Cannabis-based medicines for chronic neuropathic pain in adults.

BACKGROUND: This review is one of a series on drugs used to treat chronic neuropathic pain. Estimates of the population prevalence of chronic pain with neuropathic components range between 6% and 10%. Current pharmacological treatment options for neuropathic pain afford substantial benefit for only a few people, often with adverse effects that outweigh the benefits. There is a need to explore other treatment options, with different mechanisms of action for treatment of conditions with chronic neuropathic pain. Cannabis has been used for millennia to reduce pain. Herbal cannabis is currently strongly promoted by some patients and their advocates to treat any type of chronic pain. OBJECTIVES: To assess the efficacy, tolerability, and safety of cannabis-based medicines (herbal, plant-derived, synthetic) compared to placebo or conventional drugs for conditions with chronic neuropathic pain in adults. SEARCH METHODS: In November 2017 we searched CENTRAL, MEDLINE, Embase, and two trials registries for published and ongoing trials, and examined the reference lists of reviewed articles. SELECTION CRITERIA: We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment of conditions with chronic neuropathic pain in adults, with a treatment duration of at least two weeks and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data of study characteristics and outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias. We resolved discrepancies by discussion. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 30% and 50% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardised mean differences for pain intensity, sleep problems, health-related quality of life (HRQoL), and psychological distress. For tolerability, we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawal due to adverse events and specific adverse events, nervous system disorders and psychiatric disorders. For safety, we calculated NNTH for serious adverse events. Meta-analysis was undertaken using a random-effects model. We assessed the quality of evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). We used the Cochrane 'Risk of bias' tool to assess study quality. We defined studies with zero to two unclear or high risks of bias judgements to be high-quality studies, with three to five unclear or high risks of bias to be moderate-quality studies, and with six to eight unclear or high risks of bias to be low-quality studies. Study quality was low in two studies, moderate in 12 studies and high in two studies. Nine studies were at high risk of bias for study size. We rated the quality of the evidence according to GRADE as very low to moderate.Primary outcomesCannabis-based medicines may increase the number of people achieving 50% or greater pain relief compared with placebo (21% versus 17%; risk difference (RD) 0.05 (95% confidence interval (CI) 0.00 to 0.09); NNTB 20 (95% CI 11 to 100); 1001 participants, eight studies, low-quality evidence). We rated the evidence for improvement in Patient Global Impression of Change (PGIC) with cannabis to be of very low quality (26% versus 21%;RD 0.09 (95% CI 0.01 to 0.17); NNTB 11 (95% CI 6 to 100); 1092 participants, six studies). More participants withdrew from the studies due to adverse events with cannabis-based medicines (10% of participants) than with placebo (5% of participants) (RD 0.04 (95% CI 0.02 to 0.07); NNTH 25 (95% CI 16 to 50); 1848 participants, 13 studies, moderate-quality evidence). We did not have enough evidence to determine if cannabis-based medicines increase the frequency of serious adverse events compared with placebo (RD 0.01 (95% CI -0.01 to 0.03); 1876 participants, 13 studies, low-quality evidence).Secondary outcomesCannabis-based medicines probably increase the number of people achieving pain relief of 30% or greater compared with placebo (39% versus 33%; RD 0.09 (95% CI 0.03 to 0.15); NNTB 11 (95% CI 7 to 33); 1586 participants, 10 studies, moderate quality evidence). Cannabis-based medicines may increase nervous system adverse events compared with placebo (61% versus 29%; RD 0.38 (95% CI 0.18 to 0.58); NNTH 3 (95% CI 2 to 6); 1304 participants, nine studies, low-quality evidence). Psychiatric disorders occurred in 17% of participants using cannabis-based medicines and in 5% using placebo (RD 0.10 (95% CI 0.06 to 0.15); NNTH 10 (95% CI 7 to 16); 1314 participants, nine studies, low-quality evidence).We found no information about long-term risks in the studies analysed.Subgroup analysesWe are uncertain whether herbal cannabis reduces mean pain intensity (very low-quality evidence). Herbal cannabis and placebo did not differ in tolerability (very low-quality evidence). AUTHORS' CONCLUSIONS: The potential benefits of cannabis-based medicine (herbal cannabis, plant-derived or synthetic THC, THC/CBD oromucosal spray) in chronic neuropathic pain might be outweighed by their potential harms. The quality of evidence for pain relief outcomes reflects the exclusion of participants with a history of substance abuse and other significant comorbidities from the studies, together with their small sample sizes.

Gabapentin for chronic neuropathic pain in adults.

