Caffeine as an analgesic adjuvant for acute pain in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the relative efficacy of a single dose of analgesic plus caffeine against the same dose of analgesic alone, without restriction on the analgesic used or the pain condition studied. Serious adverse events will be examined.
Background
Description of the condition
Caffeine is added to a variety of basic analgesics that are used to treat a broad range of common painful conditions. We plan to include information from any acute painful condition, with the most commonly studied likely to be headache, postpartum pain, and postoperative pain.
Description of the intervention
Caffeine is a naturally occurring compound found in the seeds, leaves, and fruit of many plants, where it is thought to function as a natural pesticide. It has a long (at least 5000 year) history of human consumption in the form of beverages such as tea and coffee, and foodstuffs such as chocolate. Caffeine intake varies widely among individuals and populations, but can be broadly divided into low (< 100 mg/day), moderate (100 to 400 mg/day), and high intake (> 400 mg/day), with the majority of people falling within the moderate intake range. Common sources of caffeine today include coffee (100 to 150 mg/mug), tea (75 mg/mug), cola drinks (up to 40 mg/drink), energy drinks (approximately 80 mg/drink), plain chocolate (up to 50 mg/bar), and caffeine tablets (100 mg/tablet). Some "high‐energy" drinks have the caffeine content of five or six coffees.
Caffeine is a methylxanthine that is known to act as a central nervous system stimulant. It has a wide range of physiological effects in humans (Sawynok 1993) including increased wakefulness, alertness, endurance, heart rate and blood pressure, and is regarded as a psychostimulant (i.e. enhances mood; Donovan 2001).
An adjuvant in this context is an agent that enhances the effects of a drug while having few if any direct effects when given by itself. There have been several reports of an intrinsic antinociceptive effect of caffeine from preclinical studies in rodents, but in general, only at very high doses of 50 mg/kg or more (Sawynok 2011a). A recent Cochrane review examined the use of high dose caffeine (300 mg) following post‐dural puncture headache; there were very few data (Basurto Ona 2011, full review in press). Caffeine at dietary levels is not usually regarded as an analgesic in its own right in humans. Caffeine has been included as a constituent of both over‐the‐counter and prescription analgesic combinations for many years, based on the idea that it enhances analgesic efficacy.
The evidence supporting caffeine as a useful analgesic adjuvant has always been somewhat limited, with only a handful of often small studies providing any direct evidence of enhanced analgesia with a caffeine‐analgesic combination compared with the same analgesic alone. Randomised studies that have attempted to answer this question by comparing analgesic plus caffeine with the same dose of the analgesic alone have produced mixed results, with some showing a clear benefit with addition of caffeine (Laska 1983; Migliardi 1994) and others showing no significant analgesic effect (Forbes 1990; McQuay 1996). An ongoing problem is that a large number of clinical trials have only been published in part, as part of systematic reviews, without full publication or clinical trials reports made available; in one review (Laska 1984) only four of 30 studies had previously been published. With only a relatively small benefit shown in some studies, this makes any estimate of adjuvant efficacy particularly susceptible to publication bias from unpublished studies with no effect.
It is possible that part of the reason for these mixed results is differing efficacy in different clinical pain models: for example it is suggested that caffeine may be a useful adjuvant in headache, but not postsurgical pain (Sawynok 2011a; Sawynok 2011b). Another complication is the fact that several studies, including some that are often cited as supporting the addition of caffeine to analgesics, attempt to draw their conclusions from comparisons of an analgesic plus caffeine with a different dose of the analgesic, or even a completely different analgesic (Jain 1978; Schachtel 1991 (in a trial of headache)).
A small number of reviews have attempted systematically to investigate the effect of adding caffeine to individual commonly used analgesics, including paracetamol (Palmer 2010; Zhang 1996), aspirin (Zhang 1997), and ibuprofen (Li Wan Po 1998). The three reviews published in the 1990's failed to provide any conclusive evidence for an analgesic adjuvant effect with any of these three drugs. The most recent review (Palmer 2010) did demonstrate a marginal benefit of paracetamol and caffeine over paracetamol alone.
To add to the confusion, several preclinical studies have reported that very low doses of caffeine (i.e. lower than those that may exhibit adjuvant analgesic effects) actually inhibit antinociception by several agents (Sawynok 2011b), raising the possibility that dietary caffeine might interfere with the analgesic efficacy of some treatments.
How the intervention might work
The mechanisms by which caffeine may contribute to, or enhance the efficacy of other analgesics are not well understood. It is known to be a competitive antagonist of adenosine A1 and A2 receptors at plasma concentrations observed through normal dietary caffeine intake (in the 10 to 100 μM range). Many of the putative mechanisms of action are thought of in terms of this disruption of normal adenosine signalling. Proposed mechanisms of action include (Renner 2007; Sawynok 1993; Zhang 2001):
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Improved drug absorption through lower gastric pH and increased gastric blood flow.
