Systematic review of topical diclofenac for the treatment of acute and chronic musculoskeletal pain.

Aim: The objective was to systematically review the efficacy and safety of topical diclofenac in both acute and chronic musculoskeletal pain in adults.Methods: We used standard Cochrane methods. Searches were conducted in MEDLINE, EMBASE and The Cochrane Register of Studies; date of the final search was November 2018. Included studies were randomized, double blinded, with ten or more participants per treatment arm. The primary outcome of "clinical success" was defined as participant-reported reduction in pain of at least 50%. Details of adverse events (AEs) were recorded.Results: For acute pain, 23 studies (5170 participants) were included. Compared to placebo, number needed to treat (NNT) for different formulations were as follows: diclofenac plaster, 4.7 (95% CI 3.7-6.5); diclofenac plaster with heparin, 7.4 (95% CI 4.6-19); and diclofenac Emulgel, 1.8 (95% CI 1.5-2.1). 4.1% (78/1919) reported a local AE. For chronic pain, 21 studies (26 publications) with 5995 participants were included. Formulations included gel, solution with or without DMSO, emulsion and plaster. A clinical success rate of ∼60% (NNT 9.5 [95% CI 7-14.7]) was achieved with a variety of formulations. Local AEs (∼14%) were similar for both diclofenac and placebo.Conclusion: This systematic review of 11,000+ participants demonstrates that topical diclofenac is effective for acute pain, such as sprains, with minimal AEs. The effectiveness of topical diclofenac was also demonstrated in chronic musculoskeletal pain but with a higher NNT (worse) compared with acute pain. Formulation does play a part in effectiveness but needs further studies.

Pharmacological interventions for painful sickle cell vaso-occlusive crises in adults.

BACKGROUND: Sickle cell disease (SCD) is a group of inherited disorders of haemoglobin (Hb) structure in a person who has inherited two mutant globin genes (one from each parent), at least one of which is always the sickle mutation. It is estimated that between 5% and 7% of the world's population are carriers of the mutant Hb gene, and SCD is the most commonly inherited blood disorder. SCD is characterized by distorted sickle-shaped red blood cells. Manifestations of the disease are attributed to either haemolysis (premature red cell destruction) or vaso-occlusion (obstruction of blood flow, the most common manifestation). Shortened lifespans are attributable to serious comorbidities associated with the disease, including renal failure, acute cholecystitis, pulmonary hypertension, aplastic crisis, pulmonary embolus, stroke, acute chest syndrome, and sepsis. Vaso-occlusion can lead to an acute, painful crisis (sickle cell crisis, vaso-occlusive crisis (VOC) or vaso-occlusive episode). Pain is most often reported in the joints, extremities, back or chest, but it can occur anywhere and can last for several days or weeks. The bone and muscle pain experienced during a sickle cell crisis is both acute and recurrent. Key pharmacological treatments for VOC include opioid analgesics, non-opioid analgesics, and combinations of drugs. Non-pharmacological approaches, such as relaxation, hypnosis, heat, ice and acupuncture, have been used in conjunction to rehydrating the patient and reduce the sickling process. OBJECTIVES: To assess the analgesic efficacy and adverse events of pharmacological interventions to treat acute painful sickle cell vaso-occlusive crises in adults, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, Embase via Ovid and LILACS, from inception to September 2019. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomized, controlled, double-blind trials of pharmacological interventions, of any dose and by any route, compared to placebo or any active comparator, for the treatment (not prevention) of painful sickle cell VOC in adults. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio (RR) and number needed to treat for one additional event, using standard methods. Our primary outcomes were participant-reported pain relief of 50%, or 30%, or greater; Patient Global Impression of Change (PGIC) very much improved, or much or very much improved. Our secondary outcomes included adverse events, serious adverse events, and withdrawals due to adverse events. We assessed GRADE and created three 'Summary of findings' tables. MAIN RESULTS: We included nine studies with data for 638 VOC events and 594 participants aged 17 to 42 years with SCD presenting to a hospital emergency department in a painful VOC. Three studies investigated a non-steroidal anti-inflammatory drug (NSAID) compared to placebo. One study compared an opioid with a placebo, two studies compared an opioid with an active comparator, two studies compared an anticoagulant with a placebo, and one study compared a combination of three drugs with a combination of four drugs. Risk of bias across the nine studies varied. Studies were primarily at an unclear risk of selection, performance, and detection bias. Studies were primarily at a high risk of bias for size with fewer than 50 participants per treatment arm; two studies had 50 to 199 participants per treatment arm (unclear risk). Non-steroidal anti-inflammatory drugs (NSAID) compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The efficacy was uncertain regarding PGIC very much improved, and PGIC much or very much improved (no difference; 1 study, 21 participants; very low-quality evidence). Very low-quality, uncertain results suggested similar rates of adverse events across both the NSAIDs group (16/45 adverse events, 1/56 serious adverse events, and 1/56 withdrawal due to adverse events) and the placebo group (19/45 adverse events, 2/56 serious adverse events, and 1/56 withdrawal due to adverse events). Opioids compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30%, PGIC, or adverse events (any adverse event, serious adverse events, and withdrawals due to adverse events). Opioids compared with active comparator No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The results were uncertain regarding PGIC very much improved (33% of the opioids group versus 19% of the placebo group). No data were reported regarding PGIC much or very much improved. Very low-quality, uncertain results suggested similar rates of adverse events across both the opioids group (9/66 adverse events, and 0/66 serious adverse events) and the placebo group (7/64 adverse events, 0/66 serious adverse events). No data were reported regarding withdrawal due to adverse events. Quality of the evidence We downgraded the quality of the evidence by three levels to very low-quality because there are too few data to have confidence in results (e.g. too few participants per treatment arm). Where no data were reported for an outcome, we had no evidence to support or refute (quality of the evidence is unknown). AUTHORS' CONCLUSIONS: This review identified only nine studies, with insufficient data for all pharmacological interventions for analysis. The available evidence is very uncertain regarding the efficacy or harm from pharmacological interventions used to treat pain related to sickle cell VOC in adults. This area could benefit most from more high quality, certain evidence, as well as the establishment of suitable registries which record interventions and outcomes for this group of people.

