Abstract
Background
This is an updated version of the original Cochrane review published in Issue 4, 2004. Indometacin is a non‐steroidal anti‐inflammatory drug (NSAID) used most commonly for the treatment of inflammation and pain resulting from rheumatic disease (arthritis), and less commonly in postoperative pain management. When taken for chronic pain conditions, indometacin has been associated with a high incidence of adverse events. The benefits and harms of orally‐administered indometacin for postoperative pain are not clear.
Objectives
To determine the efficacy of a single dose of oral indometacin compared with placebo in treating acute postoperative pain in adults, and to analyse information relating to adverse events.
Search methods
We searched the Cochrane CENTRAL Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies in January 2002 and for the updated search in December 2007. Additional studies were sought from the reference lists of retrieved studies.
Selection criteria
Studies were included in the review if they were randomised, double blind, placebo‐controlled clinical trials using a single oral dose of indometacin in adults with acute postoperative pain.
Data collection and analysis
Studies were assessed independently by two review authors. Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of participants with at least 50% pain relief over four to six hours. The relative benefit for at least 50% pain relief was calculated.
Main results
In the original review one study of 59 women with post‐episiotomy pain met the inclusion criteria. The dose of indometacin assessed against placebo was 50 mg, and the results concluded that indometacin was not significantly better than placebo for relieving postoperative pain at four to six hours. There was insufficient information to conduct further efficacy analyses or assess adverse events. No further studies were identified in the update of this review.
Authors' conclusions
Conclusions about the clinical efficacy of indometacin for postoperative pain cannot be made unless more studies are conducted for a variety of surgical procedures, and different doses of indometacin are assessed. Since the last version of this review no new relevant studies have been identified.
Plain language summary
Indometacin in use as a single dose for treating acute postoperative pain
Indometacin is a non‐steroidal anti‐inflammatory drug (NSAID) used for treating postoperative pain. This review found only one small study of women with post‐episiotomy pain where the effectiveness of the drug (taken by mouth) was compared with a placebo. Conclusions about the effectiveness of orally administered indometacin cannot be made until more studies are undertaken.
Background
This is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 4, 2004) on 'Single dose indometacin for the treatment of acute postoperative pain'.
Indometacin (indomethacin) is a non‐steroidal anti‐inflammatory drug (NSAID) used most commonly for the treatment of inflammation and pain resulting from rheumatic disease. Indometacin is also used to treat inflammation, pain and oedema following orthopaedic procedures (Martindale 1999), and is the first line of treatment for some rare forms of headache such as chronic paroxysmal hemicrania (CPH) and episodic paroxysmal hemicrania (Pareja 2001). Indometacin is also used for treating acute attacks of gout. Indometacin is less commonly used to treat acute postoperative pain, and data on the frequency of indometacin administration in postoperative pain management is not available.
For the treatment of chronic pain, the maximum recommended daily oral dose of indometacin is 200 mg, and a relatively high incidence of adverse events has been associated with its use compared with other NSAIDs. The most commonly reported of these are gastrointestinal disturbances (including ulceration, bleeding and diarrhoea), headache and dizziness (Martindale 1999). Less common effects include drowsiness, insomnia, convulsions, psychiatric disturbances, hypertension, hyperglycaemia, peripheral neuropathy and intestinal strictures (BNF 2006). These adverse events may be less likely to occur if indometacin is taken over a comparatively short period of time, for the treatment of postoperative pain.
The postoperative pain period is often dominated by the need to find effective ways of blocking the inflammatory reaction and relieving pain (Salvato 1992). In one US study, postsurgical pain was the leading cause of concern in 57% of patients before surgery (Warfield 1995). This concern is not misplaced. A survey of 5150 newly‐discharged NHS patients in UK hospitals showed that 61% suffered pain, which was present all or most of the time in one third of cases (Bruster 1994). A recent, extensive review of postoperative pain management found that severe pain, and poor or fair pain relief, was experienced by 20% of hospital patients (Dolin 2002). Some believe that aggressive treatment of acute pain may reduce further complications, notably progression to chronic pain states (Coda 2001). Therefore, since inadequately managed pain is associated with adverse consequences, it is important to assess the efficacy of available treatments.
No other systematic review of the effectiveness of orally administered indometacin for postoperative pain has been undertaken. The results from this review of studies of indometacin versus placebo help to establish the evidence‐base for the use of indometacin for postoperative pain relief and could also enable the relative efficacy of indometacin compared to other NSAIDs to be determined.
