Cannabinoids, Pain, and Opioid Use Reduction: The Importance of Distilling and Disseminating Existing Data
Publication: Cannabis and Cannabinoid Research
Volume 4, Issue Number 3
Abstract
The high prevalence of chronic pain conditions combined with an over-reliance on opioid prescriptions has resulted in an opioid epidemic and a desperate need for solutions. There is some debate about whether cannabis might play a role in addressing chronic pain conditions as well as the opioid epidemic. Recent surveys suggest that a large number of people are using cannabis as a treatment for pain and to reduce use of opioids, and cannabis-derived products demonstrate at least modest efficacy in the treatment of pain in randomized controlled trials. In addition, surveillance studies from countries that have approved the use of Sativex, which is a cannabis-based product, have demonstrated that a combination of Δ9-tetrahydrocannabinol and cannabidiol has low potential for harm, is well tolerated, and is helpful to patients. Given the number of people in the United States who are already using cannabis to manage pain and opioid use in state-regulated markets, it is imperative to conduct additional research in these areas, and to disseminate information on how to minimize harm and maximize any benefits of using cannabinoids to mitigate pain and reduce opioid use. The purpose of this article is to call attention to the fact that cannabis is being used in the management of chronic pain. Thus, this article also provides a set of guidelines on how to approach using cannabis to treat pain.
As the nation continues to grapple with the interconnected problems of chronic pain and the opioid epidemic, practical, and effective solutions that can be deployed quickly remain elusive. Some reviews have suggested that cannabinoids may play an important role in both pain control1 and the opioid problem,2 while others have dismissed this possibility.3 A flaw among some of the more negative reviews is that they often ignore evidence from other parts of the world, indicating that a cannabis-derived medication (e.g., Sativex) is both effective at managing chronic pain and has very low potential for harm. Despite this evidence, there are currently no published guidelines on how to minimize harms and maximize benefits when using cannabis products. The intention of the present communication is to (1) call attention to the fact that many people are currently using cannabis to treat chronic pain and reduce opioid use; (2) advocate for research at the intersection of cannabis, pain, and opioids; and (3) provide preliminary evidence-based guidelines for using cannabis in light of the fact that many people are already choosing to do in the absence of such direction. To that end, we provide a brief synopsis of the twin problems of chronic pain and opioid dependence, followed by reviews of studies that have examined the effect of cannabis products on pain, and of those that have examined the effect of cannabis on opioid use. In addition, we summarize existing evidence on the safety and tolerability of different oral formulations of cannabis, and suggest evidence-based guidelines regarding the use of cannabis products in the management of pain and reduction of opioid use.
Chronic Pain and the Opioid Epidemic
The opioid epidemic is linked to the use of prescription opioids to manage pain, and recent estimates suggest that 25.3 million U.S. adults suffer from daily chronic pain.4 While there are a number of nonopioid-approved treatments for both neuropathic and somatic pain (e.g., nonsteroidal anti-inflammatory drugs (NSAIDS), tricyclic antidepressants, gabapentin, pregabalin), many of these treatments have demonstrated low efficacy, undesirable side effects, and poor tolerability.5,6 Further, adjunct therapies such as physical therapy, cognitive-behavioral treatments, and acupuncture, which are accepted as effective for chronic pain,7,8 are not always reimbursed by insurance companies.9
Over the past two decades, opioid prescriptions have risen dramatically. Between 1999 and 2010, there was a fourfold increase in opioid prescriptions,10 while the rate of opioid drug overdose deaths increased 200% since the year 2000.11 Opioid-related overdose deaths continue to increase as those who were initially prescribed opioid medications have turned to street forms of opioids, including heroin and dangerously strong synthetics (i.e., fentanyl and fentanyl derivatives12). Although there are likely multifactorial reasons why this transition occurs, results from qualitative studies suggest that people who previously used prescription opioids transitioned to illegal forms of opioids due to cost and ease of access after becoming physically and emotionally addicted to prescription opioid pills.13 Some estimates suggest that among heroin injectors, 39% report being “hooked on” prescription type opioids before transitioning to heroin.14
In addition to the high risk of overdose, there are a number of other concerns associated with long-term opioid use. For example, there is a distinct lack of evidence for the usefulness and safety of using opioids in the treatment of chronic pain conditions.15 Of the estimated 91.8 million U.S. adults who use prescription opioids for pain, 12.5% report misuse.16 The high rate of misuse could be explained, at least in part, by tolerance that develops with continued opioid use. Continued opioid use is associated with two key processes: opioid tolerance and opioid-induced pain sensitivity (hyperalgesia). In concert, these phenomena can reduce the efficacy of opioids for treating chronic pain and contribute to opioid misuse.17 Other studies suggest that opioid-induced central immune signaling underlies opioid tolerance and hyperalgesia.18 Relatedly, prolonged opioid use has been associated with neuroinflammation and damage to the brain and immune system.19 Finally, recent evidence suggests that opioid treatment for chronic pain is no more effective than nonopioid medication at facilitating better pain-related function.20 Therefore, in many cases, the adverse consequences associated with opioid use outweigh any benefit to the patient.
