January 16, 2017

Search the professional literature and reputable web sources on the topic of medical marijuana (cannabis) and the consensus seems to be the existence of an over-arching lack of consensus on use of the substance as a treatment modality.

A 395-page report by the National Academies of Sciences, Engineering and Medicine, “The Health Effects of Cannabis and Cannabinoids,” released on January 12, as this eAlert was being written, could help pave the way for greater clarity on the issue.  Essentially, the report concludes that marijuana can be effective in the treatment of pain, spasticity, nausea and other conditions, but that the drug is not harmless.  “The growing acceptance, accessibility, and use of cannabis raise important public health concerns and there is a clear need to establish what is known and what needs to be known about the health effects of cannabis use,” the report stated.

Whether you practice in one of the 28 states where medical marijuana has become legal or are completely new to the subject of medical marijuana, we hope to shed some light for you here on a controversial topic for clinicians—chronic pain practitioners and anesthesia providers included. 

At present, cannabis’s place in medicine poses a constellation of clinical, regulatory, cultural, research and policy questions that remain largely unresolved.  As psychiatrist J. Michael Bostwick, MD, wrote in “Blurred Boundaries:  The Therapeutics and Politics of Medical Marijuana” (Mayo Clinic Proceedings, February 2011): 

As recreational use continues to be endemic in the United States and medical use of smoked cannabis burgeons, it becomes increasingly clear that the two are not discreet from each other, with implications medically for both seasoned and naive users.  Even as proponents of legalization contend that smoked marijuana is a harmless natural substance that improves quality of life, a growing body of evidence links it in a small but significant number of users to addiction and the induction or aggravation of psychosis. . . As laboratory and clinical investigation exposes more of the workings of the recently discovered endocannabinoid system and potential pharmacologic applications show increasing promise, federal law puts a damper on almost any research.  As an increasing number of states legalize marijuana's medical use, the federal government maintains its resolute stance that its use for any reason is criminal, a stance that renders prescribers simultaneously law-abiding healers and defiant scofflaws.  In what has been called “medicine by popular vote,” the states formulate medical marijuana statutes based not on scientific evidence but on political ideology and gamesmanship.

In a recent article in Anesthesiology News, Kenneth Finn, MD, a member of the Colorado Medical Marijuana Scientific Advisory Council, called cannabis a “clinical conundrum.”  For Dr. Finn, the conundrum stems from the pervasiveness in Colorado (where marijuana has been legalized for both medical and recreational use) of cannabis products and usage patterns of questionable safety and quality that currently hinder the development of effective standards and treatment.

“Since legalization [in Colorado], the lines between medical and recreational marijuana have blurred to the point where they simply cease to exist,” Dr. Finn wrote.  “Patients freely share their ‘medicine’ with family and friends, and parents are self-diagnosing and subsequently dosing their children with high-concentration marijuana products for conditions that may simply not exist (attention deficit/hyperactivity disorder, anxiety, etc.) or allow their medical cards to expire and continue to grow their own.”

The remedy, according to Dr. Finn, is to “support the ongoing research that may one day give us the evidence to treat our patients.  The use of medical marijuana for medical conditions, including pain, needs robust studies, and subsequent products need more regulation and consistency for public consumption.  Colorado is an example of the societal effect across a wide spectrum of areas that comes with rampant cannabis use, particularly in youth use and impaired driving fatalities.  The problems Colorado is seeing completely transcend ‘responsible use’ or ‘marijuana as medicine.’”

Dr. Finn is not alone in his desire for more solid clinical research and his concern about the problematic blurring of distinctions between medical and recreational marijuana use.  Despite the questions, including concerns about side effects, drug interactions and the potential for dependence,¹ many clinicians and researchers believe that medical marijuana shows sufficient promise as a treatment for a wide range of conditions to merit further investigation.  Because those conditions include chronic pain and chronic postoperative pain, anesthesia providers and chronic pain practitioners could, conceivably, include the drug in their armamentarium one day.