Objectives
To determine the efficacy of a single dose of oral indometacin in treating acute postoperative pain in adults, compared with placebo.
To examine the data in included studies relating to adverse events.
To examine, where possible, evidence for the duration of action of indometacin for relieving postoperative pain.
Methods
Criteria for considering studies for this review
Types of studies
Studies were included if their design met all of the following criteria:
randomised, double blind trial in which participants received either oral indometacin or a matched placebo;
the study contained extractable, patient‐reported, single dose pain intensity or pain relief information;
the study provided pain intensity or pain relief data, or both, recorded over four to six hours using standard pain assessment scales;
the study recruited a minimum of ten participants randomly assigned to a treatment or placebo group.
Abstracts, review articles, case reports and clinical observations were considered acceptable only if they contained evaluable data. Pharmaceutical companies and individual authors were not contacted for unpublished reports.
Types of participants
Adults (aged 12 and older) who experienced moderate to severe pain following any surgical procedure, carried out in either a day surgery or in‐patient setting.
Types of interventions
Postoperative, oral administration of a single dose of indometacin (at any dose) or a matched placebo.
Types of outcome measures
The primary outcome measures were:
either patient‐reported pain relief or pain intensity, measured using validated pain scales.
The scales used were either the five‐point pain relief (PR) scale with standard or comparable wording, or the four‐point pain intensity (PI) scale or a 10 cm visual analogue scale (VAS) for pain relief or pain intensity. Global evaluations of "good" or "excellent" pain relief over four to six hours were also acceptable, if measured on a standard five‐point scale by the participant and not the investigator.
Secondary outcome measures were:
the number of participants remedicating following the initial dose and the mean or median time to remedication;
the number of participants reporting any adverse event including particular adverse events such as headache or vomiting;
the reasons for participant discontinuation or withdrawal from the study.
Search methods for identification of studies
Electronic databases The following electronic databases were searched:
Cochrane CENTRAL (Issue 2, 2004 for original review and Issue 4, 2007 for the update);
MEDLINE and Pre‐MEDLINE from 1966 to December 2002 for the original review, and MEDLINE from January 2002 to December 2007 for the update;
EMBASE from 1980 to December 2002 for the original review and January 2002 to December 2007 for the update;
the Oxford Pain Relief database (handsearch records for the years 1954 to 1995 (Jadad 1996a).
For an example of the MEDLINE search strategy which was adapted for other databases searched please see Appendix 1.
Reference lists of retrieved reports were also manually searched.
Language Relevant studies were sought regardless of language of publication.
Handsearching All in‐house randomised controlled trials (RCTs) databases (including hand searched studies) at the Oxford Pain Research Unit were searched for the years 1954 to 1995 (Jadad 1996a). No additional hand searching was conducted for this review.
Unpublished studies Neither pharmaceutical companies nor individual authors were contacted for unpublished studies.
Data collection and analysis
Selection of studies Potential studies were located and independently assessed by two review authors. (Disputes as to whether a study met the selection criteria would have been settled by discussion between all review authors). Reasons for excluding studies from the review were documented, and can be seen in the 'Characteristics of excluded studies' table.
Data extraction From each included study we intended to extract:
number of participants randomised to a treatment group;
treatment dose;
participant characteristics (sex, age, type of surgery);
baseline pain intensity;
mean TOTPAR (total pain relief) or mean SPID, or both, (summed pain intensity difference);
study duration;
information on adverse events;
number of participants remedicating and time to remedication;
reasons for participant withdrawal and number of withdrawals.
Data synthesis It was our intention to analyse study data for the number of participants randomised to each arm of the included studies as follows: Mean TOTPAR (total pain relief) or mean SPID (summed pain intensity difference) over four to six hours was to be extracted, or calculated from pain data provided by each included study. These data would be converted into %maxTOTPAR or %maxSPID (the percentage of the maximum possible total pain relief or summed pain intensity), using verified equations (Cooper 1991; Moore 1996; Moore 1997a; Moore 1997b). This data would be used to calculate the number of participants in each study with at least 50% pain relief for both indometacin and placebo. From this, number‐needed‐to‐treat‐to‐benefit (NNTB) with 95% confidence intervals (CI) could be calculated (Cook 1995). Relative benefit estimates with 95% CI could also be calculated using the fixed‐effect model (Morris 1995) in Review Manager (version 4.2.10). A statistically significant benefit of the active treatment over placebo would be assumed when the upper limit of the 95% CI of the relative benefit was greater than one.