Pharmacological interventions for chronic pain in children: an overview of systematic reviews.

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.

Pregabalin for neuropathic pain in adults.

BACKGROUND: This review updates part of an earlier Cochrane Review titled "Pregabalin for acute and chronic pain in adults", and considers only neuropathic pain (pain from damage to nervous tissue). Antiepileptic drugs have long been used in pain management. Pregabalin is an antiepileptic drug used in management of chronic pain conditions. OBJECTIVES: To assess the analgesic efficacy and adverse effects of pregabalin for chronic neuropathic pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from January 2009 to April 2018, online clinical trials registries, and reference lists. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing pregabalin (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 biases. Primary outcomes were: at least 30% pain intensity reduction over baseline; much or very much improved on the Patient Global Impression of Change (PGIC) Scale (moderate benefit); at least 50% pain intensity reduction; or very much improved on PGIC (substantial benefit). We calculated risk ratio (RR) and number needed to treat for an additional beneficial (NNTB) or harmful outcome (NNTH). We assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 45 studies lasting 2 to 16 weeks, with 11,906 participants - 68% from 31 new studies. Oral pregabalin doses of 150 mg, 300 mg, and 600 mg daily were compared with placebo. Postherpetic neuralgia, painful diabetic neuropathy, and mixed neuropathic pain predominated (85% of participants). High risk of bias was due mainly to small study size (nine studies), but many studies had unclear risk of bias, mainly due to incomplete outcome data, size, and allocation concealment.Postherpetic neuralgia: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (50% vs 25%; RR 2.1 (95% confidence interval (CI) 1.6 to 2.6); NNTB 3.9 (3.0 to 5.6); 3 studies, 589 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (32% vs 13%; RR 2.5 (95% CI 1.9 to 3.4); NNTB 5.3 (3.9 to 8.1); 4 studies, 713 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (62% vs 24%; RR 2.5 (95% CI 2.0 to 3.2); NNTB 2.7 (2.2 to 3.7); 3 studies, 537 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (41% vs 15%; RR 2.7 (95% CI 2.0 to 3.5); NNTB 3.9 (3.1 to 5.5); 4 studies, 732 participants, moderate-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 16% versus 5.5%, 600 mg 25% versus 5.8%; dizziness 300 mg 29% versus 8.1%, 600 mg 35% versus 8.8%.Painful diabetic neuropathy: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (47% vs 42%; RR 1.1 (95% CI 1.01 to 1.2); NNTB 22 (12 to 200); 8 studies, 2320 participants, moderate-quality evidence), more had at least 50% pain intensity reduction (31% vs 24%; RR 1.3 (95% CI 1.2 to 1.5); NNTB 22 (12 to 200); 11 studies, 2931 participants, moderate-quality evidence), and more had PGIC much or very much improved (51% vs 30%; RR 1.8 (95% CI 1.5 to 2.0); NNTB 4.9 (3.8 to 6.9); 5 studies, 1050 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (63% vs 52%; RR 1.2 (95% CI 1.04 to 1.4); NNTB 9.6 (5.5 to 41); 2 studies, 611 participants, low-quality evidence), and more had at least 50% pain intensity reduction (41% vs 28%; RR 1.4 (95% CI 1.2 to 1.7); NNTB 7.8 (5.4 to 14); 5 studies, 1015 participants, low-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 11% versus 3.1%, 600 mg 15% versus 4.5%; dizziness 300 mg 13% versus 3.8%, 600 mg 22% versus 4.4%.Mixed or unclassified post-traumatic neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (48% vs 36%; RR 1.2 (1.1 to 1.4); NNTB 8.2 (5.7 to 15); 4 studies, 1367 participants, low-quality evidence), and more had at least 50% pain intensity reduction (34% vs 20%; RR 1.5 (1.2 to 1.9); NNTB 7.2 (5.4 to 11); 4 studies, 1367 participants, moderate-quality evidence). Somnolence (12% vs 3.9%) and dizziness (23% vs 6.2%) were more common with pregabalin.Central neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (44% vs 28%; RR 1.6 (1.3 to 2.0); NNTB 5.9 (4.1 to 11); 3 studies, 562 participants, low-quality evidence) and at least 50% pain intensity reduction (26% vs 15%; RR 1.7 (1.2 to 2.3); NNTB 9.8 (6.0 to 28); 3 studies, 562 participants, low-quality evidence). Somnolence (32% vs 11%) and dizziness (23% vs 8.6%) were more common with pregabalin.Other neuropathic pain conditions: Studies show no evidence of benefit for 600 mg pregabalin in HIV neuropathy (2 studies, 674 participants, moderate-quality evidence) and limited evidence of benefit in neuropathic back pain or sciatica, neuropathic cancer pain, or polyneuropathy.Serious adverse events, all conditions: Serious adverse events were no more common with placebo than with pregabalin 300 mg (3.1% vs 2.6%; RR 1.2 (95% CI 0.8 to 1.7); 17 studies, 4112 participants, high-quality evidence) or pregabalin 600 mg (3.4% vs 3.4%; RR 1.1 (95% CI 0.8 to 1.5); 16 studies, 3995 participants, high-quality evidence). AUTHORS' CONCLUSIONS: Evidence shows efficacy of pregabalin in postherpetic neuralgia, painful diabetic neuralgia, and mixed or unclassified post-traumatic neuropathic pain, and absence of efficacy in HIV neuropathy; evidence of efficacy in central neuropathic pain is inadequate. Some people will derive substantial benefit with pregabalin; more will have moderate benefit, but many will have no benefit or will discontinue treatment. There were no substantial changes since the 2009 review.

