Archive for the ‘Neuropathic Pain’ Category

The growing body of evidence that marijuana (cannabis) may be effective as a pain reliever has been expanded with publication of a new study in The Journal of Pain reporting that patients with nerve pain showed reduced pain intensity from smoking marijuana.

Researchers at University of California Davis examined whether marijuana produces analgesia for patients with neuropathic pain. Thirty-eight patients were examined. They were given either high-dose (7%), low-dose (3.5%) or placebo cannabis.

The authors reported that identical levels of analgesia were produced at each cumulative dose level by both concentrations of the agent. As with opioids, cannabis does not rely on a relaxing or tranquilizing effect, but reduces the core component of nociception and the emotional aspect of the pain experience to an equal degree. There were undesirable consequences observed from cannabis smoking, such as feeing high or impaired, but they did not inhibit tolerability or cause anyone to withdraw from the study. In general, side effects and mood changes were inconsequential.

It was noted by the authors that since high and low dose cannabis produced equal analgesic efficacy, a case could be made for testing lower concentrations to determine if the analgesic profile can be maintained while reducing potential cognitive decline.

In addition, the authors said further research could probe whether adding the lowest effective dose of cannabis to another analgesic drug might lead to more effective neuropathic pain treatment for patients who otherwise are treatment-resistant.

This study aimed to give a rationale for the employment of phytocannabinoid formulations to treat neuropathic pain. It was found that a controlled cannabis extract, containing multiple cannabinoids, in a defined ratio, and other non-cannabinoid fractions (terpenes and flavonoids) provided better antinociceptive efficacy than the single cannabinoid given alone, when tested in a rat model of neuropathic pain. The results also demonstrated that such an antihyperalgesic effect did not involve the cannabinoid CB1 and CB2 receptors, whereas it was mediated by vanilloid receptors TRPV1. The non-psychoactive compound, cannabidiol, is the only component present at a high level in the extract able to bind to this receptor: thus cannabidiol was the drug responsible for the antinociceptive behaviour observed. In addition, the results showed that after chronic oral treatment with cannabis extract the hepatic total content of cytochrome P450 was strongly inhibited as well as the intestinal P-glycoprotein activity. It is suggested that the inhibition of hepatic metabolism determined an increased bioavailability of cannabidiol resulting in a greater effect. However, in the light of the well known antioxidant and antiinflammatory properties of terpenes and flavonoids which could significantly contribute to the therapeutic effects, it cannot be excluded that the synergism observed might be achieved also in the absence of the cytochrome P450 inhibition.

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. PERSPECTIVE: This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain, and may be an alternative for patients who do not respond to, or cannot tolerate, other drugs. However, the use of marijuana as medicine may be limited by its method of administration (smoking) and modest acute cognitive effects, particularly at higher doses.

n a double-blind, placebo-controlled clinical trial to assess the impact of smoked medical cannabis, or marijuana, on the neuropathic pain associated with HIV, researchers at the University of California, San Diego School of Medicine found that reported pain relief was greater with cannabis than with a placebo.

The study, sponsored by the University of California Center for Medical Cannabis Research (CMCR) based at UC San Diego, will be published on line, August 6 in the journal Neuropsychopharmacology.

Led by Ronald J. Ellis, M.D., Ph.D., associate professor of neurosciences at UCSD School of Medicine, the study looked at 28 HIV patients with neuropathic pain not adequately controlled by other pain-relievers, including opiates. They took part in the controlled study as outpatients at the UCSD Medical Center. The proportion of subjects achieving pain reduction of 30 percent or more was greater for those smoking cannabis than those smoking the placebo.

“Neuropathy is a chronic and significant problem in HIV patients as there are few existing treatments that offer adequate pain management to sufferers,” Ellis said. “We found that smoked cannabis was generally well-tolerated and effective when added to the patient’s existing pain medication, resulting in increased pain relief.”

Each trial participant participated in five study phases over seven weeks. During two five-day phases, randomly selected participants smoked either cannabis or placebo cigarettes made from whole plant material with cannabinoids (the psychoactive compound found in marijuana) removed, both provided by the National Institute on Drug Abuse. Outcome was tested by standardized tests measuring analgesia (lessened pain sensation), improvement in function and relief of pain-associated emotional distress.