Intention to treat analysis Participants for whom no outcome data were available (withdrawals, protocol violators, etc) were computed as 'available case analysis', as described in the Cochrane Handbook (Higgins 2006). Only data for known results are included, with the denominator being the total number of participants who completed the trial for the outcome being assessed.
Results
Description of studies
Twenty‐seven potential studies were identified from the search. Twenty‐six were excluded for the following reasons:
eight studies did not use a placebo comparison, (Aromaa 1978; Commisionat 1983; Katsuta 1981; Kurita 1991; Nishikii 1987; Ono 1979; Sasaki 1984; Van der Aa 1984);
six used topical (Assouline 1998) or rectal administration of indometacin (Engel 1989; Nissen 1992; Pavy 1990; Sadiq 1998; Segstro 1990)
four had no extractable analgesic efficacy data (Saggio 1985) or no four to six hour data (Asp 1974; Ohnishi 1983; Watanabe 1968);
three studies were not randomised (Gallardo 1990 (duplicate study also identified); Gutierrez 1971; Mehnert 1979);
two had no single dose data (Jaakkola 1976; Peterson 1975);
two did not measure baseline pain (Hynninen 2000; Poikkeus 1989);
one used inappropriate pain scales (Honig 1982).
Full details can be seen in the 'Characteristics of excluded studies' table.
One study (94 participants in total, 29 treated with indometacin) met the inclusion criterion (Harrison 1992) in the original searches. No further studies were identified in the updated searches.
Risk of bias in included studies
The quality of the included study was assessed using a methodological quality assessment tool devised for pain studies by Jadad 1996b. The tool comprises assessment of three aspects of quality (randomisation, blinding and consideration of study withdrawals/dropouts) and is scored as follows:
Assessment questions Question 1: was the study described as randomised (this includes the use of words such as randomly, random and randomisation)? Question 2: was the study described as double‐blind? Question 3: was there a description of withdrawals and drop outs?
Scoring Either give a score of one point for each 'yes' or 0 points for each 'no'. No in‐between marks can be allocated.
Give one additional point if
for question one the method to generate the sequence of randomisation was described and it was appropriate (table of random numbers, computer generated, coin tossing, etc);
and/or
for question two the method of double‐blinding was described and it was appropriate (identical placebo, active placebo, dummy, etc).
Deduct one point if
for question one the method to generate the sequence of randomisation was described and it was inappropriate (participants were allocated alternately, or according to date of birth, hospital number, etc);
and/or
for question two the study was described as double‐blind but the method of blinding was inappropriate (e.g., comparison of tablet versus injection with no double dummy).
Notes on the scoring system Randomisation A method to generate the sequence of randomisation is regarded as appropriate if the method allows each study participant to have the same chance of receiving each intervention and the investigators cannot predict which treatment is next. Methods of allocation using date of birth, date of admission, hospital numbers or alternation are not regarded as appropriate.
Double‐blinding A study is regarded as double‐blind if the word double‐blind is used. The method is regarded as appropriate if it is stated that neither the person doing the assessments nor the study participant can identify the intervention being assessed or if, in the absence of such a statement, the use of active placebos, identical placebos or dummies is mentioned.
Withdrawals and drop outs Participants who were included in the study but did not complete the observation period or who were not included in the analysis must be described. The number and the reasons for withdrawal must be stated. If there were no withdrawals, it should be stated in the article. If there is no statement on withdrawals, this item must be given no points.
Quality of included study The methodological quality of the included study was scored independently by two review authors, and the study achieved a score of two points out of a possible five, receiving one point each for randomisation and double blinding.
Effects of interventions
One small study of 94 women who experienced moderate to severe pain following episiotomy met the inclusion criteria for this review in the original searches, and no further studies were identified for the update. Only 29 participants were treated with indometacin, and 30 with placebo. The lack of studies meant that there were insufficient data to conduct a meta‐analysis, and it was not possible to assess the mean time to remedication, or the adverse effects of single dose oral indometacin.
