Morphine/naltrexone extended-release capsules (Embeda): Combination of mu-opioid agonist and mu-opioid antagonist approved for the management of moderate-to-severe pain when continuous analgesia is needed for an extended time period

This extended-release capsule contains a combination of morphine, a mu-opioid receptor agonist, and naltrexone, a mu-opioid receptor antagonist. This combination was approved on August 13, 2009, for the management of moderate-to-severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Efficacy. The efficacy of this combination therapy was assessed in a randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe osteoarthritis knee or hip pain. Patients began open-label treatment with combination therapy, which was titrated as necessary for pain relief. Once pain was controlled, patients were randomized to either continue receiving active treatment or to taper off active treatment and begin treatment with placebo. At the end of the study, the mean change in the weekly diary Brief Pain Inventory pain score was significantly improved among patients treated with combination therapy versus those treated with placebo.

Safety. This agent must be swallowed whole, or the contents of the capsules must be sprinkled on applesauce and swallowed; the pellets cannot be crushed, dissolved, or chewed, as the resulting morphine dose may be fatal. The 100-mg/4-mg dose is for use in opioid-tolerant patients only. This agent contains morphine, which has the potential for abuse. This morphine/naltrexone combination is likely to have additive effects when used in combination with alcohol, other opioids, or illicit drugs that cause central nervous system (CNS) depression. Patients should not consume alcoholic beverages or medications containing alcohol while taking this combination therapy. Respiratory depression may occur among patients treated with this agent; therefore, this combination should be used with caution in patients with chronic obstructive pulmonary disease (COPD) or cor pulmonale and in those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. Head injury, intracranial lesions, or a pre-existing increase in intracranial pressure may heighten the effects of respiratory depression and cerebrospinal fluid pressure elevations. This agent may cause severe hypotension. The combination therapy should be used with caution in patients who are receiving other CNS depressants. This agent should not be used in patients with gastrointestinal obstruction and should be used with caution in patients with biliary tract disease. This agent should be used with caution in elderly or debilitated patients and patients with severe renal or hepatic insufficiency, Addison's disease, myxedema, hypothyroidism, prostatic hypertrophy, urethral stricture, CNS depression, toxic psychosis, acute alcoholism, or delirium tremens. The most common adverse events associated with this agent include drowsiness, dizziness, constipation, nausea, and vomiting.

Dosing. The dosing regimen for this agent should be individualized, with consideration for the total daily dose, potency, and kind of opioid used previously; the reliability of the relative potency estimate used to calculate the equivalent dose of morphine needed; the patient's degree of opioid experience and tolerance; the general status of the patient; concurrent medication use; and the type and severity of the patient's pain. In patients for whom this agent is the first opioid analgesic to be used, the lowest dose should be used initially, with subsequent dose titrations as necessary. In patients having treatment converted from other oral morphine formulations, one-half of the previous total daily oral morphine dose should be administered as this combination every 12 hours or the full dose of total daily morphine should be administered every 24 hours. In patients having treatment converted from oral opioids, parenteral morphine, or other parenteral opioids, published relative potency data should be consulted, and dose should be individualized as necessary. Dose titration should not occur more frequently than once every 2 days. Patients with signs of excessive opioid side effects should have their dose reduced, and those who have inadequate pain relief with a once-daily dosing schedule should be switched to a twice-daily dose. This agent should not be administered more frequently than every 12 hours. Healthcare professionals should continually re-evaluate the patient for signs of side effects and the maintenance of pain relief. Therapy should not be abruptly discontinued. For patients who have difficulty swallowing whole capsules, the pellets may be sprinkled over applesauce; patients must be instructed not to chew the pellets.