rhinitis. Clinical Trials and Meta-analysis 1994;29(2-3):113-24. [PubMed] [Google Scholar]
Loose 2004 {published data only}
- Loose I, Winkel M.Clinical, double-blind, placebo-controlled study investigating the combination of acetylsalicylic acid and pseudoephedrine for the symptomatic treatment of nasal congestion associated with common cold. Arzneimittelforschung 2004;54(9):513-21. [DOI] [PubMed] [Google Scholar]
Martinez 1994 {published data only}
- Martinez Gallardo F, López Fiesco A, Zamora G.Symptomatic treatment of common cold in children with a new combination of naproxen sodium plus pseudoephedrine hydrochloride: a comparative trial against pseudoephedrine syrup. Proceedings of the Western Pharmacology Society 1994;37:157-8. [PubMed] [Google Scholar]
Middleton 1981 {published data only}
- Middleton RS.Double blind trial in general practice comparing the efficacy of "Benylin Day and Night" and paracetamol in the treatment of the common cold. British Journal of Clinical Practice 1981;35(9):297-300. [PubMed] [Google Scholar]
Mizoguchi 2007 {published data only}
- Mizoguchi H, Wilson A, Jerdack GR, Hulle JD, Goodale M, Grender JM, et al.Efficacy of a single evening dose of a syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate in subjects with multiple common cold symptoms. International Journal of Clinical Pharmacology and Therapeutics 2007;45(4):230-6. [DOI] [PubMed] [Google Scholar]
Montijo‐Barrios 2011 {published data only}
- Montijo-Barrios E, Cadena F, Ramirez-Mayans JA, Gutierrez-Castellon P.Clinical trial on the effect of buphenine, aminophenazone and diphenylpyraline hydrochloride in treating the common cold in children of 6 to 24 months of age [Ensayo clínico sobre el efecto de la bufenina, aminofenazona y el clorhidrato de difenilpiralina en el tratamiento del resfriado común en niños de seis a 24 meses de edad]. Revista de Investigacion Clinica 2011;63:335-43. [PubMed] [Google Scholar]
Robert 2004 {published data only}
- Common Cold Collaborative Group, Robert M, Llorens M, Garcia E, Luria X.Efficacy and tolerability of ebastine 10 mg plus pseudoephedrine 120 mg in the symptomatic relief of the common cold. European Journal of Internal Medicine 2004;15(4):242-7. [DOI] [PubMed] [Google Scholar]
Sachsenroder 1972 {published data only}
- Sachsenroder L, Renovanz HD, Flach D.Efficacy and tolerance of a combined oral rhinologic agent. Arzneimittelforschung 1972;22(2):392-8. [PubMed] [Google Scholar]
Scavino 1985 {published data only}
- Scavino Y.Combination therapy in patients with the common cold. Current Therapeutic Research 1985;38(5):746-54. [Google Scholar]
Schrooten 1993 {published data only}
- Schrooten P, Laekeman G, Vos P, De Munck G.Community pharmacists as clinical investigators in the self medication area: a double-blind, placebo-controlled study with astemizole-D in the common cold. International Pharmacy Journal 1993;7:147-50. [Google Scholar]
Sperber 1989 {published data only}
- Sperber SJ, Sorrentino JV, Riker DK, Hayden FG.Evaluation of an alpha agonist alone and in combination with a nonsteroidal antiinflammatory agent in the treatment of experimental rhinovirus colds. Bulletin of the New York Academy of Medicine 1989;65(1):145-60. [PMC free article] [PubMed] [Google Scholar]
Sperber 2000 {published data only}
- Sperber SJ, Turner RB, Sorrentino JV, O'Connor RR, Rogers J, Gwaltney JM Jr.Effectiveness of pseudoephedrine plus acetaminophen for treatment of symptoms attributed to the paranasal sinuses associated with the common cold. Archives of Family Medicine 2000;9(10):979-85. [DOI] [PubMed] [Google Scholar]
Thackray 1978 {published data only}
- Thackray P.A double-blind, crossover controlled evaluation of a syrup for the night-time relief of the symptoms of the common cold, containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulphate. Journal of Internal Medicine 1978;6(2):161-5. [DOI] [PubMed] [Google Scholar]
