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International Journal of Clinical... Oct 2020Intramuscular or, more rarely, local drug injection is occasionally followed by immediate local pain, livedoid skin lesions and, some days later, the development of...
AIM
Intramuscular or, more rarely, local drug injection is occasionally followed by immediate local pain, livedoid skin lesions and, some days later, the development of ischemic lesions. This very uncommon but potentially severe reaction, termed Nicolau syndrome, is traditionally associated with bismuth and β-lactam antimicrobials. The aim of this report was to review the literature associating Nicolau syndrome with the administration of non-steroidal anti-inflammatory drugs.
METHODS
The National Library, Excerpta Medica, Web of Science and Cochrane library databases were used.
RESULTS
Sixty-two cases (40 females and 22 males aged from 13 to 81, median 57 years) of Nicolau syndrome were published after 1992. Fifty-three cases occurred after diclofenac. The remaining nine cases were associated with ketoprofen (N = 2), ketorolac (N = 2), phenylbutazone (N = 2), etofenamate (N = 1), ibuprofen (N = 1) and piroxicam (N = 1).
CONCLUSION
Although Nicolau syndrome is extremely uncommon, physicians must be aware of this complication after intramuscular administration of non-steroidal anti-inflammatory drugs and should avoid unnecessary injections.
Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Drug Eruptions; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Nicolau Syndrome; Young Adult
PubMed: 32479658
DOI: 10.1111/ijcp.13567 -
Pharmacological Research Feb 2020To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations.
METHODS
PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations.
RESULTS
Results based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses.
CONCLUSIONS
The use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Europe; Humans; Randomized Controlled Trials as Topic; Skin Neoplasms; United States
PubMed: 31689521
DOI: 10.1016/j.phrs.2019.104499 -
The Cochrane Database of Systematic... Oct 2019Despite substantial improvements in the success of treatments through assisted reproduction technologies (ART), live birth rates remain constantly low, and practitioners... (Review)
Review
BACKGROUND
Despite substantial improvements in the success of treatments through assisted reproduction technologies (ART), live birth rates remain constantly low, and practitioners are seeking aetiologic treatments to improve the outcomes.Local inflammatory response is believed to contribute to implantation failure, where prostaglandins may increase uterine contractions and decrease uterine receptivity, decreasing the possibility of an IVF cycle leading to successful embryo transfer. In this context, nonsteroidal anti-inflammatory drugs (NSAIDs) have been employed to inhibit the negative prostaglandin effect. They are often offered in clinical practice to improve ART outcomes, but current robust evidence on their efficacy is lacking.
OBJECTIVES
To evaluate the effectiveness and safety of nonsteroidal anti-inflammatory drugs as co-treatments in infertile women undergoing assisted reproduction, in terms of improving live birth and miscarriage rates.
SEARCH METHODS
We designed the search using standard Cochrane methods and performed it on databases from their inception to 20 February 2019.We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials, grey literature and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, and PubMed and Google for any recent trials. There were no restrictions by language or country of origin.
SELECTION CRITERIA
All RCTs on the use of NSAIDs as co-treatment during an ART cycle compared with no use or the use of placebo or any other similar drug, along with the comparison of any NSAID to another.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods.
