Cannabis in Pain and Arthritis: A Look at the Evidence

http://www.medscape.com/viewarticle/827241_2

http://www.medscape.com/viewarticle/827241_2

Cannabis in Pain and Arthritis: A Look at the Evidence

On Thursday, June 12, 2014 -- day 2 of the 2014 European League Against Rheumatism annual congress -- Dr. Mary-Ann Fitzcharles took the podium to discuss the use of medicinal marijuana in rheumatologic diseases. Dr. Fitzcharles is Associate Professor of Medicine in the Division of Rheumatology at McGill University in Montreal, and her talk^[1]was part of a symposium looking at the possibility of repurposing old or established analgesics for rheumatic diseases.

Fitzcharles began her talk with a historical look at cannabis use. The plant was first used in Europe and Asia around 5000 years ago, at which time scientists believe it contained very little tetrahydrocannabinol (THC), the primary psychoactive substance in today's marijuana. Eventually, more THC-heavy strains were propagated, and the ancient Chinese began using the plant medicinally around 2700 years ago. "Queen Victoria used cannabis for her menstrual cramps," Fitzcharles commented.

She then posed the question of why we have an endogenous cannabinoid system in the first place, before reviewing the correct dogma among experts. It's thought that our cannabinoid system is involved in maintaining homeostasis, particularly in terms of stress, sleep, and modulation of pain. Furthermore, although they are often thought of for their neuro- and psychoactive effects, cannabinoid receptors are actually fairly ubiquitous throughout the body. They're found on cells of the joints, bone, skin, and immune system, as well as on neurons.

Preclinical work in animals has found cannabinoids to be effective in nearly every acute pain model tested, likening them to some opioids in terms of their analgesic effects. Rodent models of arthritis demonstrate increased endocannabinoids in the spinal cord and upregulation of both cannabinoid receptor subtypes, CB1 and CB2. A recent study reported at the European Calcified Tissue Society Congress 2014 found that mice with destabilized knee joints had 40% more cartilage degeneration if they were deficient in these CB2 receptors.^[2] A study in humans suggests the presence of cannabinoid receptors on the synovia.^[3] So it appears that the endocannabinoid system has relevance to rheumatology.

However, with the good comes the bad, particularly in terms of brain function. Too much cannabinoid exposure can worsen memory, affect the reward system (and therefore have addiction implications), and impair cognition.

Moving on to studies in humans that have looked at cannabis as a therapy in rheumatic disease, Fitzcharles highlighted the fact that there is a very limited body of data to go on. One study examined medical marijuana in rheumatoid arthritis, 5 have been conducted in fibromyalgia, and there isn't a single randomized controlled trial of cannabis in any rheumatic disease.

The rheumatoid arthritis study,^[4] published in 2006 inRheumatology, reported that Sativex® -- a cannabis-based medicine -- produced statistically significant improvements in multiple pain measures in 58 patients over 5 weeks. The investigators acknowledged that the differences were small yet probably clinically relevant, and that there were no adverse event-related withdrawals or serious adverse events in the active treatment group.

Two studies looked at the synthetic THC nabilone in fibromyalgia. The first^[5] was a randomized controlled trial of 40 patients; at 4 weeks, treatment was associated with significant decreases in the visual analog scale for both pain and anxiety. There were no significant improvements in the placebo group. Side effects were minimal, though more frequent, in the treatment group -- particularly drowsiness. The other study of nabilone^[6] was conducted by Fitzcharles' group in Montreal and determined the agent to be equivalent to amitriptyline in improving sleep in patients with fibromyalgia, while also being well tolerated.

Other recent work^[7] associated cannabis inhalation with a significant reduction in pain and stiffness, enhanced relaxation, and -- perhaps not surprisingly -- an increased feeling of well-being. A small study^[8] of 9 patients looked at the efficacy of oral THC on electrically induced pain, axon reflex flare, and psychometric variables. Five of the participants withdrew owing to adverse side effects. Although THC had no effect on axon reflex flare, patients' daily recorded pain was significantly reduced. The investigators concluded that the unaffected electrically induced axon reflex flare, but decreased pain perception, suggests a central mode of action of the THC.

Finally, another study by Fitzcharles and colleagues^[9] sought to provide epidemiologic clarity on cannabis use in fibromyalgia. Among 457 patients with the diagnosis, 13% were using cannabinoids, of whom 80% were using herbal cannabis (marijuana). The investigators concluded, "Although cannabinoids may offer some therapeutic effect, caution regarding any recommendation should be exercised pending clarification of general health and psychosocial problems, especially for those self-medicating."

