CRx MAGAZINE

Fall 2019

Cannabis: A Silver Bullet for the Opioid Crisis?

There’s hope that cannabis can replace opiates and offer effective, long-term analgesia for chronic pain without risk of overdose, but the research isn’t clear.

It’s hardly a secret that the opioid crisis in the United States has reached epidemic proportions. In the decade leading up to 2016, the rate of fatal drug overdoses—the majority of which involve opioids—increased from 11.5 per 100,000 to 19.8 per 100,000.1 Deaths from overdose now outnumber those due to motor vehicle accidents, suicide, and gunshots, and the total number of drug overdose deaths stands at more than 630,000—greater than the number of American deaths in World Wars I and II combined.2

In light of the havoc being wreaked by overdependence on opioids, some have proposed legalizing medical cannabis as a way of combatting the crisis. The argument is that cannabis can serve as a substitute for opiates and function as an effective, long-term analgesic for chronic pain without creating a risk of overdose. (While some cannabis users become dependent on the drug, and while use may be associated with various health risks, there are no reported cases of anyone ever overdosing on cannabis.2)

A total of 33 US states plus the District of Columbia, Guam, Puerto Rico, and the US Virgin Islands now have comprehensive laws allowing for public use of cannabis for medicinal purposes.3 But significant questions remain about how the availability and use of medical cannabis will influence opioid use and about what role cannabis could play in stemming the crisis.

State-Level Medical Cannabis Programs
There’s a growing body of population-level data on the association between cannabis laws and opioid use, and much of this literature suggests that legalization of medical cannabis holds promise for combatting the opioid epidemic. A 2018 cross-sectional analysis led by Wen and Hockenberry used Medicaid prescription data from 2011–2016 to examine the association between state cannabis laws and state-level opioid prescribing rates. The authors found that laws allowing for medical use of cannabis were associated with a 5.88% lower rate of opioid prescriptions, on average, and that laws allowing adult recreational use of cannabis were associated with a 6.38% lower rate of opioid prescribing.4 Multiple other studies have likewise reported that state medical cannabis programs are associated with a reduction in rates of opioid prescribing.5-9

Medical cannabis programs have been associated not only with reduced rates of opioid prescribing but also specifically with lower rates of opioid overdoses10 and hospitalization related to opioid use.11 One of the most significant studies was published in 2014 in JAMA Internal Medicine.10 The researchers analyzed death certificate data from all 50 US states between 1999 and 2010 and found that those with medical cannabis laws had a 24.8% lower mean annual opioid overdose rate than states without such laws. Only three states had medical cannabis laws in place prior to 1999, but an additional 10 states implemented such laws during the study period, so the researchers were able to examine how implementation affected overdose rates in states with new medical cannabis programs. They found that reductions in opioid overdose deaths were generally greater the longer such programs had been in place.

Importantly, nearly all studies that have found a relationship between state medical cannabis programs and opioid prescribing or opioid overdoses, including the JAMA analysis, have shown strictly associations, not causal connections. It’s therefore uncertain whether states’ implementation of medical cannabis programs actually caused the reductions in opioid prescribing or opioid overdoses. “None of these studies is able to show the mechanism,” says Rebecca Haffajee, JD, PhD, MPH, an assistant professor of health and management policy in the School of Public Health at the University of Michigan. “Is it that people were using opioids before, and once the marijuana became available they started using the marijuana instead? That’s the theory behind these studies, but without measurement of the use of marijuana, we can’t know with certainty that that was what was happening.”

