Medical Marijuana: A Growing Trend

Current State of the Evidence
Schedule I designation makes research examining safety and efficacy of marijuana for a range of diseases difficult but not impossible. Originally promoted for the management of chronic and neuropathic pain, there are varying amounts of evidence for efficacy in epilepsy,multiple sclerosis–associated spasticity, and inflammatory bowel disease. In contrast, current data do not support use in glaucoma or rheumatologic conditions such as arthritis.

What Do Physicians Think?
In early 2014, Medscape and WebMD conducted a survey to solicit opinions of both physicians and consumers about the medical use of marijuana. A total of 1544 physicians participated, representing 12 specialties and 48 states. The survey also included 2960 consumers. The Medscape survey ran between February 25 and March 3, 2014, and has a margin of error of ± 2.5%. Approximately one quarter of participants (24.7%) identified as primary care physicians.

How Do Physicians View the Evidence?
A sizeable majority of physicians participating in the Medscape survey see marijuana as delivering real treatment benefits. Only 15% answered this question with a definitive “no” and 17% said they were just not sure. Essentially half (49%) said the benefits of medical marijuana outweigh the risks. However, there is another sizeable contingent that expressed concern about the risk/benefit ratio, with a combined majority saying the side effects can be mild (38%) or moderate (40%). Opinions expressed are not the result of personal use; less than 1% of physicians in our survey indicated that they had ever personally used marijuana for a medical reason.

Physician Opinion: Legal vs Nonlegal Marijuana States
The majority of physicians (68%) in our survey believe that marijuana should be a medical option for patients. Of note, though, smaller percentages indicated that it should be legal, a percentage that did not vary between physicians residing in legal vs nonlegal states. Half of all physicians in the survey (48%) say their patients have asked about the benefits of medical marijuana in the past 12 months. This conversation was 12% more likely to take place in states where medical marijuana has been legalized (60%). In states considering legalization, only 38% of respondents indicated that their patients had asked.

Does Physician Opinion Vary by Specialty?
Support for medical marijuana also varied by specialty. Oncologists showed the highest level, with 82% saying marijuana delivers real benefits to patients and 69% supporting legalization nationwide. Oncologists also had the second highest level of patient inquiries, at 66%, not surprising given the role of this agent in pain control and cancer-associated cachexia. Rheumatologists ranked the lowest in support for use, with 54% saying it delivers benefits and 44% supporting legalization. It’s not surprising, given recent trials examining use of marijuana in epilepsy and MS, that neurologists reported the highest number of patients asking whether medical marijuana might help them, at 70%.

Physician Opinion vs Public Opinion
Perhaps surprising, more physicians (69%) than non-MD WebMD readers (52%) believe that marijuana can provide real benefits for patients with certain conditions or receiving certain treatments, such as chemotherapy. The minority of both MDs and non-MDs surveyed feel that it has no benefits (15% vs 11%), while 37% of non-MDs are “not sure” about the usefulness of medicinal marijuana, vs only 17% of physicians.

Availability
MDs and non-MDs differed considerably in their views on where and how medicinal marijuana should be available: 53% of physicians vs 36% of non-MDs feel that it should only be available at pharmacies with a valid prescription. Just 19% of physicians vs 41% of non-MDs believe that patients should have access via both pharmacies and licensed retailers (with a physician’s written authorization).

Medical marijuana is legal in 20 states and the District of Columbia, with pending legislation to legalize the drug for medical purposes in 4 others.[1] Although still illegal in 30 states, millions of patients are undoubtably using marijuana for medicinal purposes in these jurisdictions.

Much has been written about politics trumping science with respect to rescheduling marijuana from a Schedule I drug,[2-5] as its medical benefits become progressively more accepted by the mainstream medical community as well as the general public.[6] The Veterans Administration, which is becoming a leader in pain care in the United States, has even approved of its physicians authorizing medical marijuana in states in which it is legal.

