The precise analgesic mechanism of action of THC remains to be fully elucidated. Cannabinoids bind to receptors (to date, cannabinoid [CB] receptor types 1 and 2 have been identified, but it is suspected others exist). Their physiological ligands (endocannabinoids) have been implicated in numerous physiological pathways. Indeed, the endogenous cannabinoid system — which includes enzymes and proteins that regulate concentrations of cannabinoids — have been considered a relevant and exciting research target for analgesia.

The known CB-1 and CB-2 receptors are G-protein coupled receptors embedded in cell membranes. The ligand (endocannabinoid) binds at the receptor site and triggers second-messenger enzymatic activity, mainly producing adenylate cyclase inhibition, voltage-gated calcium-channel blocking, and activates mitogen-responsive protein kinase and protein channels. These endocannabinoid ligands are derivatives of arachidonic acid and are part of the eicosanoid-signaling network.

CB-1 receptors are expressed in parts of the brain associated with nociception and they receive nociceptive inputs from the primary afferent neurons. CB-2 receptors are found in the gastrointestinal tract and appear to inhibit adenylyl cyclase; they may play a role in immune system modulation and may mediate analgesia to the periphery.

More abundant than µ-opioid-receptors, CB-1 receptors are present in the peripheral sensory nerve endings up to the brain and in many parts of the brain itself (hypothalamus, hippocampus, cerebellum, and others). Because there is only low expression of CB receptors in the brainstem compared to µ-opioid-receptors, cannabinoids — unlike opioids — are not associated with respiratory depression.

THC may interfere with the affective aspects of pain, that is, the perception of pain signals. The frontal-limbic distribution of CB receptors suggests that cannabinoids preferentially target the affective aspects of pain.

The below table summarises the clinical studies conducted to evaluate the efficacy and safety of cannabinoids in pain management.

Cannabinoids appear to be effective in treating neuropathic pain, allodynia, medication-rebound headache, and certain types of chronic noncancer pain, but they are less or not effective in treating acute pain.

Clinicians should be aware that some studies evaluate botanical cannabinoids (which may be smoked, vaporized, or ingested with food) while others study synthetic cannabinoids. Among the synthetic cannabinoids are dronabinol, nabilone, nabiximol, THC tablets, and ajulemic acid. Thus, it is often difficult to compare studies as they may use different forms of “cannabis.”

A few studies have evaluated the use of cannabinoids as add-on therapy to combine with opioids. Cannabinoids and opioids use separate but related pathways and they may have an opioid-sparing effect.

Prolonged exposure to cannabinoids for pain control does not appear to be associated with tolerance. However, long-term use has been associated with cognitive deficits, learning difficulties, and memory problems.

The laws regarding medical marijuana are currently in a state of flux and many potential patients may be unable to obtain prescriptions. Anecdotal reports suggest that some patients obtain their own marijuana (possibly illegally) and self-medicate.