Naproxen with or without antiemetic for acute migraine headaches in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to determine the efficacy and tolerability of naproxen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches 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 (on the order of 18% versus 6% 1‐year prevalence), and in the age range 30 to 50 years (Hazard 2009; Lipton 2007; Moens 2007).
The International Headache Society (IHS) classifies two major subtypes (IHS 2004). 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.
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; Hazard 2009; 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 has the potential to reduce the need for healthcare resources and increase economic productivity (Jhingran 1996; Lofland 1999).
Description of the intervention
Naproxen is an NSAID first marketed in the mid 1970s, with proven efficacy in acute (Derry 2009) and chronic (Moore 2010a; Moore 2010b) pain. It is a propionic acid derivative (of the same family as ibuprofen), with analgesic, anti‐inflammatory and antipyretic properties. It has been widely used in treating arthritis, menstrual cramps, gout, sprains and strains, and a variety of other acute pain conditions. Naproxen and its soluble sodium salt are commonly available as 250 mg and 500 mg tablets (275 mg and 550 mg of sodium salt). In many parts of the world it remains a prescription‐only drug, but in others such as the US, UK and most parts of Canada, it is available OTC in restricted doses.
OTC medications are less expensive, more accessible and tend to have favourable safety profiles relative to many prescription treatments, although naproxen causes more serious gastrointestinal adverse events than ibuprofen, for example (Hernandez‐Diaz 2000). Naproxen may be a useful alternative for OTC migraine headache treatment in individuals who do not tolerate or respond to other OTC medication such as aspirin and ibuprofen.
In order to establish whether naproxen is an effective analgesic at a specified dose in acute migraine headaches, 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 headache 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. Naproxen inhibits both COX isoforms. Suppression of prostaglandin synthesis is believed to underlie the analgesic effects of naproxen.
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 intravenous metoclopramide alone can reduce pain in severe migraine attacks (Friedman 2005; 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 headaches with naproxen plus an antiemetic is in any way superior to treatment with naproxen alone. In a recent review of aspirin with or without an antiemetic for acute migraine (Kirthi 2010), aspirin plus metoclopramide was significantly better than aspirin alone for headache relief and relief of nausea at 2 hours, but not pain‐free at 2 hours or 24‐hour outcomes.
Why it is important to do this review
We could find no comprehensive systematic review of naproxen for acute migraine headaches in adults. Naproxen has proven efficacy in a variety of acute pain situations, is widely available and relatively 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 this review is to determine the efficacy and tolerability of naproxen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised, double‐blind, placebo‐ or active‐controlled studies using naproxen to treat a migraine headache episode. Studies must have a minimum of 10 participants per treatment arm and report dichotomous data for at least one of the outcomes specified below. We will accept studies reporting treatment of consecutive headache episodes if outcomes for the first, or each, episode are reported separately; first‐attack data will be used preferentially. Cross‐over studies will be accepted if there is adequate washout (≥ 48 hours) between treatments.
Types of participants
Studies must include adults (at least 18 years of age) with migraine. We will use the diagnosis of migraine specified by the International Headache Society (IHS 1988; IHS 2004), although we will consider other definitions if they conform in general to IHS diagnostic criteria. There will be no restrictions on migraine frequency, duration or type (with or without aura). We will accept studies that include participants taking stable prophylactic therapy to reduce the frequency of migraine attacks; details on any 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 naproxen to treat a 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 restrictions on dose or route of administration, provided the medication is self‐administered.
Included studies may use either naproxen alone, or naproxen plus an antiemetic. The antiemetic must be taken either combined with naproxen in a single formulation, or separately not more than 30 minutes before naproxen, and must be self‐administered.
A placebo comparator is essential to demonstrate that naproxen is effective in this condition. Active‐controlled trials without a placebo will be considered as secondary evidence. We will not include studies designed to demonstrate prophylactic efficacy in reducing the number or frequency of migraine headaches.
Types of outcome measures
Primary outcomes
We selected the main outcome measures for this review by taking into consideration scientific rigour, availability of data and patient preferences (Lipton 1999). Patients with acute migraine headaches 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 are:
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Pain‐free at 2 hours, without the use of rescue medication;
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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);
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Sustained pain‐free during 24 hours (pain‐free within 2 hours, with no use of rescue medication or recurrence within 24 hours);
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Sustained pain reduction during 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 must be measured by the patient (not the investigator or carer). Pain measures accepted for the primary outcomes are:
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Pain intensity (PI): 4‐point categorical scale, with wording equivalent to none, mild, moderate and severe; or 100 mm VAS, where < 30 mm will be considered equivalent to mild or no pain and ≥ 30 mm equivalent to moderate or severe pain (Collins 1997);
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Pain relief (PR): 5‐point categorical scale, with wording equivalent to none, a little, some, a lot, complete; or 100 mm VAS, where < 30 mm will be considered equivalent to none or a little, and ≥ 30 mm equivalent to some, a lot or complete.
