Chronic Pain and the Short-term Effects of Medical Cannabis

As a global health concern, chronic pain is estimated to affect 15 to 30% of the adult population.¹⁻³It negatively affects the quality of life and psychosocial function of patients, and has significant socioeconomic impacts.⁴˒⁵ In Canada, where the authors practice, the economic burden of chronic pain care is $7.2 billion⁶ and the prevalence of chronic pain conditions increased by approximately 5.7% between 2000 and 2014, suggesting a potential relationship with the aging population.⁷

Standard first-line pharmacotherapies for chronic pain are often subtherapeutic and/or not well tolerated. Opioid medications, often used to treat chronic pain, have high abuse potential, variable long-term efficacy, and have been associated with startling rates of overdose and death.⁸⁻¹¹As such, there is an urgent need for effective and safer treatment options.

Cannabis has emerged as a promising alternative for the management of chronic pain due to its high margin of safety and postulated regulatory effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) on major endogenous pain circuitry systems.¹²⁻¹⁵The therapeutic effects of cannabinoids have been demonstrated in preclinical and clinical studies. However, the evidence has been inconclusive due to an assortment of study designs, relatively small sample sizes, and other factors. There is an urgent need for larger-scale studies to evaluate the effects of medical cannabis in those who live with chronic pain.

The primary objective of the study presented below was to evaluate the short-term effects of plant-based medical cannabis on pain severity, quality of life, and tolerability in a cohort of patients with chronic pain using medical cannabis. The secondary objective was to assess whether acute responses to medical cannabis were maintained, with specific follow-up timepoints set at Months 3 and 6.

Methods

We investigated the short-term effects of medical cannabis on pain and quality of life measures in patients initiating medical cannabis treatment through a prospective, observational study design. Participants were asked to complete study questionnaires at baseline and Month 1. Further analyses were conducted via follow-up questionnaires at Month 3 and Month 6.

The study was approved by Advarra Institutional Review Board. Written consent was obtained from all participants and procedures were conducted in accordance with international standards of Good Clinical Practice, institutional research policies and guidelines, and with the ethical principles laid out in the Declaration of Helsinki. (See disclosures at end of article.)

Participants

Individuals with chronic pain initiating medical cannabis treatment were recruited between 2015 and 2019 at the Apollo Cannabis Clinics in Toronto, Canada. Subjects were enrolled based on the following eligibility criteria:

25 years of age
willing and able to provide informed consent and complete study assessments
experiencing chronic pain 3 months
newly prescribed medical cannabis for the treatment of chronic pain.

Procedures and Primary Efficacy Variables

Prior to enrolment, all participants were subjected to a clinical evaluation of medical history and health status by the attending physician and were advised on a personalized cannabis-based treatment plan with instructions on dosing, route of administration, and set THC limits based on individual risk factors and tolerability.

Demographic information and medical history were collected at baseline. In addition, the following outcomes of interest were captured at baseline and Month 1 as well as follow-up at Month 3 and Month 6:

Brief Pain Inventory (BPI): A self-administered rating scale that captures pain severity (0 = “no pain” to 10 = “pain as bad as you can imagine”) and pain interference (0 = “does not interfere” to 10=“completely interferes”)
Short Form Health Survey (SF-12): A self-reported, multi-item scale questionnaire that evaluates quality of life by deriving Physical Composite Summary (PCS) and Mental Composite Summary (MCS) scores that range from 0 = “lowest level of health” to 100 = “highest level of health”
Tolerability: Participants were asked to rate the frequency (“never to rarely” or “sometimes to frequently”) at which they experienced adverse events (AEs) such as dizziness, dry mouth, disorientation, increased appetite, and drowsiness, among others.

Statistical Analysis

Data were analyzed using IBM SPSS Statistics (Version 25.0, Armonk, NY, IBM Corp) and XLSTAT Basic (Long Island City, NY: Addinsoft). Continuous variables were checked for outliers by studentized residuals and for normality with inspection of Q-Q plots.

Normally distributed continuous variables are presented as means with standard deviation (SD) and analyzed with one-way repeated measures (ANOVA); non-normally distributed continuous variables are presented as medians (except where noted) and analyzed using Skillings-Mack tests.

