Can cannabinoids still play a role as pain medications?

KEYWORDS:

• Cannabinoids
• chronic pain
• medical cannabis

1. Introduction

Cannabinoids have been in use for millennia for the treatment of various illnesses, particularly pain. However, cannabinoids as an accepted medicine remain controversial given their Schedule I substance status in the United States, thereby limiting their investigational and applicational potential. Additional challenges remain with medication production given differences in regional laws and regulations, causing great variability in products with lack of standards and controls, as well as how the medicine is delivered to the body (e.g. ingestible, smoked, vaporized, or topical options). Despite these logistical challenges, the literal growth and development of cannabis as a pain therapy over the past decade has been driven by several key factors, including emphasis on using endogenous ‘natural’ analogs to regulate the treatment of pain and the pursuit of alternative therapies to opioids. We are in the infancy of understanding the early and long-term outcomes of cannabinoids for treating pain.

2. Overview of literature

What are cannabinoids? Cannabinoids are defined as a group of substances found in the cannabis plant. There are over 500 different chemical substances in a cannabis plant, with the most well-understood cannabinoids being delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). To date, the Food and Drug Administration (FDA) has not approved the use of the cannabis plant for medical use; however, several medications that contain cannabinoids are currently in use for specific indications, including a purified form of CBD (plant derived) for rare forms of refractory epilepsy and a purified form of THC (synthetic) for cancer treatment-related nausea/vomiting and HIV/AIDS related loss of appetite and weight.

It has been well established that the human body has an innate endocannabinoid system, much like the endogenous opioid system, where the chemical compounds found within the cannabis plant act directly on ‘natural’ pain relieving pathways. THC is the primary psychoactive component of the cannabis plant. THC acts as an agonist directly on the presynaptic cannabinoid receptors (CB₁) to inhibit neurotransmitter release and thereby reducing neuronal signaling. The clinical effects of this are observed by impaired memory, learning, and orientation, in addition to analgesia. Alternatively, CBD is not psychoactive and is believed to primarily work via several pathways including a) inhibiting the breakdown of an endogenous cannabinoid N-arachidonoylethanolamine (i.e. anandamide) which interacts with the CB₁ and CB₂ receptors; b) noncompetitive negative allosteric modulator of CB1 receptors and inverse agonist of CB2 receptors; c) activation of 5-HT1A serotonergic receptors and vanilloid receptors. The cumulative effect of the diverse action leads to membrane stabilizing neuroprotection that yields analgesia, anxiolysis, and anti-inflammation [1,2].

Do cannabinoids affect pain? The most common use of medical cannabinoid therapies globally is for the treatment of chronic pain [3]. The diversity of research evaluating the effects of cannabis use on pain is wide reaching and controversial. There have been multiple clinical trials evaluating the vaporized or smoked form of whole-plant cannabis with positive results in typically challenging neuropathic pain syndromes. Wilsey et al. conducted a double-blind placebo-controlled crossover trial examining the analgesic effect of whole-plant placebo, and low- and medium-dose vaporized cannabis (0%, 1%, and 4% THC, respectively) in 39 subjects with refractory neuropathic pain. The use of low- and medium-dose cannabis product yielded clinically significant analgesia. The number needed to treat to achieve 30% reduction in pain was 3.2 patients for placebo versus low-dose and 2.9 patients for placebo versus medium-dose, comparable to traditional neuropathic pain medications [4]. One of the most elegant randomized double-blind placebo-controlled trials was conducted in 16 patients with painful diabetic peripheral neuropathy. Wallace et al. demonstrated a statistically significant improvement in spontaneous pain scores in patients exposed to single-dose whole-plant placebo versus low- (p = 0.31), medium- (p = 0.04), and high-dose cannabis (p < 0.001) (0%, 1%, 4%, and 7% THC, respectively). As might be expected, the higher the THC dose the more significant the pain improvement (p < 0.001), but also the negative psychoactive effects on neuro-psychometric testing were more apparent [5]. Both of these studies used whole-plant product in vaporized form and were limited secondary to small sample size and short follow-up durations.

