CLINICAL PHARMACOLOGY
Morphine is a natural product that is the prototype for the class
of natural and synthetic opioid analgesics. Opioids produce a wide spectrum of
pharmacologic effects including analgesia, dysphoria, euphoria, somnolence,
respiratory depression, diminished gastrointestinal motility, altered
circulatory dynamics, histamine release and physical dependence.
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). The precise mechanism of the
analgesic action is unknown. However, 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. 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 KADIAN® 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.
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-naive 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, KADIAN® will
have, at steady-state, a lower Cmax and a higher Cmin than conventional morphine.
Pharmacokinetics
KADIAN® capsules contain polymer coated
extended-release pellets of morphine sulfate that release morphine significantly
more slowly than from conventional oral preparations. KADIAN® activity is primarily due to morphine. One metabolite,
morphine-6-glucuronide, has been shown to have analgesic activity, but does not
readily cross the blood-brain barrier.
Following oral administration of morphine, the extent of absorption is
essentially the same for immediate or extended-release formulations, although
the time to peak blood level (Tmax) will be longer and
the Cmax will be lower for formulations that delay the
release of morphine in the gastrointestinal tract.
Elimination of morphine is primarily via hepatic metabolism to glucuronide
metabolites (55 to 65%) which are then renally excreted. The terminal half-life
of morphine is 2 to 4 hours, however, a longer term half-life of about 15 hours
has been reported in studies where blood has been sampled up to 48 hours.
The single-dose pharmacokinetics of KADIAN® are linear
over the dosage range of 30 to 100 mg. The single dose and multiple dose
pharmacokinetic parameters of KADIAN® in normal
volunteers are summarized in Table 1.
Table 1: Mean pharmacokinetic parameters (% coefficient variation) resulting
from a fasting single dose study in normal volunteers and a multiple dose study
in patients with cancer pain.
|
Regimen/
|
AUC#,+
|
Cmax+
|
Tmax
|
Cmin+
|
Fluctuation*
|
Dosage Form
|
(ng.h/mL)
|
(ng/mL)
|
(h)
|
(ng/mL)
|
|
|
|
|
|
|
|
Single
Dose (n=24)
|
|
|
|
|
|
| KADIAN®
Capsule |
271.0 (19.4) |
15.6 (24.4) |
8.6 (41.1) |
na^ |
na |
| Extended-Release
Tablet |
304.3 (19.1) |
30.5 (32.1) |
2.5 (52.6) |
na |
na |
| Morphine
Solution |
362.4 (42.6) |
64.4 (38.2) |
0.9 (55.8) |
na |
na |
|
Multiple
Dose (n=24)
|
|
|
|
|
|
| KADIAN®
Capsule q24h |
500.9 (38.6) |
37.3 (37.7) |
10.3 (32.2) |
9.9 (52.3) |
3.0 (45.5) |
| Extended-Release
Tablet q12h |
457.3 (40.2) |
36.9 (42.0) |
4.4 (53.0) |
7.6 (60.3) |
4.1 (51.5) |
# For single dose AUC = AUC 0-48h, for multiple dose AUC = AUC 0-24h at steady state
+ For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours
* Steady-state fluctuation in plasma concentrations = C max- Cmin/ Cmin
^ Not applicable
Absorption
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
KADIAN® 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.
Food Effects: While concurrent administration of
food slows the rate of absorption of KADIAN®, the extent
of absorption is not affected and KADIAN® can be
administered without regard to meals.
Steady State: When KADIAN® is given on a fixed dosing regimen to patients with chronic
pain due to malignancy, steady state is achieved in about two days. At steady
state, KADIAN® will have a significantly lower Cmax and a higher Cmin than equivalent
doses of oral morphine solution and some other extended-release preparations
(see Graph 1).
Graph 1 (Study # MOB-1/90): Mean steady state plasma
morphine concentrations for KADIAN® (twice a day),
extended-release morphine tablet (twice a day) and oral morphine solution (every
4 hours); plasma concentrations are normalized to 100 mg every 24 hours,
(n=24).
