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


METHODS
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.


CONCLUSIONS
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.
The Cleveland Clinic Taussig Cancer Institute, The Harry R. Horvitz Center for Palliative Medicine, Department of Solid Tumor Oncology , 9500 Euclid Avenue R35, Cleveland, OH 44195 , USA +1 216 445 4622 ; +1 216 636 3179 ; davism6@ccf.org.
Mellar P
MP
Davis
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D063387:Cannabinoid Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002186:Cannabinoids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D063388:Endocannabinoids / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors
D000700:Analgesics; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D063388:Endocannabinoids; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
arachidonoyl; bifunctional; cannabinoid; endocannabinoid; enzyme; ethanolamine; orphan cannabinoid receptor; pain; peroxisome proliferator-activated receptor; receptor