Abstract

Background

This review updates part of an earlier Cochrane Review titled "Pregabalin for acute and chronic pain in adults", and considers only neuropathic pain (pain from damage to nervous tissue). Antiepileptic drugs have long been used in pain management. Pregabalin is an antiepileptic drug used in management of chronic pain conditions.

Objectives

To assess the analgesic efficacy and adverse effects of pregabalin for chronic neuropathic pain in adults.

Search methods

We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from January 2009 to April 2018, online clinical trials registries, and reference lists.

Selection criteria

We included randomised, double‐blind trials of two weeks' duration or longer, comparing pregabalin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant‐reported pain assessment.

Data collection and analysis

Two review authors independently extracted data and assessed trial quality and biases. Primary outcomes were: at least 30% pain intensity reduction over baseline; much or very much improved on the Patient Global Impression of Change (PGIC) Scale (moderate benefit); at least 50% pain intensity reduction; or very much improved on PGIC (substantial benefit). We calculated risk ratio (RR) and number needed to treat for an additional beneficial (NNTB) or harmful outcome (NNTH). We assessed the quality of the evidence using GRADE.

Main results

We included 45 studies lasting 2 to 16 weeks, with 11,906 participants ‐ 68% from 31 new studies. Oral pregabalin doses of 150 mg, 300 mg, and 600 mg daily were compared with placebo. Postherpetic neuralgia, painful diabetic neuropathy, and mixed neuropathic pain predominated (85% of participants). High risk of bias was due mainly to small study size (nine studies), but many studies had unclear risk of bias, mainly due to incomplete outcome data, size, and allocation concealment.

Postherpetic neuralgia: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (50% vs 25%; RR 2.1 (95% confidence interval (CI) 1.6 to 2.6); NNTB 3.9 (3.0 to 5.6); 3 studies, 589 participants, moderate‐quality evidence), and more had at least 50% pain intensity reduction (32% vs 13%; RR 2.5 (95% CI 1.9 to 3.4); NNTB 5.3 (3.9 to 8.1); 4 studies, 713 participants, moderate‐quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (62% vs 24%; RR 2.5 (95% CI 2.0 to 3.2); NNTB 2.7 (2.2 to 3.7); 3 studies, 537 participants, moderate‐quality evidence), and more had at least 50% pain intensity reduction (41% vs 15%; RR 2.7 (95% CI 2.0 to 3.5); NNTB 3.9 (3.1 to 5.5); 4 studies, 732 participants, moderate‐quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate‐quality evidence): somnolence 300 mg 16% versus 5.5%, 600 mg 25% versus 5.8%; dizziness 300 mg 29% versus 8.1%, 600 mg 35% versus 8.8%.

Painful diabetic neuropathy: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (47% vs 42%; RR 1.1 (95% CI 1.01 to 1.2); NNTB 22 (12 to 200); 8 studies, 2320 participants, moderate‐quality evidence), more had at least 50% pain intensity reduction (31% vs 24%; RR 1.3 (95% CI 1.2 to 1.5); NNTB 22 (12 to 200); 11 studies, 2931 participants, moderate‐quality evidence), and more had PGIC much or very much improved (51% vs 30%; RR 1.8 (95% CI 1.5 to 2.0); NNTB 4.9 (3.8 to 6.9); 5 studies, 1050 participants, moderate‐quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (63% vs 52%; RR 1.2 (95% CI 1.04 to 1.4); NNTB 9.6 (5.5 to 41); 2 studies, 611 participants, low‐quality evidence), and more had at least 50% pain intensity reduction (41% vs 28%; RR 1.4 (95% CI 1.2 to 1.7); NNTB 7.8 (5.4 to 14); 5 studies, 1015 participants, low‐quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate‐quality evidence): somnolence 300 mg 11% versus 3.1%, 600 mg 15% versus 4.5%; dizziness 300 mg 13% versus 3.8%, 600 mg 22% versus 4.4%.

Mixed or unclassified post‐traumatic neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (48% vs 36%; RR 1.2 (1.1 to 1.4); NNTB 8.2 (5.7 to 15); 4 studies, 1367 participants, low‐quality evidence), and more had at least 50% pain intensity reduction (34% vs 20%; RR 1.5 (1.2 to 1.9); NNTB 7.2 (5.4 to 11); 4 studies, 1367 participants, moderate‐quality evidence). Somnolence (12% vs 3.9%) and dizziness (23% vs 6.2%) were more common with pregabalin.

Central neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (44% vs 28%; RR 1.6 (1.3 to 2.0); NNTB 5.9 (4.1 to 11); 3 studies, 562 participants, low‐quality evidence) and at least 50% pain intensity reduction (26% vs 15%; RR 1.7 (1.2 to 2.3); NNTB 9.8 (6.0 to 28); 3 studies, 562 participants, low‐quality evidence). Somnolence (32% vs 11%) and dizziness (23% vs 8.6%) were more common with pregabalin.

Other neuropathic pain conditions: Studies show no evidence of benefit for 600 mg pregabalin in HIV neuropathy (2 studies, 674 participants, moderate‐quality evidence) and limited evidence of benefit in neuropathic back pain or sciatica, neuropathic cancer pain, or polyneuropathy.