Unuvar 2007 {published data only}
- Unuvar E, Yildiz I, Kilic A, Toprak S, Selvi Aslan S, Aydin S, et al.Is acetaminophen as effective as an antihistamine-decongestant-acetaminophen combination in relieving symptoms of acute nasopharyngitis in children? A randomised, controlled trial. International Journal of Pediatric Otorhinolaryngology 2007;71(8):1277-85. [DOI] [PubMed] [Google Scholar]
Virtanen 1983 {published data only}
- Virtanen H.A slow release combined preparation (dexchlorpheniramine + pseudoephedrine) for symptomatic treatment of the common cold. Journal of Laryngology and Otology 1983;97(2):159-63. [DOI] [PubMed] [Google Scholar]
Weippl 1984 {published data only}
- Weippl G.Therapeutic approaches to the common cold in children. Clinical Therapeutics 1984;6(4):475-82. [PubMed] [Google Scholar]
Zhang 2018 {published data only}
- Zhang Y, Mallefet P.Time-to-onset of cold and flu symptom relief: a randomized, double-blind, placebo controlled pilot study for a multi-symptom combination product. International Journal of Clinical Pharmacology and Therapeutics 2018;56(12):604-11. [DOI] [PubMed] [Google Scholar]
References to studies excluded from this review
Axelsson 1971 {published data only}
- Axelsson A, Hammer G.Treatment of vasomotor rhinitis with a combined antihistaminic-sympathomimetic preparation. Acta Allergologica 1971;26(5):357-62. [DOI] [PubMed] [Google Scholar]
Bachert 2005 {published data only}
- Bachert C, Chuchalin AG, Eisebitt R, Netayazhenko VZ, Voelker M.Aspirin compared with acetaminophen in the treatment of fever and other symptoms of upper respiratory tract infection in adults: a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-dose, 6-hour dose-ranging study. Clinical Therapeutics 2005;27(7):993-1003. [DOI] [PubMed] [Google Scholar]
Bhattacharya 2013 {published data only}
- Bhattacharya M, Joshi N, Yadav S.To compare the effect of dextromethorphan, promethazine and placebo on nocturnal cough in children aged 1-12 y with upper respiratory infections: a randomised controlled trial. Indian Journal of Pediatrics 2013;80(11):891-5. [DOI] [PubMed] [Google Scholar]
Bonifaci 1977 {published data only}
- Bonifaci E, Giorgi-Conciato M, Vibelli C.Symptomatic treatment of acute inflammation of the upper respiratory airways in pediatrics. Minerva Pediatrica 1970;29(5):285-96. [PubMed] [Google Scholar]
Cantekin 1980 {published data only}
- Cantekin EI, Bluestone CD, Rockette HE, Beery QC.Effect of decongestant with or without antihistamine on Eustachian tube function. Annals of Otology, Rhinology, and Laryngology Supplement 1980;89(3 Pt 2):290-5. [DOI] [PubMed] [Google Scholar]
Carta 1967 {published data only}
- Carta F.Clinical experience with the vasoconstrictor action of H 1032 on the nasal mucosa. Archivio Italiano di Otologia, Rinologia-Laringologia e Patologia Cervico-facciale 1967;78(4):510-9. [PubMed] [Google Scholar]
Chung 1991 {published data only}
- Chung BC, Kim KW, Woo UJ, Lee YS, Kim SW, Choi YH, et al.Clinical effects of SJ-002 URI. Korean Journal of Pharmacology 1991;27(2):211-4. [Google Scholar]
Cohen 2017 {published data only}
- Cohen HA, Hoshen M, Gur S, Bahir A, Laks Y, Blau H.Efficacy and tolerability of a polysaccharide-resin-honey based cough syrup as compared to carbocysteine syrup for children with colds: a randomized, single-blinded, multicenter study. World Journal of Pediatrics 2017;13(1):27-33. [DOI] [PubMed] [Google Scholar]
Connell 1967 {published data only}
- Connell JT.Long-acting antihistamine-decongestant evaluation. Archives of Otolaryngology 1967;85(2):218-22. [DOI] [PubMed] [Google Scholar]
Ghorayeb 2006 {published data only}
- Ghorayeb N, Fiss E, De Castro Brandao D.Evaluation of the clinical efficacy and safety of the use of the association between dipiron, caffeine and clorfeniramine maleate compared to the association of paracetamol, chloridrate of fenilefrine and carbinoxamine maleate on the symptomatic treatment of flu and cold. Revista Brasileira de Medicina 2006;63:219-23. [Google Scholar]