BACKGROUND: Gabapentin is commonly used to treat neuropathic pain (pain due to nerve damage). This review updates a review published in 2014, and previous reviews published in 2011, 2005 and 2000. OBJECTIVES: To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain in adults. SEARCH METHODS: For this update we searched CENTRAL), MEDLINE, and Embase for randomised controlled trials from January 2014 to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trials registries. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing gabapentin (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 potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). We performed a pooled analysis for any substantial or moderate benefit. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: We included four new studies (530 participants), and excluded three previously included studies (126 participants). In all, 37 studies provided information on 5914 participants. Most studies used oral gabapentin or gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain conditions, predominantly postherpetic neuralgia and painful diabetic neuropathy. Study duration was typically four to 12 weeks. Not all studies reported important outcomes of interest. High risk of bias occurred mainly due to small size (especially in cross-over studies), and handling of data after study withdrawal.In postherpetic neuralgia, more participants (32%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (17%) (RR 1.8 (95% CI 1.5 to 2.1); NNT 6.7 (5.4 to 8.7); 8 studies, 2260 participants, moderate-quality evidence). More participants (46%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (25%) (RR 1.8 (95% CI 1.6 to 2.0); NNT 4.8 (4.1 to 6.0); 8 studies, 2260 participants, moderate-quality evidence).In painful diabetic neuropathy, more participants (38%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (21%) (RR 1.9 (95% CI 1.5 to 2.3); NNT 5.9 (4.6 to 8.3); 6 studies, 1277 participants, moderate-quality evidence). More participants (52%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (37%) (RR 1.4 (95% CI 1.3 to 1.6); NNT 6.6 (4.9 to 9.9); 7 studies, 1439 participants, moderate-quality evidence).For all conditions combined, adverse event withdrawals were more common with gabapentin (11%) than with placebo (8.2%) (RR 1.4 (95% CI 1.1 to 1.7); NNH 30 (20 to 65); 22 studies, 4346 participants, high-quality evidence). Serious adverse events were no more common with gabapentin (3.2%) than with placebo (2.8%) (RR 1.2 (95% CI 0.8 to 1.7); 19 studies, 3948 participants, moderate-quality evidence); there were eight deaths (very low-quality evidence). Participants experiencing at least one adverse event were more common with gabapentin (63%) than with placebo (49%) (RR 1.3 (95% CI 1.2 to 1.4); NNH 7.5 (6.1 to 9.6); 18 studies, 4279 participants, moderate-quality evidence). Individual adverse events occurred significantly more often with gabapentin. Participants taking gabapentin experienced dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (14%). AUTHORS' CONCLUSIONS: Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the 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 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review.

Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews.

