Mechanism of Action
Morphine sulfate, an opioid agonist, is relatively
selective for the mu receptor, although it can interact with other
opioid receptors at higher doses. In addition to analgesia, the widely
diverse effects of morphine sulfate include analgesia, dysphoria,
euphoria, somnolence, respiratory depression, diminished gastrointestinal
motility, altered circulatory dynamics, histamine release, physical
dependence, and alterations of the endocrine and autonomic nervous
Morphine produces both
its therapeutic and its adverse effects by interaction with one or
more classes of specific opioid receptors located throughout the body.
Morphine acts as a full agonist, binding with and activating opioid
receptors at sites in the peri-aqueductal and peri-ventricular grey
matter, the ventro-medial medulla and the spinal cord to produce analgesia.
Plasma Level-Analgesia Relationships
While plasma morphine-efficacy
relationships can be demonstrated in non-tolerant individuals, they
are influenced by a wide variety of factors and are not generally
useful as a guide to the clinical use of morphine. Dosages of morphine
should be chosen and must be titrated on the basis of clinical evaluation
of the patient and the balance between therapeutic and adverse effects.
Additive pharmacodynamic effects may be expected when MS CONTIN is
used in conjunction with alcohol, other opioids, or illicit drugs
that cause central nervous system depression.
Effects on the Central Nervous System
The principal actions
of therapeutic value of morphine are analgesia and sedation. Specific
CNS opiate receptors for endogenous compounds with opioid-like activity
have been identified throughout the brain and spinal cord and are
likely to play a role in the expression of analgesic effects.
Morphine produces respiratory depression
by direct action on brainstem respiratory centers. The mechanism
of respiratory depression involves a reduction in the responsiveness
of the brainstem respiratory centers to increases in carbon dioxide
tension, and to electrical stimulation.
Morphine depresses the cough reflex by direct effect
on the cough center in the medulla. Morphine causes miosis, even
in total darkness. Pinpoint pupils are a sign of narcotic overdose
but are not pathognomonic (e.g., pontine lesions of hemorrhagic or
ischemic origins may produce similar findings). Marked mydriasis
rather than miosis may be seen with worsening hypoxia.
Effects on the Gastrointestinal
Tract and Other Smooth Muscle
Morphine causes a reduction in motility associated with
an increase in smooth muscle tone in the antrum of the stomach and
in the duodenum. Digestion of food is delayed in the small intestine
and propulsive contractions are decreased. Propulsive peristaltic
waves in the colon are decreased, while tone may be increased to the
point of spasm. The end result is constipation. Morphine can cause
a marked reduction in gastric, biliary and pancreatic secretions,
spasm of the sphincter of Oddi, and transient elevations in serum
on the Cardiovascular System
Morphine produces peripheral vasodilation which may
result in orthostatic hypotension. Release of histamine can occur
and may contribute to opioid-induced hypotension. Manifestations
of histamine release and/or peripheral vasodilation may include pruritus,
flushing, red eyes, and sweating.
Effects on the Endocrine System
Opioids inhibit the secretion
of ACTH, cortisol, testosterone, and luteinizing hormone (LH) in humans.
They also stimulate prolactin, growth hormone (GH) secretion, and
pancreatic secretion of insulin and glucagon.
Effects on the Immune System
Opioids have been
shown to have a variety of effects on components of the immune system
in in vitro and animal models. The clinical significance of these
findings is unknown. Overall, the effects of opioids appear to be
MS CONTIN is an extended-release tablet containing morphine sulfate.
Morphine is released from MS CONTIN somewhat more slowly than from
immediate-release oral preparations. Following oral administration
of a given dose of morphine, the amount ultimately absorbed is essentially
the same whether the source is MS CONTIN or an immediate-release formulation.
Because of pre-systemic elimination (i.e., metabolism in the gut
wall and liver) only about 40% of the administered dose reaches the
The oral bioavailability of morphine is approximately
20 to 40%. When MS CONTIN is given on a fixed dosing regimen, steady-state
is achieved in about a day.