Regarding opioid overdoses in particular, there are a range of other variables besides the legal status of medical cannabis that likely influence opioid deaths in a given state—including the availability of naloxone as a rescue agent for individuals who have overdosed, the availability of treatment for opioid use disorder, the purity of drugs available on the black market, and the supply of fentanyl. (Fentanyl is the leading cause of death from opioids, but the supply varies widely from one geographic region to the next.2)

While a number of studies show that medical cannabis programs are associated with a reduction in opioid overdoses, the issue is complicated by the fact that other studies suggest the opposite. Earlier this year, new research led by Chelsea Shover, PhD, a postdoctoral researcher at Stanford University, attempted to replicate the 2014 JAMA analysis and extend it through 2017. Using the same data and methodology as the original study, Shover’s widely publicized analysis concluded that the findings of the earlier JAMA study did not hold when extended over a longer period.12 In fact, the association between state-level medical cannabis programs and opioid overdose deaths actually reversed direction over the longer term, and Shover and her colleagues found that medical cannabis programs were associated with a 23% increase in opioid overdose deaths.

Accordingly, questions remain about whether legalizing medical cannabis translates to a reduction in opioid usage at the population level. Philippe Lucas, a PhD candidate at the University of Victoria and vice president of patient research and access at the Canadian cannabis company Tilray, remains optimistic about the potential for medical cannabis legalization to bring down population-level opioid usage. “You’ve got one study [the Shover paper] suggesting that it may not be useful, and a whole bunch of studies suggesting that it is.”

But Shover herself, while acknowledging that her research isn’t the final word, is far more pessimistic about claims that legalizing medical cannabis will automatically reduce opioid overdose deaths. While it’s difficult to know exactly how many individuals use cannabis for medical purposes, the rate appears to be about 2.5% nationwide.13 “That’s really pretty low,” Shover says. “It doesn’t seem likely that that small of a percentage could really affect the population overdose rate.” To the extent that some studies have shown associations between state-level medical cannabis programs and a reduction in opioid prescribing or overdose deaths, Shover argues that those reductions are likely due to factors other than cannabis legalization itself. “States that legalize cannabis early are pretty different than the rest of the country,” Shover says. “It’s quite clear that states that tend to be more liberal about cannabis legalization tend to have policies or conditions that are protecting against the greatest harms of opioid use disorder.”

Do Medical Cannabis Users Reduce or Eliminate Opioid Use?
A key weakness of the population-level studies described previously is that they indicate associations between medical cannabis laws and opioid overdoses in states as a whole, but they provide no insight about what’s occurring at the individual level. How does the availability of medical cannabis affect individual use of opioids, and, specifically, do individuals switch to using cannabis instead of opioids?

Research at the individual level is limited. However, a number of patient surveys, most of them cross-sectional, have found that medical cannabis usage indeed is associated with a reduction in the use of opioids.14,15 In a retrospective survey of medical cannabis users in Michigan, 64% of participants reported that they had reduced their use of opioids after beginning cannabis therapy, and 45% reported an increase in their quality of life.16 Similarly, in a survey of 2,897 medical cannabis users in California, 97% of respondents who had used opiates “agreed” or “strongly agreed” that using cannabis allowed them to decrease the amount of opiates they consumed, and 81% either “agreed” or “strongly agreed” that cannabis by itself was more effective at treating their condition than was using cannabis in combination with opioids.17 A cross-sectional survey of 2,032 patients in Canada’s national medical cannabis system similarly found that 69.1% of respondents reported substituting cannabis for prescription drugs, and 35.3% of those making substitutions were substituting for opioids.14

However, the evidence is not uniform. Earlier this year, a large cross-sectional study of 627,000 people examined the association between state-level enactment of medical cannabis laws with individual-level opioid use and found little evidence at the individual level of changes in nonmedical prescription opioid use or in the prevalence of prescription opioid use disorder. According to the authors, the findings contradict the hypothesis that prescription opioid users will substitute marijuana for opioids.18

Some research suggests that cannabis is being used as a complement to opioids, not a substitute, and that individuals who supplement their opioid use with cannabis may actually take higher doses of opioids than do noncannabis users and may be more likely to abuse the drugs.19,20 A survey of 371 individuals who had been prescribed long-term opioid therapy found that those who used medical cannabis in addition to opioids were at significantly higher risk of prescription opioid misuse.21 Similarly, a study of 1,514 Australians who had been prescribed opioids for chronic pain found that those who were using cannabis in addition to opioids had been taking opioids for a longer period of time, were taking higher doses of opioids, and were more likely to be nonadherent in their use of opioids.22 And a three-year prospective study of a nationally representative sample of US adults found that individuals who used cannabis were significantly more likely to be using prescription opioids for nonmedical purposes after three years, and cannabis users also had higher levels of opioid use disorder after that same period.23