BACKGROUND: Topical analgesic drugs are used for a variety of painful conditions. Some are acute, typically strains or sprains, tendinopathy, or muscle aches. Others are chronic, typically osteoarthritis of hand or knee, or neuropathic pain. OBJECTIVES: To provide an overview of the analgesic efficacy and associated adverse events of topical analgesics (primarily nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate rubefacients, capsaicin, and lidocaine) applied to intact skin for the treatment of acute and chronic pain in adults. METHODS: We identified systematic reviews in acute and chronic pain published to February 2017 in the Cochrane Database of Systematic Reviews (the Cochrane Library). The primary outcome was at least 50% pain relief (participant-reported) at an appropriate duration. We extracted the number needed to treat for one additional beneficial outcome (NNT) for efficacy outcomes for each topical analgesic or formulation, and the number needed to treat for one additional harmful outcome (NNH) for adverse events. We also extracted information on withdrawals due to lack of efficacy or adverse events, systemic and local adverse events, and serious adverse events. We required information from at least 200 participants, in at least two studies. We judged that there was potential for publication bias if the addition of four studies of typical size (400 participants) with zero effect increased NNT compared with placebo to 10 (minimal clinical utility). We extracted GRADE assessment in the original papers, and made our own GRADE assessment. MAIN RESULTS: Thirteen Cochrane Reviews (206 studies with around 30,700 participants) assessed the efficacy and harms from a range of topical analgesics applied to intact skin in a number of acute and chronic painful conditions. Reviews were overseen by several Review Groups, and concentrated on evidence comparing topical analgesic with topical placebo; comparisons of topical and oral analgesics were rare.For at least 50% pain relief, we considered evidence was moderate or high quality for several therapies, based on the underlying quality of studies and susceptibility to publication bias.In acute musculoskeletal pain (strains and sprains) with assessment at about seven days, therapies were diclofenac Emulgel (78% Emulgel, 20% placebo; 2 studies, 314 participants, NNT 1.8 (95% confidence interval 1.5 to 2.1)), ketoprofen gel (72% ketoprofen, 33% placebo, 5 studies, 348 participants, NNT 2.5 (2.0 to 3.4)), piroxicam gel (70% piroxicam, 47% placebo, 3 studies, 522 participants, NNT 4.4 (3.2 to 6.9)), diclofenac Flector plaster (63% Flector, 41% placebo, 4 studies, 1030 participants, NNT 4.7 (3.7 to 6.5)), and diclofenac other plaster (88% diclofenac plaster, 57% placebo, 3 studies, 474 participants, NNT 3.2 (2.6 to 4.2)).In chronic musculoskeletal pain (mainly hand and knee osteoarthritis) therapies were topical diclofenac preparations for less than six weeks (43% diclofenac, 23% placebo, 5 studies, 732 participants, NNT 5.0 (3.7 to 7.4)), ketoprofen over 6 to 12 weeks (63% ketoprofen, 48% placebo, 4 studies, 2573 participants, NNT 6.9 (5.4 to 9.3)), and topical diclofenac preparations over 6 to 12 weeks (60% diclofenac, 50% placebo, 4 studies, 2343 participants, NNT 9.8 (7.1 to 16)). In postherpetic neuralgia, topical high-concentration capsaicin had moderate-quality evidence of limited efficacy (33% capsaicin, 24% placebo, 2 studies, 571 participants, NNT 11 (6.1 to 62)).We judged evidence of efficacy for other therapies as low or very low quality. Limited evidence of efficacy, potentially subject to publication bias, existed for topical preparations of ibuprofen gels and creams, unspecified diclofenac formulations and diclofenac gel other than Emulgel, indomethacin, and ketoprofen plaster in acute pain conditions, and for salicylate rubefacients for chronic pain conditions. Evidence for other interventions (other topical NSAIDs, topical salicylate in acute pain conditions, low concentration capsaicin, lidocaine, clonidine for neuropathic pain, and herbal remedies for any condition) was very low quality and typically limited to single studies or comparisons with sparse data.We assessed the evidence on withdrawals as moderate or very low quality, because of small numbers of events. In chronic pain conditions lack of efficacy withdrawals were lower with topical diclofenac (6%) than placebo (9%) (11 studies, 3455 participants, number needed to treat to prevent (NNTp) 26, moderate-quality evidence), and topical salicylate (2% vs 7% for placebo) (5 studies, 501 participants, NNTp 21, very low-quality evidence). Adverse event withdrawals were higher with topical capsaicin low-concentration (15%) than placebo (3%) (4 studies, 477 participants, NNH 8, very low-quality evidence), topical salicylate (5% vs 1% for placebo) (7 studies, 735 participants, NNH 26, very low-quality evidence), and topical diclofenac (5% vs 4% for placebo) (12 studies, 3552 participants, NNH 51, very low-quality evidence).In acute pain, systemic or local adverse event rates with topical NSAIDs (4.3%) were no greater than with topical placebo (4.6%) (42 studies, 6740 participants, high quality evidence). In chronic pain local adverse events with topical capsaicin low concentration (63%) were higher than topical placebo (5 studies, 557 participants, number needed to treat for harm (NNH) 2.6), high quality evidence. Moderate-quality evidence indicated more local adverse events than placebo in chronic pain conditions with topical diclofenac (NNH 16) and local pain with topical capsaicin high-concentration (NNH 16). There was moderate-quality evidence of no additional local adverse events with topical ketoprofen over topical placebo in chronic pain. Serious adverse events were rare (very low-quality evidence).GRADE assessments of moderate or low quality in some of the reviews were considered by us to be very low because of small numbers of participants and events. AUTHORS' CONCLUSIONS: There is good evidence that some formulations of topical diclofenac and ketoprofen are useful in acute pain conditions such as sprains or strains, with low (good) NNT values. There is a strong message that the exact formulation used is critically important in acute conditions, and that might also apply to other pain conditions. In chronic musculoskeletal conditions with assessments over 6 to 12 weeks, topical diclofenac and ketoprofen had limited efficacy in hand and knee osteoarthritis, as did topical high-concentration capsaicin in postherpetic neuralgia. Though NNTs were higher, this still indicates that a small proportion of people had good pain relief.Use of GRADE in Cochrane Reviews with small numbers of participants and events requires attention.

Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults.

BACKGROUND: Paracetamol, either alone or in combination with codeine or dihydrocodeine, is commonly used to treat chronic neuropathic pain. This review sought evidence for efficacy and harm from randomised double-blind studies. OBJECTIVES: To assess the analgesic efficacy and adverse events of paracetamol with or without codeine or dihydrocodeine for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to July 2016, together with reference lists of retrieved papers and reviews, and two online study registries. SELECTION CRITERIA: We included randomised, double-blind studies of two weeks' duration or longer, comparing paracetamol, alone or in combination with codeine or dihydrocodeine, with placebo or another active treatment in chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE. MAIN RESULTS: No study satisfied the inclusion criteria. Effects of interventions were not assessed as there were no included studies. We have only very low quality evidence and have no reliable indication of the likely effect. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the suggestion that paracetamol alone, or in combination with codeine or dihydrocodeine, works in any neuropathic pain condition.

Development, Validation, and Field-Testing of an Instrument for Clinical Assessment of HIV-Associated Neuropathy and Neuropathic Pain in Resource-Restricted and Large Population Study Settings.

HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4-item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study-HIV-PINS). CHANT was alpha-tested in silico against the HIV-PINS dataset and then clinically validated and field-tested in HIV-positive cohorts in London, UK and Johannesburg, South Africa. The Utah Early Neuropathy Score (UENS) was used as the reference standard in both settings. In a second step, neuropathic pain in the presence of HIV-SN was assessed using the Douleur Neuropathique en 4 Questions (DN4)-interview and a body map. CHANT achieved high accuracy on alpha-testing with sensitivity and specificity of 82% and 90%, respectively. In 30 patients in London, CHANT diagnosed 43.3% (13/30) HIV-SN (66.7% with neuropathic pain); sensitivity = 100%, specificity = 85%, and likelihood ratio = 6.7 versus UENS, internal consistency = 0.88 (Cronbach alpha), average item-total correlation = 0.73 (Spearman's Rho), and inter-tester concordance > 0.93 (Spearman's Rho). In 50 patients in Johannesburg, CHANT diagnosed 66% (33/50) HIV-SN (78.8% neuropathic pain); sensitivity = 74.4%, specificity = 85.7%, and likelihood ratio = 5.29 versus UENS. A positive CHANT score markedly increased of pre- to post-test clinical certainty of HIV-SN from 43% to 83% in London, and from 66% to 92% in Johannesburg. In conclusion, a combination of four easily and quickly assessed clinical items can be used to accurately diagnose HIV-SN. DN4-interview used in the context of bilateral feet pain can be used to identify those with neuropathic pain.

Pregabalin for pain in fibromyalgia in adults.

BACKGROUND: 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. OBJECTIVES: To assess the analgesic efficacy and adverse events of pregabalin for pain in fibromyalgia in adults, compared with placebo or any active comparator. SEARCH METHODS: 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. SELECTION CRITERIA: 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. MAIN RESULTS: 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). AUTHORS' CONCLUSIONS: 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).

Single fixed-dose oral dexketoprofen plus tramadol for acute postoperative pain in adults.

BACKGROUND: Combining two different analgesics in fixed doses in a single tablet can provide better pain relief than either drug alone in acute pain. This appears to be broadly true across a range of different drug combinations, in postoperative pain and migraine headache. A new combination of dexketoprofen (a nonsteroidal anti-inflammatory drug) plus tramadol (an opioid) has been tested in acute postoperative pain conditions. It is not yet licensed for use. This review is one of a series on oral analgesics for acute postoperative pain. Individual reviews have been brought together in two overviews to provide information about the relative efficacy and harm of the different interventions. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single fixed-dose of oral dexketoprofen plus tramadol, compared with placebo, for moderate to severe postoperative pain in adults, using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. A secondary objective was to compare the combination with the individual analgesics alone. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via CRSO, MEDLINE via Ovid, and Embase via Ovid from inception to 31 May 2016. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries. SELECTION CRITERIA: Randomised, double-blind trials of oral dexketoprofen plus tramadol administered as a single oral dose, for the relief of acute postoperative pain in adults, and compared to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently considered trials for inclusion in the review, examined issues of study quality and potential bias, and extracted data. For dichotomous outcomes, we calculated risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) for dexketoprofen plus tramadol, compared with placebo with 95% confidence intervals (CI). We collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours, the median time to use of rescue medication, and the proportion of participants requiring rescue medication. We also collected information on adverse events and withdrawals. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table.We also collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours for dexketoprofen alone and tramadol alone. MAIN RESULTS: We included three studies with 1853 participants who had undergone surgical removal of impacted wisdom teeth, hip replacement, or hysterectomy. The overall risk of bias across the three included studies was low, with unclear risk of bias in relation to the size of the three studies. Two studies did not report all our prespecified outcomes, which limited the analyses we could do.The proportion of participants achieving at least 50% pain relief over six hours with dexketoprofen 25 mg plus tramadol 75 mg was 66%, compared to 32% with placebo, giving an NNT of 3.0 (95% CI 2.5 to 3.7) (RR 2.1 (95% CI 1.7 to 2.4); 748 participants; 3 studies) (moderate quality evidence). The response rate with dexketoprofen 25 mg alone was 53% (RR 1.3 (95% CI 1.1 to 1.4); 744 participants; 3 studies) and with tramadol alone was 45% (RR 1.5 (95% CI 1.3 to 1.7); 741 participants; 3 studies) (moderate quality evidence). We downgraded the evidence because of some inconsistency in the results.The median time to use of rescue medication could not be estimated exactly, but was probably eight hours or more, indicating a long duration of effect (moderate quality evidence). We downgraded the evidence because it was not possible to estimate the effect exactly in the two multiple dose studies, resulting in imprecision. Fewer participants used rescue medication with higher doses of active treatment (summary statistic not calculated; 123 participants; 1 study) (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events.Adverse events and serious adverse events were not reported consistently for the single dose phase of the studies. In the single dose study, 11% of participants experienced adverse events with dexketoprofen 25 mg plus tramadol 75 mg, which were mostly mild or moderate nausea, vomiting, or dizziness, and typical with these medicines. Rates were lower with placebo and lower doses (very low quality evidence). We downgraded the evidence because the data came from a single study with few participants and events. Information on multiple dosing over three and five days supported a low event rate with the combination. Overall, rates were generally low in all treatment arms, as they were for withdrawals for adverse events or other reasons. AUTHORS' CONCLUSIONS: A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief with long duration of action to more people than placebo or the same dose of dexketoprofen or tramadol alone. The magnitude of the effect was similar to other good analgesics. Adverse event rates were low.There is modest uncertainty about the precision of the point estimate for efficacy, but the NNT of 3 is consistent with other analgesics considered effective and commonly used.

