Opioid cross-tolerance

Houtsmuller EJ, Walsh SL, Schuh KJ, Johnson RE, Stitzer ML, Bigelow GE. (1998). Dose-response analysis of opioid cross-tolerance and withdrawal suppression during LAAM maintenance. J Pharmacol Exp Ther. 285(2) 387-96. 

Pasternak GW (2001) Incomplete cross tolerance and multiple p opioid peptide receptors. Trend Pharmacol Sci 22 67-70... 

Conversion from parenteral morphine or other opioids (parenteral or oral) to CR/ER/SR doseforms- Exercise particular care in the conversion process. Because of uncertainty about, and intersubject variation in, relative estimates of opioid potency and cross-tolerance, initial dosing regimens should be conservative that is, an underestimation of the 24-hour oral morphine requirement is preferred to an overestimate. To this end, estimate initial individual doses conservatively. In patients whose daily morphine requirements are expected to be 120 mg/day or less, the 30 mg tablet strength is recommended for the initial titration period. Once a stable dose regimen is reached, the patient can be converted to the 60 or 100 mg tablet strength, or appropriate combination of tablet strengths, if desired. Conversion from CR/ER/SR oral morphine to parenteral opioids - It is best to assume that the parenteral-to-oral potency is high. For example, to estimate the required 24-hour dose of morphine for IM use, one could employ a conversion of 1 mg morphine IM for every 6 mg of morphine... 

Tolerance to many of the effects of the depressants develops. Unlike opioids, barbiturate and benzodiazepine tolerance develops slowly. Also, tolerance is incomplete in some instances or does not influence some pharmacological effects. One such exception is the lack of tolerance to barbiturate lethality. The lethal dose in a tolerant individual is not much different from that of the general population. Cross-tolerance develops to some degree between the depressant classes of drugs. 

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... 

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. 

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. 

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

Lichtman and Martin have shown that cannabinoid-induced antinociception has both spinal and supraspinal components [152]. A spinal a2-noradre-nergic mechanism is involved in cannabinoid antinociception as yohimbine and/or methysergide altered z)9-THC induced antinociceptive effects in rats [153]. A supraspinal mechanism is also involved as cannabinoid analgesia can be produced in spinally transected rats [152], Both similarities and differences were noted on comparison of the antinociceptive effects produced by anandamide (and the more potent fluroanandamide) and d9-THC [154], Anandamide was cross-tolerant to d9-THC, but in contrast to THC, it did not alter opioid-induced antinociceptive effects nor was its action blocked by a k antagonist. 

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