Evidence is now beyond dispute that certain cannabinoids have a role to play in management of pain. They do this by modulating the endocannabinoid system, part of the body’s onboard cell-signaling neural network, and its downstream cascade of regulatory metabolites and enzymes. Popular optimism about cannabinoids as analgesics is warranted. It does need to be tempered, however, by data that shows that not all pain mechanisms are the same, and that not all cannabinoids regulate pain in the same way. They do not appear effective at all in post-operative or chronic abdominal pain, for example. But in other types of pain they clearly have beneficial effects, where they function through distinctly different pathways.
A commercially available oromucosal spray derived from THC and cannabidiol does appear to help patients with cancer pain that doesn’t respond to opiates. Wide clinical evidence is still weak, though. This may be in part related to using extracts of herbal cannabis rather than targeted selected full receptor site agonists.
Cannabinoids do not appear to exert the same analgesic effect in inflammatory processes as opioids do, but there is evidence that cannabidiol (CBD) can help in inflammatory pain due to its reduction of edema. Encouragingly, it is also known that oxidative stress with reactive oxygen species generation, part of how the immune system fights invading pathogens and initiates tissue repair, can cause chronic inflammation, and there is evidence that does suggest that cannabidiol may ameliorate oxidative stress. Cannabinoids do not appear effective in rheumatoid pain, another form of inflammatory distress.
Mammals possess an endo-opioid system (the mechanism behind ‘runners’ high’), and it communicates with the endocannabinoid system. Cannabinoid and opioid receptors colocalize in brain and spinal cord areas relevant to descending pain pathways, and cannabinoids provoke the release of endogenous opioid precursors. It is these precursors that function in pain relief. This is the rationale for the development of cannabinoid drugs as adjuvant analgesics in opioid-treated patients. Studies of these cannabinoid compounds to date suggest that they may be able to enhance opioid efficacy. They may also be a way to circumvent the undesirable side effects of opioids. THC has been shown to stimulate beta-endorphin production, which may at the very least allow opiate sparing in clinical application. Adjuvant therapy with opioids may produce better analgesia than therapy with cannabinoids alone, in other words. A promising candidate for co-administration with opiates is β-caryophyllene, a terpene, and FDA-approved food additive. β-caryophyllene, like other CB2 ligands inhibits the pathways triggered by activation of the receptor complex CD14/TLR4/MD2, which leads to the expression of inflammatory cytokines (e.g. IL-1 beta, IL-6, IL-8, and TNF alpha) and promotes a Th1 immune response that plays a critical role in neuro-inflammation, sensitization, and pain. β-caryophyllene is also readily bioavailable. Unlike many polyphenolic natural products, it is not metabolized immediately, which is useful in clinical settings.
Central neuropathic pain in diabetes
The etiology of neuropathic pain in diabetes is poorly understood, but recent evidence indicates that increased reactive oxygen species generation by microglial cells is the critical initiating factor. In a mouse model of type 1 diabetic peripheral neuropathic pain, intranasal or intraperitoneal administration of a moderately high dose of cannabinol has attenuated tactile allodynia and thermal hypersensitivity without affecting the diabetic state. The anti-pain effects of cannabinol were associated with less of an increase in microglial density and p38 MAPK activity in the dorsal spinal cord. It may possibly be that cannabinoids will show greater therapeutic potential for treating painful diabetic neuropathy than opioids.
Central neuropathy in MS
Several cannabinoid-based medicines have been evaluated in patients suffering from MS-related neuropathic pain. CBD in particular may mitigate pain by inhibiting the degradation of anandamide, an endocannabinoid. It may also work by modulating the antioxidant properties of that compound, or by binding to a cannabinoid receptor that is yet unknown. CBD also acts as an agonist at serotonin 5-HT1a receptors. One useful feature of CBD is that it may compete with cannabinoid agonists for cannabinoid receptor binding sites, which would explain its apparent ability to minimize the psychoactivity of drugs that use a combination of THC and CBD.
HIV sensory neuropathy
The experimental mixed cannabinoid agonist WIN55,212-2 is an effective and consistent anti-hyperalgesic agent in three distinct animal models of HIV-associated sensory neuropathy.