Cannabinoids for fibromyalgia.

BACKGROUND: This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. OBJECTIVES: To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors. SELECTION CRITERIA: We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE as very low due to indirectness, imprecision and potential reporting bias.The primary outcomes in our review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross-over design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid, with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy, tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence). Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither study reported serious adverse events during the period of both studies. We planned to create a GRADE 'Summary of findings' table, but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant-based cannabinoids or synthetic cannabinoids other than nabilone in fibromyalgia. AUTHORS' CONCLUSIONS: We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.

Antipsychotics for fibromyalgia in adults.

BACKGROUND: This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. It affects approximately 2% of the general population. Up to 70% of patients with fibromyalgia meet the criteria for a depressive or anxiety disorder. People often report high disability levels and poor health-related quality of life. Drug therapy focuses on reducing key symptoms and disability, and improving health-related quality of life. Antipsychotics might reduce fibromyalgia and associated mental health symptoms. OBJECTIVES: To assess the efficacy, tolerability and safety of antipsychotics in fibromyalgia in adults. SEARCH METHODS: We searched CENTRAL (2016, Issue 4), MEDLINE and EMBASE to 20 May 2016, together with reference lists of retrieved papers and reviews and two clinical trial registries. We also contacted trial authors. SELECTION CRITERIA: We selected controlled trials of at least four weeks duration of any formulation of antipsychotics used for the treatment of fibromyalgia in adults. DATA COLLECTION AND ANALYSIS: We extracted the data from all included studies and two review authors independently assessed study risks of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. We derived first tier evidence from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs, at least 200 participants in the comparison, eight to 12 weeks duration, parallel design), second tier evidence from data that failed to meet one or more of these criteria and that we considered at some risk of bias but with adequate numbers in the comparison, and third tier evidence from data involving small numbers of participants that we considered very likely to be biased or used outcomes of limited clinical utility, or both. We rated the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included a total of four studies with 296 participants.Three studies with 206 participants compared quetiapine, an atypical (second-generation) antipsychotic, with placebo. One study used a cross-over design and two studies a parallel-group design. Study duration was eight or 12 weeks. Quetiapine was used in all studies with a bedtime dosage between 50 and 300 mg/day. All studies had one or more sources of potential major bias and we judged them to be at moderate risk of bias overall. The primary outcomes in this review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety).Second tier evidence indicated that quetiapine was not statistically superior to placebo in the number of participants with a 50% or more pain reduction (very low quality evidence). No study reported data on PGIC. A greater proportion of participants on quetiapine reported a 30% or more pain reduction (risk difference (RD) 0.12, 95% confidence interval (CI) 0.00 to 0.23; number needed to treat for an additional benefit (NNTB) 8, 95% CI 5 to 100) (very low quality evidence). A greater proportion of participants on quetiapine reported a clinically relevant improvement of health-related quality of life compared to placebo ( RD 0.18, 95% CI 0.05 to 0.31; NNTB 5, 95% CI 3 to 20) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing sleep problems (standardised mean difference (SMD) -0.67, 95% CI -1.10 to -0.23), depression (SMD -0.39, 95% CI -0.74 to -0.04) and anxiety (SMD -0.40, 95% CI -0.69 to -0.11) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing the risk of withdrawing from the study due to a lack of efficacy (RD -0.14, 95% CI -0.23 to -0.05) (very low quality evidence). There was no statistically significant difference between quetiapine and placebo in the proportion of participants withdrawing due to adverse events (tolerability) (very low quality evidence), in the frequency of serious adverse events (safety) (very low quality evidence) and in the proportion of participants reporting dizziness and somnolence as an adverse event (very low quality evidence). In more participants in the quetiapine group a substantial weight gain was noted (RD 0.08, 95% CI 0.02 to 0.15; number needed to treat for an additional harm (NNTH) 12, 95% CI 6 to 50) (very low quality evidence). We downgraded the quality of evidence by three levels to a very low quality rating because of limitations of study design, indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed).One parallel design study with 90 participants compared quetiapine (50 to 300 mg/day flexible at bedtime) to amitriptyline (10 to 75 mg/day flexible at bedtime). The study had three major risks of bias and we judged it to be at moderate risk of bias overall. We downgraded the quality of evidence by two levels to a low quality rating because of indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed). Third tier evidence indicated no statistically significant differences between the two drugs. Both drugs did not statistically significantly differ in the reduction of average scores for pain, fatigue, sleep problems, depression, anxiety and for limitations of health-related quality of life and in the proportion of participants reporting dizziness, somnolence and weight gain as a side effect (low quality evidence). Compared to amitriptyline, more participants left the study due to adverse events (low quality evidence). No serious adverse events were reported (low quality evidence).We found no relevant study with other antipsychotics than quetiapine in fibromyalgia. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that quetiapine may be considered for a time-limited trial (4 to 12 weeks) to reduce pain, sleep problems, depression and anxiety in fibromyalgia patients with major depression. Potential side effects such as weight gain should be balanced against the potential benefits in shared decision making with the patient.

