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12 CLINICAL PHARMACOLOGY
12.1 Mechanism Of Action
Morphine sulfate, a pure 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 systems.
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 pure 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.
Effects on the Central Nervous
System
The principal actions of therapeutic value of morphine are analgesia and
sedation (i.e., sleepiness and anxiolysis). Specific CNS opiate receptors and
endogenous compounds with morphine-like activity have been identified throughout
the brain and spinal cord and are likely to play a role in the expression of
analgesic effects. In addition, when morphine binds to mu-opioid receptors, it
results in positive subjective effects, such as drug liking, euphoria, and high.
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.
Antitussive effects may occur with doses lower than those usually required for
analgesia. Morphine causes miosis, even in total darkness, and little tolerance
develops to this effect. Pinpoint pupils are a sign of opioid 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 in the setting of EMBEDA overdose [see OVERDOSAGE ].
Effects on the Gastrointestinal
Tract and Other Smooth Muscle
Gastric, biliary, and pancreatic secretions are decreased by morphine.
Morphine causes a reduction in motility associated with an increase in 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.
The end result is constipation. Morphine can cause a marked increase in biliary
tract pressure as a result of spasm of the sphincter of Oddi.
Effects on the Cardiovascular
System
Morphine produces peripheral vasodilation which may result in orthostatic
hypotension or syncope. Release of histamine may be induced by morphine and can
contribute to opioid-induced hypotension. Manifestations of histamine release
and/or peripheral vasodilation may include pruritus, flushing, red eyes and
sweating.
Mechanism of Action of
Naltrexone
Naltrexone is a pure, centrally acting mu-opioid antagonist that reverses the
subjective and analgesic effects of mu-opioid receptor agonists by competitively
binding at mu-opioid receptors.
12.2 Pharmacodynamics
Plasma Level-Analgesia
Relationships
In any particular patient, both analgesic effects and plasma morphine
concentrations are related to the morphine dose.
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. The
effective dose in opioid-tolerant patients may be 10-50 times as great (or
greater) than the appropriate dose for opioid-naïve individuals. 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.
For any fixed dose and dosing interval, EMBEDA will have, at steady-state, a
lower Cmax and a higher Cmin than
conventional immediate-release morphine.
The pharmacodynamic effect of naltrexone in the setting of crushed EMBEDA was
examined in two clinical trials. In a randomized double-blind, triple-dummy,
four-way cross-over study, 32 non-dependent recreational opioid users received
120 mg of EMBEDA whole and crushed, 120 mg of immediate-release morphine sulfate
and placebo. Overall, 87.5% of subjects had some degree of reduced drug liking
after receiving crushed EMBEDA, while 12.5% had no reduction in drug liking.
There was considerable individual variability in the degree of reduction in drug
liking, ranging between 10 and 50%. Similarly, 69% of subjects showed some
degree of a decrease in euphoria with crushed EMBEDA compared to IR morphine and
31% of subjects did not report a reduction in euphoria. There was similar
individual variability in the degree of reduction in euphoria.
A randomized double-blind, placebo-controlled, three-way cross-over trial in
28 non-dependent recreational opioid-users was performed using 30 mg of IV
morphine alone and 30 mg of IV morphine in combination with 1.2 mg of IV
naltrexone to simulate parenteral use of crushed EMBEDA. The combination of
morphine with naltrexone resulted in 71% of subjects reporting a reduction in
euphoria compared to morphine alone. Note that the intravenous injection of
crushed EMBEDA may result in serious injury and death due to a morphine overdose
or an embolic event. Intravenous injection of crushed EMBEDA may preciptitate a
severe withdrawal syndrome in opioid-dependent patients.
The clinical significance of the degree of reduction in drug liking and
euphoria reported in these studies has not yet been established. There is no
evidence that the naltrexone in EMBEDA reduces the abuse liability of
EMBEDA.
12.3 Pharmacokinetics
Absorption
EMBEDA Capsules contain extended-release pellets of morphine sulfate that
release morphine slowly compared to an oral morphine solution. Following the
administration of oral morphine solution, approximately 50% of the morphine
absorbed reaches the systemic circulation within 30 minutes. However, following
the administration of an equal amount of EMBEDA to healthy volunteers, this
occurs, on average, after 8 hours. As with most forms of oral morphine, because
of pre-systemic elimination, only about 20 to 40% of the administered dose
reaches the systemic circulation.
EMBEDA is bioequivalent to a similar morphine sulfate extended release
capsules product with regard to rate and extent of plasma morphine absorption.
The median time to peak plasma morphine levels (Tmax) was
shorter for EMBEDA (7.5 hrs) compared to KADIAN® (10
hrs). Dose-related increase in steady-state pre-dose plasma concentrations of
morphine were noted following multiple dose administration of EMBEDA in
patients.
Food effect: While concurrent administration of
high fat food decreases the rate and extent of morphine absorption from EMBEDA,
the total bioavailability is not affected. Co-administration of a high-fat meal
with EMBEDA did not compromise sequestration of naltrexone.
