Abstract
Aims
Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol‐codeine combination overdoses caused respiratory depression more than paracetamol alone.
Methods
We reviewed deliberate self‐poisoning admissions with paracetamol (>2 g) and paracetamol‐codeine combinations presenting to a tertiary toxicology unit (1987–2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression.
Results
From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol‐codeine combinations (346) or paracetamol‐codeine‐doxylamine combinations (101) without co‐ingestants. Median age was 23 years (12–89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5–20 g). Median LOS was 16 h (IQR: 6.5–27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2–1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1–1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol‐codeine combinations (0.6%; 95% CI: 0.1–2.3%; absolute difference, 0.26%; 95% CI: −0.7–1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol‐codeine‐doxylamine combinations (2%; 95% CI: 0.3–8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol‐codeine group.
Conclusions
Paracetamol‐codeine combination overdoses are rarely associated with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression.
Keywords: codeine, naloxone, overdose, paracetamol, poisoning, respiratory depression
What is Already Known about this Subject
Paracetamol‐codeine combination medications are commonly taken in overdose.
The frequency of respiratory depression in overdoses that include codeine without other sedatives is unknown.
What this Study Adds
Paracetamol‐codeine overdoses are rarely associated with respiratory depression.
Central nervous system depression was similar in paracetamol overdoses with or without codeine.
Tables of Links
| TARGETS |
|---|
| G protein‐coupled receptors 2 |
| Opioid receptors |
| LIGANDS |
|---|
| Codeine |
| Paracetamol |
Introduction
Paracetamol‐codeine combination products are commonly ingested in overdose and are a frequent presentation to emergency departments in the developed world 3. Paracetamol ingestions are one of the leading cause of phone calls to Poison Information Centres in Australia, the United States and the United Kingdom. In 2014, the most frequent call to United States Poisons Centres was due to exposures to analgesics with a total of 291 062 calls (11.3%) 4. In 2013, there were 1381 calls to the New South Wales Poisons Information Centre in Australia specifically regarding paracetamol and opioid combination analgesics 5.
Codeine, or 3‐methylmorphine, is an opioid drug found in the opium poppy that binds weakly to μ‐opioid receptors 6. Codeine is a prodrug and exerts its clinical effect by conversion to morphine which has a much higher affinity for the μ‐receptor 6. Codeine is usually taken in an oral tablet or liquid formulation with higher strength paracetamol‐codeine combinations requiring a prescription by a medical practitioner due to abuse potential. Although they are not as readily available as paracetamol alone products, they are prescribed widely and there is easy access to them in the community 7.
Codeine is metabolized in the liver by three different pathways: O‐demethylation to morphine via the enzyme CYP2D6; N‐demethylation to norcodeine via CYP3A4; and conjugation with glucuronic acid to codeine‐6‐glucuronide via glucuronyltransferase UGT2B7 8. Morphine and norcodeine are further conjugated to 3‐glucuronide and 6‐glucuronide, respectively, via YGT2B7 6. Morphine and morphine‐6‐glucuronide have analgesic properties 9. The genes responsible for CYP2D6 activity are highly polymorphic, resulting in a high degree of variability in activity 6. Patients lacking CYP2D6 activity (poor metabolizers, PM) are likely to experience reduced analgesic effects with codeine, owing to reduced conversion to the active morphine metabolite morphine‐6‐glucuronide. Ultra‐rapid metabolizers (UM), due to CYP2D6 gene duplication, may experience exaggerated toxic opioid‐like effects, including respiratory depression. Approximately 1–2% of patients are ultra‐rapid metabolizers, with the prevalence varying widely around the world. It is estimated to be up to 25% in Arabs and North Africans, 10% in Caucasians, 3% in African‐Americans, and 1% in Japanese, Chinese and Hispanics 10.
Codeine is associated with a number of common adverse effects (>1%), which include nausea, vomiting, drowsiness and constipation. Rare adverse and toxic effects of codeine include central nervous system (CNS) depression, respiratory depression, confusion and anaphylaxis. Therapeutically, codeine is rarely associated with respiratory depression, but when it does occur it can be fatal. A number of cases of codeine causing respiratory depression and death have been reported 11. A significant proportion of these patients were paediatric elective adenotonsillectomy patients who were given codeine or paracetamol‐codeine combination products postoperatively 12. Niesters et al. reviewed opioid‐induced respiratory depression in paediatric patients between 1981 and 2012 and included 12 case reports 13. Respiratory depression was attributable to codeine in eight patients with four deaths and one ischaemic brain injury secondary to hypoxia. Five patients (5/8 patients) were identified as ultra‐rapid metabolizers of codeine (CYP2D6) and three of these patients died; all had elective adenotonsillectomies.
