Morphine toxicity

McCartney, M. A. 1989. Effect of glutathione depletion on morphine toxicity in mice. Biochem. Pharmacol. iS(l) 207-9. 

Once used as an arrow poison It IS hundreds of times more powerful than morphine in relieving pain It is too toxic to be used as a drug however)... 

Codeiae (2, R = CH3) occurs ia the opium poppy along with morphine (2, R = H) but usually ia much lower concentration. Because it is less toxic than morphine and because its side effects (including depression, etc) are less marked, it has found widespread use ia the treatment of minor pain and much of the morphine found ia cmde opium is converted to codeiae. The commercial coaversioa of morphine to codeiae makes use of a variety of methylating ageats, amoag which the most common are trimethylphenylammonium salts. Ia excess of two huadred toas of codeiae are coasumed anauaHy from productioa faciUties scattered arouad the world. 

Codeine (morphine methyl ether) resembles morphine in its general effect, but is less toxic and its depressant action less marked and less prolonged, whilst its stimulating action involves not only the spinal cord, but also the lower parts of the brain. In small doses in man it induces sleep, which is not so deep as that caused by morphine, and in large doses it causes restlessness and increased reflex excitability rather than sleep. The respiration is slowed less than by morphine (cf. table, p. 261). Cases of addiction for codeine can occur but according to Wolff they are rare. The best known ethers of morphine are ethylmorphine and benzyl-morphine [cf., table, p. 261), both used to replace morphine or codeine for special purposes. 

According to Eddy, as quoted by Small, the analgesic action of neopine, n omorphine, 6-acetylneomorphine or 3 6-diacetylneomorphine (p. 218) is definitely less than that of morphine and its corresponding analogues. The first two are about half as toxic as codeine and morphine respectively, and the second pair are more toxic than their morphine analogues. None of the four shows the Straub reaction and the convulsant action is less marked. 

Lotsch J, Zimmermann M, Darimont J, et al Does the Al 18G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity Anesthesiology 97 814-819, 2002... 

Severe pain should be treated with an opioid such as morphine, hydromorphone, methadone, or fentanyl. Moderate pain can be treated effectively in most cases with a weak opioid such as codeine or hydrocodone, usually in combination with acetaminophen. Meperidine should be avoided owing to its relatively short analgesic effect and its toxic metabolite, normeperidine. Normeperidine may accumulate with repeated dosing and can lead to central nervous system side effects including seizures. 

Human toxicity values have not been established or have not been published. However, this material is between 50 and 100 times more potent than Morphine (C12-A017). 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Before delving into ways the living world uses its special chemicals, we should note that these compounds touch our own lives in important ways. For millennia, humans have been borrowing natural chemicals for their own purposes, most often as drugs. Our oldest medicine is opium, which we prepare from the opium poppy (Papaver somniferum) today much as Mediterranean peoples did four thousand years ago. Just as we do, these early communities valued opium for its ability to kill pain and impart a sense of well-being. The principal constituent responsible for these effects is a chemical compound called morphine, which remains unsurpassed in its ability to control severe pain. In poppies, morphine s toxicity and bitterness presumably repel herbivores looking for a tasty meal. 

Click SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH. (1996a). 18-Metho coronaridine, a non-toxic iboga alkaloid congener effects on morphine and cocaine selfadministration and on mesolimbic dopamine release in rats. Brain Res. 719(1-2) 29-35. 

The common side effects of naltrexone are nansea, headache, and dizziness. In addition, naltrexone has the potential for toxic effects on the liver and should not be used in an alcoholic with cirrhosis or other known liver disease. Because it blocks opiate receptors, patients treated with naltrexone are unable to benefit from the analgesic effects of opiates such as codeine or morphine. Naltrexone may increase serum levels of acamprosate in patients taking both medications. 

Methadone is an opioid analgesic that is available for oral and parenteral administration. It is used in severe pain, in palliative care and as an adjunct in the management of opioid dependence. Compared with morphine, it is less sedating and has a longer duration of action. It may lead to addiction and can still cause toxicity when used in adults with non-opioid dependency. Because of the long duration of action, in overdosage, patients need to be monitored for long periods. 

The proposal that the effects of heroin are mediated chiefly by its deacetylated metabolites, morphine and 6-monoacetylmorphine (MAM) [28], and that heroin (and MAM) function primarily as carriers to facilitate morphine availability at C.N.S. receptor sites is supported by studies in new-born rats [29]. While rats show a pronounced increase in their resistance to morphine 16 days afterbirth (probably associated with development of a blood-brain barrier), there is little change in toxicity to heroin with increasing age hence ready access of heroin to the brain is concluded, even after the barrier has developed. 

Causes of adverse effects over-dosage (A). The drug is administered in a higher dose than is required for the principal effect this directly or indirectly affects other body functions. For instances, morphine (p. 210), given in the appropriate dose, affords excellent pain relief by influencing nociceptive pathways in the CNS. In excessive doses, it inhibits the respiratory center and makes apnea imminent The dose dependence of both effects can be graphed in the form of dose-response curves (DRC). The distance between both DRCs indicates the difference between the therapeutic and toxic doses. This margin of safety indicates the risk of toxicity when standard doses are exceeded. 

CR/ER/SR tablets/capsules Swallow whole do not break, chew, crush, or dissolve because of the risk of acute overdose. Ingesting chewed or crushed beads or pellets will lead to the rapid release and absorption of a potentially toxic dose of morphine. 

Morphine and other opioids exhibit intense sedative effects and increased respiratory depression when combined with other sedatives, such as alcohol or barbiturates. Increased sedation and toxicity are observed when morphine is administered in combination with the psychotropic drugs, such as chlorpromazine and monoamine oxidase inhibitors, or the anxiolytics, such as diazepam. 

Respiratory depression, miosis, hypotension, and coma are signs of morphine overdose. While the IV administration of naloxone reverses the toxic effects of morphine, naloxone has a short duration of action and must be administered repeatedly at 30- to 45minute intervals until morphine is cleared from the body. 

Symptoms of overdose with meperidine are qualitatively different from those of morphine in that seizures rather than sedation are common. Respiratory depression and miosis are present. While naloxone reverses overdose-associated toxicity, its use in patients who have received large, frequent doses of meperidine may precipitate seizures. 

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