CRx MAGAZINE

Winter 2021

The Cancer Pain Conundrum

Evidence is limited for the role of cannabis, but should clinicians recommend it to their patients suffering from cancer pain?

Opioids play a critical role in managing cancer-associated pain, but they’re highly addictive and they don’t always provide sufficient pain relief for cancer patients. Many patients therefore turn to cannabis or cannabis-derived products to help manage their pain, using them either as stand-alone treatments or as an adjuvant therapy to opioids. But does research support cannabis use for this purpose? The evidence is mixed, and some studies suggest there may indeed be benefits for cancer pain—but there’s also reason for caution.

How Much Research Is There?
There’s a relatively strong body of research on cannabis for the treatment of chronic pain generally, according to Eloise Theisen, RN, MSN, president of the American Cannabis Nurses Association and cofounder of Radicle Health, a cannabis education and advocacy organization. However, much of this research has focused on neuropathic pain in multiple sclerosis and spinal cord injuries, and comparatively few studies have examined pain in the cancer context. Among the studies that exist for cancer, many have small sample sizes, and study design is also an issue. “We have animal studies and some clinical human studies,” Theisen says, but there’s “a lack of randomized controlled trials, which are considered to be the gold standard.”

A further complicating factor in the research on cannabis and cancer pain is that most of the existing studies on this topic have relied on products that do not match those cancer patients actually use in practice. According to Hance Clarke, MD, PhD, FRCPC, an associate professor of anesthesia at the University of Toronto and author of a recent review article on cannabis and pain,1 the products that have been studied most extensively are pharmaceutical-grade cannabis isolates, such as nabiximols (an extract containing THC and CBD in a precise 1:1 ratio), nabilone (synthetic THC), and dronabinol (also synthetic THC). However, cancer patients outside of the research context are much more likely to use dispensary cannabis and non–pharmaceutical-grade plant-based extracts. “We’re kind of stuck without enough evidence on the products that people are currently using,” Clarke says. This is important, he adds, because patients may respond quite differently to a dispensary product than to a pharmaceutical product.

Recent Reviews: What the Research Shows
With those caveats in place, what does the available evidence suggest about the effectiveness of cannabis for cancer pain?

In 2017, the National Academies of Science, Engineering, and Medicine published a comprehensive and influential report on the health effects of cannabis and cannabinoids and concluded that there’s “substantial” evidence that cannabis is a modestly effective treatment for chronic pain.2 That conclusion in turn was based largely on the findings of a previous systematic review conducted in 2015 by Whiting and colleagues.3 The Whiting review incorporated 28 different randomized trials that collectively comprised 2,454 patients. A few of the trials included in the Whiting review focused on cancer pain or chemotherapy-induced pain, but most looked at neuropathic pain generally or at pain stemming from diseases other than cancer (such as rheumatoid arthritis, fibromyalgia, or HIV). There was significant variety in the cannabis products tested in the various trials: Seventeen trials evaluated nabiximols, five evaluated smoked or whole-plant cannabis, and the other trials evaluated still other cannabis products. Thus, the conclusions of the Whiting review and the National Academies report on the effectiveness of cannabis for pain were not specific to a particular type of product, nor were they specific to a particular form of chronic pain.

While the Whiting review indicated that cannabis is effective for chronic pain generally, two other recent reviews both suggest that the efficacy may not hold in the cancer context. A 2019 review by Häuser and colleagues included five randomized controlled trials of cancer patients who were suffering moderate to severe cancer-related pain despite opioid therapy. This review noted that the quality of evidence was very low, but it concluded that neither THC nor nabiximols were more effective at reducing cancer pain than was a placebo.4 Similarly, a 2020 systematic review and meta-analysis by Boland and colleagues included six randomized trials, all of them involving patients with advanced cancer and all with a low risk of bias. This review likewise concluded that adding cannabis-based therapy to opioid therapy has no benefit over placebo in terms of pain relief.5

A few surveys have found that patients report needing lower doses of opioids to manage chronic pain if they are also taking cannabis.6,7 Findings such as these provide evidence that using cannabinoids with opioids can have a synergistic effect. But again, the evidence on this point is limited—and complicated. One randomized controlled trial—this one of cancer patients in particular—found that although cannabinoid therapy was effective for pain relief, participants receiving cannabinoids didn’t reduce their opioid use.8

Are the Benefits of Cannabis Greater in the United States?
Although neither the Häuser nor the Boland reviews found a benefit of cannabis for cancer pain overall, two of the trials that were included in both reviews deserve special mention. This is because both trials found that cannabis (specifically, nabiximols) was effective for pain in certain subgroups of cancer patients—in particular, patients living in the United States as opposed to other countries.

