OBJECTIVE: To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose.
DESIGN: Systematic review and network meta-analysis of randomised trials.
DATA SOURCES: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis.
OUTCOMES AND MEASURES: The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed.
REVIEW METHODS: Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo.
RESULTS: 192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%).
CONCLUSIONS: Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO number CRD42020213656.
Background: The efficacy, tolerability and safety of opioid therapy in chronic osteoarthritis (OA) pain is under debate. We updated a Cochrane systematic review on the efficacy and safety of opioids in chronic OA pain published in 2009.
Methods: We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in chronic osteoarthritis (OA) pain. We included double-blind randomized placebo-controlled studies lasting ≥ 4 weeks. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables.
Results: We included 20 RCTs with 33 treatment arms and 8545 participants. Median study duration was 12 (4–24) weeks. Oxycodone and tramadol were each tested in six studies; buprenorphine, hydromorphone, morphine and tapentadol each in two studies and codeine, fentanyl and oxymorphone in one study each. Results are reported with 95 % confidence intervals (CIs). Opioids were superior to placebo in reducing pain intensity (SMD − 0.22 [− 0.28, − 0.17], p < 0.00001; 16 studies with 6743 participants). Opioids were not superior to placebo in 50 % pain reduction (RD − 0.00 [− 0.07, 0.07], p = 0.96; two studies with 2684 participants). Opioids were superior to placebo in terms of reports of much or very much global improvement (RD 0.13 [0.05, 0.21], p = 0.002; three studies with 2251 participants). Opioids were superior to placebo in improving physical functioning (SMD − 0.22 [− 0.28, − 0.17], p < 0.00001; 14 studies with 5887 participants). Patients dropped out more frequently with opioids than with placebo (RD 0.17 [0.14, 0.21], p < 0.00001; 15 studies with 6834 participants; number needed to harm 5 [4–6]. There was no significant difference between opioids and placebo in the frequency of serious adverse events (SAE) or deaths over the respective observation periods.
Conclusion: Opioids were superior to placebo in terms of efficacy and inferior in terms of tolerability. The effect sizes of average reduction in pain intensity and physical disability were small. Opioids and placebo did not differ in terms of safety. The conclusion on the safety of opioids compared to placebo is limited by the low number of SAE and deaths. Short-term opioid therapy may be considered in selected chronic OA pain patients. No current evidence-based guideline recommends opioids as first-line treatment option for chronic OA pain. To provide superior evidence for future treatment guidelines, RCTs must directly compare existing pharmacological and nonpharmacological therapies and administer these in various combinations and sequences.
The English full-text version of this article is freely available at SpringerLink (under “Supplemental”).
In selected patients with chronic non-malignant pain, chronic opioid therapy is indicated. Published guidelines recommend long-acting over short-acting opioids in these patients. The aim of this systematic review was to investigate whether long-acting opioids in chronic non-malignant pain are superior to short-acting opioids in pain relief, physical function, sleep quality, quality of life or adverse events. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for relevant trials up to July 2012. Reference lists of included trials and relevant reviews were in addition searched by hand. Of the 1168 identified publications, 6 randomised trials evaluating efficacy and safety filled the criteria for inclusion. None of them found a significantly better pain relief, significantly less consumption of rescue analgesia, improved quality of sleep or improved physical function from long-acting opioids. None of the trials investigated quality of life. None of the trials investigated adverse events properly nor addiction, tolerance or hyperalgesia. Three trials in healthy volunteers with a recreational drug use, found no difference in abuse potential between long- and short-acting opioids. While long term, comparative data are lacking, there is fair evidence from short-term trials that long-acting opioids provide equal pain relief compared with short-acting opioids. Contrary to several guidelines, there is no evidence supporting long-acting opioids superiority to short-acting ones in improving functional outcomes, reducing side effects or addiction.
BACKGROUND: The interpretation of opioid studies in patients with chronic pain due to osteoarthritis is limited by a high dropout rate. Therefore, the implication of dropouts on the recommendation of opioids in chronic osteoarthritis pain was analyzed.
DATA SOURCES: The databases of Medline, Embase, the Cochrane Library, and the Internet from 1990-2009 were searched.
STUDY SELECTION: Two independent authors included randomized controlled clinical trials investigating the effects of chronic opioid treatment for the management of osteoarthritis pain. In order to calculate the odds ratio, only placebo-controlled trials were included.
DATA EXTRACTION: The primary outcome parameter was the dropout rate. Secondarily, the effect size was calculated. Data extraction was conducted by two independent authors.
RESULTS: A total of 19 studies reporting results of 3,871 treatment and 2,080 placebo outcomes were retrieved. Compared to placebo, opioid treatment was associated with a significantly increased total dropout rate (OR = 1.3, 95%CI 1.2-1.4). Discontinuation of treatment was related to adverse events (OR = 4.0, 95%CI 3.4-4.6). Lack of analgesia was associated with a significantly reduced dropout rate in opioid groups (OR = 0.4, 95%CI 0.3-0.5). Analgesic effects were significantly better in opioid-treated patients (p = 0.01).