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Reduced metabolic clearance of drugs through reduced hepatic blood flow.
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Blockade of peripheral pro‐nociceptive adenosine signalling, and activation of the central noradenosine pathway (i.e. pain‐suppressing systems).
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Transcriptional downregulation of cyclo‐oxygenase‐2 (COX‐2), via blockade of the adenosine A2a receptor.
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Relief of inhibitor adenosine actions on central cholinergic nerve terminals.
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Changes in mood and emotional state contributing to changes in the perception of pain.
Why it is important to do this review
Caffeine has been added to a large number of analgesics for years on the basis of a kind of inherited wisdom from a small number of trials showing an enhanced analgesic effect of combinations including caffeine. However, this is not the full story as some of these studies do not compare like with like, and there have been at least as many studies published suggesting no additional effect when caffeine is added. It is important to try to resolve this confusion to inform best clinical practice.
One of the major problems faced in trying to demonstrate an analgesic adjuvant effect of caffeine is the relatively small magnitude of this effect compared with normal variation in the course of an individual patient's pain and in the responses of different patients to the same analgesic, as noted 30 years ago (Beaver 1984). Many of the studies carried out have simply been underpowered to expose a statistically significant difference in treatment effects of analgesic plus caffeine versus the analgesic alone (Moore 1998). Meta‐analyses, in which data from individual comparisons are pooled, are an important tool for showing up these small effects that individual trials, on the whole, are unable to demonstrate. This methodology has been used successfully in the past to demonstrate a statistical superiority of high dose aspirin, ibuprofen, or paracetamol over low doses of the same drug (McQuay 2007).
This review provides an opportunity to systematically apply the same methodology, pooling individual comparison data wherever possible, to investigate the possible analgesic adjuvant effect of caffeine.
Objectives
To assess the relative efficacy of a single dose of analgesic plus caffeine against the same dose of analgesic alone, without restriction on the analgesic used or the pain condition studied. Serious adverse events will be examined.
Methods
Criteria for considering studies for this review
Types of studies
Studies will be included if they are double blind trials comparing a single dose of oral analgesic plus caffeine with the same dose of the analgesic alone for the treatment of acute pain in adults. Studies must have a minimum of ten participants randomly allocated to each treatment group and report some measure of patient‐reported pain relief.
We will include studies using multiple doses to treat a single episode only if appropriate data from the first dose are available. We will include cross‐over studies and studies reporting treatment of consecutive episodes (e.g. consecutive migraine attacks) in pain conditions which result in comparable, recurrent, acute pain episodes, such as migraine. We will use first dose only data where possible, but data from both phases of a cross‐over, or consecutive phases for recurrent conditions, will be accepted if there is adequate washout (at least 48 hours pain‐ and medication‐free between phases).
Types of participants
Studies must include adult participants (at least 16 years of age) with any acute painful condition. We will not include studies of experimental pain in healthy volunteers. Participants will ideally have moderate to severe pain, but mild to moderate pain will be accepted.
Types of interventions
Included studies must use a single dose of oral analgesic plus caffeine to treat an acute painful episode. The analgesics we are particularly interested in are paracetamol, ibuprofen, aspirin, diclofenac, naproxen, oxycodone, ergotamine, and the triptans, although studies using other analgesics will not be excluded. There will be no restriction on dose of analgesic or caffeine.
In order to investigate the effect of caffeine on the efficacy of the analgesic with which it is combined, it is essential that the comparator is the same drug and dose as the combination, minus caffeine.
Types of outcome measures
We will collect data on the type of painful condition and baseline pain intensity.
Primary outcomes
We will consider the following primary outcomes:
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The number of participants with at least 50% of maximum pain relief at 4 to 6 hours;
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The number of participants rating their treatment as "very good" or "excellent" on a five‐point categorical patient global evaluation of treatment (PGE) scale with the wording "poor, fair, good, very good, excellent" (or equivalent);
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The number of participants achieving a self‐defined clinically meaningful level of pain relief;
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The number of participants with headache relief at 2 hours.
In many postsurgical studies the outcome of "at least 50% of maximum pain relief at 4 to 6 hours" will have to be transformed from group‐mean pain measures, as described in the 'Data Synthesis' section.
In the full review, we will report the pain measures used in the included studies and be as explicit as possible about how we transformed data from the various scales to the dichotomous outcomes specified above.
Only data obtained directly from the patient will be considered (physician, nurse or carer reported pain will not be included in the analysis).
Secondary outcomes
Although single dose studies in acute pain are generally underpowered to assess safety and tolerability and cannot provide information on repeat dosing strategies, we will consider serious adverse events.
