BACKGROUND: Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain. Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients. With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy.
OBJECTIVES: To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions.
SEARCH METHODS: We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews.
SELECTION CRITERIA: We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause.
DATA COLLECTION AND ANALYSIS: We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively.
MAIN RESULTS: Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P < 0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias.
AUTHORS' CONCLUSIONS: Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.
BACKGROUND: This is an updated version of the original Cochrane Review published in 2010, Issue 9, and last updated in 2014, Issue 4. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS) and reduced impedance non-invasive cortical electrostimulation (RINCE).
OBJECTIVES: To evaluate the efficacy of non-invasive cortical stimulation techniques in the treatment of chronic pain.
SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, LILACS and clinical trials registers from July 2013 to October 2017.
SELECTION CRITERIA: Randomised and quasi-randomised studies of rTMS, CES, tDCS, RINCE and tRNS if they employed a sham stimulation control group, recruited patients over the age of 18 years with pain of three months' duration or more, and measured pain as an outcome. Outcomes of interest were pain intensity measured using visual analogue scales or numerical rating scales, disability, quality of life and adverse events.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and verified data. Where possible we entered data into meta-analyses, excluding studies judged as high risk of bias. We used the GRADE system to assess the quality of evidence for core comparisons, and created three 'Summary of findings' tables.
MAIN RESULTS: We included an additional 38 trials (involving 1225 randomised participants) in this update, making a total of 94 trials in the review (involving 2983 randomised participants). This update included a total of 42 rTMS studies, 11 CES, 36 tDCS, two RINCE and two tRNS. One study evaluated both rTMS and tDCS. We judged only four studies as low risk of bias across all key criteria. Using the GRADE criteria we judged the quality of evidence for each outcome, and for all comparisons as low or very low; in large part this was due to issues of blinding and of precision.rTMSMeta-analysis of rTMS studies versus sham for pain intensity at short-term follow-up (0 to < 1 week postintervention), (27 studies, involving 655 participants), demonstrated a small effect with heterogeneity (standardised mean difference (SMD) -0.22, 95% confidence interval (CI) -0.29 to -0.16, low-quality evidence). This equates to a 7% (95% CI 5% to 9%) reduction in pain, or a 0.40 (95% CI 0.53 to 0.32) point reduction on a 0 to 10 pain intensity scale, which does not meet the minimum clinically important difference threshold of 15% or greater. Pre-specified subgroup analyses did not find a difference between low-frequency stimulation (low-quality evidence) and rTMS applied to the prefrontal cortex compared to sham for reducing pain intensity at short-term follow-up (very low-quality evidence). High-frequency stimulation of the motor cortex in single-dose studies was associated with a small short-term reduction in pain intensity at short-term follow-up (low-quality evidence, pooled n = 249, SMD -0.38 95% CI -0.49 to -0.27). This equates to a 12% (95% CI 9% to 16%) reduction in pain, or a 0.77 (95% CI 0.55 to 0.99) point change on a 0 to 10 pain intensity scale, which does not achieve the minimum clinically important difference threshold of 15% or greater. The results from multiple-dose studies were heterogeneous and there was no evidence of an effect in this subgroup (very low-quality evidence). We did not find evidence that rTMS improved disability. Meta-analysis of studies of rTMS versus sham for quality of life (measured using the Fibromyalgia Impact Questionnaire (FIQ) at short-term follow-up demonstrated a positive effect (MD -10.80 95% CI -15.04 to -6.55, low-quality evidence).CESFor CES (five studies, 270 participants) we found no evidence of a difference between active stimulation and sham (SMD -0.24, 95% CI -0.48 to 0.01, low-quality evidence) for pain intensity. We found no evidence relating to the effectiveness of CES on disability. One study (36 participants) of CES versus sham for quality of life (measured using the FIQ) at short-term follow-up demonstrated a positive effect (MD -25.05 95% CI -37.82 to -12.28, very low-quality evidence).tDCSAnalysis of tDCS studies (27 studies, 747 participants) showed heterogeneity and a difference between active and sham stimulation (SMD -0.43 95% CI -0.63 to -0.22, very low-quality evidence) for pain intensity. This equates to a reduction of 0.82 (95% CI 0.42 to 1.2) points, or a percentage change of 17% (95% CI 9% to 25%) of the control group outcome. This point estimate meets our threshold for a minimum clinically important difference, though the lower confidence interval is substantially below that threshold. We found evidence of small study bias in the tDCS analyses. We did not find evidence that tDCS improved disability. Meta-analysis of studies of tDCS versus sham for quality of life (measured using different scales across studies) at short-term follow-up demonstrated a positive effect (SMD 0.66 95% CI 0.21 to 1.11, low-quality evidence).Adverse eventsAll forms of non-invasive brain stimulation and sham stimulation appear to be frequently associated with minor or transient side effects and there were two reported incidences of seizure, both related to the active rTMS intervention in the included studies. However many studies did not adequately report adverse events.
