BACKGROUND: Complex regional pain syndrome (CRPS) is a painful and disabling condition that usually manifests in response to trauma or surgery and is associated with significant pain and disability. CRPS can be classified into two types: type I (CRPS I) in which a specific nerve lesion has not been identified and type II (CRPS II) where there is an identifiable nerve lesion. Guidelines recommend the inclusion of a variety of physiotherapy interventions as part of the multimodal treatment of people with CRPS. This is the first update of the review originally published in Issue 2, 2016.
OBJECTIVES: To determine the effectiveness of physiotherapy interventions for treating pain and disability associated with CRPS types I and II in adults.
SEARCH METHODS: For this update we searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, PEDro, Web of Science, DARE and Health Technology Assessments from February 2015 to July 2021 without language restrictions, we searched the reference lists of included studies and we contacted an expert in the field. We also searched additional online sources for unpublished trials and trials in progress.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) of physiotherapy interventions compared with placebo, no treatment, another intervention or usual care, or other physiotherapy interventions in adults with CRPS I and II. Primary outcomes were pain intensity and disability. Secondary outcomes were composite scores for CRPS symptoms, health-related quality of life (HRQoL), patient global impression of change (PGIC) scales and adverse effects.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened database searches for eligibility, extracted data, evaluated risk of bias and assessed the certainty of evidence using the GRADE system.
MAIN RESULTS: We included 16 new trials (600 participants) along with the 18 trials from the original review totalling 34 RCTs (1339 participants). Thirty-three trials included participants with CRPS I and one trial included participants with CRPS II. Included trials compared a diverse range of interventions including physical rehabilitation, electrotherapy modalities, cortically directed rehabilitation, electroacupuncture and exposure-based approaches. Most interventions were tested in small, single trials. Most were at high risk of bias overall (27 trials) and the remainder were at 'unclear' risk of bias (seven trials). For all comparisons and outcomes where we found evidence, we graded the certainty of the evidence as very low, downgraded due to serious study limitations, imprecision and inconsistency. Included trials rarely reported adverse effects. Physiotherapy compared with minimal care for adults with CRPS I One trial (135 participants) of multimodal physiotherapy, for which pain data were unavailable, found no between-group differences in pain intensity at 12-month follow-up. Multimodal physiotherapy demonstrated a small between-group improvement in disability at 12 months follow-up compared to an attention control (Impairment Level Sum score, 5 to 50 scale; mean difference (MD) -3.7, 95% confidence interval (CI) -7.13 to -0.27) (very low-certainty evidence). Equivalent data for pain were not available. Details regarding adverse events were not reported. Physiotherapy compared with minimal care for adults with CRPS II We did not find any trials of physiotherapy compared with minimal care for adults with CRPS II.
AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effects of physiotherapy interventions on pain and disability in CRPS. This conclusion is similar to our 2016 review. Large-scale, high-quality RCTs with longer-term follow-up are required to test the effectiveness of physiotherapy-based interventions for treating pain and disability in adults with CRPS I and II.
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: The myocardial effects of phosphodiesterase type 5 inhibitors (PDE5i) have recently received consideration in several preclinical studies. The risk/benefit ratio in humans remains unclear.
METHODS: We performed a meta-analysis of randomized, placebo-controlled trials (RCTs) to evaluate the efficacy and safety of PDE5i on cardiac morphology and function. From March 2012 to December 2013 (update: May 2014), we searched English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and SCOPUS-selecting RCTs of continuous PDE5i administration that reported cardiovascular outcomes: cardiac geometry and performance, afterload, endothelial function and safety. The pooled estimate of a weighted mean difference between treatment and placebo was obtained for all outcomes using a random effects model. A test for heterogeneity was performed and the I2 statistic calculated.
RESULTS: Overall, 1,622 subjects were treated, with 954 randomized to PDE5i and 772 to placebo in 24 RCTs. According to our analysis, sustained PDE5 inhibition produced: (1) an anti-remodeling effect by reducing cardiac mass (-12.21 g/m2, 95% confidence interval (CI): -18.85; -5.57) in subjects with left ventricular hypertrophy (LVH) and by increasing end-diastolic volume (5.00 mL/m2; 95% CI: 3.29; 6.71) in non-LVH patients; (2) an improvement in cardiac performance by increasing cardiac index (0.30 L/min/m2, 95% CI: 0.202; 0.406) and ejection fraction (3.56%, 95% CI: 1.79; 5.33). These effects are parallel to a decline of N-terminal-pro brain natriuretic peptide (NT-proBNP) in subjects with severe LVH (-486.7 pg/ml, 95% CI: -712; -261). PDE5i administration also produced: (3) no changes in afterload parameters and (4) an improvement in flow-mediated vasodilation (3.31%, 95% CI: 0.53; 6.08). Flushing, headache, epistaxis and gastric symptoms were the commonest side effects.