Pain in chemotherapy
Cannabinoid modulation of chemotherapy-induced neuropathy has been evaluated with agents from three major classes of chemotherapeutic agents. Mixed CB1 and CB2 agonists and selective CB2 agonists have so far suppressed paclitaxel-evoked mechanical allodynia, which is to say, pain provoked by a stimulus that does not normal provoke pain.
Nerve demyelination-induced pain has been evaluated in the lysolecithin-induced animal demyelination model. WIN55,212-2 was able to attenuate mechanical allodynia and thermal hyperalgesia (temperature-sensitive pain) in this model and remained efficacious for up to 1 hour post-injection.
Cannabinoids and fatty-acid amides suppress neuropathic pain perception in at least one animal model of postherpetic neuralgia. Systemic WIN55,212-2, administered from days 18 to 21 post-infection, fully reversed mechanical allodynia to baseline levels in this model.
Traumatic nerve damage
Cannabinoids suppress neuropathic nociception in at least nine different animal models of surgically-induced traumatic nerve or nervous system injury.
In chronic constriction trauma, several classes of cannabinoids have been shown to suppress pain in rodents. These include mixed cannabinoid agonists that target both CB1 and CB2 receptors, CB2 selective agonists, and modulators of the endocannabinoid system that inhibit FAAH or MGL. Synthetic analogues of natural cannabinoid ligands containing cannabidiol attenuate or reverse established thermal and mechanical hyperalgesia in this model as well. However, anti-hyperalgesic effects observed with these compounds are likely to be independent of cannabinoid receptors. WIN55,212-2 dose-dependently inhibits windup, as well as increases in spontaneous firing of spinal wide dynamic range neurons, through a CB1-dependent mechanism. Spontaneous WIN55,212-2 also normalizes prostaglandin E2 levels and nitric oxide activity, two mediators of neuropathic pain that are increased after constriction damage.
In partial sciatic nerve ligation, spoken of as the ‘Seltzer Model’, exogenously applied endocannabinoids AEA and 2-AG suppress changes in neuropathic pain perception. AEA produced anti-hyperalgesic and anti-allodynic effects through a CB1 mechanism, and 2-AG produced anti-hyperalgesic and anti-allodynic effects through activation of both peripheral CB1 and CB2. Ajulemic acid, which was developed as a peripherally restricted cannabinoid analogue, also produced activity; antihyperalgesic effects occurred at doses lower than those producing side effects. Structurally distinct CB2-specific agonists are efficacious in suppressing pain perception in this model. Moreover, CB2 receptors in the spinal cord contribute to CB2 mediated suppression of mechanical allodynia.
In experimental spinal nerve ligation, several mixed cannabinoid CB1/CB2 agonists suppress hyperalgesia and allodynia. WIN55,212-2 suppresses all forms of pain in this model. CP55,940 produces antinociception mostly at CB1. Spinal, but not systemic, administration of HU-210 has been reported to reduce A-fiber-evoked responses on spinal wide dynamic range neurons in rats, but not C-fiber. The CB2-specific agonist GW405833, administered chronically, suppressed the development of mechanical allodynia. The structurally distinct CB2-specific agonist JWH133 also attenuates mechanically-evoked responses of WDR neurons in both naive and spinal nerve ligated rats. Systemic and spinal administration of the novel CB2 agonist A-836339 also attenuates spontaneous and mechanically-evoked neuronal firing of spinal WDR neurons in a CB2-dependent manner. Two endocannabinoid modulators have been evaluated behaviorally in this model. Compound 17, a novel FAAH inhibitor, reversed mechanical allodynia in SNL rats with the same potency as a 5-fold higher dose of gabapentin. In addition, OL135, a compound that accesses the CNS and inhibits FAAH, suppressed mechanical allodynia in a CB2 dependent manner. Low doses of locally injected URB597 reduced mechanically-evoked responses of WDR neurons and increased endocannabinoid levels.
Cannabinoids alleviate neuropathic pain perception in several other injury models. These studies support a role for CB1 in the anti-hyperalgesic effects of cannabinoids, although pharmacological specificity has not been assessed consistently in the literature and high doses of cannabinoid agonists can produce motor side effects, which complicate interpretation of behavioral studies. Common to most of these latter models, systemic WIN55,212-2 typically suppressed all forms of neuropathic pain, including thermal hyperagesia, cold allodynia, mechanical hyperalgesia, and mechanical allodynia.
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The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.
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