Single dose oral lornoxicam for acute postoperative pain in adults

Abstract

Background

Lornoxicam is one of the oxicam class of non‐steroidal anti‐inflammatory drugs (NSAIDs), producing analgesic and antipyretic effects in part through the non‐selective inhibition of cyclo‐oxygenase‐1 and ‐2. It is prescribed for osteoarthritis, rheumatoid arthritis, acute lumbar‐sciatica conditions and for postoperative pain management. Lornoxicam is available in 31 countries in Europe, the Middle East, Far East and South America, and is becoming more widely available.

Objectives

To assess the efficacy, the time to onset of analgesia, the time to use of rescue medication and any associated adverse events of single dose oral lornoxicam in acute postoperative pain.

Search methods

We searched CENTRAL, MEDLINE, EMBASE and PubMed to June 2009.

Selection criteria

Single oral dose, randomised, double‐blind, placebo‐controlled trials of lornoxicam for relief of established moderate to severe postoperative pain in adults.

Data collection and analysis

Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief over 6 hours (TOTPAR 6) was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals (CIs), the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected.

Main results

Three studies, with 628 participants, met the inclusion criteria; 434 participants were treated with various doses (2 mg to 32 mg) of lornoxicam, 118 with placebo, and 76 with other active therapies. All the participants had pain following third molar extraction, and study duration was 8 to 24 hours. The NNT for at least 50% pain relief over 6 hours after a single dose of lornoxicam 8 mg was 2.9 (2.3 to 4.0). There were insufficient data to analyse other doses or use of rescue medication. No serious adverse events or withdrawals were reported by any of the studies.

Authors' conclusions

Oral lornoxicam is effective at treating moderate to severe acute postoperative pain, based on limited data. Adverse events did not differ significantly from placebo.

Plain language summary

Single dose lornoxicam (trade names Xefo, Xafon, Lorcam, Acabel) for acute postoperative pain in adults

Lornoxicam is a non‐steroidal anti‐inflammatory drug (NSAID) that is used as a painkiller (analgesic). A high level of pain relief is experienced by about 45% of those with moderate to severe postoperative dental pain after a single dose of lornoxicam 8 mg, compared to about 10% with placebo. This is comparable to the proportion experiencing the same level of pain relief with ibuprofen 200 to 400 mg. Adverse events were generally mild and did not differ from placebo in these singe dose studies. There were insufficient data to assess duration of action, but it is likely to be similar to ibuprofen 200 mg.

Background

Acute pain occurs as a result of tissue damage either accidentally due to an injury or as a result of surgery. Acute postoperative pain is a manifestation of inflammation due to tissue injury. The management of postoperative pain and inflammation is a critical component of patient care.

This is one of a series of reviews whose aim is to increase awareness of the range of analgesics that are potentially available, and present evidence for relative analgesic efficacy through indirect comparisons with placebo, in very similar trials performed in a standard manner, with very similar outcomes, and over the same duration. Such relative analgesic efficacy does not in itself determine choice of drug for any situation or patient, but guides policy‐making at the local level. Recently published reviews include paracetamol (Toms 2008), celecoxib (Derry 2008), naproxen (Derry C 2009a), parecoxib (Lloyd 2009), diclofenac (Derry P 2009), etoricoxib (Clarke 2009), ibuprofen (Derry C 2009b) and oxycodone (Gaskell 2009).

Acute pain trials

Single dose trials in acute pain are commonly short in duration, rarely lasting longer than 12 hours. The numbers of participants are small, allowing no reliable conclusions to be drawn about safety. To show that the analgesic is working, it is necessary to use placebo (McQuay 2005). There are clear ethical considerations in doing this. These ethical considerations are answered by using acute pain situations where the pain is expected to go away, and by providing additional analgesia, commonly called rescue analgesia, if the pain has not diminished after about an hour. This is reasonable, because not all participants given an analgesic will have significant pain relief. Approximately 18% of participants given placebo will have significant pain relief (Moore 2006), and up to 50% may have inadequate analgesia with active medicines. The use of additional or rescue analgesia is hence important for all participants in the trials.

Clinical trials measuring the efficacy of analgesics in acute pain have been standardised over many years. Trials have to be randomised and double blind. Typically, in the first few hours or days after an operation, patients develop pain that is moderate to severe in intensity, and will then be given the test analgesic or placebo. Pain is measured using standard pain intensity scales immediately before the intervention, and then using pain intensity and pain relief scales over the following 4 to 6 hours for shorter acting drugs, and up to 12 or 24 hours for longer acting drugs. Pain relief of half the maximum possible pain relief or better (at least 50% pain relief) is typically regarded as a clinically useful outcome. For patients given rescue medication it is usual for no additional pain measurements to be made, and for all subsequent measures to be recorded as initial pain intensity or baseline (zero) pain relief (baseline observation carried forward). This process ensures that analgesia from the rescue medication is not wrongly ascribed to the test intervention. In some trials the last observation is carried forward, which gives an inflated response for the test intervention compared to placebo, but the effect has been shown to be negligible over 4 to 6 hours (Moore 2005). Patients usually remain in the hospital or clinic for at least the first 6 hours following the intervention, with measurements supervised, although they may then be allowed home to make their own measurements in trials of longer duration.

