The current studies that suggest caution regarding the use of cannabinoids for pain have largely been observational studies, and the best example to date regarding substituting cannabis for opioids for any pain, according to Dr Saitz, was a large systematic prospective cohort study in Australia.5 Dr Saitz acknowledged that although that study was well done, it still “has limitations based on its design.”
Dr Boehnke also expressed concerns about the Australian study; he noted that Australia “didn’t have much availability of or access to medical cannabis, so it’s not necessarily a population that’s representative of medical cannabis users.”
Additionally, as the CEO/CSO of Tetra Bio-Pharma, Guy Chamberland, MSc, PhD, noted in an email to Cancer Therapy Advisor, while the reports on the findings from the Australian study were “very attention-grabbing, the study did not fit the bill of a rigorous, double-blind, placebo-based randomized controlled trial.”
“The lack of details regarding methodology and formulations of the cannabinoid being tested [in that study] calls into question the validity of their conclusions,” Dr Chamberland added. “The study did not specify the formulation of the cannabinol, how it was obtained — for example, illegal oils often have zero CBD and/or great variances in the amount of THC, and even when there is THC present, it is often below clinically significant levels. Nor [did the study authors] mention the dosing methodology.”
Tetra is currently seeking to answer whether cannabis could be at least as effective as fentanyl in helping patients manage cancer pain. Its trial (ClinicalTrials.org Identifier: NCT03564548), dubbed “Inhaled Cannabis Versus Fentanyl Buccal Tablets for Management of Breakthrough Pain in Cancer Patients”, is examining PPP001, an investigational “pellet” made from natural dried cannabis that can be smoked or vaporized.
Other preliminary trials comparing opioids to plant-based botanicals for pain management are already under way, including a phase 3 study examining cannabis compared with oxycodone for pain that is being conducted by the University of Colorado (ClinicalTrials.gov Identifier: NCT02892591).
Furthermore, Tetra is seeking to determine whether smoked cannabis (specifically, the company’s proprietary strain) improves health-related quality of life (HRQoL) in patients with cancer (ClinicalTrials.org Identifier: NCT03339622). The company is also looking at the efficacy and safety of cannabis oil, PPP005, in the treatment of chronic pain (ClinicalTrials.org Identifier: NCT03337503), and plans to test the safety and efficacy of this product in combination with radiation therapy for patients experiencing cancer pain (ClinicalTrials.org Identifier: NCT03763851).
On February 4, 2018, Tetra announced it enrolled 946 patients in its phase 3 trial of PPP001 in Montreal, Québec, at Santé Cannabis. The trial will look at pain, but it will also look at how “cannabis has been shown to help patients beyond the immediate benefit of pain relief.”6
However, almost exactly a year later, on February 5, 2019, Tetra released another statement announcing it was temporarily suspending its phase 3 clinical program on PPP001 as a result of the detection of 3 mycotoxins in the lot of the investigational drug used for the clinical trials. As a result of the discovery of these impurities, Tetra said there will now be a “6-month delay in the submission of the Canadian New Drug Submission or Drug Identification Number (DIN) application for PPP001.”7
Depending on the findings of all of these trials, the use of cannabis to reduce the reliance on opioids for pain may become increasingly viable. However, as Dr Chamberland acknowledged, no scientific journals have published data on PPP001 at this time.
Dr Boehnke also pointed out that studies that do examine cannabis substitution for opioids have their own limitations. “They are not placebo-controlled, are often asking people about their past behaviors or medication use changes (recall bias), and may not be representative of the population as a whole because they are often conducted with dispensaries, which may not capture the full range of cannabis users. So there are limitations on all sides,” he said.
And while there are few trial results yet that either directly compare cannabis and opioids or that examine whether cannabis is an effective substitute, said Dr Boehnke, “there are numerous, consistent reports from all over the [United States], Canada, and Israel that some people are successfully able to reduce their opioid consumption after adding cannabis to their treatment regimen, or directly substitute cannabis for opioids. This isn’t quite the same thing as using cannabis for treating opioid use disorder, but it is suggestive that this may be possible.”
Dr Boehnke agreed with the JAMA assessment that the existing evidence on cannabis is marred by methodological flaws. “I would add that the dosing in clinical studies is also unrepresentative of the products that medical cannabis patients can obtain, and is also much more stringent, so patients in such trials don’t have the ability to tweak their dosing to find a regimen that works for them.”
Added Dr Boehnke, “As such, the policy is way ahead of the science, as the authors rightly note.”
At the same time, he also pointed out that the JAMA authors appear to be viewing cannabis more through the lens of substance abuse — a perspective, he noted, that is valuable to consider, but perhaps does not adequately capture all relevant viewpoints on the topic.
A separate 2018 study suggested that when opioids and cannabis were administered together in subtherapeutic doses, the synergy of the 2 medications together reduced pain, which the study authors said demonstrated the potential “opioid-sparing effects of cannabis.”8
And, there is emerging evidence that among illicit drug users — those who may arguably be at a higher risk of opioid use disorder — regular use of cannabis was associated with approximately 21% greater odds of retention in opioid-abuse treatment programs compared with those in the study who engaged in less frequent consumption of cannabis.9
On February 6, 2019, the FDA issued a final guidance on acceptable products for opioid use disorder titled, “Opioid Use Disorder: Developing Buprenorphine Depot Products for Treatment.”10 The guidance, which centered on communication about the development of depot buprenorphine products for medication-assisted treatment (MAT), “is one of the many steps we’re taking to help advance the development of new treatments for opioid use disorder, and promote novel formulations or delivery mechanisms of existing drugs to better tailor available medicines to individuals’ needs,” FDA Commissioner Scott Gottlieb, MD, stated in a press release. Within that guidance, there was no mention of cannabis.
- New York State Department of Health. New York State Department of Health announces opioid replacement now a qualifying condition for medical marijuana [press release]. Published July 12, 2018. Accessed February 4, 2019.
- Humphreys K, Saitz R. Should physicians recommend replacing opioids with cannabis? [published online February 1, 2019]. JAMA Netw Open. doi: 10.1001/jama.2019.0077
- National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington (DC): National Academies Press; 2017.
- Boehnke KF, Gangopadhyay S, Clauw DJ, and Haffajee RL. Qualifying conditions of medical cannabis license holders in the United States. Health Aff (Millwood). 2019;38(2):295-302.
- Campbell G, Hall WD, Peacock A, et al. Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study. Lancet Public Health. 2018;3(7):e341-e350.
- Tetra Bio-Pharma receives Health Canada phase 3 clinical trial approval for smokable dried cannabis prescription drug [press release]. Published February 4, 2018. Accessed February 4, 2019.
- Tetra Bio-Pharma redefines quality standards for pharmaceutical grade cannabis-derived products [press release]. https://tetrabiopharma.com/investors/press-releases/press-release-details/2019/Tetra-Bio-Pharma-Redefines-Quality-Standards-for-Pharmaceutical-Grade-Cannabis-Derived-Products/default.aspx. Published February 5, 2019. Accessed February 5, 2019.
- Cooper ZD, Bedi G, Ramesh D, Balter R, Comer SD, Haney M. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology. 2018;43(10):2046-2055.
- Socías ME, Wood E, Lake S, et al. High-intensity cannabis use is associated with retention in opioid agonist treatment: a longitudinal analysis. Addiction.2018;113(12):2250-2258.
- US Food and Drug Administration. FDA in Brief: FDA finalizes new policy to encourage widespread innovation and development of new buprenorphine treatments for opioid use disorder [press release]. Published February 6, 2019. Accessed February 6, 2019.