The results of the included study are summarised as follows:
Indometacin 50 mg versus placebo The number of participants with at least 50% pain relief at six hours was 20 out of 29 (69%) for indometacin and 16 out of 30 (53%) for placebo. There was therefore no significant difference between treatment and placebo (Relative Risk 1.3, 95% CI 0.85 to 1.96). The NNTB was not calculated. Adverse events and withdrawals Only adverse events related to the gastrointestinal tract were recorded in the included study. The number of participants reporting any adverse event was four out of 29 participants receiving indometacin 50 mg, and one out of 30 participants receiving placebo. The severity or specific nature of these events were not reported. There was one withdrawal in the indometacin 50 mg arm of the study and 15 in the placebo group. The reasons why participants withdrew from the study were not stated.
Discussion
Only one small study met the inclusion criteria for this review, and showed that indometacin 50 mg was no better than placebo for the treatment of acute postoperative pain (Relative Risk 1.3, 95% CI 0.85 to 1.96). However, this study was limited in terms of quality and size, and therefore validity. Due to the random play of chance, small studies report results that are often unreliable (Moore 1998) and therefore conclusions about the clinical efficacy of indometacin cannot be drawn from the available evidence. Efficacy can be determined only if more, high quality studies using indometacin become available. However, it is unlikely that such studies will be performed since indometacin is one of the older NSAIDs on the market; newer, safer, and efficacious NSAIDs have since been developed.
It was not possible to analyse adverse events due to lack of information. When prescribed for chronic pain conditions, indometacin use is associated with many adverse events, more than most other NSAIDs. Accurate reporting of adverse events in studies using indometacin for acute postoperative pain should be a priority. Unfortunately, poor reporting of adverse events is common in acute pain studies (Edwards 1999).
Authors' conclusions
Implications for practice.
The update of this review has not identified any further information to provide evidence for or against the use of Single dose oral indometacin for the treatment of acute postoperative pain. Until more information becomes available, it is not possible to make recommendations about the use of single dose oral indometacin for the relief of postoperative pain.
Implications for research.
More information is needed to accurately determine the efficacy of indometacin in postoperative pain. Better reporting of information in clinical trials using indometacin is required. Appropriate trial methods are needed to obtain information about adverse events and participant withdrawals, and these need to be reported consistently in individual trials. However, it is unlikely that such studies will be performed since indometacin is one of the older NSAIDs on the market; newer, safer, and efficacious NSAIDs have since been developed.
What's new
| Date | Event | Description |
|---|---|---|
| 29 May 2019 | Amended | Contact details updated. |
History
Protocol first published: Issue 3, 2003 Review first published: Issue 4, 2004
| Date | Event | Description |
|---|---|---|
| 24 September 2010 | Amended | Contact details updated. |
| 4 July 2010 | Amended | Contact details updated. |
| 12 November 2008 | Amended | Contact details updated |
| 26 June 2008 | Review declared as stable | The review authors consider that additional relevant studies are unlikely to be conducted, and that further updates of this review are unnecessary. |
| 28 May 2008 | Amended | Converted to new review format. |
| 14 December 2007 | New citation required but conclusions have not changed | Further studies satisfying our inclusion criteria were sought in MEDLINE (via Ovid), EMBASE (via Ovid) and Cochrane CENTRAL from January 2002 to December 2007. No further studies were identified, so the conclusions of the review are unchanged. |
| 14 December 2007 | New search has been performed | Review search updated |
Notes
The review authors believe that, having considered the evidence and the topic area that additional relevant studies are unlikely to be conducted, and that further updates of this review are unnecessary.
Acknowledgements
The work is supported by Pain Research funds from the Oxford Pain Relief Trust and the NHS Cochrane Collaboration Programme Grant Scheme.