Taken together, the use of opioids as a long-term treatment for chronic pain is associated with notable drawbacks and distinct danger from a public health perspective. As a result, in 2016 the CDC published new guidelines regarding the prescription of opioids, including a set of 12 recommendations.21 While changes prompted by these guidelines represent important controls, they could compound the problem, as individuals who are dependent and/or rely on opioids to control pain might turn in increasing numbers to opioids purchased illegally, leading to more overdose deaths in the short term.22,23 In conclusion, while opioids are effective short-term analgesics, they have a negative long-term impact on the individual and on society. The United States needs new, effective approaches that address both pain management and opioid dependence.
Pain Management and Cannabinoids
Patient preferences and behavior
In recent years, a number of epidemiological studies and randomized controlled clinical trials have suggested that people are trying cannabis to treat pain conditions. For example, studies indicate that relief from chronic pain is by far the most common motivation among individuals who use medical cannabis, with 87–94% of medical cannabis users reporting that they use cannabis for relief of a pain condition.24,25 Existing data further suggest that people find cannabis to be an effective strategy for pain management. For example, in a recent study of 2897 medical cannabis patients in the United States, >80% reported that cannabis was more effective than opioid medications for pain management.26 In another study, the authors surveyed 501 perioperative patients at Mt. Sinai Hospital, and found that >80% believed that cannabis would help with pain management.27 Other studies ranging from survey studies among large community samples to open-label studies of medicinal cannabis have also suggested that many chronic pain patients effectively use cannabis to control pain.28–31 Thus, even in the absence of a consensus in the medical community that cannabinoids are effective at controlling pain, patients believe that cannabis helps control pain and are using cannabis to control pain.
The conclusions drawn from the above studies should be interpreted in the context of the relevant limitations. Specifically, it should be acknowledged that many of the studies supporting the idea that cannabis is associated with decreased opioid use include survey/self-report data and time-series data at the state level. Randomized trials that test the question of whether cannabis use decreases opioid use are lacking. Therefore, additional research that more rigorously extends upon the existing literature needs to be done before concluding that a causal relationship exists between cannabis use and opioid use.
