Cannabis for the Treatment of Chronic Pain in the Era of an Opioid Epidemic: A Symposium-Based Review of Sociomedical Science

Abstract

Objective

This manuscript reviews medical literature published pertaining to the management of chronic pain with medical marijuana therapy (MMJ), with an emphasis on the social, medical, and legal aspects of therapy.

Design

Narrative review of peer-reviewed literature.

Methods

The 3rd Symposium on Controlled Substances and Their Alternatives for the Treatment of Pain was held in Boston on February 27, 2016, with a focus on MMJ for the treatment of chronic pain. Invited speakers had diverse backgrounds, including pain management, addiction psychiatry, neurology, and legal authorities. The purpose of this conference and this subsequent narrative review is to provide a medical, legal, and logistical framework for physicians and other health care providers to refer to when considering the initiation of medical marijuana therapy.

Results

The invited speakers each covered a unique aspect of MMJ therapy for the treatment of chronic pain. These presentations highlighted the current data for and against the use of MMJ as a pain therapy. Optimal patient selection and screening, in addition to policy developments, were discussed.

Conclusions

Increasing interest in MMJ for chronic pain underscores a need for primary care and pain physicians to better understand the indications and evidence for its use free from cultural bias. Given a lack of full conclusive clinical utility, continued research is needed to better understand how to best utilize MMJ therapy for the treatment of chronic pain. Policy initiatives, such as enumerated indications, should follow medical science in order to prevent another abused substance epidemic.

Introduction

The management of chronic pain with opioids has been met with widely publicized shortcomings, culminating in the current opioid epidemic affecting the United States [1]. Although opioids do have a foundational role in the management of pain, nonopioid analgesic alternatives should be investigated to increase the arsenal available to pain physicians. Several publications have reviewed the current literature for medical marijuana (MMJ) and its utility for the treatment of chronic pain [2–5]. Interestingly, there is evidence to support a population-level association between decreased opioid mortality and the passage of MMJ legislation [6–8]. On February 27th, 2016, a panel of experts with diverse backgrounds associated with chronic pain management discussed aspects of MMJ therapy for the treatment of chronic painful conditions. In this narrative review, we present the content of the presentations. The manuscript has been divided based on presenters so that topics discussed at the symposium may be properly attributed. We conclude with an epilogue of developments occurring since the date of the conference.

Kevin Hill, MD, MHS

Assistant Professor of Psychiatry at Harvard Medical School and Director of the McLean Hospital Substance Abuse Consultation Service. Author of Marijuana, the Unbiased Truth About the World’s Most Popular Weed [9].

First, I want to begin by cautioning readers about assuming an “extreme” stance either for or against medical marijuana and instead encourage readers to be critical and objective with the available literature. Marijuana should be presented not as a universal treatment for all ailments, as some have made it out to be, nor as a plague on modern society, as others have suggested. Powerful messages in favor of both expanded and more limited utilization are present in popular culture on the part of entertainers, celebrities, athletes, and from ongoing discussion regarding medical marijuana and legalization efforts. Marijuana is the most commonly utilized currently schedule 1 substance. Evidence from the Monitoring the Future Survey of 12th graders indicates that utilization in this age demographic has stabilized in recent years while perceived risks of marijuana among 12th graders have decreased in recent years. It should be noted that perceived risk was lower and utilization among 12th graders was higher than current levels during the late 1970s and early 1980s when the survey was initiated [10]. In states where recreational use has been approved, the rates of perceived risks among Monitoring the Future Survey participants do not change [11].

Nearly 22 million Americans utilized marijuana, either medically or recreationally, in 2015. About 9% of adults of those who use marijuana develop dependence. However, if use starts during adolescence, approximately 17% are at risk for development of dependence [12,13]. The potential to develop dependence of marijuana appears to be less than that of alcohol or opioids. However, Dr. Hill was cautious to underscore that although the relative risk of dependence appears to be lower, the risk is still present.

There have been several health risks identified with marijuana use. First, chronic use in both adults and adolescent subjects has been demonstrated to be associated with early onset of poor cognitive function, increased anxiety, worsening depression, and increased risk of psychosis [14–17]. There is evidence that marijuana use will increase dopamine levels in the nucleus accumbens, resulting in neuroplastic changes associated with chemical addiction. This is a similar but reduced magnitude observation, as is seen in the development of amphetamine addiction [18]. Finally, there is evidence of marijuana withdrawal, which in many ways may be similar to, but less intense than, the withdrawal experienced with tobacco [19].

There are more than 60 pharmacologically active cannabinoids found in marijuana, including tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the phytochemical thought to produce aspects of euphoria, anti-inflammatory effects, and possibly psychosis. CBD is the phytochemical thought to be minimally euphoric, anxiolytic, and antipsychotic. There are other compounds present at pharmacologically relevant concentrations that appear to have antioxidant and neuro-protective properties. Different strains have different relative concentrations of active cannabinoids; Indica is usually higher in THC, and sativa is usually lower in THC. However, significant variation exists between strains, and THC to CBD ratios can only be generalized. It should be noted that marijuana THC content is also three- to fourfold higher today than marijuana found in the 1980s. Certain plants have been developed with several-fold higher THC contents again [20].