We will consider only data obtained directly from the patient.
Secondary outcomes
Secondary outcomes to be considered include:
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Use of rescue medication;
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Participants with any adverse event during 24 hours post‐dose;
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Participants with particular adverse events during 24 hours post‐dose;
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Withdrawals due to adverse events during 24 hours post‐dose;
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Relief of headache‐associated symptoms;
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Functional disability.
Search methods for identification of studies
Electronic searches
We will search the following electronic databases:
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Cochrane CENTRAL;
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MEDLINE (via Ovid);
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EMBASE (via Ovid);
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Oxford Pain Relief Database (Jadad 1996a).
See Appendix 1 for the search strategy for MEDLINE (via OVID). We will modify this as required for searching the other databases. There will be no language restrictions.
Searching other resources
We will search for additional studies in reference lists of retrieved studies and review articles, and in two clinical trials databases (www.clinicaltrials.gov and www.gsk‐clinicalstudyregister.com). We will not search grey literature and short abstracts.
Data collection and analysis
Selection of studies
Two review authors will independently carry out the searches and select studies for inclusion. We will view the titles and abstracts of all studies identified by electronic searches on screen and exclude any that clearly do not satisfy inclusion criteria. We will read full copies of the remaining studies 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 form. Disagreements will be settled by discussion with a third review author. One author will enter data into RevMan 5.1.
Assessment of risk of bias in included studies
We will assess methodological quality using the Oxford Quality Score (Jadad 1996b).
The scale is used as follows.
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Is the study randomised? If yes, give one point.
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Is the randomisation procedure reported and is it appropriate? If yes, add one point; if no, deduct one point.
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Is the study double blind? If yes, add one point.
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Is the double blind method reported and is it appropriate? If yes, add one point; if no, deduct one point.
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Are the reasons for patient withdrawals and dropouts described? If yes, add one point.
We will report the scores for each study in the 'Characteristics of included studies' table.
We will also complete a 'Risk of bias' table for each study, using assessments of random sequence generation, allocation concealment, blinding and size.
Measures of treatment effect
We will use relative risk (or 'risk ratio', RR) to establish statistical difference. Numbers needed to treat (NNT) and pooled percentages will be used 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 naproxen than with control (placebo or active) we will use the term the number needed to treat to prevent one event (NNTp).
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When significantly more adverse outcomes occur with naproxen 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 cross‐over studies; where possible in such cases only first‐period data will be used.
For all outcomes we will carry out analyses, as far as possible, on a modified intention‐to‐treat basis, i.e. we will include all participants who were randomised and received an intervention. Where sufficient information is reported, we will re‐include missing data in the analyses we undertake. We will exclude data from outcomes where data from ≥ 10% of participants are missing with no acceptable reason provided or apparent.
Assessment of heterogeneity
We will assess heterogeneity of studies visually (L'Abbe 1987). We will not pool data from studies that are clinically heterogeneous. Where data can be pooled, we will report the I2 statistic.
Assessment of reporting biases
We will assess publication bias by examining the number of participants in trials with zero effect (relative risk of 1.0) needed for the point estimate of the NNT to increase beyond a clinically useful level (Moore 2008). In this case, we specify a clinically useful level as an NNT of ≥ 8 for pain‐free at 2 hours, and NNT ≥ 6 for headache relief at 2 hours.
Data synthesis
We will analyse studies using a single dose of naproxen in established pain of at least moderate intensity separately from studies in which medication is taken before pain was well established or in which a second dose of medication is permitted.
We will calculate effect sizes and combine data for analysis only for comparisons and outcomes where there are at least two studies and 200 participants (Moore 1998). If only one study on relevant outcomes in at least 200 participants is available, prohibiting combining of data for analysis, we will provide a summary of data on relevant outcomes. We will calculate relative risk of benefit or harm 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). We will assume a statistically significant difference from control when the 95% CI of the relative risk of benefit or harm does not include the number one.
We will use the z test (Tramer 1997) to determine significant differences between NNT, NNTp and NNH for different groups in subgroup and sensitivity analyses.
Subgroup analysis and investigation of heterogeneity
Issues for potential subgroup analysis are dose, monotherapy versus combination with an antiemetic, route of administration and formulation. For combined treatment with an antiemetic, we will compare different antiemetics 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.
