A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain

Abstract

The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use "medical marijuana," and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses. KeywordsNeuropathic pain; analgesia; cannabis; clinical trial; neuropsychological testingThe case for the clinical utility of cannabis as an analgesic derives from experimental studies as well as anecdotal reports. Activation of the endocannabinoid system suppresses HHS Public AccessAuthor manuscript J Pain. Author manuscript; available in PMC 2016 August 01. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript behavioral responses to acute and persistent noxious stimulation through both central 71 and peripheral 45 mechanisms. Cannabinoid receptors are localized in neuroanatomic regions intimately involved with transmission and modulation of pain signals: The periaqueductal gray (PAG), the rostral ventromedial medulla (RVM), 40,66 and the dorsal horn of the spinal cord. 66 Animal experimentation has clearly demonstrated that synthetic and endogenous cannabinoids not only produce analgesia but also interact in some manner to potentiate opioids, 18,70 particularly in neuropathic pain. 41 Surveys involving the use of medicinal marijuana reveal that pain, sleep, and mood improve with only modest side effects. 72,73 In one human pain experiment, subjects had a significant dose-dependent antinociception (increased finger withdrawal latency) effect that was not reversed by opioid antagonism. 31 In a somewhat contradictory manner, hyperalgesic activity and enhancement of the perception of pain on acute exposure in chronic users of marijuana was reported. 20 Experience with cancer pain revealed that 120 mg codeine and 20 mg delta-9-tetrahydrocannabinol (9-THC) were similar to each other and significantly superior to placebo for the sum of the pain intensity differences and total pain relief. 55,56 However, there was a clear dose-response relationship for sedation, mental clouding, and other central nervous system (CNS) related side effects f...

Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers

“…Peak subjective ratings of dronabinol's drug effects occurred 60 min after administration, whereas dronabinol-induced decreases in pain sensitivity and increases in pain tolerance were highest about 4 h after drug administration, suggesting that the magnitude and time course of these subjective drug effects do not necessarily predict analgesia in the CPT. Clinical studies have demonstrated the analgesic effectiveness of cannabinoids including marijuana and dronabinol in neuropathic pain populations (Svendsen et al, 2004;Abrams et al, 2007;Nurmikko et al, 2007;Wilsey et al, 2008;Ellis et al, 2009;Ware et al, 2010). However, the cannabinoids proved to be less effective in attenuating other pain modalities; dronabinol (5 mg) failed to decrease postoperative pain (Buggy et al, 2003) and sensitivity to a thermal stimulus (Roberts et al, 2006), and a higher dronabinol dose (20 mg) failed to reduce acute inflammatory pain, hyperalgesia (Kraft et al, 2008), or increase pain threshold in a pressure test (Naef et al, 2003).…”

“…Cannabinoids have long been thought to be effective in reducing pain (Russo, 2008) and findings from doubleblind, placebo-controlled studies have substantiated such hypotheses demonstrating that smoked and vaporized marijuana (Abrams et al, 2007;Ellis et al, 2009;Wilsey et al, 2008Wilsey et al, , 2013, oral D 9 -tetrahydrocannabinol (THC; dronabinol), the primary psychoactive component of marijuana (Mechoulam et al, 1970;Svendsen et al, 2004), and Sativex , an oromucuosal preparation of THC and cannabidiol, decrease subjective ratings of pain in neuropathic pain populations. Because of its recent legalization for medical use in a number of US states (Hoffmann and Weber, 2010), marijuana is now being prescribed therapeutically to manage a wide variety of pain conditions (Reinarman et al, 2011).…”

“…As discussed above, clinical studies have demonstrated the analgesic effects of cannabinoids in pain patients (Svendsen et al, 2004;Abrams et al, 2007;Nurmikko et al, 2007;Wilsey et al, 2008;Ellis et al, 2009;Ware et al, 2010), but none have compared the effects of marijuana to dronabinol. Therefore, this within-subject, randomized, placebo-controlled, double-dummy, double-blind study directly compared the therapeutic analgesic potential of marijuana to dronabinol in response to a laboratory measure of acute pain in healthy, daily marijuana smokers.…”

Potencial uso terapéutico de cannabis

“…Estas sustancias que mantienen y potencian la transmisión dolorosa, son responsables de la cronificación y amplificación del dolor 36. Al respecto, se evalúa la planta a la forma de cigarrillo o vaporizada comparado con un placebo, observándose un prometedor efecto analgésico, principalmente en aquellos preparados con mayor concentración de THC (9,6%). El problema de estos estudios, es que incluyen una pequeña muestra de pacientes y los cigarrillos empleados contenían distintas concentraciones de THC [37][38][39][40] .…”

Prescribing medical cannabis in Canada: Are we being too cautious?

“…3 Cannabinoids (e.g., Dronabinol) are considered as a fourth-line treatment option 3 and more recently, smoked or vaporized cannabis has also been clinically investigated. A PubMed review reveals five recent randomized control trials [4][5][6][7][8] (including two published in the Canadian Medical Association Journal), and two systematic reviews, 9,10 that have evaluated the analgesic efficacy of smoked or vaporized cannabis on neuropathic pain compared to a placebo. While treatment regimens (e.g., potency and dosage) and patient populations (e.g., HIV patients, multiple sclerosis patients) varied across studies, each study recorded significant neuropathic pain relief associated with cannabis treatment.…”