**6. Ketamine**

*Pain Management - Practices, Novel Therapies and Bioactives*

the treatment of diabetic neuropathy [39, 40].

**5. Cannabinoids**

cytokine release [46, 47].

form at the time of this writing.

nabinoids with the most studied being Δ<sup>9</sup>

5-HT blocking their role in descending pain pathways.

retention given the anticholinergic side effects TCAs can produce. Of note, TCAs are beneficial to both depressed and non-depressed patients as well as having the added value of helping with depression in the depressed subpopulation [36]. Serotonin-norepinephrine reuptake inhibitors (SNRIs) are also commonly used in the management of chronic pain with duloxetine having FDA approval for the management of fibromyalgia and venlafaxine showing superiority to placebo in

The primary mechanism of action of TCAs in the treatment of neuropathic pain involves the reuptake inhibition of norepinephrine (NE) and serotonin (5-hydroxytryptamine [5-HT]), which causes a blockade of the neuronal membrane ion channels and increases the activation of descending inhibitory pathways in the midbrain and spinal cord [41, 42]. SNRIs also elicit their effect through inhibition of NE and

The term cannabinoid is used to collectively describe all naturally occurring and synthetic compounds that are structurally similar to and elicit similar effects as the cannabinoid plants, most notably *cannabis*. In addition to the cannabinoids derived from plants (phytocannabinoids), there are also endogenously produced cannabinoids (endocannabinoids) and synthetic cannabinoids now being produced for medical use. Endocannabinoids are fundamental in human homeostasis with established behavioral, metabolic, immunologic, and physiologic functions [43]. Cannabinoids bind to two isotypes of G protein coupled receptors, CB1 and CB2 [44]. The CB1 receptor is found predominantly in the CNS including the brain, spinal cord, and the sensory nerve terminals and along primary pain pathways. Activation of CB1 receptors at these sites results in membrane hyperpolarization and the modulation of nociceptive neurotransmitters contributing to both the pain relief and psychotomimetic properties of cannabinoids [45]. This reduced pain with cannabinoid receptor agonists can occur at multiple levels of the CNS both peripherally and centrally. CB2 receptors are concentrated in the hematopoietic cells of the immune system and are involved in a diverse range of immunomodulatory effects including the inhibition of

Cannabis contains over 500 chemical compounds including over 150 phytocan-

nabidiol (CBD). THC is the chief psychotropic compound of *cannabis* and is found in varying concentrations in different strains of the plant. THC has a strong affinity for CB1, which is regarded as the primary receptor responsible for the psychoactive effects seen with cannabis. In contrast, CBD does not activate CB1 so it does not produce psychoactive effects and is associated more with the anti-inflammatory effects of cannabinoids [48]. There are currently three cannabinoid drugs available for use in the United States. Epidolex® is a CBD based drug used to treat epileptic disorders and is derived from cannabis. Dronabinol and Nabilone are synthetic THC compounds approved for use in chemotherapy associated nausea and as an appetite stimulant in HIV/AIDS [49]. Molecular and preclinical evidence continues to support the anti-nociceptive properties of cannabinoids although experimental human studies are more heterogeneous with varying results although ongoing research is being conducted [50]. With major legislative changes in the USA, thirty-three states and the District of Columbia have passed laws broadly legalizing cannabis in some


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Ketamine is a dissociative analgesic and amnestic medication that acts as a non-competitive antagonist of the N-Methyl-D-Aspartate (NMDA) receptor in the central nervous system [51]. It has been used since the 1960s as an anesthetic agent and continues to be studied and adapted for novel psychiatric and anesthetic purposes. Ketamine has multiple sites of drug action but its principal nociceptive effects occur at the NMDA receptors. NMDA receptors have dense expression in the temporal cortex, hippocampus, basal ganglia, cerebellum and brain stem and are known to contribute to the neuronal process that mediate nociception via activation by glutamate, an excitatory amino acid [52]. By targeting this receptor, ketamine has profound attenuating effects on ascending nociceptive transmission and amplification of descending inhibitory pathways [52, 53]. Ketamine is currently utilized in the management of many diseases and other applications including the management of chronic pain disorders (e.g., complex regional pain syndrome, phantom limb pain, fibromyalgia), acute pain, conscious sedation, and intraoperatively for antihyperalgesia and induction of anesthesia [54].