When given once-daily (every 24 hours) to 24 patients with malignancy,
KADIAN® had a similar Cmax and
higher Cmin at steady state in clinical usage, when
compared to twice-daily (every 12 hours) extended-release morphine tablets,
given at an equivalent total daily dosage (see Graph 2 and Table 1).
Drug-disease interactions are frequently seen in the older and more gravely ill
patients, and may result in both altered absorption and reduced clearance as
compared to normal volunteers (see Geriatric, Hepatic Failure, and Renal Insufficiency
sections).
Graph 2 (Study # MOR-9/92): Dose normalized mean
steady state plasma morphine concentrations for KADIAN®
(once a day), and an equivalent dose of a 12-hour, extended-release morphine
tablet given twice a day. Plasma concentrations are normalized to 100 mg every
24 hours, (n=24).
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 PRECAUTIONS-Pregnancy) and has
been found in breast milk (see PRECAUTIONS-Nursing
Mothers).
Metabolism
The major pathway of the detoxification of morphine is
conjugation, either with D-glucuronic acid in the liver to produce glucuronides
or with sulfuric acid to give morphine-3-etheral sulfate. Although a small
fraction (less than 5%) of morphine is demethylated, for all practical purposes,
virtually all morphine is converted to glucuronide metabolites including
morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5
to 15%). Studies in healthy subjects and cancer patients have shown that the
glucuronide metabolite to morphine mean molar ratios (based on AUC) are similar
after both single doses and at steady state for KADIAN®,
12-hour extended-release morphine sulfate tablets and morphine sulfate
solution.
M3G has no significant analgesic activity. M6G has been shown to have opioid
agonist and analgesic activity in humans.
Excretion
Approximately 10% of morphine dose is excreted unchanged in the
urine. Most of the dose is excreted in the urine as M3G and M6G. A small amount
of the glucuronide metabolites is excreted in the bile and there is some minor
enterohepatic cycling. Seven to 10% of administered morphine is excreted in the
feces.
The mean adult plasma clearance is about 20-30 mL/minute/kg. The effective
terminal half-life of morphine after IV administration is reported to be
approximately 2.0 hours. Longer plasma sampling in some studies suggests a
longer terminal half-life of morphine of about 15 hours.
Special Populations
Geriatric
The elderly may have increased sensitivity to morphine and may
achieve higher and more variable serum levels than younger patients. In adults,
the duration of analgesia increases progressively with age, though the degree of
analgesia remains unchanged. KADIAN® pharmacokinetics
have not been investigated in elderly patients (>65 years) although such
patients were included in the clinical studies.
Nursing Mothers
Morphine is excreted in the maternal milk, and the milk to plasma
morphine AUC ratio is about 2.5:1. The amount of morphine received by the infant
depends on the maternal plasma concentration, amount of milk ingested by the
infant, and the extent of first pass metabolism.
Pediatric
Infants under 1 month of age have a prolonged elimination
half-life and decreased clearance relative to older infants and pediatric
patients. The clearance of morphine and its elimination half-life begin to
approach adult values by the second month of life. Pediatric patients old enough
to take capsules should have pharmacokinetic parameters similar to adults, dosed
on a per kilogram basis (see PRECAUTIONS-Pediatric
Use).
Gender
No meaningful differences between male and female patients were
demonstrated in the analysis of the pharmacokinetic data from clinical
studies.
Race
Pharmacokinetic differences due to race may exist. 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 were found to be significantly
altered in individuals with alcoholic cirrhosis. The 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 patients indicating a decrease in
metabolic activity.
Renal Insufficiency
The pharmacokinetics of morphine are 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-Drug Interactions
The known drug interactions involving morphine are
pharmacodynamic, not pharmacokinetic (see PRECAUTIONS-Drug
Interactions).
|
