Neuropathic pain remains a significant clinical problem because it responds poorly to available therapies.
Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics.
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 9-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both 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.
Cannabinoids for the Treatment of Neuropathic Pain
Tannia Gutierrez; Andrea G Hohmann
The isolation of Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, set the stage for the discovery of an endogenous cannabinoid (endocannabinoid) transmitter system. Endogenous signaling molecules for this system were subsequently isolated. Anandamide and 2-arachidonoylglycerol (2-AG), the best characterized endocannabinoids isolated to date, bind to and activate cannabinoid CB1 and CB2 receptors. CB1 is the primary cannabinoid receptor found in the CNS, whereas CB2 is predominantly, but not exclusively, found in the immune system. The discovery of cannabinoid receptors allowed researchers to synthesize cannabinoids and characterize their pain-relieving properties. Anandamide and 2-AG are degraded by the enzymes fatty-acid amide hydrolase and monoacylglycerol lipase, respectively. Enzymes catalyzing endocannabinoid breakdown also represent targets for analgesic drug development. This article will briefly summarize the findings of preclinical and clinical studies evaluating the therapeutic and side-effect profile of cannabinoids as pharmacotherapies for neuropathic pain.
GW Pharmaceuticals announced preliminary results of two Phase III studies of Sativex®, its cannabinoid spray medicine, in peripheral neuropathic pain.
The results of the study in patients with neuropathic pain characterized by allodynia show that patients taking Sativex obtain clinically important improvements in their management of pain and quality of sleep. In comparison with placebo, statistically significant improvements were seen for key outcome measures, including a positive result in the primary analysis of patient response, the outcome measure recommended by regulatory authorities.
The results of the study in patients with painful diabetic neuropathy show that patients taking Sativex obtained substantial improvements in their pain, indeed among the highest level of response seen in the published literature. There was an abnormally large placebo response in this study, which means that the data are more difficult to interpret categorically.
Dr Stephen Wright, GW’s R&D Director, said, “Neuropathic pain is one of the most difficult types of chronic pain to treat. These studies focused on particularly high need patients, who were already taking the best available pain treatments, and yet still suffered severe pain. Even in this most difficult to treat population, Sativex has produced improvements over and above current treatments that are highly meaningful to the everyday lives of patients.”
This multi-centre double-blind, randomized, placebo-controlled parallel group study in 297 patients examined the effect of Sativex in patients with painful diabetic neuropathy. Patients in this study were being treated with a range of currently available analgesics, which were maintained during the course of the study.
In this study, patients taking Sativex showed a thirty percent mean improvement in pain scores, among the highest level of response seen in the published literature. One third of Sativex patients achieved over a fifty percent improvement in pain.
Sativex is approved and marketed in Canada for the symptomatic relief of central neuropathic pain in MS, and is the subject of an ongoing regulatory submission in Canada for the relief of cancer.
Neuropathic pain often does not respond well to pharmacotherapy and medications used in its
treatment often have adverse effect profiles that make it difficult to achieve maximal therapeutic
dosing, resulting in limited symptomatic relief.
At the end of follow-up, the average reduction in pain intensity scores was greater in the
THC:CBD group than in the placebo group (95%).
The authors concluded that THC:CBD had a positive effect on neuropathic pain, when used as an add-on therapy to existing analgesics.
Cannabinoid-mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain.” Molecular Pain.
The new information: This experiment involved inducing diabetes in mice in the presence and absence of cannabinoid agonists and observing the mice over a course of 8 months. There were six main experimental groups, one of which diabetes was induced without cannabinoid treatment, serving as a control. In a second group, diabetes was induced in conjunction with cannabidiol treatment. It was found that in this second group, neuropathic pain did not develop over the course of 8 months and the levels of activated microglia in the spinal cord were greatly reduced compared to the control. Additionally, when cannabidiol treatment was stopped, the mice continued to show reduced microglia as well as no signs of neuropathic pain. A third and fourth group involved the induction of diabetes and treatment with both CB1 and CB2 cannabinoid receptor agonists once symptoms of neuropathic pain started. The results indicated that both CB1 and CB2 agonists inhibited the symptoms of neuropathic pain, but the pain returned after treatment was stopped. The last two groups involved treatment with CB1 and CB2 cannabinoid receptor antagonists, which block the effect of cannabinoids, and no change was seen in the levels of pain compared to the control group.