Amitriptyline for fibromyalgia in adults.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of amitriptyline for neuropathic pain is now dealt with in a separate review. Amitriptyline is a tricyclic antidepressant that is widely used to treat fibromyalgia, and is recommended in many guidelines. It is usually used at doses below those at which the drugs act as antidepressants. OBJECTIVES: To assess the analgesic efficacy of amitriptyline for relief of fibromyalgia, and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with reference lists of retrieved papers, previous systematic reviews and other reviews, and two clinical trial registries. We also used our own hand searched database for older studies. SELECTION CRITERIA: We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in fibromyalgia. DATA COLLECTION AND ANALYSIS: We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. For efficacy, we calculated the number needed to treat to benefit (NNT), and for harm we calculated the number needed to treat to harm (NNH) for adverse events and withdrawals. We used a fixed-effect model for meta-analysis. MAIN RESULTS: We included seven studies from the earlier review and two new studies (nine studies, 649 participants) of 6 to 24 weeks' duration, enrolling between 22 and 208 participants; none had 50 or more participants in each treatment arm. Two studies used a cross-over design. The daily dose of amitriptyline was 25 mg to 50 mg, and some studies had an initial titration period. There was no first or second tier evidence for amitriptyline in the treatment of fibromyalgia. Using third tier evidence the risk ratio (RR) for at least 50% pain relief, or equivalent, with amitriptyline compared with placebo was 3.0 (95% confidence interval (CI) 1.7 to 4.9), with an NNT) of 4.1 (2.9 to 6.7) (very low quality evidence). There were no consistent differences between amitriptyline and placebo or other active comparators for relief of symptoms such as fatigue, poor sleep, quality of life, or tender points. More participants experienced at least one adverse event with amitriptyline (78%) than with placebo (47%). The RR was 1.5 (1.3 to 1.8) and the NNH was 3.3 (2.5 to 4.9). Adverse event and all-cause withdrawals were not different, but lack of efficacy withdrawals were more common with placebo (12% versus 5%; RR 0.42 (0.19 to 0.95)) (very low quality evidence). AUTHORS' CONCLUSIONS: Amitriptyline has been a first-line treatment for fibromyalgia for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against years of successful treatment in many patients with fibromyalgia. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline will be one option in the treatment of fibromyalgia, while recognising that only a minority of patients will achieve satisfactory pain relief. It is unlikely that any large randomised trials of amitriptyline will be conducted in fibromyalgia to establish efficacy statistically, or measure the size of the effect.

Estimating relative efficacy in acute postoperative pain: network meta-analysis is consistent with indirect comparison to placebo alone.

Network meta-analysis uses direct comparisons of interventions within randomized controlled trials and indirect comparisons across them. Network meta-analysis uses more data than a series of direct comparisons with placebo, and theoretically should produce more reliable results. We used a Cochrane overview review of acute postoperative pain trials and other systematic reviews to provide data to test this hypothesis. Some 261 trials published between 1966 and 2016 included 39,753 patients examining 52 active drug and dose combinations (27,726 given active drug and 12,027 placebo), in any type of surgery (72% dental). Most trials were small; 42% of patients were in trials with arms <50 patients, and 27% in trials with arms ≥100 patients. Response to placebo in third molar extraction fell by half in studies over 30 to 40 years (171 trials, 7882 patients given placebo). Network meta-analysis and Cochrane analyses provided very similar results (average difference 0.04 number needed to treat units), with no significant difference for almost all comparisons apart from some with small patient numbers or small effect size, or both. Network meta-analysis did not detect significant differences between effective analgesics. The similarity between network meta-analysis and Cochrane indirect analyses probably arose from stringent quality criteria in trials accepted in Cochrane reviews (with consequent low risk of bias) and consistency in methods and outcomes. Network meta-analysis is a useful analytical tool that increases our confidence in estimates of efficacy of analgesics in acute postoperative pain, in this case by providing similar results.

