Single dose oral sulindac for acute postoperative pain in adults

Abstract

Background

Sulindac is a non‐steroidal anti‐inflammatory drug (NSAID) licensed for use in rheumatic disease and other musculoskeletal disorders in the UK, and widely available in other countries worldwide. This review sought to evaluate the efficacy and safety of oral sulindac in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties.

Objectives

To assess the efficacy of single dose oral sulindac in acute postoperative pain, and any associated adverse events.

Search methods

We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies up to June 2009.

Selection criteria

Randomised, double‐blind, placebo‐controlled clinical trials of oral sulindac for relief of acute postoperative pain in adults.

Data collection and analysis

Two review authors independently assessed trial quality and extracted data. We planned to use area under the "pain relief versus time" curve to derive the proportion of participants with meloxicam experiencing least 50% pain relief over 4 to 6 hours, using validated equations; to use number needed to treat to benefit (NNT); the proportion of participants using rescue analgesia over a specified time period; time to use of rescue analgesia; information on adverse events and withdrawals.

Main results

No studies were identified by the searches that examined oral sulindac in patients with established postoperative pain.

Authors' conclusions

In the absence of evidence of efficacy, at present, for oral sulindac in acute postoperative pain, its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes, there is no urgent research agenda.

Plain language summary

Single dose oral sulindac for acute postoperative pain in adults

Pain is commonly experienced after surgical procedures. Postoperative pain is a good model to test whether or not drugs are effective painkillers in participants with moderate or severe pain. In this case we could find no studies that tested oral sulindac against placebo. It is possible that the studies were done, but not reported, because they were used only to register sulindac with licensing authorities throughout the world. However, this leaves an important gap in our knowledge, and it means that we cannot be confident about using oral sulindac for acute painful conditions.

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 number of participants is 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).

Sulindac

This review will look at sulindac, a non‐steroidal anti‐inflammatory drug (NSAID). It is widely available around the world, with indications for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis. In England in 2006 only 10,500 prescriptions were issued in primary care. This compares with almost eight million prescriptions for naproxen and 4.5 million prescriptions for ibuprofen in the same period (PACT 2007).

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).

Sulindac (trade names include Clinoril, Aclin, Saldac, and variants of these) is a prodrug, derived from sulphinylindene, that is converted in the body to the active NSAID. It is converted by liver enzymes to a sulphide that is excreted in the bile and then reabsorbed from the intestine (Davies 1997). This is thought to help maintain blood levels and prolong efficacy. The usual dosage is 150 to 200 milligrams twice a day, with food.

This review will look at its efficacy in the setting of acute postoperative pain.

Objectives

To assess the efficacy and adverse effects of single dose oral sulindac 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 would be included if they were double blind trials of single dose oral sulindac 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 would be included if appropriate data from the first dose were available. Cross‐over studies would be included provided that data from the first arm were 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 would be 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 years) with established postoperative pain of moderate to severe intensity following day surgery or in‐patient surgery were eligible for inclusion. 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

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

Types of outcome measures

Data was sought for the following:

• participant characteristics;

• patient reported pain at baseline (physician, nurse or carer reported pain will not be 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 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 event).

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).

Please see Appendix 1 for the MEDLINE search strategy, Appendix 2 for the EMBASE search strategy, and Appendix 3 for the Cochrane CENTRAL search strategy.

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

Language

No language restrictions were applied.

Unpublished studies

The manufacturing pharmaceutical company producing this drug was 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.

Quality assessment

It was planned that two review authors would independently assess the included studies for quality using a five‐point scale (Jadad 1996b) that considers randomisation, blinding, and study withdrawals and dropouts.

Data management

It was planned that data would be extracted by two review authors and recorded on a standard data extraction form.

Data analysis

For each study, the mean TOTPAR, SPID, VAS TOTPAR or VAS SPID (Appendix 2) values for active and placebo would be 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 can be calculated using verified equations (Moore 1996; Moore 1997a; Moore 1997b), and these proportions 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 can then be used to calculate relative benefit 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 are 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" would be used for the number of participants achieving at least 50% pain relief (Collins 2001).