Knowing the relative efficacy of different analgesic drugs at various doses can be helpful. An example is the relative efficacy in the third molar extraction pain model (Barden 2004).

Lornoxicam

Lornoxicam (trade names ‐ Xefo, Xafon, Lorcam, Acabel) is one of the oxicam class of NSAIDs, acting in part through the non‐selective inhibition of cyclo‐oxygenase‐1 and ‐2 to produce analgesic and antipyretic effects (Berg 1999). It is generally prescribed for osteoarthritis, rheumatoid arthritis, acute lumbar‐sciatica pain and for post‐operative pain management. Different preparations are available, including 4 mg or 8 mg oral (standard or quick‐release) or injection (intravenous or intra‐muscular) preparations. Maximal plasma concentrations are reached after 1 to 2 hours for the standard oral preparation and after approximately 30 minutes for the quick‐release oral version and the intra‐muscular injection. Oral preparations have a 90% bioavailability. Lornoxicam is metabolised by cytochrome P450 2C9 and has a plasma half‐life of 3 to 4 hours (Dittrich 1990; Hitzenberger 1990). It is available in 31 countries in Europe, the Middle East, Far East and South America, and will shortly be available in the UK.

Clinicians prescribe NSAIDs on a routine basis for a range of mild‐to‐moderate pain. NSAIDs are the most commonly prescribed analgesic medications worldwide, and their efficacy for treating acute pain has been well demonstrated (Moore 2003). They reversibly inhibit cyclooxygenase (prostaglandin endoperoxide synthase), the enzyme mediating production of prostaglandins (PGs) and thromboxane A2 (Fitzgerald 2001). PGs mediate a variety of physiological functions such as maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone. They also play an important role in inflammatory and nociceptive processes. However, relatively little is known about the mechanism of action of this class of compounds aside from their ability to inhibit cyclooxygenase‐dependent prostanoid formation (Hawkey 1999).

Objectives

To assess the efficacy and adverse effects of single dose oral lornoxicam for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes.

Methods

Criteria for considering studies for this review

Types of studies

Studies were included if they were double blind trials of single dose oral lornoxicam compared with placebo for the treatment of moderate to severe postoperative pain in adults, with at least 10 participants randomly allocated to each treatment group. Multiple dose studies were included if appropriate data from the first dose was available. Cross‐over studies were included provided that data from the first arm was presented separately. No language restriction was applied to the search for studies.

The following were excluded:

• review articles, case reports, and clinical observations;

• studies of experimental pain;

• studies where pain relief is assessed only by clinicians, nurses or carers (i.e., not patient‐reported);

• studies of less than 4 hours duration or studies that fail to present data over 4 to 6 hours post‐dose.

For postpartum pain, studies were included if the pain investigated was due to episiotomy or Caesarean section irrespective of the presence of uterine cramps; studies investigating pain due to uterine cramps alone were excluded.

Types of participants

Studies of adult participants (> 15 yrs) with established postoperative pain of moderate to severe intensity following day surgery or in‐patient surgery were included. For studies using a visual analogue scale (VAS), pain of at least moderate intensity was equated to greater than 30 mm (Collins 1997).

Types of interventions

Lornoxicam or matched placebo administered as a single oral dose for postoperative pain.

Types of outcome measures

Data collected included the following if available:

• participant characteristics;

• patient reported pain at baseline (physician, nurse or carer reported pain was not included in the analysis);

• patient reported pain relief expressed at least hourly over 4 to 6 hours using validated pain scales (pain intensity and pain relief in the form of VAS or categorical scales, or both);

• patient global assessment of efficacy (PGE), using a standard categorical scale;

• time to onset of analgesia;

• time to use of rescue medication;

• number of participants using rescue medication;

• number of participants with one or more adverse events;

• number of participants with serious adverse events;

• number of withdrawals (all cause, adverse events).

Search methods for identification of studies

To identify studies for inclusion in this review, the following electronic databases were searched:

• Cochrane CENTRAL (issue 2, 2009);

• MEDLINE via Ovid (June 2009);

• EMBASE via Ovid (June 2009);

• Oxford Pain Relief Database (Jadad 1996a).

See Appendix 1 for the MEDLINE search strategy, Appendix 2 for the EMBASE search strategy and Appendix 3 for the CENTRAL search strategy.

Additional studies were sought in reference lists of retrieved articles and reviews.

Language

No language restriction was applied.

Unpublished studies

The manufacturing pharmaceutical company producing this drug were not contacted for unpublished trial data.