Combination pharmacotherapy for the treatment of fibromyalgia in adults.

BACKGROUND: Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects. OBJECTIVES: To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries. SELECTION CRITERIA: Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain. DATA COLLECTION AND ANALYSIS: From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache. AUTHORS' CONCLUSIONS: There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.

Antidepressants for chronic non-cancer pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Antidepressants have been used in adults for pain relief and pain management since the 1970s. The clinical impression from extended use over many years is that antidepressants are useful for some neuropathic pain symptoms, and that effects on pain relief are divorced and different from effects on depression; for example, the effects of tricyclic antidepressants on pain may occur at different, and often lower, doses than those on depression. Amitriptyline is one of the most commonly used drugs for treating neuropathic pain in the UK. OBJECTIVES: To assess the analgesic efficacy and adverse events of antidepressants used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any antidepressant with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed the evidence using GRADE and created three 'Summary of findings' tables. MAIN RESULTS: We included four studies with a total of 272 participants (6 to 18 years of age) who had either chronic neuropathic pain, complex regional pain syndrome type 1, irritable bowel syndrome, functional abdominal pain, or functional dyspepsia. All of the studies were small. One study investigated amitriptyline versus gabapentin (34 participants), two studies investigated amitriptyline versus placebo (123 participants), and one study investigated citalopram versus placebo (115 participants). Due to a lack of available data we were unable to complete any quantitative analysis.Risk of bias for the four included studies varied, due to issues with randomisation and allocation concealment (low to unclear risk); blinding of participants, personnel, and outcome assessors (low to unclear risk); reporting of results (low to unclear risk); and size of the study populations (high risk). We judged the remaining domains, attrition and other potential sources of bias, as low risk of bias. Primary outcomesNo studies reported our primary outcomes of participant-reported pain relief of 30% or greater or 50% or greater (very low-quality evidence).No studies reported on Patient Global Impression of Change (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) as very low. We downgraded the quality of the evidence by three levels to very low because there was no evidence to support or refute. Secondary outcomesAll studies measured adverse events, with very few reported (11 out of 272 participants). All but one adverse event occurred in the active treatment groups (amitriptyline, citalopram, and gabapentin). Adverse events in all studies, across active treatment and comparator groups, were considered to be a mild reaction, such as nausea, dizziness, drowsiness, tiredness, and abdominal discomfort (very low-quality evidence).There were also very few withdrawals due to adverse events, again all but one from the active treatment groups (very low-quality evidence).No serious adverse events were reported across any of the studies (very low-quality evidence).There were few or no data for our remaining secondary outcomes (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) for these secondary outcomes as very low. We downgraded the quality of the evidence by three levels to very low due to too few data and the fact that the number of events was too small to be meaningful. AUTHORS' CONCLUSIONS: We identified only a small number of studies with small numbers of participants and insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of antidepressants to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.There is evidence from adult randomised controlled trials that some antidepressants, such as amitriptyline, can provide some pain relief in certain chronic non-cancer pain conditions.There is no evidence from randomised controlled trials to support or refute the use of antidepressants to treat chronic non-cancer pain in children or adolescents.

Antiepileptic drugs for chronic non-cancer pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can occur in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) relating to genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and for other unknown reasons.Antiepileptic (anticonvulsant) drugs, which were originally developed to treat convulsions in people with epilepsy, have in recent years been used to provide pain relief in adults for many chronic painful conditions and are now recommended for the treatment of chronic pain in the WHO list of essential medicines. Known side effects of antiepileptic drugs range from sweating, headache, elevated temperature, nausea, and abdominal pain to more serious effects including mental or motor function impairment. OBJECTIVES: To assess the analgesic efficacy and adverse events of antiepileptic drugs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews as well as online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, by any route, treating chronic non-cancer pain in children and adolescents, comparing any antiepileptic drug with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods if data were available. We assessed the evidence using GRADE and created two 'Summary of findings' tables. MAIN RESULTS: We included two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1 (CRPS-I), or fibromyalgia. One study investigated pregabalin versus placebo in participants with fibromyalgia (107 participants), and the other study investigated gabapentin versus amitriptyline in participants with CRPS-I or neuropathic pain (34 participants). We were unable to perform any quantitative analysis.Risk of bias for the two included studies varied, due to issues with randomisation (low to unclear risk), blinding of outcome assessors (low to unclear risk), reporting bias (low to unclear risk), the size of the study populations (high risk), and industry funding in the 'other' domain (low to unclear risk). We judged the remaining domains of sequence generation, blinding of participants and personnel, and attrition as low risk of bias. Primary outcomesOne study (gabapentin 900 mg/day versus amitriptyline 10 mg/day, 34 participants, for 6 weeks) did not report our primary outcomes (very low-quality evidence).The second study (pregabalin 75 to 450 mg/day versus placebo 75 to 450 mg/day, 107 participants, for 15 weeks) reported no significant change in pain scores for pain relief of 30% or greater between pregabalin 18/54 (33.3%), and placebo 16/51 (31.4%), P = 0.83 (very low-quality evidence). This study also reported Patient Global Impression of Change, with the percentage of participants feeling "much or very much improved" with pregabalin 53.1%, and placebo 29.5% (very low-quality evidence).We downgraded the evidence by three levels to very low for one of two reasons: due to the fact that there was no evidence to support or refute the use of the intervention, or that there were too few data and the number of events was too small to be meaningful. Secondary outcomesIn one small study, adverse events were uncommon: gabapentin 2 participants (2 adverse events); amitriptyline 1 participant (1 adverse event) (6-week trial). The second study reported a higher number of adverse events: pregabalin 38 participants (167 adverse events); placebo 34 participants (132 adverse events) (15-week trial) (very low-quality evidence).Withdrawals due to adverse events were infrequent in both studies: pregabalin (4 participants), placebo (4 participants), gabapentin (2 participants), and amitriptyline (1 participant) (very low-quality evidence).Serious adverse events were reported in both studies. One study reported only one serious adverse event (cholelithiasis and major depression resulting in hospitalisation in the pregabalin group) and the other study reported no serious adverse events (very low-quality evidence).There were few or no data for our remaining secondary outcomes (very low-quality evidence).We downgraded the evidence by three levels to very low due to too few data and the fact that the number of events was too small to be meaningful. AUTHORS' CONCLUSIONS: This review identified only two small studies, with insufficient data for analysis.As we could undertake no meta-analysis, we were unable to comment about efficacy or harm from the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some antiepileptics, such as gabapentin and pregabalin, can be effective in certain chronic pain conditions.We found no evidence to support or refute the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents.

