Background

Healthcare systems continue to struggle in the face of narcotic overuse and are largely uninformed in the use of cannabinoid-based medicines for harm-reduction in the opioid crisis. There have been many calls to explore the utility of cannabinoids for pain management and to alleviate the opioid epidemic [1, 2]. These calls emphasized the urgency of the opioid epidemic, the utility of cannabinoids, and the growing opportunities presented by increased legalization.

Through the present work, The Board of Medicine, a 501(c)3 nonprofit medical board, aims to answer these calls to action. We work to continuously evaluate all available peer-reviewed data to date on cannabinoids and other currently unregulated natural medicines. In this paper, we will review the history of the opioid epidemic and the evidence surrounding the use of cannabinoids for harm reduction in the opioid crisis. Then, considering the context of broadening legalization, absent provider recommendations, and research limitations, we provide one of the first evidence-based clinical frameworks for the utilization of cannabinoids to treat patients with chronic pain who are on opioids, seeking alternatives to opioids, and tapering opioids. It is also our hope that this framework will be helpful to standardize interventions to support much needed systematic reviews and meta-analyses of cannabinoids for pain.

Main text

Introduction

Despite noble intentions, many physicians feel their hands are tied when it comes to pain management and prescribing narcotics [3]. The World Health Organization (WHO) estimates that there are an annual 0.5 million worldwide deaths attributable to drug use and 70% are attributed to opioids [4]. An estimated 2 million Americans (0.7%) aged 12 years and older meet criteria for opioid use disorder [5], as we remain amid a historic shift in responsibility for the opioid epidemic, from patients to physicians to pharmaceutical companies. Purdue Pharma filed for Chapter 11 bankruptcy in 2019 [6], and it is now widely accepted that they intentionally deceived physicians and the medical community by advertising OxyContin® (oxycodone hydrochloride) as less prone to abuse than existing alternatives to increase profits [7]. In the 1960s, over 80% of people entering treatment for heroin addiction started their habit on heroin [8]. Now, about 80% of people who use heroin misused prescription opioids first [9] and most opioid overdose deaths involve synthetic opioids [10]. COVID-19 has further aggravated the opioid epidemic [11, 12], with the US reaching the grim milestone of over 100,000 overdose deaths in a 12 month period in 2021 [13]. Before COVID-19, the estimated economic burden of opioid misuse in the US was roughly $78.5 billion annually [14], but by 2022 overdoses alone were estimated to cost over $1 trillion [15].

21% of US adults experience chronic pain [16], and when opioids are used for chronic pain, evidence demonstrates that desensitization and tolerance develop quickly [17]. The need for escalating doses often causes opioid-induced hyperalgesia, making pain nearly impossible to treat, a problem that is absent with cannabinoids [18]. Further, endocannabinoid system disruptions have been linked to post-traumatic stress disorder (PTSD) [19], which is highly comorbid in patients with opioid addiction [20] and chronic pain [21], and evidence suggests cannabinoids may be therapeutic in this condition as well [22].

Despite the facts that 91% of Americans support cannabis legalization [23], there is legal medical cannabis in 38 US states [24], and cannabis is federally legal in Canada, the medical community’s utilization of cannabinoids has been limited despite a worsening opioid crisis. In February 2022, the CDC issued the agency’s first revised guidelines on opioid prescribing since 2016, which strongly urged providers to “first turn to ‘non-opioid therapies’ for both chronic and acute pain” [25]. Given the lack of educational resources and guidance around effective and minimal-risk non-opioid alternatives, this begs the question: is the medical community positioned to effectively address the changing tides of public opinion and critical public health needs when there could not be a more relevant Hippocratic sentiment to remember than “first do no harm”?

Evidence for the utility of cannabinoids

Can cannabinoids alleviate the opioid crisis?

The debate over whether cannabinoids decrease opioid demand is longstanding and has compelling evidence in the US [26,27,28,29,30,31] and Canada [32,33,34], despite heterogeneous data that are largely an effect of legal restrictions on sourcing cannabis for research.

A 2018 longitudinal analysis showed that US prescriptions for all opioids fell by 14.4% when medical cannabis dispensaries opened, particularly for hydrocodone and morphine, but also for benzodiazepines, stimulants, and many other medications known to be over-prescribed and addictive [35]. This expeditious reduction in prescriptions was previously thought to be unachievable and the trend has extended to fentanyl-related overdose deaths [31, 34], which represent the greatest driver of the current epidemic. Questions remain about the longevity and causality of this effect after a 2014 study showed medical cannabis laws slowed increases in opioid mortality by an astonishing 24.8% [36], but a 2019 follow-up study showed trend reversal [37] and a systematic review and meta-analysis showed small non-significant reductions in opioid prescriptions and overdose mortality in states with operational marijuana dispensaries [38]. These studies highlight the importance of not using ecological correlations to draw causal conclusions, but the question of cannabis’ ability to alleviate the opioid crisis has remained open and been studied in diverse settings.

