Morphine
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🧬 Receptor activity
Mechanism of action
Morphine-6-glucuronide is responsible for approximately 85% of the response observed by morphine administration. Morphine and its metabolites act as agonists of the mu and kappa opioid receptors. The mu-opioid receptor is integral to morphine's effects on the ventral tegmental area of the brain. Morphine's activation of the reward pathway is mediated by agonism of the delta-opioid receptor in the nucleus accumbens, while modification of the respiratory system and addiction disorder are mediated by agonism of the mu-opioid receptor.
Visual analysis of the direct electroencephalograph has revealed that morphine /slowed/ the predominant frequency and /increased/ high-voltage delta activity.
Pharmacodynamics
Morphine binding to opioid receptors blocks transmission of nociceptive signals, signals pain-modulating neurons in the spinal cord, and inhibits primary afferent nociceptors to the dorsal horn sensory projection cells. Morphine has a time to onset of 6-30 minutes. Excess consumption of morphine and other opioids can lead to changes in synaptic neuroplasticity, including changes in neuron density, changes at postsynaptic sites, and changes at dendritic terminals. Intravenous morphine's analgesic effect is sex dependent. The EC<sub>50</sub> in men is 76ng/mL and in women is 22ng/mL. Morphine-6-glucuronide is 22 times less potent than morphine in eliciting pupil constriction.
Pharmacokinetics
Half-life
Morphine has a half life of 2-3 hours.
... The mean terminal half-life of morphine following epidural injection is 90 minutes (range: 39-349 minutes), which is similar to the half-life of the drug reported after IV or IM administration (1.5-4.5 hours).
CSF concentrations of morphine decline in a biphasic manner following epidural injection of conventional morphine sulfate injection, with an early distribution half-life of 1.5 hours and a terminal half-life of about 6 hours.
Following epidural administration of a 10-, 15-, or 20-mg dose of morphine sulfate extended-release liposomal injection, the half-life reportedly is 16.2, 20, or 23.9 hours, respectively.
Following intrathecal administration of /morphine/, the mean reported CSF half-life is 90 minutes (range: 42-136 minutes).
For more Biological Half-Life (Complete) data for MORPHINE (6 total), please visit the HSDB record page.
Absorption
Morphine is absorbed in the alkaline environments of the upper intestine and rectal mucosa. The bioavailability of morphine is 80-100%. There is significant first-pass metabolism, therefore oral doses are 6 times larger than parenteral doses to achieve the same effect. Morphine reaches steady-state concentrations after 24-48 hours. Parenteral morphine has a Tmax of 15 minutes and oral morphine has a Tmax of 90 minutes, with a Cmax of 283nmol/L. The AUC of morphine is 225-290nmol\*h/L.
70-80% of an administered dose is excreted within 48 hours. Morphine is predominantly eliminated in the urine with 2-10% of a dose recovered as the unchanged parent drug. 7-10% of a dose of morphine is eliminated in the feces.
The volume of distribution of morphine is 5.31L/kg. Morphine-6-glucuronide has a volume of distribution of 3.61L/kg.
The apparent clearance of intravenous or subcutaneous morphine is 1600 mL/min.
Morphine crosses the placenta at term. ... Pregnant patients in labor clear the parent compound almost twice as fast. Infants younger than 1 month of age have prolonged half-life of morphine compared to older children. The clearance of morphine approaches adult values in the second month of life. The milk to plasma ratio of morphine is 2.5:1. Although significant infant plasma levels may develop, breast-feeding can usually be performed safely. A breast-feeding infant may absorb 0.8% to 12% of the maternal dose.
Morphine sulfate is variably absorbed from the GI tract. Food may increase the extent of GI absorption of morphine sulfate administered as conventional preparations. Food may decrease the rate of absorption of morphine sulfate administered as extended-release capsules; however, the extent of absorption of the drug does not appear to be affected.
Metabolism
Morphine is 90% metabolized by glucuronidation by UGT2B7 and sulfation at positions 3 and 6. Morphine can also be metabolized to codeine, normorphine, and morphine ethereal sulfate.
... patients on therapeutic codeine also test positively for morphine, because morphine is a codeine metabolite.
/Heroin/ is converted metabolically by ester hydrolysis first to 6-monoacetylmorphine (heroin-specific metabolite) and then to morphine by hydrolysis for the second acetate ester. When the heroin base enters the body, it is fairly lipophilic, so a portion of the dose readily crosses the blood-brain barrier into the central nervous system where the hydrolysis of the two esters can take place. Morphine is less lipophilic than heroin and does not cross back across the blood-brain barrier as readily. Morphine readily undergoes the additional phase I metabolic transformation of oxidative N-demethylation by CYP2D6. Phase II (conjugation) reactions of morphine include formation of the glucuronide conjugates at the hydroxyl moieties at positions 3 and 6. The glucuronides are then excreted. Note that the aromatic ring stays intact throughout the metabolic transformations, illustrating the stability imparted by aromaticity.
Morphine is metabolized principally in the liver and undergoes conjugation with glucuronic acid principally at the 3-hydroxyl group. Secondary conjugation also occurs at the 6-hydroxyl group to form the 6-glucuronide, which is pharmacologically active, and to a limited extent the 3,6-diglucuronide. Plasma concentrations of the 3-glucuronide, which is inactive, and the 6-glucuronide substantially exceed those of unchanged drug, and the latter metabolite appears to contribute substantially to the drug's pharmacologic activity. Elimination of the drug may be reduced substantially in neonates compared with older children and adults. Morphine is excreted in urine mainly as morphine-3-glucuronide. In addition to the 3,6-diglucuronide, other minor metabolites that have been described includes normorphine and the 3-ethereal sulfate. ... In patients with renal impairment, accumulation of morphine-6-glucuronide occurs, which can result in enhanced and prolonged opiate activity.
The major pathway for the metabolism of morphine is conjugation with glucuronic acid. The two major metabolites formed are morphine-6-glucuronide and morphine-3-glucuronide. Small amounts of morphine-3,6-diglucuronide also may be formed.
For more Metabolism/Metabolites (Complete) data for MORPHINE (12 total), please visit the HSDB record page.
Protein binding
Morphine is 35% protein bound, the metabolite morphine-3-glucuronide is 10% protein bound, and morphine-6-glucuronide is 15% protein bound.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.