Tolerance and Physical Dependence

The manner and severity of withdrawal symptoms varies according to the type of drug and the extent of physical dependence.50 Withdrawal after short-term benzodiazepine use may be associated with problems such as sleep disturbances (i.e., so-called rebound insomnia).34 62 As discussed earlier, withdrawal effects seem to be milder with the newer nonbenzodiazepine agents (zolpidem and zaleplon).34,62 Newer agents, however, are not devoid of these problems and care should be taken with prolonged use, especially in people with psychiatric disorders or a history of substance abuse.26 

Consequently, the long-term use of these drugs should be avoided, and other nonpharmacologic meth- 

Drug Estazolam (ProSom) Time to Peak Plasma Concentration (hr) 2.0 Relative Half-Life Intermediate Comments Rapid oral absorption 

Flurazepam (Dalmane) 0.5-1.0 Long Long elimination half-life because of active metabolites 

Quazepam (Doral) 2.0 Long Daytime drowsiness more likely than with other benzodiazepines 

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

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. 

Repeated use may result in drug tolerance and physical dependence. 

Tolerance and physical dependence may occur with repeated use. 

Cox, B.M. (1990) Drug tolerance and physical dependence. In Pratt, W.B. and Taylor, P., eds. Principles of Drug Action The Basis of Pharmacology, 1st ed. New York Churchill Livingstone,... 

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. 

It is associated with development of psychic dependence, tolerance and physical dependence and sudden withdrawal of alcohol may lead to withdrawal syndrome. 

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. 

Liaw WI et al Distinct expression of synaptic NR2A and NR2B in the central nervous system and impaired morphine tolerance and physical dependence in mice deficient in postsynaptic density-93 protein. Mol Pain 2008 4 45. [PMID 18851757]... 

Tolerance, physical dependence and receptors. A theory of the genesis of tolerance and physical dependence through drug-induced changes in the number of receptors, 3, 171... 

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. 

The development of acute tolerance and dependence evoked in mice by morphine can be suppressed by pretreatment with NTI. Multiple administration of either NTI or 5 NTII before and during chronic implantation with morphine pellets also substantially inhibits the development of morphine tolerance and dependence. These results suggest the use of 8 antagonists to be useful for the prevention of opioid tolerance and physical dependence without compromising the antinociceptive potency of p opioid receptor agonists (Abdelhamid et al., 1991). 

Prevention of p-opioid tolerance and physical dependence by 8 antagonists... 

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