There are no reported large cohort studies of paracetamol‐codeine combination products in overdose. Respiratory depression is rare when codeine and paracetamol‐codeine combination products are used therapeutically, but it is not known if and how often respiratory depression occurs with overdose. The aim of this study was to investigate whether paracetamol‐codeine combination overdoses caused more severe effects, such as respiratory depression, compared to overdoses of paracetamol alone.
Methods
Study design and setting
This was a retrospective single centre observational study of patients who presented with overdoses of paracetamol and paracetamol‐codeine combination products. A large cohort of patients using a retrospective design was chosen because severe respiratory depression is a rare complication. We reviewed all presentations to a tertiary toxicology unit over 26 years between January 1987 and January 2013. The toxicology unit provides an inpatient service to a population of over 500 000. All overdose presentations are recruited prospectively with patient information and admission data collected using a specifically designed toxicology admission data sheet. All admitted patients are reviewed on a daily basis by a member of the toxicology team with treatment determined by the admitting toxicology consultant 14. The Institutional Ethics Committee has granted an exemption with regard to analysis of patient information collected using the toxicology service database.
Selection of participants
The inclusion criteria was age >12 years and a single ingestion of greater than 2 g paracetamol or paracetamol‐codeine combination product, where no other drugs had been co‐ingested. Paracetamol‐codeine‐doxylamine combinations were also included because there were a sufficient numbers of cases. However, all other paracetamol‐based products containing other active ingredients such as pseudoephedrine, ephedrine, chlorpheniramine, dextropropoxyphene, dextromethorphan and belladonna were excluded from the data analysis due to small numbers of each type. Paracetamol‐codeine combinations can contain 8 mg, 15 mg or 30 mg of codeine with 500 mg of paracetamol. Preparations containing codeine alone are Schedule 8 drugs [Controlled Drug (Possession without authority illegal)], so are rarely taken in overdose. Exclusion of patients co‐ingesting other medications was to avoid any potential CNS depression or respiratory depression due to other drugs. The ingestion was confirmed with patient history, collateral history and staff from the ambulance service, emergency department and mental health services.
Data collection and processing
During all patients' admissions, clinical information is recorded including standard observations and Glasgow Coma Score (GCS), treatment and outcomes. The clinical data collected is then entered into a toxicology database by trained research staff unaware of any outcomes or any study hypotheses. On discharge all admissions are reviewed with additional information added to the database from the clinical notes or speaking directly to the admitting toxicology consultant.
In this study, the information extracted from the clinical database included patient demographic details, information on paracetamol ingestion (including dose, formulation, slow‐release preparation), clinical effects (GCS), specific complications [including hepatic injury defined as an alanine transaminase (ALT) greater than 1000 U l−1], treatment (including naloxone, acetylcysteine), length of hospital stay (LOS), mechanical ventilation and intensive care unit (ICU) admission.
Outcome measures
The primary outcome aimed to identify patients with severe respiratory depression and was defined as either the administration of naloxone or requirement for mechanical ventilation. All patients ingesting sedative agents or who appear to be sedated, have oxygen saturations, respiratory rate and GCS monitored in the emergency department to assess for respiratory depression. Oxygen saturations are not recorded by the toxicology database and could not be used as an outcome in this study. Secondary outcomes included ICU admission, GCS < 9 and hepatotoxicity (ALT > 1000 U l−1).
Analysis
The median, interquartile range (IQR) and range are reported for all continuous variables. Ninety‐five percent confidence intervals (95% CI) were calculated for dichotomous outcomes with Wilson's procedure and a continuity correction. Dichotomous outcomes were compared using Fisher's exact or Chi‐square test. The primary outcome was analysed comparing just the paracetamol alone overdoses and paracetamol‐codeine combination overdoses (excluding paracetamol‐codeine‐doxylamine overdoses). All analyses were done in GraphPad Prism version 6 for Windows (GraphPad Software, San Diego, CA).
Results
A total of 4488 presentations, from January 1987 to January 2013, were extracted from the toxicology service database. All presentations with co‐ingestants including alcohol were excluded (Figure 1). There were 1376 admissions included, with paracetamol alone (929), paracetamol‐codeine combinations (346) or paracetamol‐codeine‐doxylamine combinations (101). The median age was 23 years (12–89 years) and 1002 out of 1376 (73%) were female. The median dose ingested was 12 g of paracetamol (IQR: 7.5–20 g). The median LOS was 16 h (IQR: 6.5–27 h). There were no deaths.
Figure 1.
Flow chart of the patient admissions included in the study and the numbers of excluded patients for each exclusion criterion
A total of 564 out of 1376 (41%) were given acetylcysteine to prevent or treat hepatotoxicity. Sixty three patients (4.6%) developed hepatotoxicity with a peak ALT > 1000 U l−1. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses (Table 1). More patients with paracetamol alone overdoses developed hepatotoxicity, but this was not statistically significant (Chi‐square test, P = 0.32).
