Analgesics, Pain and Tolerance: The St John's Discussion

Four of the articles in the present issue of Pain Research & Management discuss preclinical issues relevant to understanding the changes that occur to the analgesic efficacy of opiates over an extended interval of delivery (pages 25 to 57). The articles reflect the extended and interesting discussions that transpired at the Canadian Pain Society meeting held in St John’s, Newfoundland, May 14 to 16, 1999. The role of changes in opiate responsiveness in long term opiate exposure in clinical pain states is controversial. While few argue that opiate dosing does not rise over time, it is evident that, with chronic exposure, many patients show a very stable dosing requirement. When the dosing necessary to sustain pain relief rises, the rise may occur by several mechanisms, including the appearance of more intense pain and the evolution of opiate-insensitive pain states. Yaksh reviews some of these issues in his contribution (pages 33-39). Nevertheless, clinical and preclinical studies aimed at defining specific dose requirements have emphasized that, of the several mechanisms, pharmacodynamic plasticity can contribute to the ongoing changes in dose requirements. Several of the articles in this issue focus on this component of the process, with an emphasis on the potential importance of changes in receptor coupling and function. An emerging concept is the role of glutamate, and the several ionotropic and metabotropic receptors on which it works. Importantly, such observations are in agreement with the review by Jhamandas and colleagues (pages 25-32) of the potential contributions of a variety of spinal transmitters and second messengers in the development of a reduced response to the chronically delivered opiate. Fundytus (pages 40-48) considers the potential contribution of several neurotransmitter systems and emphasizes the potential role of metabotropic receptors. She draws parallels between the mechanisms of neuropathic pain states and opioid tolerance. Yaksh discusses the role of spinal glutamate receptors in spinal tolerance to opioid and alpha2-adrenergic agonists, and the contribution of phosphorylation to spinal tolerance. Cahill and Coderre (pages 49-57) discuss the interactions of nerve growth factor and the expression of cholecystokinin in the opiate insensitivity noted in some neuropathic states. The reviews, thus, strongly focus on the local neuronal network and the cell type on which the opiate receptor is found. Rather than repetitiously detailing the conclusions of each article, I will consider some of the implications of the opinions of the author(s) of each paper regarding the mechanisms responsible for a rise in opiate dosing. I hope that my interpretations will be viewed forgivingly by each contributor in the possible event that I erred in my reading of their interpretation.