Regarding ballot initiatives for the legalization for marijuana, the important question is not “are you in favor of legalization?” but rather “how should the policy be written into law?” Massachusetts decriminalized the possession of less than 1 ounce in 2008 and approved the development of a medical marijuana dispensary and physician certification system in 2012. The 2012 Massachusetts Medical Marijuana Initiative allowed for individuals to possess up to 10 ounces of medical marijuana for “debilitating conditions.” Although this represents a potentially useful policy that may aid in the treatment of certain conditions, the implementation may have several shortfalls. First, the amount of medical marijuana that is legal for individual possession may have been able to meet the spirit of the law, allowing for a more moderate or decreased amount, which may decrease individual and societal risk. Second, data suggest that the majority of patients who are certified for treatment with medical marijuana do not have a pain-related diagnosis such as cancer, HIV- and hepatitis C–associated neuropathies, or the painful manifestations of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease, or Crohn’s disease.

There are approximately 50 prospective randomized controlled trials exploring the medical utilization of cannabinoids. The US Food and Drug Administration (FDA) has approved oral cannabinoids for the treatment of nausea and vomiting associated with chemotherapy, in addition to appetite stimulation in wasting illnesses associated with HIV/AIDS [3]. Aside from these indications, the best data from randomized controlled trials are for the treatment of chronic pain, neuropathic pain, and spasticity associated with multiple sclerosis [3]. Other studied conditions, such as glaucoma, have not yielded positive data for the clinical utility of medical marijuana. Reckless recommendation of medical marijuana by some physicians for indications not supported or even refuted by medical literature is a major discrediting factor stigmatizing legitimate providers utilizing MMJ appropriately. Currently, state policy allows for some physicians to recommend use of a medication with abuse potential with little or even counterfactual scientific evidence. It should be noted that the American Psychological Association (APA), American Medical Association (AMA), and American Society of Addiction Medicine (ASAM) currently recommend against referral for medical marijuana treatment [21]. If physicians do decide to recommend MMJ therapy, policies should be developed for management of these patients, including plans to attempt alternative therapies and address the risk of cannabis use disorder (CUD) development stratified by age.

Nearly 25,000 individuals have been provided with certifications for MMJ in the state of Massachusetts by a relatively small number of physicians. One of the major concerns expressed by physicians interested in certifying patients for MMJ, beyond the need to strengthen the clinical evidence, is the legal vulnerability of physician licensure and the possible loss of federal research grants from federal organizations such as the National Institutes of Health or National Institute of Drug Abuse at an institutional level. Ninth circuit court rulings in 2002 determined that patient–physician conversations regarding medical marijuana therapy are protected by the first amendment. Further, additionally FDA indications may arise in the future [3].

Ronald Kulich, PhD

Professor at the Craniofacial Pain and Headache Center at Tufts University School of Dental Medicine and the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital, Harvard School of Medicine.

As a psychologist, I help prescribers decide whether a patient has psychosocial risk factors for medication misuse. Screening potential patients for risk when considering initiation of MMJ is imperative. Screening individuals involves evaluation for 1) the risks of abusing marijuana, 2) current substance abuse, 3) the risk of psychiatric and medical comorbidities, 4) the probability of nonadherence, 5) the likely efficacy of the indicated treatment, and 6) medical–legal risk. The major concern among physicians is that the current screening instruments for MMJ abuse risk are inadequate and do not allow for optimal risk stratification to predict who will develop complications resulting from MMJ therapy and who is an appropriate candidate. Current opioid screening tools such as the Cannabis Abuse Screening Test (CAST), Cannabis Use Disorder Identification Test (CUDIT), Drug Use Disorder Identification Test (DUDIT), and Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) have been developed but have not been used in the context of screening for possible MMJ [22,23]. Unfortunately, current brief screening tools are not designed to generate a score predictive of risky or aberrant behavior but rather designed to initiate a focused physician–patient dialogue. When screening a patient for cannabis misuse risk, the physician should start by determining the rationale for screening. Currently, the tools to assess other substance risks include patient interviews, prior medical records, physical exams, and urine toxicology. Objective tests of function should also be strongly considered for risk stratification in certain situations. Objective measures used in disability assessment such as the World Health Organization Disability Assessment Schedule (WHODAS) and Roland-Morris Disability Index (RMDI) have not been validated for cannabis abuse screening, although some measures of disability should be considered. There are additional questions including whether or not patients should be evaluated by specific objective behavioral tests such as driving exams, work performance exams, and electronic activity trackers and, if so, at what point this testing should be conducted [24]. Unfortunately, the criteria for referral for such tests have not been agreed upon and are largely at the discretion of the physician. The patient should be counseled on the available alternatives. A treatment agreement with the certifying provider should be used [25]. Assessment of patients should also be an ongoing, regularly repeated component of treatment as the patient’s medical condition may evolve over time. Finally, collaboration with physicians in a multidisciplinary team, including psychologists, mental health clinicians, and substance abuse counselors should be considered in order to obtain a more complete perspective of individual patient risk.

Certain acute medical conditions may arise from marijuana use. The risk is prognosticated by age, dose utilized, frequency, mode and situation of use, and the individual patient’s disposition. Such acute medical conditions may include panic attacks, psychotic symptoms, deficient attention, impaired concentration, motor incoordination, nausea, withdrawal symptoms, affective disorders, psychosis, anxiety disorders, and the previously mentioned pulmonary and cardiac diseases. The DSM-V states that cannabis intoxication does not typically result in severe behavioral and cognitive dysfunction. Use is associated with an increased risk in the duration of long-lasting paranoid symptoms and increased risk of the intoxication phenomenon.