MAIN RESULTS
We found 11 RCTs (1884 women) suitable for inclusion in the review. Most studies were at unclear or high risk of bias. The main limitations in the overall quality of the evidence were high risk of bias, unexplained heterogeneity and serious imprecision and indirectness.There were no data on our primary outcome - live birth per woman randomised - in any review comparisons.NSAIDs vs. placebo/no treatmentWe are uncertain of an effect on ongoing pregnancy when NSAIDs were compared to placebo/no treatment (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.71 to 1.59; 4 studies, 1159 participants; I² = 53%; very low quality evidence). Results suggest that if the chance of ongoing pregnancy following placebo or no treatment is assumed to be 15%, the chance following the use of NSAIDs is estimated to be between 12% and 24%. Subgroup analysis according to the type of NSAID yielded similar results.We are also uncertain of an effect on miscarriage rates when NSAIDs were compared to placebo/no treatment (RR 0.62, 95% CI 0.33 to 1.16; 4 studies, 525 participants; I² = 43%; very low quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 21%, the chance following the use of NSAIDs is estimated to be between 7% and 27%. The results were similar when two studies were excluded due to high risk of bias.Concerning the secondary outcomes, we are uncertain of an effect on clinical pregnancy rates (RR 1.23, 95% CI 1.00 to 1.52; 6 studies, 1570 participants; I² = 49%; low-quality evidence); on ectopic pregnancy (RR 0.56, 95% CI 0.05 to 5.89; 1 study, 72 participants); on multiple pregnancy (RR 2.00, 95% CI 0.18 to 21.67; 1 study, 180 participants); and on side effects (RR 1.39, 95% CI 0.02 to 119.35; 3 studies, 418 participants; I² = 79%). The evidence suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 30%, the chance following the use of NSAIDs is estimated to be between 31% and 45%. If the chance of ectopic pregnancy following placebo or no treatment is assumed to be 5%, the chance following the use of NSAIDs is estimated to be between 0.3% and 31%. If the chance of multiple pregnancy following placebo or no treatment is assumed to be 1%, the chance following the use of NSAIDs is estimated to be between 0.2 % and 24%.There were no cases of congenital anomalies during antenatal ultrasound screening of the women in one study.NSAID vs. another NSAIDOnly one study compared piroxicam with indomethacin: we are uncertain of an effect on ongoing pregnancy (RR 1.12, 95% CI 0.63 to 2.00; 1 study, 170 participants; very low quality evidence); and on miscarriage (RR 1.00, 95% CI 0.44 to 2.28; 1 study, 170 participants; very low quality evidence). The evidence suggests that if the chance of ongoing pregnancy following indomethacin is assumed to be 20%, the chance following the use of piroxicam is estimated to be between 13% and 40%; while for miscarriage, the evidence suggests that if the chance following indomethacin is assumed to be 12%, the chance following the use of piroxicam is estimated to be between 5% and 27%.Similar results were reported for clinical pregnancy (RR 1.07, 95% CI 0.71 to 1.63; 1 study, 170 participants; very low quality evidence).There were no data for the other outcomes specified in this review.NSAID vs. aspirinNo study reported this comparison.
AUTHORS' CONCLUSIONS
Currently we are uncertain of an effect of the routine use of NSAIDs as co-treatments in infertile women undergoing assisted reproduction in order to improve ongoing pregnancy and miscarriage rates. This is based on available data from RCTs, where very low quality evidence showed that there is no single outcome measure demonstrating a benefit with their use. Further large, well-designed randomised placebo-controlled trials reporting on live births are required to clarify the exact role of NSAIDs.
PubMed: 31628860
DOI: 10.1002/14651858.CD007618.pub2 -
The Cochrane Database of Systematic... Sep 2019Progressive lung damage causes most deaths in cystic fibrosis. Non-steroidal anti-inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration...
BACKGROUND
Progressive lung damage causes most deaths in cystic fibrosis. Non-steroidal anti-inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration and morbidity in cystic fibrosis. This is an update of a previously published review.
OBJECTIVES
To assess the effectiveness of treatment with oral non-steroidal anti-inflammatory drugs in cystic fibrosis.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We contacted manufacturers of non-steroidal anti-inflammatory drugs and searched online trials registries.Latest search of the Group's Trials Register: 21 November 2018.
SELECTION CRITERIA
Randomized controlled trials comparing oral non-steroidal anti-inflammatory drugs, at any dose for at least two months, to placebo in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trials for inclusion the review and their potential risk of bias. Two authors independently rated the quality of the evidence for each outcome using the GRADE guidelines.