Opioids for cancer-related pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child. OBJECTIVES: To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer-related pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid and Embase via Ovid from inception to 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer-related pain in children and adolescents, comparing opioids with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were identified that were eligible for inclusion in this review (very low quality evidence). Several studies tested opioids on adults with cancer-related pain, but none in participants aged from birth to 17 years.We rated the quality of evidence as very low, downgraded due to a lack of available data; no analyses could be undertaken. AUTHORS' CONCLUSIONS: No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents.

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer pain in adults.

BACKGROUND: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat cancer pain, and are recommended for this purpose in the World Health Organization (WHO) cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on paracetamol, updates the evidence. OBJECTIVES: To assess the efficacy of oral NSAIDs for cancer pain in adults, and the adverse events reported during their use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to April 2017, together with reference lists of retrieved papers and reviews, and two online study registries. SELECTION CRITERIA: We included randomised, double-blind, single-blind, or open-label studies of five days' duration or longer, comparing any oral NSAID alone with placebo or another NSAID, or a combination of NSAID plus opioid with the same dose of the opioid alone, for cancer pain of any pain intensity. The minimum study size was 25 participants per treatment arm at the initial randomisation. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Eleven studies satisfied inclusion criteria, lasting one week or longer; 949 participants with mostly moderate or severe pain were randomised initially, but fewer completed treatment or had results of treatment. Eight studies were double-blind, two single-blind, and one open-label. None had a placebo only control; eight compared different NSAIDs, three an NSAID with opioid or opioid combination, and one both. None compared an NSAID plus opioid with the same dose of opioid alone. Most studies were at high risk of bias for blinding, incomplete outcome data, or small size; none was unequivocally at low risk of bias.It was not possible to compare NSAIDs as a group with another treatment, or one NSAID with another NSAID. Results for all NSAIDs are reported as a randomised cohort. We judged results for all outcomes as very low-quality evidence.None of the studies reported our primary outcomes of participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). With NSAID, initially moderate or severe pain was reduced to no worse than mild pain after one or two weeks in four studies (415 participants in total), with a range of estimates between 26% and 51% in individual studies.Adverse event and withdrawal reporting was inconsistent. Two serious adverse events were reported with NSAIDs, and 22 deaths, but these were not clearly related to any pain treatment. Common adverse events were thirst/dry mouth (15%), loss of appetite (14%), somnolence (11%), and dyspepsia (11%). Withdrawals were common, mostly because of lack of efficacy (24%) or adverse events (5%). AUTHORS' CONCLUSIONS: There is no high-quality evidence to support or refute the use of NSAIDs alone or in combination with opioids for the three steps of the three-step WHO cancer pain ladder. There is very low-quality evidence that some people with moderate or severe cancer pain can obtain substantial levels of benefit within one or two weeks.

Oral paracetamol (acetaminophen) for cancer pain.

BACKGROUND: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat mild to moderate cancer pain, and are recommended for this purpose in the WHO cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on NSAIDs, updates the evidence. OBJECTIVES: To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries. SELECTION CRITERIA: We included randomised, double-blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single-blind and open studies were also eligible for inclusion. The minimum study size was 25 participants per treatment arm at the initial randomisation. DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel-group, and two had a cross-over design. All used paracetamol as an add-on to established treatment with strong opioids (median daily morphine equivalent doses of 60 mg, 70 mg, and 225 mg, with some participants taking several hundred mg of oral morphine equivalents daily). Other non-paracetamol medication included non-steroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, or neuroleptics. All studies were at high risk of bias for incomplete outcome data and small size; none was unequivocally at low risk of bias.None of the studies reported any of our primary outcomes: participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with pain no worse than mild at the end of the treatment period; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). What pain reports there were indicated no difference between paracetamol and placebo when added to another treatment. There was no convincing evidence of paracetamol being different from placebo with regards to quality of life, use of rescue medication, or participant satisfaction or preference. Measures of harm (serious adverse events, other adverse events, and withdrawal due to lack of efficacy) were inconsistently reported and provided no clear evidence of difference.Our GRADE assessment of evidence quality was very low for all outcomes, because studies were at high risk of bias from several sources. AUTHORS' CONCLUSIONS: There is no high-quality evidence to support or refute the use of paracetamol alone or in combination with opioids for the first two steps of the three-step WHO cancer pain ladder. It is not clear whether any additional analgesic benefit of paracetamol could be detected in the available studies, in view of the doses of opioids used.

