Opioids in chronic osteoarthritis pain - A systematic review and meta-analysis of efficacy and harms of randomized placebo-controlled studies of at least four weeks duration R. Schaefert 1, P. Welsch 2, P. Klose 3, C. Sommer 4, F. Petzke 5, W. Häuser 6,7 1 Klinik für Allgemeine Innere Medizin und Psychosomatik, Universitätsklinikum Heidelberg, Heidelberg, Germany 2 Stichting Rugzorg Nederland, Ede, The Netherlands 3 Abteilung für Natuheilkunde und Integrative Medizin, Kliniken Essen-Mitte, Essen, Germany 4 Neurologische Klinik, Universitätsklinikum Würzburg, Germany 5 Schmerz-Tagesklinik und Ambulanz, Universitätsmedizin Göttingen, Göttingen, Germany 6 Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, Technische Universität München, Germany 7 Innere Medizin I, Klinikum Saarbrücken gGmbH, Germany Korrespondenzadresse: PD Dr.med. Winfried Häuser Innere Medizin 1 Klinikum Saarbrücken gGmbH Winterberg 1 D - 66119 Saarbrücken Germany Tel: +49 681 9632020 Fax: +49 681 9632022 Email: [email protected] 1 Background: The efficacy, tolerability and safety of opioid therapy in chronic osteoarthritis (OA) pain are under debate. We updated Cochrane systematic reviews on the efficacy and safety of opioids in chronic OA pain published in 2008. Methods: We screened Medline, Scopus, and the Cochrane Library (through October 2013), as well as reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in chronic non-cancer pain. We included double-blind randomized placebo-controlled studies 4 weeks. Relative risk differences (RD) of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model. Results: We included 20 RCTs with 33 treatment arms, with 8545 participants and a median study duration of 12 (4 - 24) weeks. Six studies each tested oxycodone, respectively tramadol, two studies each buprenorphine, hydromorphone, morphine, respectively tapentadol, and one study each codeine, fentanyl, and oxymorphone. Results are reported with [95% confidence intervals] 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 -0.01 [-0.07, 0.06], p = 0.82; two studies with 2709 participants). Opioids were superior to placebo in 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) and of deaths over the respective observation periods. Conclusions: In short-term studies (4 - 12 weeks), opioids were superior in terms of efficacy and inferior in terms of tolerability to placebo. The effect sizes of average reduction of 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 serious adverse events and deaths. Short- term opioid therapy in patients with chronic OA pain may be considered in selected 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 non- 2 pharmacological therapies with each other, as well as administer them in various combinations and sequences. The English full-text version of this article is available at SpringerLink (under “Supplemental”). This article is published with free access at Springerlink.com Key words: Osteorthritis; chronic pain; systematic review; meta-analysis; efficacy; tolerability; safety 3 Introduction Osteoarthritis (OA) is the most common disease of joints in adults around the world (10,24). In epidemiologic studies, OA is typically defined by radiographic findings and consideration of symptoms (31). About one-third of all adults have radiological signs of osteoarthritis (10). However, clinically significant osteoarthritis of the knee, hand, or hip in terms of chronic pain and/ or disability was found in only 8.9% of the adult population (2). The incidence and prevalence of OA are rising, likely related to the aging of the population and increasing obesity (24). Non-pharmacological as well as pharmacological modalities were recommended for OA by a recent guideline of the American College of Rheumatology (ACR) (16). Opioid analgesics were strongly recommended by the ACR in patients who were either not willing to undergo or had contraindications for total joint arthroplasty after having failed medical therapy. However, a Cochrane review on opioids in hip or knee OA pain published in 2009 concluded that the small to moderate beneficial effects of non-tramadol opioids were outweighted by large increases in the risk of adverse events. Non-tramadol opioids should therefore not be routinely used, even if osteoarthritic pain is severe (26). The debate on the use of opioids in OA also depends on the duration of opioid use. Short-term (< 4 weeks) opioid therapy might be appropriate in case of acute (on) chronic OA pain from a clinical point of view. However, if long-term opioid therapy in chronic OA pain is clinically useful, is under debate. Chronic opioid therapy has been defined by daily or near-daily use of opioids for at least 90 days, but in practice often used indefinitely (27). A systematic review on opioid therapy in chronic low back pain distinguished between short-term (4 - 12 weeks), intermediate term (13 - 26 weeks) and long-term (> 26 weeks) trials (4). To our knowledge, the last systematic review of opioids in chronic OA pain searched the literature until July 2008 and included short-term studies (< 4 weeks) into the analyses of efficacy and harms. Studies with opioid agonists with additional mode of action (e.g. tramadol, tapentadol) were excluded (24). In the meanwhile, new randomized controlled trials (RCTs) with opioids in chronic OA pain have been published. Therefore, we updated the search of literature of systematic reviews on opioids in OA pain for the update of the German 2008 guideline on the long-term administration of opioids in chronic non-cancer pain (CNCP) (LONTS) (7). The objectives of this 4 review were to determine the efficacy, tolerability and safety of opioids compared to placebo in adult patients with chronic OA pain in placebo-controlled RCTs 4 weeks. Methods The review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (21) and the recommendations of the Cochrane Collaboration (15). Criteria for considering studies for this review Types of studies We included fully published double blind RCTs that compared any opioid to placebo (pure or pseudo) for therapeutic purposes in OA pain. We included studies with a parallel design and an enriched enrolment randomized withdrawal (EERW) design. Studies with a cross-over design were included if a.) separated data of the two periods were reported or b.) data were presented which excluded statistically significant carry-over effect or c.) statistical adjustments were carried out in case of a significant carry-over effect. Study duration should be at least 4 weeks (tapering and maintenance phase for parallel and cross-over design; double blind withdrawal phase for EERW design). Studies should include at least 10 patients per treatment arm. We grouped outcome measures according to the duration of postrandomization follow-up, as proposed by Chaparro et al. (4): short-term (4 - 12 weeks), intermediate (12 - 26 weeks) and long-term (> 26 weeks). We had no restriction on the language of the publication. We excluded studies which conducted a tapering phase after open-label run-in and a consecutive double-blind parallel design with responders of the open-label run-in period. We excluded studies with a duration of the tapering/ maintenance or withdrawal period of less than 4 weeks, with an experimental design (i.e. if the primary purpose was to study pain mechanisms and not pain relief) and studies which were only published as abstracts. Furthermore, we excluded studies in which different dosages of one opioid were compared without a placebo control group. Types of participants We included men and women of all ages and races or ethnicities diagnosed with clinically or radiologically confirmed peripheral joint OA and associated pain of at least three months duration. Trials exclusively including patients with inflammatory 5 arthritis, such as rheumatoid arthritis were not included. We excluded studies with mixed study samples (participants with OA and low back pain) were if data of the two groups were not presented separately. Types of interventions We included trials that examined the use of any opioid prescribed in an outpatient setting, for a period of at least 4 weeks (titration and maintenance). We considered trials with opioids given by oral or transdermal routes. We included studies in which opioids were combined with abuse deterrent formulations (ADFs) (e.g. naloxone). We included studies