Categorical variables are presented as counts and/or as valid percentages of the total. Associations between categorical variables, such as gender distribution across timepoint groups, were analyzed with chi-square tests. Measures of safety, presented as categorical options, were tested for the first and second assumptions of sample size adequacy and analyzed with McNemar’s test.

(See also, medical marijuana withdrawal severity and stability.)

Results

Demographics

A total of 580 participants completed study questionnaires at baseline and at the end of Month 1. The study sample had a mean age of 50.33 ± 14.44 (25 to 88 years), and 55% of patients were female.

The most commonly reported pain conditions in this study population were back pain, osteoarthritis, fibromyalgia, and chronic headaches; the reported duration of pain conditions ranged from 3 months to over 10 years; and about half of the study population were suffering from two or more concurrent pain conditions.

Prior to initiating medical cannabis treatment, 37.6% of the study sample had no previous experience with cannabis, and 25.8% had used the substance when younger. See Tables Ia and Ib.

Of the 580 patients who completed baseline and Month 1 reports (Phase 1 group), 184 patients also completed Month 3 reports (Phase 2a group); and out of these 184 patients, 60 also completed Month 6 reports (Phase 2b group). The baseline demographics described above did not differ between Phase 1, Phase 2a, and Phase 2b groups (see Table Ia).

After one month of treatment, the reported mean dose of medical cannabis (in grams of dry flower or oil equivalent) was 1.44 ± 2.78 grams/day. Similar daily mean doses were reported at Month 3 and Month 6 follow-ups. Although data on exact THC and CBD doses were not collected in the study, strains used by the study population typically ranged from 7% to 29% THC and/or CBD (see Table II).

Changes in Pain Severity and Quality of Life

Pain severity was assessed with the BPI, from which pain interference (BPI-I) and pain severity (BPI-S) scores were derived. There were statistically significant reductions in BPI-I [F(1, 579) = 190.58, P < 0.0001, partial n²= 0.25] and BPI-S [F(1,576) = 201.58, P < 0.0001, partial n²= 0.26] scores from baseline and Month 1 Further score reductions were observed from Month 1 to Month 3, and from Month 3 to Month 6 but these did not reach statistical significance (see Table IIIa).

Pain interference was further evaluated by examining the scores of the individual domains of the BPI-I subscale: specifically, general activity, mood, walking ability, normal work, relationships with other people, sleep, and enjoyment of life. Participants showed significant improvements in the subdomains of mood, walking ability, and sleep from baseline to Month 1; and for patients in the Phase 2a group, further statistically significant (albeit small) reductions in these same subdomains were observed from Month 1 to Month 3. The remaining BPI-I subdomains were reduced significantly from baseline to Month 1 but no further reductions were observed from Month 1 to Month 3 or from Month 3 to Month 6 (see Table IIIb).

Quality of life was evaluated using the SF-12, from which PCS and MCS scores were derived. As evidenced by Shapiro Wilk’s tests, PCS and MCS data were not normally distributed and, thus, were evaluated with Skillings-Mack tests. There were statistically significant improvements in PCS and MCS scores from baseline to Month 1, but no further changes from Month 1 to Month 3, nor from Month 3 to Month 6 (see Table IV).

Tolerability

Study participants were asked to rate the frequency at which they experienced undesired symptoms commonly associated with cannabis use (see Tables V–VII). There were statistically significant changes in the reported frequencies of 16 out of the 23 AEs from baseline to Month 1. However, the majority of these AEs decreased in frequency between the two timepoints. In patients who also completed Month 3 follow-up reports (ie, Phase 2a group), there were statistically significant decreases in the reported frequencies of dry mouth (P = 0.049), suspiciousness (P = 0.031), and throat irritation (P = 0.004) from Month 1 to Month 3.

