Pregabalin for pain in fibromyalgia in adults
This review updates part of an earlier Cochrane review on 'Pregabalin for acute and chronic pain in adults' (Moore 2009), and considers only fibromyalgia pain.
Antiepileptic drugs have been used in pain management since the 1960s. Pregabalin is an antiepileptic drug also used in management of chronic pain conditions, including fibromyalgia. Pain response with pregabalin is associated with major benefits for other symptoms, and improved quality of life and function in people with chronic painful conditions.
To assess the analgesic efficacy and adverse events of pregabalin for pain in fibromyalgia in adults, compared with placebo or any active comparator.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE for randomised controlled trials from inception to May 2009 for the original review and to 16 March 2016 for this update. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries.
We included randomised, double‐blind trials of eight weeks' duration or longer, comparing pregabalin with placebo or another active treatment for relief of pain in fibromyalgia, and reporting on the analgesic effect of pregabalin, with subjective pain assessment by the participant.
Data collection and analysis
Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with moderate pain relief (at least 30% pain relief over baseline or much or very much improved on Patient Global Impression of Change scale (PGIC)) or substantial pain relief (at least 50% pain relief over baseline or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and number needed to treat (NNT), using standard methods. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables.
Our searches identified two new published studies with classic design, and one new published study with an enriched enrolment randomised withdrawal (EERW) design.
We included eight studies. Five (3283 participants) had a classic design in which participants were randomised at the start of the study to pregabalin (150, 300, 450, or 600 mg daily) or placebo, with assessment after 8 to 13 weeks of stable treatment. No studies included active comparators. Studies had low risk of bias, except that the last observation carried forward (LOCF) imputation method used in analyses of the primary outcomes could overestimate treatment effect.
Pregabalin increased the number of participants experiencing substantial benefit (at least 50% pain intensity reduction after 12 or 13 weeks' stable treatment (450 mg: RR 1.8, 95% CI 1.4 to 2.1, 1874 participants, 5 studies, high quality evidence)). Substantial benefit with pregabalin 300 to 600 mg was experienced by about 14% of participants with placebo, but about 9% more with pregabalin 300 to 600 mg (22% to 24%) (high quality evidence). Pregabalin increased the number of participants experiencing moderate benefit (at least 30% pain intensity reduction after 12 or 13 weeks' stable treatment) (450 mg: RR 1.5, 95% CI (1.3 to 1.7), 1874 participants, 5 studies, high quality evidence). Moderate benefit with pregabalin 300 to 600 mg was experienced by about 28% of participants with placebo, but about 11% more with pregabalin 300 to 600 mg (39% to 43%) (high quality evidence). A similar magnitude of effect was found using PGIC of 'very much improved' and 'much or very much improved'. NNTs for these outcomes ranged between 7 and 14 (high quality evidence).
A small study (177 participants) compared nightly with twice‐daily pregabalin, and concluded there was no difference in effect.
Two studies (1492 participants began initial dose titration, 687 participants randomised) had an EERW design in which those with good pain relief after titration were randomised, double blind, to continuing the effective dose (300 to 600 mg pregabalin daily) or a short down‐titration to placebo for 13 or 26 weeks. We calculated the outcome of maintained therapeutic response (MTR) without withdrawal, equivalent to a moderate benefit. Of those randomised, 40% had MTR with pregabalin and 20% with placebo (high quality evidence). The NNT was 5, but normalised to the starting population tested it was 12. About 10% of the initial population would have achieved the MTR outcome, similar to the result from studies of classic design. MTR had no imputation concerns.
The majority (70% to 90%) of participants in all treatment groups experienced adverse events. Specific adverse events were more common with pregabalin than placebo, in particular dizziness, somnolence, weight gain, and peripheral oedema, with number needed to harm of 3.7, 7.4, 18, and 19 respectively for all doses combined (high quality evidence). Serious adverse events did not differ between active treatment groups and placebo (very low quality evidence). Withdrawals for any reason were more common with pregabalin than placebo only with the 600 mg dose in studies of classic design. Withdrawals due to adverse events were about 10% higher with pregabalin than placebo, but withdrawals due to lack of efficacy were about 6% lower (high quality evidence).
