Ketamine for Chronic Pain Management: An Umbrella Review

Abstract

Background. Chronic pain affects a substantial proportion of the adult population and remains difficult to treat due to limited pharmacological options that can offer adequate efficacy and safety. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and has been attracting interest as a non-opioid analgesic on the rationale that inhibition of NMDA receptors may attenuate central sensitization, tolerance to opioids, and opioid-induced hyperalgesia. A large number of systematic reviews have studied ketamine across individual chronic pain diagnoses, but their conclusions are heterogeneous, and the methodological quality has not been appraised systematically. Therefore, a narrative synthesis at the level of existing evidence syntheses is warranted. Objective. To summarise, evaluate, and synthesise the evidence based on published systematic reviews and/or meta-analyses on the efficacy and safety of ketamine for the management of chronic pain, and to appraise the methodological quality of the evidence base. Methods. We plan to conduct an umbrella review in accordance with PRISMA 2020 guidance. All eligible studies are systematic reviews, with or without meta-analysis, of ketamine or esketamine administered by any route, dose, or duration, in adults with chronic pain of any etiology including neuropathic pain, complex regional pain syndrome, chronic postsurgical and post-thoracotomy pain, craniofacial pain and chronic headaches, fibromyalgia, cancer-related pain, and osteoarthritis-related pain. Comparators/controls include placebo, saline, no treatment, standard or alternative analgesic therapy. Primary studies (randomised controlled trials, observational studies, case reports), reviews unrelated to ketamine in pain management, and reviews reporting only acute pain outcomes will be excluded. Only English-language publications will be considered. The search will be conducted in the Cochrane Library, PubMed, and Scopus, combining terms for ketamine and esketamine with terms for chronic pain. Records are to be screened by title and abstract, and full texts of eligible reports will be analyzed independently by reviewers, with disagreements resolved by discussion. Extracted data will include the number of included trials and participants, population and pain diagnosis, ketamine dose, route and duration, comparators, risk-of-bias tools used, and reported benefits/harms. Methodological quality of each included review will be assessed using AMSTAR 2, with overall confidence rated as high, moderate, low, or critically low according to the number of critical flaws. Overlap of primary studies across the included reviews will be calculated by developing a citation matrix and calculating the Corrected Covered Area (CCA), interpreted as slight (0–5%), moderate (6–10%), high (11–15%), or very high (>15%) overlap. Due to the anticipated clinical and methodological heterogeneity, findings will be synthesised narratively and organised by pain diagnosis; a new meta-analysis is not planned. Primary outcome. Reduction in pain intensity. Secondary outcomes. Adverse events, functional status, opioid consumption, and quality of life. Expected outcomes. We expect that the available reviews will report short-term/long-term analgesic benefit in several chronic pain diagnoses. We further anticipate that the methodological quality of much of this literature will be moderate. The review will map where the evidence is strongest, identify areas of uncertainty, and highlight methodological weaknesses that future systematic reviews and trials should address.

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