Discussion

In this prospective, open-label study of medical cannabis treatment in 580 chronic pain patients, we found statistically significant BPI mean score reductions and SF-12 mean score increases, indicating positive effects of medical cannabis on pain severity and quality of life within one month of treatment. These effects were sustained over subsequent follow-up timepoints in patients who completed Month 3 reports (n = 180), and those who also completed Month 6 reports (n = 60), as evidenced by comparable BPI and SF-12 scores at Months 1, 3, and 6 (see Table IIIa and IV).

These findings are in line with other studies evaluating plant-based cannabis for chronic pain. For instance, significant pain reductions as well as improvements in quality of life were reported in a 3-month retrospective study of THC:CBD oil capsules by Bellnier and colleagues,¹⁶and in a 6-month prospective, open-label study of cannabis by Harotounian and colleagues.¹⁷As well, acute analgesic effects of inhaled plant-based cannabis have been reported in shorter-duration studies (ranging from hours to 2 weeks).¹⁸⁻²¹

While the mechanisms underlying the therapeutic effects of cannabinoids in chronic pain have not yet been fully elucidated, it has been postulated that THC exerts anti-inflammatory and antinociceptive effects through presynaptic CB1 receptors in areas of the central nervous system associated with pain modulation;²²⁻²⁵while CBD exerts analgesic, anti-inflammatory, anticonvulsant, and anxiolytic effects through ionotropic cannabinoid receptors, as well as 5-HT1A receptors and and opioid receptors.²⁶⁻²⁹Importantly, the treatment of chronic pain should focus not only on pain reduction, but also on global measures of functioning and quality of life, as these outcomes have clinically meaningful implications in patients who experience disabling pain and substantial impairment in daily functioning.³⁰In this regard, our finding that measures of pain interference and quality of life improved after one month of treatment with medical cannabis, with sustained effects thereafter, is meaningful as it suggests global improvements in chronic pain disease states.

Nevertheless, it should be noted that not all studies of medical cannabis for chronic pain have reported positive results. For instance, longer-term studies, such as a one-year prospective cohort study by Merlin and colleagues,³¹and a 4-year cohort study by Campbell, et al,¹⁵found no change in pain symptomatology with cannabis use. Part of the discrepancy in results is likely to stem from differences in study methodologies, including duration of treatment and observation periods, patient populations, and sample sizes. Moreover, it must be noted that the studies by Merlin, et al,³¹and Campbell, et al,¹⁵were based on recreational and/or illicit cannabis use, which may have negative effects in relation to quality-controlled, government-regulated medical cannabis.

Finally, there is evidence that CBD and THC have biphasic effects, meaning that there is an optimal dose below and above which these cannabinoids are not as effective.³²˒³³(Editor’s Note: Mark Wallace discusses these effects in PPM’s Side Chat conversation.) As such, it is important to highlight the importance of using cannabis for therapeutic purposes under the guidance of a healthcare practitioner, and obtaining cannabis through regulated, legal channels to maximize therapeutic benefits while minimizing adverse events and issues with tolerability.

The gravitation toward medical cannabis as a therapeutic alternative in pain conditions is partly due to its high safety index. The substance is associated with mild to moderate adverse events, which most patients describe as tolerable,³⁴and there have been no reported fatalities associated with using cannabis alone. In line with the most commonly reported adverse events in the literature,¹¹˒¹³˒³⁵˒³⁶dry mouth, increased appetite, and feeling “high” were the only adverse events in our study that increased in frequency from baseline to Month 1.

Interestingly, a large number of other undesired effects reported at baseline actually decreased in frequency after one month of treatment, supporting the possibility that medical cannabis may be helpful in the management of these symptoms. In patients who also completed Month 3 reports (Phase 2a group), the reported frequencies of dry mouth and suspiciousness decreased, while throat irritation increased from Month 1 to 3, and there were no significant changes in the reported frequencies of any AEs from Month 3 to 6 in patients who completed Month 6 reports (Phase-2b group), suggesting good tolerability and long-term safety. Nonetheless, it is worth noting that – although medical cannabis has a high margin of safety³⁷˒³⁸– precautions must be taken for some vulnerable populations, such as in those with a history of substance abuse, cardiovascular and respiratory disease, and/or anxiety disorders, among others; as well as in patients taking medications that could lead to dangerous drug-drug interactions.³⁹