Observational research has explored the role that adult cannabis use plays for patients in pain management, substance use and mental health treatment, and harm reduction [39,40,41], especially among people who inject drugs (PWID) [42, 43]. This harm reduction role has also been confirmed in studies with vulnerable young people experiencing street entrenchment in Canada, who have a prevalence of cannabis use estimated as high as 98% [44, 45], with nearly 20% having sold cannabis in the past 6 months [46]. Research on patterns of use in these street-involved youth has observed associations with lower rates of initiation of injection drug use [47], the role of cannabis to be considered medicinal rather than recreational [48], harm-reduction from other more deadly substances [49], and transitioning away from more harmful forms of substance abuse [50].

Research among opioid users who are financially stable enough to frequent dispensaries has also been promising. A survey of 2897 medical cannabis patients found that, of the 34% who used opioid-based pain medication in the prior six months, 97% decreased their opioid consumption with medical cannabis and 81% said cannabis alone was more effective than cannabis plus opioids [43]. A retrospective cross-sectional survey of 1513 dispensary members indicated that 76.7% of regular opioid-using respondents reduced their use after starting medical cannabis, an effect that extended to use of alcohol (42.0%) and psychoactive medications for anxiety (71.8%), migraine (66.7%), sleep (65.2%), and depression (37.6%). When these participants were asked what they like most about cannabis, the most common response was that it helped with pain [51].

While the data supporting cannabinoids for pain are compelling, it is also conflicting and heterogeneous. For example, some data indicate that cannabis reduces self-efficacy in the frequently co-morbid conditions of depression and anxiety [52]. A four-year longitudinal observational study of cannabis use for cancer-related pain showed no opioid-sparing effect or reduction in pain severity, but only 6.5% of the 1514 patients used cannabis regularly 21–31 days per month, quality and type of cannabis was not assessed, and all patients were using black-market cannabis due to illegality during the study period [53]. For over 50 years, prospective studies of cannabis in the USA could only source plant material from one university until 2021 when the Drug Enforcement Agency (DEA) expanded access in response to quality issues [54]. This makes available data with interventional and longitudinal trials on the popular use of cannabinoids heterogeneous and extremely difficult to filter for systematic reviews and meta-analyses [55, 56].

Pure cannabinoid drugs such as oral synthetic tetrahydrocannabinol (THC) (dronabinol or Marinol®) and oral CBD (Epidiolex®) represent the most conventional prescription cannabinoid-based medicines. Dronabinol was FDA-approved in 1985 for nausea and vomiting associated with chemotherapy. In 1992, this product was approved to treat cachexia in AIDS patients [57]. In 2018 and after much public outcry, Epidiolex® was approved for the treatment of two rare seizure disorders (Lennox-Gastaut Syndrome and Dravet Syndrome) [58, 59]. Despite the growing availability of these cannabinoid-containing mainstream pharmaceuticals, there remains a significant disconnect between provider prescribing habits and the popular utilization of cannabis, which can be largely attributed to absent prescribing guidelines and unavailable standards for over-the-counter phytocannabinoid products.

Cannabinoid safety and utilization despite low provider knowledge

The safety of high-quality CBD has been well-established [60, 61]. Compared to most drugs for pain, psychiatric, or mood disorders, side effects of cannabis when misused are mild and can occasionally include sleepiness, diarrhea, changes in appetite/weight, cognitive effects, hyperemesis, nausea, sedation, and addiction/dependence [61, 62]. Recent research has shown a role for CBD in treating cannabis use disorder [63]. THC ingestion by children and young adults has also been associated with an increased risk of psychosis [64] and schizophrenia [65], though new research has shed light on the complexity of this correlation with shared genetic susceptibility [66]. Comparing the number needed to treat and the number needed to harm (NNH) for opiates and cannabinoids is challenging as the NNH rarely accounts for the long-term risk of opioid use disorder (OUD). However, the number needed to kill after 2.6 years of opioid therapy is 550 [67], while deaths secondary to CBD and THC have not been reported [68].

While the evidence to date suggests that cannabis is likely safe and potentially impactful, prescribers are largely uninformed about the use of cannabis-based medicines and the endocannabinoid system [69], leaving patients to self-medicate with cannabis in experimental ways [70]. A survey of 489 dispensary customers in Quebec, Canada showed that 74% had spent over one year self-medicating with cannabis, 56% were taking prescription medications, and 39% never consulted a resource on cannabis. 47% said they sometimes or never declared cannabis use to physicians and 80% said they would like to access advice from healthcare professionals about cannabis [71]. A study of 628 cannabis for therapeutic purposes (CTP) users in Canada demonstrated that barriers exist due to stigma, specifically related to patients’ perception of their providers’ attitude toward them. 48% wanted to discuss CTP with a physician but did not, and the most frequent reason (62%) for not discussing it despite a desire to do so was “don’t feel comfortable” [72]. A 2018 study in the Journal of Clinical Oncology shed light on critical gaps in research, education, and policy, with its survey of 400 medical oncologists that found, while 46% recommended medical cannabis and almost 80% discussed it, only 30% of oncologists felt sufficiently informed to recommend medical cannabis [69].

