Project description: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.
Project description:BackgroundAntiepileptic drugs have been used in pain management since the 1960s; some seem to be especially useful for neuropathic pain. Lacosamide is an antiepileptic drug that has recently been investigated for neuropathic pain relief, although it failed to get approval for painful diabetic peripheral neuropathy from either the Food and Drug Administration or the European Medicines Agency.ObjectivesTo evaluate the analgesic efficacy and adverse effects of lacosamide in the management of chronic neuropathic pain or fibromyalgia.Search methodsWe searched the Cochrane Neuromuscular Disease Group Specialized Register (2011, Issue 4), CENTRAL (2011, Issue 3), MEDLINE (January 2000 to August 2011) and EMBASE (2000 to August 2011) without language restriction, together with reference lists of retrieved papers and reviews.Selection criteriaWe included randomised, double-blind studies of eight weeks duration or longer, comparing lacosamide with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.Data collection and analysisTwo review authors independently extracted data for efficacy and adverse events and examined issues of study quality, including risk of bias assessments. Where possible, we calculated numbers needed to treat to benefit from dichotomous data for effectiveness, adverse events and study withdrawals.Main resultsWe included six studies; five (1863 participants) in painful diabetic neuropathy (PDN) and one (159 participants) in fibromyalgia. All were placebo-controlled and titrated to a target dose of 200 mg, 400 mg or 600 mg lacosamide daily, given as a divided dose. Study reporting quality was generally good, although the imputation method of last observation carried forward used in analyses of the primary outcomes is known to known to impart major bias where, as here, adverse event withdrawal rates were high. This, together with small numbers of patients and events for most outcomes at most doses meant that most results were of low quality, with moderate quality evidence available for some efficacy outcomes for 400 mg lacosamide.There were too few data for analysis of the 200 mg dose for painful diabetic neuropathy or any dose for fibromyalgia.In painful diabetic neuropathy, lacosamide 400 mg provided statistically increased rates of achievement of "moderate" and "substantial" benefit (at least 30% and at least 50% reduction from baseline in patient-reported pain respectively) and the patient global impression of change outcome of "much or very much improved". In each case the extra proportion benefiting above placebo was about 10%, yielding numbers needed to treat to benefit compared with placebo of 10 to 12. For lacosamide 600 mg there was no consistent benefit over placebo.There was no significant difference between any dose of lacosamide and placebo for participants experiencing any adverse event or a serious adverse event, but adverse event withdrawals showed a significant dose response. The number needed to treat to harm for adverse event withdrawal was 11 for lacosamide 400 mg and 4 for the 600 mg dose.Authors' conclusionsLacosamide has limited efficacy in the treatment of peripheral diabetic neuropathy. Higher doses did not give consistently better efficacy, but were associated with significantly more adverse event withdrawals. Where adverse event withdrawals are high with active treatment compared with placebo and when last observation carried forward imputation is used, as in some of these studies, significant overestimation of treatment efficacy can result. It is likely, therefore, that lacosamide is without any useful benefit in treating neuropathic pain; any positive interpretation of the evidence should be made with caution if at all.
Project description:BackgroundValproic acid and its sodium salt (sodium valproate) are antiepileptic drugs that are sometimes used to treat chronic neuropathic pain and fibromyalgia, although they are not licensed for this use.ObjectivesTo evaluate the analgesic efficacy and adverse effects of valproic acid and sodium valproate in the management of chronic neuropathic pain and fibromyalgia.Search strategyWe identified randomised controlled trials (RCTs) of valproic acid and sodium valproate in acute, and chronic pain by searching MEDLINE, EMBASE and Cochrane CENTRAL to June 2011, together with reference lists of retrieved papers and reviews.Selection criteriaRCTs that were double blind and of eight-weeks duration or longer, reporting on analgesic effects and adverse events with valproic acid and sodium valproate in the treatment of chronic neuropathic pain and fibromyalgia.Data collection and analysisTwo review authors independently extracted results and scored for quality. We extracted efficacy and adverse event data, and examined issues of study quality.Main resultsWe included three studies, two in diabetic neuropathy (42 participants treated with valproate, 42 with placebo), and one in post-herpetic neuralgia (23 treated with divalproex sodium, 22 with placebo). Study duration was eight or 12 weeks. No studies were found in fibromyalgia.Only one study reported one of our primary outcomes (≥ 50% pain relief), while all three reported group means for pain reduction from baseline to endpoint. In all three studies; efficacy results were given only for participants who completed the study. One study in diabetic neuropathy and the study in post-herpetic neuralgia reported significant differences between active and placebo groups, but there were insufficient data for reliable pooled analysis.More adverse events were reported with active treatment than placebo, and included nausea, drowsiness and abnormal liver function tests. One participant taking sodium valproate withdrew due to serious derangement of liver enzymes.Authors' conclusionsThese three studies no more than hint that sodium valproate may reduce pain in diabetic neuropathy, and divalproex sodium in post-herpetic neuralgia, but the use of 'completer' analysis may overestimate efficacy, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. There is insufficient evidence to support the use of valproic acid or sodium valproate as a first-line treatment for neuropathic pain. There is more robust evidence of greater efficacy for a small number of other drugs.
