Topical non-steroidal anti-inflammatory drugs for osteoarthritis (OA) provide equivalent analgesia, improved physical function, decreased stiffness, and are associated with a low rate of systemic adverse events. Topical formulations of diclofenac have proven themselves well in OA of the knee and hand joints, however, data on the exact time of onset of the effect, its duration and the minimum effective concentration are still limited. We present to your attention a review by F.Bariguian Revel et al., available in an online publication (Rheumatology and Therapy, 2020), in which the authors analyzed current literature data on the efficacy, tolerability, pharmacokinetic / pharmacodynamic properties of topical forms of diclofenac for the treatment of OA and identified areas requiring additional research.
Approximately 300 million people worldwide currently suffer from OA (GBD Collaborators, 2017). Risk factors for this pathology include older age and obesity, so the global prevalence and severity of diseases associated with OA are expected to increase (Vina, 2018; Hunter and Bierma-Zeinstra, 2019). OA suggests the presence of structural changes in the articular cartilage, subchondral bone, ligaments, joint capsule, synovium, and periarticular tissues (Tan et al., 2006). In addition to mechanical and metabolic factors, inflammation is now considered a key mediator of OA, which leads to cartilage loss and progressive degeneration of the affected joints (Sohn et al., 2012; Sokolove and Lepus, 2013). Joint destruction associated with OA causes pain, which leads to the development of functional limitations, a decrease in the quality of life of patients, etc. (Hawker et al., 2008; Wright et al., 2010; Menon and Mishra, 2018).
Current guidelines for the management of people with OA note the need for NSAIDs to relieve pain. Thus, in the current settings of the American College of Rheumatology (ACR, 2019), it is said that the topical use of NSAIDs for the treatment of OA of the knee and hand joints is reasonable compared to oral forms due to an increased risk of systemic adverse events associated with their use (Kolasinski et al, 2020 ). In particular, the topical form of diclofenac is well absorbed through the skin, easily penetrates into the subcutaneous tissues, and is practically not absorbed into the general bloodstream. By inhibiting predominantly cyclooxygenase 2 enzymes responsible for the conversion of arachidonic acid to thromboxanes, prostacyclins and prostaglandins, diclofenac reduces the production of the latter, thereby limiting the associated peripheral sensitization of nociceptors that activate mechanical/painful stimuli (Ricciotti, FitzGerald, 2017; Minami et al ., 2001).
The authors conducted a multi-stage analysis of the existing literature in the PubMed database, including trial results, systematic reviews, meta-analyses, recommendations for OA. The search criteria were the overall efficacy and safety of topical diclofenac in OA, the onset and duration of pain relief, the minimum effective concentration of the drug in plasma and target tissues, pain relief with other topical NSAIDs in adults, etc. The search was performed from October 2018 without date restrictions.
The effectiveness of topical forms of diclofenac in OA
A network meta-analysis of randomized controlled trials (RCTs) and observational studies that studied people with predominantly knee OA demonstrated the benefits of diclofenac solution or patch versus placebo in pain relief and functional improvement (Zeng et al., 2018). Wiffen et al. (2020) conducted a systematic review of placebo-controlled trials of topical diclofenac in patients with knee or hand OA. Five trials lasting 6-12 weeks showed clinical benefit of diclofenac gel or solution, defined as a 50% reduction in pain intensity or an International Society for the Study of Osteoarthritis response rate, in 59% of patients compared with 48% of the placebo group. In five studies, the authors reported more effective use of diclofenac patch, gel, or solution than placebo in people with knee OA for 2-6 weeks (43% and 23%, respectively). Positive results were indicated by a 50% reduction in pain severity or a score on the Patient’s Cumulative Pain Assessment (PGA) instrument as very good or excellent.
A 12-week double-blind study examined the effect of topical and oral diclofenac (maximum daily dose of 50 mg tid) in 492 patients with symptomatic knee OA (Tugwell et al., 2004). Improvement was comparable across all dimensions of pain (44 vs 49%), physical function (39 vs 46%), joint stiffness (39 vs 45%), overall patient score (43 vs 49%), and the Western Universities Osteoarthritis Severity Index. Ontario and McMaster (WOMAC) for 12 weeks. A double-blind, 12-week trial in 722 people with knee OA compared five therapies: diclofenac dimethyl sulfoxide (DMSO) solution + oral placebo, diclofenac-free DMSO solution + oral placebo, topical and sustained-release tablets + placebo vs. diclofenac solution + oral form of the drug (Simon et al., 2009). WOMAC and PGA stiffness scores were secondary results. At the end of treatment, the effectiveness of topical and oral diclofenac was comparable in all parameters, for example, change in pain score from baseline, physical functions, general condition of the patient, joint stiffness scores and PGA. Topical diclofenac was more effective than GMMO in all outcomes and outperformed oral placebo in all measures except for rigidity.
A direct comparative, randomized, double-blind study included 321 patients with OA of the fingers who received diclofenac diethylamine gel and oral ibuprofen for 21 days (Zacher et al., 2011). As assessed on a 100 mm visual analog scale (VAS) at the end of treatment, there was a 40% reduction in total pain during movement of 44% and 34% with diclofenac diethylamine and ibuprofen, respectively. Both therapies were associated with comparable reductions in morning joint stiffness, improved grip strength, and better patient and physician assessments of their condition, quality of life, and disease activity. In a meta-analysis by Stewart et al. (2018) analyzed pain relief in knee and hand OA with topical diclofenac or ketoprofen in seven RCTs and oral naproxen, ibuprofen or diclofenac for the treatment of knee or hip OA in nine RCTs. Pain was assessed by WOMAC and VAS. According to the results obtained, topical forms of NSAIDs were associated with a more intense reduction in pain than oral ones.
Safety profile of topical forms of diclofenac
Behind obvious denim, unfriendly appearances, associated with topical forms of diclofenac, – dermatological reactions in the field of stosuvannya, like dryness of the skin, blackening / erythema, sverbіzh, which are insignificant that shvidko pass. When treated with an oral drug, patients with OA of the knee joint had few gastrointestinal problems, such as dyspepsia, diarrhea, abdominal distention, and also in the upper part of the stomach (Roth, Fuller, 2011). Similarly, there was no evidence of an increase in liver enzymes in vicarious development of diclofenac + DSMO in patients with knee OA (Simon et al., 2009). In studies conducted with the use of the drug in people with OA of the joints of the knee and hand, there were no severe or systemic side effects (Honvo et al., 2019). Because topical diclofenac provides at least equivalent analgesia to some oral NSAIDs and is associated with a lower incidence of adverse events, it may be the best treatment option, especially for the elderly with OA, patients with comorbidities, and/or systemic risk factors ( gastrointestinal, hepatic, renal or cardiovascular) adverse events.
Thus, topical NSAIDs, such as diclofenac, are recommended as an effective, well-tolerated first-line treatment for OA-related joint pain. The results of modern studies indicate that topical forms of diclofenac reduce the severity of pain, joint stiffness in OA and improve physical functions. Limited data indicate that pain relief begins within hours of topical use and is preferably maintained over a 12-hour period, especially with regular use.
Prepared by Elena Korobko