Climbing the Evidence Pyramid: Dosing Considerations for Medical Cannabis in the Management of Chronic Pain

Key Points

• •The lack of clinical data and dosing recommendations for medical cannabis in the management of chronic pain limits accessibility to this potential treatment option.
• •A recent consensus statement from international experts proposes a framework for dosing and administering medical cannabis in chronic pain, consisting of three protocols based on safety, tolerability, and effectiveness considerations.
• •The consensus statement recommends a CBD-centric approach in two of the three protocols, balancing the beneficial safety profile of CBD compared to THC against the weaker evidence base for the effectiveness of CBD in managing chronic pain.
• •The provided protocols offer a much-needed framework for clinicians when managing chronic pain with medical cannabis, but require further considerations, such as how to select a specific oral product, determining the right THC and CBD concentrations in inhalable products, and making protocol adjustments based on patient-specific characteristics.
• •Additional research is needed to provide comprehensive dosing and administration recommendations for medical cannabis in chronic pain, particularly to better understand the effectiveness of CBD in this context.

Introduction

Chronic pain is a prevalent condition, affecting more than 30% of people worldwide [1]. Medical cannabis (MC) has emerged as an increasingly available potential treatment option, with moderate evidence supporting its effectiveness in treating chronic pain, particularly neuropathic pain [2, 3]. However, the lack of clinical studies on MC, combined with the various compositions, routes of administration, and individual patient factors, makes it difficult to identify the appropriate dose of cannabis to treat chronic pain. This poses a significant challenge for healthcare professionals, patients, and caregivers when initiating and titrating MC treatment for chronic pain.

Physicians and patients have expressed a need for more guidance regarding the dosing of MC, and the lack of specific guidelines for the dosing of MC has been a topic of concern in the literature [4]. In a 2018 review, MacCallum et al. [5] evaluated the literature on the use of MC in the treatment of chronic pain. The authors provided comprehensive recommendations for dosing and administration, with a particular focus on oral delta-9-tetrahydrocannabinol (THC) preparations. They differentiated between day and nighttime use and proposed a maximum recommended daily dosage of 30 mg THC. However, it should be noted that these recommendations were general in nature and not tailored explicitly toward chronic pain management. A later commentary by Boehnke and Clauw provided recommendations for cannabinoid dosing for chronic pain management, emphasizing the use of oral formulations and vaping over smoking, and advocating for a “start-low go-slow” dosing approach [6]. Specifically, they proposed starting with 5–10 mg of cannabidiol (CBD) extract twice daily and only incorporating THC if CBD alone is insufficient for pain relief, due to the potential adverse effects associated with THC. However, these recommendations did not account for individual patient factors. In the following, Bhaskar et al. [7] developed expert guidance for dosing medical marijuana in chronic pain, by employing a modified Delphi process; they consulted international experts to generate a consensus statement on instructions for clinicians to dose and administer MC for chronic pain. This commentary will elaborate on the resulting consensus statement, as well as provide additional information for consideration when determining the appropriate dosing approach for patients with chronic pain.

Consensus Recommendation for Dosing of MC to Manage Chronic Pain

Bhaskar et al. proposed a differentiated approach for dosing MC in chronic pain, based on safety, tolerability, and effectiveness, and focusing specifically on safety considerations. They suggested three protocols: the standard, conservative, and rapid protocols. The standard protocol is recommended for most patients, and it suggests starting with 5 mg of CBD twice a day, increasing it by 10 mg every 2–3 days until reaching a maximum dose of 40 mg/day. If this dose is ineffective, THC is added starting at 2.5 mg per day, increasing by 2.5 mg every 2–7 days until reaching a maximum dose of 40 mg/day or achieving the desired outcome. The conservative protocol is designed for patients with lower tolerance toward drug effects, and it follows the same CBD starting and ending points as the standard protocol but increases the dose more gradually at intervals of 5–10 mg every 2–3 days. If 40 mg of CBD fails to produce the desired outcome, the patient can start with a low dose of 1 mg of THC per day, increasing it by 1 mg every 7 days until reaching a maximum dose of 40 mg/day or achieving the desired outcome. The rapid protocol is intended for patients who require urgent care for severe pain and palliation or have had prior experience with cannabis. It suggests starting with a product containing a balanced THC:CBD ratio, at doses of 2.5–5 mg of each cannabinoid once or twice daily. The dose is then increased by 2.5–5 mg every 2–3 days until reaching a maximum dose of 40 mg/day or achieving the desired outcome. For breakthrough pain relief, vaporizing a balanced THC:CBD or THC-predominant product is recommended, and modifying the dose or frequency of the oral MC treatment.