Concern arises for the potential for cannabis use disorder (CUD), which is seen in approximately 9% of cannabis users and 17% of those who initiate use while in their adolescence [12,13]; 25% to 50% of patients who utilize cannabis on a daily basis are thought to be at increased risk for CUD [26]. Early age of chronic use seems to be a robust prognosticating factor for the development of CUD. Similar to other substance use disorders, it is characterized by impaired control, social impairment, high-risk use behavior, and substance-specific pharmacologic criteria. The behavior and cognitive dysfunction seen with CUD may not be as severe as that seen with other substances but may have significant impact on individuals. Long-term abstinence is often not achieved, with only 35% achieving durable abstinence [27]. As with other substance use disorders, there is a 50% to 90% overlap with comorbid psychological conditions such as post-traumatic stress disorder or a history of impairment from other substances at some point in their lives [28]. Additionally, patients often have poly-substance use disorders [28]. Heritable factors may contribute between 30% and 80% of the total variance in the development of CUD [29]. Other conditions related to cannabis use specified in the Diagnostic and Statistical Manual-fifth edition (DSM-V) include cannabis intoxication, cannabis withdrawal, and other cannabis-induced disorders [26]. The DSM-V recommends consideration be given as to whether or not marijuana is used medically or recreationally when formulating diagnoses [26].

The prevalence of cannabis use among chronic pain patients who are prescribed opioids is believed to range between 6.2% and 39%, compared with 5.8% of the general population [30]. The variation in the reported range of use may be due to sampling of different populations at different times. Veterans with chronic pain and sleep disorders appear to be more likely to use MMJ [31]. Among veterans, there is an association between CUD and the number of opioid prescriptions [32].

Several risk factors for cannabis consumption have been identified. There is a possible positive relationship between cannabis consumption and bipolar disorders and manic symptoms [33]. The relationship between consumption and depression is less clear [34]. Early age and long-term and heavy consumption are defined risk factors. Early onset is defined as initiation of use at an age younger than 15 years. Additionally, a family or personal history of violence or a family history of psychoses is associated with CUD [29]. A number of additional risk factors have been identified, but these are not specific to cannabis misuse.

The occupational danger posed by MMJ is a subject of debate and likely dependent on the patient’s occupation and its potential for harm to self and others. Some have found no difference in the incidence of heavy MMJ use and after-work-related accidents [35]. Evidence does suggest that marijuana use is associated with increased risk of motor vehicle accidents, especially fatal collisions [36]. The established legal thresholds for driver impairment due to cannabis are inconsistent and vary by region. Serum testing may not be a reflective measure of impairment as serum THC levels may be very low despite high levels of impairment [36]. It should be noted that other chronic pain treatments, including prescription opioids, benzodiazepines, and muscle relaxants, may impair focus and lead to consequent motor vehicle accidents [37]. There is also concern regarding the use of marijuana in pregnant females as positive screening tests are more indicative of poly-substance use rather than mono-substance use. The effects of marijuana on fetal tissue development have not been clearly defined or compared with other therapeutic options [38]. There is a higher risk of adverse events, but not life-threatening events, among MMJ-utilizing patients compared with similar controls [39].

David DiBenedetto, MD

Medical Director at Boston PainCare.

I am going to review the current MMJ literature and give special attention to the difficulty in determining treatment efficacy due to the use of small sample sizes and brief study durations, the heterogeneity in the formulations and delivery routes of study drugs, the use of placebo rather than standard-of-care control groups, and the reliance on pain scores rather than functional outcome measures as primary study end points in the majority of MMJ studies [3,40,41]. There are real difficulties in discussing the realistic benefits of MMJ treatment with patients given the current poor state of evidence. We have collected preliminary research data regarding the association between cannabis use and aberrant drug behaviors in 209 patients undergoing opioid treatment during a 12-month study period. Individuals presenting with THC-positive urine drug test (UDT) results at the time of initial assessment were found to be five times more likely to have future aberrant UDT results compared with those presenting with THC-negative UDTs (25%+ THC group vs 5%– THC group, x² (1, N = 209) = 18.961, P < 0.001). The full results of this study have yet to be published.

Patients presenting for opioid treatment at Boston PainCare undergo a comprehensive interdisciplinary evaluation with medical, functional, and behavioral specialists to determine the appropriateness for opioid treatment, the risk for aberrant drug behaviors, and the potential for treatment nonresponse. Critical to this process is the evaluation of a patient’s functional abilities (both actual and perceived), medical and psychological comorbidities, and addiction behaviors. Reviewing the peer-reviewed material, there is a noted lack of guidance regarding the evaluation and management for MMJ relative to published guidelines regarding opioid treatment. The adoption of clinical protocols similar to those recommended for opioid treatment is strongly recommended given the risks associated with cannabis use [12,14,42–45].

A patient’s entrenched beliefs regarding MMJ, either for or against its utilization, may distort their perceptions regarding the risks and benefits associated with MMJ treatment of pain [46]. Patients with positive views of MMJ tend to report better pain relief while those with negative views of MMJ tend to report decreased benefit. He noted that similar outcomes have appeared in the historical pain research literature regarding the effects of alcohol use for the treatment pain and discussed the historical similarities of social perception influencing the outcomes and acceptance of the medicinal use of both substances [46,47].

