Single dose dipyrone (metamizole) for acute postoperative pain in adults Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract Background

Dipyrone (metamizole) is a nonsteroidal anti‐inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in other countries because of an association with life‐threatening blood disorders. This review replaces a 2010 Cochrane review that has been withdrawn.

Objectives

To assess the analgesic efficacy and associated adverse events of single dose dipyrone for moderate to severe acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and LILACS to 11 August 2015; the Oxford Pain Relief Database; two clinical trial registries; and the reference lists of articles.

Selection criteria

We included randomised, double‐blind, placebo‐controlled trials of single dose dipyrone for relief of established moderate to severe postoperative pain in adults. We accepted oral, rectal, intramuscular, and intravenous routes of administration.

Data collection and analysis

Two review authors independently considered studies for inclusion in the review, assessed risk of bias, and extracted data. We used summed total pain relief or pain intensity difference (TOTPAR or SPID) over four to six hours to calculate the number of participants achieving at least 50% pain relief. From derived results, we calculated the risk ratio and number needed to treat for an additional beneficial outcome (NNT), with 95% confidence intervals (CI), for one participant to experience at least 50% pain relief over four to six hours compared to placebo. We looked at use of rescue medication and time to use of rescue medication as additional measures of efficacy. We also looked for information on adverse events and withdrawals.

Main results

We included eight studies, involving 809 participants, comparing oral dipyrone 500 mg (143 participants), oral dipyrone 1000 mg (57 participants), and intramuscular dipyrone 2000 mg (35 participants) with placebo (236 participants). In addition to placebo, all studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen; 338 participants). Seven studies used the oral route of administration, and one study used the intramuscular route. The mean age ranged from 23 to 62 years. Six studies included both men and women, and two studies included only women. All the studies were small, but were otherwise of moderate to good quality.

Over 70% of participants experienced our primary outcome of at least 50% pain relief over four to six hours with oral dipyrone 500 mg compared to 30% with placebo (five studies, 288 participants; NNT 2.4 (95% CI 1.8 to 3.1)) (moderate quality evidence). There were insufficient data to assess other doses or routes of administration of dipyrone.

Fewer participants needed rescue medication within four to six hours with dipyrone 500 mg than with placebo (7% with dipyrone versus 34% with placebo; four studies, 248 participants) (low quality evidence).

The data on numbers of participants experiencing any adverse event was inconsistently reported and no analysis was possible. No serious adverse events or adverse event withdrawals were reported (very low quality evidence).

There were too few data to compare dipyrone directly with other active treatments.

Authors' conclusions

Based on very limited information, a single dose of dipyrone 500 mg provides good pain relief to about 70% of people treated, compared to about 30% with placebo. For every five people given dipyrone 500 mg, two people would experience this level of pain relief over four to six hours who would not have done with placebo, and fewer people would need rescue medication.

We were unable to compare dipyrone directly with other active treatments, or to assess the effects of different doses or routes of administration, or the number of participants experiencing adverse events, because of insufficient data and inadequate reporting.

Author(s)

Leslie Hearn, Sheena Derry, R Andrew Moore

Abstract

Plain language summary

Single dose dipyrone for the treatment of acute postoperative pain

Bottom line

Dipyrone (metamizole) at a single oral dose of 500 mg produces acceptable pain relief in about 7 out of 10 people with moderate or severe acute pain.

Background

Acute pain is short lasting and often felt soon after injury. Most people who have surgery have moderate or severe pain afterwards. Painkillers (analgesics) are tested by giving them to people who are in pain, often following the removal of wisdom teeth or other minor surgery. This pain is usually treated with painkillers taken by mouth. Results can be applied to other types of acute pain. This is one of a series of Cochrane reviews looking at how good painkillers are.

Dipyrone is a popular medicine for pain relief in some countries and is used to treat postoperative pain, colic pain (sharp pain in the tummy), cancer pain, and migraine (severe headache). Other countries (Japan, UK, USA) have banned its use because of an association with potentially life‐threatening blood disorders such as agranulocytosis (deficiency of certain blood cells).