CONCLUSIONS: This meta-analysis suggests for the first time that PDE5i have anti-remodeling properties and improve cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5i could be reasonably offered to men with cardiac hypertrophy and early stage heart failure. Given the limited gender data, a larger trial on the sex-specific response to long-term PDE5i treatment is required.
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.
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.
We conducted a systematic review of the literature on the effectiveness of spinal cord stimulation (SCS) in relieving pain and improving functioning for patients with failed back surgery syndrome and complex regional pain syndrome (CRPS). We also reviewed SCS complications. Literature searches yielded 583 articles, of which seven met the inclusion criteria for the review of SCS effectiveness, and 15 others met the criteria only for the review of SCS complications. Two authors independently extracted data from each article, and then resolved discrepancies by discussion. We identified only one randomized trial, which found that physical therapy (PT) plus SCS, compared with PT alone, had a statistically significant but clinically modest effect at 6 and 12 months in relieving pain among patients with CRPS. Similarly, six other studies of much lower methodological quality suggest mild to moderate improvement in pain with SCS. Pain relief with SCS appears to decrease over time. The one randomized trial suggested no benefits of SCS in improving patient functioning. Although life-threatening complications with SCS are rare, other adverse events are frequent. On average, 34% of patients who received a stimulator had an adverse occurrence. We conclude with suggestions for methodologically stronger studies to provide more definitive data regarding the effectiveness of SCS in relieving pain and improving functioning, short- and long-term, among patients with chronic pain syndromes.
Complex regional pain syndrome (CRPS) is a painful and disabling condition that usually manifests in response to trauma or surgery and is associated with significant pain and disability. CRPS can be classified into two types: type I (CRPS I) in which a specific nerve lesion has not been identified and type II (CRPS II) where there is an identifiable nerve lesion. Guidelines recommend the inclusion of a variety of physiotherapy interventions as part of the multimodal treatment of people with CRPS. This is the first update of the review originally published in Issue 2, 2016.
OBJECTIVES:
To determine the effectiveness of physiotherapy interventions for treating pain and disability associated with CRPS types I and II in adults.
SEARCH METHODS:
For this update we searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, PEDro, Web of Science, DARE and Health Technology Assessments from February 2015 to July 2021 without language restrictions, we searched the reference lists of included studies and we contacted an expert in the field. We also searched additional online sources for unpublished trials and trials in progress.
SELECTION CRITERIA:
We included randomised controlled trials (RCTs) of physiotherapy interventions compared with placebo, no treatment, another intervention or usual care, or other physiotherapy interventions in adults with CRPS I and II. Primary outcomes were pain intensity and disability. Secondary outcomes were composite scores for CRPS symptoms, health-related quality of life (HRQoL), patient global impression of change (PGIC) scales and adverse effects.
DATA COLLECTION AND ANALYSIS:
Two review authors independently screened database searches for eligibility, extracted data, evaluated risk of bias and assessed the certainty of evidence using the GRADE system.
MAIN RESULTS:
We included 16 new trials (600 participants) along with the 18 trials from the original review totalling 34 RCTs (1339 participants). Thirty-three trials included participants with CRPS I and one trial included participants with CRPS II. Included trials compared a diverse range of interventions including physical rehabilitation, electrotherapy modalities, cortically directed rehabilitation, electroacupuncture and exposure-based approaches. Most interventions were tested in small, single trials. Most were at high risk of bias overall (27 trials) and the remainder were at 'unclear' risk of bias (seven trials). For all comparisons and outcomes where we found evidence, we graded the certainty of the evidence as very low, downgraded due to serious study limitations, imprecision and inconsistency. Included trials rarely reported adverse effects. Physiotherapy compared with minimal care for adults with CRPS I One trial (135 participants) of multimodal physiotherapy, for which pain data were unavailable, found no between-group differences in pain intensity at 12-month follow-up. Multimodal physiotherapy demonstrated a small between-group improvement in disability at 12 months follow-up compared to an attention control (Impairment Level Sum score, 5 to 50 scale; mean difference (MD) -3.7, 95% confidence interval (CI) -7.13 to -0.27) (very low-certainty evidence). Equivalent data for pain were not available. Details regarding adverse events were not reported. Physiotherapy compared with minimal care for adults with CRPS II We did not find any trials of physiotherapy compared with minimal care for adults with CRPS II.
AUTHORS' CONCLUSIONS:
The evidence is very uncertain about the effects of physiotherapy interventions on pain and disability in CRPS. This conclusion is similar to our 2016 review. Large-scale, high-quality RCTs with longer-term follow-up are required to test the effectiveness of physiotherapy-based interventions for treating pain and disability in adults with CRPS I and II.
