Preclinical and clinical investigation of the efficacy of “burst ketamine” for chronic pain

For over a decade, many clinics have offered multiday infusions of ketamine in conjunction with opioids as an off-label treatment for intractable chronic pain. Originally termed “burst ketamine” (BK), the proposed therapeutic effects of this treatment are to (1) provide lasting pain relief otherwise unattainable with standard pharmacotherapy, and (2) reduce opioid tolerance and thereby improve analgesic opioid response (i.e. an opioid dose-sparing effect). Although the use of BK is increasing, its efficacy is debated. This is due to the variability of outcomes reported in the limited clinical literature, and the absence of preclinical evidence investigating this technique using an animal model of neuropathy. In response, this PhD program evaluated BK using a translational approach that integrated experimental animal studies (preclinical component) with studies in patients with severe chronic pain (clinical component). In both components, chronic pain was evaluated as a multidimensional condition. This meant that therapeutic outcomes extended beyond the measurement of pain and opioid response, in acknowledgement of the impact of chronic pain on quality of life more generally, including mood, anxiety, sleep quality, and cognition. The preclinical component comprised two studies utilising the rodent model of streptozotocin-induced diabetic neuropathy. In the first, the antihyperalgesic and opioid-sparing effects of BK were evaluated. Antihyperalgesic effects and acute antinociceptive responsiveness to morphine were assessed using paw withdrawal latency from noxious heat (thermal hyperalgesia; Hargreaves’ method) and from mechanical touch (tactile allodynia; electronic von Frey). In this study, BK facilitated a long-term reversal of hyperalgesia and enhanced antinociceptive responsiveness to acute morphine treatment, effects that persisted at least 12 and 6 weeks, respectively. The second study investigated whether neuropathic rats developed anxiety-like behaviours and cognitive impairments; and if so, whether BK was able to normalise their behaviour in concordance with its antihyperalgesic effects. It was found that neuropathic rats exhibited increased anxiety-like behaviour and impaired visuo-spatial-learning and memory. The lasting antihyperalgesic effect produced by BK was accompanied by a concomitant decrease in anxiety-like behaviour, and an improvement in visuo-spatial learning. In the clinical component, BK was evaluated in female patients with chronic neuropathic-related pain (n=39). The endpoints assessed included pain thresholds (evaluating the degree of hypersensitivity to tactile, thermal, cold, and pressure stimuli using quantitative sensory testing), sensitivity to opioid analgesia (measuring pain thresholds after the patient had taken her prescribed oral opioid medication), mental health, sleep quality, and cognitive processing. BK provided pain relief persisting at least 12 weeks in over half of the patients. In patients who were taking opioids as part of their pre-treatment regimen (n=28), half showed a significant post-treatment improvement in opioid response that also lasted at least 12 weeks. Pain relief following BK was concomitant with improvements on measures of anxiety, depression, and some aspects of cognitive functioning (specifically processing speed). The findings in this thesis provides compelling new evidence for the therapeutic utility of BK for patients with severe chronic pain who do not benefit from standard analgesic treatments, or who have developed tolerance to opioid analgesics due to prolonged use.