Data collection and analysis

Selection of studies

Two review authors independently assessed and agreed the search results for studies that might be included in the review. Disagreements were resolved by consensus or referral to a third reviewer.

Quality assessment

Two review authors independently assessed the included studies for quality using a five‐point Oxford Quality scale (Jadad 1996b) that considers randomisation, blinding, and study withdrawals and dropouts.

The scale used is as follows.

• Is the study randomised? If yes give one point.

• Is the randomisation procedure reported and is it appropriate? If yes add one point, if no deduct one point.

• Is the study double blind? If yes then add one point.

• Is the double blind method reported and is it appropriate? If yes add one point, if no deduct one point.

• Are the reasons for patient withdrawals and dropouts described? If yes add one point.

The results are described in the 'Methodological quality of included studies' section below, and 'Characteristics of included studies' table.

Data management

Data was extracted by two review authors and recorded on a standard data extraction form. Data suitable for pooling were entered into RevMan 5.

Data analysis

For each study, the mean TOTPAR, SPID, VAS TOTPAR or VAS SPID (Appendix 4) values for active and placebo were converted to %maxTOTPAR or %maxSPID by division into the calculated maximum value (Cooper 1991). The proportion of participants in each treatment group who achieved at least 50%maxTOTPAR were calculated using verified equations (Moore 1996; Moore 1997a; Moore 1997b). These proportions were then converted into the number of participants achieving at least 50%maxTOTPAR by multiplying by the total number of participants in the treatment group. Information on the number of participants with at least 50%maxTOTPAR for active and placebo was used to calculate relative benefit (RB) or relative risk (RR), and number needed to treat to benefit (NNT).

Pain measures accepted for the calculation of TOTPAR or SPID were:

• five‐point categorical pain relief (PR) scales with comparable wording to "none, slight, moderate, good or complete";

• four‐point categorical pain intensity (PI) scales with comparable wording to "none, mild, moderate, severe";

• VAS for pain relief;

• VAS for pain intensity.

If none of these measures were available, the number of participants reporting "very good or excellent" on a five‐point categorical global scale with the wording "poor, fair, good, very good, excellent" was used for the number of participants achieving at least 50% pain relief (Collins 2001).

The number of participants reporting treatment‐emergent adverse effects was extracted for each treatment group. RB and RR estimates were calculated with 95% confidence intervals (CI) using a fixed‐effect model (Morris 1995). NNT and number needed to treat to harm (NNH) and 95% CI were calculated using the pooled number of events using the method devised by Cook and Sackett (Cook 1995). A statistically significant difference from control was assumed when the 95% CI of the RR or RB did not include the number one. Homogeneity was examined visually using L'Abbé plots (L'Abbé 1987).

Sub‐group analyses were planned to determine the effect of dose, presenting condition (pain model), and high versus low (two or fewer versus three or more) quality trials. A minimum of two trials and 200 participants had to be available in any sensitivity analysis (Moore 1998). The z test (Tramèr 1997) would be used to determine if there was a significant difference between NNTs for different groups in the sensitivity analyses when the 95% CIs do not overlap.

Results

Description of studies

Results of the search

Four potentially relevant papers were identified and examined in detail (Cooper 1996; Moller 2008; Norholt 1995; Patel 1991). Of these, three met the inclusion criteria for this review (Moller 2008; Norholt 1995; Patel 1991).

Included studies

The three included studies all examined the effective of lornoxicam on moderate to severe pain in participants undergoing third molar dental surgery.

Moller 2008 recruited 200 participants, with 80 receiving 8 mg standard‐release (SR) lornoxicam tablets, 80 receiving 8 mg quick‐release (QR) lornoxicam tablets, and 40 receiving placebo tablets. Study duration was 24 hours, with follow up at one week.

Norholt 1995 recruited 278 participants, with 43 receiving 4 mg lornoxicam, 45 receiving 8 mg lornoxicam, 48 receiving 16 mg lornoxicam, 48 receiving 32 mg lornoxicam, 46 receiving 10 mg ketorolac and 48 receiving placebo. Study duration was 8 hours, with follow up at one week.

Patel 1991 recruited 150 participants, with 30 in each group of 2 mg lornoxicam, 4 mg lornoxicam, 8 mg lornoxicam, 650 mg aspirin and placebo. Study duration was 8 hours.

All studies were conducted in participants with pain of moderate to severe intensity following surgical extraction of at least one impacted third molar tooth.

Excluded studies

Cooper 1996 was excluded on the basis that lornoxicam was administered pre‐emptively before pain became moderate to severe.

Risk of bias in included studies

Studies were assessed for methodological bias using the three‐point Oxford Quality Score (Jadad 1996b). All studies were randomised and double blind. One study (Moller 2008) scored 4/5 on the Oxford Quality scale, and the other two scored 3/5 (Norholt 1995; Patel 1991). Points were lost for not giving adequate details of the methods of randomisation and blinding. Withdrawals and exclusions were reported, and missing data analysed appropriately; none were considered likely to influence the results.

