Ketamine combined with structured psychological therapy for chronic pain with comorbid depression

Abstract

Project Description. Chronic pain and depression are leading causes of disability worldwide and commonly co-occur. Individuals experiencing both conditions have greater functional impairment, higher healthcare utilisation, and poorer outcomes than those with either condition alone. Although the relationship between chronic pain and depression is increasingly recognised as sharing overlapping neurobiological mechanisms, including glutamatergic signalling and neural plasticity, clinical care is typically delivered through separate pain and mental health pathways. Few interventions directly target both conditions simultaneously. Ketamine is of interest in this context because it has demonstrated both antidepressant and analgesic effects and may facilitate a temporary period of enhanced neuroplasticity during which psychological interventions could be more effective. Consequently, there is growing interest in ketamine-assisted psychotherapy (KAP), whereby ketamine is administered alongside a structured psychological intervention. Several reviews have examined KAP in psychiatric populations, including depression, treatment-resistant depression, post-traumatic stress disorder, and substance use disorders. However, no review has comprehensively mapped evidence relating to the combination of ketamine and structured psychological therapy in chronic pain populations or in populations selected for the coexistence of chronic pain and depression. This gap is particularly relevant to chronic post-surgical pain (CPSP), the target population for the planned K-ADAPT feasibility trial. CPSP is a distinct chronic pain phenotype with a defined temporal onset following surgery and a high burden of comorbid depression. While the mechanistic rationale for combining ketamine with psychological therapy is strong, important questions remain regarding intervention design, including ketamine dosing strategies, the timing of psychotherapy relative to ketamine administration, therapist training and fidelity procedures, blinding methods, feasibility outcomes, and the measurement of psychological process variables. The purpose of this scoping review is to map the extent, range, and nature of evidence relating to ketamine combined with structured psychological therapy in adults with chronic pain, depression, or both. Particular attention will be paid to intervention characteristics, psychotherapy models, dose-to-session timing, feasibility parameters, fidelity assessment, blinding procedures, outcome measurement, and implementation approaches. Chronic post-surgical pain will be treated as a predefined reporting stratum so that CPSP-specific evidence can be distinguished from evidence derived from other chronic pain populations. The review will follow JBI methodology for scoping reviews and will include descriptive critical appraisal using the Mixed Methods Appraisal Tool (MMAT). The objective is not to estimate treatment effects but to characterise the existing evidence base, identify methodological and knowledge gaps, and inform the design, justification, and reporting of future trials. Expected outputs include an evidence map, detailed intervention and methodology tables, identification of gaps in CPSP-specific evidence, and recommendations relevant to the design of feasibility studies involving ketamine-assisted psychotherapy for chronic post-surgical pain with comorbid depression.

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