Search methods for identification of studies
Electronic searches
We will search the following 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). 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. We know of a number of unpublished trials using a caffeine analgesic combination, and will contact the manufacturers to try to determine the extent of, and obtain, any unpublished data. Internet searches will be carried out to identify any studies or study results that may have been reported to agencies such as the Food and Drug Administration (FDA).
Grey literature and short 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. We will obtain full copies of the remaining studies to identify those suitable for inclusion, and will settle any disagreements by discussion with the 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 the third review author. One review 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.
The scores for each study will be reported in the 'Characteristics of included studies' table.
We will also complete a risk of bias table, using assessments of randomisation, allocation concealment, blinding, and size.
Measures of treatment effect
We will use relative risk, calculated using a fixed‐effect model, to determine statistical difference between treatment groups, and number needed to treat to benefit (NNT) to provide an absolute measure of treatment effect. See 'Data Synthesis' section for details.
Unit of analysis issues
We will accept randomisation to individual patient only.
Dealing with missing data
Any studies with substantial missing data (more than 10% of treated participants excluded from the final analysis) will be included, but we will perform sensitivity analyses to investigate any bias they may confer on the results. This is particularly relevant to cross‐over studies reporting completer analyses, in which multiple successive attacks are treated. In these studies, participants are excluded from the efficacy analyses after taking an initial dose simply because they do not have a sufficient number of qualifying pain episodes (e.g. separate migraine attacks) to complete the cross‐over study. Where provided, we will use first‐period only data from cross‐over studies to avoid the need for sensitivity analyses, but we do not intend to exclude studies from the review because of exclusions from the analysed population, unless there is clear evidence of bias between treatment groups.
Assessment of heterogeneity
We will assess heterogeneity of studies visually (L'Abbe 1987).
Assessment of reporting biases
Unpublished studies in this field are known to exist, as demonstrated in the summary by Laska et al. (Laska 1984) which analysed data from 30 clinical trials ‐ of which only four have been published in full. Obtaining unpublished studies, many of which were conducted 25 or more years ago, from the pharmaceutical companies sponsoring them is extremely unlikely at this stage. It is therefore difficult to make any meaningful assessment of reporting bias, and results must be interpreted with caution, with the knowledge that some degree of reporting bias is likely. We are aware of a number of unpublished studies, and are working to obtain permission to use data from them.
We will assess the number of trials of average size amongst the included studies, with a relative benefit of one (no effect), needed to reduce any statistically significant result to one that fails to meet statistical significance (following Moore 2008).
Data synthesis
Where possible, we will use dichotomous data to calculate relative risk (RR) of benefit with 95% confidence intervals (CIs) using a fixed‐effect model (Morris 1995). We will calculate NNT with 95% CIs using the pooled number of events by the method of Cook and Sackett (Cook 1995). A statistically significant difference from control is assumed when the 95% CI of the RR of benefit or harm does not include the number one.
Many studies are likely to provide data on pain measures using:
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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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Visual analogue scale (VAS) for pain relief;
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VAS for pain intensity.
These pain measures will then be summed over a 4 to 6 hour period to generate a measure of total pain relief (TOTPAR) or summed pain intensity difference (SPID) over this time period.
Where only non‐dichotomous, mean data are reported, we will transform them into dichotomous data using standardised methods. Any mean TOTPAR, SPID, VAS TOTPAR or VAS SPID values will be converted to %maxTOTPAR or %maxSPID by division into the calculated maximum value (Cooper 1991). The proportion of participants in each treatment group achieving at least 50%maxTOTPAR will be calculated using verified equations (Moore 1996; Moore 1997a; Moore 1997b), and these proportions converted into the number of participants achieving at least 50%maxTOTPAR by multiplying by the total number of participants in the treatment group. Information on the number of participants with at least 50%maxTOTPAR for the analgesic plus caffeine and the analgesic alone will then be used to calculate estimates of RR and NNT as before.
We will test for significant differences between groups in sensitivity analyses using the z test (Tramer 1997).
Subgroup analysis and investigation of heterogeneity
Data for different analgesics and pain conditions will be analysed separately where there are sufficient data (minimum of two studies and 200 participants).
Sensitivity analysis
We plan to carry out sensitivity analyses for dose of caffeine (< 65 mg versus ≥ 65 mg), methodological quality (2 versus ≥ 3 on the Oxford Quality Scale), baseline pain intensity (mild versus ≥ moderate), size (< 50 versus ≥ 50 participants in each treatment arm), and attrition (≤ 10% versus > 10%), where there are sufficient data (minimum of two studies and 200 participants). If possible, we will also try to ascertain whether any adjuvant effect of caffeine depends on the particular analgesic drug with which it is combined, and will investigate whether analgesic effect size with analgesic drug alone affects any adjuvant effects of caffeine through limiting the upside sensitivity of the analgesic assay (Cooper 1991).
