Pain can be a major symptom of a huge variety of illnesses, conditions, and traumas. Chronic pain conditions are estimated to affect around 34% of the population in England alone, and specifically neuropathic pain, musculoskeletal pain, and cancer-associated pain may affect a significant proportion of the population during their lifetimes. This makes effective analgesic treatment options a vital area of consideration in medical research and practice.
Opioids such as morphine and codeine are still routinely prescribed to treat pain in the UK, despite low-quality evidence of their analgesic potential. In recent years, there have been growing calls for reducing the prescription rates of these medications due to concerns related to their potential harm, including their high potential for abuse and addiction. As a result, researchers and medical practitioners are on the look-out for potential alternative therapies that could help to reduce both opioid dosage and the duration of opioid treatment. One potential therapy that is being assess for its effectiveness in this regard is medical cannabis.
A growing number of studies have aimed to understand the opioid-sparing potential of medical cannabis products in patients with analgesia. A recent systematic review and meta-analysis assessed the results of existing preclinical and clinical studies in this area.
Opioids and Cannabinoids
There is a biological basis for comparing the effects of opioids and cannabinoids: both opioid and cannabinoid receptors are expressed throughout the central and peripheral nervous systems in areas involved with anti-nociception. Both opioid and cannabinoid receptors are Gi/o-protein-coupled receptors with similar intracellular signaling mechanisms. Several studies have assessed the potential synergistic interaction between opioids and cannabinoids in these mechanisms which could promote a more efficacious analgesic effect.
Design and Methods
The researchers of this review also authored another systematic review and meta-analysis in 2017 which found “robust clinical evidence supporting the opioid-sparing potential of delta-9-tetrahydrocannabinol (THC), but limited clinical research testing the opioid-sparing effects of [other] cannabinoids.” However, given the increase of studies over the last five years, the researchers aimed to provide a more up-to-date synthesis of preclinical and clinical studies in this area.
Studies were identified using a systematic literature search on 20th December 2020. The results were combined with the results identified in the previous search, carried out on 29th October 2015. A combination of search terms relating to opioids, cannabinoids, and analgesia were used. Eligible studies included both animal and human studies: for human studies, controlled clinical and preclinical studies where cannabinoids were administered within a medical or clinical therapeutic framework and the study outlined details of cannabinoid administration.
Eligible studies must also have documented administration of opioids and cannabinoids, and an outcome of analgesia/pain (including acute, chronic, cancer, and non-cancer and experimental pain studies) or opioid requirements/opioid-sparing.
For preclinical studies, the primary outcome was the dose of opioid required to give an equivalent antinociceptive effect in the presence and absence of cannabinoids. For clinical studies, the outcomes of interest were: (1) reduction in total opioid doses, (2) reductions in pain through the addition of a cannabinoid, (3) adverse events, and (4) evidence of abuse liability.
Analysis and Findings of the Review
In total, 92 studies were identified: 40 preclinical and 37 clinical studies were included in the review. Fifteen of the identified studies were excluded as their data was yet not available.
Preclinical Studies
The majority of preclinical trials examined THC, while other studies examined 20 other cannabinoids. Opioids examined included morphine, codeine, fentanyl, oxycodone, and methadone. The majority of preclinical studies used rodents.
Evidence of opioid-sparing effects or synergism were found for all mixed CB1/CB2 agonists, including THC, CP55,940, HU-210, and WIN55,212–2; however, effects varied with different cannabinoids, opioids, and pain assays. Meta-analyses showed that morphine dose required to produce an equivalent analgesic effect was 3.5 times lower when administered alongside THC – an effect that would be clinically significant if replicated in well-controlled clinical studies.
Overall, while the researchers noted the limitations of preclinical studies, they concluded that the studies included in this review support the opioid-sparing effect of THC and other mixed CB1/CB2 agonists.
Clinical Studies
Thirty-seven clinical studies, with 5,180 participants, were included for review. Clinical trials included for review assessed experimental pain (n = 5), acute pain (n = 3), cancer pain (n = 7), and chronic non-cancer pain (n = 5):
Experimental Pain
Eighty-two healthy volunteers participated across five laboratory-based double-blind studies in which researchers examined pain responses with co-administered opioids and cannabinoids. Four of these studies examined dronabinol while one examined smoked cannabis. Mixed outcomes were observed.
While one study found low dose dronabinol was associated with a decreased analgesic effect of oxycodone, another study noted the potential hyperalgesic effects of cannabinoids; this second study found a higher analgesic effect when smoked cannabis was co-administered with oxycodone than when either medication was administered alone. Other studies found that dronabinol was associated with reduced pain when co-administered with morphine and hydromorphone.
Chronic Non-Cancer Pain
All five clinical trials in chronic non-cancer pain included for review examined either the effects of dronabinol or smoked cannabis. One study found that patients with various types of chronic non-cancer pain who were prescribed opioids experienced significant overall reductions from baseline pain ratings following co-administration of cannabinoids.
A sub-analysis in patients with chronic postsurgical abdominal pain found lower pain among those who received dronabinol compare with placebo. Another study in patients with mixed-chronic pain conditions found that dronabinol was associated with increased analgesia compares with placebo.
While some studies presented promising results, others demonstrated no significant analgesic or opioid-sparing effect of cannabinoids for chronic non-cancer pain.
Cancer Pain and Acute Pain
A total of 1,795 participants were included across seven controlled trials designed to investigate the opioid-sparing effect of cannabinoids in patients with different forms of cancer pain.
The researchers assessed three double-blind randomised controlled trials designed to assess the opioid-sparing effect of cannabinoids in acute pain (one study focused on general acute pain, one on acute post-operative pain, and one on acute low back pain). Overall, mixed results were observed, and no significant analgesic effect was identified through the co-administration of cannabinoids and opioids.
Conclusions
While preclinical studies demonstrated the significant analgesic and opioid-sparing effect of cannabinoids, overall results presented a more mixed picture. The researchers concluded that while “a limited number of controlled studies demonstrated benefits of combining cannabinoids with opioids for analgesia, further studies are needed to clarify these results”.
The authors note that their review draws similar conclusions to earlier reviews in this subject area which found large reductions in opioid doses. However, it is also noted that existing clinical trials tend to present low quality evidence due to factors such as small patient samples and the absence of control groups. Nonetheless, this is an area of research that continues to expand and draw increasing attention.