Improving a chronic pain patient’s overall quality of life is best reflected in the simple reduction of pain scores alone, but also through improvements in physical functioning and the embrace of adaptive coping strategies. Anecdotally, patients who claim benefit with cannabis use often report 1) experiencing some modest degree of pain relief; 2) dissociation from the pain experience without alteration in pain severity; or 3) modest functional improvement, most often in the form of improved sleep. Achieving meaningful treatment outcomes with MMJ is unlikely as long as the medical community conceptualizes pain purely in terms of biological function/dysfunction rather than as an illness defined by social and psychological factors [48]. The widespread prescribing of MMJ for chronic pain is not supported by the current level of scientific evidence. I agree with the AMA’s position advocating for the rescheduling of the the drug to allow for further and higher-quality research into the potential benefits of cannabis and cannabis-derived drugs.

Edward M. Moriarty, JD

Senior Partner at Moriarty, Shay and Associates, specializing in Massachusetts’s workers’ compensation ligation.

I will begin with two cases that I believe illustrate common workers’ compensation issues. They are both workers’ compensation patients who were injured and given certification for MMJ in 2015. MMJ has the potential to be very expensive to the individual and is likely not covered by workers’ compensation insurance under current regulations. The current legislation governing the infrastructure for MMJ certification and prescribing (“An Act for the Humanitarian Use of Marijuana”) was written by the Department of Public Health (DPH) in 2012. It does not have any provisions regarding billing. The presumption that underlies the entire system is that third party payers will pay for the therapy. The question that I pose to the reader is who will pay if a patient presents to a dispensary with a medical marijuana certificate, approved physician certification, a Department of Industrial Accidents (DIA) “utilization review,” and an order from an administrative judge at the DIA stipulating that a workers’ compensation insurer pay for medical marijuana? Under the current regulation, there is no structure in place for an insurer to be directly billed. Patients who are certified must pay for the product out of pocket. These expenses may then be submitted to the DIA for reimbursement. The cost of medical marijuana is covered under the same protections afforded to out-of-pocket expenses such as mileage.

As with all health care services managed by the DIA, MMJ is handled on a case-by-case basis, and there needs to be evidence that the therapy for the treatment of chronic pain is reasonable, reliable, necessary, and causally related to the work injury. This system provides an opportunity for insurance providers to challenge appropriateness. Currently, most insurance providers do not consider MMJ therapy to be reasonable or reliable. The industry points to a lack of large prospective randomized trials with positive results, which are required for medical and scientific validation of most new medications and medical devices [2]. Additionally, under the Controlled Substances Act, the current federal status of marijuana as a schedule 1 substance does not provide a mechanism for insurers to pay for it. Currently, marijuana is still federally illegal, with deferment to the states and local authority for enforcement of marijuana law. In order to develop acceptance by the insurance industry, the legal status of marijuana would need to be changed at the federal level as federal law continues to supersede state law in cases where state law is contrary to federal law. For individual reimbursement, a DIA judge must act as a gatekeeper to determine if the available scientific and medical literature supports utilization. The lack of scientific evidence for marijuana for the treatment of chronic pain and a lack of an FDA indication also call into question whether MMJ can be considered “reliable” under the law. The burden of proving a necessary entitlement is currently on the injured worker. The necessity may be limited by insurance companies placing limitations on the strength, dose, and length of time as an approved substance. In this way, benefits will not be lengthy, open ended, or involve “mega-dosage” treatments. The insurance providers’ major concerns, aside from a lack of evidence, are the potential for addictive behavior, drug diversion, and the perception that some doctors may be inappropriately certifying patients without defined medical need.

I would like to conclude by remarking that this is a rapidly evolving legal situation and that it is too early to determine the overall effect of Massachusetts MMJ regulations on the workers’ compensation claims industry.

Brian E. McGeeney, MD, MPH

Assistant Professor of Neurology at Boston University School of Medicine.

Marijuana is classified federally by the Controlled Substances Act of 1970 as a schedule 1 substance. This schedule contains substances thought to have no medical use and a high abuse potential. Examples also include heroin, mescaline, and LSD. However, comparing drugs by their abuse potential and ratio of active dose to lethal dose reveals marijuana to be relatively safe in comparison with alcohol, opioids, and nicotine [49]. MMJ has a dependence potential that is thought to be approximately equivalent to caffeine and nitrous oxide. Dependence potential estimates of various drugs have been available for a long time. It is important to note that these risks are not independent, that is, having a substance dependence disorder for one drug changes a future estimate of dependence for another drug, such as marijuana.

As with all medications that can decrease alertness, cognition, and coordination, there is concern about driving while under the influence [36]. The overall potential for harm to individuals, and on a societal level, of cannabis is less than amphetamines but greater than GHB, benzodiazepines, or methadone [50]. As it remains legally prohibited (at a federal level) for a physician to write a prescription for any schedule 1 substance, physicians do not “prescribe” MMJ in the traditional sense but may “certify” that such therapy is appropriate for individuals. These physicians are properly referred to as “certifiers” in Massachusetts.

In order to discuss the future of MMJ, it is essential to provide a limited historical context of MMJ. The first recorded nonrecreational use is recorded in a Chinese document dating from the 2nd century AD describing use during the reign of emperor Shen Nuang in the 3rd century BC. Greek records indicate that Galen and Hippocrates prescribed cannabis orally. However, the medical indication for either the Chinese or Greek prescriptions of marijuana was not clearly defined. Hildegard of Bingen, a German writer and philosopher who lived from 1098 to 1179, stated, “Whoever has an empty brain and head pains may eat it [cannabis], and the head pains will be reduced.” Dr. William B. O’Shaughnessy, an Irish physician, is credited with introducing marijuana into Western medicine after his experience with Indian hemp while working in India. His writings date back to 1839 and describe the clinical use of marijuana for a variety of illnesses. Dr. O’Shaughnessy was also responsible for advocating electrolyte replacement to treat cholera and was later knighted by Queen Victoria for the introduction of the telegraph to India. Dr. John Russell Reynolds, an esteemed British physician, wrote a manuscript in 1890 in The Lancet describing his 30-year experience with medical marijuana for the treatment of subjects afflicted with migraines, neuralgia, cramps, and dysmenorrhea, among other conditions.