Given the diversity and inconsistency of the cannabinoid data, the National Academies of Sciences, Engineering and Medicine (NASEM) reviewed and published a thorough literature review on the effects of cannabinoids. The panel of reviewers surveyed numerous cannabis studies, including different cannabis concentrations, modes of delivery, and disease states. One of the key primary conclusions suggested cannabis was an effective treatment for chronic pain [6]. The challenge with this conclusion was that not all cannabis products were considered equal. Mucke et al., who published the Cochrane Database Systematic Reviews, suggest that the beneficial effects of cannabis on neuropathic pain might outweigh the potential harms; however, the quality of evidence is low and ambiguous when evaluating the mean pain intensity [7]. Most recently, the International Association for the Study of Pain (IASP) put together a presidential task force on cannabis and cannabinoid therapies and based on their review of the available literature concluded that there is a lack of sufficient evidence to support the regular use of cannabinoids for the treatment of pain [8]. Compounding the challenges when analyzing task force recommendations, clinical trial data and systematic reviews, in the United States the federally illegal nature of this medication has resulted in state-based regulatory oversight to govern each individual cannabis program. Such regional regulations have resulted in a very diverse cannabis environment in the US, with little known about the true efficacy of a particular product for a particular disease state, effective therapeutic dosing strategies, or beneficial routes of administration. Ultimately, clinicians need to recognize the dichotomy that exists balancing the unintended deficits of knowledge with good scientific evidence that cannabis might confer as a pain medication.

Do cannabinoids affect opioid use? Interestingly, the concept of using cannabinoids to stem the use of opioids may seem counterproductive given the change from one concerning substance to another. The well-established potential harmful outcomes from chronic opioid use and the resulting sequalae offers an opportunity for discovery and advancement of cannabinoid therapies as a safer and viable treatment option for chronic pain. Several studies have documented that in states with medical cannabis programs the rate of opioid prescriptions is lower [9,10]. The reduction of opioid prescribing inherently is a positive step toward reducing the burden of opioid-related ill effects. In fact, additional studies have demonstrated that in states with a medical cannabis program the use of cannabis reduces the average use of opioid in patients with chronic pain and may have the potential to reduce the unintentional aspects of opioid overdose due to misuse, abuse, or diversion [11,12]. Taking things a step further, the concurrent use of cannabis with opioid therapies may also have a synergistic effect, as data suggests that concurrent use may lead to reduced dosing thereby potentially mitigating the typical side effects associated with higher dose of either opioids or cannabis as an individual medication [13–15].

Are cannabinoids safe? Medical cannabis appears to be a safe chronic pain therapy. Importantly, unlike opioid therapy, there has not been a reported death due to direct suppression of life sustaining vital organ function with cannabis use. When counseling patients, the primary side effects include euphoric ‘high’ feeling, dizziness/vertigo, dry mouth, cough, drowsiness, and gastrointestinal symptoms [16,17]. Initiation of medical cannabis dosing and escalation should occur under close medical supervision to minimize the untoward side effects, adhering to the adage of ‘start low, go slow’ when dosing a novel medication [18].

3. Expert opinion

There remains a great degree of uncertainty and apprehension in the medical community when considering the use of cannabis as a viable and durable therapy for chronic pain. Although the science and data suggest positive trends for some with chronic pain, much more information is needed to solidify that cannabis is a more efficacious medication than current well-studied strategies. It is recognized that patients are readily accepting of cannabis as a viable treatment option for chronic pain, as this is the most common indication for which patients get certified [2]. Providers must foster an inquisitive approach when counseling patients on cannabinoid therapies and encourage patients to be honest to better understand the practical and clinical implications of cannabis use. Dosing should begin low and titration should occur slowly until symptomatic pain control to mitigate common side effects. Despite the preclinical and clinical evidence proposing synergy, it is not commonly recommended to have patients on both opioid and cannabis therapies for obvious reasons, namely the abuse potential associated with these two medications in the chronic pain population. Numerous challenges still exist with the current medical cannabis environment, including the federally illegal nature of cannabis as a medicine, access to reliable products, quality control of cannabis products, and accepted dosing of cannabis products. It is critical that we advocate for expanded high-quality research and understanding of cannabinoid therapies given its pharmaceutical potential.

Declaration of interest

JM Hagedorn is a consultant for Abbott, Boston Scientific, and Nevro. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One reviewer has served on a data safety and monitoring committee for Vireo Health in an unpaid capacity. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has not been funded.