One of the studies to find a country-specific effect was a 2018 report published by Lichtman and colleagues in the Journal of Pain Symptom Management. The Lichtman study was a randomized double-blind Phase III trial that evaluated the effectiveness of nabiximols as an add-on therapy in 397 patients with advanced cancer. Participants were randomized to either nabiximols or placebo, then allowed to titrate their own medication doses over a two-week period. After the initial titration period, participants then continued receiving the titrated dose for an additional three weeks.9

In the Lichtman study, nabiximols failed to demonstrate a benefit over placebo for pain relief in the initial analysis of the entire study population. However, in the per-protocol analysis of participants who were fully compliant with the treatment protocols, those randomized to nabiximols reported a median of 15.5% improvement in pain over baseline, compared with just 6.3% improvement over baseline in the placebo group. Further analysis then revealed that the treatment benefit from nabiximols was restricted to patients in the United States; it didn’t extend to patients elsewhere in the world. According to the study authors, this may be due to the fact that US patients were on lower doses of opioids to start with, or to the fact that the US cohort had a different distribution of types of cancer pain than did the other patients studied.9

The other study to find a country-specific effect was published by Fallon and colleagues in the British Journal of Pain in 2017. The Fallon study actually was a report on a pair of randomized placebo-controlled trials. As in the Lichtman study, both of the Fallon trials evaluated nabiximols as an add-on to opioids in patients with advanced cancer. In the first of the two Fallon trials, which included 399 patients, participants were randomized to either nabiximols or placebo. After a two-week titration period, all participants continued for an additional three-week treatment period at the titrated dose. In the second trial, which included 406 patients, all participants underwent a two-week titration period with nabiximols, and those who reported improvement in pain greater than 15% were then randomized to receive either nabiximols or placebo for an additional five-week treatment period. All patients in both trials reported pain scores greater than 4 on a 10-point scale at baseline.10

Neither of the Fallon trials found that nabiximols had any advantage over placebo in reducing participants’ self-reported pain scores overall. But further analysis once again demonstrated that participants in the United States experienced a statistically significant benefit even while their European counterparts didn’t. The researchers concluded that there’s a need for further exploration of the differences between cancer patients in the United States and those elsewhere in the world.10

Prospective Findings from Israel
An additional study that has attracted attention is a 2018 report from Israel. The Israeli study was a prospective analysis, not a randomized controlled trial, but it’s significant because it had a relatively large sample size (3,619 participants). This study examined the effects of cannabis in cancer patients with a range of different types of cancers, including breast, lung, pancreatic, and colorectal. All participants received one or more of 16 different strains of medical cannabis over the course of the six-month study period, and the researchers assessed both pain and quality of life at the conclusion of the study.11

At baseline, 52.9% of patients in the Israeli study reported pain at an intensity of between 8 and 10 on a 10-point scale, whereas only 4.6% reported pain of this intensity at the conclusion of the study. Thirty-six percent of participants were able to cease opioid use altogether during the study period, and an additional 10% reported decreasing their opioid dosage (though another 10% reported increasing their opioid use during the study period). With respect to quality of life, 69.5% of patients reported good quality of life at the conclusion of the study, up from just 18.7% who reported good quality of life at baseline.11

A major caveat with the Israeli study is that it had no control group. An additional weakness is that almost 25% of the participants died and an additional 20% either stopped treatment or switched to a different cannabis supplier during the course of the six-month treatment period. Thus, at six months, researchers were only able to assess quality of life in 1,165 of the participants who remained, and pain in only 1,144 of the participants.11

To Recommend or Not to Recommend?
For clinicians, the conundrum remains: Their cancer patients are in pain. But given the limited body of research to date and the conflicting evidence in the data on cannabis for cancer pain, should clinicians recommend cannabis products?

For Theisen, the answer is a clear yes. “I’d much rather start with cannabis,” she says. “Opioids have so many side effects, and now there’s so much stigma around them, and restrictions.”

Clarke agrees that if there were better regulation of cannabis products in the United States, he would favor more clinical experimentation with cannabis for cancer care. “There are so many of these potential benefits in the cancer patient that if you had a reliable product, you could certainly start to use it for cancer pain,” he says. In places such as Canada, where Clarke practices and where cannabis products are much more standardized, “it’s absolutely worthwhile for physicians to start to dip their toes into the water to see how this is going to play out.”

Others, however, are substantially more cautious. “I don’t think anybody would be concerned if a patient with terminal cancer who had pain would want to use or try cannabis. I don’t think anybody would argue with [the] right to try; give them what they want, that’s fine,” says Ken Finn, MD, a pain medicine physician in private practice in Colorado Springs, Colorado, and editor of Cannabis in Medicine: An Evidence-Based Approach. But he remains concerned that the pharmaceutical cannabis products on which most studies have been conducted haven’t proven effective, and there’s simply no literature available on the dispensary cannabis products that most patients end up using. Meanwhile, Finn is concerned about putting patients at risk of cannabis side effects. “The American Heart Association came out with a position paper in August [of 2020],12 saying that the use of cannabinoids might put you at risk for acute myocardial infarction, stroke, sudden death, arrhythmia,” he says. “It’s not necessarily benign.”

