Perspectives on opioid tolerance from basic research: Behavioural studies after spinal administration in rodents

For tolerance development studies, computer modelling and statistical tests suggested that the equation which best described the decrement of analgesic effect was best served by an exponential decay function. Further analysis of the time course data led to the tentative conclusion that all groups of animals became tolerant at the same rate, regardless of drug or dose. A literature search revealed then, as it does now, that although there are many statements regarding the rate of opioid tolerance, there has been little systematic investigation of this. The Holy Grail of obtaining the rates of tolerance for a number of opioid agents in a systematic study is well within grasp. This information will be needed in clinical practice for the rational choice of opioid with regard to rate of the development of tolerance. The working hypothesis that emerges for the magnitude of opioid tolerance is that more potent agonists produce less tolerance. Further confirmation of this hypothesis has been forthcoming. This suggests that clinical use of more potent opioids, such as fentanyl, should be considered as a substitute for morphine in long term treatment regimens. The working hypothesis for cross-tolerance is that agents acting on the same receptors will show cross-tolerance. Cross-tolerance will also be observed among agents acting on different receptors, but only those that exhibit pharmacological synergy after short term administration. Asymmetry of cross-tolerance can occur, as the magnitude of this cross-tolerance is determined by the relative potency of the toleragen with regard to that of the probe agent. Given the additional factor of receptor selectivity with agents of different receptor classes, types and subtypes, new studies need to be designed combining the toleragen with a selective antagonist to determine the precise receptor mediation of the magnitude of tolerance, and thus cross-tolerance. For example, the δ opioid DADLE infused with a μ selective opioid antagonist would produce an animal strictly tolerant at δ receptors, as DADLE has been implicated to have some effects at μ receptors. In any event, consideration of the quantitative measures of cross-tolerance are extremely important to help shape a rationale treatment plan for patients who may become tolerant to a particular class of analgesics. In general, direct toleragen administration by constant dose, constant rate infusion into local central nervous system (CNS) regions will provide the most rigorous tolerance studies for examination of the pharmacodynamic theories of tolerance, as adaptations in processes affecting central bioavailability, such as dispositional changes in the blood-brain barrier or fibrous encapsulation of an implanted subcutaneous pellet, are circumvented. The above considerations also are relevant for studies of tolerance and cross-tolerance after intracerebroventricular administration or, in general, for tolerance studies after systemic administration. The possibility of probe administration to the same region of CNS that was rendered tolerant, as in the Y-catheter method, further enhances the focus on the pharmacodynamic mechanisms of tolerance without the ancillary and literally peripheral concerns of a dispositional nature. A posological approach to these studies cannot be overemphasized, as it is only through such time consuming and costly experiments that rigorous, quantitative data can be obtained. Such data may help to guide the hand of the physician towards rational therapeutic intervention in the treatment of patients with chronic pain and opioid tolerance.