"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
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 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 full agonist, binding with and activating opioid receptors at sites in the periaqueductal and peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to produce analgesia.
Morphine 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. The effective dose in opioid-tolerant patients may be 10-50 times as great (or greater) than the appropriate dose for opioid-na´ve 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.
CNS Depressant/Alcohol Interaction
Additive pharmacodynamic effects may be expected when EMBEDA is used in conjunction with alcohol, other opioids, or illicit drugs that cause CNS depression.
Effects on the CNS
The principal actions of therapeutic value of morphine are analgesia and sedation. 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.
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 morphine overdose.
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. Morphine may also cause spasm of the sphincter of the urinary bladder.
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 or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, 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 modestly immunosuppressive.
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, compared to 8 hours with an equal amount of EMBEDA. Because of pre-systemic elimination, only about 20 to 40% of the administered dose reaches the systemic circulation.
EMBEDA is bioequivalent to a similarly formulated 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 the comparator (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 decreased the rate and extent of morphine absorption from EMBEDA, the total bioavailability was not affected. Co-administration of a high-fat meal with EMBEDA did not compromise the sequestration of naltrexone.
Following single dose administration of intact EMBEDA 60/2.4 – 120/4.8 mg, a limited number (~2%) of blood samples had low plasma naltrexone levels (median = 7.74 pg/mL, range 4-132 pg/mL); naltrexone was not detected in the remaining samples. In patients titrated up to 60/2.4–80/3.2 mg EMBEDA twice daily, naltrexone levels (4-26 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 of morphine administered twice daily for 12 months, 11% of blood samples at pre-dose timepoints at steady-state had detectable plasma naltrexone concentrations ranging from 4 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.
When EMBEDA is crushed or chewed, up to 100% of the sequestered naltrexone dose could be released, bioequivalent to an immediate-release oral solution of the same dose.
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].
Major pathways of morphine metabolism include glucuronidation in the liver 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-3etheral 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.
Approximately 10% of a morphine dose is excreted unchanged in the urine. Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites M3G and M6G 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 of morphine is about 20 to 30 mL/minute/kg. The effective half-life of morphine after IV administration is reported to be approximately 2 hours. The terminal elimination half-life of morphine following single dose EMBEDA administration is approximately 29 hours.
The pharmacokinetics of EMBEDA have not been investigated in elderly patients ( > 65 years) although such patients were included in clinical studies. In a long-term open label safety study, the pre-dose plasma morphine concentrations after dose normalization were similar for subjects < 65 years and those ≥ 65 years of age.
The pharmacokinetics of EMBEDA have not been evaluated in a pediatric population.
No meaningful differences were noted between male and female patients in the analysis of pharmacokinetic data of morphine from clinical studies.
Chinese subjects given IV morphine in one study had a higher clearance when compared to Caucasian subjects (1852 + 116 mL/min vs. 1495 + 80 mL/min).
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. M3G and M6G to morphine plasma AUC ratios also decreased in these patients, indicating a decrease in metabolic activity. Adequate studies of the pharmacokinetics of morphine in patients with severe hepatic impairment have not been conducted.
The pharmacokinetics of morphine are altered in patients with renal failure. The AUC is increased and clearance is decreased. Metabolites, M3G and M6G, accumulate several-fold in patients with renal failure compared to healthy subjects. Adequate studies of the pharmacokinetics of morphine in patients with severe renal impairment have not been conducted.
Drug Interaction/Alcohol Interaction
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 water.
The analgesic efficacy of EMBEDA has been evaluated in one randomized, double-blind, placebo-controlled clinical trial in osteoarthritis patients with moderate to severe pain (Study ALO-KNT-301). This study, with a randomized withdrawal design, was conducted in subjects with moderate to severe pain from osteoarthritis of the hip or knee over a 12-week treatment period. Subjects started open-label treatment with EMBEDA and titrated to effect. Once their pain was controlled (Brief Pain Inventory [BPI] Average 24-hour Pain Intensity ≤ 4 AND at least a 2-point drop from screening baseline), they were randomized to either active treatment with EMBEDA or were tapered off EMBEDA using a double-dummy design and placed on placebo. Of these, 75.1% of the randomized subjects were opioid-na´ve and distributed evenly between the 2 groups.
The mean change in the weekly diary BPI average pain score from randomization baseline (Visit Y) to the end of study (Visit Y + 12 Weeks/Early Termination) was statistically significantly superior for those treated with EMBEDA compared to the placebo group.
Last reviewed on RxList: 2/13/2017
This monograph has been modified to include the generic and brand name in many instances.
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