Using verbal descriptors of pain magnitude, cannabis was associated with an average reduction of pain intensity from ‘strong’ ‘to mild-to-moderate’ in cannabis smokers, according to Ellis. Also, cannabis was associated with a sizeable (46% versus 18% for placebo) proportion of patients reporting clinically meaningful pain relief.

The study’s findings are consistent with and extend other recent research supporting the short-term efficacy of cannabis for neuropathic pain, also sponsored by the CMCR.

“This study adds to a growing body of evidence that indicates that cannabis is effective, in the short-term at least, in the management of neuropathic pain,” commented Igor Grant, M.D., professor of psychiatry and director of the CMCR.

Grant noted that this is the fourth CMCR sponsored study to provide convergent evidence that cannabis can help in relieving these types of pain. The previous studies were conducted with CMCR support by Donald I. Abrams, M.D., Professor of Clinical Medicine at UCSF, who reported efficacy in short-term treatment of HIV neuropathy (Neurology, 2007, 68:515-521); by Mark Wallace, M.D., Program Director for the UCSD Center for Pain Medicine, who found that normal volunteers subjected to chemically induced pain which mimics neuropathy also responded to medium doses of cannabis (Anesthesiology, 2007, 107(5):785-796); and by Barth Wilsey, M.D., Director of the UC Davis Analgesic Research Center, who also reported benefit from smoked cannabis in a group of patients with neuropathy of multiple origins (Journal of Pain, 2008 Jun;9(6):506-21).

Additional contributors to the study, all from the UCSD School of Medicine, include Will Toperoff, RN, FNP, Department of Neurosciences; Florin Vaida, Ph.D., Family and Preventive Medicine; Geoff van den Brande, RN, Medicine; J. Gonzales, Pharm.D., Pharmacy; Ben Gouaux, Heather Bentley, CCRA, and J. Hampton Atkinson, M.D., Psychiatry.

Neuropathy is the most common complication of diabetes and it is still considered to be relatively refractory to most of the analgesics. The aim of the present study was to explore the antinociceptive effect of a controlled cannabis extract (eCBD) in attenuating diabetic neuropathic pain. Repeated treatment with cannabis extract significantly relieved mechanical allodynia and restored the physiological thermal pain perception in streptozotocin (STZ)-induced diabetic rats without affecting hyperglycemia. In addition, the results showed that eCBD increased the reduced glutathione (GSH) content in the liver leading to a restoration of the defence mechanism and significantly decreased the liver lipid peroxidation suggesting that eCBD provides protection against oxidative damage in STZ-induced diabetes that also strongly contributes to the development of neuropathy. Finally, the nerve growth factor content in the sciatic nerve of diabetic rats was restored to normal following the repeated treatment with eCBD, suggesting that the extract was able to prevent the nerve damage caused by the reduced support of this neurotrophin. These findings highlighted the beneficial effects of cannabis extract treatment in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and a specific action upon nerve growth factor. Copyright (c) 2009 John Wiley & Sons, Ltd.

Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB(1)/CB(2) agonists, CB(2) selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Delta(9)-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Delta(9)-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research.

A significant complaint associated with spinal cord injury (SCI) is chronic pain, which includes symptoms such as cutaneous hypersensitivity and spontaneous unevoked pain and is difficult to treat with currently available drugs. One complication with current analgesics is tolerance, a decrease in efficacy with repeated treatment over time. One promising class of pharmacological treatment is cannabinoid (CB) receptor agonists. The current study assessed the efficacy of the CB receptor agonist WIN 55,212-2 (WIN) in a rat model of neuropathic SCI pain. Brief spinal compression leads to significant hindpaw hypersensitivity to tactile stimulation. WIN dose-dependently increased withdrawal thresholds and continued to demonstrate efficacy over a twice-daily 7-day treatment regimen. By contrast, the efficacy of morphine in SCI rats decreased over the same treatment period. Similarly, the antinociceptive efficacy of WIN to acute noxious heat in uninjured rats diminished over time. These data suggest that the sustained efficacy of a CB receptor agonist for pain could depend on the pain state. Such agonists may hold promise for long-term use in alleviating chronic SCI pain.