Chronic pain is the most common condition (87-94%) cited by individuals who are seeking to use cannabis for medical purposes (National Academies of Sciences, Engineering, and Medicine, 2017a). A meta-analysis (Whiting et al., 2015) of eight placebo-controlled trials involving 254 patients with chronic pain showed >30% reduction in pain in 37% of patients using cannabis or cannabinoids compared to 31% of patients getting placebo (OR, 1.41 [95% CI, 0.99-2.00]; 8 trials). Seven of these eight trials used nabiximols, an oral mucosal spray with a 1:1 ratio of THC:CBD, and 1 trial used smoked inhaled cannabis. The single placebo-controlled trial in this review that used smoked cannabis (3.6% THC) looked at patients with pain due to HIV-associated peripheral neuropathy and showed an odds ratio for significant pain reduction of 3.43 (CI = 1.03-11.48) when compared with placebo (Abrams et al., 2007).

A 2021 systematic review conducted by the Pacific Northwest Evidence-based practice center found insufficient or no evidence for benefits or risks for low THC, oral cannabidivarin, whole-plant THC (12% THC), all cannabinoids vs. non-placebo comparators (McDonagh et al., 2021). The 2021 review found that cannabinoids, particularly those with high THC:CBD or equal THC:CBD, may improve some short- term pain outcomes, especially among people with neuropathic pain.

A 2015 systematic review looked at chronic peripheral neuropathic pain treated with inhaled forms of cannabis (smoked or vaporized flower) (Andreae et al., 2015). Underlying conditions included neuropathy due to HIV, trauma, spinal cord injury, diabetes mellitus, and complex regional pain syndrome. In this review meta- analysis of five randomized placebo-controlled trials performed in the USA involving a total of 178 middle-aged patients showed an odds ratio for significant pain relief (>30% reduction) of 3.22 (CI = 1.59 – 7.42) when compared with placebo and that inhaled cannabis appeared to provide significant short term relief from chronic neuropathic pain for one in 5-6 patients being treated.

A review on the use of smoked cannabis for the treatment of neuropathic pain suggested that the efficacy of smoked cannabis (NNT = 3.6, for a 30% reduction in pain) was comparable to that of traditional therapeutic agents (e.g. gabapentin, NNT = 3.8), slightly less than that observed with tricyclic antidepressants (NNT = 2.2), but better than lamotrigine (NNT = 5.4) and selective serotonin reuptake inhibitors (NNT = 6.7) (Grant, 2013). In this review, the concentrations of THC in smoked cannabis ranged between 2% and 9%, with an average concentration of 4% yielding good efficacy. Furthermore, the authors suggest that cannabis may present a reasonable alternative or adjunctive treatment for patients with severe, refractory painful peripheral neuropathy who have tried other therapeutic avenues without satisfactory results.

A 12-week blinded randomized placebo-controlled study from England (2012) involved 279 patients with stable multiple sclerosis (Zajicek et al., 2012). Active treatment (N= 144) was an oral extract from Cannabis sativa in soft gelatin capsules containing cannabidiol (range 0.8 -1.8 mg) and Δ9 THC (2.5mg). Treatment consisted of a starting dose of one capsule (2.5mg Δ9 THC) twice daily with a two- week dose titration phase and a ten-week maintenance phase. The total treatment duration was 12 weeks. Participants were assessed at two, four, eight, and 12 weeks after the start of treatment. The maximum allowable total daily dose was 25mg Δ9 THC. By the end of the 12-week study, 46% of those receiving the active oral cannabis extract treatment had self-titrated to maximum dose of 25mg/day of Δ9 THC vs. 70% of the placebo group. The rate of relief from muscle stiffness and body pain after 12 weeks was almost twice as high with oral cannabis extract group than with the placebo (29.4% vs. 15.7%; OR 2.26; 95% CI 1.24 to 4.13; p=0.004). Adverse reactions were mild to moderate in intensity and were two times more frequent in the treatment group than the placebo group.

The 2017 report from the National Academies of Sciences Medicine and Engineering on the health effects of cannabis concludes that “There is substantial evidence that cannabis is an effective treatment for chronic pain in adults” (National Academies of Sciences, Engineering, and Medicine, 2017b). However, the authors of this report also cautiously note that only a handful of studies have evaluated the use of cannabis in the United States, and all of them evaluated cannabis in flower form provided by the National Institute on Drug Abuse. They also note that many of the cannabis products that are sold in state-regulated markets bear little resemblance to the products that are available for research at the federal level in the United States and that very little is known about the efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States.