Balancing Safety and Effectiveness Considerations

A review of the literature on the use of MC in the treatment of chronic pain reveals that the majority of clinical evidence supporting its effectiveness is based on studies utilizing THC-dominant products or products with a comparable THC:CBD ratio. However, data demonstrating the efficacy of CBD-dominant products in the alleviation of chronic pain are limited. The current body of literature suggests a need for further research to establish the clinical utility of CBD in the management of chronic pain [2]. Therefore, it is crucial for clinicians to consider the rapid protocol for patient who has an urgent need to manage pain and palliation, with significant prior use of cannabis, and to make use of adding THC if CBD alone is insufficient to achieve the desired treatment outcome in the standard and conservative protocol. Despite the limited clinical evidence supporting the efficacy of CBD in the treatment of chronic pain, safety must always be a consideration when making treatment decisions. A recent meta-analysis of randomized controlled trials found that the use of nabilone, a synthetic form of THC, was not statistically significantly associated with more adverse event than CBD. However, only 4.5% of all trials with CBD reported severe or serious adverse events, compared to 23% of all nabilone trials, further supporting the perception that THC is generally less well tolerated than CBD [8]. As such, starting treatment with CBD-dominant products, particularly for patients who are considered “frail” or have lower tolerance, and only introducing THC-CBD-balanced products in more severe cases or for “heavy users” represent a conservative treatment approach, prioritizing safety considerations over effectiveness considerations.

Capitalizing on the Complexity and Variety of MC Products

To mitigate the potential side effects associated with smoking cannabis, Bhaskar et al. [9] recommended oral products, such as oils and gel capsules, for managing baseline pain due to their longer lasting effects. Physicians should consider the variety of oral products available, such as capsules, decoctions, oil, tablets, and baked goods, and the large inter-individual variations in plasma concentrations when treating patients with oral MC [10]. A study by Poyatos et al. found significant variations in the correlation between the dose of THC administered and the maximum concentration of THC in the bloodstream between products; e.g., capsules, decoctions, and tablets had in general stronger correlation to the peak plasma concentration (Pearson’s r > 0.90) as did baked goods (Pearson’s r = 0.63) or oil products (Pearson’s r = 0.38). Clinicians should be aware of these differences when recommending oral products, especially when patients are considering switching products, and dosing recommendations may need to be adjusted accordingly. To manage breakthrough pain, which is characterized by sudden, severe, and transient pain in addition to baseline pain, the authors recommend the vaping of THC:CBD-balanced products, due to its faster onset compared to oral products, but did not provide a consensus recommendation for specific THC and CBD concentrations in vaporizable products for chronic pain management. Inhalable herbal MC products vary in THC and CBD content, with some containing as low as 0% and as high as 50% THC [11]. Potent products may increase exposure to THC and risk of adverse events, and choosing the right amount is therefore relevant to reduce the risk of adverse events [12]. Clinicians might however find guidance in previously published studies that assessed the effect of inhalable cannabis for chronic pain management, which mainly used THC concentrations below 10% and reported positive outcomes at 1.29% THC [13].