Hosseini 2016 {published data only}
- Hosseini F, Mahjoub H, Amanati A, Fazlian MM, Sedighi I.Comparison of zataria multiflora extract syrup and diphenhydramine in the treatment of common cold-induced cough in children: a double-blind, randomized, clinical trial. Archives of Pediatric Infectious Diseases 2016;4(3):e35495. [Google Scholar]
Kaminszczik 1983 {published data only}
- Kaminszczik I, Barbon L.Relieving symptoms of upper respiratory allergies and the common cold: azatadine maleate/pseudoephedrine sulfate syrup versus placebo. Journal of International Medical Research 1983;11(2):101-7. [DOI] [PubMed] [Google Scholar]
Krishnaprasad 2012 {published data only}
- Krishnaprasad K, Manshani P, Karankumar J.Health outcome and safety assessment of a fixed dose combination of amantadine, paracetamol, chlorpheniramine maleate, and phenylephrine introduction in India: a prescription event monitoring study. Perspectives in Clinical Research 2012;3:62-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kuspert 1965 {published data only}
- Kuspert A.On the vaso-active therapy of the nasal mucosa with a new adrianol-imidazol combination [Über die vasoaktive Therapie der Nasenschleimhaut mit einer neuartigen Adrianol-Imidazolin-Kombination]. Medizinische Welt 1965;45:2563-4. [PubMed] [Google Scholar]
Lea 1984 {published data only}
- Lea P.A double-blind controlled evaluation of the nasal decongestant effect of Day Nurse in the common cold. Journal of International Medical Research 1984;12(2):124-7. [DOI] [PubMed] [Google Scholar]
Lu 1993 {published data only}
- Lu C, Zhiqiang H, Qinming H.Studies on simultaneous determination of paracetamol, caffeine and chlorpheniramine maleate in multicomponent cold-curing medicine by GCS. Chinese Journal of Pharmaceutical Analysis 1993;13:15-8. [Google Scholar]
Lu 2010 {published data only}
- Lu Q, for the Clinical Research Coordination Group of Guaifenesin Compound Pseudoephedrine Hydrochloride Oral Solution.A prospective multicenter randomized controlled clinical study on the efficacy and safety of guaifenesin compound pseudoephedrine hydrochloride oral solution. Zhonghua Erke Zazhi 2010;48:204-7. [PubMed] [Google Scholar]
Mariano 2011 {published data only}
- Mariano HG, Solomon G, Steward EC, Albrecht HH.Quality of life in patients taking guaifenesin and pseudoephedrine in an extended-release bi-layer tablet as first-line symptomatic therapy for acute upper respiratory tract infections (URI). Journal of Allergy and Clinical Immunology 2011;127(Suppl 2):AB201. [DOI: 10.1016/j.jaci.2010.12.804] [DOI] [Google Scholar]
McLaurin 1966 {published data only}
- McLaurin JW, Graves TA, Komet H.Efficacy of Actifed as a decongestant. Laryngoscope 1966;76(9):1612-4. [DOI] [PubMed] [Google Scholar]
Mora 1993 {published data only}
- Mora A, Priego O, Morales F, Melgarojo MA.Experiences with a combination of astemizol and pseudoephedrine in the treatment of children with rhinitis [Experiencia en ninos con astemizol combinado con pseudoefedrina en el tratamiento de la rinitis]. Investigacion Medica International 1993;20:167-71. [Google Scholar]
NCT01938144 {unpublished data only}
- NCT01938144.Evaluation of the efficacy and safety of two ibuprofen combination products for the treatment of the common cold and flu in Latin America. clinicaltrials.gov/ct2/show/nct01938144 (first received 10 September 2013).
NCT02678234 {published data only}
- NCT02678234.An efficacy and safety study of Theraflu Day Powder as oral solution for cold and flu. clinicaltrials.gov/ct2/show/nct02678234 (first received 9 February 2016).
NCT02730364 {published data only}
- NCT02730364.An efficacy and safety study of Theraflu Night Powder as oral solution for cold and flu. clinicaltrials.gov/ct2/show/nct02730364 (first received 6 April 2016).