Randomized controlled trials of cannabinoids and pain
Systematic reviews of the available randomized controlled trials by the National Academy of Sciences and others have concluded that cannabinoids and cannabis products can be an effective tool with respect to the management of chronic pain.1,32–34 For example, 22 of 29 primary studies included in a systematic review by Lynch and Ware indicated that cannabinoids demonstrated at least modest efficacy and were a safe alternative for pain management.32 Importantly, all of these studies included either an active comparator or a placebo control. While there is a high degree of consistency in the direction of the effect, the estimate of the size of the effect for the effectiveness of cannabinoids varies from randomized controlled trial (RCT) to RCT. Variability in the estimates of effect size is not surprising given differences across studies, such as the clinical characteristics of the patients who were included, the types of cannabinoids that were included (e.g., plant-derived, synthetic, THC, THC+CBD), and the routes of administration (e.g., oral, oral mucosal, inhaled). Despite the differences in estimates of effect sizes across studies, the critical point is that the direction of the effect (i.e., that cannabinoids are at least modestly effective) is consistent across the majority of studies.32 Of note is the fact that there are no published randomized clinical trials in which cannabis is substituted for opioids among patients misusing opioids for treatment of chronic pain.35
Cannabinoids and Opioids
Given evidence that patients believe that cannabinoids are an effective tool for pain management and objective evidence from RCTs that cannabinoids are effective in terms of controlling pain, a logical next question is whether there is evidence that individuals are actively substituting cannabinoids for opioids in the management of pain. In a large survey of patients (n=2897), 97% of respondents “strongly agreed/agreed” that they are able to decrease the amount of opioids they consume when they also use cannabis.26 Similarly, a retrospective study found that medical cannabis use was associated with a 64% decrease in opioid use and improved ratings of quality of life.36 The “substitution effect” whereby patients appear to be using cannabis in place of opioids is also consistent with an open-label, prospective trial, which found that cannabis was associated with less opioid use, as well as reduced pain and improved quality of life.30
It is likely that survey studies and open-label trials suggesting that cannabis use is associated with decreases in opioid use may be biased by patient expectations. However, supporting the findings above, there is also robust pre-clinical evidence demonstrating that Δ9-tetrahydrocannabinol (THC), a cannabinoid receptor type 1 (CB1) agonist, increases the analgesic potency of opioids by eliciting additive and synergistic effects across routes of administration and species.37,38 This opioid-sparing effect of THC means that lower opioid doses are needed for effective analgesia, and that both adverse effects and reinforcing effects from opioids are reduced.39 Cannabidiol (CBD), which has a low affinity for the CB1 receptor and does not produce intoxication, produces pain-blocking effects in animal models of neuropathic pain,40–42 and may act to increase the effect of opioids on reducing acute pain.43 CBD may also diminish abuse-related effects of opioids and THC.44–47 These findings suggest that cannabinoids may enhance opioid analgesia while decreasing its abuse-related end-points.
There is also supporting evidence from studies that have examined opioid use through prescription data that are consistent with the findings described above. For example, one recent study examined opioid prescription records from a New Mexico state Prescription Monitoring Program to examine the effect of cannabis on opioid cessation (defined as the absence of opioid prescriptions) and opioid reduction (calculated in average daily morphine equivalents48). Using the prescription data, the results indicated that individuals who enrolled in the New Mexico Medical Cannabis Program were significantly more likely to quit or reduce using opioids than a control group of patients who were not enrolled in the cannabis program, and that those in the cannabis program reported greater increases in quality of life. Recent analyses of large pools of prescription data in states with access to medical cannabis also suggest a significant reduction in the filling of prescriptions for traditional pain medications.49 Most recently, a study used Multiple Cause of Death files available through the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) system to examine opioid-related deaths in Colorado before and after cannabis legalization. Findings suggest that legalization of cannabis was associated with a reduction of 0.7 opioid-related deaths per month.50 Thus, data from multiple sources suggest that cannabis may be associated with a reduction in opioid use and managing pain.
