Morphine physical dependence

Schrater, Paul A., Albert C. Russo, Toni I.. Stanton, J. Robert Newman, Lynn M. Rodriguez, and Alexander L. Beckman. 1993. "Changes in Striatal Dopamine Metabolism During the Development of Morphine Physical Dependence in Rats Observations Using In Vivo Microdialysis." Life Sciences 52 1535—45. 

Studies examined the physical dependence associated with chronic treatment of rats with DPI-3290 and compared this with the physical dependence measured in rats treated for 3 days with morphine. Physical dependence was facilitated by injection with naloxone. Illustrated in Figure 3 is the dose-response relationship for DPI-3290 and morphine induced abstinence (physical dependence). At all doses tested, the magnitude of DPI-3290-mediated abstinence was markedly smaller than the abstinence associated with morphine. Most interestingly, at the higher doses of DPI-3290, abstinence appears to plateau whereas the abstinence associated with morphine continues to increase with dose. 

Molecular modifications of the morphine skeleton have produced numerous derivatives with antitussive properties, some of which have become commercially significant. Ethyknorphine [76-58-4] (29), a simple homologue of codeine, is prepared by ethylating morphine. It is pharmacologically similar to codeine but is seldom used clinically. Pholcodine [509-67-1] (30), the morpholinoethyl derivative of morphine, is used as an antitussive in a number of European countries. It is about one and a half times as potent as codeine, has Htde or no analgesic activity, and produces minimal physical dependence. The compound is prepared by the amino alkylation of morphine (48). 

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... 

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... 

Blasig, J. Hen, A. Reinhold, K. and Zieglgansberger, S. Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia 33 19-38, 1973. 

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. 

The history of this class of analgesics might have stopped there were it not for the manifold ancillary activities shown by that molecule. Although still one of the most widely used agents for treatment of severe pain, morphine is a drug that must be used with caution. Side effects include respiratory depression, induction of constipation, and sometimes marked sedation. The one property that most severely limits use of this drug is its propensity to induce physical dependence in patients subjected to more than casual exposure. 

Martin, W. R., and Eades, C. G. (1967) Pharmacological studies of spinal cord adrenergic and cholinergic mechanisms and their relation to physical dependence on morphine. Psycho-pharmacologia, 11 195-223. 

Schedule II—The drug or other substance has (1) a high potential for abuse, (2) a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions, and (3) abuse of the drug or other substances may lead to severe psychological or physical dependence. Examples cocaine, PCP, morphine, fentanyl and meperidine, codeine, amphetamine and methamphetamine, Ritalin . 

Cyclo(His-D-Leu) acts as a hydrolytic catalyst. Cyclo(Leu-Gly) blocks the development of (1) physical dependence on morphine, (2) tolerance to the pharmacological effects of /3-endorphin, (3) tolerance to haloperidol-induced catalepsy and hypothermia, and (4) dopaminergic supersensitivity after chronic morphine administration. Cyclo(Tyr-Arg), a synthetic analogue of kyortorphin (an endogenous analgesic peptide), and its A-methyl tyrosine derivatives are more potent than kyotorphin in the mouse tail pressure test. ... 

Cyclo(Pro-Phe) isolated from Rosellinia necatrix is potent in blocking physical dependence to morphine in... 

Many benzomorphan derivatives with morphine-like potencies or better have a low physical dependence capacity (PDC) in monkeys especially potent members, however, such as phenazocine and the /3-isomers (Table 5.2, Nos. 8 and 16) have high to intermediate PDC properties [5, 63, 68]. Unusual results have been reported. for the enantiomorphs of a-(X) (R = Me, R = = Et) the... 

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... 

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. 

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