Safety Study to Assess Opiate Withdrawal Signs and Symptoms in Opioid Dependent Patients

A Single-Center, Randomized, Double-Blind, Two-Way Crossover Study to Evaluate Whether a Single-Dose Administration of Crushed and Whole EMBEDA Induces Clinical Opiate Withdrawal Signs and Symptoms in Opioid-Dependent Patients With Chronic, Non-Cancer Pain Who Are Stabilized on EMBEDA¿

This study will evaluate whether crushed EMBEDA capsules induce clinical opiate withdrawal signs and symptoms in opioid-dependent patients with chronic non-cancer pain who are stabilized on EMBEDA.

Study Overview

• Status: Terminated
• Conditions: Chronic Pain
• Intervention / Treatment: Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush; Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole

Detailed Description

The decision to terminate the trial was due to a lack of study drug supply. Decision was not based on any safety concerns. The date of the notification of termination letter was March 11, 2011.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Lifetree Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chronic moderate to severe non-cancer pain that has been treated with opioid analgesics for at least three months (with stabilized pain control and stabilized dose for 28 days prior to enrollment).
• Receiving an opioid dose equivalent to 20 mg - 120 mg morphine once or twice daily.
• Patient displays signs and symptoms of withdrawal (i.e., COWS score ≥5) following naloxone administration during the Naloxone Challenge.

If female and able to become pregnant, must use an approved method of birth control.

• Excluding the chronic moderate to severe non-cancer pain, the patient is judged by the Investigator to be in generally good health at screening based upon the results of a medical history, physical examination, laboratory profile, and 12 lead electrocardiogram (ECG).

Exclusion Criteria:

• Female who is pregnant or breastfeeding.
• Patient has a known allergy or history of significant adverse reaction to morphine, other opioids, naltrexone, acetaminophen, or related compounds.
• Patient is receiving systemic chemotherapy, has an active malignancy of any type, or has been diagnosed with cancer within the 5 years prior to screening (excluding squamous or basal cell carcinoma of the skin).
• History of, or ongoing, alcohol or drug abuse.
• Patient has made a donation of blood or has had a significant blood loss within 30 days prior to screening.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush; EMBEDA (morphine sulfate plus naltrexone hydrochloride ER) capsules crushed and mixed in solution and administered orally at each patient's stable dose, given either once daily or twice daily.	Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush; Placebo capsules plus EMBEDA capsules crushed and mixed in solution administered orally at each patient's stable dose, given either once daily or twice daily
Experimental: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole; EMBEDA (morphine sulfate plus naltrexone hydrochloride ER) capsules, administered orally and intact at each patient's stable dose, given either once daily or twice daily	Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole; EMBEDA capsules, administered orally and intact at each patient's stable dose, given either once daily or twice daily with 150mL placebo solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase	COWS is an 11 section clinical assessment of withdrawal symptoms, each section is rated from 0 (no symptom) to 4 or 5 (most severe symptom). Total score is classified into a 4 point rating scale (mild 5-12, moderate 13-24, moderately severe 25-36 and severe more than 36 points).	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24 hours (hr) post-dose and unscheduled assessment (UA)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases	Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10).	Baseline up to Day 63
Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase	Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase	Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase	Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Apparent Oral Clearance (CL/F) During the Treatment Phase	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Volume of Distribution (Vd/F)During the Treatment Phase	Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Plasma Decay Half-Life (t1/2) During the Treatment Phase	Average plasma decay half-life of morphine, naltrexone and 6-β-Naltrexol. Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase	Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase	Average AUC0-last for Morphine, Naltrexone and 6-β-Naltrexol. Area under the plasma concentration time-curve from time zero to the last measured concentration.	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). Average AUC 0-∞ for Morphine, Naltrexone and 6-β-Naltrexol reported.	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase	Average time to first occurrence of a COWS score ≥ 13	Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24 hr post-dose and UA
Morphine Plasma Concentration at First COWS ≥ 13 in the Treatment Phase		Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Naltrexone Plasma Concentration at First COWS ≥ 13 in the Treatment Phase		Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
6-β-Naltrexone Plasma Concentration at First COWS ≥ 13 in Treatment Phase		Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose
Maximum Post-dose COWS in the Treatment Phase	COWS is an 11 section clinical assessment of withdrawal symptoms, each section is rated from 0 (no symptom) to 4 or 5 (most severe symptom). Total score is classified into a 4 point rating scale (mild 5-12, moderate 13-24, moderately severe 25-36 and severe more than 36 points).	Between 0.5 and 24 hours post-dose

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Setnik B, Roland CL, Goli V, Sommerville K, Webster L. A clinical trial to determine if corelease of morphine and naltrexone from crushed extended-release capsules induces withdrawal in opioid-dependent patients: a descriptive analysis of six patients. J Opioid Manag. 2013 Mar-Apr;9(2):139-50. doi: 10.5055/jom.2013.0155.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: April 7, 2010
• First Submitted That Met QC Criteria: April 7, 2010
• First Posted (Estimate): April 9, 2010

Study Record Updates

• Last Update Posted (Estimate): July 13, 2012
• Last Update Submitted That Met QC Criteria: July 5, 2012
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Keywords: opioid; morphine; withdrawal symptoms; naltrexone; withdrawal signs
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Chronic Pain; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Alcohol Deterrents; Naltrexone; Morphine
• Other Study ID Numbers: ALO-01-09-111; B4541002