Although there are several studies supporting the promise of cannabis on reducing pain and opioid use, one recent observational study did not find any effect of cannabis on pain and opioid use.51 In addition, other prominent researchers have raised questions as to whether physicians should recommend replacing opioids with cannabis.35
Safety and Tolerability of Cannabis in Various Formulations
Health care providers are often reluctant to discuss the use of cannabis products with their patients and cite the lack of studies regarding (1) safety and tolerability, (2) efficacy in general and efficacy of specific formulations, and (3) dosing information and guidelines. In fact, a survey of 532 family health care providers in Colorado indicated that only 31% had ever recommended cannabis products to patients and 71% of those health care providers had recommended it to <5 patients.52 One reason for this may be that cannabis use has some documented adverse side effects and tolerability concerns that could complicate its utility in treating pain. One meta-analysis of the efficacy and tolerability of cannabis products for chronic pain suggests that cannabis is associated with a variety of adverse events and side effects, including mood disturbance, disassociation/acute psychosis, dizziness/drowsiness, and cognitive problems.53 In addition, some side effects might be pronounced among patient populations who are experiencing psychiatric disorders or symptoms. For example, cannabis use has been associated with increased levels of depression and anxiety among patients who were experiencing elevated symptoms of depression and being treated in a psychiatric outpatient setting.54 Importantly, these adverse events and side effects might differ depending on the type and chemovar of cannabis. For example, cannabis products with higher ratios of CBD:THC are associated with fewer cognitive and psychiatric negative consequences.55
While it is true that there have been very few studies on efficacy, safety, and tolerability in the United States, pharmaceutical companies have been actively developing and testing plant-derived cannabis compounds that contain both THC and CBD in Europe, Canada, and Israel for some time. Specifically, Sativex is a plant-derived cannabis medication that consists of approximately equal parts of THC and CBD and is administered orally through a spray. Sativex has recognized analgesic effects,56–58 and has been approved for use in the United Kingdom, Canada, and 28 countries in Europe, South America, and Asia.
One of the potential side effects of Sativex that was evaluated very carefully was the potential for abuse. Importantly, studies of adverse events related to the abuse potential of Sativex suggest that few (∼2.2%) patients experience intoxication, euphoria, tolerance, or withdrawal.59–62 Consistent with these data, Sativex is currently a Schedule IV (Part 1) controlled drug in the United Kingdom, due to its low potential for abuse and diversion. Schedule IV in the United Kingdom is similar to Schedule IV in the United States. One putative mechanism that may explain an even lower potential for harm appears to be the combination of CBD with THC in Sativex. In fact, studies have suggested that CBD may attenuate the effects of THC on cognitive processing as well as on mood.63–66 Thus, a 1:1 formulation of THC plus CBD may mitigate some of the deleterious effects of THC.
Because Sativex has been approved for use in Canada since 2005 and the European Union (EU) since 2010, there are now postmarketing data that provide additional evidence regarding the safety and tolerability of a cannabis-derived medication with equal parts of THC to CBD. Global exposure to Sativex since it was marketed in the EU was estimated to be >45,000 patient years in 2016.67 After approval in 2010, a formal registry was implemented in the United Kingdom, Germany, and Switzerland to provide data on safety and tolerability, which includes 941 patients with 2213 patient years of exposure. The mean number of days of use was 954 days, and the mean daily dose across all patients was 14.6 mg of THC and 13.5 mg of CBD. In terms of perceived benefits, 83% reported that they benefited from the medication, and no long-term adverse cognitive effects were noted. A smaller registry in Spain reported results consistent with the larger study.68 Thus, both studies provide data consistent with past RCTs on safety and tolerability,60 suggesting that Sativex is safe and well tolerated with low abuse potential.67,68
While data on plant-derived, oral formulations (i.e., edible or pill form) similar to Sativex with equal amount of THC and CBD that are now widely available in state-regulated markets in the United States are lacking, these formulations will likely have a profile highly similar to Sativex. While Sativex is an oral spray that is partially absorbed through mucosa, a direct comparison of Sativex with a formulation of oral THC without mucosal absorption indicated no significant differences in plasma pharmacokinetics.69 In addition, studies of serious adverse events related to formulations other than Sativex are broadly consistent with the studies on the safety profile of Sativex.70 Thus, it is likely that oral formulations combining THC and CBD, which are commonly available in state-regulated markets, will perform similarly to Sativex.
Conclusions and Guidelines
In summary, retrospective studies suggest that many individuals have already turned to cannabis to alleviate pain and are already substituting cannabis for opioids. Systematic reviews of RCTs have indicated that cannabis products demonstrate efficacy in the management of pain.1,32–34 RCTs, patient registries, and the experience of 30 countries that have approved a cannabis plant-derived product that is equal parts of THC to CBD (i.e., Sativex) indicate that this product is well tolerated with low potential for harm.60,67,68 Subjective and objective data suggest that individuals who use cannabis for pain are able to decrease their use of opioids and potentially other medications.26,71 These findings provide an empirical basis for the role of cannabis in pain management and the opioid epidemic.
