Virginia Thornley, M.D., Neurologist, Epileptologist
June 17, 2018
Fibromyalgia used to be a condition denoting excessive pain and was previously questionable as there was no testing that could prove or disprove it. Now, the current thought is that it is attributed to hypersensitivity of the nervous system to pain impulses resulting in multiple points of pain in the body.
Endocannabinoid system in pain modulation
The endocannabinoid system is a major chemical neurotransmitter system that has only come to light as to physiology in the last 20 years. The CB1 receptor is found predominantly in the nervous system on which the endogenous endocannabinoid anandamide exerts its effects. The CB2 receptor is found mostly in the immune system on which 2-Arachidonoylglycerol acts. In the nervous system, cannabinoid receptors are seen in the periaqueductal gray area, ventromedial medulla and dorsal horn of the spinal cord which are areas where pain transmission takes place. This suggests that endocannabinoids play a major role in modulation of pain and can impact pain control through manipulation of this system.
Anandamide and and 2-Arachidonoylglycerol are synthesized on demand. It is released immediately after production. 2-AG is formed from a 2 step process. Anandamide has a low affinity to the TPRV1 receptor (2).
1,2-diacylglycerol (DAG) is a precursor or 2-AG which is formed by hydrolysis of membrane phosphoinositides. DAG is hydrolyzed by 2-AG hydrolase to form 2-AG. 2-AG may be stimulated by activation of G protein receptor such as glutamate receptors. It activates both CB1 and CB2 receptors. Cannabidiol which is found in the cannabis sativa plant is a natural mimetic of 2-AG. Endogenous 2-AG is found 170 times more than Anandamide in the brain. Exogenous 2-AG suppresses nociceptive stimulus (2). 2-AG activity is potentiated with natural 2-acylglycerols which enhances the effects which does not happen when used alone. This is an entourage effect found in the brain where the combination of substances give a combined resulting effect which does not occur if used alone (2).
Mechanisms in pain modulation
Cannabinoids were found to reduce nociceptive transmission at the level of the pain c-fiber responses in the spinal dorsal horn.
Randomized controlled trial in fibromyalgia
In one study of 40 patients in a randomized controlled clinical trial, nabilone which is a synthetic cannabinoid was given over a 4 week period. Measures that were evaluated included the visual analog scale for primary outcome and for secondary outcome measure, tender points, secondary outcome measure, Fibromyalgia Impact Questionnaire (FIQ) at weeks 2 and 4 were used. There was statistical difference in treated vs. control groups for pain (P value< 0.02), anxiety (P<0.02 and FIQ (P<0.02). There were more side effects for the treated cohort compared tot he placebo controlled group. This study demonstrates that cannabinoids may be an effective treatment for fibromyalgia (1).
In one paper that reviewed 18 randomized controlled clinical trials of cannabinoids in chronic pain syndromes including fibromyalgia, cannabinoids were found to be an effective type of treatment. Despite the short duration of the trials, pain relief was effective and mild to moderate adverse effects were noted. Larger clinical trials are needed (2).
Virginia Thornley, M.D., Neurologist, Epileptologist
March 24, 2018
Any news outlet you peruse is bound to have mention of the current opioid crisis looming on the horizon. Opioids are commonly prescribed as the last resort for patients with chronic pain who have failed conventional medications, interventional measures such as epidural injections or surgery, non-pharmacologic measures such as physical therapy and even Eastern techniques such as acupuncture. With tolerance a common problem and patients needing higher and higher dosages for pain control because of the properties of opioids, it is little wonder that chronic pain control is difficult to maintain.
The hot topic of debate in many states is the recognition of medical marijuana as a legitimate medication for chronic ailments. However, because of the stigma it has incurred being well-known for its psychoactive properties and widely seen in pop culture in movies with kingpins smoking it for recreation, the medicinal values are often overshadowed and lack of side effects in low doses is easily overlooked.
