Chronic pain is associated with enormous personal, social, and economic burden and is estimated to affect one in five people (Yong, Mullins, and Bhattacharyya 2022). In cancer patients, prevalence of pain was reported by: 39.3% of patients after curative therapy, 55% of patients on anticancer treatment, 66.4% of patients with advanced disease, and 50.7% of patients with all stages of cancer (Perez et al. 2016; Haumann, Joosten, and van den Beuken-van Everdingen 2017). However, despite significant advancements in the medical and pharmaceutical fields, pharmacological options to treat pain remain limited and new therapeutical approaches are welcomed.
Opioids are important medications in our arsenal to combat pain; however, they are not without downsides. Indeed, opioids are associated with a higher risk of side effects, such as constipation, nausea, falls, confusion, hypogonadism, opioid-induced hyperalgesia, respiratory depression, sedation and use disorder (Busse et al. 2017; Volkow and McLellan 2016). Opioids have been associated with a 5.5% risk of opioid use disorder, even at very low doses (Busse et al. 2017). They are also linked to non-fatal and fatal overdose, risk of overdose and harm increasing at higher dosages of opioids (Busse et al. 2017). Another problem with opioids is the development of opioid tolerance, i.e. loss of efficacy over time, which results in escalating doses (Volkow and McLellan 2016).
The many inconveniences associated with opioid therapy call for safer treatment approaches. One mitigating strategy for decreasing opioid use is combination therapies, with the objective to maximize analgesia while using a lower dose of opioids and resulting in an improved side effect profile. Cannabis is a promising candidate for combination therapy with opioids as it is one of the least physiologically toxic analgesics, with a very high therapeutic index (Fitzgerald, Bronstein, and Newquist 2013), it is not associated with respiratory depression and could therefore provide a safe alternative for patients living with chronic pain. Additionally, the benefit of cannabinoids in chronic pain syndrome has been increasingly recognized in the last decades (National Academies of Sciences 2017).
Cannabinoid Modulation of Pain
Cannabinoids have a unique mechanism of action that encompasses several cellular targets. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) bind to G-protein-coupled cannabinoid receptors, CB1 and CB2, within the endocannabinoid system, which plays a critical role in suppressing inflammation, neuronal sensitization, and pain by acting on targets within the peripheral and central nervous systems (Vukovic et al. 2018). CBD is also an agonist of the transient receptor potential vanilloid 1 (TPRV1) which may have an anti-inflammatory and pain-relieving effect (White 2019).
In humans, cannabinoids have been shown to relieve acute and chronic pain often refractory to conventional analgesics. A systematic review investigating the efficacy of various cannabinoid products at treating pain in a total of 2,454 subjects with chronic pain showed improvement in pain measures with the use of cannabinoids compared with placebo (Whiting et al. 2015). Later, a meta-analysis confirmed that cannabinoids may offer benefit in pain management (Yanes et al. 2019).
Some patients are already reporting benefits from the use of cannabis. In a survey conducted in a sample of American patients using cannabis for medical purposes, 97% of respondents reported using cannabis primarily for the management of chronic pain. They reported a 64% relative decrease in average pain. They also reported benefits from the management of other problems including relief from stress/anxiety (50% of respondents), relief from insomnia (45%), improved appetite (12%), decreased nausea (10%), and relief from depression (7%). Some respondents also declared that cannabis helped them to decrease or to discontinue other medications including opioids and benzodiazepines. Most patients (71%) reported no adverse effects, and no serious adverse effects were reported (Webb and Webb 2014).
Capacity of Cannabinoids to Reduce Opioid Use
Human and animal data suggest that opioids and cannabinoids may offer synergistic analgesic effects when used concomitantly, i.e., cannabinoids have the potential to enhance the antinociceptive property of opioids. A meta-analysis of preclinical data found that, when combined with THC, the median effective dose (ED50) for morphine is 3.6 times lower than morphine alone (Nielsen et al. 2017).
In humans, cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (i.e., an opioid-sparing effect). Data from retrospective, observational and open-label studies suggest that cannabinoids have the potential to reduce opioid dosage, or even to fully substitute opioid analgesics (Nielsen et al. 2017). For instance, in a large (N = 600) observational study of opioid-using patients given medical cannabis it was observed that over a six-month period, 26% of patients had stopped using opioids, and an additional 55% had reduced their average opioid dose by 30% (Rod 2019). In another study including 186 patients with chronic back pain certified for medical cannabis use and taking opioids, a significant decrease in morphine equivalent dose in milligrams per day was found at 6 months as well as a significant reduction in pain intensity at 3, 6 and 9 months (Greis et al. 2022).
