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Ibuprofen with or without an antiemetic for acute migraine in adults

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The objective of the review will be to determine the efficacy and tolerability of ibuprofen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine in adults.

Background

Description of the condition

Migraine is a common, disabling headache disorder, affecting about 12% of Western populations, and with considerable social and economic impact. It is more prevalent in women than men (18% versus 6%), and in the age range 30 to 50 years (Hazard 2009; Lipton 2007; Moens 2007).

The International Headache Society (IHS) classifies two major subtypes. Migraine without aura is the most common, and usually more disabling, subtype. It is characterised by attacks lasting 4 to 72 hours that are typically of moderate to severe pain intensity, unilateral, pulsating, aggravated by normal physical activity and associated with nausea and/or photophobia and phonophobia. Migraine with aura is characterised by reversible focal neurological symptoms that develop over a period of 5 to 20 minutes and last for less than 60 minutes, followed by headache with the features of migraine without aura. In some cases the headache may lack migrainous features or be absent altogether (IHS 2004).

A recent large prevalence study in the US found that over half of migraineurs had severe impairment or required bed rest during attacks. Despite this high level of disability and a strong desire for successful treatment, only a proportion of migraine sufferers seek professional advice for the treatment of attacks. The majority were not taking any preventive medication, although one‐third met guideline criteria for offering or considering it. Nearly all (98%) migraineurs used acute treatments for attacks, with 49% using over‐the‐counter (OTC) medication only, 20% using prescription medication, and 29% using both. OTC medication included aspirin, other non‐steroidal anti‐inflammatory drugs (NSAIDs), paracetamol (acetaminophen) and paracetamol with caffeine (Bigal 2008; Diamond 2007; Lipton 2007). Similar findings have been reported from other large studies in France and Germany (Lucas 2006; Radtke 2009).

The significant impact of migraine with regard to pain, disability, social functioning, quality of relationships, emotional well‐being and general health (Edmeads 1993; Osterhaus 1994; Solomon 1997) results in a huge burden for the individual, health services and society (Clarke 1996; Ferrari 1998; Hu 1999; Solomon 1997). The annual US economic burden relating to migraine, including missed days of work and lost productivity, is US$14 billion (Hu 1999). Thus successful treatment of acute migraine attacks not only benefits patients by reducing their disability and improving health‐related quality of life, but also reduces the need for healthcare resources and increases economic productivity (Jhingran 1996; Lofland 1999).

Description of the intervention

Ibuprofen is an effective and well tolerated NSAID which has been available as an OTC medication in the UK and US for 25 years. Ibuprofen is a propionic acid derivative with analgesic, anti‐inflammatory and antipyretic properties. It has been widely used in treating arthritis, dental pain, menstrual cramps and a variety of other acute pain conditions. OTC medications are less expensive, more accessible and have favourable safety profiles relative to many prescription treatments. Ibuprofen is an attractive candidate for OTC migraine treatment.

In order to establish whether ibuprofen is an effective analgesic at a specified dose in acute migraine, it is necessary to study its effects in circumstances that permit detection of pain relief. Such studies are carried out in individuals with established pain of moderate to severe intensity, using single doses of the interventions. Participants who experience an inadequate response with either placebo or active treatment are permitted to use rescue medication, and the intervention is considered to have failed in those individuals. In clinical practice, however, individuals would not normally wait until pain is of at least moderate severity, and may take a second dose of medication if the first dose does not provide adequate relief. Once analgesic efficacy is established in studies using single doses in established pain, further studies may investigate different treatment strategies and patient preferences. These are likely to include treating the migraine early while pain is mild, and using a low dose initially, with a second dose if response is inadequate.

How the intervention might work

NSAIDs act by inhibiting the activity of cyclooxygenase (COX), now recognised to consist of two isoforms (COX‐1 and COX‐2), which catalyses the production of prostaglandins responsible for pain and inflammation. Ibuprofen inhibits both COX isoforms. Suppression of prostaglandin synthesis is believed to underlie the analgesic effects of ibuprofen.

