Single dose dipyrone (metamizole) for acute postoperative pain
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and adverse effects of a single dose of dipyrone for acute postoperative pain using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes.
Background
Description of the condition
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 to 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. The series covers all analgesics licensed for acute postoperative pain in the UK, and dipyrone (metamizole) because it is commonly used in Spain, Portugal, and Latin‐American countries. The results have been examined in an overview (Moore 2011a). This new review of dipyrone replaces the original review, which has been withdrawn and replaced with an up‐to‐date protocol (Derry 2010).
Description of the intervention
Dipyrone is a non‐steroidal anti‐inflammatory drug (NSAID). It was first synthesised in 1920 in Germany, and the drug was launched there in 1922. NSAIDs have pain‐relieving, antipyretic, and anti‐inflammatory properties, and have proven efficacy following day surgery and minor surgery. The usual adult dose of dipyrone is 1.0 to 2.5 mg daily, when given orally. It is also available for intravenous, intramuscular, or rectal administration.
Dipyrone is a controversial analgesic. It is used most commonly to treat postoperative pain, colic pain, cancer pain, and migraine, and in many countries (for example, Russia, Spain, Mexico, and in many parts of South America, Asia, and Africa) it remains a popular non‐opioid first‐line analgesic, either by prescription only, as in Germany and Spain, or over the counter. In others it has been banned (for example, the USA, UK, Japan, Canada, and parts of Europe and Scandinavia) because of its association with potentially life‐threatening blood dyscrasias such as agranulocytosis. In countries where it is banned it may still be available and widely used by immigrant populations (Bonkowsky 2002). It is sold under many different brand names, including Analgin and Novalgin, and is also known in some areas as 'Mexican aspirin'. In addition to use as a single agent, it is commonly used in combination products.
There is a wealth of literature on agranulocytosis associated with dipyrone: a large, international study found vastly differing rates of agranulocytosis in the 11 countries in which information was collected (IAAAS 1986). There are a number of published criticisms of this study (Kramer 1988). None of these criticisms mention the importance of size (of the population studied and the analyses) for detecting true incidence rates for rare events. Size is an important criterion of study validity (Moore 1998). A report from Sweden suggested a rate of 1 case of agranulocytosis in 1439 prescriptions (Hedenmalm 2002), although there may be differences between populations in their susceptibility to agranulocytosis (Mérida Rodrigo 2009). A case‐control study in Berlin identified 10 probable dipyrone‐induced cases (of 63 drug‐related cases) of agranulocytosis between 2000 and 2010, more than for any other drug (Huber 2014). A review of non‐chemotherapy drug‐induced agranulocytosis identified dipyrone in six definite and five probable high quality case reports, with a median time to onset of only two days (Andersohn 2007). While the risk of agranulocytosis remains uncertain (Edwards 2002), dipyrone is one of the 10 drugs most commonly associated with it (Andersohn 2007).
The use of dipyrone has been reported to be associated with other potentially serious adverse events such as chronic interstitial nephritis and gastrointestinal disturbances (Zukowski 2009), as well as allergic/idiosyncratic reactions like anaphylaxis, bronchospasm, and toxic epidermal necrolysis (Arellano 1990). A review of hospital admissions for adverse drug reactions in Brazil identified 20 dipyrone‐related admissions over an eight‐month period (Lobo 2013).
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 comparison (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 four to six hours for shorter‐acting drugs, and over 12 to 24 hours for longer‐acting drugs. Pain relief of half the maximum possible 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 of this has been shown to be negligible over four to six hours (Moore 2005). Patients usually remain in the hospital or clinic for at least the first six hours following the intervention, with measurements supervised, although they may then be allowed home to make their own measurements in trials of longer duration.
How the intervention might work
NSAIDs have pain‐relieving, antipyretic, and anti‐inflammatory properties, and are thought to relieve pain by inhibiting cyclo‐oxygenases (prostaglandin endoperoxide synthase) and thus the production of prostaglandins (Hawkey 1999). Prostaglandins occur throughout body tissues and fluids and act to stimulate pain nerve endings and inhibit the aggregation of blood platelets. Dipyrone, and some of its active metabolites, may also act by directly blocking ongoing inflammatory hypersensitisation (hyperalgesia).
Inhibition of prostaglandin production may be involved with some of the known problems associated with NSAIDs, including gastrointestinal, cardiovascular, renal, and hypertensive adverse effects (FitzGerald 2001; Hawkey 1999; Hawkey 2002; Patrono 2009).