In summary, most systematic reviews of controlled clinical trials using cannabis and cannabis-based medicines support the conclusion that cannabis and cannabis-based medicines demonstrate a modest analgesic effect and provide an option for the treatment of chronic non-cancer pain, particularly chronic neuropathic pain that has not adequately responded to treatment attempts using FDA-approved conventional treatments and interventions (Health Canada, 2018).

General considerations for recommending medicinal cannabis in the treatment of chronic pain (adapted from MacCallum and Russo, 2018):

1. In some patients, oral preparations may be more helpful than vaporized cannabis flower due to the longer duration of action of oral preparations and first-pass hepatic metabolism of orally ingested THC to 11-hydroxy THC (more potent than THC).
2. In patients using orally ingested cannabis-based medicines for treatment of pain, sublingual administration of medical cannabis extracts, vaporization of cannabis flower, or use of a medical cannabis vape pen can be utilized as add-on treatments for episodic exacerbations of symptoms.
3. CBD may attenuate THC side effects, which may be useful for daytime dosing, or when driving is required.
4. Medical cannabis patients, in contrast to recreational users, frequently use chemotypes with significant amounts of CBD and generally use the smallest amount of THC needed to get the greatest improvement in symptom control, function, and quality of life, with the fewest adverse events.
5. Data from blinded controlled clinical trials comparing various ratios of CBD:THC and therapeutic synergy (entourage effect) of various cannabis chemotypes and cultivars are lacking, but anecdotal reports and preclinical and observational data suggest that terpenoids and phytocannabinoids other than THC and CBD may have some pain-reducing and/or anti- inflammatory effects, and relative amounts of CBD may alter the effects and side-effects of THC (Russo, 2011). Because of this, changing ratios of CBD:THC or using a different chemotype or cultivar may result in improved outcomes in pain management with fewer side effects in the individual patient, where N=1.
6. Management of pain using medical cannabis may follow a bell-shaped dose-response curve, and escalation of doses of medical cannabis products past a certain amount may not always result in improved control of pain and, in some cases, may actually result in loss of therapeutic effect along with increased risk of adverse reactions (Portenoy et al., 2012).
7. THC tolerance may be abrogated via a drug vacation of at least 48 hours, preferably longer. Patients may then find that much lower doses provide symptomatic benefit equal to or better than previously experienced (see suggested regimen devised by Dustin Sulak, DO).
8. Patients should keep a ‘symptom inventory’ chart indicating response or efficacy for each cannabis product for each symptom as an aid for qualified medical providers in determining treatment response to medical cannabis in follow-up visits. (See Patient Tracking Journal at the end of this document).

Treatment suggestions for use of orally ingested extracts of cannabis for cannabis-naïve individuals with chronic pain (adapted from MacCallum and Russo, 2018):

1. Review currently-used prescription medications and check for drug-drug interactions between THC/CBD and any prescribed medications the individual is taking.
2. When treating chronic pain, consider beginning treatment with a chemotype containing both THC and CBD. Anecdotal reports from some experienced cannabis treatment providers suggest that a product with a 1:1 ratio of CBD:THC (chemotype II) or higher levels of CBD is a reasonable starting place with a lower risk of adverse reactions. However, based on other anecdotal reports, some individuals may do subjectively better with other CBD:THC ratios (CBD predominant chemotype III, or THC predominant chemotype I) or cultivars containing higher levels of other specific cannabinoids and/or terpenes.
3. Follow general dosing titration recommendations for orally-administered medical cannabis cited earlier in this document
4. Do not expect rapid onset of analgesia using orally-administered cannabis extracts. Orally-ingested THC is metabolized to 11-hydroxy THC during first- pass hepatic metabolism. 11-hydroxy THC is up to 5x more potent than THC and can cause significant intoxication and bothersome adverse reactions, especially in cannabis-naive individuals. Absorption of orally-administered medical cannabis products and the 11-hydroxylation process may take several hours and can be variable depending on bioavailability factors such as concurrent dietary intake. Start low and go slow.
5. Absorption and bioavailability of orally-administered cannabis-based medicines are usually increased when taken with a fatty meal.
6. If treatment of acute exacerbations of chronic pain is desired, the use of sublingually administered cannabis extract or inhalation of vaporized flower or vaporized cannabis extract (vape pen) may be preferable to orally ingested (swallowed) cannabis extract due to relatively rapid onset of effects with these alternative treatment modalities. Follow the general dosing suggestions in this document for vaporization of herbal cannabis or use of a vape pen.