Milnacipran for pain in fibromyalgia in adults.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of milnacipran for neuropathic pain is now dealt with in a separate review.Milnacipran is a serotonin-norepinephrine (noradrenaline) reuptake inhibitor (SNRI) that is licensed for the treatment of fibromyalgia in some countries, including Canada, Russia, and the United States. OBJECTIVES: To assess the analgesic efficacy of milnacipran for pain in fibromyalgia in adults and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to 18 May 2015, together with reference lists of retrieved papers and reviews, and two clinical trial registries. For the earlier review, we also contacted the manufacturer. SELECTION CRITERIA: We included randomised, double-blind studies of eight weeks' duration or longer, comparing milnacipran with placebo or another active treatment in fibromyalgia in adults. DATA COLLECTION AND ANALYSIS: We extracted efficacy and adverse event data, and two review authors examined issues of study quality independently. MAIN RESULTS: We identified one new study with 100 participants for the pooled analysis. We identified two additional reports of a study using an enriched enrolment randomised withdrawal (EERW) design that included participants from earlier randomised controlled trials and an open-label study. Because this study used the same participants already included in our main analysis, and a different design, we dealt with it separately.The main analysis included six studies (five from the earlier review; 4238 participants in total), all of which were placebo-controlled, and used titration to a target dose of milnacipran 100 or 200 mg, with assessment after 8 to 24 weeks of stable treatment. There were no studies with active comparators. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect.Both doses of milnacipran provided moderate levels of pain relief (at least 30% pain intensity reduction) to about 40% of participants treated, compared to 30% with placebo, giving a number needed to treat for an additional beneficial outcome (NNT) of 6 to 10 (high quality evidence). Using a stricter definition for responder and a more conservative method of analysis gave lower levels of response (while maintaining a 10% difference between milnacipran and placebo) and increased the NNT to 11 (high quality evidence). One EERW study was broadly supportive.Adverse events were common in both milnacipran (86%) and placebo (78%) groups (high quality evidence), but serious adverse events did not differ between groups (less than 2%) (low quality evidence). Nausea, constipation, and headache were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome (NNH) of 5.7 for nausea, 13 for constipation, and 29 for headache) (moderate quality evidence).Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg (NNH 9) than 100 mg (NNH 23), compared with placebo. This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg and 7.0 for 200 mg (high quality evidence). Withdrawals due to lack of efficacy were less common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome (NNTp) of 41) (moderate quality evidence). AUTHORS' CONCLUSIONS: The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Using stricter criteria for 'responder' and a more conservative method of analysis gave lower response rates (about 26% with milnacipran versus 17% with placebo). Milnacipran was associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose.

Milnacipran for neuropathic pain in adults.

BACKGROUND: Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) that is sometimes used to treat chronic neuropathic pain and fibromyalgia. This is an update of an earlier review of milnacipran for neuropathic pain and fibromyalgia in adults originally published in The Cochrane Library Issue 3, 2012. We split that review so that this one looked only at neuropathic pain, and a separate review looks at fibromyalgia. OBJECTIVES: To assess the analgesic efficacy and associated adverse events of milnacipran for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE to 23 February 2015, together with reference lists of retrieved papers and reviews. SELECTION CRITERIA: We included randomised, double-blind studies of eight weeks' duration or longer, comparing milnacipran with placebo or another active treatment in chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality. We did not carry out any analysis. MAIN RESULTS: We included a single study of 40 participants with chronic low back pain with a neuropathic component. It found no difference in pain scores between milnacipran 100 mg to 200 mg daily or placebo after six weeks (very low quality evidence). Adverse event rates were similar between treatments, with too few data to draw conclusions (very low quality evidence). AUTHORS' CONCLUSIONS: There was no evidence to support the use of milnacipran to treat neuropathic pain conditions.

Desipramine for neuropathic pain in adults.

