"Nov. 2, 2012 -- Safety steps taken in the wake of the fungal meningitis outbreak have worsened drug shortages, raising questions about whether the U.S. must choose between the safety and the availability of crucial medicines.
Mechanism of Action
Epidural administration of morphine sulfate results in analgesia without attendant loss of motor, sensory, or sympathetic function. Morphine released from DepoDur (morphine sulfate xr liposome injection) is absorbed both neuraxially and systemically.
Morphine, a pure opiate agonist, is relatively selective for the µ-receptor, although it can interact with other opiate receptors at higher doses. In addition to analgesia, the widely diverse effects of morphine include respiratory depression, drowsiness, changes in mood, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system.
The effects described below are common to all morphine-containing products.
Effects on the Central Nervous System (CNS): The principal therapeutic action of morphine is analgesia. Other therapeutic effects of morphine include anxiolysis, euphoria and feelings of relaxation. Although the precise mechanism of the analgesic action is unknown, 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 and perception of analgesic effects. As with all drugs in the opiate class, morphine can cause respiratory depression, in part by a direct effect on the brainstem respiratory centers. Morphine and related opiates depress 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 may cause miosis, even in total darkness. Pinpoint pupils are a sign of opiate overdose; however, when asphyxia is present during opiate overdose, marked mydriasis occurs.
Effects on the Gastrointestinal Tract and on Other Smooth Muscle: Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility and is 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 can be increased to the point of spasm, often resulting in constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. Morphine may also cause spasm of the sphincter of the urinary bladder.
Effects on the Cardiovascular System: In therapeutic doses, morphine does not usually exert major effects on the cardiovascular system. Morphine, like other opiates, produces peripheral vasodilatation that may result in orthostatic hypotension and fainting. Release of histamine can occur, which may play a role in opiate-induced hypotension. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes and sweating.
Epidural administration of DepoDur results in both systemic absorption of morphine sulfate and absorption of morphine sulfate through the meninges into the intrathecal space. The relative absorption systemically versus intrathecally is unknown for DepoDur (morphine sulfate xr liposome injection) .
Relative systemic bioavailability of DepoDur (morphine sulfate xr liposome injection) compared to epidurally administered morphine injection was determined in 19 patients (Table 1).
Table 1: Pharmacokinetics of DepoDur and Morphine Sulfate
Injection (Mean ± SD)
| DepoDur 5 mg
(n = 10)
| Morphine Sulfate Injection
(n = 9)
|tmax (hr) *||1.0||(0.3–4.0)||0.3||(0.3–2.0)|
DepoDur systemic AUC was comparable to that of morphine sulfate injection (approximately 90%), however, systemic Cmax was 30 % of that of morphine sulfate injection.
Based on systemic AUC, DepoDur (morphine sulfate xr liposome injection) appears to exhibit dose proportionality over a dose range of 5 to 25 mg. In contrast, systemic Cmax did not exhibit dose-proportionality and tended to increase by an amount less than the proportional change in dose (Table 2).
Table 2: Morphine Plasma Pharmacokinetic Parameters (Mean,
SD) Following Epidural Administration of DepoDur (morphine sulfate xr liposome injection)
5 mg (n=14)
10 mg (n=36)
15 mg (n=71)
20 mg (n=63)
25 mg (n=32)
30 mg (n=25)
|Cmax (ng/mL)|| 9.4
|AUC0–∞ (ng•hr/mL)|| 41.0
|t1/2 (hr)|| 4.2
After morphine sulfate has been released from DepoDur (morphine sulfate xr liposome injection) and is absorbed systemically, morphine distribution is expected to be the same as for other morphine formulations.
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. The volume of distribution of morphine is approximately 1 to 4 L/kg. Morphine is 20 to 35% reversibly bound to plasma proteins. Morphine also crosses the placental membranes and has been found in breast milk.
After morphine sulfate has been released from DepoDur (morphine sulfate xr liposome injection) and is absorbed systemically, morphine metabolism is expected to be the same as for other morphine formulations.