Study Limitations

The results presented herein should be interpreted in light of some study limitations, including the open-label design of the study, lack of controls, selection/volunteer bias, and recall and expectancy bias. As well, the heterogeneity in dose, THC/CBD ratio, and routes of administration during the study prevented further analysis of dose-related effects with respect to THC and CBD content, as well as the synergistic effects of other cannabinoids, flavonoids, and terpenes, which have been hypothesised to contribute to the analgesic effects of plant-based medical cannabis.⁴⁰

Conclusion

In this larger scale, prospective, open-label study of medical cannabis, we found that treatment was associated with significant improvements in pain symptomatology and quality of life within one month of initiating treatment and that these effects were sustained at three- and six-month follow-ups. The treatment was also found to be tolerable; the only adverse events that increased in frequency were dry mouth, increased appetite, and feeling “high.” Taken together, the findings add to the evidence that, under the care and supervision of a healthcare professional, medical cannabis can be a safe and effective treatment option or adjunct therapy for the management of pain and quality of life in chronic pain patients.

Disclosures: Ramin Safakish, MD, FRCPC, does not have anything to disclose. He did not receive any payment as the form of salary, honoraria or support, consultancy fees or grants. Authors Vahid Salimpour, Sun Young Rosalia Yoon, and Nevetda Gengeswaran were affiliated with, and Bryan Hendin was an employee of, Apollo Applied Research during the time the study was conducted and/or the manuscript was written. Apollo Applied Research is an independent subsidiary of Canopy Growth Corp. Author Gordon Ko was affiliated with Apollo Applied Research at the time the study was conducted/the manuscript was written and has received CME honoraria or support, consultancy fees or grants from the following companies between 2016-2019: Aurora (CanniMed, MedReleaf), Canopy (Mettrum, Tweed, Apollo), Canntrust/Tetra BioPharma; Tilray (CBM talks/clinical advisory boards participation).

This article was originally published November 13, 2020 and most recently updated January 20, 2022.

         Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. _Eur J Pain_. 2006;10(4):287-333.

         Johannes CB, Le TK, Zhou X, et al. The Prevalence of Chronic Pain in United States Adults: Results of an Internet-Based Survey. _J Pain_. 2010;11(11):1230-1239.

         Pitcher MH, Von Korff M, Bushnell MC, Porter L. Prevalence and Profile of High-Impact Chronic Pain in the United States. _J Pain_. 2019;20(2):146-160.

         Goldberg DS, McGee SJ. Pain as a global public health priority. _BMC Public Health_. 2011;11(1):1-5.

         Schopflocher D, Taenzer P, Jovey R. The Prevalence of Chronic Pain in Canada. _Pain Res Manag_. 2011;16(6):445-450.

         Hogan M-E, Taddio A, Katz J, et al. Health utilities in people with chronic pain using a population-level survey and linked health care administrative data. _Pain_. 2017;158(3):408–416.

         Shupler MS, Kramer JK, Cragg JJ, et al. Pan-Canadian Estimates of Chronic Pain Prevalence From 2000 to 2014: A Repeated Cross-Sectional Survey Analysis. _J Pain_. 2019;20(5):557-565.

         Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical Overdose Deaths, United States, 2010. _JAMA_. 2013;309(7):657-659.

         Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. _Pain_. 2004;112(3):372-380.

      Noble M, Treadwell JR, Tregear SJ, et al. Long‐term opioid management for chronic noncancer pain. _Cochrane Database Syst Rev_. 2010;(1).

      Rudd RA, Aleshire N, Zibbel JE, Gladden RM. Increases in drug and opioid overdose deaths – United States, 2000-2014. _MMWR Morb Mortal Wkly Rep_2016;64:1378-1382.

      Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. _JAMA Intern Med_. 2014;174(10):1668-1673.

      Vyas MB, LeBaron VT, Gilson AM. The use of cannabis in response to the opioid crisis: A review of the literature. _Nurs Outlook_. 2018;66(1):56-65.