MAIN RESULTS
The searches identified 17 trials; four are included (287 participants aged five to 39 years; maximum follow-up of four years) and one is currently awaiting classification pending publication of the full trial report and two are ongoing. Three trials compared ibuprofen to placebo (two from the same center with some of the same participants); one trial assessed piroxicam versus placebo.The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a lower annual rate of decline for lung function, % predicted forced expiratory volume in one second (FEV), mean difference (MD) 1.32 (95% confidence interval (CI) 0.21 to 2.42) (moderate-quality evidence); forced vital capacity (FVC), MD 1.27 (95% CI 0.26 to 2.28) (moderate-quality evidence); forced expiratory flow (FEF), MD 1.80 (95% CI 0.15 to 3.45). The post hoc analysis of data from two trials split by age showed a slower rate of annual decline of FEV % predicted and FVC in the ibuprofen group in younger children, MD 1.41% (95% CI 0.03 to 2.80) (moderate-quality evidence) and MD 1.32% (95% CI 0.04 to 2.60) (moderate-quality evidence) respectively. Data from four trials demonstrated the proportion of participants with at least one hospitalization may be slightly lower in the ibuprofen group compared to placebo, Peto odds ratio 0.61 (95% CI 0.37 to 1.01) (moderate-quality evidence). In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low.We did not have any concerns with regards to risk of bias for the trial comparing piroxicam to placebo. However, the trial did not report many data in a form that we could analyze in this review. No data were available for the review's primary outcome of lung function; available data for hospital admissions showed no difference between the groups. No analyzable data were available for any other review outcome.
AUTHORS' CONCLUSIONS
High-dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis.
Topics: Administration, Oral; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Child; Cystic Fibrosis; Female; Humans; Ibuprofen; Male; Piroxicam; Randomized Controlled Trials as Topic; Young Adult
PubMed: 31499593
DOI: 10.1002/14651858.CD001505.pub5 -
Journal of Endodontics Apr 2019This review aimed to find the most effective oral premedication in reducing pain in adults after nonsurgical root canal therapy (NSRCT) using network meta-analysis. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
This review aimed to find the most effective oral premedication in reducing pain in adults after nonsurgical root canal therapy (NSRCT) using network meta-analysis.
METHODS
The review protocol was registered in the PROSPERO database (CRD42017071899). A literature search was performed in the MEDLINE and EBSCOhost databases until June 2017 with no language restriction. Randomized controlled trials evaluating the efficacy of oral premedications, whether given alone or in combination, compared with other agents, placebo, or no treatment in adult patients before NSRCT for postoperative pain were included. Nonintervention studies, nonendodontic studies, animal studies, and reviews were excluded. The quality of the studies was assessed using the revised Cochrane risk of bias tool. Pair-wise meta-analysis, network meta-analysis, and quality of evidence assessment using the Grading of Recommendations Assessment, Development and Evaluation criteria was performed.
RESULTS
Eleven studies comparing pharmacologic groups of medications were included in the primary analysis. Compared with placebo, corticosteroids (prednisolone 30-40 mg) was ranked best for reducing postoperative pain (median difference [MD] = -18.14 [95% confidence interval (CI), -32.90 to -3.37] for the pain score at 6 hours; MD = -22.17 [95% CI, -36.03 to -8.32] for the pain score at 12 hours; and MD = -21.50 [95% CI, -37.95 to -5.06] for the pain score at 24 hours). However, the evidence was very low (6 and 24 hours) to moderate quality (12 hours). Nonsteroidal anti-inflammatory drugs were ranked least among the medications, and the quality of this evidence was very low. Additional analysis based on the chemical name showed that sulindac, ketorolac, and ibuprofen significantly reduced pain at 6 hours, whereas piroxicam and prednisolone significantly reduced the pain at 12 and 24 hours. Etodolac was found to be least effective in reducing pain. Overall, the evidence was of moderate to very low quality.
CONCLUSIONS
Based on the limited and low-quality evidence, oral premedication with piroxicam or prednisolone could be recommended for controlling postoperative pain after NSRCT. However, more trials are warranted to confirm the results with a higher quality of evidence.
Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Databases, Bibliographic; Female; Humans; Ibuprofen; Ketorolac; Male; Middle Aged; Pain, Postoperative; Piroxicam; Prednisolone; Premedication; Randomized Controlled Trials as Topic; Root Canal Therapy; Sulindac; Treatment Outcome; Young Adult
PubMed: 30737050
DOI: 10.1016/j.joen.2018.10.016 -
Experimental Gerontology Dec 2018Ageing-related low-grade inflammation is suggested to aggravate sarcopenia and frailty. This systematic review investigates the influence that drugs with...
BACKGROUND
Ageing-related low-grade inflammation is suggested to aggravate sarcopenia and frailty. This systematic review investigates the influence that drugs with anti-inflammatory effects (AIDs) have on inflammation and skeletal muscle.
METHODS
PubMed and Web of Science were systematically screened for articles reporting the effects of AIDs on inflammation on one hand and on muscle mass and/or performance on the other.
RESULTS
Twenty-eight articles were included. These articles were heterogeneous in terms of the subjects studied, intervention components, setting, and outcome measures. Articles on older humans with acute inflammation showed evidence that celecoxib and piroxicam could reduce inflammation and improve performance and that ibuprofen improves exercise-induced muscle hypertrophy and gains in strength. In younger humans, only the effects of AIDs combined with exercise were investigated; no significant benefits of non-selective COX-inhibitors were reported, but improved strength gains with etanercept and reduced muscle soreness with celecoxib were noted. Indomethacin increased acute exercise-induced inflammation and reduced satellite cell differentiation in exercising muscle. Most articles did not systematically report occurrences of side effects.
CONCLUSIONS
Although AIDs showed significant reduction in inflammation-induced muscle weakness in older hospitalised patients with acute inflammation, robust evidence is still lacking. When combined with exercise, AIDs presented a protective effect against age-related loss of muscle mass, thus enhancing muscle mass and performance. The mechanism regulating muscle strength and its mass seems to differ between individuals of old and young age. However, the effects seem drug-specific and dose-dependent and appear to be influenced by subjects' trainability and the clinical context. In addition, the balance between benefits and harm remains unclear.
Topics: Aged; Aging; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Exercise; Humans; Inflammation; Muscle Strength; Muscle, Skeletal; Randomized Controlled Trials as Topic; Sarcopenia
PubMed: 30367977
DOI: 10.1016/j.exger.2018.10.011 -
International Journal of Hepatology 2018Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medication in several countries, including Thailand. NSAIDs have been associated with hepatic side... (Review)
Review
BACKGROUND
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medication in several countries, including Thailand. NSAIDs have been associated with hepatic side effects; however, the frequency of these side effects is uncertain.
AIM OF THE REVIEW
To systematically review published literature on randomized, controlled trials that assessed the risk of clinically significant hepatotoxicity associated with NSAIDs.
METHODS
Searches of bibliographic databases EMBASE, PubMed, and the Cochrane Library were conducted up to July 30, 2016, to identify randomized controlled trials of ibuprofen, naproxen, diclofenac, piroxicam, meloxicam, mefenamic acid, indomethacin, celecoxib, and etoricoxib in adults with any disease that provide information on hepatotoxicity outcomes.
RESULTS
Among the 698 studies, 18 studies met the selection criteria. However, only 8 studies regarding three NSAIDs (celecoxib, etoricoxib, and diclofenac) demonstrated clinically significant hepatotoxic evidence based on hepatotoxicity justification criteria. Of all the hepatotoxicity events found from the above-mentioned three NSAIDs, diclofenac had the highest proportion, which ranged from 0.015 to 4.3 (×10), followed by celecoxib, which ranged from 0.13 to 0.38 (×10), and etoricoxib, which ranged from 0.005 to 0.930 (×10).
CONCLUSION
Diclofenac had higher rates of hepatotoxic evidence compared to other NSAIDs. Hepatotoxic evidence is mostly demonstrated as aminotransferase elevation, while liver-related hospitalization or discontinuation was very low.
