BACKGROUND: This review is an update of a review of tramadol for neuropathic pain, published in 2006; updating was to bring the review in line with current standards. Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Peripheral neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the peripheral nervous system.
OBJECTIVES: To assess the analgesic efficacy of tramadol compared with placebo or other active interventions for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials.
SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from inception to January 2017. 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 two weeks' duration or longer, comparing tramadol (any route of administration) with placebo or another active treatment for neuropathic pain, 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 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). 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), using standard methods. We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.
MAIN RESULTS: We identified six randomised, double-blind studies involving 438 participants with suitably characterised neuropathic pain. In each, tramadol was started at a dose of about 100 mg daily and increased over one to two weeks to a maximum of 400 mg daily or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months due to cancer, cancer treatment, postherpetic neuralgia, peripheral diabetic neuropathy, spinal cord injury, or polyneuropathy. The mean age was 50 to 67 years with approximately equal numbers of men and women. Exclusions were typically people with other significant comorbidity or pain from other causes. Study duration for treatments was four to six weeks, and two studies had a cross-over design.Not all studies reported all the outcomes of interest, and there were limited data for pain outcomes. At least 50% pain intensity reduction was reported in three studies (265 participants, 110 events). Using a random-effects analysis, 70/132 (53%) had at least 50% pain relief with tramadol, and 40/133 (30%) with placebo; the risk ratio (RR) was 2.2 (95% confidence interval (CI) 1.02 to 4.6). The NNT calculated from these data was 4.4 (95% CI 2.9 to 8.8). We downgraded the evidence for this outcome by two levels to low quality because of the small size of studies and of the pooled data set, because there were only 110 actual events, the analysis included different types of neuropathic pain, the studies all had at least one high risk of potential bias, and because of the limited duration of the studies.Participants experienced more adverse events with tramadol than placebo. Report of any adverse event was higher with tramadol (58%) than placebo (34%) (4 studies, 266 participants, 123 events; RR 1.6 (95% CI 1.2 to 2.1); NNH 4.2 (95% CI 2.8 to 8.3)). Adverse event withdrawal was higher with tramadol (16%) than placebo (3%) (6 studies, 485 participants, 45 events; RR 4.1 (95% CI 2.0 to 8.4); NNH 8.2 (95% CI 5.8 to 14)). Only four serious adverse events were reported, without obvious attribution to treatment, and no deaths were reported. We downgraded the evidence for this outcome by two or three levels to low or very low quality because of small study size, because there were few actual events, and because of the limited duration of the studies.
AUTHORS' CONCLUSIONS: There is only modest information about the use of tramadol in neuropathic pain, coming from small, largely inadequate studies with potential risk of bias. That bias would normally increase the apparent benefits of tramadol. The evidence of benefit from tramadol was of low or very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood is very high that the effect will be substantially different from the estimate in this systematic review.
Methods: We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CNP. We included double-blind randomized placebo-controlled studies of at least 4 weeks duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables.
Results: We included 12 RCTs with 1192 participants. The included diagnostic entities were painful diabetic neuropathy (four studies), postherpetic neuralgia (three studies), mixed polyneuropathic pain (two studies), and lumbar root, spinal cord injury and postamputation pain (one study each). Mean study duration was 6 (4–12) weeks. Four studies tested morphine, three studies tramadol, two studies oxycodone and one study tapentadol. These are the pooled results of studies with a parallel or cross-over design: opioids were superior to placebo in reducing pain intensity (SMD − 0.64 [95 % confidence interval, CI − 0.81, − 0.46], p < 0.0001; 11 studies with 1040 participants). Opioids were not superior to placebo in 50 % pain reduction (RD 0.16 [95 % CI − 0.04, 0.35], p = 0.11; one study with 93 participants). Opioids were not superior to placebo in reports of much or very much improved pain (RD 0.17 [95 % CI − 0.01, 0.36], p = 0.07; one study with 53 participants). Opioids were superior to placebo in improving physical functioning (SMD − 0.28 [95 % CI − 0.43, − 0.13], p < 0.0001; seven studies with 680 participants). Patients dropped out less frequently due to lack of efficacy with opioids than with placebo (RD − 0.07 [95 % CI − 0.13, − 0.02], p = 0.008; six studies with 656 participants). Patients dropped out due to adverse events more frequently with opioids than with placebo (RD 0.08 [95 % CI 0.05, 0.12], p < 0.0001; ten studies with 1018 participants; number needed to harm 11 [95 % CI 8–17]). There was no significant difference between opioids and placebo in terms of the frequency of serious adverse events (SAE) or deaths.
Background: The efficacy and safety of opioid therapy in chronic neuropathic pain (CNP) is under debate. We updated a recent Cochrane systematic review on the efficacy, tolerability and safety of opioids in CNP.
