The use of cannabinoids for medical indications is the subject of ongoing debate. Some medical professionals and patients argue that cannabinoids have marked analgesic properties, while other physicians, who cite the still relatively scant literature supporting their use, are skeptical about their efficacy, especially in comparison with other currently available analgesics.
There are currently 2 cannabinoids available by prescription in the United States: dronabinol (Marinol) and nabilone (Cesamet). Both are FDA-approved for the management of nausea and vomiting associated with cancer chemotherapy in patients who have not responded to conventional antiemetic treatments.1 Dronabinol is also approved for the treatment of anorexia associated with AIDS. Both dronabinol and nabilone are administered orally. Dronabinol is a synthetic form of delta-9-tetrahydrocannabinol (THC)-the psychoactive ingredient of cannabis. Nabilone is also a synthetic cannabinoid that is similar to THC but appears to be more potent.
Although no cannabinoids are currently FDA-approved as analgesics, there is ongoing research on their efficacy. A recent study on use of nabilone in patients with fibromyalgia found a significant reduction in pain compared with placebo.2 Patients receiving nabilone reported significantly more adverse effects, including drowsiness, but none of these were considered serious. Nabilone is also being studied in the United States for its efficacy in neuropathic pain associated with cancer chemotherapy.
Sativex, a combination of THC and cannabidol (the latter agent is not psychoactive), is in phase 3 trials in the United States for relief of cancer-related pain. Sativex is approved in Canada for the treatment of neuropathic pain associated with multiple sclerosis and as an adjunctive analgesic for moderate to severe pain in patients with cancer who have pain despite strong opioid therapy. Unlike dronabinol and nabilone, Sativex is administered in an oral spray.
Both sides of the debate
The use of marijuana itself as a medicine is controversial. Several states have approved medical marijuana use and others have considered approving it. However, so far, the federal government has remained unalterably opposed to its legalization, and it remains a Drug Enforcement Administration Schedule I drug.
The debate over whether marijuana should be available for the management of pain has centered on several issues. Those who support its use point out that there is much anecdotal evidence and some formal research supporting marijuana's beneficial effects. Regarding concerns about its potential for abuse, proponents counter that opioids, which also can be abused, are legal.
In addition to concerns about efficacy, opponents of the legalization of medical marijuana cite the lack of standardization of the ingredients or potency of the marijuana available in the states where its use has been legalized. Furthermore, there is limited information on optimal dosing. In Canada, where medical marijuana is legal, there is controversy over whether the government's recommendation that the dosage be limited to 1 to 3 g daily has a scientific basis.3
Smoking marijuana also carries the potential for lung damage. In addition, as previously mentioned, there is the debate over whether medical use of marijuana is simply an attempt to subvert the current laws on recreational use. There have been many reports that where medical marijuana use is allowed, some physicians who are recommending it and some providers of it are lax about confirming the medical conditions of the patients who request it.
There is literature suggesting that marijuana may provide pain relief. A study of patients with HIV-associated neuropathic pain found that smoking marijuana reduced pain by 34%, compared with a 17% reduction in patients who were provided with placebo cigarettes in which THC had been removed.4 Patients smoked either the active or placebo cigarettes 3 times daily for 5 days. Adverse events, including sedation, dizziness, and confusion, were significantly more likely to occur among marijuana users. However, these were relatively infrequent, and no subjects had to withdraw from the study because of them. Because the National Institute on Drug Abuse provided the cigarettes, it was possible to standardize the amount of cannabis and the percentage of THC provided to patients.
How cannabinoids offer pain relief is still unclear, but several possible mechanisms have been theorized. Two cannabinoid (CB) receptors have been identified. CB1 receptors are located throughout the central and peripheral nervous systems and many other tissues, while CB2 receptors are primarily limited to immune tissue, including the spleen, tonsils, B cells, and T cells.5 It is thought that activation of CB1 receptors may alter pain pathways, although the mechanism is unclear. These receptors are also linked to calcium and potassium channels, alterations of which have been implicated in the development of neuropathic pain.
Other potential sites of analgesia include the effects of cannabinoids on various serotonin receptors, anti-inflammatory effects mediated through the inhibition of prostaglandin synthesis, the inhibition of glutamate release by presynaptic nerves, and an increase in dynorphin release.
A recent study involving mice reported that the analgesic effect cannabinoids exhibit appears to be primarily mediated via peripheral rather than CNS CB1 receptors.6 This suggests that it may be possible to develop analgesic cannabinoids while avoiding their psychoactive adverse effects. The results of this study are also important because animal studies indicate that stimulation of the spinal CB1 receptors may be involved in the development of opioid tolerance and physical dependence.7
Slatkin N. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting: beyond prevention of acute emesis.
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Skrabek RQ, Galimova L. A randomized double-blind placebo controlled trial assessing the effect of the oral cannabinoid nabilone for pain and quality of life in patients with fibromyalgia. Presented at: the Annual Meeting of the American Pain Society; May 5-7, 2007; Washington, DC.
Comeau P. New dosage limits for medical marijuana: but where's the science?
Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial.
Walker JM, Huang S. Cannabinoid analgesia.
Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors.
Trang T, Sutak M, Jhamandas K. Involvement of cannabinoid (CB1)-receptors in the development and maintenance of opioid tolerance.