Pregabalin 300 to 600 mg produces a major reduction in pain intensity over 12 to 26 weeks with tolerable adverse events for a small proportion of people (about 10% more than placebo) with moderate or severe pain due to fibromyalgia. The degree of pain relief is known to be accompanied by improvements in other symptoms, quality of life, and function. These results are similar to other effective medicines in fibromyalgia (milnacipran, duloxetine).
Sheena Derry, Malene Cording, Philip J Wiffen, Simon Law, Tudor Phillips, R Andrew Moore
Plain language summary
Pregabalin for treating fibromyalgia pain in adults
We found high quality evidence that pregabalin at daily doses of 300 to 600 mg produces a large fall in pain in about 1 in 10 people with moderate or severe pain from fibromyalgia. Pain reduction comes with improvements in other symptoms, in quality of life, and in ability to function.
Fibromyalgia is characterised by persistent, widespread pain and tenderness, sleep problems, and fatigue. Common pain‐relieving medicines such as paracetamol and ibuprofen are not usually considered effective. Medicines used to treat epilepsy or depression can be effective in some people with fibromyalgia and other forms of chronic (persistent, long‐lasting) pain where there may be nerve damage. Pregabalin is an antiepileptic licensed to treat fibromyalgia in some parts of the world, in particular the USA.
This review is an update of one originally published in 2009, which examined the effects of pregabalin on all types of pain. In this review we have only examined fibromyalgia pain. The earlier review showed that pregabalin worked in a small proportion of people with fibromyalgia. This is the same as all other fibromyalgia treatments to date, and for chronic pain conditions generally. Our definition of 'worked' involved both a high level of pain relief and being able to take the medication over a longer period without intolerable side effects.
We searched scientific databases for studies that looked at the effects of pregabalin in adults with fibromyalgia who had moderate or severe pain. The treatment had to last at least eight weeks. The evidence is current to March 2016.
Eight studies satisfied the inclusion criteria, including three new studies for this update. Five studies randomised 3283 participants to immediate treatment with pregabalin or placebo. Two studies identified 687 out of 1492 participants who had a good pain response and could take the medicine, and then randomised them to continued treatment with pregabalin or placebo. Study quality was good. One other had no useful data.
High quality evidence showed that 1 in 10 people with moderate or severe fibromyalgia pain reported a large fall in pain by a third to a half over 12 to 26 weeks. This is an outcome that people with fibromyalgia consider to be useful. The dose of pregabalin was 300 to 600 mg daily.
Side effects occurred in 8 or 9 people in 10, often while adjusting to the medicine. Particular side effects were dizziness (affecting 1 in 4 participants), drowsiness (1 in 7), weight gain (1 in 18), and peripheral oedema (1 in 19) (high quality evidence). Serious side effects were no more common with pregabalin than with placebo, affecting 1 or 2 in 100. About 1 in 10 more participants taking pregabalin withdrew from the study because of side effects, and 1 in 17 fewer withdrew because the medicine was not working.
Quality of the evidence
The evidence was mostly of high quality, which means we are very confident that the true effect lies close to that of the estimate of the effect in this review. Concern about how information was handled when people left the studies was offset by other information showing that results were not impacted by this to any important degree.
Sheena Derry, Malene Cording, Philip J Wiffen, Simon Law, Tudor Phillips, R Andrew Moore
Implications for practice
For people with fibromyalgia
Pregabalin offers good pain relief to only a minority of people with fibromyalgia; it will not work for most people. This is also the case for other treatments for fibromyalgia, such as duloxetine and milnacipran. These treatments provide moderate or substantial pain benefit to about 10% more people than does placebo. The good news is that pain relief comes together with improved sleep, relief of any depression, less impact on life, and improved quality of life and ability to work.