The efficacy of oral medications is reduced in many migraineurs because of impaired gastrointestinal motility, which is associated with nausea, and because of non‐absorption of the drug due to vomiting (Volans 1974). The addition of an antiemetic may improve outcomes by alleviating the often incapacitating symptoms of nausea and vomiting, and (at least potentially) by enhancing the bioavailability of the co‐administered analgesic. In particular, prokinetic antiemetics such as metoclopramide, which stimulate gastric emptying, may improve outcomes by increasing absorption of the analgesic. This has been investigated for metoclopramide and aspirin (Ross‐Lee 1983; Volans 1975). It has been claimed that treatment with metoclopramide alone can reduce pain in severe migraine (Salazar‐Tortolero 2008), but this claim requires further investigation, since metoclopramide has not been shown to be an analgesic in classical pain studies. The present review will seek to determine whether treatment of acute migraine with ibuprofen plus an antiemetic is in any way superior to treatment with ibuprofen alone.

Why it is important to do this review

Population surveys show that ibuprofen is frequently used to treat migraine headaches, but we could find no systematic review of the efficacy of this intervention in adults. Ibuprofen has proven efficacy in a variety of acute pain situations, is widely available and inexpensive, and it is important to know where it fits in the range of therapeutic options for migraine therapy. For many migraineurs, non‐prescription therapies offer convenience, and may be the only therapies available or affordable.

Objectives

The objective of the review will be to determine the efficacy and tolerability of ibuprofen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine in adults.

Methods

Criteria for considering studies for this review

Types of studies

Randomised, double‐blind, placebo‐controlled studies using ibuprofen to treat a discrete migraine headache episode will be included. Studies must have a minimum of 10 participants per treatment arm and report dichotomous data for at least one of the outcomes specified below. Studies reporting treatment of consecutive headache episodes will be accepted if outcomes for the first, or each, episode are reported separately. Crossover studies will be accepted if there is adequate washout between treatments.

Types of participants

Studies must include adults (at least 18 years of age) with migraine. The diagnosis of migraine specified by the International Headache Society (IHS 1988; IHS 2004) will be used, although other definitions will be considered if they conform in general to IHS diagnostic criteria. There will be no restrictions on migraine frequency, duration or type (with or without aura). Participants taking stable prophylactic therapy to reduce migraine frequency will be accepted; details on the prophylactic therapy prescribed or allowed will be provided in the 'Characteristics of included studies' table.

Types of interventions

Included studies must use either a single dose of ibuprofen to treat a discrete migraine headache episode when pain is of moderate to severe intensity, or investigate different dosing strategies and/or timing of the first dose in relation to headache intensity. There will be no restriction on dose, or route of administration, provided the medication is self‐administered.

Included studies may use either ibuprofen alone, or ibuprofen plus an antiemetic. The antiemetic must be taken either combined with ibuprofen in a single formulation, or separately not more than 30 minutes before ibuprofen, and must be self‐administered.

A placebo comparator is essential to demonstrate that ibuprofen is effective in this condition. Active‐controlled trials without a placebo will be considered as secondary evidence. Studies to demonstrate prophylactic efficacy in reducing the number or frequency of migraine headaches will not be included.

Types of outcome measures

Primary outcomes

The choice of main outcome measures for this review was made by taking into consideration scientific rigour, availability of data and patient preferences (Lipton 1999). Patients with acute migraine have rated complete pain relief, no headache recurrence, rapid onset of pain relief, and no side effects as the four most important outcomes (Lipton 1999).

In view of these patient preferences, and in line with the guidelines for controlled trials of drugs in migraine issued by the IHS (IHS 2000), the main outcomes to be considered will be:

  • Pain‐free at 2 hours, without the use of rescue medication;

  • Reduction in headache pain ('headache relief') at 1 and 2 hours (pain reduced from moderate or severe to none or mild without the use of rescue medication);

  • Sustained pain‐free over 24 hours (pain‐free within 2 hours, with no use of rescue medication or recurrence within 24 hours);

  • Sustained pain reduction over 24 hours (headache relief at 2 hours, sustained for 24 hours, with no use of rescue medication or a second dose of study medication).

