Effect of ketamine on endogenous pain modulation in healthy volunteers

Abstract

Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-d-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-d-aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40mg per 70kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P<0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC. Diffuse noxious inhibitory control responses following a 1-hour low-dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation.

Altered Central Sensitization and Pain Modulation in the CNS in Chronic Joint Pain

“…Ketamine [76], tapentadol [77], opioid agonists [78], [79], and an opioid antagonist [78] have not shown any modulatory effect.…”

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

“…This study also looked into the response to prolonged heat pain stimulation, producing off-set analgesia. Ketamine was not significantly different from placebo in affecting this response (Niesters et al, 2011). A trial applying the "thermal grill" found that ketamine reduced the "paradoxical pain" but not the normal heat pain sensations and nonpainful heat sensations (Kern et al, 2008).…”

Assessment and manifestation of central sensitisation across different chronic pain conditions

“…The evidence on the effect of ketamine on CPM is still conflicting (Niesters et al, 2013), but it may enhance pain facilitation and thereby reduce CPM (Niesters et al, 2011).…”