BACKGROUND: Antidepressants are widely used to treat chronic neuropathic pain (pain due to nerve damage), usually in doses below those at which they exert antidepressant effects. An earlier review that included all antidepressants for neuropathic pain is being replaced by new reviews of individual drugs examining individual neuropathic pain conditions.Desipramine is a tricyclic antidepressant that is occasionally used for treating neuropathic pain. OBJECTIVES: To assess the analgesic efficacy of desipramine for chronic neuropathic pain in adults, and to assess the associated adverse events. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE from inception to 29 April 2014, and the reference lists of retrieved papers and other reviews. We also used our own hand searched database to identify older studies, and two clinical trials databases for ongoing or unpublished studies. SELECTION CRITERIA: We included randomised, double-blind studies of at least two weeks duration comparing desipramine with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 years and over. We included only full journal publication articles. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts, at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design); second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison; and third tier from data involving small numbers of participants and considered very likely to be biased or that used outcomes of limited clinical utility, or both. MAIN RESULTS: Five studies treated 177 participants with painful diabetic neuropathy (104) or postherpetic neuralgia (73). The mean or median ages in the studies were 55 to 72 years. Four studies used a cross-over, and one a parallel group design; 145 participants were randomised to receive desipramine 12.5 mg to 250 mg daily, with most taking 100 mg to 150 mg daily following titration. Comparators were placebo in three studies (an 'active placebo' in two studies), fluoxetine, clomipramine (one study each), and amitriptyline (two studies), and treatment was for two to six weeks. All studies had one or more sources of potential major bias.No study provided first or second tier evidence for any outcome. No data were available on the proportion of people with at least 50% or 30% reduction in pain, but data were available from three studies for our other primary outcome of Patient Global Impression of Change, reported as patient evaluation of pain relief that was 'complete' or 'a lot'. No pooling of data was possible, but third tier evidence in individual studies indicated some improvement in pain relief with desipramine compared with placebo, although this was very low quality evidence, derived mainly from group mean data and completer analyses in small, short duration studies where major bias was possible. There were too few participants in comparisons of desipramine with another active treatment to draw any conclusions.All studies reported some information about adverse events, but reporting was inconsistent and fragmented. Participants taking desipramine experienced more adverse events, and a higher rate of withdrawal due to adverse events, than did participants taking placebo (very low quality evidence). AUTHORS' CONCLUSIONS: This review found little evidence to support the use of desipramine to treat neuropathic pain. There was very low quality evidence of benefit and harm, but this came from studies that were methodologically flawed and potentially subject to major bias. Effective medicines with much greater supportive evidence are available. There may be a role for desipramine in patients who have not obtained pain relief from other treatments.

Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study.

HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of HIV infection and a major source of morbidity. A cross-sectional deep profiling study examining HIV-SN was conducted in people living with HIV in a high resource setting using a battery of measures which included the following: parameters of pain and sensory symptoms (7day pain diary, Neuropathic Pain Symptom Inventory [NPSI] and Brief Pain Inventory [BPI]), sensory innervation (structured neurological examination, quantitative sensory testing [QST] and intraepidermal nerve fibre density [IENFD]), psychological state (Pain Anxiety Symptoms Scale-20 [PASS-20], Depression Anxiety and Positive Outlook Scale [DAPOS], and Pain Catastrophizing Scale [PCS], insomnia (Insomnia Severity Index [ISI]), and quality of life (Short Form (36) Health Survey [SF-36]). The diagnostic utility of the Brief Peripheral Neuropathy Screen (BPNS), Utah Early Neuropathy Scale (UENS), and Toronto Clinical Scoring System (TCSS) were evaluated. Thirty-six healthy volunteers and 66 HIV infected participants were recruited. A novel triumvirate case definition for HIV-SN was used that required 2 out of 3 of the following: 2 or more abnormal QST findings, reduced IENFD, and signs of a peripheral neuropathy on a structured neurological examination. Of those with HIV, 42% fulfilled the case definition for HIV-SN (n=28), of whom 75% (n=21) reported pain. The most frequent QST abnormalities in HIV-SN were loss of function in mechanical and vibration detection. Structured clinical examination was superior to QST or IENFD in HIV-SN diagnosis. HIV-SN participants had higher plasma triglyceride, concentrations depression, anxiety and catastrophizing scores, and prevalence of insomnia than HIV participants without HIV-SN.

Imipramine for neuropathic pain in adults.

BACKGROUND: Antidepressants are widely used to treat chronic neuropathic pain (pain due to nerve damage), usually in doses below those at which they exert antidepressant effects. An earlier review that included all antidepressants for neuropathic pain is being replaced by new reviews of individual drugs examining individual neuropathic pain conditions.Imipramine is a tricyclic antidepressant that is occasionally used to treat neuropathic pain. OBJECTIVES: To assess the analgesic efficacy of imipramine for chronic neuropathic pain in adults, and to assess the associated adverse events. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE on 18 November 2013, as well as the reference lists of retrieved papers and other reviews. We also used our own handsearched database for older studies, and two clinical trials databases. SELECTION CRITERIA: We included randomised, double-blind studies of at least two weeks' duration comparing imipramine with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 and over. We included only articles with full journal publication and extended trial abstracts and summaries. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design); second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison; and third tier from data involving small numbers of participants which was considered very likely to be biased or used outcomes of limited clinical utility, or both. MAIN RESULTS: Five studies treated 168 participants with painful diabetic neuropathy or polyneuropathy. The mean age in individual studies was between 47 and 56 years. Four studies used a cross-over, and one a parallel group design; 126 participants were randomised to receive imipramine 25 mg to 350 mg daily (most took 100 mg to 150 mg daily). Comparators were placebo (an active placebo in one study), paroxetine, mianserin, venlafaxine, and amitriptyline, and treatment was given for 2 to 12 weeks. All studies had one or more sources of potential major bias.No study provided first or second tier evidence for any outcome. No data were available on the proportion of people with at least 50% or 30% reduction in pain or equivalent, and data were available from only one study for our other primary outcome of Patient Global Impression of Change, reported as patient evaluation of pain relief of complete or good. No pooling of data was possible, but third tier evidence in individual studies indicated some improvement in pain relief with imipramine compared with placebo, although this is was very low quality evidence, derived mainly from group mean data and completer analyses, in small, short duration studies where major bias is possible.Four studies reported some information about adverse events, but reporting was inconsistent and fragmented, and the quality of evidence was very low. Participants taking imipramine generally experienced more adverse events, notably dry mouth, and a higher rate of withdrawal due to adverse events, than did participants taking placebo. AUTHORS' CONCLUSIONS: This review found little evidence to support the use of imipramine to treat neuropathic pain. There was very low quality evidence of benefit but this came from studies that were methodologically flawed and potentially subject to major bias. Effective medicines with much greater supportive evidence are available.