Project description:Neuropathic pain is a chronic debilitating condition caused by injury or disease of the nerves of the somatosensory system. Although several therapeutic approaches are recommended, none has emerged as an optimal treatment leaving a need for developing more effective therapies. Given the small number of approved drugs and their limited clinical efficacy, combining drugs with different mechanisms of action is frequently used to yield greater efficacy. We demonstrate that the combination of trazodone, a multifunctional drug for the treatment of major depressive disorders, and gabapentin, a GABA analogue approved for neuropathic pain relief, results in a synergistic antinociceptive effect in the mice writhing test. To explore the potential relevance of this finding in chronic neuropathic pain, pharmacodynamic interactions between low doses of trazodone (0.3 mg/kg) and gabapentin (3 mg/kg) were evaluated in the chronic constriction injury (CCI) rat model, measuring the effects of the two drugs both on evoked and spontaneous nociception and on general well being components. Two innate behaviors, burrowing and nest building, were used to assess these aspects. Besides exerting a significant antinociceptive effect on hyperalgesia and on spontaneous pain, combined inactive doses of trazodone and gabapentin restored in CCI rats innate behaviors that are strongly reduced or even abolished during persistent nociception, suggesting that the combination may have an impact also on pain components different from somatosensory perception. Our results support the development of a trazodone and gabapentin low doses combination product for optimal multimodal analgesia treatment.
Project description:BackgroundNeuropathic pain is thought to arise from damage to the somatosensory nervous system. Its prevalence is increasing in line with many chronic disorders such as diabetes. All treatments have limited effectiveness. Given the evidence regarding psychological treatment for distress and disability in people with various chronic pain conditions, we were interested to investigate whether psychological treatments have any effects for those with chronic neuropathic pain.ObjectivesTo assess the effects of psychological treatments on pain experience, disability, mood, and health-care use in adults with chronic neuropathic pain.Search methodsWe searched for randomised controlled trials (RCTs) published in any language in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and PsycINFO, from database inception to March 2015.Selection criteriaFull publications of RCTs on psychological interventions for neuropathic pain. Trials had to have lasted at least three months, had at least 20 participants in each arm at the end of treatment, and compared a psychological intervention with any active or inactive intervention.Data collection and analysisWe used the standard methodological procedures expected by Cochrane.Main resultsTwo small studies (enrolling a total of 105 participants) met the inclusion criteria. One was a standard cognitive behavioural treatment (CBT) programme for 61 people with pain from spinal cord injury, followed up for three months, and compared with a waiting list. The other was weekly group psychotherapy for 44 people with burning mouth syndrome, compared with a daily placebo tablet. The overall risk of bias was high in both trials.The CBT study assessed participants for pain, disability, mood, and quality of life, with improvement in treatment and control groups. However, there was no more improvement in the treatment group than in the control for any outcome, either post-treatment or at follow-up. The group psychotherapy study only assessed pain, classifying participants by pain severity. There is a lack of evidence on the efficacy and safety of psychological interventions for people with neuropathic pain.Authors' conclusionsThere is insufficient evidence of the efficacy and safety of psychological interventions for chronic neuropathic pain. The two available studies show no benefit of treatment over either waiting list or placebo control groups.