By contrast, the United States has a relatively brief history with MMJ. Sir William Osler in the 1916 edition of The Principles and Practice of Medicine recommended the use of cannabis indica as the most satisfactory treatment of migraines. The recreational use of marijuana was associated with immigrants and minorities, especially Southern African Americans. Racism, especially toward the latter group, stigmatized marijuana use. MMJ was on formulary and could be obtained in American pharmacies through the 1930s. Unfortunately, racism and xenophobia often fueled the banning of marijuana at the state level, and then later federally with the 1937 Marijuana Tax Act.

In 1996, California introduced medical marijuana legislation, becoming the first state to do so. As of early 2015, 23 other states and Washington DC have enacted similar legislation. Canada additionally approved marijuana for certain medical indications. A 2013 review of the stated indications for MMJ in Canada suggested that the most common use is for anxiety disorders and chronic pain conditions [51–53]. Interestingly, MMJ use for cancer patients and those with wasting illnesses, the two FDA indications for cannabinoids, is relatively sparse in Canada. In Colorado, where both recreational and medical use are currently allowed, most patients receiving chronic MMJ are treated for chronic pain [54].

Following the development and passage of MMJ legislation in 1996 in California, the Drug Enforcement Agency (DEA) attempted to apply legal pressure upon physicians to limit discussions with patients regarding MMJ. The issue of physician–patient discussions and their content was reviewed by the courts and resulted in the protection of such discussions. The court also clarified that stated disciplinary action toward physicians by the DEA is permissible if there is substantial evidence that a physician “aided and abetted the purchase, cultivation, and possession of marijuana.” The federal government appealed the ruling on the nature of physician–patient discussions. In 2002, the Ninth Circuit Court of Appeals ruled that the first amendment prohibits the government from punishing physicians “on the basis of the content [potential usefulness of medical marijuana] of a doctor patient communication” [55]. The widely held legal consensus is that the Supreme Court would follow the ruling of the lower courts if challenged today.

Medical marijuana is available in several forms. In general, consumption is either oral through baked goods, cooking products, or tincture (and other concentrates) or inhaled through either traditional combustion or vaporization. Vaporizers heat the plant material to 355°F to 375 °F, at which point vapors form, but below the point of combustion. This is thought to avoid potentially carcinogenic and toxic by-products of burning. Commercially available vaporizers are available for either complete plant products or marijuana oils. Oils and other concentrates have recently gained significant popularity as California dispensaries report concentrates accounting for more than 40% of sales.

There have been many criticisms of MMJ, including abuse potential, lack of dosing control, illegal federal status, lack of supporting scientific evidence, potential for diversion to minors, the use of legalization for medical purposes as a “back door” for recreational use, memory or cognitive impairment, brain maldevelopment, lung damage, lung cancer, psychosis, or schizophrenia.

Certain adverse effects of medical marijuana have been characterized in the medical literature. Although medical marijuana therapy has been associated with a lower rate of pulmonary complications compared with tobacco, there is clearly an increased risk of chronic bronchitis but no evidence for the development of emphysema. The evidence is inconclusive regarding the risk of lung cancer with long-term heavy use of MMJ [56]. There is no demonstrable risk of cancer from long-term light or moderate use. However, the inhaled-smoking form of medical marijuana therapy is known to contain carcinogenic substances, and as physicians we should not recommend smoking anything because of this potential risk [56]. Acute MMJ utilization has been demonstrated to transiently increase heart rate and blood pressure, likely through enhanced sympathetic tone [57]. Several reports have been published noting a temporal relationship between marijuana use and myocardial infarction in the hour following in people with otherwise normal coronary arteries. Further evidence suggests that use can precipitate myocardial infarctions (MIs) in patients with coronary artery disease and that mortality rates are higher following MI in MMJ users than in nonusers. This apparent risk needs to be quantified. It is not clear from the existing literature if MMJ increases the risk of stroke [58,59]. Finally, there are associations between marijuana use and brain abnormalities in young people. Studies are small and not designed to assign causation as young people who use marijuana also may use other substances and may have different lifestyles than those who do not use marijuana [60].

As stated earlier, there are current logistical barriers to conducting quality research on MMJ. The National Institute of Drug Abuse (NIDA) contracts with the University of Mississippi to serve as the sole provider for the growth and dispensation of MMJ for research. A marijuana study requires DEA registration for experimenting with a schedule 1 substance and an Independent New Drug (IND) application to be on file with the FDA. In June 2015, the Department of Health and Human Services removed a regulation that privately funded studies to undergo Public Health Service Review in addition to FDA review. Further, recent regulatory changes have increased the amount that may be produced by the University of Mississippi for research purposes from 46 pounds to 1,400 pounds [61].

There are currently two FDA-approved cannabinoids: dronabinol and nabilone. Dronabinol is the trans-isomer of THC. It is currently a schedule 3 medication and is indicated for chemotherapy-induced nausea and vomiting, and anorexia associated with weight loss in the setting of HIV. Nabilone is a schedule 2 synthetic analogue of THC that is indicated for chemotherapy-induced nausea and vomiting. There is a suggestion that MMJ may offer benefits over therapy with individual cannabinoids due to the multiple pharmacologically active agents providing an “entourage effect” that may not be reproducible in individual synthetic molecules. This hypothesis awaits experimental confirmation.