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%). M3G has no significant analgesic activity. M6G has been shown to have opiate agonist and analgesic activity in humans.
After morphine sulfate has been released from DepoDur (morphine sulfate xr liposome injection) and is absorbed systemically, morphine excretion is expected to be the same as for other morphine formulations. DepoDur (morphine sulfate xr liposome injection) is intended for single dose administration, therefore, accumulation of morphine or its metabolites is not expected even in patients with impaired hepatic or renal function.
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 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine of about 15 hours was reported.
Geriatric: Elderly patients (aged 65 years or older) may have increased sensitivity to DepoDur (morphine sulfate xr liposome injection) , as with other opiates. In elderly patients (over 65 years of age), the Cmax was similar to that of patients 65 years of age or younger, but the clearance in elderly patients was reduced by approximately 13%.
Pediatric: The pharmacokinetics of DepoDur (morphine sulfate xr liposome injection) have not been studied in pediatric patients.
Hepatic Failure: Systemic morphine pharmacokinetics have been reported to be significantly altered in patients 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. DepoDur (morphine sulfate xr liposome injection) is intended for single-dose administration, therefore accumulation of morphine or its metabolites is not expected even in patients with impaired hepatic function.
Renal Insufficiency: Systemic morphine pharmacokinetics are altered in patients with renal failure. 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. DepoDur (morphine sulfate xr liposome injection) is intended for single-dose administration, therefore accumulation of morphine or its metabolites is not expected even in patients with impaired renal function.
Pharmacokinetic drug-drug interactions with a test dose of lidocaine and an analgesic dose of bupivacaine have been evaluated in vivo (see below). In-vitro studies suggest a similar interaction is anticipated with other amide local anesthetics.
No in-vitro or in-vivo studies have been performed with ester local anesthetics. Known drug-drug interactions involving morphine are pharmacodynamic, not pharmacokinetic (see PRECAUTIONS: DRUG INTERACTIONS).
Test Dose Interaction
Epidural administration of a 3-mL test dose (lidocaine 1.5% and epinephrine 1:200,000) may affect the release of morphine sulfate from DepoDur (see PRECAUTIONS: DRUG INTERACTIONS). This issue has been examined in patients who received epidural administration of 15 mg of DepoDur (morphine sulfate xr liposome injection) at various time intervals after the test dose (Table 3). The test groups included a no-test-dose group and 3-, 10- and 15-minute delays between test dose and DepoDur (morphine sulfate xr liposome injection) administration. Additionally, saline flush after the test dose was assessed. The serum concentration of morphine was measured as a biomarker.
Table 3: Impact of Test Dose Administration on Peak Serum
Concentration of DepoDur (morphine sulfate xr liposome injection)
|Minutes Between Test Dose and DepoDur Administration||N||Mean tmax hr (SD)||Mean Cmax ng/mL (SD)||Median Cmax ng/mL||Min–Max ng/mL|
|No test dose||6||2.5 (2.1)||11.5 (7.4)||10.2||4.1–23.5|
|Flush + 3||8||0.2 (0.04)||30.2 (8.5)||31.4||15.8–40.1|
|Flush + 10||7||0.6 (0.7)||15.6 (9.3)||13.3||7.4–34.0|
|Flush + 15||8||0.5 (0.3)||11.4 (6.4)||11.4||2.0–20.0|
|No Flush + 3||8||0.4 (0.7)||25.6 (10.1)||22.6||15.2–45.4|
Serum morphine Cmax was comparable to that of the no-test-dose group if DepoDur (morphine sulfate xr liposome injection) was administered 15 minutes after the test dose. Anesthetics other than lidocaine with epinephrine have not been evaluated as a test dose.
Analgesic Dose Interaction
Administering DepoDur (morphine sulfate xr liposome injection) after analgesic dose of epidural local anesthetic may affect the release of morphine sulfate from DepoDur (see PRECAUTIONS: DRUG INTERACTIONS). This issue has been examined in patients who received 15 mg of DepoDur (morphine sulfate xr liposome injection) epidurally at various time intervals after the administration of an analgesic dose of bupivacaine 0.25% - 20 mL.