Additional Considerations for Dosing and Administering MC to Manage Chronic Pain

Despite the comprehensive recommendations provided on dosing and administration of MC for the treatment of chronic pain, there remain several crucial considerations for treating physicians that are only partially covered by the current consensus guidelines. These considerations include how to define significant prior cannabis use, how to incorporate body weight-dependent dosing, dosing across different pain types, age-dependent effects, and incorporating sex-specific differences. When it comes to prior cannabis use, it is not clear how significant prior use, warranting the use of the rapid protocol, can be defined. While frequent cannabis users may be less susceptible to the acute side effects of THC exposure, it is not clear how previous cannabis use may impact treatment response to the conservative and routine protocols [14]. A cautious approach could be for a physician to consider daily cannabis use within the last month as significant prior use, as this level of use has been linked with partial or full tolerance to neurocognitive impairments and detectable neuroadaptive changes [15]. Dosing protocol adjustments beyond the proposed stratifications should be considered based on the body weight, as this might impact distributions of MC in the body, the age, since older and younger patients are at increased risk of side effects from cannabis, and sex, as research suggests that effectiveness of cannabis for pain relief and the risk for developing cannabis use disorder might differ across sex [14, 16–21]. Moreover, existing evidence supporting the use of MC for chronic pain largely excludes younger and older populations, as well as patients with a history of psychiatric disorder (excluding depression or anxiety), pregnant or lactating women [2]. Given that these populations may be more susceptible to negative side effects of MC, extrapolating the limited evidence is even more challenging, and treating clinicians must exercise extreme caution when recommending MC for these patient groups. In fact, the author of the consensus statement suggests that for pregnant and breastfeeding women, as well as patients with cardiovascular or psychotic disorders, the use of cannabis should be avoided [7]. In addition, it is important for clinicians to be aware that cannabis withdrawal can occur in over half of cannabis users, and that MC users are at an increased risk of developing a cannabis use disorder. As such, it is crucial for clinicians to monitor for severe cannabis-related adverse effects, particularly those indicative of a cannabis use disorder. Furthermore, clinicians should be familiar with existing literature on safe discontinuation of cannabis use in order to reduce withdrawal symptoms. This highlights the importance of careful monitoring and individualized treatment planning for patients using MC to manage chronic pain [22–25].

Conclusion

MC dosing is an emerging topic in which physicians have expressed interest but lack sufficient knowledge [26]. Bhaskar et al. have addressed this gap by providing expert-based guidance for initiating and treating patients with MC for chronic pain. This information can be used to increase accessibility to this evolving treatment option for chronic pain and reduce the risk of side effects associated with its use. Furthermore, it can be used as a foundation for developing dosing guidelines for MC in other conditions. However, many unanswered questions remain, such as how to incorporate factors such as sex, body weight, and age into MC dosing, as well as questions about switching between MC products, discontinuation approaches, and how to deal with specific populations, such as younger and older patients. As the use of MC increases, it is hoped that more research will be conducted in the future to address these questions and provide more guidance. In the meantime, Bhaskar et al.’s recommendations can serve as a starting point for general dosing considerations when using MC for the treatment of chronic pain.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

Sebastian Jugl, Amie J. Goodin, and Joshua D. Brown are supported by State of Florida appropriations to the Consortium for Medical Marijuana Clinical Outcomes Research (mmjoutcomes.org).

Author Contributions

Sebastian Jugl and Joshua D. Brown conceptualized and drafted the work. Amie J. Goodin drafted and revised. All approved the final version.

Editor’s Note

Evidence in Context is part of the outreach effort of the Consortium for Medical Marijuana Clinical Outcomes Research to examine and discuss implications of research into cannabis and cannabinoids for clinical practice, thus providing a translational approach to these studies to make clear, concise, and actionable evidence available for clinicians and patients.

Funding Statement

Sebastian Jugl, Amie J. Goodin, and Joshua D. Brown are supported by State of Florida appropriations to the Consortium for Medical Marijuana Clinical Outcomes Research (mmjoutcomes.org).