Nelson 1970 {published data only}
- Nelson LS, Stoesser AV.An oral combination of antihistamines and nasal decongestants. Minnesota Medicine 1970;53(2):149-51. [PubMed] [Google Scholar]
Pasotti 1966 {published data only}
- Pasotti C, Brembilla E, Corvi G.Sequential clinical analysis of a new product with an antirhinitis action. Il Farmaco 1966;21(1):40-8. [PubMed] [Google Scholar]
Paul 2004 {published data only}
- Paul IM, Yoder KE, Crowell KR, Shaffer ML, McMillan HS, Carlson LC, et al.Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics 2004;114(1):e85-90. [DOI] [PubMed] [Google Scholar]
Peter 1972 {published data only}
- Peter M.Treatment of common cold with a new drug Co-Tylenol. Schweizerische Rundschau fur Medizin Praxis 1972;61(20):682-3. [PubMed] [Google Scholar]
Picon 2013 {published data only}
- Picon PD, Costa MB, da Veiga Picon R, Costa Cabral Fendt L, Leichter Suksteris M, Carmanim Saccilotto I, et al.Symptomatic treatment of the common cold with a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine: a randomized, placebo-controlled trial. BMC Infectious Diseases 2013;13:556. [DOI] [PMC free article] [PubMed] [Google Scholar]
Randall 1979 {published data only}
- Randall JE, Hendley JO.A decongestant-antihistamine mixture in the prevention of otitis media in children with colds. Pediatrics 1979;63(3):483-5. [PubMed] [Google Scholar]
Sakchainanont 1990 {published data only}
- Sakchainanont B, Ruangkanchanasetr S, Chantarojanasiri T, Tapasart C, Suwanjutha S.Effectiveness of antihistamines in common cold. Journal of the Medical Association of Thailand 1990;73(2):96-101. [PubMed] [Google Scholar]
Schachtel 2010 {published data only}
- Schachtel BP, Voelker M, Sanner KM, Gagney D, Bey M, Schachtel E, et al.Demonstration of the analgesic efficacy and dose-response of acetylsalicylic acid with pseudoephedrine. Journal of Clinical Pharmacology 2010;50:1429-37. [DOI] [PubMed] [Google Scholar]
Schuetz 2014 {published data only}
- Schuetz P.Randomized controlled trial: neither ibuprofen nor steam improves symptom control compared with paracetamol in patients with acute respiratory tract infection in primary care. BMJ Evidence-Based Medicine 2014;19(3):120. [DOI] [PubMed] [Google Scholar]
Septimus 2017 {published data only}
- Septimus EJ, Albrecht HH, Solomon G, Shea T, Guenin EP.Extended-release guaifenesin/pseudoephedrine hydrochloride for symptom relieve in support of a wait-and-see approach for the treatment of acute respiratory tract infections: a randomized, double-blind, placebo-controlled study. Current Therapeutic Research 2017;84:54-61. [DOI] [PMC free article] [PubMed] [Google Scholar]
Taborelli 1975 {published data only}
- Taborelli G, Chierichetti S.New contributions to the symptomatic treatment of non-specific rhinitis and its complications [Nuovo contributo alla terapia sintomatica delle riniti aspecifiche e delle loro complicazioni]. Minerva Otorinolaringologica 1975;25:266-77. [Google Scholar]
Todd 1984 {published data only}
- Todd JK, Todd N, Damato J, Todd WA.Bacteriology and treatment of purulent nasopharyngitis: a double blind, placebo-controlled evaluation. Pediatric Infectious Disease Journal 1984;3(3):226-32. [DOI] [PubMed] [Google Scholar]
Virtanen 1982 {published data only}
- Virtanen H.The effect of an oral combined preparation (antihistamine and decongestant) on Eustachian tube function in the common cold. ORL: Journal for Oto-Rhino-Laryngology and its Related Specialties 1982;44(5):268-76. [DOI] [PubMed] [Google Scholar]
Yong 1991 {published data only}
- Yong SJ, Lee JG.A clinical study of SJ-002. Korean Journal of Pharmacology 1991;27(2):207-10. [Google Scholar]
References to studies awaiting assessment
NCT02246166 {published data only}
- NCT02246166.The effect of paracetamol, pseudoephedrine hydrochloride, dextromethorphan hydrobromide and chlorpheniramine maleate tablets compared to placebo in subjects suffering from the common cold or influenza. clinicaltrials.gov/show/nct02246166 (first received 22 September 2014).
References to ongoing studies
NCT02904304 {published data only}
- NCT02904304.Desloratadine, phenylephrine Hcl, ibuprofen compared to placebo in treatment of symptoms associated with common cold/flu. clinicaltrials.gov/show/nct02904304 (first received 16 September 2016).
