Introduction
Morphine sulfate and naltrexone hydrochloride, combined in extended-release formulations like EMBEDA, represent a significant advancement in the management of chronic, moderate-to-severe pain while incorporating abuse-deterrent properties. This article delves into the clinical trials, market analysis, and future projections for this drug combination.
Clinical Trials Overview
Phase 4 Studies on EMBEDA
Pfizer conducted several Phase 4 studies to evaluate the abuse potential and efficacy of EMBEDA. These studies included double-blind, cross-over designs in non-dependent, recreational opioid users and opioid-dependent patients.
-
Studies ALO-01-10-4005 and ALO-01-10-4004: These studies compared the subjective measures of abuse potential of crushed EMBEDA with crushed extended-release morphine sulfate and placebo. The results showed that EMBEDA was associated with significantly lower scores on "drug liking" and "high" compared to extended-release morphine sulfate[1][4].
-
Study ALO-01-09-111: This study assessed the ability of a single dose of crushed EMBEDA to induce withdrawal symptoms in opioid-dependent patients. Although the study was discontinued early due to the voluntary recall of EMBEDA, it indicated that crushing EMBEDA could induce moderate to severe withdrawal symptoms in some patients[1].
Pharmacodynamic Effects
A key study published in the Pain Physician journal highlighted the pharmacodynamic effects of morphine sulfate and naltrexone hydrochloride extended-release capsules (MSN). When MSN was crushed and administered orally, it significantly decreased positive subjective ratings such as "drug liking" and "high" compared to crushed morphine sulfate controlled-release tablets. This was attributed to the release of naltrexone, which mitigated the morphine-induced effects[2][4].
Mechanism of Action and Abuse Deterrence
Naltrexone Release
The formulation of MSN is designed such that naltrexone remains sequestered when the capsule is taken as directed. However, when the capsule is tampered with (e.g., crushed or chewed), the naltrexone is released, which then attenuates the effects of morphine. This mechanism is crucial in reducing the abuse potential of the drug[2][4].
Pharmacokinetics
The pharmacokinetic profile of MSN shows that when taken whole, the plasma levels of naltrexone are negligible. However, when crushed, the plasma levels of naltrexone and its metabolite, 6-β-naltrexol, are similar to those following an oral solution of naltrexone. This rapid release of naltrexone upon tampering helps in mitigating the euphoric effects of morphine[2][4].
Market Analysis
Market Need for Abuse-Deterrent Opioids
The opioid crisis has highlighted the need for abuse-deterrent formulations. Drugs like EMBEDA, Morphabond, and Hysingla ER have been developed to address this issue. The market demand for such formulations is increasing as healthcare providers and regulatory bodies seek to reduce opioid abuse[3].
Competitive Landscape
The market for extended-release opioids with abuse-deterrent properties is competitive, with several products available. EMBEDA competes with other formulations like Morphabond (an extended-release morphine sulfate product) and Hysingla ER (an extended-release hydrocodone product). Each of these products has unique physicochemical properties designed to deter abuse via different routes of administration[3].
Regulatory Environment
FDA Approval and Post-Marketing Requirements
EMBEDA received FDA approval with the condition that Pfizer would conduct post-marketing studies to assess the impact of its abuse-deterrent properties. This includes monitoring the real-world effectiveness of EMBEDA in reducing opioid abuse[5].
Advisory Committee Recommendations
The FDA's Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee have reviewed various abuse-deterrent opioid formulations, including EMBEDA. These committees have emphasized the importance of human abuse potential studies and in vitro data to support the abuse-deterrent claims of these products[3].
Safety and Adverse Events
Common Adverse Events
Clinical trials have identified common adverse events associated with EMBEDA, including somnolence, nausea, pruritis, and dizziness when administered orally, and euphoric mood, somnolence, and headache when administered intranasally[1][2].
Long-Term Safety
Long-term safety studies have shown that when taken as directed, EMBEDA does not lead to significant accumulation of naltrexone or observable opioid withdrawal symptoms. However, the release of naltrexone upon tampering can induce withdrawal symptoms in opioid-dependent individuals[2].
Market Projections
Growing Demand for Abuse-Deterrent Opioids
The demand for abuse-deterrent opioids is expected to grow as healthcare systems and regulatory bodies continue to prioritize measures to combat the opioid epidemic. EMBEDA, with its proven abuse-deterrent properties, is well-positioned to capture a significant share of this market[3].
Expanding Indications
Future clinical trials may explore the use of EMBEDA in additional patient populations, such as those with cancer pain or acute pain, which could further expand its market potential.
Key Takeaways
- Abuse Deterrence: EMBEDA's formulation releases naltrexone upon tampering, significantly reducing the drug's abuse potential.
- Clinical Efficacy: Studies have shown that EMBEDA is effective in managing chronic, moderate-to-severe pain while minimizing euphoric effects.
- Regulatory Compliance: EMBEDA has met FDA requirements for post-marketing studies to assess its abuse-deterrent properties.
- Market Potential: The growing need for abuse-deterrent opioids positions EMBEDA for significant market growth.
FAQs
Q: What is the mechanism of action of EMBEDA in preventing opioid abuse?
A: EMBEDA releases naltrexone when tampered with, which attenuates the euphoric effects of morphine, thereby reducing its abuse potential.
Q: What are the common adverse events associated with EMBEDA?
A: Common adverse events include somnolence, nausea, pruritis, and dizziness when administered orally, and euphoric mood, somnolence, and headache when administered intranasally.
Q: How does EMBEDA compare to other extended-release opioids in terms of abuse deterrence?
A: EMBEDA has unique physicochemical properties that make it difficult to abuse via intranasal or intravenous routes, similar to other products like Morphabond and Hysingla ER.
Q: What are the regulatory requirements for EMBEDA post-marketing?
A: Pfizer must conduct post-marketing studies to assess the impact of EMBEDA's abuse-deterrent properties in real-world settings.
Q: What is the projected market growth for EMBEDA?
A: The market for abuse-deterrent opioids is expected to grow, and EMBEDA is well-positioned to capture a significant share due to its proven efficacy and abuse-deterrent properties.
Sources
- Pfizer Reports Results From Three Phase 4 Studies Demonstrating EMBEDA® (morphine sulfate and naltrexone hydrochloride) Extended Release Capsules CII Impact On Drug Liking And Withdrawal Symptoms. Pfizer Inc.
- Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules: Naltrexone Release, Pharmacodynamics, and Pharmacokinetics. Pain Physician.
- Joint Meeting of Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee. FDA.
- Assessment of Pharmacodynamic Effects Following Oral Administration of Crushed Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules. Pain Medicine.
- EMBEDA (morphine sulfate and naltrexone hydrochloride) extended-release capsules. FDA Supplement Approval Letter.