In the United States, half of the population and more than half of our aging population are actively looking for strategies to manage pain. Meanwhile, the opioid epidemic is a major public health threat. These realities combined with the shifting legal and political landscape in which >20% of the nation now has access to state-regulated cannabis suggest that guidance is needed from scientists or policy makers for the millions of Americans who will turn to cannabis products over the next several years. In this context, it is a disservice to the public not to provide evidence-based guidelines that are intended to enhance public health and safety. Unbiased information, education, and communication about the potential benefits and potential risks of cannabis products are sorely needed. While the evidence base is far from mature, there is sufficient evidence to develop and disseminate some basic information to the public and to the medical community. To that end, specific guidelines are provided below. These guidelines will change as the evidence base continues to develop.
Clinical Guidelines Based on Existing Evidence
Based on the evidence presented above, we propose several evidence-based guidelines for patients who have already decided to use cannabis products for pain and/or to reduce opioid use as well as for health care providers who have decided to discuss these options with their patients.
(1)
Oral formulations (e.g., pill, edible, oromucosal) that have equal amounts of THC and CBD are likely to have some benefits and minimal risks, consistent with the data on Sativex in Canada, Europe, and elsewhere.
(2)
Although doses vary widely, studies suggest that the average THC dose individuals use for medical purposes is 3 mg daily.72 Further, based on the dosing regimen for Sativex and research indicating that other oral formulations have a highly similar pharmacokinetic profile,61 patients may achieve therapeutic benefit and minimal psychoactivity with oral doses as low as 2.5 mg THC.73
(3)
If needed, patients can then work with their physician to slowly increase the THC dose by 2.5 mg until the desired effect (i.e., reduction in pain, reduction in opioid use) is achieved. Careful monitoring is critical with oral THC formulations, as patients may be at risk of taking more than the intended dose. Note CBD dosing can start higher and progress faster as it is not psychoactive, with careful physician monitoring at high doses for potential pharmacokinetic interactions. It is also critical that all cannabis products be kept out of reach of children.
(4)
Patients should avoid products that have not been manufactured in cGMP compliant facilities and have accurate dosing information on the label. To that end, state regulatory officials should provide information to the public regarding the accuracy of labeling using data from reputable laboratories to verify the dose of cannabinoids in products available in state-regulated markets. While this has increasingly become the case as states have adopted more stringent regulatory practices, studies suggest that many products are not labeled accurately.74 Labeling accuracy needs to be addressed at the state level. In addition, patients should be made aware of the variation in state medical marijuana programs regarding regulatory practices.75
(5)
In cases where patients experience unwanted cognitive side effects, patients should discontinue use or switch to products with greater levels of CBD and lower levels of THC, as this might reduce deleterious cognitive and mood-related consequences.55
(6)
The risk and benefits of cannabis use should be evaluated carefully in some individuals because the risks of using cannabis may outweigh the benefits for people who
7.
a. are under the age of 25
8.
b. have a personal history or strong family history of psychosis
9.
c. are actively treated for or are symptomatic with mood/depressive and anxiety disorders
10.
d. have a current or past cannabis use disorder or another active substance use disorder
11.
e. have cardiovascular or respiratory disease
12.
f. are pregnant, planning to become pregnant, or are breastfeeding.
Abbreviations Used
- CBD
- cannabidiol
- RCT
- randomized controlled trial
- THC
- Δ9-tetrahydrocannabinol
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Cite this article as: Hutchison KE, Hagerty SL, Galinkin J, Bryan AD, Bidwell LC (2019) Cannabinoids, pain, and opioid use reduction: the importance of distilling and disseminating existing data, Cannabis and Cannabinoid Research 4:3, 158–164, DOI: 10.1089/can.2018.0052.
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Published In
Cannabis and Cannabinoid Research
Volume 4 • Issue Number 3 • September 2019
Pages: 158 - 164
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Copyright 2019, Mary Ann Liebert, Inc., publishers.
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Published online: 23 September 2019
Published in print: September 2019
Published ahead of print: 30 July 2019
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