Effects of interventions

All studies contributed data for analysis of the primary efficacy outcome. No sensitivity analyses were carried out since all studies used the dental pain model, and all scored at least 3/5 for methodological quality.

Number of participants achieving at least 50% pain relief

(Table 1)

Lornoxicam 2 mg versus placebo

Only one study used lornoxicam 2 mg (Patel 1991), with 60 participants in the comparison. There were insufficient data to analyse.

Lornoxicam 4 mg versus placebo

Two studies used lornoxicam 4 mg (Norholt 1995; Patel 1991), with 151 participants in the comparison. There were insufficient data to draw firm conclusions but results are presented below for comparison (Analysis 1.1; Figure 1).

Lornoxicam 8 mg versus placebo

All three studies used lornoxicam 8 mg SR (Moller 2008; Norholt 1995; Patel 1991), with 273 participants in the comparison.

• The proportion of participants experiencing at least 50% pain relief over 6 hours with lornoxicam 8 mg was 46% (71/155; range 34% to 64%).

• The proportion of participants experiencing at least 50% pain relief with placebo was 11% (13/118; range 0% to 30%).

• The RB of treatment compared with placebo was 4.7 (2.7 to 8.1), giving an NNT for at least 50% pain relief over 6 hours of 2.9 (2.3 to 4.0) (Analysis 1.1; Figure 1).

1.

Forest plot of comparison: 3 Lornoxicam versus placebo, outcome: 3.1 Participants with at least 50% pain relief over 6 hours.

One study (Moller 2008) used 8 mg lornoxicam in the quick release formulation, with 120 participants in the comparison. This formulation appeared to give better efficacy than the standard formulation, but there were insufficient data from this one study to draw any conclusions.

Lornoxicam 16 mg and 32 mg versus placebo

Only one study used lornoxicam 16 mg and 32 mg (Norholt 1995), with 96 participants in each comparison. There were insufficient data for analysis.

Summary of results A: Number of participants with ≥ 50% pain relief over 6 hours
Dose	Studies	Participants	Lornoxicam (%)	Placebo (%)	NNT (95%CI)
4 mg	2	151	40	17	4.3 (2.7 to 11)
8 mg SR	3	273	46	11	2.9 (2.3 to 4.0)

Use of rescue medication

(see additional Table 1)

Proportion of participants using rescue medication

Only one study (Moller 2008) reported this outcome. While fewer participants required rescue medication over 6 hours with lornoxicam 8 mg than with placebo, there were insufficient data to draw conclusions.

Time to use of rescue medication

Moller 2008 reported the median time to use of rescue medication as 4.0 hours for lornoxicam 8 mg SR, 5.7 hours for lornoxicam 8 mg QR, and 1.1 hours for placebo.

Norholt 1995 reported the mean time to use of rescue medication as 4.1 hours for lornoxicam 8 mg, and 1.7 for placebo.

While there were insufficient data for any analysis, these results indicate a duration of action of around 4 hours for the standard release 8 mg dose.

Adverse events

(see additional Table 2)

Adverse events were recorded by means of questionnaires and verbal questioning during the trial, and sometimes at follow‐up one week later (Moller 2008; Norholt 1995). There were no serious adverse events, and most events were reported as mild, and unlikely to be related to the study medication. No participants withdrew from any of the trials due to adverse events. Norholt 1995 did not provide adequate information to determine the number of adverse events in each group and therefore cannot be included in the data analysis, although events were reported to be evenly distributed between the treatment groups.

Combining data from the remaining two studies, 88/250 (35%) of participants treated with lornoxicam (2 mg to 8 mg) reported adverse events, compared with 16/70 (23%) of participants treated with placebo. The difference was not statistically significant (RR 1.4 (0.92 to 2.2)).

For lornoxicam 8 mg only, 84/190 (44%) of participants treated with lornoxicam and 16/70 (23%) of participants treated with placebo reported adverse events. Once again, the difference was not statistically significant (RR 1.4 (0.92 to 2.2)) (Analysis 1.2).

1.2. Analysis.

Comparison 1 Lornoxicam versus placebo, Outcome 2 Participants with any adverse event.

There was no data on time of onset of analgesia.

Withdrawals

(see additional Table 2)

None of the studies reported withdrawals after administration of the test medication, other than withdrawals due to lack of efficacy, which are dealt with under 'Use of rescue medication', above.

See Table 1 for details of analgesia and use of rescue medication, and Table 2 for details of adverse events and withdrawals.