Serum morphine Cmax levels were comparable after administration of DepoDur (morphine sulfate xr liposome injection) alone or DepoDur (morphine sulfate xr liposome injection) administered > 30 minutes after the administration of the bupivacaine.
The efficacy of DepoDur (morphine sulfate xr liposome injection) was demonstrated in four clinical trials comprised of 876 patients undergoing surgical procedures such as hip arthroplasty, prostatectomy, colon resection and cesarean section. In these clinical trials, efficacy was assessed for at least 48 hours and safety for up to 30 days after DepoDur (morphine sulfate xr liposome injection) administration.
Two randomized, double-blind, placebo-controlled, parallel-group, dose-ranging studies evaluated the safety and efficacy of 10, 15, 20, 25, and 30 mg DepoDur (morphine sulfate xr liposome injection) in 314 patients undergoing hip arthroplasty. The mean age of patients was 59 years (range 18 to 88 years). Study medication was administered approximately 30 minutes before surgery. Post-operatively, patients self-administered intravenous fentanyl via patient-controlled analgesia (PCA) to maintain satisfactory analgesia.
In one study (N=194), single epidural administration of 15, 20, and 25 mg DepoDur (morphine sulfate xr liposome injection) provided superior analgesic efficacy compared to placebo (epidural saline injection followed by IV fentanyl PCA), as measured by decreased fentanyl use (Figure 1) and Visual Analog Scores (VAS) (Figure 2). The second clinical study in hip arthroplasty revealed similar results.
Figure 1: Cumulative Fentanyl Usage Over 48 Hours (Mean,
Figure 2: Pain Intensity Scores Over 48 hours (Mean, SE)
Lower Abdominal Surgery
A randomized, double-blind, parallel-group study evaluated the safety and efficacy of single epidural doses of 10, 15, 20, and 25 mg DepoDur compared to 5 mg DepoDur or 5 mg morphine sulfate in 487 patients undergoing lower abdominal surgery (i.e. surgery via an abdominal incision below umbilicus). Study medication was administered approximately 30 minutes prior to surgery. Post operatively, patients self-administered intravenous fentanyl via patient-controlled analgesia (PCA) to maintain satisfactory analgesia. A dose response was observed, demonstrating a reduction in IV fentanyl use over the 48-hour period.
A randomized, double-blind, parallel-group study evaluated the safety and efficacy of single epidural doses of 5, 10, and 15 mg DepoDur compared to epidural morphine sulfate injection (5 mg) in 75 patients undergoing elective cesarean section under intrathecal anesthesia. Study medication was administered following delivery and clamping of the umbilical cord. At the investigator's discretion, patients were permitted to receive acetaminophen with codeine or intravenous morphine sulfate as an intermittent bolus or via PCA pump, post-operatively. DepoDur (morphine sulfate xr liposome injection) doses of 10 and 15 mg resulted in reduced use of rescue medication and improved post-operative analgesia based on AUC analysis of VAS pain scores at rest (R) and with activity (A), compared to morphine sulfate on average over the 48-hour period following elective cesarean section (Table 4).
Table 4: Cesarean Section: Total Opiate Use, Pain VAS at
Rest and with Activity
|Efficacy Parameters||Morphine Sulfate Injection||DepoDur|
|5 mg||10 mg||15 mg|
|Opiate use (mg, morphine equivalents *) 0-48 h, median†||38.2||19.0||18.0|
|Opiate use (mg, morphine equivalents*) 24–48 h, median§||16.3||9.0||6.0|
|VAS-R AUC 0-48 h, mean ± SD†||1186 ± 939||454 ± 334||484 ± 425|
|VAS-A AUC 0-48 h, mean ± SD†||2086 ±875||1235 ± 775||1036 ± 726|
|Median;† p < 0.05; § p < 0.001|
Last reviewed on RxList: 10/13/2009
This monograph has been modified to include the generic and brand name in many instances.
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