People who take pregabalin are likely to experience adverse events, which may be troublesome. Pregabalin is not licensed to treat fibromyalgia in many countries, but has been licensed by the US Food and Drug Administration and a number of other countries worldwide.
Pregabalin offers good pain relief to only a minority of people with fibromyalgia; it will not work for most people. This is also the case for other treatments for fibromyalgia, such as duloxetine and milnacipran, which are the only other drug treatments with good evidence of efficacy in fibromyalgia. Pregabalin is not licensed to treat fibromyalgia in many countries.
Since relatively few participants achieve a worthwhile response with pregabalin, it is important to establish switching rules, so that when someone does not respond within a specified time, they can be switched to an alternative treatment. Emerging evidence indicates that the lack of any worthwhile pain relief within four to six weeks means that no pain relief is likely in the longer term. Stopping or switching rules will reduce the number of participants exposed to adverse events in the absence of benefit.
The available evidence shows that there is no difference between nighttime dosing and divided, twice‐daily dosing.
Because adverse events are common, dosing in clinical practice often follows the following general principles to generate maximum likelihood of benefit and minimal likelihood of early withdrawal.
- Start with low doses. For those patients who work, changes might be made over the weekend, with five to seven days on the new dose before any further increase.
- Giving the drug at bedtime may increase the benefit and decrease side effects.
- Adverse effects are common, so carefully balance these to analgesia.
- Do not expect any major pain relief until 150 mg is reached.
- While some patients may achieve good relief with lower doses, it is likely that 450 mg daily will provide the most effective balance between benefit and adverse events for most patients.
Since no single treatment is effective in a majority of individuals with fibromyalgia, this relatively small number who benefit may be considered worthwhile, particularly if switching rules are in place.
Since no single treatment is effective in a majority of individuals with fibromyalgia, this relatively small number who benefit may be considered worthwhile, particularly if switching rules are in place. The magnitude of benefit in those people who do respond is worthwhile, and it extends to major improvement in quality of life, function, and ability to work. This probably makes successful treatment of fibromyalgia cost‐effective, as people with moderate or severe chronic pain consume much greater health service and non‐health service resources than those with well‐treated pain.
Implications for research
Because the trials of classic design in this review used the last‐observation‐carried‐forward (LOCF) imputation method for study withdrawals, post‐hoc individual participant level analyses using baseline observation carried forward (BOCF) would be regarded as appropriate to strengthen the findings, especially if the pain reduction was linked to improved quality of life and function. For pregabalin we are in the unique situation of having individual patient level analyses for both pain response and the link between pain and other important outcomes in fibromyalgia.
However, there is a gap between the dosing regimens used in the clinical trials, where fairly rapid dose elevations are made over a few weeks, and clinical practice, where dosing increases can be quite slow. Practical research about the most effective use of medicines known to be effective in only a small proportion of patients could be very important. Indeed, situations could be envisaged where the degree of recruitment to successful treatment might have a major impact on treating a very difficult, debilitating, and costly condition.
The design of trials was adequate, but reporting of clinically relevant outcomes using appropriate imputation for withdrawal would improve the relevance of the findings for clinical practice. The use of EERW designs for comparison with classic trial designs indicates that good‐quality EERW designs of long duration may be appropriate for fibromyalgia.
No immediate design for testing initial dosing regimens presents itself.
Assessment of fibromyalgia symptoms should be based on dichotomous participant‐reported outcomes of proven clinical utility. The endpoint used in this review, of maintenance of therapeutic response without withdrawal, might be more clearly stated in trial reports, and used as a primary outcome in future trials, including pragmatic trials of dosing regimens.
Comparison between active treatments
Studies involving other treatments, including non‐pharmacological interventions, may be valuable in this context. A multicomponent approach reflects current practice.