Study characteristics

We searched medical databases for studies of dipyrone used to treat pain following surgery in adults and compared with placebo (a pretend treatment). The medicines could be given by mouth, into a vein, into a muscle, or into the rectum. The evidence is current to 11 August 2015. We found eight studies, involving 809 participants treated with dipyrone, placebo, and various other painkillers. The studies were all small, but otherwise of moderate to good quality.

Key results

A single 500 mg dose of dipyrone provided effective pain relief (50% or more reduction in pain over four to six hours) for 7 in 10 (70%) participants, compared with 3 in 10 (30%) with placebo (five studies, 288 participants in the comparison; moderate quality evidence), and fewer participants need additional painkillers within four to six hours (7% with dipyrone, 34% with placebo; four studies, 248 participants; low quality evidence).

There were too few data to compare dipyrone directly with other painkillers.

There was too little information available to draw any conclusions about other doses and ways of giving dipyrone used in these studies, or about the number of people who had side effects. The studies reported no serious side effects or people withdrawing from the studies because of side effects, although not all studies provided information on these outcomes.

Author(s)

Leslie Hearn, Sheena Derry, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions

Implications for practice For people with acute postoperative pain

Dipyrone 500 mg taken by mouth provides good pain relief for about 7 in 10 people. We found little evidence for other doses or other routes of administration. This analysis was based on information from relatively few participants and the quantitative estimates were not robust; the results should be interpreted with caution. Use of dipyrone is banned or restricted in many countries because it has been associated with serious blood disorders, particularly agranulocytosis. Susceptibility to these adverse effects may vary between different populations, and the single dose studies used in this review are inadequate to assess adverse events.

For clinicians

Dipyrone 500 mg taken by mouth provides good pain relief for about 7 in 10 people. We found little evidence for other doses or other routes of administration. This analysis was based on information from relatively few participants and the quantitative estimates were not robust; the results should be interpreted with caution.

Use of dipyrone is banned or restricted in many countries because it has been associated with serious blood dyscrasias, particularly agranulocytosis. Susceptibility to these adverse effects may vary between different populations, and the single dose studies used in this review are inadequate to assess adverse events. While dipyrone may provide adequate analgesia, patients should be monitored for blood dyscrasias as recommended by the manufacturers, if resources allow. The short onset of agranulocytosis seen in case reports is cause for concern.

In many countries, other drugs for which more evidence exists are readily available, while in other countries, dipyrone may be one of only a few drugs available.

For policy makers

The potential for good levels of pain relief with dipyrone must be balanced against the potential for life‐threatening adverse effects in some people. The single dose studies used in this review were inadequate to assess adverse events properly, and in particular the serious blood disorders with which dipyrone is associated. In many countries, other drugs for which more evidence exists are readily available, while in other countries, dipyrone may be one of only a few drugs available.

The need for monitoring has implications for non‐prescription (over‐the‐counter) availability.

For funders

The potential for good levels of pain relief with dipyrone must be balanced against the potential for life‐threatening adverse effects in some people. The single dose studies used in this review were inadequate to assess adverse events properly. While dipyrone may provide adequate analgesia, patients should be monitored for blood disorders as recommended by the manufacturers, if resources allow.

Implications for research General

There were few studies that satisfied inclusion criteria for this review, so any results were not robust. Larger studies, with at least 200 participants, and studies using different doses and routes of administration of dipyrone, would be required to clarify its relative efficacy amongst other analgesics.

Information about uncommon, serious adverse events are best obtained from other study types, such as cohort and case‐control studies.

Design

The current design of acute pain studies is well understood, and has proven to be robust for assessing efficacy.

Measurement (endpoints)

Endpoints in these studies have been extensively validated, as have standard pain scoring systems. The main outcome used is one valued by patients with pain, and has economic benefits in most circumstances.

Comparison between active treatments

The standardised nature of the study design means that indirect comparisons with placebo are valid, as evidenced by independent research on the topic. However, there is a very large body of information amenable to network meta‐analysis. While unlikely to provide much in the way of new insights, it could prove an invaluable tool for testing network meta‐analytical methods.

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