The number of participants reporting treatment‐emergent adverse effects would be extracted for each treatment group. Relative benefit and relative risk (RB and RR) estimates would be 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 would be calculated using the pooled number of events by the method of Cook and Sackett (Cook 1995). A statistically significant difference from control will be assumed when the 95% CI of the relative benefit or risk does not include the number one. Homogeneity will be examined visually using L'Abbé plots (L'Abbé 1987).

Sub‐group analyses were planned if data was available to determine the effect of dose, presenting condition (pain model), and low versus high (two versus three or more) quality trials. A minimum of two trials and 200 participants must be available in any sensitivity analysis (Moore 1998). The z test (Tramér 1997) would be used to determine if there is 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

No studies were found matching the inclusion criteria.

Included studies

There were no included studies.

Excluded studies

There were no excluded studies.

Risk of bias in included studies

There were no included studies, so bias could not be evaluated.

Effects of interventions

There were no included studies, so effects could not be evaluated.

Discussion

Sulindac is a widely available NSAID, and oral sulindac is used to treat chronic painful conditions like arthritis. It is disappointing that no classical analgesic studies of efficacy of oral sulindac compared with placebo in patients with established pain have been published.

It is almost certain that such studies have been performed, as they would have been required for registration purposes. Previously, large numbers of unpublished trials of this design have been included in systematic reviews of tramadol (Moore 1997c), and large numbers of analgesic trials of many designs with dexketoprofen (Moore 2008). Obtaining unpublished clinical trial data is, however, a long and complicated process, made more difficult by drugs being older, and with original trial data hard to find.

We could find no reviews of the efficacy of sulindac in any painful condition, nor any reports of studies in pain since 1992 (Ahern 1992). Sulindac is currently being investigated for use in precancerous gastrointestinal polyps (Meyskens 2008), diabetic retinopathy (Hattori 2007), and control of preterm labour (Sawdy 2003).

Authors' conclusions

Implications for practice.

In the absence of evidence of efficacy for oral sulindac in acute postoperative pain, its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully.

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.

What's new

Date	Event	Description
29 May 2019	Amended	Contact details updated.
10 November 2010	Review declared as stable	The authors declare that there is unlikely to be any further studies to be included in this review and so it should be published as a 'stable review'.

Notes

The authors declare that there is unlikely to be any further studies to be included in this review and so it should be published as a 'stable review'.

Appendices

Appendix 1. MEDLINE search strategy (via OVID)

[mp=title, original title, abstract, name of substance word, subject heading word]

1     sulindac/ (1073)

2     sulindac*.mp. (1574)

3     (arthrobid or clinoril or arthrocine or klinoril or mk‐231 or mk 231 or mk231 or aclin or nu‐sulindac or nu sulindac or sulindal or chibret or novo‐sundac).mp. (61)

4     (Arthrocine or Artribid or Clinoril or Dorindac or Imbaral or Lyndak or Mk 231 or Mk231 or Sudac or Sulindac Sulfoxide or Sulindal).mp. (71)

5     (aclin or clinoril or saldac or apo‐sulin or novo‐sundac or arthrocine or aflodac or algocetil or citireuma or clinoril or lyndak or sulatrene or sulen or sulinol or bio‐dac or copal or kenalin or daclin or artribid or cenlidac).mp. (142)

6     1 or 2 or 3 or 4 or 5 (1681)

7     Pain, Postoperative/ (19630)

8     ((postoperative adj4 pain*) or (post‐operative adj4 pain*) or post‐operative‐pain* or (post* adj4 pain*) or (postoperative adj4 analgesi*) or (post‐operative adj4 analgesi*) or "post‐operative analgesi*").mp. (31472)

9     ((post‐surgical adj4 pain*) or ("post surgical" adj4 pain*) or (post‐surgery adj4 pain*)).mp. (160)

