Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands.

INTRODUCTION: Commercially available cannabinoids are subject to psychotomimetic and addiction (cannabinomimetic) adverse effects largely through activation of the cannabinoid 1 receptor (CB1r). The available commercial cannabinoids have a narrow therapeutic index. Recently developed peripherally restricted cannabinoids, regionally administered cannabinoids, bifunctional cannabinoid ligands and cannabinoid enzyme inhibitors, endocannabinoids, which do not interact with classic cannabinoid receptors (CB1r and CB2r), cannabinoid receptor antagonists and selective CB1r agonists hold promise as analgesics. AREAS COVERED: This author provides a review of the current investigational cannabinoids currently in development for pain management. The author also provides their perspective on the future of the field. EXPERT OPINION: Regional and peripherally restricted cannabinoids will reduce cannabinomimetic side effects. Spinal cannabinoids may increase the therapeutic index by limiting the dose necessary for response and minimize drugs exposure to supraspinal sites where cannabinomimetic side effects originate. Cannabinoid bifunctional ligands should be further explored. The combination of a CB2r agonist with a transient receptor potential vanilloid (TRPV-1) antagonist may improve the therapeutic index of the CB2r agonist. Enzyme inhibitors plus TRPV-1 blockers should be further explored. The development of analgesic tolerance with enzyme inhibitors and the pronociceptive effects of prostamides limit the benefits to cannabinoid hydrolyzing enzyme inhibitors. Most clinically productive development of cannabinoids over the next 5 years will be in the area of selective CB2r agonists. These agents will be tested in various inflammatory, osteoarthritis and neuropathic pains.