1. Summary of outcomes: analgesia and rescue medication.

		Analgesia			Rescue medication
Study ID	Treatment	PI or PR	Number with 50% PR	PGE: v good or excellent	Median time to use (h)	% using
Moller 2008	(1) Lornoxicam 8 mg SR, n = 80 (2) Lornoxicam 8 mg QR, n = 80 (3) Placebo, n = 40	TOTPAR 6: (1) 8.1 (2) 11.3 (3) 1.8	(1) 27/80 (2) 41/80 (3) 0/40	No usable data	(1) 4.0 (2) 5.7 (3) 1.1	at 8 h: (1) 48/80 (2) 50/80 (3) 37/40
Norholt 1995	(1) Lornoxicam 4 mg, n = 43 (2) Lornoxicam 8 mg, n = 45 (3) Lornoxicam 16 mg, n = 48 (4) Lornoxicam 32 mg, n = 48 (5) Ketorolac 10 mg, n = 46 (6) Placebo, n = 48	TOTPAR 6: (1) 9.6 (2) 13.7 (3) 15.0 (4) 17.7 (6) 3.7	(1) 18/43 (2) 29/45 (3) 34/48 (4) 42/48 (6) 4/48	(1) 12/43 (2) 23/45 (3) 27/48 (4) 32/48 (5) 25/46 (6) 4/48	Mean: (1) 3.1 (2) 4.1 (3) 4.9 (4) 5.1 (6) 1.7	No data
Patel 1991	(1) Lornoxicam 2 mg, n = 30 (2) Lornoxicam 4 mg, n = 30 (3) Lornoxicam 8 mg, n = 30 (4) Aspirin 650 mg, n = 30 (6) Placebo, n = 30	TOTPAR 6: (1) 8.43 (2) 8.99 (3) 11.12 (5) 7.38	(1) 11/30 (2) 11/30 (3) 15/30 (5) 9/30	No usable data	No data	No data

QR ‐ quick release; SR ‐ slow release

2. Summary of outcomes: adverse events and withdrawals.

		Adverse events		Withdrawals
Study ID	Treatment	Any	Serious	Adverse event	Other
Moller 2008	(1) Lornoxicam 8 mg SR, n = 80 (2) Lornoxicam 8 mg QR, n = 80 (3) Placebo, n = 40	at 7 days: (1) 39/80 (2) 43/80 (3) 14/40	None	None	None
Norholt 1995	(1) Lornoxicam 4 mg, n = 43 (2) Lornoxicam 8 mg, n = 45 (3) Lornoxicam 16 mg, n = 48 (4) Lornoxicam 32 mg, n = 48 (5) Ketorolac 10 mg, n = 46 (6) Placebo, n = 48	No usable data	None reported	None	None
Patel 1991	(1) Lornoxicam 2 mg, n = 30 (2) Lornoxicam 4 mg, n = 30 (3) Lornoxicam 8 mg, n = 30 (4) Aspirin 650 mg, n = 30 (6) Placebo, n = 30	at 8 h: (1) 3/30 (2) 1/30 (3) 2/30 (4) 2/30 (5) 2/30	None	None	None

QR ‐ quick release; SR ‐ slow release

Discussion

Summary of main results

This review examined the efficacy of the non‐steroidal anti‐inflammatory drug (NSAID), lornoxicam, in providing postoperative pain relief. Three studies, all in dental pain, were identified as fulfilling the inclusion criteria (Moller 2008; Norholt 1995; Patel 1991). For lornoxicam 8 mg (273 participants), the RB compared to placebo was 4.7 (2.7 to 8.1), and the NNT for at least 50% pain relief over 6 hours was 2.9 (2.3 to 4.0). There were insufficient data for analysis of other doses. No serious adverse events or adverse event withdrawals were reported in any of the studies. Limited results indicate a duration of action of about 4 hours for the standard release 8 mg dose.

Indirect comparisons of NNTs for at least 50% pain relief over 4 to 6 hours in reviews of other analgesics using identical methods indicate that lornoxicam 8 mg has equivalent efficacy to ibuprofen 200 mg (Derry C 2009b), is more effective than paracetamol 1000 mg (Toms 2008; NNT 3.6 (3.4 to 4.0)) and less effective than celecoxib 400 mg (Derry 2008; NNT 2.1 (1.8 to 2.5)) and etoricoxib (Clarke 2009; NNT 1.6 (1.5 to 1.8)).

Overall completeness and applicability of evidence

The included studies were identified from a comprehensive search of published papers. 

The studies were clinically homogeneous, in that they all investigated pain relief following third molar dental surgery. This alleviated any confounding factors due to different pain models. However, pain relief was the only outcome consistently reported by the included studies. It would be useful to have more data on other outcomes, such as time to use of rescue medication and numbers of participants needing rescue medication within 6 hours. 

The efficacy of lornoxicam in pain relief following other types of surgery or in chronic medical conditions (e.g. arthritis) has not been addressed by this review. Lornoxicam has been reported to be effective for postoperative pain following a range of different surgeries, including septoplasty, cholecystectomy and myomectomy (Erdogan 2008; Papadima 2007; Sener 2008). However, the route of administration in these studies was either intramuscular or intravenous, thereby precluding direct comparison with the results of this review. Similarly, lornoxicam has been found to be effective in relieving pain due to osteoarthritis (Berry 1992), indicating analgesic efficacy for a range of clinical conditions.