The effect of food upon the systemic bioavailability
of MS CONTIN has not been systematically evaluated for all strengths.
One study, conducted with the 30 mg MS CONTIN tablets, showed no
significant differences in Cmax and AUC (0-24h) values, whether the tablet was taken while fasting
or with a high-fat breakfast.
Once absorbed, morphine is distributed to skeletal
muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain.
Morphine also crosses placental membranes and has been found in breast
milk. The volume of distribution (Vd) for morphine is approximately
3 to 4 liters per kilogram and morphine is 30 to 35% reversibly bound
to plasma proteins.
The major pathways of morphine metabolism include glucuronidation
to produce metabolites including morphine-3-glucuronide, M3G (about
50%) and morphine-6-glucuronide, M6G (about 5 to 15%) and sulfation
in the liver to produce morphine-3-etheral sulfate. A small fraction
(less than 5%) of morphine is demethylated. M6G has been shown to
have analgesic activity but crosses the blood-brain barrier poorly,
while M3G has no significant analgesic activity.
The elimination of morphine occurs primarily
as renal excretion of M3G and its effective half-life after intravenous
administration is normally 2 to 4 hours. Approximately 10% of the
dose is excreted unchanged in urine. In some studies involving longer
periods of plasma sampling, a longer terminal half-life of about 15
hours was reported. A small amount of the glucuronide conjugate is
excreted in the bile, and there is some minor enterohepatic recycling.
of MS CONTIN have not been studied in elderly patients.
The pharmacokinetics of MS CONTIN have
not been studied in pediatric patients below the age of 18.
A gender analysis of pharmacokinetic data from healthy
subjects taking MS CONTIN indicated that morphine concentrations were
similar in males and females.
subjects given intravenous morphine had a higher clearance when compared
to Caucasian subjects (1852 +/- 116 ml/min compared to 1495 +/- 80
Morphine pharmacokinetics are
altered in individuals with cirrhosis. Clearance was found to decrease
with a corresponding increase in half-life. The M3G and M6G to morphine
plasma AUC ratios also decreased in these subjects, indicating diminished
metabolic activity. Adequate studies of the pharmacokinetics of morphine
in patients with severe hepatic impairment have not been conducted.
Morphine pharmacokinetics are altered in
patients with renal failure. The AUC is increased and clearance is
decreased and the metabolites, M3G and M6G, may accumulate to much
higher plasma levels in patients with renal failure as compared to
patients with normal renal function. Adequate studies of the pharmacokinetics
of morphine in patients with severe renal impairment have not been
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Studies in animals to evaluate the carcinogenic potential
of morphine have not been conducted.
Mutagenesis: No formal studies to assess the mutagenic potential of morphine
have been conducted. In the published literature, morphine was found
to be mutagenic in vitro increasing DNA fragmentation in human T-cells.
Morphine was reported to be mutagenic in the in vivo mouse micronucleus
assay and positive for the induction of chromosomal aberrations in
mouse spermatids and murine lymphocytes. Mechanistic studies suggest
that the in vivo clastogenic effects reported with morphine in mice
may be related to increases in glucocorticoid levels produced by morphine
in this species. In contrast to the above positive findings, in vitro
studies in the literature have also shown that morphine did not induce
chromosomal aberrations in human leukocytes or translocations or lethal
mutations in Drosophila.
Impairment of Fertility: No formal
nonclinical studies to assess the potential of morphine to impair
fertility have been conducted. Several nonclinical studies from the
literature have demonstrated adverse effects on male fertility in
the rat from exposure to morphine. One study in which male rats were
administered morphine sulfate subcutaneously prior to mating (up to
30 mg/kg twice daily) and during mating (20 mg/kg twice daily) with
untreated females, a number of adverse reproductive effects including
reduction in total pregnancies, higher incidence of pseudopregnancies,
and reduction in implantation sites were seen. Studies from the literature
have also reported changes in hormonal levels (i.e., testosterone,
luteinizing hormone, serum corticosterone) following treatment with
morphine. These changes may be associated with the reported effects
on fertility in the rat.