Botanical marijuana has been used for medicinal purposes for centuries, but scientific research on it is still relatively new and inconclusive, and large, long-term, controlled studies are sparse.  The discovery of the human endocannabinoid system, which mediates cannabis’s psychoactive effects, and the clarification of two chemical compounds in cannabis—tetrahydrocannabinol (THC, the euphoria-producing cannabinoid), and cannabidiol (CBD, considered to have a wide range of potential medical uses due to its lack of side effects, including psychoactivity)—have drawn considerable interest.

Still, though the drug’s efficacy as an agent for the management of such conditions as chronic cancer pain, neuropathic pain and some symptoms of multiple sclerosis is fairly well established, the lack of research and medications with demonstrated safety and efficacy means that the jury is still out on many other conditions.  The Food and Drug Administration (FDA) “has not approved a marketing application for a drug product containing or derived from botanical marijuana and has not found any such product to be safe and effective for any indication,” the agency states on its website. 

However, the FDA has approved two THC-based medications, dronabinol (Marinol^®) and nabilone (Cesamet^®) prescribed for the treatment of nausea in patients receiving cancer chemotherapy and to stimulate appetite in patients with wasting syndrome related to AIDS.  In addition, nabiximols (Sativex^®) is currently available in the United Kingdom, Canada and several European countries for treating the spasticity and neuropathic pain of multiple sclerosis.  The drug may also be useful in the treatment of seizure disorders and other conditions.  These medications use purified chemicals derived from or based on those in the marijuana plant and are generally considered by researchers to be more promising therapeutically than use of the whole marijuana plant or its crude extracts, according to the National Institute on Drug Abuse (NIDA).²

Research on medical marijuana has been stymied by the fact that marijuana remains classified by the Drug Enforcement Administration (DEA) as a Schedule I drug (along with ecstasy, LSD and heroin), which means it is viewed as having a high potential for abuse with “no accepted medical use in treatment” and is technically banned by federal law.  This classification means that physicians can only “recommend” marijuana for medical reasons; they cannot write a prescription for a medication that can be filled at a pharmacy.

And as Mayo Clinic states on its consumer website, because marijuana remains a Schedule I drug under federal law, and federal law regulating marijuana supersedes state law, “people may still be arrested and charged with possession in states where marijuana for medical use is legal.”  Conditions that qualify patients for medical marijuana also vary among states, but include: 

• Amyotrophic lateral sclerosis (ALS)
• Anorexia due to HIV/AIDS
• Chronic pain
• Crohn's disease
• Epilepsy or seizures
• Glaucoma, although the American Academy of Ophthalmology doesn't recommend medical marijuana
• Multiple sclerosis or severe muscle spasms
• Nausea, vomiting or severe wasting associated with cancer treatment
• Terminal illness
• Tourette syndrome

Until recently, research marijuana was obtainable only from a single source—the University of Mississippi in Oxford—grown through a contract with the NIDA—and obtaining access to the drug for research purposes involved jumping through bureaucratic hoops.  Some doors opened for researchers this past August when the DEA announced that it would allow institutions to apply for permission to grow their own marijuana for research, despite the agency’s decision not to reschedule the drug. 

The FDA states that it does not object to the clinical investigation of marijuana for medical use.  It “believes that scientifically valid research conducted under an IND [investigational new drug] application is the best way to determine what patients could benefit from the use of drugs derived from marijuana.  The FDA notes that it provides information on the process needed to conduct clinical marijuana research and the specific requirements to develop a drug derived from a plant, which are contained in its guidance on botanical drug products.

One area of research with implications for anesthesia and chronic pain clinicians suggests medical marijuana’s potential as a substitute for opioids.  For example, a 2014 study of data from 1999 to 2010 published in JAMA Internal Medicine found that states in which medical marijuana was legal had an average of nearly 25 percent fewer opioid overdose deaths annually than states in which marijuana was illegal.  Although the study does not prove cause and effect, “I think medical cannabis could fall into the category of alternatives for treating chronic pain so that people don't use opioids or use a lower dose of opioids than they otherwise would,” said principal author Marcus Bachhuber, MD, of Montefiore Medical Center.

Other research shows a possible connection between medical marijuana use and reduced opioid dependence.  A study published in the February 2016 issue of the Clinical Journal of Pain found that 44 percent of a group of 176 chronic pain patients stopped taking prescription opioids within seven months of starting to take medical marijuana.