AUTHORS' CONCLUSIONS: There is very low-quality evidence that single doses of high-frequency rTMS of the motor cortex and tDCS may have short-term effects on chronic pain and quality of life but multiple sources of bias exist that may have influenced the observed effects. We did not find evidence that low-frequency rTMS, rTMS applied to the dorsolateral prefrontal cortex and CES are effective for reducing pain intensity in chronic pain. The broad conclusions of this review have not changed substantially for this update. There remains a need for substantially larger, rigorously designed studies, particularly of longer courses of stimulation. Future evidence may substantially impact upon the presented results.
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.
BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews, 2005, Issue 4 (and last updated in the Cochrane Database of Systematic Reviews, 2013 issue 8), on local anaesthetic blockade (LASB) of the sympathetic chain to treat people with complex regional pain syndrome (CRPS).
OBJECTIVES: To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure.
SEARCH METHODS: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (Ovid), EMBASE (Ovid), LILACS (Birme), conference abstracts of the World Congresses of the International Association for the Study of Pain, and various clinical trial registers up to September 2015. We also searched bibliographies from retrieved articles for additional studies.
SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that evaluated the effect of sympathetic blockade with local anaesthetics in children or adults with CRPS compared to placebo, no treatment, or alternative treatments.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The outcomes of interest were reduction in pain intensity, the proportion who achieved moderate or substantial pain relief, the duration of pain relief, and the presence of adverse effects in each treatment arm. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table.
MAIN RESULTS: We included an additional four studies (N = 154) in this update. For this update, we excluded studies that did not follow up patients for more than 48 hours. As a result, we excluded four studies from the previous review in this update. Overall we included 12 studies (N = 461), all of which we judged to be at high or unclear risk of bias. Overall, the quality of evidence was low to very low, downgraded due to limitations, inconsistency, imprecision, indirectness, or a combination of these.Two small studies compared LASB to placebo/sham (N = 32). They did not demonstrate significant short-term benefit for LASB for pain intensity (moderate quality evidence).One small study (N = 36) at high risk of bias compared thoracic sympathetic block with corticosteroid and local anaesthetic versus injection of the same agents into the subcutaneous space, reporting statistically significant and clinically important differences in pain intensity at one-year follow-up but not at short term follow-up (very low quality evidence).Of two studies that investigated LASB as an addition to rehabilitation treatment, the only study that reported pain outcomes demonstrated no additional benefit from LASB (very low quality evidence).Eight small randomised studies compared sympathetic blockade to various other active interventions. Most studies found no difference in pain outcomes between sympathetic block versus other active treatments (low to very low quality evidence).One small study compared ultrasound-guided LASB with non-guided LASB and found no clinically important difference in pain outcomes (very low quality evidence).Six studies reported adverse events, all with minor effects reported.
AUTHORS' CONCLUSIONS: This update's results are similar to the previous versions of this systematic review, and the main conclusions are unchanged. There remains a scarcity of published evidence and a lack of high quality evidence to support or refute the use of local anaesthetic sympathetic blockade for CRPS. From the existing evidence, it is not possible to draw firm conclusions regarding the efficacy or safety of this intervention, but the limited data available do not suggest that LASB is effective for reducing pain in CRPS.
BACKGROUND: This review is an update of a review first published in Issue 2, 2003, which was substantially updated in Issue 7, 2010. The concept that many neuropathic pain syndromes (traditionally this definition would include complex regional pain syndromes (CRPS)) are "sympathetically maintained pains" has historically led to treatments that interrupt the sympathetic nervous system. Chemical sympathectomies use alcohol or phenol injections to destroy ganglia of the sympathetic chain, while surgical ablation is performed by open removal or electrocoagulation of the sympathetic chain or by minimally invasive procedures using thermal or laser interruption.
OBJECTIVES: To review the evidence from randomised, double blind, controlled trials on the efficacy and safety of chemical and surgical sympathectomy for neuropathic pain, including complex regional pain syndrome. Sympathectomy may be compared with placebo (sham) or other active treatment, provided both participants and outcome assessors are blind to treatment group allocation.
SEARCH METHODS: On 2 July 2013, we searched CENTRAL, MEDLINE, EMBASE, and the Oxford Pain Relief Database. We reviewed the bibliographies of all randomised trials identified and of review articles and also searched two clinical trial databases, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, to identify additional published or unpublished data. We screened references in the retrieved articles and literature reviews and contacted experts in the field of neuropathic pain.
SELECTION CRITERIA: Randomised, double blind, placebo or active controlled studies assessing the effects of sympathectomy for neuropathic pain and CRPS.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and validity, and extracted data. No pooled analysis of data was possible.