Appendices
Appendix 1. MEDLINE search strategy
Search strategy in MEDLINE 1. indomethacin [single term MeSH] 2. indometacin 3. OR/1‐2 4. PAIN, POSTOPERATIVE [single term MeSH] 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$) or ("post‐operative analgesi$")) [in title, abstract or keywords] 6. ((post‐surgical adj4 pain$) or ("post surgical" adj4 pain$) or (post‐surgery adj4 pain$)) [in title, abstract or keywords] 7. (("pain‐relief after surg$") or ("pain following surg$") or ("pain control after")) [in title, abstract or keywords] 8. (("post surg$" or post‐surg$) AND (pain$ or discomfort)) [in title, abstract or keywords] 9. ((pain$ adj4 "after surg$") or (pain$ adj4 "after operat$") or (pain$ adj4 "follow$ operat$") or (pain$ adj4 follow$ surg$")) [in title, abstract or keywords] 10. ((analgesi$ adj4 "after surg$") or (analgesi$ adj4 "after operat$") or (analgesi$ adj4 "follow$ operat$") or (analgesi$ adj4 follow$ surg$")) 11. OR/5‐10 12. randomized controlled trial.pt. 13. controlled clinical trial.pt. 14. randomized controlled trials.sh. 15. random allocation.sh. 16. double‐blind method.sh. 17. single blind method.sh. 18. clinical trial.pt. 19. exp clinical trials/ 20. (clin$ adj25 trial$).ti,ab. 21. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,ab. 22. placebos.sh. 23. placebo$.ti,ab. 24. random$.ti,ab. 25. research design.sh. 26. OR/12‐25 27. 3 AND 11 AND 26
Data and analyses
Comparison 1. Participants with 50% pain reduction.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Indometacin 50 mg | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only |
1.1. Analysis.
Comparison 1 Participants with 50% pain reduction, Outcome 1 Indometacin 50 mg.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Harrison 1992.
| Methods | RCT, DB, 3 parallel groups, oral administration, moderate to severe baseline pain, assessments at 0, 0.5, 1, 2, 3, 4, 5 and 6 hours | |
| Participants | n = 94 Mean age: Indometacin group = 22 years Placebo group = 24 years All females with post medio‐lateral episiotomy pain | |
| Interventions | indometacin 50 mg + etham sylate 500 mg: n = 35 indometacin 50 mg: n = 29 placebo: n = 30 | |
| Outcomes | pain relief 5 point scale
pain intensity 4 point scale
global 5 point scale 6 hour SPID: indometacin = 7.0 placebo = 5.6 50% pain relief at 6 hours: indometacin = 20/29 placebo = 16/30 |
|
| Notes | Only gastro‐intestinal adverse events reported;
indometacin = 4/29
placebo = 1/30 QS R = 1 DB = 1 W/E = 0 Total = 2/5 |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Aromaa 1978 | No placebo arm in the study |
| Asp 1974 | No 4 to 6 hour efficacy data |
| Assouline 1998 | Topical formulation of indomethacin |
| Commisionat 1983 | No placebo arm in the study |
| Engel 1989 | Rectal administration of indomethacin |
| Gallardo 1990 | Participants not randomised to treatment/placebo arms |
| Gutierrez 1971 | Participants not randomised to treatment/placebo arms |
| Honig 1982 | Non‐standard pain scales |
| Hynninen 2000 | Baseline pain not assessed |
| Jaakkola 1976 | No single dose data |
| Katsuta 1981 | No placebo arm in the study |
| Kurita 1991 | No placebo arm in the study |
| Mehnert 1979 | Participants not randomised to treatment/placebo arms |
| Nishikii 1987 | No placebo arm in the study |
| Nissen 1992 | Rectal administration of indomethacin |
| Ohnishi 1983 | No 4 to 6 hour efficacy data |
| Ono 1979 | No placebo arm in the study |
| Pavy 1990 | Rectal administration of indomethacin |
| Peterson 1975 | No single dose data |
| Poikkeus 1989 | No baseline pain measurement |
| Sadiq 1998 | Rectal suppository administered pre‐operatively |
| Saggio 1985 | No extractable pain data |
| Sasaki 1984 | No placebo arm in the study |
| Segstro 1990 | Rectal administration of indomethacin |
| Van der Aa 1984 | No placebo arm in the study |
| Watanabe 1968 | No 4 to 6 hour efficacy data |
Contributions of authors
Original review LM: involved with searching, data extraction, analysis and writing. JR: involved with data extraction, analysis and writing. AM and HJM were involved with the analysis and writing.
Update 2008 SD and AM carried out the searching and writing.
Sources of support
Internal sources
Pain Research Unit Funds, Oxford, UK.
External sources
NHS Cochrane Collaboration Programme Grant Scheme, UK.
Declarations of interest
LM and SD have no interests to declare. RAM has been a consultant for MSD. RAM and HJM have consulted for various pharmaceutical companies. RAM, HJM and JR have received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions. All authors have received research support from charities, government and industry sources at various times: no such support was received for this work.
Stable (no update expected for reasons given in 'What's new')
References
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