____________________________________________________ Medical Marijuana and Other Cannabinoids
high-dose (9.4%) THC than with placebo. Intermediate poten- cies showed reduced but non-significant pain reduction vs. pla- cebo. In addition, the 9.4% THC dose significantly improved ability to fall asleep and sleep quality compared with placebo. Side effects were more frequent with 9.4% THC cannabis and included headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness, and cough. Most side effects were mild, and no serious or unexpected adverse events occurred. The authors concluded that single-inhalation 9.4% THC cannabis reduced pain intensity, improved sleep, and was well tolerated in these patients [134]. Vaporized Cannabis in Chronic Neuropathic Pain In an RCT with crossover, patients with central or peripheral neuropathic pain resistant to conventional drug therapies received single-dose 3.53% THC, 1.29% THC, or 0% THC (placebo) cannabis [182]. Significant analgesic response was found with active but not placebo cannabis. Analgesia was equivalent with medium- vs. low-dose cannabis. Psychoactive effects were minimal and well tolerated, and neuropsychologic effects reversed within one to two hours. The authors state their findings of analgesic efficacy with low-dose cannabis in treatment-refractory neuropathic pain have large clinical value and that a negative impact on daily functioning is unlikely based on the observed side effects [182]. Experimental Neuropathic Pain To examine the dose-by-time analgesic effect of cannabis, 19 healthy volunteers received capsaicin injection under the skin to simulate neuropathic pain and were administered in random sequence low-, medium-, and high-dose cannabis (2%, 4%, and 8% THC) or placebo cigarettes [183]. No effect on capsaicin-induced pain was found at any dose five minutes after smoking. At the 45-minute time point, there was a significant pain decrease with 4% THC, a significant pain increase with 8% THC, and no differences with 2% THC or placebo. A significant inverse relationship between pain perception and plasma THC was also found. The authors conclude a “thera- peutic window” (or optimal dose) may exist for smoked can- nabis with acute neuropathic pain, with low doses ineffective, medium doses efficacious, and higher doses pain-enhancing [183]. This biphasic dose-response effect of cannabinoids in acute neuropathic pain is consistent with the previous body of research [60]. Nociceptive Pain Cannabis has not been found effective in acute nociceptive pain and has shown a biphasic dose-response effect with acute neuropathic pain [60]. However, chronic pain results from the development of abnormal sensory processing and other alterations in peripheral and CNS pain pathways [184]. The endocannabinoid receptor complex interacts with signaling pathways and pain circuitries expressing abnormal function in chronic pain, accounting for therapeutic effect not seen in acute pain [61].
Clinical trials of cannabinoids in patients with chronic pain due to rheumatoid arthritis, fibromyalgia syndrome, or can- cer pain found statistically significant pain relief consistently around 30% in magnitude [185]. When considered alone, changes in pain scores understate the extent of overall relief in these patients, because improved mood, sleep, coping, and quality-of-life scores have been consistently reported with cannabis and cannabinoids. Patients with fibromyalgia and clinically relevant depression showed greater benefit from can- nabinoids than non-depressed patients with fibromyalgia [60]. Reducing Opioid Requirements Studies of chronic non-malignant pain have found significant pain relief, reduced bother from pain, and prevention or reduc- tion of opioid tolerance with cannabinoid addition to opioid therapy [186; 187]. An RCT with patients with severe cancer pain found cannabinoid addition to opioid therapy led to pain level reduction of 30% to 50% in 43% of patients [60; 188]. In patients with pain from chronic progressive multiple sclerosis, HIV-related neuropathy, or spinal trauma pain poorly controlled with high-dose opioids, one study found adding smoked cannabis led to opioid dose decreases of 60% to 100% and improvements in pain relief and function [189]. Abrams studied the effect on pain from giving four days of vaporized cannabis to 21 patients with mixed persistent chronic pain despite stable long-term use of morphine sustained-release (SR) or oxycodone SR (mean dose: 62 mg and 53 mg, respectively) [117]. Cannabis slightly reduced morphine levels, had no effect on oxycodone levels, and reduced pain by roughly 30%. A survey of 29 medicinal cannabis patients with chronic pain found that of the eight using cannabis as their sole analgesic, all had been prescribed but abandoned opioids for cannabis due to the greater perceived pain relief, fewer side effects, or absence of problematic opioid use risk [190]. Combining opioids and cannabis in pain therapy offers the added potential advantage of synergistic analgesic action that decreases the dosage requirements and side effects of both agents. Such an approach exploits the considerable functional interaction between endogenous opioid and cannabinoid systems and may also reduce the development of tolerance with both agents [176].
NEUROPSYCHIATRIC DISORDERS Multiple Sclerosis and Spasticity
Spasticity is a core symptom of multiple sclerosis, is common after stroke and with other neurologic conditions, and greatly limits movement, activities of daily living, and participation in life by those afflicted. Oral antispasmodic agents are of limited effectiveness, and beneficial treatment options for spasticity have not significantly expanded since the late 1990s [191]. Consequently, many patients with multiple sclerosis have sought relief through cannabis use. The oromucosal cannabi- noid spray nabiximols appears efficacious in multiple sclerosis
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