pain equally. Ware looked at the effect of cannabis on posttraumatic and postsurgical neuropathic pain. Twenty-three patients inhaled different doses of cannabis (including 0 percent THC) three times daily for five days, with nine days of rest between doses. The average daily pain intensity was significantly lower on the highest THC strength (9.4 percent), with patients also reporting improved quality of sleep. An ongoing study funded by the University of California Center for Medicinal Cannabis Research is investigating cannabis in diabetic neuropathy. A study in chemotherapy-induced neuropathy is clearly warranted. Cannabinoids and opioids share several pharmacologic properties including antinociception, sedation, hypothermia, hypotension, and inhibition of intestinal motility. Unlike opioid receptors, however, there is a dearth of cannabinoid receptors located in the brain stem, so respiratory suppression is not a risk of cannabinoid therapies. Cannabinoids interact with kappa and delta receptors in production of pain relief, while the analgesic effects of opioids are mediated by mu receptors but may be enhanced by cannabinoid effects. In mice and rats, THC greatly augments the analgesic effects of morphine in a synergistic fashion. If such an interaction were reproduced in humans, enhanced and persistent analgesic effects at lower opioid doses with cannabinoid boosting could be possible. To investigate the potential cannabinoid:opioid interaction, we conducted a classical pharmacokinetic interaction study involving ten patients with chronic pain on a stable dose of sustained-release morphine and eleven patients on sustainedrelease oxycodone. Patients inhaled vaporized cannabis three times daily for four days after their initial twelve-hour opioid area concentration versus time curve was obtained. Repeat opioid kinetics were drawn on day five. Despite no change in the oxycodone concentration curves and a mild decrease in the plasma levels of morphine after cannabis exposure, patients reported a significant 27 percent decrease in their chronic pain with the combination therapy, suggesting a possible pharmacodynamic—not pharmacokinetic—effect. A larger follow-on trial with pain as the primary endpoint, perhaps also investigating a high CBD strain of cannabis, is warranted. Nabiximols (Sativex) is a whole-cannabis extract medicine with a standardized THC:CBD ratio, available in Canada and European nations. Originally approved for treatment of pain and spasticity associated with multiple sclerosis, nabiximols as an oromucosal spray is being evaluated in an ongoing phase III trial in the U.S., investigating the medication in patients with cancerassociated pain. In the meantime, as an oncologist, I am faced daily with patients suffering from anorexia, nausea and vomiting, depression/anxiety, insomnia, and pain—on opioids or not. Instead of writing prescriptions for five or six different pharmaceuticals to address these troublesome symptoms, I can recommend that patients try a single agent: cannabis. Increasingly, patients with advanced disease receiving palliative care come with stories of how they were unpleasantly oversedated and cognitively altered by heavy doses of opioids, to the point that they were unable to effectively communicate with their loved ones during their precious final days. Many have weaned way down, or even come totally off of, their opiates while adding cannabis to their regimen. A word about delivery systems is in order, as so many of my www.sfms.org
patients accessing medicinal cannabis at dispensaries feel that eating is good and smoking is bad, so they seek edible products. First of all, there is really very little evidence that inhaling cannabis has significant deleterious pulmonary consequences—in fact, a recent study suggested potential benefit. Second, the pharmacokinetic profiles of ingested and inhaled cannabis are quite different. When taken by mouth, bioavailability is low (6–20 percent) and variable, with a peak concentration in 2.5 hours. First-pass metabolism through the liver creates a secondary metabolite, 11-OH-THC, which is also psychoactive. In addition, the terminal half-life of orally ingested cannabis is twenty to thirty hours. When inhaled, the peak plasma concentration is achieved in two-and-a-half minutes, with a rapid decline over the next thirty minutes, and much less of the secondary psychoactive metabolite is formed. Hence patients are much less likely to experience a dysphoric overdosing and more able to titrate the onset and magnitude of the effect through inhalation, with vaporization becoming an increasingly popular smokeless delivery system for this useful, albeit still misclassified as Schedule I, medicine. Donald I. Abrams, MD, is chief of hematology-oncology at San Francisco General Hospital and professor of clinical medicine at University of California San Francisco.
References Abrams DI, Jay C, Shade S, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham M, Petersen K. Cannabis in painful HIV-associated sensory neuropathy: A randomized, placebo-controlled trial. Neurology. 2007; 68:515-521. Abrams DI, Couey P, Shade SB, Dhruva A, Kelly ME, Benowitz NL. Cannabinoid:opioid interaction in chronic pain. Clinical Pharmacology and Therapeutics. 2011; 90:844-851. Carter GT, Flanagan AM, Earlywine M, Abrams DI, Aggarwal SK, Grinspoon L. Cannabis in palliative medicine: Improving care and reducing opioid-related morbidity. Am J Hosp Palliat Care. 2011; 28:297-303. Elikottil J, Gupta P, Gupta K. The analgesic potential of cannabinoids. Journal of Opioid Management. 2009; 5:341-357. Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, Bentley H, Atkinson JH. Smoked medical cannabis for neuropathic pain in HIV: A randomized, cross-over clinical trial. Neuropsychopharmacology. 2009; 34:672-680. Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets. 2009; 8:403-421. Leung L. Cannabis and its derivatives: Review of medical use. J Am Board Fam Med. 2011: 24:452-462. Russo EB. Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology. 2011; 163:1344-1364. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett CJ, Collet JP. Smoked cannabis for chronic neuropathic pain: A randomized controlled trial. CMAJ. 2010; 182:E694-701. Pletcher MJ, Vittinghoff E, Kalham R, Richman J, Safford M, Sidney S, Lin F, Kertesz S. Association between marijuana exposure and pulmonary function over 20 years. JAMA 307:173-181, 2012.
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