CHRONIC NEUROPATHIC PAIN

Chronic pain is not just a problem of incidence and pathophysiology; it is one of unique individual suffering. Chronic neuropathic pain (CNP) causes untoward amounts of suffering, and costs millions of dollars a year in lost work and healthcare costs. In terms of physiology, neuropathic pain is described by the International Association for the Study of Pain as, "pain initiated or caused by a primary lesion or dysfunction in the nervous system," and has an annual incidence of 1% in the general population.

Treatments for CNP

Unfortunately, our current treatments for CNP are limited. Although polypharmacy is common in the treatment of neuropathic pain, few studies have evaluated combination therapies. The current treatments do help some patients, but many patients do not respond and their suffering continues. Furthermore, current research tends to focus on disease states that can be clearly specified, eg, postherpetic neuralgia and HIV neuropathy. Many neuropathic pain states are either rare in incidence or poorly defined in presentation. It is not clear whether the results from current research for disorders, such as postherpetic neuralgia, will translate into similar outcomes for other neuropathic pain conditions.

A Search for New Treatment Options

The current limited treatment options and patient suffering have energized a search for new and more effective treatments. Research into the mechanisms of CNP has provided insight into some of these potential new treatment targets. Two such targets, the transient receptor potential (TRP) channel agonists (and antagonist) and cannabinoid agonists, are areas of increased excitement.

The TRP channels are a large family of cation channels. They influence a multitude of physiologic processes in the body from pain to thermosensation. There are 6 subfamilies, 1 of which is the TRPV(1-6). When activated, these receptors conduct mostly calcium, with some sodium and potassium conductance. The TRPV1 receptor, found in the central nervous system (CNS), in sensory ganglia (dorsal root ganglia), and peripheral C and A delta sensory fibers, is of particular interest. This receptor is activated by temperatures > 43°C (noxious), low pH ≤ 5.2, low voltage, and low lipid levels. Of note, the receptor is also activated by certain venomous insects and arachnids, although the exact mechanism for this is unknown.

Capsaicin

Capsaicin, the chemical that gives jalapeño peppers their "heat," has been found to be an exogenous agonist. The history of the use of capsaicin in pain goes back millennia. The benefits of capsaicin include the fact that it is lipophilic, readily crosses cell membranes, and is relatively easily synthesized.
Research in TRPV1 agonist has focused on topical, intravenous, intranasal, and oral routes of administration. The transdermal route has been shown to be the most effective and is now commercially available in an 8% transdermal patch under the trade name Qutenza®.

Clinical Trials of Capsaicin

Clinical trials with the 8% capsaicin patch have shown clinical efficacy. Unfortunately, meta-analyses for neuropathic pain treatments have continued to compare these studies, which used active controls (0.04%) and not placebos, with placebo-controlled trials. This artificially elevates the numbers needed to treat. The Cochrane Collaboration review and the recent review of neuropathic pain treatments by Finnerup and colleagues, published in the journal Pain, both compared 8% capsaicin clinical trials with placebo-controlled trials.

Indications and Use of Capsaicin

The 8% capsaicin patch has efficacy similar to other treatments, is topical, and avoids the systemic problems of daily medications. However, certain barriers accompany its application. It must be applied in a physician's office and takes 2-3 hours of a physician's (and patient's) time. In Europe, the 8% patch is indicated for neuropathic pain syndromes other than diabetic peripheral neuropathy. In the United States, the patch is indicated only for postherpetic neuralgia. It has been used, however, for trigeminal neuralgia (reported in case studies), and other neuropathic conditions. Research continues in the use of capsaicin for migraine (although the data have been conflicting), pruritus, musculoskeletal pain, osteoarthritis, and other pain conditions
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. 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. In a 2007 review, the THC/cannabidiol combination was shown to be effective in 125 patients with neuropathic pain of peripheral origin. In multiple sclerosis, Sativex was found to reduce spasticity. 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.

Pharmacologic vs Recreational Marijuana

The Cannabis sativa plant contains over 300 compounds, 66 of which are cannabinoids. 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.

In conclusion, TRPV1 receptor agonists have shown efficacy in relieving pain of different neuropathic pain states. There is controversy over the use of smoked Cannabis in the treatment of pain; however, the use of specific cannabinoids agonists holds promise for the future. Additional mechanisms are being investigated as well.

References

1. International Association for the Study of Pain. IASP pain terminology. Irving GA, Backonja MM, Dunteman E, et al. A multicenter, randomized, double-blind, controlled study of NGX-4010, a high-concentration of capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med. 2010 Nov 18. [Epub ahead of print].
2. Webster LR, Malan TP, Tuchman MM, Mollen MD, Tobias JK, Vanhove GF. A multicenter, randomized, double-blind, controlled dose finding study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia.
3. Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neurpathic pain in adults. Cochrane Database Syst Rev. 2009;(4):CD007393.
4. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150:573-581.
5. Ware MA, Wang T, Shapiro S. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182:E694-701.
6. Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy. Diabetes Care. 2010;33:128-130.
7. Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;133:210-220.
8. Wade DT, Collin C, Stott C, Duncombe P. Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis. Mult Scler. 2010;16:770-714.