Interestingly, a study using the Medicaid program data in the United States revealed that states where cannabis is legalized had lower rates of opioid prescribing (Bradford et al. 2018). Furthermore, compared with states without medical cannabis laws, states with such laws had a 24.8% lower mean annual opioid overdose mortality rate (Bachhuber et al. 2014).
What is QIXLEEF™?
In Canada, a recent survey conducted by Health Canada revealed that 14% of Canadians indicated that they used cannabis for medical purposes in the past 12 months (Health Canada 2021). The majority of people reported that cannabis use helped decrease their use of other medications (52%). However, the cannabis that they used is rarely standardized and the THC and CBD potency may vary between different products and even between the different batches of a same product and therefore, the efficacy of these cannabis products may vary.
Furthermore, a recent survey that took place in the United States (Philpot, Ebbert, and Hurt 2019) revealed that physicians reported a lack of information about cannabis and its benefit and risk profile, lack of robust clinical trials on cannabis efficacy, uncertainty resulting from differences between cannabis products, insufficient information regarding potential interactions, lack of long-term safety data, etc. Therefore, this perceived lack of information about cannabis appeared to be a barrier to its use with patients as physicians have the responsibility to prescribe clinical treatments that are based on robust scientific information.
One solution to batch-to-batch variability and lack of clinical information may be pharmaceutical-grade cannabis, like QIXLEEF™, a cannabis-based investigational new drug developed by Tetra Bio-Pharma. Indeed, pharmaceutical-grade cannabis products are products that meet the requirements of drug development. Their molecular profile is well defined, and there is very little variability from batch-to-batch. To receive approval from regulatory authorities, they must demonstrate their efficacy and safety through well-conducted clinical trials. Furthermore, their pharmacokinetics and toxicity profiles are well characterized, and the therapeutic doses are also identified (Koltai, Poulin, and Namdar 2019). Thus, a lot of information is available on these products, which meets the need for information reported by doctors. These products could also address the issue of reimbursement because, since they meet the criteria of a drug, they could be reimbursed by public and/or private insurance schemes. This is what QIXLEEF™ could offer to patients.
More precisely, QIXLEEF™ contains dried, ground cannabis with standardized levels of THC and CBD. QIXLEEF™ is intended for use in an inhalation device, the Mighty® Medic vaporizer.
Tetra Bio-Pharma has completed two phase 1 clinical trials in healthy volunteers to characterize the pharmacokinetics, pharmacodynamics, and safety profile of QIXLEEF™ and is currently conducting two U.S. FDA-authorized phase 2 clinical trials in the United States in advanced cancer pain and breakthrough cancer pain. If QIXLEEF™ demonstrates clinical efficacy for pain management, a long-awaited new alternative to opioids could be available for patients and could contribute to improving their quality of life.
About the author
Dr. Emilie Thomas, PhD, cumulates 14 years’ experience in clinical research with expertise in neuropsychology, psychopharmacology, and overall drug development. She completed a master in pharmaceutical sciences and a PhD in neuropsychology. Before joining Tetra Bio-Pharma, she worked in neurology and psychiatry departments where she conducted clinical research in Alzheimer and posttraumatic stress disorder (PTSD) studies. Her work helped to build one of the largest cohorts of Alzheimer’s patients in Canada and to develop a new approach to treat PTSD. She joined Tetra 2019 where she is contributing to the clinical development of QIXLEEF™ for the management of pain.
References
Bachhuber, M. A., B. Saloner, C. O. Cunningham, and C. L. Barry. 2014. 'Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010', JAMA Intern Med, 174: 1668-73.
Bradford, A. C., W. D. Bradford, A. Abraham, and G. Bagwell Adams. 2018. 'Association Between US State Medical Cannabis Laws and Opioid Prescribing in the Medicare Part D Population', JAMA Intern Med, 178: 667-72.