In sum, the question of whether medical cannabis use reduces opioid use on an individual level remains open. “There are many studies that support the substitution hypothesis and fewer that show the complement hypothesis,” Haffajee says. Nevertheless, “a handful of studies do suggest that when medical marijuana becomes available, people just supplement cannabis on top of their opioid use. In that case, it could be worse, because people are using multiple controlled substances.”

An Effective Analgesic Substitute for Opioids?
Closely related to the question of whether individuals who use medical cannabis reduce their use of opioids is the question of whether cannabis actually is an effective analgesic. Once again, there’s significant debate on this question.

It seems clear from multiple analyses that cannabis has analgesic effects in humans.24-27 A number of surveys suggest that patients perceive that cannabis relieves their chronic pain,16,17,28 and several controlled trials likewise have found that smoked cannabis provides relief from chronic pain (for neuropathic pain in particular).29-34 An influential 2017 report from the National Academies of Sciences, Engineering, and Medicine on the health impact of cannabis concluded that there’s “substantial evidence that cannabis is an effective treatment for chronic pain in adults.”35

Not all are persuaded, however. Kenneth Finn, MD, a board-certified pain medicine physician in private practice in Colorado Springs, Colorado, counts himself among the skeptics based on his experience in his own practice of treating chronic pain patients. “I can tell you anecdotally, when I ask my patients that are using marijuana for pain, ‘Does the marijuana help you for the problem you’re seeing me today for,’ 99% of time they say no. It doesn’t help with their pain. It [just] makes them sleepy, and it makes them not care.”

Others, too, remain unconvinced about the evidence base for the efficacy of cannabis in treating chronic pain. Of the few controlled trials that exist, most have included only a small number of participants and were conducted over a short period of time (a few days or a few weeks); many of the existing trials also have methodological flaws.2 For these reasons, a number of reviews have come to relatively cautious conclusions about the potential for medical cannabis use to relieve chronic pain on a widespread basis.27 A 2017 review from the VA found only “low-strength” evidence that cannabis preparations could improve neuropathic pain and “insufficient” evidence regarding its efficacy for treating other types of chronic pain.36 Similarly, a 2018 review in Pain found “limited” evidence of the effectiveness of cannabis for chronic noncancer pain and concluded that use of cannabis decreased pain intensity by a mean of only 3 mm on a 100-mm scale over placebo. The authors observed that the number needed to treat to benefit is high with cannabis, whereas the number needed to treat to harm is low.37

Also, in 2018, a Cochrane review found that there’s no high-quality evidence that cannabis-based medicines are effective for pain management in any condition involving chronic neuropathic pain. The authors concluded that, at best, a small percentage of patients with neuropathic pain might benefit, but they also cautioned that the harms of using cannabis for long-term management of chronic pain might outweigh the benefits.38

Even if cannabis is not sufficient to manage chronic pain if used alone, there’s been some suggestion that using cannabis alongside opioids can increase the effectiveness of the opioids, thereby reducing the dosage of opioids required for pain management. Some experiments in animals support this theory. A study involving both mice and rats found that certain cannabinoids (which are the chemical compounds in cannabis that act on cannabinoid receptors in the brain) have a synergistic analgesic effect when used in combination with an opioid (specifically, morphine). The authors concluded that cannabinoid use could reduce the amount of opioids required to manage pain in certain pain conditions.39 In a separate experiment, male rats who had been trained to self-administer oxycodone were then exposed to THC, either by vapor inhalation or injection. The researchers found that the rats obtained fewer oxycodone infusions after exposure to THC, leading the authors to suggest that THC may enhance the efficacy of opioids and could therefore hold potential for reducing opioid abuse.40