Serious adverse events, all conditions: Serious adverse events were no more common with placebo than with pregabalin 300 mg (3.1% vs 2.6%; RR 1.2 (95% CI 0.8 to 1.7); 17 studies, 4112 participants, high‐quality evidence) or pregabalin 600 mg (3.4% vs 3.4%; RR 1.1 (95% CI 0.8 to 1.5); 16 studies, 3995 participants, high‐quality evidence).

Authors' conclusions

Evidence shows efficacy of pregabalin in postherpetic neuralgia, painful diabetic neuralgia, and mixed or unclassified post‐traumatic neuropathic pain, and absence of efficacy in HIV neuropathy; evidence of efficacy in central neuropathic pain is inadequate. Some people will derive substantial benefit with pregabalin; more will have moderate benefit, but many will have no benefit or will discontinue treatment. There were no substantial changes since the 2009 review.

Author(s)

Sheena Derry, Rae Frances Bell, Sebastian Straube, Philip J Wiffen, Dominic Aldington, R Andrew Moore

Abstract

Plain language summary

Pregabalin for chronic neuropathic pain in adults

Bottom line

Moderate‐quality evidence shows that oral pregabalin at doses of 300 mg or 600 mg daily has an important effect on pain in some people with moderate or severe neuropathic pain after shingles, or due to diabetes. Low‐quality evidence suggests that oral pregabalin is effective after trauma due to stroke or spinal cord injury. Pregabalin appears not to be effective in neuropathic pain associated with HIV. Very limited evidence is available for neuropathic back pain, neuropathic cancer pain, and some other forms of neuropathic pain.

Background

Neuropathic pain comes from damage to the nervous system. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, from a fall or a cut, or from an arthritic knee). Neuropathic pain is often treated by different medicines (drugs) from those used for pain from damaged tissue, which we often think of as painkillers. Medicines that are sometimes used to treat depression or epilepsy can be effective in some people with neuropathic pain. One of these is pregabalin. Our definition of a good result was a high level of pain relief and ability to keep taking the medicine without side effects making people stop.

Study characteristics

In April 2018, for this update we searched for clinical trials that used pregabalin to treat neuropathic pain in adults. We found 31 new studies with 8045 participants. In total, we included 45 studies randomising 11,906 participants to treatment with pregabalin, placebo, or other drugs. Studies lasted 2 to 16 weeks. Most studies reported beneficial outcomes that people with neuropathic pain think are important. Results are available mainly for pain after shingles and pain resulting from nerve damage in diabetes.

Key results

For pain after shingles, 3 in 10 people had pain reduced by half or more with pregabalin 300 mg or 600 mg daily, and 2 in 10 with placebo. Pain was reduced by a third or more for 5 in 10 with pregabalin 300 mg or 600 mg daily, and 3 in 10 with placebo. For pain caused by diabetes, 3 or 4 in 10 people had pain reduced by half or more with pregabalin 300 mg or 600 mg daily, and 2 or 3 in 10 with placebo. Pain was reduced by a third or more for 5 or 6 in 10 people with pregabalin 300 mg or 600 mg daily, and 4 or 5 in 10 with placebo. Pregabalin also helped people with a mixed diagnosis (probably mainly pain after shingles and with diabetes) and people with pain after stroke. It did not work in people with HIV with neuropathic pain. There was no reliable evidence for any other type of neuropathic pain.

Side effects were more common with pregabalin (6 in 10) than with placebo (5 in 10). Dizziness and sleepiness occurred in about 1 to 3 in 10 people who took pregabalin. Serious side effects were uncommon and were not different between pregabalin and placebo. About 1 in 10 people taking pregabalin stopped taking it because of side effects.

Pregabalin is helpful for some people with chronic neuropathic pain. It is not possible to know beforehand who will benefit and who will not. Current knowledge suggests that a short course of treatment (perhaps four weeks) is the best way of telling.

Quality of the evidence

We rated the quality of the evidence using four levels: very low, low, moderate, and high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results. We judged that most evidence was of moderate quality, which means that even though research provides a good indication of the likely effect, effects may be substantially different. The main issues were small size for some studies and inadequate reporting of important methodological information. Results have not changed substantially since the 2009 review.

Author(s)

Sheena Derry, Rae Frances Bell, Sebastian Straube, Philip J Wiffen, Dominic Aldington, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with neuropathic pain

Pregabalin at daily oral doses of 300 to 600 mg can provide good levels of pain relief for some people with postherpetic neuralgia and painful diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. Pregabalin appears not to be effective for HIV‐associated painful peripheral neuropathy. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by people with chronic neuropathic pain, and achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 to 4 out of 10 achieved this degree of pain relief with pregabalin, compared with 1 to 2 out of 10 for placebo. More than half of those treated with pregabalin will not attain worthwhile pain relief. Around 6 or 7 out of 10 will experience at least one adverse event with pregabalin (somnolence and dizziness are common), compared with 5 or 6 out of 10 with placebo. Serious adverse events are rare and are of similar proportions with pregabalin and placebo.

