Cannabinoids & Opioids
Impact of Medical Marijuana Use on the Use of Opioids – Overview
Historically, opioids have been the backbone of pain management. Due to the growing concern in recent years regarding the complications of opioid use for pain, there is a growing and at times a desperate effort to identify alternative means of treating pain that would have a better safety profile. Marijuana has been used for the management of pain for 4000 years, with pain being a major indication for cannabis medicines in Western society between 1842 and 1942.
Questions have been raised as to the effect that the use of medical marijuana and cannabinoids may have on both the use and the effectiveness of opioids, especially regarding the potential benefits and harms associated with the use of both agents together. Research on these topics is limited but is explored below.
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Marijuana (Cannabis) & Opioids
A Word of Caution
Regarding data gained from currently available research on the medical use of cannabis, it should be noted that research on “medical marijuana” is compromised by a lack of consistant marijuana product being evaluated. Because most studies are not performed in populations using consistent marijuana products with respect to dose, cannabinoid constituents and constituent ratios, the accuracy and application of conclusions related to the research is limited. Many studies are performed using experimental pain models in which volunteers are subjected to pain in an experimental setting rather than evaluating clinical pain in patients with chronic pain. Furthermore, it is likely there may be inherent bias in reported data collection from cannabis users who have personal opinions reflecting cannabis use.
These studies often do not offer the benefit of double-blind studies in which neither the subjects nor the researchers know the actual content of the drugs used which helps eliminate the bias introduced by either the subjects or the researchers. Given these limitations however, the following information is presented to encourage better informed decision making regarding the use of medical marijuana and related cannabinoids along with opioids.
Socioeconomic Impact of Medical Marijuana Use on the Use of Opioids
With the legalization and increased access to the use of marijuana medicinally in many states over the last decade, researchers have looked at the impact of the use of marijuana for pain on the use of opioids. Recent studies have shown that medical cannabis laws have resulted in significant (up to 33%) reductions in opioid-related causes of death and opioid usage. In addition, it has been noted there have been reductions in the number and cost of prescription medications used by Medicare patients, suggesting that some patients use cannabis as a substitute for various conventional pharmaceutical treatments.
A study published in 2017 evaluated the association between enrollment in the New Mexico Medical Cannabis Program (MCP) and opioid prescription use. By the end of the 21 month observation period, MCP enrollment was associated with 17 times higher odds of discontinuing opioid prescriptions, 5 times higher odds of reducing daily prescription opioid dosages, and a 47 percentage point reduction in daily opioid dosages. In this study, over 80% of the MCP subjects reduced their daily opioid prescription dosages, and over 40% stopped filling opioid prescriptions altogether within 1.5 years of starting use of medical marijuana.
Does the Use of Medical Marijuana Contribute to Opioid and/or Other Drug Abuse/Addiction?
A 2015 publication evaluated medical cannabis users who used or did not use opioids, to gain an understanding whether concurrent use of cannabis and opioids is associated with more serious forms of alcohol and other drug involvement. Those medical cannabis users who used opioids tended to be older with higher levels of pain and lower levels of functioning. However, no significant difference was found between medical cannabis users who used or did not use opioids with either lifetime or past-3-month use of other drugs, including alcohol, cocaine, sedatives, street opioids, and amphetamines. Also, medical cannabis users who used opioids rated the effectiveness of cannabis higher than opioids for pain and indicated a strong desire to reduce use of opioids. As explored further below, there appears to be a synergistic analgesic effect with the combination of opioids and cannabinoids providing greater analgesic benefit than either cannabis or opioids alone.
Pharmacology of Cannabis and Opioids
Synergism Between Opioids and Cannabinoids
There appears to be a synergistic analgesic benefit when cannabis is added to opioid treatment for pain in which there is a decrease in the lowest effective pain-relieving opioid dose (i.e., an opioid-sparing effect). Pre-clinical studies (animal and laboratory-based studies) indicate a trend towards reduced use of opioids when patients taking opioids add cannabis to their regimen. Through meta-analyses, it was found that the doses of morphine and codeine required to produce the same analgesic effect were 3.6 and 9.5 times lower, respectively, when co-administered with delta-9-THC.
There are significant limitations in translating findings from pre-clinical studies to clinical practice, especially when evaluating doses and effect sizes. Although the outcomes of pre-clinical studies are often consistent with clinical studies, pre-clinical studies may over-represent effects. The reasons for lesser effect sizes in human studies have been attributed to the wide mixes of clinical populations or the response being limited to sub-populations. This stresses the importance of clinical studies to assess the effects found in pre-clinical studies.