All sides agree that the lack of regulation surrounding cannabis products in the United States is a significant concern. “Dispensary cannabis […] is poorly regulated, poorly tested, frequently contaminated,” Finn says. Indeed, numerous recalls of cannabis have occurred in various states in recent years because the products were contaminated with arsenic, Viagra, and mold, among other substances.13-16 There are also serious issues with mislabeling. “What’s in the bottle may not be what’s on the label,” he adds.

Clarke agrees that there’s an urgent need for regulation. “We need […] third-party testing to know that if I send my patient for this product, it’s actually the product they are consuming, and that what’s on the label is actually in the bottle.”

Guiding Cancer Patients Who Want to Try Cannabis
Even in the absence of needed regulation, the reality is that cancer patients want to use cannabis. For this reason alone, Clarke says, it’s critical that clinicians be prepared to guide patients in their use. “People are going to use it anyway” if they’re in a state where they can get access, he says. “If I’m a physician, and my patient asks me for help, and I say, ‘I don’t know anything about it, I can’t help you,’ [the patient] is now at the mercy of whatever dispensary they walk into and sometimes whatever 16- or 18- or 19-year-old is behind the counter.” To help keep patients as safe as possible, Clarke recommends that clinicians take a CME course on cannabis, familiarize themselves with the cannabis industry and what’s being sold to patients, and be able to offer recommendations to patients who want to experiment.

As for what products to recommend to a cancer patient who wants to try cannabis, it may depend on what type of pain the patient is experiencing. According to Clarke, some studies suggest that THC has a better effect than CBD for neuropathic pain, but when it comes to myofascial pain or pain stemming from inflammation, CBD may be more promising.

Theisen, for her part, finds that isolated cannabinoids work in certain cases, but she generally prefers to recommend whole-plant cannabis products. This recommendation is based on anecdotal evidence rather than published data, but in Theisen’s own experience, patients are generally able to achieve results with lower doses when using whole-plant products than when using isolates.

As for the best route of administration, Theisen’s go-to is tinctures, but she finds that inhalation can be the most effective in some cases. “It’s very counterintuitive for the medical community to adopt inhalation, because they automatically equate smoking anything with being harmful, even though most studies with inhalation of cannabis long term haven’t demonstrated an increase in head and neck cancers or lung cancers,” Theisen says. But she adds, “I wouldn’t want clinicians to automatically dismiss inhalation, because in some instances it’s the more appropriate method.”

The most important point is simply that clinicians should be willing to have the conversation. “I think it’s pretty clear that patients are going to gravitate toward cannabis,” Clarke says. “People have been telling us how cannabis has been helpful for their pain symptoms.” He adds, “We have to get […] that regulatory framework so we as physicians feel comfortable with the product, but it doesn’t mean we can’t have those discussions.”

— Jamie Santa Cruz is a health and medical writer in the greater Denver area.

References

1. Meng H, Dai T, Hanlon JG, Downar J, Alibhai SMH, Clarke H. Cannabis and cannabinoids in cancer pain management. Curr Opin Support Palliat Care. 2020;14(2):87-93.

2. National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. https://www.nap.edu/read/24625/chapter/1. Published 2017.

3. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456-2473.

4. Häuser W, Welsch P, Klose P, Radbruch L, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain: a systematic review with meta-analysis of randomised controlled trials. Schmerz. 2019;33(5):424-436.

5. Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care. 2020;10(1):14-24.

6. Reiman A, Welty M, Solomon P. Cannabis as a substitute for opioid-based pain medication: patient self-report. Cannabis Cannabinoid Res. 2017;2:160-166.

7. Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. J Pain. 2016;17(6):739-744.

8. 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. 2010;39:167-179.

9. 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. 2018;55(2):179-188.e1.

10. 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. 2017;11(3):119-133.

11. Bar-Lev Schleider L, Mechoulam R, Lederman V, et al. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med. 2018;49:37-43.

12. Page RL 2nd, Allen LA, Kloner RA, et al. Medical marijuana, recreational cannabis, and cardiovascular health: a scientific statement from the American Heart Association. Circulation. 2020;142(10):e131-e152.

13. Mitchell T. Colorado issues first marijuana recall over heavy metal contaminants. Westword. October 9, 2020. https://www.westword.com/marijuana/colorado-marijuana-recall-alpinstash-heavy-metal-contaminants-11818833. Accessed October 21, 2020.

14. Med Man issues voluntary nationwide recall of Up2 due to presence of undeclared sildenafil. US Food & Drug Administration website. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/med-man-issues-voluntary-nationwide-recall-up2-due-presence-undeclared-sildenafil. Published November 8, 2019. Accessed October 21, 2020.

15. Nicholson K. Denver marijuana cultivator issues statewide recall over high mold and yeast levels. The Denver Post. October 14, 2019. https://www.denverpost.com/2019/10/14/denver-marijuana-recall/. Accessed October 21, 2020.

16. Mold fungus forces recall of medical marijuana product in Florida. CBS Miami website. https://miami.cbslocal.com/2020/08/19/mold-fungus-forces-recall-of-medical-marijuana-product-in-florida/. Published August 19, 2020. Accessed October 21, 2020.

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