Tolerance, drug opioid analgesics

Elliott K, Kest B, Man A, Kao B, Inturrisi CE. (1995). N-methyl-D-aspartate (NMDA) receptors, mu and kappa opioid tolerance, and perspectives on new analgesic drug development. Neuropsychopharmacology. 13(4) 347-56. 

All of the opioid agonists produce some degree of tolerance and physical dependence. The biochemical mechanisms underlying tolerance and physical dependence are unclear. It is known, however, that intracellular mechanisms of tolerance to opioids include increases in calcium levels in the cells, increased production of cAMP, decreased potassium efflux, alterations in the phosphorylation of intracellular and intranuclear proteins, and the resultant return to normal levels of release of most neurotransmitters and neuromodulators. Tolerance to the analgesic effects of opioids occurs rapidly, especially when large doses of the drugs are used at short intervals. However, tolerance to the respiratory depressant and emetic effects of the opioids occurs more slowly. The miotic and constipative effects of the opioids rarely show tolerance. 

Use of opioid drugs in acute situations may be contrasted with their use in chronic pain management, in which a multitude of other factors must be considered, including the development of tolerance to and physical dependence on opioid analgesics. 

Obviously, the risk of causing dependence is an important consideration in the therapeutic use of these drugs. Despite that risk, under no circumstances should adequate pain relief ever be withheld simply because an opioid exhibits potential for abuse or because legislative controls complicate the process of prescribing narcotics. Furthermore, certain principles can be observed by the clinician to minimize problems presented by tolerance and dependence when using opioid analgesics ... 

Drug dependence and self- or cross-tolerance develop with the use of opioid analgesics. Abrupt termination of therapy leads to severe withdrawal symptoms... 

When used in excessive doses, propoxyphene can be a major cause of drug-related death. Toxic long-lived metabolites can cause delirium, seizures, and cardiotoxic-ity. These effects can occur when the drug is used alone but especially when it is used in combination with other CNS depressants snch as alcohol. It is prudent to avoid propoxyphene or other opioid analgesics in depressed or suicidal patients and instead use nonnarcotic analgesics as tolerated for pain relief. 

Opioid analgesics are one of the few classes of medications available to treat severe levels of pain. Adding another drug to an opioid (compounding) may enhance analgesia, minimize adverse effects, reduce opioid tolerance and/or potentially deter overuse or abuse. Most astute chnicians recognize that concerns about abuse and addiction should not prevent the proper management of pain. In response. 

---