Clinical reports indicate that it is not uncommon for patients started on cannabis to be able to taper off opioids. In a 2017 systematic review and meta-analysis evaluating the opioid-sparing effect of cannabinoids, it was concluded that while pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, there is a lack of human studies demonstrating the opioid sparing effects of cannabis. Only one of the nine clinical studies identified provided very-low-quality evidence of such an effect. One large controlled study reported a sparing effect in a fairly large sample utilizing smoked cannabis, however, a reduction in opioid use did not achieve statistical significance.
Alternatively, a small 2018 study demonstrated significantly reduced opioid consumption with the use of oral THC/CBD capsules along with vaped cannabis for breakthru pain. In this study, using Pain Quality Assessment Scale scores ranging from 0 to 10, paroxysmal pain decreased from 6.76 to 2.04; surface pain decreased from 4.20 to 1.30, deep pain decreased from 5.87 to 2.03, and unpleasant rating declined from ‘‘miserable’’ to ‘‘annoying’’ after 3 months therapy. Opioid consumption was reduced from an average of 79.94 ME (range 0 to 450) to 19.65 (range 0 to 150) morphine equivalents per day. In fact, it was reported that all but 3 of the 27 patients in the study completely discontinued use
of their opioids, and the remaining patients reduced their doses by approximately 75%.
Additionally, no studies have yet examined the opioid-sparing effect of cannabidiol (CBD) alone, in combination with delta-9-THC outside of a 1 : 1 ratio, or with other cannabinoids. Further, the lack of high- quality studies in humans exploring the opioid-sparing effect of cannabinoids means that the evidence for this benefit is largely limited to pre-clinical studies.
Preclinical Study Evaluating Synergy Between Morphine and a CBD-2 Agonist
A 2017 pre-clinical study showed for the first time that morphine and a CB2 agonist, JWH015 (like CBD) interact synergistically to suppress inflammatory, post-operative, and neuropathic pain. Furthermoe, the synergy extends to preventing opioid-induced reward behaviors in animals, suggesting that CBD may reduce abuse risk when taken with opioids. Additionally, the combination of morphine with the CB2 agonist reduces constipation associated with morphine. The authors conclude that their data support the use of opioid-CB2 combination therapy in treating chronic pain while limiting abuse liability.
Oral Oxycodone and Smoked THC
A small 2018 study evaluating the combined use of low dose oxycodone 2.5-5 mg) along with smoked cannabis (5.6% THC) in an experimental pain model found a synergistic analgesic benefit with the combination.
Oral Morphine, Oral Oxycodone and Vaporized THC
A small 2011 study evaluating the combined use of oral morphine ER dosing (average 62mg, ranging 10-200mg twice/day) or oral oxycodone ER dosing (average 53mg, ranging 10-200mg twice/day)along with vaporized THC found a synergistic analgesic benefit with the combination. This study evaluated clinical pain in chronic paint patients.
Mean plasma THC levels in the subjects were 1.8 ng/ml at baseline, 126.1 ng/ml at 3 min, 33.7 ng/ml at 10 min, 10.9 ng/ml at 30 min, and 6.4 ng/ml at 60 min. The peak THC concentration occurred at 3 min in all the participants and THC plasma levels did not vary significantly by opioid group nor did the supplementation with THC affect the subjects opioid levels.
Morphine and Oral THC
Another small 2006 study evaluating the combined use of morphine 0.02 mg/kg intravenously along with 5mg oral THC in an experimental pain model found a synergistic analgesic benefit with the combination.
Mechanisms of Synergy between Opioids and Cannabinoids
The mechanism(s) that allow for the cannabinoid-opioid synergism is unknown. Additionally, two studies have found that with specific opioids and cannabinoids the analgesic effect was additive rather than synergistic.
CBD has been described as a modulator of μ (mu) and δ (delta) opioid receptors; there are, however, no studies demonstrating this behaviorally. The mechanism(s) may be due to THC activation of kappa opiate receptors. Cannabinoid and opioid receptors have similar signal transduction systems and are found in several brain regions involved in pain modulation, including the periaqueductal gray, raphe nuclei, and central-medial thalamic nuclei . In addition, mu-opioid receptors and cannabinoid (CB1) receptors are both present in the spinal cord in the primary afferent pain circuits that deliver pain signals to the brain.