Nabiximols (Sativex) is a tincture derived from marijuana plant material produced by GW Pharmaceuticals. The tincture is delivered as a controlled oral spray that delivers 2.7 mg THC and 2.5 mg CBD per spray. It is available in 27 countries for the treatment of spasticity in the setting of multiple sclerosis but is not available in the United States.

A meta-analysis of medical marijuana studies identified approximately 50 controlled studies from which to draw conclusions [2]. There have been 28 clinical trials that specifically examined MMJ for the treatment of chronic pain [2]. The majority of the pain studies examined the use of nabiximols (Sativex), which is a branded product administered by mouth. Few MMJ studies have studied administration by smoking, preferring oral options. There have been few efficacy or effectiveness trials comparing MMJ with firstline agents for the treatment of chronic pain. Further, many of the studies do not use at least a 30% reduction in pain as a primary end point, which has been established as a clinically meaningful reduction in pain symptoms by most patients [62]. Although the use of lesser reductions in pain may produce results that are statistically significant, they may not represent a clinically significant reduction in pain. There is moderate quality evidence that MMJ may be beneficial for the treatment of certain neuropathic pain conditions [40,41]. In addition, there are four short-term randomized controlled trials for the treatment of rheumatoid arthritis pain with MMJ that do not address the long-term management of rheumatic conditions with MMJ, instead focusing on relatively short-duration outcomes [63]. Generally the studies are conducted for a short period of time only. Admittedly this is true of clinical analgesic trials generally and not just those studying marijuana. The naturally occurring cannabinoid anandamide (in humans) has been shown to reduce trigeminal nerve sensitivity to multiple provoking factors. This effect is hypothesized to be a possible mechanism of action in successfully treating headache, although clinical studies are needed to demonstrate that marijuana is helpful in headache [64]. Four studies have been published demonstrating an anti-epileptic effect [2,65]. The American Academy of Neurology (AAN) has given a grade A recommendation to medical marijuana for the treatment of spasticity-related pain in patients with multiple sclerosis [66]. However, the AAN takes the position that MMJ is probably ineffective for the treatment of spasticity or tremor without painful features [66]. Further, MMJ therapy on a compassionate use basis for the treatment of refractory seizures has recently become well known among the families of children with refractory seizure disorders [66]. There is no evidence to support the use of MMJ or CBD as a firstline agent in seizures, but in recent weeks a positive randomized controlled study was announced by GW Pharmaceuticals [66]. Interestingly, THC has been demonstrated to lower the seizure threshold, while cannabidiols are thought to have antiseizure activity [67]. Small open-label studies have demonstrated cannabinoids to be effective for the treatment of Dravet syndrome and Lenox-Gastaut syndrome [67].

There are many published negative studies of MMJ for the treatment of certain types of pain. HIV neuropathy studies are often difficult to generalize given the relatively small number of subjects studied and modest reductions in pain that are described [68,69]. Sativex has produced negative results for the treatment of cancer pain when compared with a placebo in three separate large phase 3 trials [70]. Another study of MMJ demonstrated evidence for a decrease in intraocular pressure with MMJ that theoretically could make it useful to treat glaucoma. However, administration would have to be frequent and uninterrupted, making MMJ impractical, especially when other options are available. Thus, MMJ is not recommended for glaucoma [71].

The available literature and state of MMJ research provide little guidance for the long-term management of chronic pain. First, there is a paucity of comparative efficacy or effectiveness trials against commonly used pain medications, such as opioids, gabapentinoids, and tricyclic antidepressants. Clinical studies do not clearly establish MMJ’s comparative usefulness vs more well-studied and predictable medications with known safety and side effect profiles. Second, it is difficult to design a randomized controlled study in which the patient and the observer may be blinded to group allocation due to the obvious CNS effects of MMJ therapy. This is a problem for trials of most medications with significant subjective effects. However, I would suggest that this is actually an opportunity to compare MMJ with common pain medications with mild psychotomimetic effects, such as gabapentin, in randomized trials where gabapentin would act as a control. Many studies of chronic pain treatments have relatively short-term follow-up, providing little guidance for the long-term management of chronic pain. Third, direct comparison of published studies is often difficult given the heterogeneity of studied substances and outcome measures used. Fourth and last, there is no data yet as to whether a low-THC/high-CBD concentration strain of MMJ would provide optimal medical therapy without the psycotomimetic effects. Whether the alteration of this ratio will alter the so-called “entourage effect” is also unknown.

Daniel B. Carr, MD, DABPM, FFPMANZCA

Professor of Public Health, Anesthesiology and Community Medicine at the Tufts University School of Dental Medicine, Chairman of the American Academy of Pain Medicine, and Founding Director of Tufts Program on Pain Research, Education and Policy.

This Third Annual Tufts Symposium on Controlled Substances and their Alternatives for the Treatment of Pain focused on a class of compounds—cannabinoids—that in recent years has been in the spotlight as more and more US states legalize its possession and use. Together, the presentations, as summarized here, show the broad range of research, clinical, legal, and social aspects involved as the population strives to formulate coherent processes to:

• define the clinical value of various cannabinoids,

• understand the biological basis for their effects, and

• set into place policies to translate such insights into improved clinical care.

What Have We Learned about Each of These Three Goals?

