Cannabis has been used in health care for millennia, and its use has been well documented, albeit never definitively integrated into clinical practice. Recent societal changes and the increasing acceptance and availability of cannabis have reignited the medical and public debate around its role in controlling cancer pain, but even after all this time, the evidence of its benefits is still inconclusive, according to Paul Farquhar-Smith, PhD, MA, MB, BChir, FRCA, consultant in pain management and anesthetics and cancer pain specialist at the Royal Marsden NHS Foundation Trust in London.
“The bottom line is, cannabinoids may be beneficial, but there is a potential for side effects,” he said at the 2018 Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) Annual Meeting in Vienna.1
“There are typically two schools of thought in regard to using cannabis for cancer pain: ‘Danger: Do Not Use!’ or ‘Keep Calm and Give it a Go,’” he said. “You get caught between these two ideas: should we avoid them because of side effects, or could they possibly help?”
According to Dr. Farquhar-Smith, the jury is still out. When asked if he thinks cannabinoids can help control cancer pain, he responds with an emphatic “Possibly yes, possibly no, definite maybe.”
Evidence in Humans
One meta-analysis of 119 patients in 9 pain trials, 5 of which were exclusive to cancer pain, found that tetrahydrocannabinol (THC) had an effect approximately equivalent to codeine, but dose-related and dose-limiting central nervous system (CNS) adverse events were common.2
A more recent meta-analysis of 11 randomized controlled trials in chronic neuropathic pain demonstrated an insignificant overall change in pain scores, resulting in a weak recommendation for the use of cannabinoids.3
What About Cancer Pain?
A meta-analysis of the effects of cannabinoids on cancer pain in 43 randomized controlled trials revealed a beneficial effect in favor of cannabinoids, but patients were highly likely to experience significant CNS and gastrointestinal side effects.4 When THC was given at a dose of 20 mg vs placebo, “alarming adverse reactions were observed…. In this study, cannabinoids were associated with a large and beneficial effect, but that benefit was tempered by a high incidence of side effects,” said Dr. Farquhar-Smith.
In another study of individuals who had refractory cancer pain and were already on opiates, 117 patients were randomized 1:1:1 to nabiximols (a combination of THC and cannabidiol), THC alone, or placebo.5 The investigators observed a modest improvement in pain with nabiximols but no significant difference with THC alone.
The bottom line is, cannabinoids may be beneficial, but there is a potential for side effects.— Paul Farquhar-Smith, PhD, MA, MB, BChir, FRCA
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They also observed a 30% reduction from baseline pain in 43% of patients, vs a 23% reduction in controls. “These results are not great but not bad,” he said. “As far as pain medicine is concerned, we’ll take that.” There was, however, an increase in side effects. Cannabinoid use in this study led to an increase in nausea and vomiting: 85% vs 75% in the placebo arm.
Another study randomized almost 300 patients to low-, medium-, and high-dose spray nabiximols for a period of 5 weeks.6 They found no significant benefit from the drug but did report that the low and medium doses provided more of an analgesic effect in terms of average daily pain, with no difference in side effects.
A study of almost 400 patients looked at self-titration of nabiximols over a period of 2 weeks.7 Investigators observed a 10.7% improvement in pain scores, compared to 4.5% in the control group, though this was not a significant difference. A subgroup analysis revealed that quality of life was improved in some patients, with a trend toward more improvement in patients recruited from the United States.
NOTE TO READER
In the four articles addressing cannabinoids in cancer care in this issue of The ASCO Post, conclusions may differ on the efficacy of cannabinoids in controlling chemotherapy-related nausea and vomiting and other effects of cancer and its treatment. This may be due in part to differences in the evidence reviewed, differences in individual perspectives, differences in the characteristics of cannabis or cannabinoid exposure (ie, oral cannabinoids, marijuana plant, other formulations), among other differences.
These articles are not intended to accept or reject the associated risks and benefits of cannabinoids in cancer care. Rather, these articles are intended to call attention to the need for more research on the use of medical marijuana in oncology. Marijuana is legal in many states and patients may ask their clinicians about the drug’s role in their care. Oncologists need to be able to provide informed guidance and evidence-based care for their patients with cancer.
Another study looked at two randomized controlled trials in patients with refractory cancer pain.8 The first study compared nabiximols to placebo in about 400 patients; about one-third of patients in the nabiximols group withdrew from the study due to side effects, and the primary study outcome was not met. The second randomized controlled trial utilized an enriched enrollment design in about 200 patients; those who exhibited a 15% improvement in their pain with the use of nabiximols for 2 weeks went on to be randomized to the drug vs placebo. After randomization, mean average pain scores were not significantly improved, and a high instance of adverse events occurred compared to placebo. There was again, however, a favorable treatment effect for nabiximols in patients from the United States.
According to Dr. Farquhar-Smith, another problem lies in the association between cannabinoids and psychotic episodes. A historical cohort study of 50,000 Swedish conscripts looked at the relationship between drug use and psychiatric admissions between 1970 and 1996.9 The study revealed a significant, dose-dependent, increased risk of developing schizophrenia with cannabis use, raising questions about its safety when used over the long term.
‘Underwhelming’ Data
“The problem is, these are the available data,” said Dr. Farquhar-Smith. “Meta-analyses demonstrate a side-effect issue, but if you look at the papers individually, they aren’t terribly overwhelming. In fact, they’re pretty underwhelming, and it makes it difficult to know where we stand clinically.” He noted a caveat, however, that many of the studies conducted have been in patients with refractory pain, already on high doses of opioids and exhibiting complex problems.
He said the pros and cons are slightly imbalanced, but addressing certain factors—such as long-term issues, CNS side effects, legal issues, and the argument over herbal vs synthetic cannabis—“can perhaps readdress the balance.” ■
DISCLOSURE: Dr. Farquhar-Smith reported no conflicts of interest.
REFERENCES
2. Campbell FA, Tramèr MR, Carroll D, et al: Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 323:13-16, 2001.
3. Meng H, Johnston B, Englesakis M, et al: Selective cannabinoids for chronic neuropathic pain: A systematic review and meta-analysis. Anesth Analg 125:1638-1652, 2017.
4. Aviram J, Samuelly-Leichtag G: Efficacy of cannabis-based medicines for pain management: A systematic review and meta-analysis of randomized controlled trials. Pain Physician 20:E755-E796, 2017.
5. Johnson JR, Burnell-Nugent M, Lossignol D, et al: Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 39:167-179, 2010.
6. Portenoy RK, Ganae-Motan ED, Allende S, et al: Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial. J Pain 13:438-449, 2012.
7. Lichtman AH, Lux EA, McQuade R, et al: Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain. J Pain Symptom Manage 55:179-188.e1, 2018.
8. Fallon MT, Albert Lux E, McQuade R, et al: Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: Two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain 11:119-133, 2017.
9. Zammit S, Allebeck P, Andreasson S, et al: Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: Historical cohort study. BMJ 325:1199, 2002.