      Boehnke KF, Scott JR, Litinas E, Sisley S, et al. Pills to Pot: Observational Analyses of Cannabis Substitution Among Medical Cannabis Users With Chronic Pain. _J Pain_. 2019;20(7):830-841.

      Campbell G, Hall WD, Peacock A, et al. Cannabis use, pain and prescription opioid use in people living with chronic non-cancer pain: Findings from a four-year prospective cohort. _Lancet Public Health_. 2018;3(7):e341-e350.

      Bellnier T, Brown GW, Ortega TR. Preliminary evaluation of the efficacy, safety, and costs associated with the treatment of chronic pain with medical cannabis. _Ment Health Clin_. 2018;8(3):110-115.

      Haroutounian S, Ratz Y, Ginosar Y, et al. The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study. _Clin J Pain_. 2016;32(12):1036-1043.

      Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial. _Neurology_. 2007;68(7):515-521.

      Ellis RJ, Toperoff W, Vaida F, et al. Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. _Neuropsychopharmacology._ 2009;34(3):672-680.

      Wilsey B, Marcotte TD, Deutsch R, et al. Low Dose Vaporized Cannabis Significantly Improves Neuropathic Pain. _J Pain Off J Am Pain Soc_. 2013;14(2):136-148.

      Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. _J Pain Off J Am Pain Soc_. 2015;16(7):616-627.

      Piper BJ, DeKeuster RM, Beals ML, et al. Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. _J Psychopharmacol (Oxf)_. 2017;31(5):569-575.

      Fride E, Mechoulam R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur J Pharmacol. 1993 Feb 9;231(2):313-314.

      Tsou K, Brown S, Sañudo-Peña MC, et al. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. _Neuroscience_. 1998;83(2):393-411.

      Walker JM, Huang SM, Strangman NM, et al. Pain modulation by release of the endogenous cannabinoid anandamide. _Proc Natl Acad Sci U S A_. 1999;96(21):12198-12203.

      Wilson-Poe AR, Morgan MM, Aicher SA, Hegarty DM. Distribution of CB1 cannabinoid receptors and their relationship with mu-opioid receptors in the rat periaqueductal gray. _Neuroscience_. 2012;213:191-200.

      Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. _Eur J Pain Lond Engl_. 2016;20(6):936-948.

      Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. _Br J Pharmacol_. 2008;153(2):199-215.

      Resstel LBM, Tavares RF, Lisboa SFS, et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. _Br J Pharmacol_. 2009;156(1):181-188.

      Campbell G, Stockings E, Nielsen S. Understanding the evidence for medical cannabis and cannabis-based medicines for the treatment of chronic non-cancer pain. _Eur Arch Psychiatry Clin Neurosci_. 2019;269(1):135-144.

      Merlin JS, Samet JH, Cheng DM, et al. Marijuana Use and Its Associations With Pain, Opioid Dose, and HIV Viral Suppression Among Persons Living With HIV on Chronic Opioid Therapy. _J Acquir Immune Defic Syndr_. 2019;82(2):195–201.

      Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. _Proc Natl Acad Sci U S A_. 2000;97(17):9561-9566.

      Casey SL, Atwal N, Vaughan CW. Cannabis constituent synergy in a mouse neuropathic pain model. _Pain_. 2017;158(12):2452-2460.

      Bridgeman MB, Abazia DT. Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting. _Pharm Ther_. 2017;42(3):180-188.

      CDC. Multiple causes of death 1999-2014 on CDC WONDER online database 2015. Available at: https://wonder.cdc.gov/mcd.html. Accessed October 2020.

      Aviram J & Samuelly-Leichtag G. Efficacy of cannabis-based medicines for pain management: a systematic review of meta-analysis of randomized controlled trials. _Pain Physician._ 2017;20:755-796.

      MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. _Eur J Intern Med_. 2018;49:12-19.

      Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. _Proc Natl Acad Sci U S A_. 1990;87(5):1932-1936.

      Kahan M, Srivastava A, Spithoff S, Bromley L. Prescribing smoked cannabis for chronic noncancer pain. _Can Fam Physician_. 2014;60(12):1083-1090.

      Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. _Headache_. 2018;58(7):1139-1186.