Not your stereotypical patient and not your direct referral
Patients and even physicians likely have a preconceived notion of who seeks medical marijuana. While chronic pain is top of the list, often times, it is discovered by the hard-working carpenter who discovered it online and found a small scientific article on non-pharmacologic treatments trying to come off sedating pain-relieving medications. It will be the former business owner who lived an enjoyable life being active dancing or the woman afflicted with an autoimmune disorder and has failed every medication under the sun. Many times patients come in not because they want to feel good but because it is their last resort and they’ve exhausted every treatment option known to mankind. They dislike the side effects of the strong painkillers such as opioids and just want the pain to stop and live a normal life. It is amazing how indirectly patients hear about the wonders of medical marijuana, it will usually be a neighbor who swears by it, or somebody’s friend who mentions it out of the blue. Oftentimes, it is by word of mouth since the few physicians interested in recommending it are very reluctant to advertise with good reason.
Mechanisms of cannabidiol and tetrahydrocannabinol
Medical marijuana has been used since B.C. period for thousands of years as a medication. It was incorporated into the pharmacopeia of American medicine in the 1850’s until it was banned in the 1930’s. It regained popularity and notoriety as a recreational substance. However, more and more patients are turning towards this now alternative medication after years of frustration towards the ineffectiveness and adverse effects of conventional medications. The endocannabinoid pathway is found inherently in the system and is responsible for the runner’s high that people get after a vigorous run or after exercising and gives the sense of well-being. The CB1 receptor is found most abundantly in the central nervous system which is likely why many neurological conditions are found to benefit from its use. The CB2 receptor is most commonly found in the immune system. As more research is pursued, there are CB receptors found diffusely throughout many organ systems. Cannabidiol weakly interacts with the CB1 receptor. It takes at least 100 times cannabidiol to attain the same intoxication one gets with tetrahydrocannabinol, the substance which is more popular and found in the marijuana joints people smoke to obtain euphoria. THC at low concentrations is effective in treating many different medical conditions. It must be used in conjunction with CBD so that side effects are offset. Cannabidiol has no intoxication while low doses of THC does not give euphoria one associates with this drug. There is no tolerance.
Scientific evidence cannabidiol and tetrahydrocannabinol work in chronic pain and other medical diseases
In animal studies, it is well known to reduce seizures by inhibiting the excitation within the hippocampus of the brain where seizures are commonly propagated (http://www.pnas.org/content/early/2017/09/26/1711351114).There are many clinical trials in humans attesting its efficacy at controlling seizures effectively. CB1 receptors appear to be increased in many neurological disorders which implies it is a compensatory mechanism for diseases. In Parkinson’s disease, there are increased CB1 receptors which may help with the reduced dopamine commonly found in Parkinson’s disease. 9tetrahydrocannabinol was found to lower intraocular pressure in glaucoma in rabbits (https://www.ncbi.nlm.nih.gov/pubmed/6329602). Sativex is a combination of THC:CBD which reduces spasms in patients with multiple sclerosis and has been available in Europe for several years now with very little side effects http://jnnp.bmj.com/content/87/9/944. There is extensive evidence in both animal and human models that it works in chronic pain (https://www.ncbi.nlm.nih.gov/pubmed/26830780). Many diseases are being evaluated for mechanisms on which CBD and THC may exert its effects. It has been found to have anti-oxidant and anti-inflammatory properties which are important mechanisms by which many diseases cause pathology. In cancer cell cultures, it has been found to reduce proliferation of tumor cells in urologic cancer and reduce the pro-inflammatory states that are necessary for metastatic conditions (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434502/).CBD interacts with the 5HT1 receptor where many anti-depressants and anxiolytic medications exert their effects, making CBD an effective anxiolytic. It works to stimulate appetite and is commonly used by patients with cancer for anorexia and end-stage cancer pain.
In summary, cannabidiol and tetrahydrocannabinol are effective medications in treating pain from many chronic illnesses and is not reserved for patients with terminal illness. Despite the reticence of physicians, Congress and even patients, there is overwhelming evidence that cannabidiol and tetrahydrocannabinol are effective in many different diseases, although in some conditions there’s a long way to go from preclinical data to human trials. It is fairly clear in many disease states, medical marijuana is significantly effective. There is no tolerance and may be an effective treatment for patients with chronic pain. CBD by itself has no euphoric properties and low concentrations of THC do not give intoxicating psychoactive effects. These are 2 alternatives that may provide relief and solution to the growing epidemic of the opioid crisis.