Clinical framework for prescribing cannabinoids in clinical practice and research

The Board of Medicine aims to address the lack of provider knowledge of cannabis, heterogenous research interventions, and untapped harm-reduction potential with an evidence-based clinical framework for utilizing cannabinoids to treat chronic pain in patients who are on opioids, seeking alternatives to opioids, and tapering opioids. The expertise of the board members was called on for review and discussion of the available evidence to generate the clinical framework found in Table 1. Board members met regularly to discuss cannabinoid dosing and opioid tapering regimens, until the final framework was agreed upon.

Table 1 Evidence-based guidelines for the clinical use of cannabinoids for management of chronic pain in the absence of opioids, in the presence of opioids, and for those attempting to taper opioids
Full size table

The open-access framework includes opioid tapering recommendations that are in accordance with the CDC’s newest clinical practice guidelines for managing opioids for pain. The new CDC guideline recommends the following opioids tapers: “Tapers of approximately 10% per month or slower are likely to be better tolerated than more rapid tapers when patients have been taking opioids for longer durations (e.g., ≥ 1 year). When patients have taken opioids for shorter durations (e.g., weeks to months rather than years), a decrease of 10% of the original dose per week or slower (until approximately 30% of the original dose is reached, followed by a weekly decrease of approximately 10% of the remaining dose)” [73]. We invite any clinician and researcher to access this framework to help our medical community expand our toolbox to combat the opioid epidemic and other complex public health crises with less risky non-opioid tools.

Due to the resulting low quality of available research, the International Association for the Study of Pain Presidential Task Force could not endorse the general use of cannabis and cannabinoids for pain relief [74]. Further, new CDC guidelines on prescribing opioids for pain cites the evidence base supporting cannabis for pain management as limited [73]. While these authors agree with the CDC that more research is needed to understand how to best use cannabinoids in clinical care, the gravity of the opioid epidemic, the rapid expansion of recreational cannabinoid use, and the lack of clinician education in this domain suggest an urgent need for general guidelines focused around patient safety that can be utilized in research and clinical practice, particularly for our most vulnerable patients currently dependent on opioids.

Conclusion

Moving forward

As opioid deaths continue to be a global problem, patients are increasingly self-medicating with cannabis [71, 75] while researchers struggle to standardize protocols and providers feel uncomfortable recommending cannabinoids amidst absent prescribing guidelines [69]. If we consider cannabis as a harm reduction tool that patients are already using without medical guidance, we can realign our focus to supporting researchers and providers with a clinical framework for standardizing research and recommending cannabinoids more informatively as safe, effective, accessible tools for assisting in the management of chronic pain. To our knowledge, this is one of the first comprehensive evidence-based peer-reviewed clinical frameworks for the safe use of cannabinoid products for chronic pain and OUD.

We believe that there is a precedent for the safe use of cannabinoids as risk-reduction tools in the clinical settings described, and that healthcare systems can integrate cannabinoids into viable treatment options as well as areas of clinical inquiry. However, there are many issues to confront. One question regards understanding the difference between phytocannabinoids compared to isolated and synthetic cannabinoids in treatment for pain. Another question regards whether the entourage effect plays a role in the action, tolerance, and side effect profile of cannabis. Most research on the cannabis plant’s molecular constituents has focused entirely on CBD and delta-9-THC, despite hundreds of known biologically active molecules present. New studies of novel phytocannabinoids suggest benefits from acidic cannabinoids [76, 77], cannabinol (CBN) [78, 79], cannabigerol (CBG) [80,81,82,83,84,85,86,87], and cannabichromene (CBC) [83, 88,89,90] among others.

Indeed, if phytocannabinoids prove to be non-inferior in safety and efficacy, then dissemination of this knowledge becomes a matter of social justice, because it could offer individuals of low socioeconomic status dramatically improved access to non-opioid pain management options. Furthermore, clinical adoption of cannabis-based therapies could justify insurance coverage of cannabis, which may be critical for lower income patients [72]. A foreseeable regulatory challenge regards the self-production of cannabis, and the resources patients may need (land, power, etc.) or legal obstacles they could face based on their state or regional location. Finally, until there is a federal consensus on the legality of medical cannabis, safeguards for cannabis-using patients may be limited including, for example, cannabis possession-related child endangerment laws.

Resistance to cannabis-based medicines for the opioid epidemic may have many origins, particularly the stigma associated with recreational cannabis use. That said, the evidence to date suggests that it is time for a sea change in the clinical approach to cannabis for pain management and OUD. Throughout the history of science and clinical medicine, there have been transformative changes that were initially considered heretical: hand hygiene as a means to prevent infection prior to germ theory, therapy for H. pylori to combat peptic ulcer disease, and even the genetic basis of cancer were all dismissed by their era’s established medical communities. Similarly, we face great resistance to the implementation of CBD and other cannabinoids for treatment-resistant chronic illnesses, despite the compelling evidence, strong overall safety profile, and urgent need. Many of our patients have already begun their own self-guided journey into pain management with cannabinoids and the burden is now on providers to consolidate the information available, conduct more rigorous research, form best practices, and implement guidelines that will inform both the field and those we care for without stigma.

“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all.”—William Osler