Earlier this year, Kondrad and Reid[8]published a large-scale survey-based study of family physicians’ attitudes toward medical marijuana in Colorado — a state in which medical marijuana has been legal since 2000. The results of their investigation were both startling and disturbing. They found that only 19% of respondents believed that physicians should recommend medical marijuana to their patients. However, they also found that 80% of respondents believed that education about medical marijuana should be incorporated into medical school curricula, 82% believed that such education should be included in family practice residency training, and 92% agreed that continuing medical education on medical marijuana should be made available to them. Opposition to recommending medical marijuana as a result of concerns about legal liability or licensure was reported by 23% of respondents, whereas only 13% cited a lack of medical evidence as their reason for opposition. These figures indicate that science is clearly not the primary issue of concern.

These intriguing data tell us that a lack of education is the primary cause of physicians’ discomfort in recommending medical marijuana. Schatman recently addressed the ethical imperative for physicians to consider medical marijuana as a part of their pain management armamentaria. This is particularly important, given the lack of an evidence base for chronic opioid therapy and physicians’ reluctance to prescribe opioids in this era of fear of legal and regulatory sanction.

Why So Reluctant?

In clinical practice, physicians have been found to refuse to authorize medical marijuana out of concern that doing so will place their controlled substances licenses in jeopardy. Although 20 states have “legalized” medical marijuana, it remains a violation of the federal Controlled Substances Act, and the reality of the license to prescribe controlled substances being issued by the US Department of Justice’s Drug Enforcement Administration (DEA) clearly has served, for many physicians, as a deterrent to the authorization of medical marijuana.[10] Physicians who treat patients with chronic pain rely on their abilities to prescribe controlled substances, and fear of losing the privilege to do so has resulted in an unfortunate reluctance to authorize what can be an extremely effective and relatively safe alternative to opioid analgesics.[9]

An unintended consequence of this fear has been naturopathic doctors (NDs) developing “doc-in-the-box” medical marijuana authorization practices in states in which NDs are permitted to authorize medical marijuana. These practices are often cash-only entities; this is particularly troubling in such states as Washington, in which health insurers are required to compensate NDs. Given the financial incentives, these naturopathic providers have loose and easy criteria for authorization of medical marijuana, because they have no controlled substance registrations to lose.[11]

The result is that many recreational users are obtaining legal access to high-tetrahydrocannabinol (THC) “medical marijuana” at a relatively low price from dispensaries. However, a small number of allopathic and osteopathic physicians have overcome their fears of legal and regulatory sanction and have brazenly developed specialized practices consisting primarily of medical marijuana authorization, without expertise in the treatment of the conditions for which they are authorizing its use.

By: DONALD I. ABRAMS, M.D. and JODIE TRAFTON, PH.D.

POINT: Cannabis can relieve neuropathic pain.

As an oncologist, I treat cancer patients who have nausea, vomiting, weight loss, pain with and without opioids, insomnia, and depression. With cannabis, I can recommend that they try one medicine instead of five or six prescriptions that will interact either with one another or with their cancer chemotherapy.

Studies show that cannabis and cannabinoids are effective for peripheral neuropathic syndromes associated with HIV, multiple sclerosis, or posttraumatic or postsurgical causes. A study of diabetic neuropathy is ongoing; cannabis has not yet been studied for chemotherapy-induced neuropathy. Other data show that cannabis and cannabinoids may be synergistic with opioids in relief of chronic pain without altering pharmacokinetics.

We conducted a randomized, placebo-controlled study of cannabis for patients with HIV-related peripheral neuropathy at San Francisco General Hospital because preclinical studies and anecdotal patient reports said it was helpful. Average neuropathic pain scores in the week before being admitted to our research center were about 60 out of 100. After a 2-day run-in period, patients were randomized to smoke cannabis or placebo three times a day for 5 days. Among 50 patients who completed the study, neuropathic pain decreased by about 34% with cannabis versus 17% with placebo. Our threshold for a positive response was at least a 30% reduction in pain; this was reported by 52% on cannabis and 24% on placebo (Neurology 2007;68:515-21).

