Opioid tolerance physical dependence

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Coderre TJ. The opioid p agonist/6 antagonist DIPP-NH2 i 1 produces a potent analgesic effect, no physical dependence and less tolerance than morphine in rats. J Med Chem 1999 42 3520-3526. 

Bailey, C.R, Connor, M. Opioids cellular mechanisms of tolerance and physical dependence. Curr. Opin. Pharmacol. 5 60, 2005. 

Patients tolerant to or physically dependent on op/o/c/s. Nalmefene may cause acute withdrawal symptoms in individuals who have some degree of tolerance to and dependence on opioids. Closely observe these patients for symptoms of withdrawal. Administer subsequent doses with intervals of at least 2 to 5 minutes between doses to allow the full effect of each incremental dose of nalmefene to be reached. Reversal of postoperative opioid depression Use 100 mcg/mL dosage strength (blue label) refer to the following table for initial doses. The goal of treatment with nalmefene in the postoperative setting is to achieve reversal of excessive opioid effects without inducing a complete reversal and acute pain. This is best accomplished with an initial dose of 0.25 mcg/kg followed by 0.25 mcg/kg... 

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. 

The answers are 264-c, 263-c. (Katzung, pp 519, 535-537.) Heroin and other opioids (such as morphine and meperidine) exhibit a high degree of tolerance and physical dependence. The tolerance rate magnitudes to all of the effects of opioids are not necessarily the same. The physical dependence is quite clear from the character and severity of withdrawal symptoms, which include vomiting spasms, abdominal cramps, diarrhea, and acid-base imbalances among others. 

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. 

The development of physical dependence is an invariable accompaniment of tolerance to repeated administration of an opioid of the - type. Failure to continue administering the drug results in a characteristic withdrawal or abstinence syndrome that reflects an exaggerated rebound from the acute pharmacologic effects of the opioid. 

Methadone is widely used in the treatment of opioid abuse. Tolerance and physical dependence develop more slowly with methadone than with morphine. The withdrawal signs and symptoms occurring after abrupt discontinuance of methadone are milder, although more prolonged, than those of morphine. These properties make methadone a useful drug for detoxification and for maintenance of the chronic relapsing heroin addict. 

Patients who are prescribed opioids for a period of time may develop a physical dependence on them, which is not the same as addiction. Repeated exposure to opioids causes the body to adapt, sometimes resulting in tolerance (that is, more of the drug is needed to achieve the desired effect compared with when it was first prescribed) and in withdrawal symptoms upon abrupt cessation of drug use. Thus, individuals taking prescribed opioid medications should not only be given these medications under appropriate medical supervision, but they should also be medically supervised when stopping use in order to reduce or avoid withdrawal symptoms. Symptoms of withdrawal can include restlessness, muscle and bone pain, insomnia,... 

Many myths surround the stronger opioids and their use can become restricted when the definitions of addiction, tolerance and physical dependence are confused. Some opioids, e.g. codeine, are less potent and are readily available in OTC products. 

Taylor, D.A. and Fleming, W.W. Unifying perspectives of the mechanisms underlying the development of tolerance and physical dependence to opioids, J. Pharmacol. Exp. Ther. 2001, 297, 11-18. 

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