The limited clinical evidence available, however, raises questions about the theory that cannabis use could reduce the need for opioids. In 2018, researchers in Australia published findings from a four-year prospective analysis of 1,514 participants from the Pain and Opioids in Treatment study, all of whom had been prescribed opioids. In this study—one of the longest prospective studies to date on the topic of cannabis use in chronic noncancer pain—the researchers found that cannabis use was common in patients with chronic pain, and that patients reported reductions in pain with using cannabis. But they also found, paradoxically, that cannabis users had greater pain overall and lower self-efficacy in managing pain than did noncannabis users. They concluded that there was no evidence that cannabis actually reduced pain severity and no evidence that it reduced usage of opioids.41 Additionally, as noted previously, some retrospective and prospective research suggests that cannabis use may increase, rather than decrease, use of opioids.20,23

In Sum: The Role of Medical Cannabis in Stemming the Opioid Crisis
On the population level, there simply isn’t a clear association between availability of cannabis and decreases in opioid overdoses. “This has been touted as an effective strategy to prevent opioid overdose. Is it working on a population level? Is it working as a policy? Based on the available data including our research, we say, no, it doesn’t seem to be,” Shover says. It’s equally unclear whether cannabis can legitimately function as a substitute or complement to opiate-based therapy.42

Although Finn sometimes recommends cannabis to his own terminally ill patients, he also points to data showing that opioid overdoses have continued to increase in his own state of Colorado despite having one of the nation’s longest-running medical cannabis programs.43 “Colorado had a record number of opioid overdose deaths 16 years after passing their medical marijuana program,” Finn says. “I think it’s important to understand that if cannabis or cannabinoids were a good opioid substitute, over time Colorado should be seeing a decrease. But over time, the number of people dying from opioids has continued to climb.”

In large part, the issue of whether cannabis is an appropriate substitute for opioids hinges on whether it can effectively manage pain. But Shover describes the data on this question as “fuzzy.” “You’re not going to die from using cannabis for pain relief,” Shover says. In the sense that it has essentially no fatal overdose risk in adults, cannabis is pharmacologically safer than opium-based treatments. At the same time, “we don’t really have medical evidence yet to say that this is a good treatment for chronic pain.”

But research on many issues related to cannabis and opioids is still unfolding, and even experts who call for caution believe that cannabis may play some role in combatting the opioid epidemic. One particularly relevant (and still contested) issue is whether cannabis use could aid individuals in combatting addiction if they already have an opioid use disorder.44,45 “There is limited but very convincing evidence that cannabis may help increase the treatment success rate for opioid use disorder when it comes to methadone and Suboxone treatment,” Lucas says. “There are a lot of biological mechanisms that help with this. It’s been shown empirically that cannabis and THC in particular can reduce the cravings and withdrawal effects associated with opioids. And therefore, it may make cutting down or giving up opioids easier.”

The takeaway for now, according to Haffajee: “Proceed with caution.” Haffajee has a number of concerns related to increased use of cannabis, such as how cannabis impacts the risk of automobile accidents, how it impacts lung health, and how it affects adolescent brain development, and she’s skeptical that cannabis is a solution to the opioid crisis. But she adds that there may still be significant advantages associated with increased access. “Cannabis could be potentially very beneficial to some patients,” she says. “Just weigh the pros and cons carefully.”

— Jamie Santa Cruz, a freelance writer who specializes in health and medical topics, is based in Parker, Colorado.

References

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38. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3:CD012182.

39. Chen X, Cowan A, Inan S, et al. Opioid-sparing effects of cannabinoids on morphine analgesia: participation of CB1 and CB2 receptors. Br J Pharmacol. 2019;176(17):3378-3389.

40. Nguyen JD, Grant Y, Creehan KM, et al. Δ9-tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions. Neuropharmacology. 2019;151:127-135.

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45. Franklyn AM, Eibl JK, Gauthier GJ, Marsh DC. The impact of cannabis use on patients enrolled in opioid agonist therapy in Ontario, Canada. PLoS One. 2017;12(11):e0187633.

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