Conclusion: In short-term studies (4–12 weeks) in CNP, opioids were superior to placebo in terms of efficacy and inferior in terms of tolerability. Opioids and placebo did not differ in terms of safety. The conclusion relating to the safety of opioids compared to placebo in CNP is limited by the low number of SAE and deaths. Short-term opioid therapy may be considered in selected CNP patients.
The English full-text version of this article is freely available at SpringerLink (under “Supplementary Material”).
BACKGROUND: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.
METHODS: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.
FINDINGS: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.
INTERPRETATION: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.
FUNDING: NeuPSIG of the International Association for the Study of Pain.
OBJECTIVE: To conduct a systematic review of available data from reports of randomized controlled trials on the efficacy, safety, and tolerability of drugs used to treat postherpetic neuralgia (PHN), a common type of neuropathic pain.
DATA SOURCES: The MEDLINE (1950-June 30, 2009) and EMBASE (1974-June 30, 2009) databases were used to identify source studies, in conjunction with a review of reference citations from identified published reports.
STUDY SELECTION AND DATA EXTRACTION: We selected all English-language reports of randomized placebo-controlled trials of the efficacy, tolerability, and safety of drugs (oral or transdermal) used for treatment in patients with PHN. Studies with treatment duration less than 4 weeks were excluded. From each identified trial, we extracted information on (1) placebo-corrected percentage reductions in pain intensity from randomization to end of active treatment; (2) relative risks of withdrawal due to lack of efficacy; (3) relative risks of various adverse events; and (4) relative risks of withdrawal due to adverse events.
DATA SYNTHESIS: Twelve reports of randomized controlled trials in patients with PHN were identified, involving 8 different agents (amitriptyline, capsaicin, divalproex sodium, gabapentin, morphine, nortriptyline, pregabalin, tramadol). Most studies were small, involving fewer than 200 patients. Pain intensity was reported to have been reduced significantly with all drugs (range: 13.8% [tramadol] to 42.4% [amitriptyline]); data were pooled using techniques of meta-analysis when information was available from more than 1 trial. No clinical trial reported a significant reduction in risk of withdrawal as a result of lack of efficacy. Analysis of adverse events was greatly limited by erratic and inconsistent reporting and wide variation in sample sizes.
CONCLUSIONS: While available literature establishes the efficacy of 8 drugs in treatment of PHN, it does not provide adequate guidance as to which agents are best to treat this condition, in part because of inadequate reporting of data on tolerability and safety.
BACKGROUND: An enriched enrollment randomized withdrawal (EERW) design excludes potential participants who are nonresponders or who cannot tolerate the experimental drug before random assignment. It is unclear whether EERW design has an influence on the efficacy and safety of opioids for chronic noncancer pain (CNCP).
OBJECTIVES: The primary objective was to compare the results from EERW and non-EERW trials of opioids for CNCP. Secondary objectives were to compare weak versus strong opioids, subgroups of patients with different types of pain, and the efficacy of opiods compared with placebo versus other drugs.
METHODS: MEDLINE, EMBASE and CENTRAL were searched up to July 2009, for randomized controlled trials of any opioid for CNCP. Metaanalyses and meta-regressions were conducted to compare the results. Treatment efficacy was assessed by effect sizes (small, medium and large) and the incidence of adverse effects was assessed by a clinically relevant mean difference of 10% or greater.
RESULTS: Sixty-two randomized trials were included. In 61 trials, the duration was less than 16 weeks. There was no difference in efficacy between EERW and non-EERW trials for both pain (P=0.6) and function (P=0.3). However, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness and dry skin⁄itching compared with non-EERW. Opioids were more effective than placebo in patients with nociceptive pain (effect size=0.60, 95% CI 0.49 to 0.72) and neuropathic pain (effect size=0.56, 95% CI 0.38 to 0.73).
CONCLUSION: EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta- analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin.
Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.
This systematic review summarizes existing evidence regarding the efficacy, safety, and abuse and misuse potential of opioids as treatment for chronic noncancer pain in older adults. Multiple databases were searched to identify relevant studies published in English (1/1/80-7/1/09) with a mean study population age of 60 and older. Forty-three articles were identified and retained for review (40 reported safety and efficacy data, the remaining 3 reported misuse or abuse outcome data). The weighted mean subject age was 64.1 (mean age range 60-73). Studies enrolled patients with osteoarthritis (70%), neuropathic pain (13%), and other pain-producing disorders (17%). The mean duration of treatment studies was 4 weeks (range 1.5-156 weeks), and only five (12%) lasted longer than 12 weeks. In meta-analyses, effect sizes were -0.557 ( P<.001) for pain reduction, -0.432 ( P<.001) for physical disability reduction, and 0.859 ( P=.31) for improved sleep. The effect size for the Medical Outcomes Study 36-item Health Survey was 0.191 ( P=.17) for the physical component score and -0.220 ( P=.04) for the mental component score. Adults aged 65 and older were as likely as those younger than 65 to benefit from treatment. Common adverse events included constipation (median frequency of occurrence 30%), nausea (28%), and dizziness (22%) and prompted opioid discontinuation in 25% of cases. Abuse and misuse behaviors were negatively associated with older age. In older adults with chronic pain and no significant comorbidity, short-term use of opioids is associated with reduction in pain intensity and better physical functioning but poorer mental health functioning. The long-term safety, efficacy, and abuse potential of this treatment practice in diverse populations of older persons remain to be determined.