Opioids for cancer pain - an overview of Cochrane reviews.

BACKGROUND: Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Opioid (morphine-like) drugs are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. The most commonly-used opioid drugs are buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, tramadol, and tapentadol. OBJECTIVES: To provide an overview of the analgesic efficacy of opioids in cancer pain, and to report on adverse events associated with their use. METHODS: We identified systematic reviews examining any opioid for cancer pain published to 4 May 2017 in the Cochrane Database of Systematic Reviews in the Cochrane Library. The primary outcomes were no or mild pain within 14 days of starting treatment, withdrawals due to adverse events, and serious adverse events. MAIN RESULTS: We included nine reviews with 152 included studies and 13,524 participants, but because some studies appeared in more than one review the number of unique studies and participants was smaller than this. Most participants had moderate or severe pain associated with a range of different types of cancer. Studies in the reviews typically compared one type of opioid or formulation with either a different formulation of the same opioid, or a different opioid; few included a placebo control. Typically the reviews titrated dose to effect, a balance between pain relief and adverse events. Various routes of administration of opioids were considered in the reviews; oral with most opioids, but transdermal administration with fentanyl, and buprenorphine. No review included studies of subcutaneous opioid administration. Pain outcomes reported were varied and inconsistent. The average size of included studies varied considerably between reviews: studies of older opioids, such as codeine, morphine, and methadone, had low average study sizes while those involving newer drugs tended to have larger study sizes.Six reviews reported a GRADE assessment (buprenorphine, codeine, hydromorphone, methadone, oxycodone, and tramadol), but not necessarily for all comparisons or outcomes. No comparative analyses were possible because there was no consistent placebo or active control. Cohort outcomes for opioids are therefore reported, as absolute numbers or percentages, or both.Reviews on buprenorphine, codeine with or without paracetamol, hydromorphone, methadone, tramadol with or without paracetamol, tapentadol, and oxycodone did not have information about the primary outcome of mild or no pain at 14 days, although that on oxycodone indicated that average pain scores were within that range. Two reviews, on oral morphine and transdermal fentanyl, reported that 96% of 850 participants achieved that goal.Adverse event withdrawal was reported by five reviews, at rates of between 6% and 19%. Participants with at least one adverse event were reported by three reviews, at rates of between 11% and 77%.Our GRADE assessment of evidence quality was very low for all outcomes, because many studies in the reviews were at high risk of bias from several sources, including small study size. AUTHORS' CONCLUSIONS: The amount and quality of evidence around the use of opioids for treating cancer pain is disappointingly low, although the evidence we have indicates that around 19 out of 20 people with moderate or severe pain who are given opioids and can tolerate them should have that pain reduced to mild or no pain within 14 days. This accords with the clinical experience in treating many people with cancer pain, but overstates to some extent the effectiveness found for the WHO pain ladder. Most people will experience adverse events, and help may be needed to manage the more common undesirable adverse effects such as constipation and nausea. Perhaps between 1 in 10 and 2 in 10 people treated with opioids will find these adverse events intolerable, leading to a change in treatment.

Opioids for chronic non-cancer pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Opioids are used worldwide for the treatment of pain. They bind to opioid receptors in the central nervous system (mu, kappa, delta, and sigma) and can be agonists, antagonists, mixed agonist-antagonists, or partial agonists. Opioids are generally available in healthcare settings across most high-income countries, but access may be restricted in low- and middle-income countries. For example, opioids currently available in the UK include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are used in varying doses (generally based on body weight for paediatric patients) by means of parenteral, transmucosal, transdermal, or oral administration (immediate release or modified release). To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is a lower dose gradually titrated to effect in the child. OBJECTIVES: To assess the analgesic efficacy and adverse events of opioids used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing opioids with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were eligible for inclusion in this review. We rated the quality of the evidence as very low. We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome. AUTHORS' CONCLUSIONS: There was no evidence from randomised controlled trials to support or refute the use of opioids to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of opioids to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that some opioids, such as morphine and codeine, can be effective in certain chronic pain conditions.This means that no conclusions could be made about efficacy or harm in the use of opioids to treat chronic non-cancer pain in children and adolescents.

Tramadol for neuropathic pain in adults.

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.

Gabapentin for chronic neuropathic pain in adults.

