Morphine syndrome

Hien DA, Nunes E, Levin FR, et al Posttraumatic stress disorder and short-term outcome in early methadone treatment. J Subst Abuse Treat 19 31-37, 2000 Himmelsbach CK The morphine abstinence syndrome, its nature and treatment. Ann Intern Med 13 829-839, 1941... 

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. 

Chesher GB and Jackson DM (1985). The quasi-morphine withdrawal syndrome Effect of cannabinol, cannabidiol and THC. Pharmacology, Biochemistry and Behaviour, 23, 13-15. 

There are two main treatments for the opiate withdrawal syndrome. One is replacement therapy with methadone or other X agonists that have a longer half-life than heroin or morphine, and produce mild stimulation rather than euphoria. They also produce cross-tolerance to heroin, lessening heroin s effect if patients relapse. Withdrawal is also treated with the 0C2 agonist clonidine, which inhibits LC neurons, thus counteracting autonomic effects of opiate withdrawal — such as nausea, vomiting, cramps, sweating, tachycardia and hypertension — that are due in part to loss of opiate inhibition of LC neurons. 

Opioids also interact with excitatory amino acid neurotransmitters. At lower micromolar concentrations, p agonists (e.g., DAMGO) enhance NMDA activity in the nucleus accumbens, but inhibit non-NMDA activity (Martin et al. 1997). At higher concentrations (5 pM), NMDA currents are reduced. Conversely, central administration of glutamate can precipitate a withdrawal syndrome in morphine-dependent animals, similar to the opioid antagonist naloxone. NMDA mechanisms also appear to be involved in the development of morphine tolerance. Competitive and noncompetitive NMDA antagonists and inhibitors of nitric oxide synthase reduce or eliminate tolerance to morphine (Elliott et al. 1995 Bilsky et al. 1996). However, this does not occur for tolerance to k opioids. Pharmacokinetics... 

Aiicioglu-Kartal F, Kayir H, Tayfun U1 (2003) Effects of harman and harmine on naloxone-precipitated withdrawal syndrome in morphine-dependent rats. Life Sci 73 2363-2371 Balerio GN, Aso E, Berrendero E, Murtra P, Maldonado R (2004) Delta9- tetrahydrocanabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice, Eur J Neurosci 20 2737-2748... 

In retrospect, the reason for this is not all that obscure. Most of the soldiers were in hypo-volaemic shock with low blood pressure, low blood volume, and as part of the shock syndrome, systemic circulation was minimal with intense vasoconstriction - hence the poor therapeutic effect. The repeated doses of morphine were usually given intramuscularly into the buttock or thigh but their clearance into the systemic circulation was minimal until resuscitation occurred and the peripheral circulation was restored. Blood flow to the muscle increased and all the morphine injected became available - all at once. This was the reason for the morphine overdoses and the occasional death. Thereafter it has become standard practice to give morphine in emergency directly into the veins and not into poorly perfused muscles. 

In addition to all of the adverse effects and contraindications previously described for morphine, the following contraindications apply specifically to these drugs. They are contraindicated in pregnant women because of their potential teratogenic effects. They also can cause respiratory depression in the mother, which reduces oxygenation of fetal blood, and in the newborn the incidence of sudden infant death syndrome (SIDS) in the newborn is also increased. 

---