Background

Chronic pain, defined as pain lasting longer than 3 to 6 months or past normal time for tissue healing,^1,2 is a serious public health issue in the United States, affecting approximately 100 million people³ and resulting in over $560 billion annually in costs.⁴ Chronic pain substantially impacts physical and mental functioning, reducing productivity and quality of life. It is the leading cause of disability and is often refractory to treatment.^5,6 Opioids are often prescribed for chronic pain. In the United States, prescription of opioid medications for chronic pain more than tripled from 1999 to 2015.⁷ This increase was accompanied by marked increases in rates of opioid use disorder and drug overdose mortality^7–9 involving prescription opioids. From 1999 to 2014, over 165,000 people died from overdoses related to prescription opioids in the United States,¹ with an estimated 17,087 prescription opioid overdose deaths in 2016 ⁷ In October 2017, the U.S. Department of Health and Human Services declared a nationwide public health emergency regarding the opioid crisis.¹⁰

While opioids are often prescribed for chronic pain, they are associated with small to moderate effects on pain and overall function with frequent adverse effects,¹¹ and the 2016 Centers for Disease Control and Prevention Guideline for Prescribing Opioids for Chronic Pain recommends nonopioid therapy as the preferred treatment of chronic pain.^1,2 Recent systematic reviews found that several nonopioid drugs,¹² and some nonpharmacologic treatments¹³ also have small to moderate effects on chronic pain and overall function. Some nonopioid pharmacological treatments had frequent overall adverse events and some less frequent but serious adverse effects, while nonpharmacological treatments typically reported few adverse events.¹²

The challenges of treating chronic pain in light of the limited benefits of commonly prescribed prescription medications and the ongoing opioid crisis drive a search for alternative pain treatments, including cannabis. The goals of current research are to identify alternative treatments with equal or better benefits for pain while avoiding potential unintended consequences that could result in harms. Plants have historically been evaluated for medicinal properties, with some being developed into drug therapies (i.e., the field of pharmacognosy). Some preclinical data suggest that cannabinoids may have analgesic properties, though research in this area is mixed.¹⁴ Tetrahydrocannabinol (THC), one of over 140 cannabinoids in cannabis,¹⁵ has demonstrated analgesic properties,^16,17 though its psychoactive effects and abuse potential may increase its risk and suitability as an analgesic. Other cannabinoids (e.g., cannabidiol [CBD], cannabigerol [CBG], and cannabichromene [CBC]) may also have some analgesic or anti-inflammatory properties and are not thought to be intoxicating or addictive,^18,19 but may not be as potent as THC. Observational studies indicate that some patients use cannabis and related compounds as a substitute for opioids.^20–23

Other plant-based compounds (PBCs) such as kratom, though pharmacologically distinct from cannabis, may be considered as analgesics, in part due to their community-use as substitutes for opioids.^24,25 They may also have serious harms, such as dependence, addiction, and physiological withdrawal potential.²⁶ Although some PBCs thought to reduce pain are currently classified as Schedule I by the Drug Enforcement Administration, there is disagreement on scheduling others, such as kratom.²⁷ Recent legalization of cannabis by several states²⁸ may lead to more and higher quality research on PBCs with potential for treating chronic pain.²⁹ Initiatives to develop and study alternative interventions for chronic pain are expected to contribute to this increase in research on PBCs, specifically for pain. This living review was initiated in response to a request from Congress on PBCs for chronic pain.^29,30

The key decisional dilemmas for treating chronic pain with cannabis and other PBCs include the effectiveness in treating chronic pain and the effect of specific formulations, doses or potencies, routes of administration, types of pain, and other patient characteristics on outcomes. Similarly, it is important to identify harms and adverse effects of these interventions which may include risks of frequent or daily use, risk of developing dependence or addiction (e.g., cannabis use disorder), mental health effects, and impacts on harms of co-prescribed opioids. It is also unclear what the impact of using cannabis or other PBCs for pain has on opioid use, and, how their effectiveness compares to other interventions.

Purpose and Scope of the Systematic Review

This is an update of a “living systematic review” which assesses the effectiveness and harms of plant-based treatments for chronic pain conditions. The review is living in the sense that it uses methods to identify and synthesize recently published literature on an ongoing basis. For the purposes of this review, PBCs included are those that have potential analgesic effects as well as the potential for addiction, misuse, and serious adverse effects; other PBCs, such as herbal treatments are not included. The intended audience includes policy and decision makers, funders and researchers of treatments for chronic pain, and clinicians who treat chronic pain.