Pharmacology/Drug Development

The objective was to systematically review the efficacy and safety of topically applied diclofenac in both acute and chronic musculoskeletal pain in adults. We used standard Cochrane methods. Searches were conducted in MEDLINE, EMBASE, and the Cochrane Register of Studies; the date of the final search was November 2018. Included studies had to be randomised and double blinded, with ten or more participants per treatment arm. Risk of bias was assessed. The primary outcome of "clinical success" was defined as participant-reported reduction in pain of at least 50%. Details of adverse events (AE) and numbers of withdrawals due to lack of efficacy (LoE) or AE were recorded. For acute pain, 23 studies (5170 participants) were included. All participants were treated for at least 5 days; most were treated for 7-14 days. Compared to placebo, number needed to treat (NNT) for different formulations were as follows: diclofenac flector plaster, 4.7 (95%CI 3.7-6.5); diclofenac plaster with heparin, 7.4 (95%CI 4.6-19); and diclofenac emulgel, 1.8 (95%CI 1.5-2.1).4.7% (65/1373) participants reported a systemic AE; 4.1% (78/1919) reported a local AE; and 1.3% (14/1063) withdrew due to an AE. Few participants withdrew due to LoE.For chronic pain, 21 studies (26 publications) with 5995 participants were included. The majority of studies focused on knee osteoarthritis pain. Formulations of diclofenac included gel, solution with or without DMSO, emulsion, and plaster. A clinical success rate of approximately 60% (NNT 9.5 [95%CI 7-14.7]) was achieved with a variety of diclofenac formulations. Local AEs (approximately 14%) were similar for both diclofenac and placebo. Event rate for systemic events was approximately 10%. Few serious events were reported, and between 0% and 17% of participants withdrew due to AEs. AEs were likely higher in the chronic group because participants were exposed to treatment for weeks rather than days. This large systematic review of over 11,000 participants demonstrates that topical diclofenac is effective for acute pain, such as sprains and strains, with minimal AEs. The effectiveness of topical diclofenac was also demonstrated in chronic musculoskeletal pain, such as osteoarthritis, but with a higher NNT (worse) compared with acute pain. Again, the incidence of AEs was low. Formulation does play a part in effectiveness, and studies are needed to investigate this further. Studies of chronic pain outside of osteoarthritis would also be helpful.

The attrition of novel analgesic drugs in the clinic can be attributed in the main to two factors: failure of preclinical research findings translating into human pain conditions, and a drop-off of efficacy between proof-of-concept (i.e., Phase II trials) and pivotal, confirmatory (Phase III trials) testing. In order to enhance the efficiency of the clinical drug evaluation process and determine rapidly whether a potential therapeutic candidate gives pain relief, by modulating central pain neurobiology, we propose a 'pre-proof-of-concept' approach, in which an efficacy assessment is performed in a single individual (N-of-1) using subjective clinical pain assessments supported by objective validated functional neuroimaging measures. Using an N-of-1 + i methodology, clinical- and neuroimaging-based metrics can be quantified under conditions of drug versus placebo or drug versus current standard of care conditions.

Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.