Both CB1 and CB2 agonists may be able to induce antinociception by increasing opioid precursors’ gene expression or via release of endogenous opioids. Further, pharmacological modulation of the opioid system can modify the effects of delta-9- THC, a partial agonist at the CB1 and CB2 receptor, on nociception and vice versa: cannabinoid antagonists have been shown to reverse the antinociception induced by morphine . Taking these findings together, it strongly supports shared mechanisms between both systems in regard to analgesia.
Synergy – Opioids & CB2 Agonists
A primary function of the endocannabionoid system is to moderate pain. Yet, few studies have evaluated whether opioids (mu opioid agonists) and CB2 agonists act synergistically to inhibit pain, particularly chronic pain, or reduce unwanted side effects including stimulating reward effects that contribute to addiction.
A 2017 study, “Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists,“ determined that combining opioids with CB2 agonists results in a significant synergistic inhibition of pain while significantly reducing opioid-induced unwanted side effects. This study suggests that BCP (β-caryophyllene), a CB2 receptor agonist, may have a synergistic effect in managing chronic pain. More clinical trials are needed.
Interestingly, animals studies suggest that use of cannabis may reduce the development of tolerance to the analgesic benefits of opioids, resulting in less need for opioid dose escalation.
Cannabis, Opioids and Overdose Risk
There is no enhancement of cardiorespiratory suppression from opioids with the addition of cannabinoids due to the very low density of cannabinoid (CB) receptors in brainstem cardiorespiratory centers. However, while there is no increased risk of fatal overdose when combining cannabinoids with opioids, both classes of drugs share adverse clinical effects including sedation and cognitive impairment that can be additive when taken together. Caution is advised when taking these two classes of medications together.
Cannabis, Opioids and Metabolic Interactions
CBD has been identified as a potent inhibitor of the liver enzyme CYP2D6 which may have significant impact on the metabolism of opioids that are broken down by CYP2D6, including hydrocodone (Norc0, Vicodin, Zohydro, Hysingla), tramadol and codeine. As such, use of CBD with tramadol, codeine or hydrocodone may significantly reduce the analgesic effectiveness of these opioids.
National Academy of Sciences
This website appears to be good resource for exploring medical marijuana.
Cannabinoids & Opioids – Consequences of Medical Marijuana and Opioid Use
- It is premature to expand access to medicinal cannabis in hopes of solving the US opioid crisis – 2018
- Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
- Patterns and correlates of medical cannabis use for pain among patients prescribed long-term opioid therapy. – PubMed – NCBI
- Associations between medical cannabis and prescription opioid use in chronic pain patients – A preliminary cohort study – 2017
- The prevalence and significance of cannabis use in patients prescribed chronic opioid therapy: a review of the extant literature. – PubMed – NCBI
- The use of cannabis in response to the opioid crisis: A review of the literature. – PubMed – NCBI
- Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999–2010 – 2014
- Rationale for cannabis-based interventions in the opioid overdose crisis – 2017
- Cannabis and the Opioid Crisis – 2018
- Effects of Legal Access to Cannabis on Scheduled II-V Drug Prescriptions. – PubMed – NCBI
- Association of Medical and Adult-Use Marijuana Laws With Opioid Prescribing for Medicaid Enrollees. – PubMed – NCBI
- The prevalence and significance of cannabis use in patients prescribed chronic opioid therapy: a review of the extant literature. – PubMed – NCBI – 2009
- Experience of adjunctive cannabis use for chronic non-cancer pain: findings from the Pain and Opioids IN Treatment (POINT) study. – PubMed – NCBI 2015
Cannabinoids & Opioids – Pain
- Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. – PubMed – NCBI
- Cannabinoid–Opioid Interaction in Chronic Pain
- Synergistic interactions between cannabinoid and opioid analgesics. – PubMed – NCBI
- Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine – 2006
- Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists – 2017
- The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study. – PubMed – NCBI – 2016
- Cannabinoids and Pain – New Insights From Old Molecules – 2018
- Opioid-Sparing Effect of Cannabinoids – A Systematic Review and Meta-Analysis – 2017
- Preliminary evaluation of the efficacy, safety, and costs associated with the treatment of chronic pain with medical cannabis – 2018
Cannabinoids & Opioids – Synergy
Cannabinoids & Opioids – Opioid Drug Interactions
- The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness – 2014
- Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6 – 2011
Cannabinoids & Opioids – Impact on Drug Abuse
Emphasis on Education
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