Until medications can be developed that are of sufficient quality and safety to receive FDA approval, the controversy that swirls around medical marijuana continues to create “a difficult environment for physicians who seek to treat their patients with compassion,” according to Eric A. Voth, MD, FACP, of the Institute for Global Drug Policy in a 2001 article in the Western Journal of Medicine. 

The ballot initiatives to legalize medical marijuana “bypass the Food and Drug Administration’s processes that are meant to ensure both efficacy and safety,” said Dr. Voth, who does not support recommending the use of medical marijuana.  “Physicians who provide such recommendations are, at a minimum, exposing themselves to civil litigation from marijuana smokers who have adverse outcomes.  Considering that the patients at highest risk of complications for marijuana use are those for whom it allegedly has benefit, physicians should carefully evaluate the risks involved before recommending marijuana use.”

Dr. Voth encourages physicians to ask themselves the following questions before recommending marijuana to a patient:

• Is there documentation that the patient has had failure of all other conventional medications to treat his or her ailment?  Have you counseled the patient (documented by the patient's signed informed consent) regarding the medical risks of the use of marijuana—at a minimum to include infection, pulmonary complications, suppression of immunity, impairment of driving skills, and habituation?
• Has the patient misused marijuana or other psychoactive and addictive drugs?
• Do you periodically provide drug testing of the patient who has been prescribed marijuana, and have patients been excluded from being prescribed marijuana who are found to be using other illicit drugs?  Who does the drug testing and by what means?
• Is the use of smoked marijuana part of a study and/or will the monitoring of that use be under the supervision of an investigational review board?
• Have you carefully reviewed exactly which patients should be allowed to use this drug medicinally and for how long?
• Do you carefully examine and consistently follow up patients who use smoked marijuana as a medical treatment, including pulmonary function testing, evaluation of immune status, and the presence of any superadded infection?
• Have you exercised due care in assuring the standardization of the tetrahydrocannabinol potency content of the marijuana to be considered for medicinal use and whether it is free of microbial contaminants?
• Because marijuana is a federally controlled substance, has a system been established in the state to track all patients and their source of marijuana, as with other controlled substances?  Are you complying with such requirements?
• Will you be required to be licensed by the state or federal government?
• Have you shown knowledge, training, or certification in addiction medicine?  Do you have demonstrable knowledge of the physiologic effects of marijuana, its side effects, and its interaction with other drugs before prescribing it?

This past June, the American Pain Society published clinical practice recommendations regarding the use of herbal cannabis in The Journal of Pain.  The recommendations recognize the broad range of opinion among pain clinicians and researchers regarding the use of herbal cannabis, according to APS, which notes that “many pain clinicians and researchers agree that cannabinoids are clinically promising chemical compounds, and there is a critical need for robust research on herbal cannabis to identify targets for medical development.”

Clinical practice recommendations include:

• Know the federal and state laws governing use of medical cannabis
• Be clear with patients about goals for therapeutic cannabis
• Counsel patients about routes of administration and potential benefits and risks, based on scientific evidence and individual symptoms, conditions and comorbidities
• Advise patients on cannabis strains, cannabinoid medications or extracts, explaining limitations due to lack of herbal/substance uniformity and regulatory oversight
• Monitor patients the same as for treatment with opioids or other controlled substances.
• Patient follow up should assess progress toward achieving treatment goals, incidence of side effects, and evidence of psycho-behavioral changes.

APS supports the following research goals:

• Increase federal funding for pain-related cannabis research
• Broaden pain conditions being studied to include cannabis for non-neuropathic pain
• Ease regulatory restrictions that impede approvals of cannabis and cannabinoid research
• Improve access to high-quality plant cannabis for research studies
• Encourage states to collect individual and population level data on patients receiving medical cannabis.

The use of medical cannabis is a complex issue that requires clinicians to weigh a host of factors before determining whether to recommend the drug to patients.  We hope this eAlert has provided some food for thought and will stimulate meaningful discussion with your colleagues.

With best wishes,

Tony Mira
President and CEO

References
¹Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, et al. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend. 2011;115(1-2):120-130.
²National Institute on Drug Abuse, Research Report Series: Marijuana, December 2014, p. 11. https://www.drugabuse.gov/sites/default/files/mjrrs_3.pdf