Why it is important to do this review
Although use of dipyrone is banned or restricted in many countries, it remains a drug of choice in others. It is important that information about its benefits and harms is carefully reviewed and made available to a world‐wide audience.
Objectives
To assess the efficacy and adverse effects of a single dose of dipyrone 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
We will include double‐blind studies of a single dose of dipyrone 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. We will include multiple dose studies, if appropriate data from the first dose are available, and cross‐over studies, provided that data from the first arm are presented separately.
We will exclude the following:
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review articles, case reports, and clinical observations;
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studies of experimental pain;
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studies where pain relief is assessed only by clinicians, nurses, or carers (ie not patient‐reported);
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studies of less than four hours duration or studies that fail to present data over four to six hours post dose.
For postpartum pain, we will include studies if the pain investigated is due to episiotomy or Caesarean section, irrespective of the presence of uterine cramps; we will exclude studies investigating pain due to uterine cramps alone.
Types of participants
We will include studies of adult participants (15 years or older) with established postoperative pain of moderate to severe intensity following day surgery or in‐patient surgery. For studies using a visual analogue scale (VAS), we will assume that pain intensity of greater than 30/100 mm equates to pain of at least moderate intensity (Collins 1997).
Types of interventions
Dipyrone, administered as a single dose, compared with matched placebo, administered postoperatively for pain relief. Where studies have also included an active comparator we will extract data for direct comparison. We will include oral, rectal, intravenous, and intramuscular routes of administration.
Types of outcome measures
We will collect the following data where available.
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Participant characteristics.
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Dose and route of administration.
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Patient‐reported pain at baseline (physician, nurse, or carer‐reported pain was not included in the analysis).
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Patient‐reported pain relief expressed at least hourly over four to six hours using validated pain scales (pain intensity and pain relief in the form of VAS or categorical scales, or both).
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Patient global assessment of efficacy (PGE), using a standard categorical scale.
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Time to use of rescue medication.
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Number of participants using rescue medication.
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Number of participants with one or more adverse events.
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Number of participants with serious adverse events.
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Number of withdrawals (all‐cause, adverse events).
Primary outcomes
Participants achieving at least 50% of maximum pain relief over four to six hours.
Secondary outcomes
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Median (or mean) time to use of rescue medication.
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Number of participants using rescue medication.
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Number of participants with: any adverse event; any serious adverse event (as reported in the study); withdrawal due to an adverse event.
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Other withdrawals: withdrawals for reasons other than lack of efficacy (participants using rescue medication).
Search methods for identification of studies
Electronic searches
We will search the following databases.
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The Cochrane Central Register of Controlled Trials (CENTRAL; latest issue).
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MEDLINE (via OVID).
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EMBASE (via OVID).
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LILACS (via VHL).
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Oxford Pain Relief Database (Jadad 1996a).
See Appendix 1 for the MEDLINE search strategy. We will not limit the searches by language or date.
Searching other resources
We will search for additional studies in reference lists of the earlier Cochrane review, retrieved articles, and other reviews, and in two clinical trials databases (clinicaltrials.gov and apps.who.int/trialsearch/).
Data collection and analysis
Selection of studies
Two review authors will independently assess and agree the search results for studies to be included in the review. Disagreements will be resolved by consensus or referral to a third review author.
Data extraction and management
Two review authors will extract data and record them on a standard data extraction form. One review author will enter data suitable for pooling into RevMan 5.3 (RevMan 2014).
Assessment of risk of bias in included studies
Two review authors will independently assess each study for methodological quality using a three‐item, five‐point scale (Jadad 1996b).
We will also complete a 'Risk of bias' table, using methods adapted from those described by the Cochrane Pregnancy and Childbirth Group. Two authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), with any disagreements resolved by discussion. We will assess the following for each study.
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Random sequence generation (checking for possible selection bias). We will assess the method used to generate the allocation sequence as: low risk of bias (ie any truly random process, eg random number table; computer random number generator); unclear risk of bias (when the method used to generate the sequence is not clearly stated). We will exclude studies at a high risk of bias that use a non‐random process (eg odd or even date of birth; hospital or clinic record number).