The clinical value of any treatment reflects the balance of safety and efficacy. The history—and in some accounts, prehistory—provided by the speakers proves beyond doubt that cannabinoids are among the earliest known medications. In contrast to nearly every other substance of abuse, over millennia marijuana, hemp, or other cannabinoids have simply not been found to cause lethal overdoses. Other risks have been described, such as cognitive and psychomotor impairment with acute ingestion of large doses; the possibility to serve as a “gateway” drug or to be associated with tolerance or abstinence; pulmonary issues related to smoking medical marijuana; or an increase in the likelihood of (or earlier onset of) schizophrenia in genetically vulnerable subjects. But the fundamental lack of lethality tilts the benefit-to-risk ratio incontrovertibly—which is fortunate because efficacy data across specific indications are sparse and difficult to synthesize, particularly as they relate to pain treatment. The literature on the efficacy and effectiveness of cannabinoids suffers from the same shortcomings as seen in much early pain literature (chiefly, small study size, brief duration, and nonuniformity of participants and outcomes assessed across trials). To these may be added an element of stigma, even scandal associated with their ingestion, and resulting politicization and polarization among their proponents and detractors. For the painful conditions described in the talks, particularly neuropathic pain, spasticity-related pain in multiple sclerosis, and various forms of headache, the analgesic effect is detectable but not dramatic. The complex phytochemistry, pharmacokinetics, and pharmacodynamics of cannabinoids thwart current efforts to develop evidence-based dosing recommendations. Variations in relative contents of THC and CBD in different sativa strains, different routes of drug delivery and absorption leading to differences in pharmacokinetics and pharmacodynamics, and entourage effects with natural associated compounds that are still not fully characterized make the path forward for drug or natural product approval a challenging one. We learned that blood levels are not closely linked to the pharmacodynamics of the class as a whole. Looking at the sparse and heterogeneous evidence for the efficacy and effectiveness of cannabinoids, one is struck by the contrast between the wide availability of legal medical marijuana with low-quality evidence for its efficacy and effectiveness and the decreasing availability of opioids or increasingly harsh warnings in the product labels for NSAIDs despite voluminous preclinical and clinical evidence to support their use in appropriately selected populations.

The state of medical marijuana “certification” (i.e., prescribing) is a caricature of the fragmented nature of medical care in America today. The inability of most practicing clinicians to prescribe or dispense medical marijuana forces patients to have this element of their care delivered through a process that is largely disconnected from the other dimensions of their pain care. Speakers surveyed the inconsistent, frankly conflicting policies that affect clinicians seeking to prescribe medical marijuana for patients with a variety of conditions: in essence, prohibition at the federal level vs full legality under many states’ laws. Although the speakers alluded to the very big business that cultivation of marijuana has become and pointed out the complexities of paying for evaluation and treatment with cannabinoids, time constraints precluded more than a mention of these forbidding issues.

The symposium took place at a time when the epidemic of opioid abuse and misuse, much of it originating in prescription pain medications, dominated not only the field of public health but also the news in general. Society is desperately seeking alternatives to opioid analgesics for severe pain. Pain medicine physicians have reminded us that pharmacologic and nonpharmacologic alternatives to opioids already exist and are likely underutilized owing to prescribers’ low level of education in pain assessment and treatment. For the time being, clinicians are left to follow prudent if generic recommendations for prescribing any substance with a risk for abuse. Soon after the symposium, “Medical Board Expectations for Physicians Recommending Marijuana” were published by the Federation of State Medical Boards [72]. These included:

• documenting the patient–physician relationship (avoiding treating themselves or a family member);

• a documented, in-person medical evaluation that assesses addictive potential and confirms the ineffectiveness of other prior therapies;

• informed and shared decision-making (e.g., instruction not to drive or use heavy equipment while using medical marijuana);

• a treatment agreement setting forth the terms and conditions expected of physician and patient, including trials of other measures besides marijuana to alleviate symptoms;

• review of qualifying medical conditions when applicable, according to relevant (including local) laws;

• regular, ongoing monitoring and reassessment;

• consultation and referral, for example, for patients with problematic substance use disorder or other comorbid mental health issues;

• meticulous records;

• other expectations including the avoidance of conflict of interest (e.g., the certifying physician should not be associated with a dispensary or cultivation center) as well as that the medical practitioner will abstain from the recreational use of marijuana while practicing medicine.

During this crisis of substance use disorder and opioid-related morbidity and mortality, and possibly because of the booming economics of cannabinoid cultivation and dispensing, flaws and gaps in the scientific literature concerning cannabinoid use have been minimized. Although speakers spanned the spectrum for and against medical marijuana use, we should pay particular attention to those who expressed concern that the pace of widespread marijuana use has outstripped its scientific (including epidemiologic) evidence, particularly for long-term treatment. Time will tell whether this current upsurge in marijuana use will be seen as a long-overdue reform that provides access to an efficacious and benign medication, whose beneficial use over millennia has recently been forgotten or suppressed, or the start of yet another unregulated and ultimately calamitous social experiment associated with well-intentioned efforts to alleviate suffering.

Conclusions

The medical treatment of chronic pain is a continuously evolving endeavor that changes with refinement of existing strategies, development of new medications and procedures, and awareness of potential harms and side effects. One of the most complicating changes in chronic pain has been the development of near-epidemic levels of opioid use disorders, prompting the need for alternative strategies. The symposium provided a unique forum for stakeholders from diverse backgrounds to discuss the many facets of providing MMJ therapy for the treatment of chronic pain. There are several conclusions that can be reached based on the discussion from the gathered presenters.

