New Treatments for Neuropathic Pain

John F. Peppin, DO


January 20, 2011

In This Article

Endocannabinoid Receptor Agonists

In contrast to the history of capsaicin, the endocannabinoid signaling system was only recently discovered. These receptors are involved in a number of different physiologic processes, from food intake to immunomodulation. Two cannabinoid receptors have been identified, CB1 and CB2. Both of these receptors are 7-domain G protein-coupled receptors and affect cyclic adenosine monophosphate. Endocannabinoid agonists include both endogenous and exogenous substances. The endogenous cannabinoids, anandamide and 2-arachidonoylglycerol, were identified in the 1990s. Naturally occurring compounds are found solely in plants of the genus Cannabis. The most commonly known is delta9-tetrahydrocannabinol (THC). Exogenous endocannabinoid agonists include the "manufactured" drugs Sativex® (THC/cannabidiol) and nabilone.

Effects of Cannabinoids

Of interest, the endocannabinoid system interacts with a number of other pain control systems, eg, endorphins and TRPV receptors. They function mostly as neuromodulator agents and have potent anti-inflammatory effects. CB1 is expressed in the CNS, and CB2 is found on immune cells, but CB2 also has a role in pain and inflammation. CB2 receptors are found in the CNS, mainly in microglia, but in low densities. The CB1 receptor is low in density in the brainstem, which may account for its low lethality and toxicity. CB1 antagonists, when given to mice, result in hyperalgesia. Moreover, endocannabinoid deficiency may lead to certain conditions, such as migraine, irritable bowel syndrome, and fibromyalgia. In experimental models, cannabinoids inhibit release of glutamate, and it has been postulated that glutamate and glutamatergic systems are important for the maintenance of CNP.

Similar to capsaicin, cannabinoids have been used for centuries in the treatment of mood and pain. The naturally occurring THC has 20 times the anti-inflammatory potential of aspirin and nonsteroidal anti-inflammatory drugs. However, THC has no cyclooxygenase inhibitory capability. Cannabidiol, the second component in the product Sativex, is noneuphoriant, but has some of the same actions as THC. Of note, cannabidiol is also a TRPV1 agonist.

Clinical Trials

Cannabinoids have been evaluated in multiple animal models. Nerve injury models, streptozotocin-induced diabetic neuropathy, chemotherapy-induced neuropathy, HIV-associated sensory neuropathy, demyelination-induced neuropathy, multiple sclerosis-associated neuropathy, and postherpetic neuralgia animal models have all been used. Studies in all of these models have shown efficacy in suppression of hyperalgesia and allodynia.

In humans, both smoked and oral cannabinoids have been evaluated. Unfortunately, well-designed randomized, placebo-controlled trials are lacking for smoked cannabis. A recent study in the Canadian Medical Association Journal enrolled only 23 patients.[6] Smoked cannabis was used and the design was a crossover randomized trial. This is one of the few well-designed studies with smoked cannabis. Unfortunately, to achieve a power of 80% the study needed to enroll 32 patients, a number that was not achieved.

In a study with THC/cannabidiol for diabetic neuropathic pain, the combination cannabinoids were no more effective than placebo.[7] In a 2007 review, the THC/cannabidiol combination was shown to be effective in 125 patients with neuropathic pain of peripheral origin.[8] In multiple sclerosis, Sativex was found to reduce spasticity.[9] Furthermore, cannabinoids have not only been evaluated for the treatment of chronic pain, but also for dementia, some psychiatric illnesses, and chemotherapy-induced nausea and vomiting.[9]

Pharmacologic vs Recreational Marijuana

The Cannabis sativa plant contains over 300 compounds, 66 of which are cannabinoids.[10] Many of these are biologically active; some have unknown activity. The percentages of many of the metabolites of Cannabis can be dramatically influenced by where the plant is grown, how much water that it receives, and other factors. Of interest, GW Pharmaceuticals plc (Salisbury, United Kingdom) has genetically developed specific strains of Cannabis that produce single specific metabolites. It should be obvious that studies with smoked Cannabis, even if with standardized herbal material, cannot be translated to the marijuana shops of California. Therefore, the use of smoked marijuana for chronic pain cannot be supported by current data.


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