No serious adverse events were reported by the included studies. This is in agreement with an earlier study, which found that lornoxicam did not cause more adverse events than placebo in healthy adults, when given at a dose of 4 mg twice daily for 28 days (Warrington 1990a). Likewise, there was no significant increase in faecal blood loss compared to placebo and no adverse effect on coagulation or renal function (Warrington 1990a; Warrington 1990b). Thus, lornoxicam has a good safety profile, at least in short term use.

Quality of the evidence

The methodological quality of the evidence was assessed using to the Oxford Quality scoring system, based on whether the study was randomised, double‐blinded and if withdrawals were accounted for (Jadad 1996b). One study scored 4/5, and two scored 3/5, indicating that they were relatively free of bias (Jadad 1996b). Points were lost for failure to provide details of the method of randomisation and allocation concealment, and of blinding (except Moller 2008).

A common problem with pain relief trials is what to do with the data from participants who use the rescue medication before the end of the study. There are two possibilities. Firstly, the last pain relief measurement from the time point immediately prior to remedication can be used for all further observations (last observation carried forward), as used by Patel 1991. Alternatively, the pain relief score can be set to zero for all remaining time points (baseline observation carried forward), as used by Norholt 1995 and Moller 2008. Studies have shown that the use of baseline observation carried forward is a more conservative measurement resulting in higher NNTs, thus reducing the chance of bias (Moore 2005). However, differences with last observation carried forward measurements only become apparent after 8 hours, which is greater than the 6 hour time point used for analysis in this review (Moore 2005). Therefore, the choice of method to deal with missing values is unlikely to have biased the outcomes.

Another consideration when assessing whether the outcomes of the included studies may contain any bias is the source of funding. Involvement by Nycomed, the producers of lornoxicam, was acknowledged by Moller 2008 and Norholt 1995, and is likely in Patel 1991 through Advisory Services. Such involvement does not necessarily imply bias, as long as original data rather than conclusions are utilised, and study validity is not compromised (Barden 2006), and these criteria have been satisfied.

Authors' conclusions

Implications for practice.

This review has found that lornoxicam is effective at providing postoperative pain relief in approximately half of adult patients. This is similar to results for ibuprofen 200 mg. Lornoxicam was not associated with any serious adverse events in this limited data set.

Implications for research.

Given the large number of available drugs of this and similar classes to treat postoperative pain, there is no urgent research agenda. More studies would be helpful to more accurately determine efficacy, particularly in areas other than dental surgery. Improvements could be made to the reporting of outcomes other than pain relief, such as time to remedication. Much of the recent literature on lornoxicam has evaluated intravenous administration in the perioperative setting, rather than oral administration in established pain.

What's new

Date	Event	Description
29 May 2019	Amended	Contact details updated.
11 October 2017	Review declared as stable	No new studies likely to change the conclusions are expected.

History

Protocol first published: Issue 4, 2008
 Review first published: Issue 4, 2009

Date	Event	Description
3 August 2016	Review declared as stable	See Published notes.
15 September 2011	Review declared as stable	The authors scanned the literature in August 2011 and are confident that there will be no need to update the search until at least 2015.

Notes

A restricted search in August 2016 did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors. If appropriate, we will update the review if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.

Appendices

Appendix 1. MEDLINE search strategy (via OVID)

1. Lornoxicam.sh

2. (lornoxicam OR Xefo OR Xafon OR Lorcam OR Acabel).ti,ab,kw.

3. OR/1‐2

4. Pain, postoperative.sh

5. ((postoperative adj4 pain$) or (post‐operative adj4 pain$) or post‐operative‐pain$ or (post$ NEAR pain$) or (postoperative adj4 analgesi$) or (post‐operative adj4 analgesi$) or ("post‐operative analgesi$")).ti,ab,kw.

6. ((post‐surgical adj4 pain$) or ("post surgical" adj4 pain$) or (post‐surgery adj4 pain$)).ti,ab,kw.

7. (("pain‐relief after surg$") or ("pain following surg$") or ("pain control after")).ti,ab,kw.

8. (("post surg$" or post‐surg$) AND (pain$ or discomfort)).ti,ab,kw.

9. ((pain$ adj4 "after surg$") or (pain$ adj4 "after operat$") or (pain$ adj4 "follow$ operat$") or (pain$ adj4 "follow$ surg$")).ti,ab,kw.

10. ((analgesi$ adj4 "after surg$") or (analgesi$ adj4 "after operat$") or (analgesi$ adj4 "follow$ operat$") or (analgesi$ adj4 "follow$ surg$")).ti,ab,kw.

11. OR/4‐10

12. randomized controlled trial.pt.

13. controlled clinical trial.pt.

14. randomized.ab.

15. placebo.ab.

16. drug therapy.fs.

17. randomly.ab.

18. trial.ab.