We also used a more objective heat-capsaicin method to assess pain. An area on the forearm was heated to 40°   C for half an hour and then capsaicin (the active ingredient in chili peppers) was applied. This creates an area of hypesthesia and allodynia that can be measured using a brush and a piece of foam while the patient looks in another direction.

On the heat-capsaicin tests, the area of hypesthesia or allodynia either increased or was the same after smoking placebo but decreased approximately 30% after smoking cannabis. We calculated that the number needed to treat to get a beneficial effect was 3.6, which is equivalent to that with gabapentin, the mainstay treatment for our patients with HIV-related peripheral neuropathy.

A crossover study in 28 patients with HIV-associated neuropathy at the University of California, San Diego found that pain decreased with cannabis versus placebo. The number needed to treat was 3.5. (Neuropsychopharmacology 2009;34:672-680).

Investigators at the University of California, Davis, randomized 38 patients with central and peripheral neuropathic pain to low- or high-dose cannabis or placebo. They found a linear analgesic dose response for both doses of cannabis, compared with placebo, and reported that the effect was not due to lysis of anxiety but to reduction of core nociception as well as emotional responses to pain. (J. Pain 2008;9:506-21).

A randomized, double-blind, four-period crossover study in Montreal looked at 23 participants with postsurgical neuropathic pain who inhaled increasing dosages of tetrahydrocannabinol (THC). Results showed that the average daily pain intensity was significantly lower and quality of sleep improved in the highest-dose THC group, compared with the placebo group (CMAJ 2010;182:e694-701).

We recently completed a study funded by the National Institute on Drug Abuse to look at effects of combined use of opioids and cannabis, in which we also assessed effects on pain.

We saw a significant 26% reduction in pain with the addition of vaporized cannabis in the cohort as a whole. Pain reduction was greater in the morphine group (a 31% decrease) compared with the oxycodone group (a 23% decrease). We saw no adverse safety effects. Although we know quite well that the study was too small to make a definitive claim, this was a tantalizing demonstration of potential synergy between opioids and cannabinoids, (Clin. Pharmacotherapeutics 2011;90:844-51).

Every 10 years since cannabis was removed from the medical formulary in 1942, some august government body in the United States looks at cannabis in medicine. They all conclude the same thing – that it’s a valuable medicine, and should be available. That usually goes ignored, however. An Institute of Medicine report in 1999 said the accumulated data indicate a potential therapeutic value for cannabinoid drugs in the treatment of pain, control of nausea and vomiting, and appetite stimulation.

Dr. Donald I. Abrams is a professor of clinical medicine at the University of California, San Francisco. He declared having nothing to disclose except that he went to college in the 1960s. This debate took place at the annual meeting of the American Academy of Pain Medicine.

Marijuana doesn’t meet standards to be considered a medicine.

There’s a massive lack of standardization in the product. Compounds have very different, in some cases opposing, effects. Potency varies depending on the strain and how it was prepared.

There’s also no standardization around administration. Smoking or inhaling marijuana – the most common routes speed drug uptake and the effects of cannabinoids on reward processing, which increases addictiveness.

Smoking marijuana is carcinogenic and causes lung damage. Yes, a study suggested twice-a-month use doesn’t really change your lung capacity, but that changed with daily, frequent use. The typical use pattern is about four times per day, daily, in medical patients.

Pain studies looked at acute use of cannabis for a week or so. They haven’t looked at chronic effects. We don’t know the impact of tolerance and dependence in patients with chronic pain, or the effect of constant activation of reward circuits by marijuana on new behavior patterns over time. That’s typically what you have trouble with in chronic pain patients – getting them up, getting them going, getting them back into life. Marijuana could make that more difficult.