Pain intensity or pain relief should be measured by the patient (not the investigator or carer). Pain measures accepted for the primary outcomes will be:

  • Pain intensity (PI): 4‐point categorical scale, with wording equivalent to none, mild, moderate and severe; or 100 mm VAS;

  • Pain relief (PR): 5‐point categorical scale, with wording equivalent to none, a little, some, a lot, complete; or 100 mm VAS.

Only data obtained directly from the patient will be considered.

Secondary outcomes

Secondary outcomes considered will include:

  • Participants with any adverse event over 24 hours post dose;

  • Participants with particular adverse events over 24 hours post dose;

  • Withdrawals due to adverse events over 24 hours post dose;

  • Relief of headache‐associated symptoms;

  • Functional disability.

Search methods for identification of studies

Electronic searches

The following electronic databases will be searched:

  • Cochrane CENTRAL;

  • MEDLINE (via Ovid);

  • EMBASE (via Ovid);

  • Oxford Pain Relief Database (Jadad 1996a).

See Appendix 1 for the search strategy for MEDLINE (via OVID). This will be modified for searching the other databases. There will be no language restrictions.

Searching other resources

Reference lists of retrieved studies and review articles will be searched for additional studies. Grey literature and abstracts will not be searched.

Data collection and analysis

Selection of studies

Two review authors will independently carry out the searches and select studies for inclusion. Titles and abstracts of all studies identified by electronic searches will be viewed on screen, and any that clearly do not satisfy inclusion criteria will be excluded. Full copies of the remaining studies will be read to identify those suitable for inclusion. Disagreements will be settled by discussion with a third review author.

Data extraction and management

Two review authors will independently extract data from included studies using a standard data extraction from. Disagreements will be settled by discussion with a third review author. Data will be entered into RevMan 5.0 by one author.

Assessment of risk of bias in included studies

Methodological quality will be assessed using the Oxford Quality Score (Jadad 1996b).

The scale is used 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, 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 scores for each study will be reported in the 'Characteristics of included studies' table.

A risk of bias table will also be completed, using assessments of randomisation, allocation concealment and blinding.

Measures of treatment effect

Relative risk (or 'risk ratio', RR) will be used to establish statistical difference. Numbers needed to treat (NNT) and pooled percentages will be used as absolute measures of benefit or harm.

The following terms will be used to describe adverse outcomes in terms of harm or prevention of harm:

  • When significantly fewer adverse outcomes occur with ibuprofen than with control (placebo or active) we will use the term the number needed to treat to prevent one event (NNTp).

  • When significantly more adverse outcomes occur with ibuprofen compared with control (placebo or active) we will use the term the number needed to harm or cause one event (NNH).

Unit of analysis issues

We will accept randomisation to individual patient only.

Dealing with missing data

The most likely source of missing data is in crossover studies. Where this is an issue only first‐period data will be used.

Assessment of heterogeneity

Heterogeneity of studies will be assessed visually (L'Abbe 1987).

Data synthesis

Studies using a single dose of ibuprofen in established pain of at least moderate intensity will be analysed separately from studies in which medication is taken before pain is well established or in which a second dose of medication is permitted.

Data will be combined for analysis where there are at least two studies and 200 participants (Moore 1998). Relative risk of benefit or harm will be calculated with 95% confidence intervals (CIs) using a fixed‐effect model (Morris 1995). NNT, NNTp and NNH with 95% CIs will 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 risk of benefit or harm includes the number one.

Significant differences between NNT, NNTp and NNH for different doses of active treatment, or between groups in the sensitivity analyses, will be determined using the z test (Tramer 1997).

Subgroup analysis and investigation of heterogeneity

Issues for subgroup analysis are dose, monotherapy or combination with an antiemetic, formulation, and route of administration. For combined treatment with an antiemetic, different antiemetics will be compared if there are sufficient data.

Sensitivity analysis

Sensitivity analysis is anticipated for study quality (Oxford Quality Score of 2 versus 3 or more), and for migraine type (with aura versus without aura). A minimum of two studies and 200 participants must be available for any sensitivity analysis.