10     ("pain‐relief after surg*" or "pain following surg*" or "pain control after").mp. (370)

11     (("post surg*" or post‐surg*) and (pain* or discomfort)).mp. (610)

12     ((pain* adj4 "after surg*") or (pain* adj4 "after operat*") or (pain* adj4 "follow* operat*") or (pain* adj4 "follow* surg*")).mp. (1718)

13     ((analgesi* adj4 "after surg*") or (analgesi* adj4 "after operat*") or (analgesi* adj4 "follow* operat*") or (analgesi* adj4 "follow* surg*")).mp. (413)

14     or/7‐13 (32743)

15     exp Surgical Procedures, Operative/ (1835032)

16     14 or 15 (1847360)

17     randomized controlled trial.pt. (270902)

18     controlled clinical trial.pt. (79205)

19     randomized.ab. (180817)

20     placebo.ab. (112078)

21     drug therapy.fs. (1310207)

22     randomly.ab. (131272)

23     trial.ab. (188036)

24     groups.ab. (903955)

25     or/17‐24 (2392260)

26     humans.sh. (10721434)

27     25 and 26 (1952386)

28     27 and 6 and 16 (52)

Cochrane highly sensitive search strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision); Ovid format

1.  randomized controlled trial.pt.

2.  controlled clinical trial.pt.

3.  randomized.ab.

4.  placebo.ab.

5.  drug therapy.fs.

6.  randomly.ab.

7.  trial.ab.

8.  groups.ab.

9.  1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10.humans.sh.

11.9 and 10

Appendix 2. EMBASE search strategy (via OVID)

[mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]

1     sulindac/ (4842)

2     sulindac*.mp. (5323)

3     (arthrobid or clinoril or arthrocine or klinoril or mk‐231 or mk 231 or mk231 or aclin or nu‐sulindac or nu sulindac or sulindal or chibret or novo‐sundac).mp. (974)

4     (Arthrocine or Artribid or Clinoril or Dorindac or Imbaral or Lyndak or Mk 231 or Mk231 or Sudac or Sulindac Sulfoxide or Sulindal).mp. (712)

5     (aclin or clinoril or saldac or apo‐sulin or novo‐sundac or arthrocine or aflodac or algocetil or citireuma or clinoril or lyndak or sulatrene or sulen or sulinol or bio‐dac or copal or kenalin or daclin or artribid or cenlidac).mp. (704)

6     1 or 2 or 3 or 4 or 5 (5683)

7     Pain, Postoperative/ (19734)

8     ((postoperative adj4 pain*) or (post‐operative adj4 pain*) or post‐operative‐pain* or (post* adj4 pain*) or (postoperative adj4 analgesi*) or (post‐operative adj4 analgesi*) or "post‐operative analgesi*").mp. (38214)

9     ((post‐surgical adj4 pain*) or ("post surgical" adj4 pain*) or (post‐surgery adj4 pain*)).mp. (206)

10     ("pain‐relief after surg*" or "pain following surg*" or "pain control after").mp. (333)

11     (("post surg*" or post‐surg*) and (pain* or discomfort)).mp. (676)

12     ((pain* adj4 "after surg*") or (pain* adj4 "after operat*") or (pain* adj4 "follow* operat*") or (pain* adj4 "follow* surg*")).mp. (1593)

13     ((analgesi* adj4 "after surg*") or (analgesi* adj4 "after operat*") or (analgesi* adj4 "follow* operat*") or (analgesi* adj4 "follow* surg*")).mp. (391)

14     or/7‐13 (39306)

15     exp Surgical Procedures, Operative/ (1518942)

16     14 or 15 (1528414)

17     random*.ti,ab. (398413)

18     factorial*.ti,ab. (8318)

19     (crossover* or cross over* or cross‐over*).ti,ab. (39736)

20     placebo*.ti,ab. (110903)

21     (doubl* adj blind*).ti,ab. (85344)