Table 1.
Comparison of the demographics, hepatotoxicity, treatment and central nervous system complications between the three groups: paracetamol alone, paracetamol/codeine and paracetamol/codeine/doxylamine
| Paracetamol alone | Paracetamol + codeine | Paracetamol + codeine + doxylamine | ||||
|---|---|---|---|---|---|---|
| Number of cases | 929 | 346 | 101 | |||
| Sex (female) | 679 | 73.1% | 240 | 69.4% | 83 | 82.2% |
| Age (years; median + IQR) | 21 | (17–31) | 26 | (21–39) | 30 | (23–40) |
| Paracetamol dose (g; median + IQR) | 12 | (8–22.5) | 10 | (6–18) | 9 | (6.5–12) |
| Codeine dose (mg; median + IQR) | – | – | 420 | (300–675) | 195 | (137–234) |
| NAC treatment | 405 | 43.6% | 130 | 37.6% | 29 | 28.7% |
| Hepatotoxicity (ALT > 1000) | 48 | 5.2% | 12 | 3.5% | 3 | 3.0% |
| Intubated | 2 | 0.2% | 1 | 0.3% | 1 | 1.0% |
| Naloxone | 1 | 0.1% | 2 | 0.6% | 1 | 1.0% |
| Intensive care admission | 6 | 0.6% | 3 | 0.9% | 1 | 1.0% |
| GCS < 15 | 30 | 3.2% | 20 | 5.8% | 9 | 8.9% |
| GCS < 9 | 2 | 0.2% | 3 | 0.9% | 1 | 1.0% |
Seven out of 1376 patients were either intubated or received naloxone (0.5%; 95% CI: 0.2–1.1%): three were intubated, three received naloxone and one in the paracetamol‐codeine group received naloxone and was intubated. Three patients out of 929 ingesting paracetamol alone (0.3%; 95% CI: 0.1–1%) required intubation or received naloxone, compared to, two patients (out of 346) ingesting paracetamol‐codeine combinations (0.6%; 95% CI: 0.1–2.3%; absolute difference 0.26%; 95% CI: −0.7–1.2%; P = 0.62). Two patients (out of 101) ingesting paracetamol‐codeine‐doxylamine combinations (2%; 95% CI: 0.3–8%) required intubation or received naloxone.
Four patients out of 1376 (0.3%; 95% CI: 0.1–0.8%) were administered naloxone which was more common in the paracetamol‐codeine group (Table 1). One patient with a staggered paracetamol‐codeine combination ingestion presented with a severe lactic acidosis (pH 6.9) and hepatotoxicity, and was given 100 mcg naloxone with no response and was then intubated; one patient ingested paracetamol‐codeine (13 g/540 mg) and was given 2 mg naloxone by the ambulance service due to the history of codeine ingestion despite a normal GCS and respiratory observations; one patient ingested a paracetamol‐codeine‐doxylamine overdose (6 g/117 mg/60 mg) and was given 2 mg naloxone despite a GCS of 15; one patient ingested a 18 g paracetamol overdose, presented with a GCS 11 and hypotension secondary to atrial flutter, and was given 2 mg naloxone by the ambulance service with no response.
Four patients (out of 1376) (0.3%; 95% CI: 0.1–0.8%) required intubation (Table 1). One patient was intubated with a staggered paracetamol‐codeine combination ingestion with severe lactic acidosis and hepatotoxicity; one patient with an acute ingestion of a paracetamol‐codeine‐doxylamine combination (27 g/585 mg/30 mg) presented with encephalopathy secondary to hepatotoxicity and cerebral oedema; one patient with an acute ingestion of paracetamol alone (25 g) was morbidly obese and needed intubation in order to be transported to hospital; one patient with an acute ingestion of paracetamol alone (12.5 g) was intubated, but there was no information about the reason for this. No patient was intubated for respiratory depression solely attributable to codeine.
Ten patients (out of 1376) (0.7%; 95% CI: 0.4–1.4%) were admitted to ICU which was similar for paracetamol alone and paracetamol‐codeine combinations. Four were ventilated and a further six patients did not require naloxone or intubation and were admitted to ICU for other reasons: drowsiness attributed to codeine but no respiratory depression (1); hepatotoxicity secondary to paracetamol requiring acetylcysteine (2); acute coronary syndrome secondary to chronic amphetamine use (1); no data available (2).
Two patients (out of 929) (0.2%; 95% CI: 0.04–0.9%) in the paracetamol alone group had a GCS < 9 compared to four patients (out of 447) (0.9%; 95% CI: 0.3–2.4%) in the paracetamol‐codeine group (P = 0.09).
