Cross-tolerance with opioids

Alcohol-dependent people with a physical tolerance are relatively tolerant of some other cerebral depressant drugs (hydrocarbon anaesthetics), but of course the synergism with these drugs still occurs. There is no significant acquired cross-tolerance with opioids. 

Multimodal therapy clonidine seems to have a synergistic effect with opioids. This provides for more intense analgesia with the minimization of some of the adverse effects of either class of drugs. There is some cross-tolerance with opioids however, for patients with high opioid tolerance clonidine is an excellent adjimct... 

Adverse effects Large doses of meperidine cause tremors, muscle twitches, and rarely, convulsions. The drug differs from opioids in that in large doses it dilates the pupil and causes hyperactive reflexes. Severe hypotension can occur when the drug is administered postoperatively. When used with major neuroleptics, depression is greatly enhanced. Administration to patients taking monoamine oxidase inhibitors (see p. 123) can provoke severe reactions such as convulsions and hyperthermia. Meperidine can cause dependence, and can substitute for morphine or heroin in use by addicts. Cross-tolerance with the other opioids occurs. 

Indeed d9-THC is cross-tolerant with k opioid receptor agonists... 

Electrical stimulation of the periaqueductal gray matter has produced naloxone-reversible analgesia that displays cross-tolerance with morphine analgesia and releases endogenous opioid peptides into the CSF. Enkephalins also exist in cells whose functions relate to bowel motility (nerve plexuses and exocrine glands of the stomach and intestine). 

In the chemistry described in Scheme 6.151, Coats and a group of researchers from Johnson and Johnson utilized successive reductive aminations and Suzuki cross-coupling reactions to prepare a 192-member library of tropanylidene benz-amides [295], This series of tropanylidene opioid agonists proved to be extremely tolerant with regard to structural variation while maintaining excellent opioid activity. 

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

Another important consideration promoting the view that subtypes of the 6-opioid receptor exist is the remarkable lack of cross-tolerance between agonists at the and 2 opioid receptors. Furthermore, no cross-tolerance exists between 5 -and p-opioid receptors [33,38,44,45]. In one of the earliest studies, acute tolerance to spinal DPDPE or to DSLET was elicited in (3-FNA-pretreated (i.e., p receptors blocked) mice [45]. Pretreatment with DPDPE attenuated the antinociceptive effect of subsequent spinal DPDPE but not that of DSLET, whereas pretreatment with DSLET attenuated the effect of DSLET and not DPDPE [45]. A similar lack of cross-tolerance... 

Wagner EJ, Zhang W, LaGrang A, Ronnekleiv O, Kelly M (1997) Tolerance to mu-opioid receptor agonists but not cross-tolerance to y-aminobutyric acid B receptor agonists in arcuate A12 dopamine neurons with chronic morphine treatment. J Pharmacol Exp Ther 250 1057-1064. 

Occurs with continued use and is functional (pharmacodynamic), with changes in cellular adaptive responses but not receptor numbers. Tolerance can be marked for the CNS actions including analgesia, euphoria, and respiratory depression, but it occurs minimally in terms of miosis and the effects on GI motility. Cross-tolerance occurs between individual opioid analgesics. 

Synthetic opioids compared with morphine and ketamine catalepsy, cross-tolerance and interactions in the rat Benthuysen, J. L. Hance, A. J. Quam, D. D. Winters, W. D. Neuropharmacology (1989), 28(10), 1011-15... 

Tolerance Marked tolerance develops to the above acute pharmacologic effects, with the exception of miosis and constipation. There is cross-tolerance between different opioid agonists. 

Receptor interactions clonidine interacts at the G protein-coupled alpha receptors with a greater affinity for the alpha-2 receptors. The activation of the alpha-2 receptors results in decreased cAMP, K efflux as well as Ca entry into the nerve terminals. Activation of receptors in the sympathetic nerve endings and in the noradrenergic neurons in the CNS inhibits release of norepinephrine and may release acetylcholine. The locus coeruleus is an important modulator of alertness and may be the major site for the hypnotic effects of clonidine. Additionally, the G protein pathway has a similar transduction pathway to the opioids, explaining some of the cross-tolerance and synergy between the two classes of drugs. 

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