What does the ecological and epidemiological evidence indicate about the potential for cannabinoids to reduce opioid use and harms ? A comprehensive review, Gabrielle Campbell, 2018

What does the ecological and epidemiological evidence indicate about the potential for cannabinoids to reduce opioid use and harms ? A comprehensive review

Gabrielle Campbell, Wayne Hall and Suzanne Nielsen

International Review of Psychiatry, 2018, 1-16.

Doi : 10.1080/09540261.2018.1509842



Pre-clinical research supports that cannabinoids reduce opioid dose requirements, but few studies have tested this in humans. This review evaluates ecological and epidemiological studies that have been cited as evidence that medical cannabis use may reduce opioid use and opioidrelated harms. Medline and Embase were searched for relevant articles. Data were extracted on study setting, analyses approach, covariates, and outcomes. Eleven ecological and 14 epidemiological studies were found. In ecological studies, states that allow medical cannabis laws have reported a slower rate of increase in opioid overdose deaths compared with states without such laws. These differences have increased over time and persisted after controlling for state sociodemographic characteristics and use of prescription monitoring programmes. Few studies have controlled for other potential confounders such as opioid dependence treatment and imprisonment rates. Some epidemiological studies provide evidence that cannabis availability may reduce opioid use, but are limited by selection bias, cross-sectional designs, and self-reported assessments of the opioid-sparing effects of cannabis. Some epidemiological and ecological
studies suggest that cannabis may reduce opioid use and harms, although important methodological weaknesses were identified. Well-designed clinical studies may provide more conclusive evidence on whether cannabinoids can reduce opioid use and related harm.



In the US, opioid overdose deaths have reached epidemic levels, bringing into sharp focus the need for strategies to reduce use and harms (Seth, Scholl, Rudd, & Bacon, 2018). The US has some of the highest rates of opioid prescribing per capita in the world (Berterame et al., 2016), which has contributed to the dramatic increases in opioid-related overdose deaths observed (Compton, Boyle, & Wargo, 2015; Kolodny et al., 2015; Madras, 2017).

Deaths were initially attributed to the liberal prescribing of high-dose sustained-release opioids, such as
oxycodone for chronic non-cancer pain (Kolodny et al., 2015). Recently, some shifts have been observed
from use of pharmaceutical opioids to heroin, including heroin laced with fentanyl (Compton, Jones, & Baldwin, 2016; Kolodny et al., 2015). In the US, since the introduction of more restrictive opioid prescribing guidelines and prescription monitoring programmes, heroin is reported to be cheaper and more readily available than pharmaceutical opioids (Kolodny et al., 2015).

Overdose deaths from prescription opioids and heroin have reduced life expectancy among middleaged
white Americans, one population group badly affected by the opioid epidemic (Case & Deaton, 2015). These trends have increased community and political interest in finding ways to reduce the huge toll of opioid overdose deaths and opioid addiction in the US (National Academies of Sciences & Medicine, 2017).

One policy proposal to reduce opioid overdose deaths has been expanding access to medical cannabis
programmes for chronic pain and opioid dependence (New York State Department of Health, 2018). This
policy was prompted by a paper of Bachhuber, Saloner, Cunningham, and Barry (2014) which attracted considerable media attention because it reported that rates of opioid overdose deaths had increased at a slower rate in US states that allowed medical use of cannabis than in states that did not. Media stories suggested that this was because patients with chronic pain substituted medical cannabis for opioid use, or used medical cannabis to reduce their opioid doses, thereby reducing their risks of fatal opioid overdoses (Lake, 2017).

The hypothesis is prima facie plausible. Pain relief is a common reason given for medical cannabis use in the US states that allow it (National Academies of Sciences & Medicine, 2017). Numerous reviews of the
analgesic effects of cannabinoids in humans have found that cannabinoids produce statistically significant but clinically modest reductions in pain (Mucke, Phillips, Radbruch, Petzke, & Hauser, 2018; Nugent et al., 2017; Stockings et al., 2018; Whiting et al., 2015).

There is also robust evidence from pre-clinical studies that co-administration of cannabinoids and opioids reduces opioid dose requirements (Nielsen et al., 2017). Meta-analysis of these pre-clinical studies indicated clear opioid-sparing effects; the median effective dose of morphine when administered with tetrahydrocannabinol (THC) is 3.6-times lower (95% CI¼1.95–6.76) than when morphine is administered alone, enabling opioids to produce the same analgesic effects at much lower doses (Nielsen et al., 2017).

A small number of low quality clinical studies have tested the opioid-sparing effects of cannabinoids (Nielsen et al., 2017). Most clinical trials that have examined concurrent opioid and cannabinoids administration have required that participants maintained stable opioid doses while trialling cannabinoids (Nielsen et al., 2017) or have not measured or reported changes in opioid dose. There remains a lack of high-quality clinical trials that clearly demonstrate whether cannabinoids may reduce opioid dose requirements.

A major gap in our understanding remains as to whether the correlation reported by Bachhuber et al. (2014) can be explained by large enough numbers of patients using medical cannabis instead of opioids, thereby reducing opioid-related deaths at the population level. The aim of this paper is to review the extant literature to assess how convincing the evidence from ecological and epidemiological studies in the US and elsewhere is that the use of cannabis and cannabinoids for medical purposes can reduce opioidrelated mortality.