Discussion
Our study found that codeine ingested in overdose in adults without co‐ingestants is very unlikely to cause significant respiratory depression, based on a large cohort of patients taking paracetamol‐codeine combination overdoses in comparison to paracetamol alone overdoses. Only 0.6% of patients taking a paracetamol‐codeine combination overdose were given naloxone and no patient was intubated for severe respiratory depression solely attributable to codeine. In addition, there was no difference in decreased level of consciousness (GCS < 9) or interventions for respiratory depression between paracetamol alone and paracetamol‐codeine combination products. Paracetamol alone overdoses were associated with larger ingestions and more patients requiring acetylcysteine.
There have been case reports of severe respiratory depression and death after therapeutic use of codeine but this is rare and was predominantly in children who had undergone adenotonsillectomy surgery. A review of case reports by Niesters et al. (2013) identified three common risk factors that predispose patients to respiratory depression, including renal impairment, ultra‐rapid CYP2D6 genetics and adenotonsillectomy surgery 13. However, since these case reports were restricted to paediatric postoperative patients, they are not comparable to those in our cohort. In 2013, the US Food and Drug Administration (FDA) issued a restriction on the use of codeine in post‐operative pain management in children following adenotonsillectomy 15. There have not been any new warnings or restrictions on the use of codeine in adults, likely due to a lack of serious adverse reactions or deaths secondary to codeine use in the literature.
There have only been a few case reports of codeine overdoses in adult patients 16, 17, and reports of deaths associated with codeine 18. In these studies patients who experienced respiratory depression secondary to codeine were effectively managed with naloxone. There are more case reports with adverse outcomes from codeine in paediatric patients. It is unclear why there is only a very small number of case reports in the literature for adults, but it appears to be similar to therapeutic adverse effects with codeine, where the majority of cases are in children 19.
A major limitation of this study was the retrospective design. This design was chosen because severe respiratory depression secondary to paracetamol‐codeine combination products appeared to be rare, so a large patient cohort was required. Prospective collection of data would have been superior but would have taken over 10 years to complete. Although the data were reviewed retrospectively, the data were entered prospectively into the database and all outcomes used in this study were predefined data elements in the database. Another problem with the retrospective design was the incorrect use of naloxone in many cases. A prospective design could have avoided this and allowed the use of other measures of respiratory depression, such as oxygen desaturation or respiratory acidosis.
A second limitation of the study was that reported codeine ingestion was not confirmed by laboratory drug analysis, although all paracetamol cases were confirmed by paracetamol concentrations. A previous study using the same database of paracetamol overdoses found a strong association between dose and paracetamol concentration 20. It has been shown in a number of studies that using patient history is reliable in identifying the drug taken and a good estimate of the drug dose ingested 20, 21, 22.
There were 3001 patients excluded due to reported co‐ingestants, which ensured that any CNS depression or respiratory depression could only be attributed to codeine or codeine‐doxylamine. All co‐ingestants were excluded in preference to attempting to exclude only drugs or substances with a known sedative effect. Although this decreased the number of patients included in the study, it would have been highly problematic to determine exactly which toxins are regarded as sedative and at what dose they are sedative.
The study was large enough to exclude clinically important respiratory depression in paracetamol‐codeine combination overdoses. The difference between paracetamol alone and paracetamol combination overdoses was 0.26% (95% CI: −0.7–1.2%), equivalent to a number needed to treat of 392. A larger study may demonstrate a statistically significant difference less than 0.26%, but this would not be considered clinically significant. Severe respiratory depression may be more likely to occur in the subgroup of ultra‐rapid metabolizers. However, because of the low frequency of this genetic variant in the general population, a much larger study would be required to determine the risk in this small subgroup.
A final limitation was potential errors in entering the data into the database. However, because the data was entered prospectively without knowledge of any study aims, there is unlikely to be any bias in the extraction of the data. The primary outcome of respiratory depression requiring mechanical ventilation or naloxone is likely to be objective with medical professionals using respiratory rate, GCS and oxygen saturations to guide patient management. Unfortunately oxygen saturations are not recorded prospectively.
Conclusion
In our study paracetamol‐codeine combination overdoses were rarely associated with severe respiratory depression, with only 0.6% requiring naloxone and no patients were intubated for respiratory depression solely attributable to codeine. Patients who have taken acute paracetamol‐codeine combination overdoses, in the absence of other sedative medications, are very unlikely to develop severe respiratory depression. In cases in which respiratory depression occurs, other causes should be considered.
Competing Interests
All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work.
The study was supported by an NHMRC Program Grant (1055176). GKI is supported by an NHMRC Senior Research Fellowship ID1061041.
Heppell, S. P. E. , and Isbister, G. K. (2017) Lack of respiratory depression in paracetamol‐codeine combination overdoses. Br J Clin Pharmacol, 83: 1273–1278. doi: 10.1111/bcp.13224.
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