Fitzcharles then walked the audience through some background data. In the United States, 10% of patients seen in chronic pain clinics use cannabis medicinally. Furthermore, she continued, 65% of those registered in Canada's medical marijuana access program report having severe arthritis.

Next up was a short botanical chemistry lesson. "Marijuana" typically refers to the leaves and buds of the Cannabis sativa plant and contains at least 60 cannabinoid molecules and around 100 noncannabinoid compounds. Pharmacologically, it's a complicated plant.

Where Do Clinicians Stand?

What does the medical community think about using marijuana as medicine? Fitzcharles presented data showing that in Colorado -- where both medicinal and recreational marijuana use are now legal -- 2% of the state's population were registered for medical marijuana in 2012.^[10] However, these findings come with a major red flag: 50% of physician marijuana recommendations came from just 15 prescribers. When polled, only 20% of Colorado physicians felt there was a medical role.^[11] Relatedly, Fitzcharles and her group polled Canadian rheumatologists,^[1] 75% of whom reported being uncomfortable about their knowledge around the effects of cannabinoids on the human body and their potential medical uses.

Of note, a Medscape survey from earlier this year of 1544 US physicians reported somewhat different results:

• 69% say it can help with certain treatments and conditions;
• 67% say it should be a medical option for patients;
• 56% support making it legal nationwide;
• 50% of doctors in states where it is not legal say it should be legal in their states and
• 52% of doctors in states considering new laws say that it should be legal in their states.

  So Does Cannabis Belong in the Clinic?

  The overarching theme of much of Fitzcharles' talk was that the majority of the medical community seems reticent to fully embrace medical marijuana, on the basis of the current body of knowledge. Despite the availability of purified THC formulations, most marijuana used for medical purposes is smoked -- not a practice encouraged by most physicians, because it could come with inhaling numerous potentially toxic substances. In addition, the wildly different THC concentrations -- ranging from 1% to 30% -- in today's marijuana strains and varied bioavailability make it incredibly tough to dose with any accuracy.

  Fitzcharles feels that beyond limited efficacy data and nonstandardized formulations, the use of cannabis in rheumatic and other conditions is further hindered by potential acute risks.

  Short-term use alters sensory perception, temporarily impairs memory, and induces thought fragmentation. Psychomotor effects are common, as are mood alterations and even -- perhaps paradoxically given marijuana's relaxed reputation -- anxiety. However, Fitzcharles continued, "Pain relief...that's good. That's what we're looking for." Then, speaking about the potential benefits of medical marijuana, she continued, "and increased appetite might be good for wasting diseases."

  Another ding for medical cannabis are potential cardiovascular risks including tachycardia and, per a new French study,^[12] an increased rate of cardiovascular events. But then again, cannabis has also been shown to decrease blood pressure. In short, the jury is still out.

  Fitzcharles then highlighted a Dutch study^[13] looking at the cognitive effects of acute marijuana use in young, healthy regular users. Participants smoked marijuana in a monitored research setting, and various mental faculties were assessed. Even in seasoned users, there were marked dose-related reductions in reaction time, selective attention, short-term memory, and motor control. A recent meta-analysis correlated acute cannabis use with twice the risk for injury or death by motor vehicle accident.^[14]

  Fitzcharles then pointed out that cannabis use also comes with increased risk for psychological disorders, such as psychotic disease, depression, and anxiety, as well as suicide. Also, despite frequent rumors to the contrary, there is a risk for dependence and abuse associated with cannabis use. Psychological dependence appears to be equal to that of alcohol and occurs in at least 8% of users within 1 year of starting marijuana use. Even pharmacologic formulations can be abused, but they're expensive -- and, somewhat ironically, not as easy to come by for many.

  "We need to distinguish herbal vs pharmacologic cannabis preparations, and also think about the increased risks that come with use of any kind," said Fitzcharles, nearing the end of her talk, before concluding that the cannabinoid system appears to be quite important in rheumatic disease and that researchers and clinicians should push for research to better understand how this system is involved in rheumatologic disease and how cannabinoid therapies could be beneficial. In her opinion, pharmacologic preparations are a more desirable approach, given that smoking herbal cannabis comes with many medical and societal questions. Ideally, a medicinal compound would be more therapeutically targeted and less psychoactive. In addition, she feels strongly that clinicians should discourage their patients from smoking cannabis.

  After the talk, California Pacific Medical Center rheumatologist and Session Co-chair Neal Birnbaum, MD, commented that he lives near some of the best marijuana in the United States -- adding, "So I'm told," to audience laughter -- and that many patients walk out with a marijuana and a hydrocodone script. "I'm not sure they realize how serious this is," he commented.