A meta-analysis of 18 randomized, double-blind, controlled trials of cannabis for chronic pain found a greater effect with cannabis than with placebo, but this was not huge. If a patient starts out with a pain score of 8 out of 10, it will drop to about 7.4 – a 7.5% reduction in score. We’re talking about going from severe to a little less severe pain. Patients on cannabis were much more likely to have alterations in perception, motor function, and cognitive function (Pain Med. 2009;10:1353-68).

In the crossover study of 23 patients that Dr. Abrams cites, low-dose and high-dose THC decreased pain, but there was no difference in the middle doses, compared with placebo. And look at the levels of pain scores: You’re going from an average of 6.1 to 5.4, from moderate pain to moderate pain. That’s less than 1 point on a 10-point scale, and you’re getting all of the adverse effects and behavioral changes in conjunction with that. Is that worth it?

The 28-patient crossover study he cites started with 34 patients. There were some serious cannabis-related issues, including acute psychosis and intractable cough, in the patients who didn’t complete it. One patient started using methamphetamine again. This is not a particularly low rate of problems.

We don’t have a lot of data to say what happens to patients with chronic pain who use marijuana over time. There are more data on what happens when people in the general population use marijuana chronically. The best characterized chronic effects include a motivational syndrome, poor concentration, attention and judgment, impaired social skills, introversion, deteriorating personal habits and depersonalization, mood disorders, anxiety disorders, insomnia, increased risk of schizophreniform illness and psychosis, more negative life events, and withdrawal.

Studies have found functional impairments related to chronic marijuana use. People who use marijuana over long periods of time develop at least partially persistent problems on neuropsychological tests – problems that don’t go away even if they stop using marijuana.

There’s also evidence of a relationship between cannabis and mood disorders. Cross-sectional studies show that people who use cannabis daily or near-daily are 3.4 times more likely to have major depression. Longitudinally, if you are diagnosed with cannabis dependence, you have a 6.4-fold increased chance of being diagnosed with major depression within a 12-month time period.

It appears that cannabis is inducing the mood disorders, not the mood disorders driving cannabis use. A Dutch study of 3,854 adults with no history of mood disorders found that cannabis use at baseline was associated with a doubling in risk for developing any mood disorder, a 60% increased risk for major depression, and a five-fold increased risk for bipolar disease (Addiction 2007;102:1251-60).

If cannabis use makes people tend toward mood disorders, and chronic pain patients tend toward mood disorders, how much harder are you making it by suggesting they try marijuana to get that 1-point decrease in pain?

Frequent marijuana use is associated with development of dependence. Withdrawal symptoms occur whenever drug levels start to decrease over time. Withdrawal starts within 2-4 hours, and symptoms last for weeks. Symptoms include irritability, anger or aggression, nervousness or anxiety, sleep difficulty, decreased appetite or weight loss, restlessness, depressed mood, and a variety of physical symptoms causing significant discomfort.

The main reasons that people say they want to use medical marijuana are to treat nervousness, anxiety, insomnia, and depressed mood. All of these potentially are withdrawal symptoms.

One study showed a vast majority of California patients seeking a physician’s recommendation for medical marijuana – well over 95% were already self-medicating with marijuana. We would expect that population to be dependent.

A separate study confirmed that 10 of the 15 “clinical benefits” reported by 1,746 medical marijuana users were the easing of problems that can be found on a list of withdrawal symptoms (J. Psychoactive Drugs 2011;43:128-35).

Chronic pain patients already have high comorbidity with depression, functional problems, and high rates of disability. Recommending medical marijuana increases risk in an already at-risk population.

Jodie Trafton, Ph.D., is director of the Program Evaluation and Resource Center in the Office of Mental Health Operations, Veterans Affairs Palo Alto (Calif.) Health Care System. The views expressed are those of Dr. Trafton and do not necessarily represent those of the Department of Veterans Affairs. She declared having no financial disclosures.