Opioids physical dependence

Heishman SJ, Stitzer ML, Bigelow GE, et al Acute opioid physical dependence in postaddict humans naloxone dose effects after brief morphine exposure. J Pharmacol Exp Ther 248 127-134, 1989... 

This book is mainly concerned with the treatment of opiate misuse, for the simple reason that that is the form of drug misuse for which there are the most effective clinical approaches. As we have discussed, the treatment scene for opiate misusers, in contrast to other groups, is fundamentally altered by the widespread availability of the substitution option, in the form of methadone or alternative opioids. Physical dependence is part of the rationale for that approach, and the occurrence of clear-cut withdrawal symptoms also indicates the use of drugs such as lofexidine or clonidine, followed where possible by naltrexone. For reasons of severity of dependence and treatment options, it is therefore understandable that services are inclined to have caseloads dominated by opiate users. 

Bisaga, A., Comer, S. D., Ward, A. S., Popik, P., Kleber, H., Fischman, M. W. The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology 2001, 157, 1-10. 

Tolerance also results from metabolic changes (enzyme induction) and physiological/behavioural adaptation to drug effects, e.g. opioids. Physical dependence develops to a substantial degree with... 

The agonist-antagonists drug can cause opioid witii-drawal symptoms in tiiose who are physically dependent on die opioids. There is an increased risk of respiratory... 

These dm may produce withdrawal symptoms in those physically dependent on the narcotics. The patient must not have taken any opiate for the last 7 to 10 days. Naloxone may prevent die action of opioid antidiarrheals, antitussives, and analgesics. This drug is used cautiously during lactation. 

Administration of sufficient doses of an opioid antagonist after only a single therapeutic dose of morphine results in withdrawal phenomena (Bickel et al. 1987 Heishman et al. 1989 Jones 1979). Some degree of physical dependence... 

Most of the work has been based on opioids since it is the easiest system to manipulate as administration of the antagonist, naloxone, precipitates withdrawal. Flere, the idea that physical dependence results from opposing changes in the neuronal systems depressed by the drug of dependence is borne out by consideration of the acute effects of an opioid and the withdrawal symptoms. They are mirror images of each other ... 

Figure 23.2 A schematic diagram illustrating the ways in which the CNS counters the depressant effects of a drug such as alcohol or an opioid and how this leads to the manifestation of physical dependence when there is abstinence from the drug. These excitatory compensations produce symptoms opposite to the acute effects of the drug...

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. 

Nicotinic cholinergic receptors are located on cells that release a wide variety of transmitters (see chapter by Barik and Wonnacott, in this volume), so that nicotine interacts with multiple neurochemical pathways. The roles of cholinergic, dopaminergic, and endogenous opioid systems in physical dependence and withdrawal have been most thoroughly studied and documented. Research on the role of other transmitters and neurochemical mechanisms is rather scattered. Overall, however, research with rodent models of physical dependence has provided a wealth of potential targets for experimental treatments to aid smoking cessation. 

Opioids. Activation of opioid receptors in the enteric nerve plexus results in inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not Lullmann, Color Atlas of Pharmacology... 

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... 

Risk of precipitated withdrawal Nalmefene is known to produce acute withdrawal symptoms and, therefore, should be used with extreme caution in patients with known physical dependence on opioids or following surgery involving high uses of opioids. 

Drug dependence Administer cautiously to people who are known or suspected to be physically dependent on opioids, including newborns of mothers with narcotic dependence. Reversal of narcotic effect will precipitate acute abstinence syndrome. Repeat administration The patient who has satisfactorily responded should be kept under continued surveillance. Administer repeated doses as necessary, because the duration of action of some narcotics may exceed that of the narcotic antagonist. Respiratory depression Not effective against respiratory depression due to nonopioid drugs. 

Narcotic-dependent patients Because of the narcotic antagonist activity of buprenorphine, use in physically dependent individuals may result in withdrawal effects. Buprenorphine, a partial agonist, has opioid properties that may lead to psychic dependence because of a euphoric component of the drug. The drug may not be substituted in acutely dependent narcotic addicts because of its antagonist component. 

Diphenoxylate is a synthetic meperidine analog with little or no analgesic activity. However in high doses it shows opioid activity such as euphoria and a morphine-like physical dependence after chronic administration. Its insolubility however, in aqueous solution prevents parenteral abuse. Nevertheless, diphenoxylate has in most countries been replaced by loperamide. 

Opioid binding at medullary sites is consistent with the respiratory depressant effects of the drugs. Binding in the nucleus accumbens and the resultant release of dopamine by the /x- and 8-opioids is linked to the development of physical dependence. However, the K-opioids, which also bind extensively in the nucleus accumbens, are linked to a decrease in dopamine release, possibly explaining their lower abuse liability. The localization of different receptor subtypes within different-size fiber pathways has been established. The x- and 8-receptors appear associated with the large-diameter fibers, while the K-receptors appear to be located in the small to medium-size fiber bundles of the dorsal root ganglia. Such differences may explain the modulation of specific types of nociceptive stimuli by the different opioid agonists and opioid peptides. 

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