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Pain Management Cannabinoids and Pain The Medical Application Explained Donald I. Abrams, MD Cannabis is one of the oldest-known psychoactive plants. Contents of the tomb of a presumed shaman in northern China dating back 2,700 years include two receptacles containing the flowers of the female plant. Cannabis medications were produced by most pharmaceutical companies in this country in the early part of the twentieth century, prescribed for putative analgesic, sedative, antispasmodic, and anti-inflammatory effects. Cannabis was removed from the U.S. Pharmacopoeia in 1942 following the passage of the Marijuana Tax Act and was classified as a Schedule I drug with high potential for abuse and no known medical use by the Controlled Substances Act of 1970. Despite the ongoing prohibition against cannabis as medicine, much has been learned about how the plant’s main components— the cannabinoids—affect the body. Two cannabinoid receptors have been identified. The CB1 receptor has its highest concentration in the central nervous system but is found diffusely in organs throughout the body. The CB2 receptor was initially identified in cells of the immune system— the spleen, B lymphocytes, and natural killer cells—suggesting it may play a role in immune function and inflammation. These receptors, members of the superfamily of seven-transmembranespanning G protein-coupled receptors, are found in virtually all animal species. Surely these receptors are not present solely to complex with plant cannabinoids from Cannabis species? Just as we produce endogenous opiates—the endorphins—so we also produce endocannabinoids, specifically anandamide and 2-arachidonyl-glycerol (2-AG). The endocannabinoids are produced on demand from cell membrane lipids, complex with the cannabinoid receptors, and effect changes within target cells. Upon docking with the CB1 receptor, endocannabinoid-induced signal transduction is thought to modulate pain, appetite, cognition, emesis, reward, neuroexcitability, and thermoregulation, as well as other functions. By way of the CB2 receptor, endocannabinoids impact pain, inflammation, immune function, and cell proliferation. Just as the endocannabinoids modulate pain via interaction with the cannabinoid receptors, the plant cannabinoids (phytocannabinoids) and synthetic cannabinoid receptor agonists and antagonists also effect processing of noxious stimuli. Elevated levels of the CB1 receptor—like the opioid—are found in areas of the brain involved with nociceptive processing. Analgesic effects of cannabinoids are not blocked by opioid antagonists, suggesting that they work by way of different receptors, although the two systems appear to cross talk. CB1 and CB2 agonists also have peripheral analgesic actions in addition to 20 San 21 SanFrancisco FranciscoMedicine Medicine April April2012 2012 their central effects. Finally, cannabinoids exert anti-inflammatory effects that may also provide relief from pain. The plant contains at least seventy different twenty-onecarbon terpenophenolic cannabinoid compounds. Delta-9-tetrahydrocannabinol (THC) is the primary active ingredient and main psychoactive component in the plant. The other phytocannabinoids, as well as terpenoids and flavonoids, create an “entourage effect” to enhance the beneficial effects of THC and to reduce some of the potential adverse effects. Cannabidiol (CBD), for example, is a nonpsychoactive cannabinoid that is felt to have potent analgesic and anti-inflammatory effects. Although most strains of Cannabis geared toward recreational use have been enriched for THC, savvy medicinal consumers are now seeking strains high in CBD with lower THC to obtain desired pain relief without as much psychoactive effect. Cannabis is effective in a rat model of neuropathic pain. Current therapy for neuropathic pain is generally inadequate. Opioids are often ineffective with high addiction potential in treatment of patients with chronic, non-life-threatening neuropathic conditions. In the past, patients with HIV infection were frequently troubled by painful peripheral neuropathy, caused either by the virus itself or some of the earlier antiretroviral therapies. Based on the preclinical model and anecdotal information from patients, we conducted a clinical trial of inhaled cannabis in fifty patients with painful HIV-related peripheral neuropathy. For an objective “anchor,” we subjected the participants to a heatcapsaicin experimental pain model. After smoking the first study cigarette, the cannabis group experienced a 72 percent reduction in their neuropathic pain, versus a 15 percent reduction in the placebo group. Over the five-day study period, 52 percent of the cannabis group reached the threshold 30-percent reduction in their chronic neuropathic pain compared to only 24 percent in the placebo group. Finally, the area of secondary hyperalgesia in the experimental pain model was unchanged in the placebo group but did decline significantly in the cannabis cohort. The number needed to treat (NNT) in our study was 3.6, which is comparable to the NNT for gabapentin in other peripheral neuropathic pain syndromes. In a subsequent placebo-controlled, crossover dose-escalating study of cannabis for HIV neuropathy, Ellis also found the NNT was 3.5, suggesting that cannabis may be a useful agent in HIV-related neuropathy. Two additional trials investigated cannabis in neuropathic pain of other etiologies. Wilsey looked at thirty-eight patients with neuropathic pain in complex regional pain syndrome. A linear analgesic dose response was seen in the high- and low-dose cannabis groups but not with the placebo. These investigators concluded that the effect was not anxiolytic but that the treatment reduced core nociception and the emotional response to

April 2012

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