Cochrane in CORR®: Topical NSAIDs for Chronic Musculoskeletal Pain in Adults

Importance of the Topic Osteoarthritis carries a high global-health and economic burden and will become the fourth-leading cause of disability by 2020 [11]. One study estimated that loss of productivity from chronic pain and loss of mobility owing to the disease costs the Canadian economy CAD17.5 billion (USD 13.4 billion) annually [10]. As the population ages and the prevalence of obesity rises, it has been estimated that the lifetime risk of symptomatic osteoarthritis in at least one knee is 44.7% [8]. Current consensus guidelines for the nonoperative treatment of arthritis focus initially on weight loss and exercise and physiotherapy with progressive escalation to slow acting topical analgesics followed by consideration of oral nonsteroidal anti-inflammatory drugs (NSAIDs) [2, 6, 7, 9]. There is also a growing interest in moving away from long-term opioid use for chronic noncancer pain because of the modest effectiveness of that approach in most patients and high risk of serious harms [3]. However, oral NSAIDs can cause important gastrointestinal, renal, and cardiovascular adverse effects [12]. Topical NSAIDs, by contrast, are increasingly being used as an alternative to oral NSAIDs in an effort to minimize systemic adverse effects [12]. As indicated in this Cochrane review, (see appendix) it is valuable for the treating clinicians to have a clear understanding of the current state of the evidence on topical NSAIDs to help guide them in critically appraising current consensus guideline publications and to inform their prescribing behaviors [4]. Upon Closer Inspection In this Cochrane review of 39 studies (10,631 patients), the authors concluded that the topical NSAIDs diclofenac and ketoprofen were superior to placebo (moderate quality of evidence) and had few harmful systemic effects (very low quality of evidence). The authors judged the efficacy evidence to be moderate quality due to inconsistency between studies and statistically fragile effect sizes (ie, effect sizes that can change from significant to nonsignificant with few events added or removed). The authors judged the safety evidence to be very low quality because reporting was poor and inconsistent, and there were very few events on which to base decisions. The authors conducted two separate meta-analyses comparing topical diclofenac and ketoprofen to an inactive carrier gel (placebo). The review also identified several other topical NSAIDs that were each evaluated in a single study, including felbinac, nimesulide, ibuprofen, piroxicam, and etoricoxib. The authors chose not to include these studies in a quantitative synthesis; however, the authors could have used network meta-analysis techniques [5] to include these studies and determine the ranking of superiority of topical NSAIDs. Network meta-analysis is a relatively new methodology for synthesizing evidence that compares three or more treatments by leveraging both direct and indirect comparisons. For example, if Treatment A is compared to placebo in one trial and Treatment B is compared to placebo in another trial, Treatments A and B can be indirectly compared using statistical techniques even though no trial exists that directly compares Treatment A to treatment B [5]. A 2018 systematic review of topical NSAIDs for osteoarthritis conducted a network meta-analysis and reached similar overall conclusions to the current Cochrane review, but they were able to add that the diclofenac (patch) was the best topical NSAID for pain piroxicam [12] was and the best topical NSAID for functional improvement. It should be noted that about 50% of participants in the carrier (placebo) group reported clinically meaningful pain relief, and only about 10% more patients in the NSAID groups reported clinically meaningful improvements. Previous research has shown that placebo treatment reduces osteoarthritis pain, and topical placebos perform better than oral placebos [1]. Take-home Messages Based on the addition of five recent, larger, moderate-quality studies, this Cochrane update review found that gel preparations of diclofenac and ketoprofen provided good pain relief over carrier alone for patients with osteoarthritis; however, the authors were unable to comment on the efficacy of other topical NSAIDs because they were unable to pool study results of other NSAIDs due to small numbers of studies [5]. Further, the authors found no evidence that orally administered ketoprofen and diclofenac were superior to topical administration (OR = 1.03; 95% CI; 0.95-1.12). Although the evidence was judged as very poor due to inconsistent reporting and low event rates, the data suggest that the serious systemic side effects seen with oral NSAID administration was lower in the topical NSAID preparations [5]. The number needed to treat of 9.8 for diclofenac and 6.9 for ketoprofen [5] means that almost 10 patients need to be treated with diclofenac to have one additional patient with a beneficial outcome, and almost seven for ketoprofen. This review demonstrates the likely efficacy and safety of topical NSAIDs and highlights the need for further basic science research to help elucidate the mechanism of pain mediation for topical pain relievers, as well as clinical research to determine the relative efficacy of different topical NSAIDS and non-NSAID topical pain relievers such as capsaicin, cannabis, and others. For example, a high-quality randomized controlled trial could be conducted that directly compares several topical pain relievers to determine their relative efficacy in the treatment of knee arthritis pain.