When taken as directed, the sequestered naltrexone in EMBEDA is not
consistently absorbed into systemic circulation following single dose
administration. In some subjects, a limited number (~2%) of blood samples had
low and highly variable plasma naltrexone levels (median = 7.74 pg/mL, range
4.05-132 pg/mL) following single dose administration of 60 – 120 mg EMBEDA
compared to oral naltrexone solution. In patients titrated up to 60 – 80 mg BID
EMBEDA, naltrexone levels (4-25.5 pg/mL) were detected in 13 out of 67 patients
at steady-state. In a long-term safety study where an average dose of EMBEDA was
up to 860 mg administered twice a day for 12 months, 11.0% of blood samples at
pre-dose timepoints at steady-state had detectable plasma naltrexone
concentrations ranging from 4.03 to 145 pg/mL.
Compared to 2.4 mg naltrexone oral solution, which produced mean (SD)
naltrexone plasma levels of 689 (+ 429 pg/mL) and
mean (SD) 6β-naltrexol plasma levels of 3920 (+
1350 pg/mL), administration of intact 60 mg EMBEDA produced no naltrexone plasma
levels and mean (SD) 6β-naltrexol plasma levels of 16.7 (+ 13.5 pg/mL). Trough levels of plasma naltrexone and
6-β-naltrexol did not accumulate upon repeated administration of EMBEDA.
Tampering with the EMBEDA formulation by crushing or chewing the pellets,
results in the rapid release and absorption of both morphine and naltrexone
comparable to an oral solution. This has not been shown to reduce the abuse
liability of EMBEDA.
Distribution
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver,
intestinal tract, lungs, spleen, and brain. The volume of distribution of
morphine is approximately 3 to 4 L/kg. Morphine is 30 to 35% reversibly bound to
plasma proteins. Although the primary site of action of morphine is in the CNS,
only small quantities pass the blood brain barrier. Morphine also crosses the
placental membranes [see USE IN SPECIFIC
POPULATIONS ] and has been found in breast milk [see
USE IN SPECIFIC
POPULATIONS (8.3)
].
Metabolism
Major pathways of morphine metabolism include glucuronidation and sulfation
in the liver to produce including morphine-3-glucuronide, M3G (about 50%) and
morphine-6-glucuronide, M6G (about 5 to 15%) or morphine-3-etheral sulfate. A
small fraction (less than 5%) of morphine is demethylated. M3G has no
significant contribution to the analgesic activity. Although M6G does not
readily cross the blood-brain barrier, it has been shown to have opioid agonist
and analgesic activity in humans.
Naltrexone is extensively metabolized into 6-β-naltrexol.
Excretion
Approximately 10% of morphine dose is excreted unchanged in the urine.
Elimination of morphine is primarily via hepatic metabolism to glucuronide
metabolites M3G and M6G (55 to 65%) which are then renally excreted. A small
amount of the glucuronide metabolites is excreted in the bile and there is some
minor enterohepatic cycling.
The mean adult plasma clearance is about 20-30 mL/minute/kg. The effective
half-life of morphine after IV administration is reported to be approximately
2.0 hours. The terminal elimination half-life of morphine following single dose
EMBEDA administration is approximately 29 hours.
Special Populations
Geriatric: Pharmacokinetics of EMBEDA have not
been investigated in elderly patients (greater than 65 years) although such patients were
included in clinical studies. However, in a long-term open label safety study,
the pre-dose plasma morphine concentrations after dose normalization were
similar for subjects less than 65 years and those greater than or equal to 65 years of age [see USE IN
SPECIFIC POPULATIONS ].
Pediatric: Pharmacokinetics of EMBEDA were not
evaluated in pediatric population.
Gender: No meaningful differences were noted
between male and female patients in the analysis of pharmacokinetic data of
morphine from clinical studies.
Race: Pharmacokinetic differences due to race
may exist. Additionally, Chinese subjects given intravenous morphine in one
study had a higher clearance when compared to Caucasian subjects (1852 + 116 mL/min versus 1495 +
80 mL/min).
Hepatic Failure: The pharmacokinetics of
morphine was found to be significantly altered in individuals with alcoholic
cirrhosis. The clearance was found to decrease with a corresponding increase in
half-life. The morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) to
morphine plasma AUC ratios also decreased in these patients indicating a
decrease in metabolic activity.
Renal Insufficiency: The pharmacokinetics of
morphine is altered in renal failure patients. AUC is increased and clearance is
decreased. The metabolites, M3G and M6G, accumulate several fold in renal
failure patients compared with healthy subjects.
Drug Interaction/Alcohol Interaction: As such
additive pharmacodynamic effects may be expected when EMBEDA is used in
conjunction with alcohol, other opioids, or illicit drugs that cause central
nervous system depression. Additionally, a pharmacokinetic drug interaction is
noted with concomitant administration of 40% alcohol and EMBEDA, where an
average 2-fold (range 1.4- to 5-fold increase) higher Cmax of morphine was noted compared to EMBEDA consumed with
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