Role of cannabinoids in the treatment of pain and (painful) spasticity.

Both the discovery of the endocannabinoid system (ECS) and its role in the control of pain and habituation to stress, as well as the significant analgesic and antihyperalgesic effects in animal studies, suggest the usefulness of cannabinoids in pain conditions. However, in human experimental or clinical trials, no convincing reduction of acute pain, which may be caused by a pronociceptive, ECS-triggered mechanism on the level of the spinal cord, has been demonstrated. In contrast, in chronic pain and (painful) spasticity, an increasing number of randomized, double-blind, placebo-controlled studies have shown the efficacy of cannabinoids, which is combined with a narrow therapeutic index. Patients with unsatisfactory response to other methods of pain therapy and who were characterized by failed stress adaptation particularly benefited from treatment with cannabinoids. None of the attempts to overcome the disadvantage of the narrow therapeutic index, either by changing the route of application or by formulating balanced cannabinoid preparations, have resulted in a major breakthrough. Therefore, different methods of administration and other types of cannabinoids, such as endocannabinoid modulators, should be tested in future trials.

Cannabinoids against pain. Efficacy and strategies to reduce psychoactivity: a clinical perspective.

The clinical use of cannabinoids is currently a topic of interest not exclusively, but most importantly, concerning different areas of pain therapy. One of the major obstacles in developing clinically acceptable compounds is the cannabimimetic side-effect profile of delta-9-tetrahydrocannabinol (THC) and other cannabinoids. This article gives a brief overview of the endocannabinoid system, its components and functions and explains the current approaches to avoiding cannabimimetic side effects by separating them from the therapeutic effects. One of these approaches is the addition of cannabidiol (CBD) as well as the use of preparations suitable for oromucosal application. Also cannabinoids, which primarily stimulate peripheral cannabinoid-1 (CB1) receptors or selectively cannabinoid-2 (CB2) receptors, can further separate analgesic activity from cannabimimetic activity. Local or topical modes of application are another attempt aiming in the same direction. Modulating the endogenous cannabinoid tone (via the inhibition of endocannabinoid-metabolising enzymes) is another strategy. The combination of THC in low, non-psychoactive doses with opioids has a synergistic effect and reduces opioid tolerance effects. Available data from these approaches are summarised and their more and less promising aspects are discussed.