The level of efficacy found for pregabalin is consistent with efficacy estimates for other drug therapies for these conditions.

For clinicians

Pregabalin at daily oral doses of 300 to 600 mg can provide good levels of pain relief for some people with postherpetic neuralgia and painful diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. Pregabalin appears not to be effective for HIV‐associated painful peripheral neuropathy. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by people with chronic neuropathic pain, and achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 to 4 out of 10 achieved this degree of pain relief with pregabalin, compared with 1 to 2 out of 10 for placebo. More than half of those treated with pregabalin will not have achieved worthwhile pain relief. Around 6 or 7 out of 10 will experience at least one adverse event with pregabalin (somnolence and dizziness are common), compared with 5 or 6 out of 10 with placebo. Serious adverse events are rare and are of similar proportions with pregabalin and placebo.

The level of efficacy found for pregabalin is consistent with efficacy estimates for other drug therapies for these conditions.

For policy makers

Pregabalin at daily oral doses of 300 to 600 mg can provide good levels of pain relief for some people with postherpetic neuralgia and painful diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. Pregabalin appears not to be effective for HIV‐associated painful peripheral neuropathy. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by people with chronic neuropathic pain, and achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 to 4 out of 10 achieved this degree of pain relief with pregabalin, compared with 1 to 2 out of 10 for placebo. More than half of those treated with pregabalin will not attain worthwhile pain relief. Around 6 or 7 out of 10 will experience at least one adverse event with pregabalin (somnolence and dizziness are common), compared with 5 or 6 out of 10 with placebo. Serious adverse events are rare and are of similar proportions with pregabalin and placebo.

The level of efficacy found for pregabalin is consistent with efficacy estimates for other drug therapies for these conditions.

For funders of the intervention

Pregabalin at daily oral doses of 300 to 600 mg can provide good levels of pain relief for some people with postherpetic neuralgia and painful diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. Pregabalin appears not to be effective for HIV‐associated painful peripheral neuropathy. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by people with chronic neuropathic pain, and achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 to 4 out of 10 achieved this degree of pain relief with pregabalin, compared with 1 to 2 out of 10 for placebo. More than half of those treated with pregabalin will not attain worthwhile pain relief. Around 6 or 7 out of 10 will experience at least one adverse event with pregabalin (somnolence and dizziness are common), compared with 5 or 6 out of 10 with placebo. Serious adverse events are rare and are of similar proportions with pregabalin and placebo.

The level of efficacy found for pregabalin is consistent with efficacy estimates for other drug therapies for these conditions.

Implications for research 

General

The design and outcomes of studies in neuropathic pain are well understood, but as the number of people experiencing good pain relief with pregabalin over the longer term (12 weeks) is likely to be small, an enriched‐enrolment randomised‐withdrawal (EERW) design might provide the highest sensitivity to detect a signal (Moore 2015c).

Use of combinations of drugs for neuropathic pain is common and may be more effective than monotherapy (Chaparro 2012). Future studies might examine combinations, especially the combined use of pregabalin with tricyclic antidepressants, weak opioids, or tramadol. Studies might specifically examine the the timing and sequencing of these drugs with pregabalin.

More research is warranted to examine the efficacy of pregabalin in painful neuropathic pain conditions for which current information is inadequate. These conditions tend to be uncommon, and studies can be difficult and can include few possible participants. We have little evidence concerning use of pregabalin among the older elderly (Gaskell 2014).

Design

Reporting of clinically relevant outcomes using appropriate imputation for withdrawal would improve the relevance of findings for clinical practice. Use of EERW designs for comparison with classic trial designs indicates that good quality EERW designs of long duration may be appropriate for neuropathic pain.

Stratification by phenotype (observable to testable characteristics) might be an interesting possibility for future studies (Baron 2017), as well as the possibility of measuring pain scores with activity (including dynamic tactile allodynia) versus at rest or on average/worst/best over the prior 24 hours. Participant‐level data might be of importance for identifying responder clusters and characteristics.

Although pain is important, other outcomes related to function, sleep, fatigue, and quality of life are also important, and are probably closely linked (Hoffman 2010). Participant‐level data could shed light on these relationships.

However, the main issue is not whether pregabalin is effective, but rather how it can best be used in clinical practice to generate the best results for most people with a chronic neuropathic pain condition, in the shortest time, and at the lowest cost. New study designs have been proposed to examine this (Moore 2010f).

Measurement (endpoints)

Assessment of neuropathic pain and associated symptoms such as sleep, fatigue, depression, and quality of life should be based on dichotomous participant‐reported outcomes of proven clinical utility.

Comparison between active treatments

There seems little point in comparing pregabalin directly with other treatments; the issue is what works for whom. Although the quality and weight of evidence supporting pregabalin in these conditions probably surpass that available for other interventions, this information has been generated largely for regulatory purposes. We need more information about which patients are likely to benefit most from this drug, how dose can best be titrated to effect to minimise adverse events, and whether patients who experienced treatment failure on other drugs can still benefit from pregabalin.

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