Ketamine-assisted Integrative Treatment for Veterans With Chronic Low Back Pain and Comorbid Depression

Pain interference, defined as the extent to which pain impedes enjoyment of and participation in life activities (including cognitive, social, recreational, and self-care activities), will be the primary outcome. Raw scores (range 6 - 30, higher scores indicating more interference) are normed to mean of general population (T-score 50; SD 10); higher T-scores indicate higher pain interference. Minimum clinically important change is 3.0 - 3.5 point reduction in the T-score.

Pain intensity will be measured using the NRS, a single-item measure where participants rate their pain intensity on a scale of 0 (no pain) to 10 (worst pain imaginable). In chronic pain, a reduction of 2 points or 30% is considered a meaningful improvement.

The Quick Inventory of Depressive Symptoms - Self Report (QIDS-SR) is a 16-item rating scale assessing self-report of depressive symptoms. Scores range from 0 - 27, with higher scores indicating more severe depressive symptoms. Reductions of approximately 30% are considered clinically meaningful improvements in depressive symptoms.

Enrollment benchmarks involve aiming to enroll 2-4 participants/month.

Safety will be assessed via Adverse event (AE) assessment which will be obtained by means of a standard form assessing the presence of AEs.

Pain interference will also be measured at these additional time points. Participants rate each item regarding experiences over the past 7 days on a Likert scale from 1 (not at all) to 5 (Very much). Raw scores (range 6 - 30, higher scores indicating more interference) are normed to mean of general population (T-score 50; SD 10); higher T-scores indicate higher pain interference. Minimum clinically important change is 3.0 - 3.5 point reduction in the T-score.

Pain intensity will also be measured at these additional time points. Pain intensity will be measured using the NRS, a single-item measure where participants rate their pain intensity on a scale of 0 (no pain) to 10 (worst pain imaginable). In chronic pain, a reduction of 2 points or 30% is considered a meaningful improvement.

Depression will also be measured at these additional time points.

Participants will rate acceptability in multiple domains (helpfulness; convenience and comfort; satisfaction) on a 1-4 scale (1=very dissatisfied, 2=somewhat dissatisfied, 3=somewhat satisfied, 4=very satisfied). Benchmarks for acceptability include >70% "somewhat" or "very satisfied" in all domains.

Participants rate their change overall on a 7-point Likert scale ranging from 1 (very much improved) to 7 (very much worse).

Cognitive flexibility refers to individuals' awareness of alternatives to a given situation, willingness to consider them, and belief that they can adapt. Individuals rate 12-items of the Cognitive Flexibility Scale (CFS) on a 6 point Likert scale ranging from 1 (strongly disagree) to 6 (strongly agree), total score range 12 - 72. Higher scores indicate more cognitive flexibility.

Psychological flexibility refers to individuals' ability to both recognize and accept emotions and choose their subsequent action based on core beliefs and values (rather than a reflexive emotional response). It will be assessed via the 9-item Emotion Regulation Questionnaire (ERQ-9).

Psychological inflexibility will be assessed by the 7-item Acceptance and Action Questionnaire-II (AAQII).

The Psychological Insight Questionnaire (PIQ) is a 23-item questionnaire developed to assess acute discoveries or realizations occasioned by a psychedelic experience, such as those regarding one's personality, relationships, behavioral patterns, or emotions. We will use the PIQ to assess changes in response to ketamine.

The Mystical Experience Questionnaire (MEQ) is a 30-item validated measure assessing 4 factors of a mystical or psychedelic experience occasioned by ketamine. These include a mystical experience (e.g., "freedom from the limitations of your personal self and feeling a unity or bond with what was felt to be greater than your personal self"), positive mood (e.g., "sense of awe or awesomeness"), transcendence of time and space, and ineffability (feeling that the experience cannot be conveyed in words).

Catastrophizing (the tendency to think of the future as irrationally negative) associates with poor outcomes in the setting of chronic pain, including poorer functional status. It will be measured via the 6-item Catastrophizing Subscale from the Coping Strategies Questionnaire (CSQ-CAT).

Self-efficacy is a cognitive tendency to perceive oneself as capable of managing life's problems. It will be measured via the 4-item PROMIS Self-Efficacy for Chronic Conditions - Managing Daily Activities -Short Form 4a.

Fear-avoidance beliefs refers to the cognitive appraisal that certain kinds of activities may cause additional damage or pain; more fear-avoidance beliefs for physical activity (also called kinesiophobia) predict development of chronic pain and disability in those with acute low back pain. Fear-avoidance beliefs will be measured using the 4-item Fear-Avoidance Beliefs Questionnaire-Physical Activity Subscale (FABQ-PA).

The Fibromyalgia Survey Questionnaire (FSQ), adapted from the American College of Rheumatology Fibromyalgia Survey score, will be used to measure pain widespreadness and accompanying symptoms, also known as nociplastic features. It consists of two scales, the Widespread Pain Index (WPI) and the Symptom Severity score (SSS). The WPI instructs participants to indicate location(s) of pain (range 0 - 19, higher scores indicate more areas of pain). The SS score assesses additional symptoms including fatigue, unrefreshing sleep, and cognitive disruption (range 0 -12, higher scores indicate more symptoms). Total score range is 0 - 31, with higher scores indicating more nociplastic features of pain. Fibromyalgia screening positive cut points are WPI >=7 and SSS >=5 OR WPI of 4-6 and SSS >= 9.

PainDETECT will be used to evaluate presence of neuropathic features of back pain. PainDETECT instructs individuals to rate pain at different time points (range 0 - 10, with higher scores indicating more severe pain), and to select/rate agreement with items on a Likert scale from never to very strongly. Total score range is 0 - 38, with those scoring >18 having likely neuropathic components of back pain.

Target >70% of participants who complete baseline measures will complete all four ketamine infusion sessions, the behavioral intervention (if assigned) and the initial post-intervention assessment battery.

Target >80% of participants complete follow-up assessments.