19. groups.ab.

20. OR/12‐19

21. humans.sh.

22. 20 AND 21

23. 3 AND 11 AND 22

Appendix 2. Search strategy for EMBASE (via OVID)

1. Lornoxicam.sh

2. (lornoxicam OR Xefo OR Xafon OR Lorcam OR Acabel).ti,ab,kw.

3. OR/1‐2

4. Postoperative pain.sh

5. ((postoperative adj4 pain$) or (post‐operative adj4 pain$) or post‐operative‐pain$ or (post$ NEAR pain$) or (postoperative adj4 analgesi$) or (post‐operative adj4 analgesi$) or ("post‐operative analgesi$")).ti,ab,kw.

6. ((post‐surgical adj4 pain$) or ("post surgical" adj4 pain$) or (post‐surgery adj4 pain$)).ti,ab,kw.

7. (("pain‐relief after surg$") or ("pain following surg$") or ("pain control after")).ti,ab,kw.

8. (("post surg$" or post‐surg$) AND (pain$ or discomfort)).ti,ab,kw.

9. ((pain$ adj4 "after surg$") or (pain$ adj4 "after operat$") or (pain$ adj4 "follow$ operat$") or (pain$ adj4 "follow$ surg$")).ti,ab,kw.

10. ((analgesi$ adj4 "after surg$") or (analgesi$ adj4 "after operat$") or (analgesi$ adj4 "follow$ operat$") or (analgesi$ adj4 "follow$ surg$")).ti,ab,kw.

11. OR/4‐10

12. clinical trials.sh

13. controlled clinical trials.sh

14. randomized controlled trial.sh

15. double‐blind procedure.sh

16. (clin$ adj25 trial$).ab

17. ((doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ab

18. placebo$.ab

19. random$.ab

20. OR/12‐19

21. 3 AND 11 AND 20

Appendix 3. Search strategy for Cochrane CENTRAL

1. MESH descriptor Lornoxicam

2. (lornoxicam OR Xefo OR Xafon OR Lorcam OR Acabel).ti,ab,kw.

3. OR/1‐2

4. MESH descriptor Pain, Postoperative

5. ((postoperative adj4 pain$) or (post‐operative adj4 pain$) or post‐operative‐pain$ or (post$ NEAR pain$) or (postoperative adj4 analgesi$) or (post‐operative adj4 analgesi$) or ("post‐operative analgesi$")):ti,ab,kw.

6. ((post‐surgical adj4 pain$) or ("post surgical" adj4 pain$) or (post‐surgery adj4 pain$)):ti,ab,kw.

7. (("pain‐relief after surg$") or ("pain following surg$") or ("pain control after")):ti,ab,kw.

8. (("post surg$" or post‐surg$) AND (pain$ or discomfort)):ti,ab,kw.

9. ((pain$ adj4 "after surg$") or (pain$ adj4 "after operat$") or (pain$ adj4 "follow$ operat$") or (pain$ adj4 "follow$ surg$")):ti,ab,kw.

10. ((analgesi$ adj4 "after surg$") or (analgesi$ adj4 "after operat$") or (analgesi$ adj4 "follow$ operat$") or (analgesi$ adj4 "follow$ surg$")):ti,ab,kw.

11. OR/4‐10

12. Clinical trials:pt.

13. Controlled Clinical Trial:pt.

14. Randomized Controlled Trial.pt.

15. MESH descriptor Double‐Blind Method

16. (clin$ adj25 trial$):ti,ab,kw.

17. ((doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)):ti,ab,kw.

18. placebo$:ti,ab,kw.

19. random$:ti,ab,kw.

20. OR/12‐19

21. 3 AND 11 AND 20

Appendix 4. Glossary

Categorical rating scale: The commonest is the five category scale (none, slight, moderate, good or lots, and complete). For analysis numbers are given to the verbal categories (for pain intensity, none = 0, mild = 1, moderate = 2 and severe = 3, and for relief none = 0, slight = 1, moderate = 2, good or lots = 3 and complete = 4). Data from different subjects is then combined to produce means (rarely medians) and measures of dispersion (usually standard errors of means). The validity of converting categories into numerical scores was checked by comparison with concurrent visual analogue scale measurements. Good correlation was found, especially between pain relief scales using cross‐modality matching techniques. Results are usually reported as continuous data, mean or median pain relief or intensity. Few studies present results as discrete data, giving the number of participants who report a certain level of pain intensity or relief at any given assessment point. The main advantages of the categorical scales are that they are quick and simple. The small number of descriptors may force the scorer to choose a particular category when none describes the pain satisfactorily.

VAS: Visual analogue scale: lines with left end labelled "no relief of pain" and right end labelled "complete relief of pain", seem to overcome this limitation. Patients mark the line at the point which corresponds to their pain. The scores are obtained by measuring the distance between the no relief end and the patient's mark, usually in millimetres. The main advantages of VAS are that they are simple and quick to score, avoid imprecise descriptive terms and provide many points from which to choose. More concentration and coordination are needed, which can be difficult post‐operatively or with neurological disorders.

