Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Amdipharm UK Limited, Capital House, 85 King William Street, London EC4N 7BL, UK
Pharmacotherapeutic group: Opiods
ATC code: N02A
Morphine acts as an agonist at opiate receptors in the CNS particularly Mu and to a lesser extent Kappa receptors. Mu receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria, and Kappa receptors, spinal analgesia, miosis and sedation.
The principal actions of therapeutic value of morphine are analgesia and sedation (i.e. sleepiness and anxiolysis). Morphine produces respiratory depression by direct action on brain stem respiratory centres. Morphine depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g. pontine lesions of haemorrhagic or ischaemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of morphine overdose.
Morphine and related analgesics may produce both physical and psychological dependence and should therefore be used with discrimination. Tolerance may also develop.
Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm resulting in constipation. Morphine generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts. Morphine may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.
Morphine may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Some premenopausal women may have low oestrogen levels. Clinical symptoms may be manifest from these hormonal changes.
In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown.
Routes of administration include the oral, subcutaneous, intramuscular, intravenous, intraspinal and rectal routes. Parenteral doses may be intermittent injections or continuous or intermittent infusions adjusted according to individual analgesic requirements.
Morphine is immediately absorbed from the digestive tract following oral administration. Morphine has a plasma half life of about 2 to 3 hours and if given IV must be administered frequently. Rhotard Morphine SR/Morphgesic SR tablets, being a sustained release preparation of morphine, has the advantage that it is only administered twice daily.
The percentage of binding to plasma proteins after absorption is low. There is no clearly defined correlation between the plasma concentration of morphine and the analgesic effect.
A considerable quantity of morphine is metabolised by the liver to glucuronides, which undergo enterohepatic recirculation.
The product is eliminated essentially in the urine, by glomerular filtration, mainly as glucuronides. A small amount (less than 10%) is eliminated in the faeces.
A summary of the morphine pharmacokinetic parameters is given below:
Pharmacokinetic parameters pertinent to Rhotard Morphine SR/Morphgesic SR tablets are summarised in the following table:
| Parameters | Rhotard Morphine SR/Morphgesic SR Tablets | Rhotard Morphine SR/Morphgesic SR Tablets |
|---|---|---|
| <>_.Fasting (A) | Food (B) | |
| AUC(0-t) (ng.h/ml) | 46.02 ± 18.85 | 59.88 ± 20.52 |
| Cmax (ng/ml) | 9.2 ± 3.6 | 13.6 ± 4.6 |
| Tmax hours | 2.5 ± 1.7 | 3.9 ± 1.6 |
No bacterial mutagenicity studies with morphine have been reported. A review of the literature has indicated that morphine was negative in gene mutation assays in Drosophila melanogaster, but was positive in a mammalian spermatocyte test. The results of another study has indicated that morphine causes chromosomal aberrations, in germ cells of male mice when given at dose levels of 10, 20, 40 or 60 mg/kg bodyweight for 3 consecutive days.
No long term studies have been conducted in animals to determine whether morphine is potentially carcinogenic.
Morphine was not teratogenic in rats when dosed for up to 15 days at 70mg/kg/day. Morphine given subcutaneously to mice at very high doses (200, 300 or 400 mg/kg/day) on days 8 or 9 of gestation, resulted in a few cases of exencephaly and axial skeletal fusions. The hypoxic effects of such high doses could account for the defects seen.
Lower doses of morphine (40, 4.0 or 0.4 mg/ml) given to mice as a continuous i.v. infusion (at a dose volume of 0.3 ml/kg) between days 7 and 10 of gestation, caused soft tissue and skeletal malformations as shown in previous studies.
In male rats, reduced fertility and chromosomal damage in gametes have been reported.
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