22     (singl* adj blind*).ti,ab. (7530)

23     assign*.ti,ab. (109692)

24     allocat*.ti,ab. (34710)

25     volunteer*.ti,ab. (99811)

26     CROSSOVER PROCEDURE.sh. (21330)

27     DOUBLE‐BLIND PROCEDURE.sh. (72527)

28     RANDOMIZED CONTROLLED TRIAL.sh. (169143)

29     SINGLE BLIND PROCEDURE.sh. (8180)

30     or/17‐29 (666530)

31     ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/ (3463355)

32     HUMAN/ (6496483)

33     31 and 32 (542095)

34     31 not 33 (2921260)

35     30 not 34 (580485)

36     6 and 16 and 35 (65)

Search filter for EMBASE (Ovid format) 2008

1.  random*.ti,ab.

2.  factorial*.ti,ab. (5987)

3.  (crossover* or cross over* or cross‐over*).ti,ab.

4.  placebo*.ti,ab.

5.  (doubl* adj blind*).ti,ab.

6.  (singl* adj blind*).ti,ab.

7.  assign*.ti,ab.

8.  allocat*.ti,ab.

9.  volunteer*.ti,ab.

10.CROSSOVER PROCEDURE.sh.

11.DOUBLE‐BLIND PROCEDURE.sh.

12.RANDOMIZED CONTROLLED TRIAL.sh.

13.SINGLE BLIND PROCEDURE.sh.

14.or/1‐13

15.ANIMAL/ or NONHUMAN/ or ANIMAL EXPERIMENT/

16.HUMAN/

17.15 and 16

18.15 not 17

19.14 not 18

Appendix 3. CENTRAL search strategy (The Cochrane Library)

#1    MeSH descriptor Sulindac explode all trees

#2    (sulindac):ti,ab,kw

#3    (#1 OR #2)

#4    MeSH descriptor Pain, Postoperative explode all trees

#5    (postoperative near/4 pain*) or (post‐operative near/4 pain*) or post‐operative‐pain* or (post* near/4 pain*) or (postoperative near/4 analgesi*) or (post‐operative near/4 analgesi*) or "post‐operative analgesi*"

#6    (post‐surgical near/4 pain*) or ("post surgical" near/4 pain*) or (post‐surgery near/4 pain*)

#7    "pain‐relief after surg*" or "pain following surg*" or "pain control after"

#8    ("post surg*" or post‐surg*) and (pain* or discomfort)

#9    (pain* near/4 "after surg*") or (pain* near/4 "after operat*") or (pain* near/4 "follow* operat*") or (pain* near/4 "follow* surg*")

#10   (analgesi* near/4 "after surg*") or (analgesi* near/4 "after operat*") or (analgesi* near/4 "follow* operat*") or (analgesi* near/4 "follow* surg*")

#11   (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)

#12   #3 and #11

#13   Limit to CLINICAL TRIALS (CENTRAL)

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: For pain intensity, lines with left end labelled "no pain" and right end labelled "worst pain imaginable", and for pain relief lines with left end labelled "no relief of pain" and right end labelled "complete relief of pain", seem to overcome the limitation of forcing patient descriptors into particular categories. Patients mark the line at the point which corresponds to their pain or pain relief. 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).

Differences between protocol and review

There are no differences between the protocol and the review.

Contributions of authors

SD, and RAM performed searching and study selection. HJM acted as arbitrator. All review authors contributed to the writing of the protocol and contributed to the writing of the final review. SD will be responsible for any update of this review.

Sources of support

Internal sources

• Oxford Pain Research Funds, UK.

External sources

• NHS Cochrane Collaboration Grant, UK.

• European Union Biomed 2 Grant no. BMH4 CT95 0172, UK.

Declarations of interest

SD, RAM & HJM have received research support from charities, government and industry sources at various times, this work was supported by NHS Cochrane Collaboration Grant and NIHR Biomedical Research Centre Programme. 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')