1. The data supporting the use of cannabinoids (specifically THC and THC/CBD products) for the treatment of chronic pain are either limited due to study quality or suggest only modest analgesic activity in certain types of pain, such as neuropathic pain and multiple sclerosis–associated spasticity. There are promising studies that suggest a usefulness of MMJ in the treatment of chronic pain. However, MMJ has not been able to demonstrate the same effectiveness for the treatment of chronic pain in high-quality studies that other pain medications have shown, which raises concerns and leaves physicians without guidance regarding efficacy and safety.

2. As with all chronic pain treatments, MMJ carries risks of adverse health effects that must be considered when initiating therapy. The risk of a fatal overdose from MMJ appears to be relatively low, especially compared with chronic opioid therapy. The reduced risk of accidental overdose is one of the major reasons to consider MMJ over opioids for the treatment of chronic pain. The chronic and especially daily use of cannabinoids has a genuine risk of cannabis dependence. Sustained daily use is associated with impaired cognition, impaired work performance, and increased problems with anxiety, depression, and psychoses. As these conditions are common among chronic pain patients, the potential for additional adverse effects must be seriously considered. There is also a financial consideration as most health insurers do not cover MMJ. The poorly defined risks prevent physicians from adequately discussing MMJ therapy with their patients using a risk/benefit framework.

3. The route of legislative approval of MMJ has been via the unorthodox process of public ballot. This has often led to its medical benefits being oversold by enthusiastic proponents. Biased interpretation of the literature has also led to spurious conclusions, such as MMJ causing, instead of only being associated with, population-level changes in the incidence of opioid mortality. These features of MMJ’s rise to prominence understandably make many physicians reluctant to recommend it patients. This situation could easily be mitigated by dispassionate interpretation and advocacy purely based only on science.

4. Certifications of medical necessity for MMJ therapy are made by a relatively small number of physicians who have obtained proper credentialing. Unfortunately, some of these physicians engage in ethically dubious behavior by endorsing widespread use in exchange for financial compensation, adding a further layer of distrust by many physicians.

5. There are insufficient data to provide evidence-based clinical guidance even in the case of pharmaceutical cannabinoids and cannabis extracts (e.g., nabixmols). Methodological problems with the published literature include a paucity of trials comparing MMJ with other pain treatment strategies, small samples sizes, woefully inadequate masking, short follow-up periods, and the use of subjects on heterogeneous pain regimens. Further, much of the literature has evaluated MMJ as a salvage therapy.

6. There are currently a vast number of nonstandardized forms of MMJ, leading to difficulty in formulating conclusive recommendations. MMJ products available for putative medical use in dispensaries in US states that have MMJ legislation allow for use beyond the scope of what is supported by the medical literature. The use of MMJ must be firmly grounded on high-quality evidence. To do otherwise undermines MMJ therapy due to the appearance that MMJ is either being diverted for recreational purposes or being used to gain increased social acceptance for future lucrative recreational legislation passage.

7. MMJ financial stakeholders have little incentive to continue to scientifically evaluate medical efficacy after the passage of legislation. It is imperative that continued evaluation by unbiased and professional researchers continue in order to better understand the role, if any, that MMJ plays in chronic pain.

8. The wider issue of MMJ use is highly subject to socio-political complications. MMJ utilization has the potential to be used as a Trojan horse for the highly profitable legalization of recreational use. There is now a robust cannabis industry, with lobbyists and representatives to promote medical (and increasingly nonmedical) cannabis use in the absence of sound evidence of efficacy for medical uses and to downplay evidence of harms arising from the recreational use of their products.

9. The conflict between federal law (the Controlled Substances Act, which bans all use at the federal level) and competing state laws that allow medical use complicates the issue. This creates barriers for doctors to recommend cannabis and hampers patients’ ability to obtain independent medical advice.

Epilogue

During the interval between the 2016 symposium and the publication of this manuscript, the landscape of MMJ policy in the United States has greatly shifted, largely due to ballot measures during the US elections in November 2016. Collectively, these resulted in an additional three states developing policies for the medical use of marijuana and three additional states, including California, developing policies for the recreational use of marijuana. Approximately 17.6 million Americans now live in territories where marijuana is, in some form, recreationally allowed, and 156.8 million Americans live in states where MMJ policy has or is being developed. The effects of such legislation on the management of chronic pain or the development of societally challenging consequences in these territories may take years to be fully realized. Whether expanded use will result in improved management of pain or will decrease the mortality associated with opioid use remains to be seen. Each of the US states that currently has legislation for the recreational use of marijuana initially allowed for medical use of marijuana, possibly representing an interval for a local population to grow accustomed to the idea of marijuana in their communities. Although the authors would like to believe in purely altruistic objectives for the passage of MMJ legislation, the passage of exceptionally lucrative recreational legislation may, in some cases, be the ultimate goal. Investigation continues to more clearly define the role of MMJ in the management of patients with chronic pain. However, significantly more work is needed to delineate how to optimally deploy this therapy in order to help those who suffer while not resulting in unintentionally hazardous consequences. Separation of the divergent goals of developing MMJ and recreational marijuana policies is needed to reach such conclusions regarding optimal use. There are many legal, ethical, and medical aspects to consider when forming comprehensive cannabis policies. As the landscape shifts toward greater acceptance of this potentially beneficial therapeutic option, shaping policies for evidence-based usage and emphasizing continued research are imperative.