All opiates in clinical use produce analgesia via the same molecular mechanism, that is, binding to G-protein–coupled opioid receptors with subsequent inhibition of adenylate cyclase, activation of inwardly rectifying K+ channels, and inhibition of voltage-gated Ca2+ channels, all of which decrease neuronal excitability. Given the commonality of the mechanism, one might reasonably ask why there are such clear clinical differences among opioids with respect to pharmacokinetic and pharmacodymanic characteristics such as minimal effective plasma concentration, elimination half-time, and volume of distribution (Table 9.1).

The net analgesic effect of any opiate is the result of numerous processes that must occur prior to G-protein activation. Opiates must first redistribute from their site of administration (IV, IM, epidural, intrathecal) to their site of action (brain, spinal cord, peripheral opioid receptors), they must traverse anatomic and physiologic barriers (blood-brain-barrier, spinal meninges), they must diffuse through tissue (brain, spinal cord) to reach opioid receptors, they must bind to their receptor, and finally they must induce a conformational change in the receptor to activate the G-protein. The rate and extent to which any individual opiate completes these steps is largely dependent on its molecular structure and its physicochemical properties. This chapter discusses what is known about which physicochemical properties (Table 9.1) underlie the clinical pharmacology of opiates.