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Allocation concealment (checking for possible selection bias). We will assess the method used to conceal allocation to interventions prior to assignment as to whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We will assess the methods as: low risk of bias (eg telephone or central randomisation; consecutively numbered, sealed, opaque envelopes); unclear risk of bias (when the method is not clearly stated); and high risk of bias (open random allocation; unsealed or non‐opaque envelopes; alternation; date of birth).
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Blinding of outcome assessment (checking for possible detection bias). We will assess the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We will consider studies to be at low risk of bias if they state that they are blinded and describe the method used to achieve blinding (eg identical tablets; matched in appearance and smell); or at unclear risk of bias if they state that they are blinded, but do not provide an adequate description of how this is achieved. We will exclude single‐blind and open studies at a high risk of bias.
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Size (checking for possible biases confounded by small size). Small studies have been shown to overestimate treatment effects, probably due to methodological weaknesses (Nuesch 2010). We will consider studies to be at low risk of bias if they have 200 participants or more; at unknown risk of bias if they have 50 to 200 participants; and at high risk of bias if they have fewer than 50 participants.
Measures of treatment effect
We will use risk ratio (RR) to establish statistical difference. We will use numbers needed to treat (NNT) and pooled percentages as absolute measures of benefit or harm.
We will use the following terms to describe adverse outcomes in terms of harm or prevention of harm.
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When significantly fewer adverse outcomes occur with treatment than with control (placebo or active), we use the term the number needed to treat to prevent one event (NNTp).
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When significantly more adverse outcomes occur with treatment compared with control (placebo or active), we use the term the number needed to harm or cause one event (NNH).
Unit of analysis issues
We will accept only randomisation of the individual patient.
Dealing with missing data
The only likely issue with missing data in these studies is from imputation using last observation carried forward when a patient requests rescue medication. We have previously shown that this does not affect results for up to six hours after taking study medication (Barden 2004).
Assessment of heterogeneity
We will examine heterogeneity visually using L'Abbé plots (L'Abbé 1987), a visual method for assessing differences in results of individual studies, and with the I2 statistic.
Assessment of reporting biases
We will assess publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean a NNT of 10 or higher) (Moore 2008).
Data synthesis
For efficacy analyses, we will use the number of participants in each treatment group who were randomised, received medication, and provided at least one post‐baseline assessment. For safety analyses, we will use the number of participants randomised to each treatment group who took the study medication. We plan to analyse for different doses separately.
For each study, we will convert the mean TOTPAR, SPID, VAS TOTPAR, or VAS SPID (Appendix 2) values for active and placebo to %maxTOTPAR or %maxSPID by division into the calculated maximum value (Cooper 1991), and we will calculate the proportion of participants in each treatment group who achieved at least 50%maxTOTPAR using verified equations (Moore 1996; Moore 1997a; Moore 1997b). We will then convert these proportions into the number of participants achieving at least 50%maxTOTPAR by multiplying by the total number of participants in the treatment group.
We will use dichotomous information on the number of participants with an outcome of interest in the active and placebo groups to calculate the RR with 95% confidence intervals (CI), using a fixed‐effect model (Morris 1995). We will assume a statistically significant difference from control when the 95% CI of the RR does not include the number '1'. We will calculate NNT and NNH with 95% CIs using the pooled number of events using the method devised by Cook and Sackett (Cook 1995).
We will accept the following pain measures for the calculation of TOTPAR or SPID.
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Five‐point categorical pain relief (PR) scales with comparable wording to 'none, slight, moderate, good or complete'.
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Four‐point categorical pain intensity (PI) scales with comparable wording to 'none, mild, moderate, severe'.
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VAS for pain relief.
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VAS for pain intensity.
If none of these measures is available, we will use 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' for the number of participants achieving at least 50% pain relief (Collins 2001).
Subgroup analysis and investigation of heterogeneity
We will analyse separately the data for different routes of administration. We plan subgroup analyses to determine the effect of dose and presenting condition (pain model: dental versus other postoperative pain).
Sensitivity analysis
We plan sensitivity analyses for quality score (two versus three or more) and trial size (39 or fewer versus 40 or more per treatment arm).
A minimum of two studies and 200 participants will have to be available in any subgroup or sensitivity analysis (Moore 1998), which will be restricted to the primary outcome (50% of maximum pain relief over four to six hours) and the dose with the greatest amount of data. We will determine significant differences between NNT or NNH for different groups in subgroup and sensitivity analyses using the z test (Tramèr 1997).