BACKGROUND: There is little evidence that short-acting opioids as rescue medication for breakthrough pain is an optimal long-term treatment strategy in chronic non-malignant pain. We compared clinical studies of long-acting opioids that allowed short-acting opioid rescue medication with those that did not, to determine the impact of opioid rescue medication use on the analgesic efficacy and tolerability of chronic opioid therapy in patients with chronic non-malignant pain.
METHODS: We searched MEDLINE (1950 to July 2006) and EMBASE (1974 to July 2006) using terms for chronic non-malignant pain and long-acting opioids. Independent review of the search results identified 48 studies that met the study selection criteria. The effect of opioid rescue medication on analgesic efficacy and the incidence of common opioid-related side-effects were analysed using meta-regression.
RESULTS: After adjusting for potentially confounding variables (study design and type of opioid), the difference in analgesic efficacy between the 'rescue' and the 'no rescue' studies was not significant, with regression coefficients close to 0 and 95% confidence intervals that excluded an effect of more than 18 points on a 0-100 scale in each case. There was also no significant difference between the 'rescue' and the 'no rescue' studies for the incidence of nausea, constipation, or somnolence in both the unadjusted and the adjusted analyses.
CONCLUSIONS: We found no evidence that rescue medication with short-acting opioids for breakthrough pain affects analgesic efficacy of long-acting opioids or the incidence of common opioid-related side-effects among chronic non-malignant pain patients.
This review is an update of a review of tramadol for neuropathic pain, published in 2006; updating was to bring the review in line with current standards. Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Peripheral neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the peripheral nervous system.
OBJECTIVES:
To assess the analgesic efficacy of tramadol compared with placebo or other active interventions for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials.
SEARCH METHODS:
We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from inception to January 2017. 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 two weeks' duration or longer, comparing tramadol (any route of administration) with placebo or another active treatment for neuropathic pain, 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 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). 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), using standard methods. We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.
MAIN RESULTS:
We identified six randomised, double-blind studies involving 438 participants with suitably characterised neuropathic pain. In each, tramadol was started at a dose of about 100 mg daily and increased over one to two weeks to a maximum of 400 mg daily or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months due to cancer, cancer treatment, postherpetic neuralgia, peripheral diabetic neuropathy, spinal cord injury, or polyneuropathy. The mean age was 50 to 67 years with approximately equal numbers of men and women. Exclusions were typically people with other significant comorbidity or pain from other causes. Study duration for treatments was four to six weeks, and two studies had a cross-over design.Not all studies reported all the outcomes of interest, and there were limited data for pain outcomes. At least 50% pain intensity reduction was reported in three studies (265 participants, 110 events). Using a random-effects analysis, 70/132 (53%) had at least 50% pain relief with tramadol, and 40/133 (30%) with placebo; the risk ratio (RR) was 2.2 (95% confidence interval (CI) 1.02 to 4.6). The NNT calculated from these data was 4.4 (95% CI 2.9 to 8.8). We downgraded the evidence for this outcome by two levels to low quality because of the small size of studies and of the pooled data set, because there were only 110 actual events, the analysis included different types of neuropathic pain, the studies all had at least one high risk of potential bias, and because of the limited duration of the studies.Participants experienced more adverse events with tramadol than placebo. Report of any adverse event was higher with tramadol (58%) than placebo (34%) (4 studies, 266 participants, 123 events; RR 1.6 (95% CI 1.2 to 2.1); NNH 4.2 (95% CI 2.8 to 8.3)). Adverse event withdrawal was higher with tramadol (16%) than placebo (3%) (6 studies, 485 participants, 45 events; RR 4.1 (95% CI 2.0 to 8.4); NNH 8.2 (95% CI 5.8 to 14)). Only four serious adverse events were reported, without obvious attribution to treatment, and no deaths were reported. We downgraded the evidence for this outcome by two or three levels to low or very low quality because of small study size, because there were few actual events, and because of the limited duration of the studies.
AUTHORS' CONCLUSIONS:
There is only modest information about the use of tramadol in neuropathic pain, coming from small, largely inadequate studies with potential risk of bias. That bias would normally increase the apparent benefits of tramadol. The evidence of benefit from tramadol was of low or very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood is very high that the effect will be substantially different from the estimate in this systematic review.