Project description:This study aimed to explore the influence of chronic stress, measured through hair cortisol, on executive functions in individuals with chronic pain. We expected that there would be significant differences in chronic stress and executive functioning between pain patients and healthy controls, as well as between primary and secondary pain classifications. We also hypothesized that hair cortisol concentration was predictive of worse performance on tests of executive functions, controlling for objective and subjective covariates. For this study, 122 participants provided a hair sample (n = 40 with fibromyalgia; n = 24 with peripheral neuropathic pain; n = 58 matched healthy controls). Eighty-four of these participants also completed highly detailed testing of executive functions (n = 40 with fibromyalgia; n = 24 with peripheral neuropathic pain; n = 20 healthy controls). To assess differences in stress levels and executive functions, t-tests were used to compare patients with controls as well as fibromyalgia with peripheral neuropathic pain. Then, univariate regressions were used to explore associations between stress and executive functioning in both chronic pain classifications. Any significant univariate associations were carried over to hierarchical multivariate regression models. We found that patients with chronic pain had significantly higher cortisol levels than healthy controls, but all groups showed similar executive functioning. Hierarchical multiple regression analyses disclosed that in a model controlling for age, sex and pain medication usage, hair cortisol levels explained 8% of the variance in spatial working memory strategy in individuals with chronic pain. The overall model explained 24% of the variance in spatial working memory. In a second model using imputed data, including both objective and subjectively reported covariates, hair cortisol levels explained 9% of the variance, and the full model 31% of the variance in spatial working memory performance. Higher levels of cortisol indicated worse performance. In this study, an applied measure of chronic stress, namely hair cortisol, explained a substantial part of the variance on a spatial working memory task. The current results have important implications for understanding and treating cognitive impairments in chronic pain.
Project description:Existing studies on cognitive impairments in chronic pain do not investigate peripheral neuropathic pain (PNP) or compare pain conditions in a satisfactory manner. Here we aimed to compare executive dysfunctions in PNP patients with fibromyalgia (FM) and healthy controls (HC). Patients who self-reported cognitive impairments were assessed according to criteria for PNP or FM. Seventy-three patients met criteria and completed testing on executive functioning and IQ measures. We also included twenty matched healthy controls. Regression models controlling for age, sex and IQ, tested associations between group category (PNP, FM or HC) and outcomes. If a substantial association was detected, we followed up with head-to-head comparisons between PNP and FM. Multivariate regression models then tested associations between executive functioning and pain type, controlling for significant confounders. Results from head-to-head comparison between pain conditions showed significant differences on years lived with pain (FM?>?PNP), the use of anticonvulsants (PNP?>?FM) and use of analgesics (PNP?>?FM). When controlled for all significant differences, PNP patients had significantly lower scores on an attention-demanding cued-recall task compared to FM. Poor performance on attention-demanding cued-recall task was associated with PNP, which translate into problems with retaining fast-pace or advanced information.
Project description:ObjectiveTo determine whether duloxetine is noninferior to (as good as) pregabalin in the treatment of pain associated with diabetic peripheral neuropathy.Patients and methodsWe performed a 12-week, open-label study of patients with diabetic peripheral neuropathic pain who had been treated with gabapentin (≥ 900 mg/d) and had an inadequate response (defined as a daily pain score of ≥ 4 on a numerical rating scale [0-10 points]). The first patient was enrolled on September 28, 2006, and the last patient visit occurred on August 26, 2009. Patients were randomized to duloxetine monotherapy (n=138), pregabalin monotherapy (n=134), or a combination of duloxetine and gabapentin (n=135). The primary objective was a noninferiority comparison between duloxetine and pregabalin on improvement in the weekly mean of the diary-based daily pain score (0- to 10-point scale) at end point. Noninferiority would be declared if the mean improvement for duloxetine was no worse than the mean improvement for pregabalin, within statistical variability, by a margin of -0.8 unit.ResultsThe mean change in the pain rating at end point was -2.6 for duloxetine and -2.1 for pregabalin. The 97.5% lower confidence limit was a -0.05 difference in means, establishing noninferiority. As to adverse effects, nausea, insomnia, hyperhidrosis, and decreased appetite were more frequent with duloxetine than pregabalin; insomnia, more frequent with duloxetine than duloxetine plus gabapentin; peripheral edema, more frequent with pregabalin than with duloxetine; and nausea, hyperhidrosis, decreased appetite, and vomiting, more frequent with duloxetine plus gabapentin than with pregabalin.ConclusionDuloxetine was noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had an inadequate pain response to gabapentin.Trial registrationclinicaltrials.gov Identifier: NCT00385671.