MAIN RESULTS: Only one study satisfied our inclusion criteria, comparing percutaneous radiofrequency thermal lumbar sympathectomy with lumbar sympathetic neurolysis using phenol in 20 participants with CRPS. There was no comparison of sympathectomy versus sham or placebo. No dichotomous pain outcomes were reported. Average baseline scores of 8-9/10 on several pain scales fell to about 4/10 initially (1 day) and remained at 3-5/10 over four months. There were no significant differences between groups, except for "unpleasant sensation", which was higher with radiofrequency ablation. One participant in the phenol group experienced post sympathectomy neuralgia, while two in the radiofrequency group and one in the phenol group complained of paraesthesia during needle positioning. All participants had soreness at the injection site.
AUTHORS' CONCLUSIONS: The practice of surgical and chemical sympathectomy for neuropathic pain and CRPS is based on very little high quality evidence. Sympathectomy should be used cautiously in clinical practice, in carefully selected patients, and probably only after failure of other treatment options. In these circumstances, establishing a clinical register of sympathectomy may help to inform treatment options on an individual patient basis.
Journal»International journal of rehabilitation research. Internationale Zeitschrift für Rehabilitationsforschung. Revue internationale de recherches de réadaptation
The objective of this study was to evaluate the clinical aspects of mirror therapy (MT) interventions after stroke, phantom limb pain and complex regional pain syndrome. A systematic literature search of the Cochrane Database of controlled trials, PubMed/MEDLINE, CINAHL, EMBASE, PsycINFO, PEDro, RehabTrials and Rehadat, was made by two investigators independently (A.S.R. and M.J.). No restrictions were made regarding study design and type or localization of stroke, complex regional pain syndrome and amputation. Only studies that had MT given as a long-term treatment were included. Two authors (A.S.R. and S.M.B.) independently assessed studies for eligibility and risk of bias by using the Amsterdam-Maastricht Consensus List. Ten randomized trials, seven patient series and four single-case studies were included. The studies were heterogeneous regarding design, size, conditions studied and outcome measures. Methodological quality varied; only a few studies were of high quality. Important clinical aspects, such as assessment of possible side effects, were only insufficiently addressed. For stroke there is a moderate quality of evidence that MT as an additional intervention improves recovery of arm function, and a low quality of evidence regarding lower limb function and pain after stroke. The quality of evidence in patients with complex regional pain syndrome and phantom limb pain is also low. Firm conclusions could not be drawn. Little is known about which patients are likely to benefit most from MT, and how MT should preferably be applied. Future studies with clear descriptions of intervention protocols should focus on standardized outcome measures and systematically register adverse effects.
Purpose This narrative review summarizes the evidence derived from randomized controlled trials pertaining to the treatment of complex regional pain syndrome (CRPS). Source Using the MEDLINE (January 1950 to April 2009) and EMBASE (January 1980 to April 2009) databases, the following medical subject headings (MeSH) were searched: "Complex Regional Pain Syndrome", "Reflex Sympathetic Dystrophy", and "causalgia" as well as the key words "algodystrophy", "Sudeck's atrophy", "shoulder hand syndrome", "neurodystrophy", "neuroalgodystrophy", "reflex neuromuscular dystrophy", and "posttraumatic dystrophy". Results were limited to randomized controlled trials (RCTs) conducted on human subjects, written in English, published in peer-reviewed journals, and pertinent to treatment. Principal findings The search criteria yielded 41 RCTs with a mean of 31.7 subjects per study. Blinded assessment and sample size justification were provided in 70.7% and 19.5% of RCTs, respectively. Only biphosphonates appear to offer clear benefits for patients with CRPS. Improvement has been reported with dimethyl sulfoxide, steroids, epidural clonidine, intrathecal baclofen, spinal cord stimulation, and motor imagery programs, but further trials are required. The available evidence does not support the use of calcitonin, vasodilators, or sympatholytic and neuromodulative intravenous regional blockade. Clear benefits have not been reported with stellate/lumbar sympathetic blocks, mannitol, gabapentin, and physical/ occupational therapy. Conclusions Published RCTs can only provide limited evidence to formulate recommendations for treatment of CRPS. In this review, no study was excluded based on factors such as sample size justification, statistical power, blinding, definition of intervention allocation, or clinical outcomes. Thus, evidence derived from "weaker" trials may be overemphasized. Further well-designed RCTs are warranted.
Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain. Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients. With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy.
OBJECTIVES:
To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions.
SEARCH METHODS:
We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews.
SELECTION CRITERIA:
We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause.
DATA COLLECTION AND ANALYSIS:
We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively.
MAIN RESULTS:
Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI.: -15 to -7; P < 0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI.: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias.
AUTHORS' CONCLUSIONS:
Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.