Additional references
Atkins 2004
- Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al, GRADE Working Group.Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
Barret 2005
- Barret B, Brown R, Mundt M, Safdar N, Dye L, Maberry R, et al.The Wisconsin Upper Respiratory Symptom Survey is responsive, reliable, and valid. Journal of Clinical Epidemiology 2005;58:609-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
Barret 2007
- Barret B, Haraban B, Brown D, Zhang Z, Brown R.Sufficiently important difference for common cold: severity reduction. Annals of Family Medicine 2007;5:216-23. [DOI] [PMC free article] [PubMed] [Google Scholar]
Deckx 2016
- Deckx L, De Sutter AIM, Guo L, Mir NA, Driel ML.Nasal decongestants in monotherapy for the common cold. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No: CD009612. [DOI: 10.1002/14651858.CD009612.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
De Sutter 2015
- De Sutter A, Saraswat A, Driel ML.Antihistamines for the common cold. Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No: CD009345. [DOI: 10.1002/14651858.CD009345.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]
Eccles 2006b
- Eccles R.Efficacy and safety of over-the-counter analgesics in the treatment of common cold and flu. Journal of Clinical Pharmacy and Therapeutics 2006;31:309-19. [DOI] [PubMed] [Google Scholar]
FDA 2005
- Food and Drug Administration, Department of Health and Human Services.21 CFR parts 310, 341, and 357. Phenylpropanolamine-containing drug products for over-the-counter human use. Tentative final monographs. Federal Register/proposed rules 2005;70(245):75988-97.
GRADEpro GDT [Computer program]
- GRADEpro GDT.Version accessed 13 April 2020. Hamilton (ON): McMaster University (developed by Evidence Prime). Available at gradepro.org.
Gummin 2018
- Gummin D, Mowry J, Spyker D, Brooks D, Beuhler M, Rivers L, et al.2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 36th Annual Report. Clinical Toxicology 2019;57(12):1220-413. [DOI] [PubMed] [Google Scholar]
Gwaltney 2002a
- Gwaltney JM.Clinical significance and pathogenesis of viral respiratory infections. American Journal of Medicine 2002;112(Suppl 6A):13-8. [DOI] [PubMed] [Google Scholar]
Gwaltney 2002b
- Gwaltney JM.Viral respiratory infection therapy: historical perspective and current trials. American Journal of Medicine 2002;112(Suppl 6A):33-41. [DOI] [PubMed] [Google Scholar]
Heikkinnen 2003
- Heikkinnen T, Järvinen A.The common cold. Lancet 2003;361(9351):51-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Higgins 2011
- Higgins JP, Green S, editor(s).Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 (updated March 2011). The Cochrane Collaboration, 2011. Available from training.cochrane.org/handbook/archive/v5.1/.
Jacobs 2013
- Jacobs S, Lamson D, St George K, Walsh T.Human rhinoviruses. Clinical Microbial Reviews 2013;26:135-62. [DOI] [PMC free article] [PubMed] [Google Scholar]
Kim 2015
- Kim SY, Chang YJ, Cho HM, Hwang YW, Moon YS.Non-steroidal anti-inflammatory drugs for the common cold. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No: CD006362. [DOI: 10.1002/14651858.CD006362.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]
NIAID 2007
- NIAID.Common cold. Review. www3.niaid.nih.gov/healthsicence/healthtopics/colds/overview.htm (accessed 1 February 2007).
Review Manager 2020 [Computer program]
- Review Manager 5 (RevMan 5).Version 5.4. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2020.
Sharfstein 2007
- Sharfstein JM, North M, Serwint JR.Over the counter but no longer under the radar - pediatric cough and cold medications. New England Journal of Medicine 2007;357(23):2321-3. [DOI] [PubMed] [Google Scholar]
Smith 1993
- Smith MB, Feldman W.Over-the-counter cold medications. A critical review of clinical trials between 1950 and 1991. JAMA 1993;269(17):2258-63. [DOI] [PubMed] [Google Scholar]
Smith 2014
- Smith SM, Schroeder K, Fahey T.Over-the-counter (OTC) medications for acute cough in children and adults in community settings. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No: CD001831. [DOI: 10.1002/14651858.CD001831.pub5] [DOI] [PMC free article] [PubMed] [Google Scholar]
Wat 2004
- Wat D.The common cold: a review of the literature. European Journal of Internal Medicine 2004;15(2):79-88. [DOI] [PMC free article] [PubMed] [Google Scholar]
References to other published versions of this review
De Sutter 2004
- De Sutter A, Driel M, Kenyon L.Oral antihistamine-decongestant-analgesic combinations for the common cold. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No: CD004976. [DOI: 10.1002/14651858.CD004976] [DOI] [Google Scholar]
De Sutter 2012
- De Sutter A, Driel M, Kumar AA, Lesslar O, Skrt A.Oral antihistamine-decongestant-analgesic combinations for the common cold. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No: CD004976. [DOI: 10.1002/14651858.CD004976.pub3] [DOI] [PubMed] [Google Scholar]