BACKGROUND: Gabapentin is commonly used to treat neuropathic pain (pain due to nerve damage). This review updates a review published in 2014, and previous reviews published in 2011, 2005 and 2000. OBJECTIVES: To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain in adults. SEARCH METHODS: For this update we searched CENTRAL), MEDLINE, and Embase for randomised controlled trials from January 2014 to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trials registries. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing gabapentin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). We performed a pooled analysis for any substantial or moderate benefit. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: We included four new studies (530 participants), and excluded three previously included studies (126 participants). In all, 37 studies provided information on 5914 participants. Most studies used oral gabapentin or gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain conditions, predominantly postherpetic neuralgia and painful diabetic neuropathy. Study duration was typically four to 12 weeks. Not all studies reported important outcomes of interest. High risk of bias occurred mainly due to small size (especially in cross-over studies), and handling of data after study withdrawal.In postherpetic neuralgia, more participants (32%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (17%) (RR 1.8 (95% CI 1.5 to 2.1); NNT 6.7 (5.4 to 8.7); 8 studies, 2260 participants, moderate-quality evidence). More participants (46%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (25%) (RR 1.8 (95% CI 1.6 to 2.0); NNT 4.8 (4.1 to 6.0); 8 studies, 2260 participants, moderate-quality evidence).In painful diabetic neuropathy, more participants (38%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (21%) (RR 1.9 (95% CI 1.5 to 2.3); NNT 5.9 (4.6 to 8.3); 6 studies, 1277 participants, moderate-quality evidence). More participants (52%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (37%) (RR 1.4 (95% CI 1.3 to 1.6); NNT 6.6 (4.9 to 9.9); 7 studies, 1439 participants, moderate-quality evidence).For all conditions combined, adverse event withdrawals were more common with gabapentin (11%) than with placebo (8.2%) (RR 1.4 (95% CI 1.1 to 1.7); NNH 30 (20 to 65); 22 studies, 4346 participants, high-quality evidence). Serious adverse events were no more common with gabapentin (3.2%) than with placebo (2.8%) (RR 1.2 (95% CI 0.8 to 1.7); 19 studies, 3948 participants, moderate-quality evidence); there were eight deaths (very low-quality evidence). Participants experiencing at least one adverse event were more common with gabapentin (63%) than with placebo (49%) (RR 1.3 (95% CI 1.2 to 1.4); NNH 7.5 (6.1 to 9.6); 18 studies, 4279 participants, moderate-quality evidence). Individual adverse events occurred significantly more often with gabapentin. Participants taking gabapentin experienced dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (14%). AUTHORS' CONCLUSIONS: Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review.

Tramadol with or without paracetamol (acetaminophen) for cancer pain.

BACKGROUND: Tramadol is an opioid analgesic licensed for use in moderate to severe pain. It is considered as a low risk for abuse, so control regulations are not as stringent as for 'strong' opioids such as morphine. It has a potential role as a step 2 option of the World Health Organization (WHO) analgesic ladder. OBJECTIVES: To assess the benefits and adverse effects of tramadol with or without paracetamol (acetaminophen) for cancer-related pain. SEARCH METHODS: We searched the following databases using a wide range of search terms: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched three clinical trials registry databases. The date of the last search was 2 November 2016. SELECTION CRITERIA: We selected studies that were randomised, with placebo or active controls, or both, and included a minimum of 10 participants per treatment arm. We were interested particularly in blinded studies, but also included open studies.We excluded non-randomised studies, studies of experimental pain, case reports, and clinical observations. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standard form and checked for agreement before entry into Review Manager 5. We included information about the number of participants treated and demographic details, type of cancer, drug and dosing regimen, study design (placebo or active control) and methods, study duration and follow-up, analgesic outcome measures and results, withdrawals, and adverse events. We collated multiple reports of the same study, so that each study, rather than each report, was the unit of interest in the review. We assessed the evidence using GRADE and created a 'Summary of findings' table.The main outcomes of interest for benefit were pain reduction of 30% or greater and 50% or greater from baseline, participants with pain no worse than mild, and participants feeling much improved or very much improved. MAIN RESULTS: We included 10 studies (12 reports) with 958 adult participants. All the studies enrolled participants with chronic malignant tumour-related pain who were experiencing pain intensities described as moderate to severe, with most experiencing at least 4/10 with current treatment. The mean ages were 59 to 70 years, with participants aged between 24 and 87 years. Study length ranged from one day to six months. Five studies used a cross-over design. Tramadol doses ranged from 50 mg as single dose to 600 mg per day; doses of 300 mg per day to 400 mg per day were most common.Nine studies were at high risk of bias for one to four criteria (only one high risk of bias for size). We judged all the results to be very low quality evidence because of widespread lack of blinding of outcome assessment, inadequately described sequence generation, allocation concealment, and small numbers of participants and events. Important outcomes were poorly reported. There were eight different active comparators and one comparison with placebo. There was little information available for any comparison and no firm conclusions could be drawn for any outcome.Single comparisons of oral tramadol with codeine plus paracetamol, of dihydrocodeine, and of rectal versus oral tramadol provided no data for key outcomes. One study used tramadol combined with paracetamol; four participants received this intervention. One study compared tramadol with flupirtine - a drug that is no longer available. One study compared tramadol with placebo and a combination of cobrotoxin, tramadol, and ibuprofen, but the dosing schedule poorly explained.Two studies (191 participants) compared tramadol with buprenorphine. One study (131 participants) reported a similar proportion of no or mild pain at 14 days.Three studies (300 participants) compared tramadol with morphine. Only one study, combining tramadol, tramadol plus paracetamol, and paracetamol plus codeine as a single weak-opioid group reported results. Weak opioid produced reduction in pain of at least 30% from baseline in 55/117 (47%) participants, compared with 91/110 (82%) participants with morphine. Weak opioid produced reduction in pain of at least 50% in 49/117 (42%) participants, compared with 83/110 (75%) participants with morphine.There was no useful information for any other outcome of benefit or harm. AUTHORS' CONCLUSIONS: There is limited, very low quality, evidence from randomised controlled trials that tramadol produced pain relief in some adults with pain due to cancer and no evidence at all for children. There is very low quality evidence that it is not as effective as morphine. This review does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high. The place of tramadol in managing cancer pain and its role as step 2 of the WHO analgesic ladder is unclear.

Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults.

BACKGROUND: This review is an update of "Single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults" last updated in Issue 4, 2009. Ketoprofen is a non-selective nonsteroidal anti-inflammatory drug (NSAID) used to treat acute and chronic painful conditions. Dexketoprofen is the (S)-enantiomer, which is believed to confer analgesia. Theoretically dexketoprofen is expected to provide equivalent analgesia to ketoprofen at half the dose, with a consequent reduction in gastrointestinal adverse events. This review is one of a series on oral analgesics for acute postoperative pain. Individual reviews have been brought together in two overviews to provide information about the relative efficacy and harm of the different interventions. OBJECTIVES: To assess the efficacy and safety of single dose oral ketoprofen and oral dexketoprofen compared with placebo for acute postoperative pain, using methods that permit comparison with other analgesics evaluated in the same way, and criteria of efficacy recommended by an in-depth study at the individual patient level. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from 2009 to 28 March 2017. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials of single dose orally administered ketoprofen or dexketoprofen in adults with moderate to severe acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors independently considered studies for inclusion in the review, examined issues of study quality and potential bias, and extracted data. For dichotomous outcomes, we calculated risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH) with 95% confidence intervals (CI) for ketoprofen and dexketoprofen, compared with placebo, where there were sufficient data. We collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours, the median time to use of rescue medication, and the proportion of participants requiring rescue medication. We also collected information on adverse events and withdrawals. We assessed the quality of the evidence using GRADE, and created 'Summary of findings' tables. MAIN RESULTS: This updated review included 24 studies; six additional studies added 1001 participants involved in comparisons of ketoprofen or dexketoprofen and placebo, with a 12% increase in participants taking ketoprofen and a 65% increase for dexketoprofen. Most participants (70%) were women. Dental studies typically involved young participants (mean age 20 to 30 years); other types of surgery involved older participants (mean age 37 to 68 years). Overall, we judged the studies at high risk of bias only for small size, which can lead to an overestimation of benefit.Ketoprofen doses ranged between 6.5 mg and 150 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual ketoprofen oral dose of 50 mg was 57%, compared to 23% with placebo, giving an NNT of 2.9 (95% CI 2.4 to 3.7) (RR 2.5, 95% CI 2.0 to 3.1; 594 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 1.8) than other surgery (NNT 4.2). The proportion of participants using rescue medication within six hours was lower with ketoprofen (32%) than with placebo (75%), giving a number needed to treat to prevent use of rescue medication (NNTp) of 2.3 (95% CI 1.8 to 3.1); 263 participants; 4 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with ketoprofen (18%) and placebo (11%) (RR 1.6, 95% CI 0.98 to 2.8; 342 participants; 5 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence).Dexketoprofen doses ranged between 5 mg and 100 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual dexketoprofen oral dose of 20 mg or 25 mg was 52%, compared to 27% with placebo, giving an NNT of 4.1 (95% CI 3.3 to 5.2) (RR 2.0, 95% CI 1.6 to 2.2; 1177 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 2.7) than other surgery (NNT 5.7). The proportion of participants using rescue medication within six hours was lower with dexketoprofen (47%) than placebo (69%), giving an NNTp of 4.7 (95% CI 3.3 to 8.0); 445 participants; 5 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with dexketoprofen (14%) and placebo (10%) (RR 1.4, 95% CI 0.89 to 2.2; 536 participants, 6 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence). AUTHORS' CONCLUSIONS: Ketoprofen at doses of 25 mg to 100 mg is an effective analgesic in moderate to severe acute postoperative pain with an NNT for at least 50% pain relief of 2.9 with a 50 mg dose. This is similar to that of commonly used NSAIDs such as ibuprofen (NNT 2.5 for 400 mg dose) and diclofenac (NNT 2.7 for 50 mg dose). Dexketoprofen is also effective with an NNT of 4.1 in the dose range 10 mg to 25 mg. Differential efficacy between dental surgery and other types of surgery seen for both drugs is unusual. Both drugs were well tolerated in single doses.

Morphine for chronic neuropathic pain in adults.

BACKGROUND: Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. 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 nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews. OBJECTIVES: To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 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 morphine (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). 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 identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg 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. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. AUTHORS' CONCLUSIONS: There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.

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

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