Busse, J. W., S. Craigie, D. N. Juurlink, D. N. Buckley, L. Wang, R. J. Couban, T. Agoritsas, E. A. Akl, A. Carrasco-Labra, L. Cooper, C. Cull, B. R. da Costa, J. W. Frank, G. Grant, A. Iorio, N. Persaud, S. Stern, P. Tugwell, P. O. Vandvik, and G. H. Guyatt. 2017. 'Guideline for opioid therapy and chronic noncancer pain', CMAJ, 189: E659-E66.
Fitzgerald, K. T., A. C. Bronstein, and K. L. Newquist. 2013. 'Marijuana poisoning', Top Companion Anim Med, 28: 8-12.
Greis, Ari, Bryan Renslo, Adrianne R. Wilson-Poe, Conan Liu, Anjithaa Radakrishnan, and Asif M. Ilyas. 2022. 'Medical Cannabis Use Reduces Opioid Prescriptions in Patients With Chronic Back Pain', Cureus.
Haumann, Johan, E. Bert A. Joosten, and Marieke H. J. van den Beuken-van Everdingen. 2017. 'Pain prevalence in cancer patients: Status quo or opportunities for improvement?', Current Opinion in Supportive and Palliative Care, 11: 99-104.
Health Canada. 2021. 'Canadian Cannabis Survey 2021: Summary'. https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/research-data/canadian-cannabis-survey-2021-summary.html.
Koltai, H., P. Poulin, and D. Namdar. 2019. 'Promoting cannabis products to pharmaceutical drugs', Eur J Pharm Sci, 132: 118-20.
National Academies of Sciences, Engineering, and Medicine. 2017. "The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research." In. Washington, D.C.: National Academies Press.
Nielsen, Suzanne, Pamela Sabioni, Jose M. Trigo, Mark A. Ware, Brigid D. Betz-Stablein, Bridin Murnion, Nicholas Lintzeris, Kok Eng Khor, Michael Farrell, Andrew Smith, and Bernard Le Foll. 2017. 'Opioid-sparing effect of cannabinoids: A systematic review and meta-analysis', Neuropsychopharmacology, 42: 1752-65.
Perez, Jordi, Sara Olivier, Emmanouil Rampakakis, Manuel Borod, and Yoram Shir. 2016. 'The McGill University Health Centre Cancer Pain Clinic: A retrospective analysis of an interdisciplinary approach to cancer pain management', Pain Research and Management.
Philpot, L. M., J. O. Ebbert, and R. T. Hurt. 2019. 'A survey of the attitudes, beliefs and knowledge about medical cannabis among primary care providers', BMC Fam Pract, 20: 17.
Rod, Kevin. 2019. 'A Pilot Study of a Medical Cannabis - Opioid Reduction Program', American Journal of Psychiatry and Neuroscience, 7: 74-77.
Volkow, N. D., and A. T. McLellan. 2016. 'Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies', N Engl J Med, 374: 1253-63.
Vukovic, Sonja, Dragana Srebro, Katarina Savic Vujovic, edomir Vuetic, and Milica Prostran. 2018. 'Cannabinoids and pain: New insights from old molecules', Frontiers in Pharmacology, 9: 1259-59.
Webb, C. W., and S. M. Webb. 2014. 'Therapeutic benefits of cannabis: a patient survey', Hawaii J Med Public Health, 73: 109-11.
White, C. Michael. 2019. "A Review of Human Studies Assessing Cannabidiol's (CBD) Therapeutic Actions and Potential." In, 923-34. Blackwell Publishing Inc.
Whiting, Penny F., Robert F. Wolff, Sohan Deshpande, Marcello Di Nisio, Steven Duffy, Adrian V. Hernandez, J. Christiaan Keurentjes, Shona Lang, Kate Misso, Steve Ryder, Simone Schmidlkofer, Marie Westwood, and Jos Kleijnen. 2015. 'Cannabinoids for medical use: A systematic review and meta-analysis', JAMA - Journal of the American Medical Association, 313: 2456-73.
Yanes, Julio A., Zach E. McKinnell, Meredith A. Reid, Jessica N. Busler, Jesse S. Michel, Melissa M. Pangelinan, Matthew T. Sutherland, Jarred W. Younger, Raul Gonzalez, and Jennifer L. Robinson. 2019. 'Effects of cannabinoid administration for pain: A meta-analysis and meta-regression', Experimental and clinical psychopharmacology.
Yong, R. J., P. M. Mullins, and N. Bhattacharyya. 2022. 'Prevalence of chronic pain among adults in the United States', Pain, 163: e328-e32.