Milnacipran for neuropathic pain and fibromyalgia in adults.

BACKGROUND: Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) that is sometimes used to treat chronic neuropathic pain and fibromyalgia. OBJECTIVES: To evaluate the analgesic efficacy and adverse effects of milnacipran in the management of chronic neuropathic pain or fibromyalgia. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE to 4th of January 2012, together with reference lists of retrieved papers and reviews. SELECTION CRITERIA: We included randomised, double-blind studies of eight weeks duration or longer, comparing milnacipran with placebo or another active treatment in chronic neuropathic pain or fibromyalgia. DATA COLLECTION AND ANALYSIS: We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. MAIN RESULTS: Five studies (4138 participants) were included, all of which were placebo-controlled, involved participants with fibromyalgia, and used titration to a target dose of 100 mg or 200 mg milnacipran. There were no other active comparators or studies in other neuropathic pain conditions. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect.Both doses of milnacipran provided moderate levels of pain relief to about 40% of those treated, compared to 30% with placebo, giving a number needed to treat of 8 to 10. Adverse events were common in both milnacipran (87%) and placebo (78%) groups, but serious adverse events (< 2%) did not differ between groups. Nausea and constipation were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome of 7 and 13 respectively, compared with placebo).Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg than 100 mg (NNH of 23 and 8.8 respectively, compared with placebo). This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg, and 7.0 for 200 mg). Withdrawals due to lack of efficacy were more common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome of 45 and 41 respectively). AUTHORS' CONCLUSIONS: The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Milnacipran is associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose. There were no data for the use of milnacipran for other chronic neuropathic pain conditions.

Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Significant pain from HIV-associated sensory neuropathy (HIV-SN) affects ∼40% of HIV infected individuals treated with antiretroviral therapy (ART). The prevalence of HIV-SN has increased despite the more widespread use of ART. With the global HIV prevalence estimated at 33 million, and with infected individuals gaining increased access to ART, painful HIV-SN represents a large and expanding world health problem. There is an urgent need to develop effective pain management strategies for this condition. OBJECTIVE: To evaluate the clinical effectiveness of analgesics in treating painful HIV-SN. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Cochrane central register of controlled trials, www.clinicaltrials.gov, www.controlled-trials.com and the reference lists of retrieved articles. SELECTION CRITERIA: Prospective, double-blinded, randomised controlled trials (RCTs) investigating the pharmacological treatment of painful HIV-SN with sufficient quality assessed using a modified Jadad scoring method. REVIEW METHODS: Four authors assessed the eligibility of articles for inclusion. Agreement of inclusion was reached by consensus and arbitration. Two authors conducted data extraction and analysis. Dichotomous outcome measures (≥ 30% and ≥ 50% pain reduction) were sought from RCTs reporting interventions with statistically significant efficacies greater than placebo. These data were used to calculate RR and NNT values. RESULTS: Of 44 studies identified, 19 were RCTs. Of these, 14 fulfilled the inclusion criteria. Interventions demonstrating greater efficacy than placebo were smoked cannabis NNT 3.38 95%CI(1.38 to 4.10), topical capsaicin 8%, and recombinant human nerve growth factor (rhNGF). No superiority over placebo was reported in RCTs that examined amitriptyline (100mg/day), gabapentin (2.4 g/day), pregabalin (1200 mg/day), prosaptide (16 mg/day), peptide-T (6 mg/day), acetyl-L-carnitine (1g/day), mexilitine (600 mg/day), lamotrigine (600 mg/day) and topical capsaicin (0.075% q.d.s.). CONCLUSIONS: Evidence of efficacy exists only for capsaicin 8%, smoked cannabis and rhNGF. However,rhNGF is clinically unavailable and smoked cannabis cannot be recommended as routine therapy. Evaluation of novel management strategies for painful HIV-SN is urgently needed.