What this means: This experiment provided more evidence that cannabinoids may be used in the treatment of neuropathic pain. However, the novel information obtained is much more surprising. When treated with cannabidiol at the onset of diabetes, the diabetic mice did not have any symptoms of neuropathic pain even when treatment was stopped. This suggests that treatment with cannabidiol at the onset of diabetes may produce permanent protective changes for nerve cells. Therefore, cannabis could hypothetically be used short-term at the onset of type II diabetes in adults for lifetime or long-term prevention of diabetic peripheral neuropathy.
Cannabis/Cannabinoids/Neuropathic pain (Part 1)
Where ever you look on the internet, the general conclusion regarding effective treatments for neuropathic pain seems to suggest that only three things really work: capsaicin, smoked cannabis and rhNGF (nerve growth factor). The latter has not been approved by the major national organisations and we have discussed capsaicin at length in other posts on the blog. This is the first of two more posts with reasonable explanations supporting Cannabinoids. Legal problems aside, there seems to be a growing cache of evidence supporting the efficacy of cannabis, not only as an analgesic but as something with positive effects on the nervous and other body systems.
Opiates do not have clear indications for neuritis and neuropathy although they are widely prescribed for the pain but marijuana actually has been shown to relieve peripheral neuropathy due to HIV and diabetic neuropathy. THC has been useful for treating phantom pain with amputees, causalgias (another peripheral neuropathy condition), neuralgias, and conditions like trigeminal neuralgia. Medical marijuana has also found success with chronic cancer pain. A study at the University of Iowa found oral THC at 5 to 10 mg was as effective as 60mg of Codeine for terminal cancer pain relief.
One question that is obvious – Does marijuana alleviate pain simply because patients no longer care about it? Do the psychoactive effects of marijuana simply influence a patient’s attitude towards the pain and allow him or her to mask it out?
5/5/2011 – Recent scientific articles reviewed the ability of cannabis and cannabinoids to treat pain, especially neuropathic pain. This may be new hope for doctors who are struggling to treat these conditions. Clinical trials on humans using cannabis in various forms (smoked, extracts, oral THC, synthetic analogues) were reviewed by different research teams. Three recent reviews of those human trials demonstrate that cannabis and cannabinoids are effective for treating certain types of chronic pain with acceptable side effects.
A review on the treatments for HIV neuropathic pain concluded that, “evidence of efficacy exists only for capsaicin, smoked cannabis and rhNGF (nerve growth factor). However, rhNGF is clinically unavailable and smoked cannabis cannot be recommended as routine therapy (Phillips et al).”
Meaning, the only medications that have been shown to effectively alleviate HIV/AIDS neuropathic pain are not available on the market. Notably “smoked cannabis” was shown to be effective for the treatment of HIV neuropathy, a condition that affects more than 40% of the estimated 33 million people currently living with HIV.
A University of Pennsylvania research team published a similar review concluding that, “there is strong evidence for a moderate analgesic effect in peripheral neuropathic and central pain conditions, and conflicting evidence for their use in nociceptive pain. For spasticity, most controlled studies demonstrate significant improvement. Adverse effects are not uncommon with cannabinoids, though most are not serious and self-limiting.”
Last but not least, researchers from Canada concluded, that “overall the quality of trials was excellent. Fifteen of the eighteen trials that met inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared to placebo, several reported significant improvements in sleep. There were no serious adverse effects. Adverse effects most commonly reported were generally well tolerated, mild to moderate in severity and led to withdrawal from the studies in only a few cases (Lynch et al).”
This team from was from Dalhousie University Department of Anesthesia and Pain Medicine, Hospital for Sick Children, University of Toronto. The researchers go on to say, “this systematic review of 18 recent good quality randomized trials demonstrates that cannabinoids are a modestly effective and safe treatment option for chronic non-cancer (predominantly neuropathic) pain.”
Traumatic pain is scratching your arm, banging your thumb with a hammer or post-operative pain (surgery). But neuropathic pain is something completely different because it is generated by diseases (Multiple Sclerosis, HIV/AIDS, amputation) or as a side effect from medication toxicity. Essentially the brain begins sending pain signals out to the body for no reason. Patients say they experience it as a burning or shooting pain sensation in their hands and feet at first. Neuropathic pain often progresses to become much more intense. Opiates do not seem to have any impact in certain groups.
Jahan Marcu is currently investigating the pharmacology of cannabinoid receptors. He was working at the California Pacific Medical Center Research Institute when exciting discoveries were made showing enhanced anti-cancer effects with THC and CBD from the Cannabis plant. The findings were published in the Journal of Molecular Cancer Therapeutics. In 2009 he received the Billy Martin Award from the International Cannabinoid Research Society (ICRS). Jahan is currently the vice-chair the Medical and Scientific Advisory Board at Americans for Safe Access (ASA).