CONCLUSION: In spite of analgesic effects, many osteoarthritis patients prefer to stop chronic opioid use, because of adverse events. Therefore, opioids are not generally recommended in osteoarthritis.
BACKGROUND: An enriched enrollment randomized withdrawal (EERW) design excludes potential participants who are nonresponders or who cannot tolerate the experimental drug before random assignment. It is unclear whether EERW design has an influence on the efficacy and safety of opioids for chronic noncancer pain (CNCP). OBJECTIVES: The primary objective was to compare the results from EERW and non-EERW trials of opioids for CNCR. Secondary objectives were to compare weak versus strong opioids, subgroups of patients with different types of pain, and the efficacy of opioids compared with placebo versus other drugs. METHODS: MEDLINE, EMBASE and CENTRAL were searched up to July 2009, for randomized controlled trials of any opioid for CNCR Meta-analyses and meta-regressions were conducted to compare the results. Treatment efficacy was assessed by effect sizes (small, medium and large) and the incidence of adverse effects was assessed by a clinically relevant mean difference of 10% or greater. RESULTS: Sixty-two randomized trials were included. In 61 trials, the duration was less than 16 weeks. There was no difference in efficacy between EERW and non-EERW trials for both pain (P = 0.6) and function (P = 0.3). However, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness and dry skin/itching compared with non-EERW. Opioids were more effective than placebo in patients with nociceptive pain (effect size = 0.60, 95% CI 0.49 to 0.72) and neuropathic pain (effect size = 0.56, 95% CI 0.38 to 0.73). CONCLUSION: EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta-analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin. (PsycInfo Database Record (c) 2025 APA, all rights reserved)
BACKGROUND: There is little evidence that short-acting opioids as rescue medication for breakthrough pain is an optimal long-term treatment strategy in chronic non-malignant pain. We compared clinical studies of long-acting opioids that allowed short-acting opioid rescue medication with those that did not, to determine the impact of opioid rescue medication use on the analgesic efficacy and tolerability of chronic opioid therapy in patients with chronic non-malignant pain.
METHODS: We searched MEDLINE (1950 to July 2006) and EMBASE (1974 to July 2006) using terms for chronic non-malignant pain and long-acting opioids. Independent review of the search results identified 48 studies that met the study selection criteria. The effect of opioid rescue medication on analgesic efficacy and the incidence of common opioid-related side-effects were analysed using meta-regression.
RESULTS: After adjusting for potentially confounding variables (study design and type of opioid), the difference in analgesic efficacy between the 'rescue' and the 'no rescue' studies was not significant, with regression coefficients close to 0 and 95% confidence intervals that excluded an effect of more than 18 points on a 0-100 scale in each case. There was also no significant difference between the 'rescue' and the 'no rescue' studies for the incidence of nausea, constipation, or somnolence in both the unadjusted and the adjusted analyses.
CONCLUSIONS: We found no evidence that rescue medication with short-acting opioids for breakthrough pain affects analgesic efficacy of long-acting opioids or the incidence of common opioid-related side-effects among chronic non-malignant pain patients.
OBJECTIVES: To determine the analgesic effectiveness, the effect on physical function and the safety of opioids in patients with osteoarthritis (OA).
SEARCH STRATEGY: A systematic literature search was performed in electronic databases up to October 2006. A hand search of references was also performed.
SELECTION CRITERIA: All randomized controlled trials evaluating the efficacy and/or the safety of opioids vs placebo or non-opioid analgesics in patients with OA were selected.
DATA COLLECTION AND ANALYSIS: Data were collected using a predetermined form. Statistical analysis determined in each trial the effect size to assess the magnitude of treatment effect and the number needed to harm (NNH) to evaluate opioids safety.
MAIN RESULTS: Eighteen randomized placebo-controlled trials were analyzed, i.e., a total of 3244 participants who received opioids and 1612 who received placebo. The mean trial duration was 13+/-18 weeks. The pooled effect sizes of all opioids vs placebo for pain intensity and physical function were -0.79 (95% confidence interval, CI, -0.98 to -0.59) and -0.31 (95% CI -0.39 to -0.24), respectively. The NNH was calculated to be 5 vs placebo. The number of studies (n=4) that compared opioids with non-opioid analgesics (paracetamol and non-steroidal anti-inflammatory drugs) was too limited to provide robust data.
CONCLUSIONS: Opioids significantly decrease pain intensity and have small benefits on function compared with placebo in patients with OA. Adverse events, although reversible and not life threatening, often cause participants to stop taking the medication and could limit opioid usefulness. Moreover, the long-term efficacy and safety of these drugs for OA is yet to be determined due to the short mean trial duration.
To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose.
DESIGN:
Systematic review and network meta-analysis of randomised trials.
DATA SOURCES:
Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES:
Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis.
OUTCOMES AND MEASURES:
The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed.
REVIEW METHODS:
Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo.
RESULTS:
192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%).
CONCLUSIONS:
Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis.