PubMed: 29568654
DOI: 10.1155/2018/5253623 -
International Endodontic Journal Sep 2018This systematic review (SR; PROSPERO database: CRD42017075160) and network meta-analysis (NMA) identified the most effective oral premedication for anaesthetic success... (Meta-Analysis)
Meta-Analysis
Effect of oral premedication on the anaesthetic efficacy of inferior alveolar nerve block in patients with irreversible pulpitis - A systematic review and network meta-analysis of randomized controlled trials.
This systematic review (SR; PROSPERO database: CRD42017075160) and network meta-analysis (NMA) identified the most effective oral premedication for anaesthetic success of inferior alveolar nerve blocks (IANB) in cases of irreversible pulpitis. Medline and Ebscohost databases were searched up until 10/2017. Randomized controlled trials (RCT) studying the effect of oral premedication, alone or in combination, on the success of IANB for cases of irreversible pulpitis, compared to placebo or other oral premedications, were included. Quality of the included studies was appraised by the revised Cochrane risk of bias tool for randomized trials. Pairwise analysis, NMA and quality of evidence assessment using GRADE criteria were performed. Nineteen studies (n = 1654 participants) were included. NMA demonstrated that compared to placebo, dexamethasone was most effective in increasing anaesthetic success (RR, 2.92 [95% CI 1.74,4.91]; SUCRA = 0.96), followed by NSAIDs (RR, 1.92 [95% CI 1.63,2.27], SUCRA = 0.738) and Tramadol (RR, 2.03 [95% CI 1.18,3.49], SUCRA = 0.737). Premedication with acetaminophen added to NSAIDs demonstrated similar efficacy as NSAIDs alone (RR, 1.06 [95% CI 0.79,1.43]). Sensitivity analyses proved the superiority of dexamethasone or NSAIDs over any other premedications. Subgroup analyses of specific dosages in comparison with placebo demonstrated that dexamethasone 0.5 mg was most effective, followed by ketorolac 10 mg, piroxicam 20 mg, ibuprofen 400 mg + acetaminophen 500 mg and Tramadol 50 mg. Ibuprofen 400 mg, 600 mg and 800 mg had a significantly improved IANB success, while Ibuprofen 300 mg had no effect. Oral premedication with dexamethasone, NSAIDs or Tramadol significantly increased anaesthetic success. More trials are needed to evaluate the premedication effects of dexamethasone or Tramadol for improved anaesthetic success of IANB when treating irreversible pulpitis.
Topics: Administration, Oral; Anesthesia, Dental; Humans; Mandibular Nerve; Nerve Block; Preanesthetic Medication; Pulpitis; Randomized Controlled Trials as Topic
PubMed: 29480930
DOI: 10.1111/iej.12912 -
British Journal of Sports Medicine May 2018To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA). (Meta-Analysis)
Meta-Analysis Review
Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies.
OBJECTIVES
To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA).
METHODS
PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies.
RESULTS
43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=-0.30, 95% CI -0.40 to -0.20) and improving function (SMD=-0.35, 95% CI -0.45 to -0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=-0.81, 95% CI -1.12 to -0.52) and piroxicam was most effective for functional improvement (SMD=-1.04, 95% CI -1.60 to -0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs.
CONCLUSIONS
Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study.
Topics: Administration, Cutaneous; Anti-Inflammatory Agents, Non-Steroidal; Bayes Theorem; Humans; Network Meta-Analysis; Osteoarthritis; Pain; Randomized Controlled Trials as Topic; Salicylates; Transdermal Patch
PubMed: 29436380
DOI: 10.1136/bjsports-2017-098043 -
The Cochrane Database of Systematic... May 2017Topical analgesic drugs are used for a variety of painful conditions. Some are acute, typically strains or sprains, tendinopathy, or muscle aches. Others are chronic,... (Review)
Review
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.
Topics: Acute Pain; Adult; Analgesics; Arthritis, Rheumatoid; Capsaicin; Chronic Pain; Diclofenac; Humans; Ketoprofen; Musculoskeletal Pain; Neuralgia; Numbers Needed To Treat; Osteoarthritis; Piroxicam; Publication Bias; Review Literature as Topic
PubMed: 28497473
DOI: 10.1002/14651858.CD008609.pub2