Medical marijuana (cannabinoids) is an excellent adjunct treatment choice for Neuropathy.
Indica x Sativa hybrid (CBD:THC)
Strains: Herijuana x Trainwreck (I/S), Hog (I), Agent Orange (S/I), Bubba Kush (I), Sweet Cheese (I/S), OG Kush (I), Kandy Kush (H)
Whole plant extracts: Teas, Tinctures, Edibles, Sprays, Vaporizer, Topicals
^ “Peripheral Neuropathy Fact Sheet: National Institute of Neurological Disorders and Stroke (NINDS)”. http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm. Retrieved 2008-11-30.
^ “Dorlands Medical Dictionary:mononeuropathy”. http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/five/000067367.htm.
^ “neuritis” at Dorland’s Medical Dictionary
^ Gabriel JM, Erne B, Pareyson D, Sghirlanzoni A, Taroni F, Steck AJ (1997). “Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies”. Neurology 49 (6): 1635–40. PMID 9409359.
^ Kiziltan ME, Akalin MA, Sahin R, Uluduz D (2007). “Peripheral neuropathy in patients with diabetes mellitus presenting as Bell’s palsy”. Neuroscience Letters 427 (3): 138. doi:10.1016/j.neulet.2007.09.029. PMID 17933462.
^ Cohen JS (December 2001). “Peripheral Neuropathy Associated with Fluoroquinolones” (PDF). Ann Pharmacother 35 (12): 1540–7. doi:10.1345/aph.1Z429. PMID 11793615. http://fqvictims.org/fqvictims/News/neuropathy/Neuropathy.pdf.
^ Heck AW, Phillips LH 2nd (1989). “Sarcoidosis and the nervous system”. Neurol Clin 7 (3): 641–54. PMID 2671639.
^ Gonzalez-Duarte A, Cikurel K, Simpson DM (2007). “Managing HIV peripheral neuropathy”. Current HIV/AIDS reports 4 (3): 114–8. doi:10.1007/s11904-007-0017-6. PMID 17883996.
^ Wilkes G (2007). “Peripheral neuropathy related to chemotherapy”. Seminars in oncology nursing 23 (3): 162–73. doi:10.1016/j.soncn.2007.05.001. PMID 17693343.
^ Liu N, Varma S, Tsao D, Shooter EM, Tolwani RJ (2007). “Depleting endogenous neurotrophin-3 enhances myelin formation in the Trembler-J mouse, a model of a peripheral neuropathy”. J. Neurosci. Res. 85 (13): 2863–9. doi:10.1002/jnr.21388. PMID 17628499.
^ Skrabek RQ, Galimova L, Ethans K, Perry D (2008). “Nabilone for the treatment of pain in fibromyalgia”. J. Pain 9 (2): 164–73. doi:10.1016/j.jpain.2007.09.002. PMID 17974490.
^ Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D (2008). “Comparison of analgesic effects and patient toleration of nabilone and dihydrocodeine for chronic neuropathic pain: randomized, crossover, double blind study”. BMJ 336 (7637): 119–201.
^ Abrams DI, Jay CA, Shade SB, Vizozo H, Reda H, Press S, Kelly ME, Rowbotham Mc, Petersen KL (2007). “Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trail”. J. Neurology 68 (7): 515–21. doi:10.1212/01.wnl.0000253187.66183.9c. PMID 17296917.
^ Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, Fishman S (2008). “A randomized, placebo-controlled, crossover trail of cannabis cigarettes in neuropathic pain”. J. Pain 9 (6): 506–21. doi:10.1016/j.jpain.2007.12.010. PMID 18403272.
^ Jin DM, Xu Y, Geng DF, Yan TB (July 2010). “Effect of transcutaneous electrical nerve stimulation on symptomatic diabetic peripheral neuropathy: a meta-analysis of randomized controlled trials”. Diabetes Res. Clin. Pract. 89 (1): 10–5. doi:10.1016/j.diabres.2010.03.021. PMID 20510476.
^ Pieber K, Herceg M, Paternostro-Sluga T (April 2010). “Electrotherapy for the treatment of painful diabetic peripheral neuropathy: a review”. J Rehabil Med 42 (4): 289–95. doi:10.2340/16501977-0554. PMID 20461329.
Latov, Norman; ‘Peripheral Neuropathy: When the Numbness, Weakness, and Pain Won’t Stop; American Academy of Neurology Press Demos Medical Publishing; N.Y., N.Y.; 2007
Shy ME. Peripheral neuropathies. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier;2007:chap 446.