TOTPAR: Total pain relief (TOTPAR) is calculated as the sum of pain relief scores over a period of time. If a patient had complete pain relief immediately after taking an analgesic, and maintained that level of pain relief for six hours, they would have a six‐hour TOTPAR of the maximum of 24. Differences between pain relief values at the start and end of a measurement period are dealt with by the composite trapezoidal rule. This is a simple method that approximately calculates the definite integral of the area under the pain relief curve by calculating the sum of the areas of several trapezoids that together closely approximate to the area under the curve.

SPID: Summed pain intensity difference (SPID) is calculated as the sum of the differences between the pain scores over a period of time. Differences between pain intensity values at the start and end of a measurement period are dealt with by the trapezoidal rule.

VAS TOTPAR and VAS SPID are visual analogue versions of TOTPAR and SPID.

See "Measuring pain" in Bandolier's Little Book of Pain, Oxford University Press, Oxford. 2003; pp 7‐13 (Moore 2003).

Data and analyses

Comparison 1. Lornoxicam versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with at least 50% pain relief over 6 hours	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 Lornoxicam 4 mg	2	151	Risk Ratio (M‐H, Fixed, 95% CI)	2.35 [1.33, 4.14]
1.2 Lornoxicam 8 mg	3	273	Risk Ratio (M‐H, Fixed, 95% CI)	4.69 [2.70, 8.12]
2 Participants with any adverse event	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 Lornoxicam 2 to 8 mg	2	320	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.92, 2.17]
2.2 Lornoxicam 8 mg	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.92, 2.21]

1.1. Analysis.

Comparison 1 Lornoxicam versus placebo, Outcome 1 Participants with at least 50% pain relief over 6 hours.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Moller 2008.

Methods	RCT, DB, DD, placebo‐controlled parallel‐group study, single oral dose after onset of moderate‐severe pain, 24 hour study
Participants	Postoperative dental surgery ‐ third molar tooth extraction N = 200 M = 93, F = 107 Age 18‐40 years Mean age 25 years
Interventions	Lornoxicam 8 mg standard release, n = 80 Lornoxicam 8 mg quick release, n = 80 Placebo, n = 40
Outcomes	PI: 100 mm VAS PR: standard 5 point scale PGE: standard 5 point scale Number using rescue medication Time to use of rescue medication Adverse events: any, serious Withdrawals: all cause, adverse event
Notes	QS = 4 (R1, D2, W1)

Norholt 1995.

Methods	RCT, DB, placebo and active controlled, parallel group study, single oral dose after moderate‐severe pain, 8 hour study
Participants	Postoperative dental surgery ‐ third molar tooth extraction N = 278 M = 160, F = 118 Age 17‐40 years Mean age 26 years
Interventions	Lornoxicam 4 mg, n = 43 Lornoxicam 8 mg, n = 45 Lornoxicam 16 mg, n = 48 Lornoxicam 32 mg, n = 48 Ketorolac 10 mg, n = 46 Placebo, n = 48
Outcomes	PI: non‐standard scale PR: standard 5 point scale PGE: standard 5 point scale Time to use of rescue medication Adverse events: any Withdrawals: all cause withdrawal, adverse event withdrawal
Notes	QS = 3 (R1, D1, W1)

Patel 1991.

Methods	RCT, DB, placebo and active controlled, parallel group study, single oral dose after moderate‐severe pain, 8 hour study
Participants	Postoperative dental surgery ‐ third molar tooth extraction N = 150 M = 71, F = 79 Age >16 years Mean age 24 years
Interventions	Lornoxicam 2 mg, n = 30 Lornoxicam 4 mg, n = 30 Lornoxicam 8 mg, n = 30 Aspirin 650 mg, n = 30 Placebo, n = 30
Outcomes	PI: standard 4 point scale PR: standard 5 point scale PGE: standard 5 point scale Adverse events: any, serious Withdrawals: all cause, adverse event
Notes	QS = 3 (R1, D1, W1)

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Cooper 1996	Pre‐emptive pain relief

Differences between protocol and review

There are no differences between protocol and review.

Contributions of authors

PEH, SD, and RAM carried out searching, data extraction, and analysis, including assessment of study quality. HJM helped with analysis and acted as arbitrator. All review authors contributed to writing. SD will be responsible for the update of this review.

Sources of support

Internal sources

• Oxford Pain Research Funds, UK.

External sources

• NHS Cochrane Collaboration Grant, UK.

• NIHR Biomedical Research Centre Programme, UK.

Declarations of interest

PH, SD, RAM & HJM have received research support from charities, government and industry sources at various times, but no such support was received for this work. RAM and HJM have consulted for various pharmaceutical companies. RAM, and HJM have received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions.

Stable (no update expected for reasons given in 'What's new')