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

Phase 4

Terminated

Conditions: Chronic Pain

Interventions: Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush
Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole

Registration Number: NCT01100437

Lead Sponsor: Pfizer

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 14

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush	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.
EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole	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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 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, 24 hours (hr) post-dose and unscheduled assessment (UA)	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).

Secondary Outcome Measures

Name	Time	Method
Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases	Baseline up to Day 63	Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10).
Time to Reach Maximum Observed Plasma Concentration (Tmax) During 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	Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol
Maximum Observed Plasma Concentration (Cmax) During 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	Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol
Minimum Observed Plasma Concentration (Cmin) During 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	Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol
Apparent Oral Clearance (CL/F) During 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	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.
Volume of Distribution (Vd/F)During 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	Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol
Plasma Decay Half-Life (t1/2) During 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	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.
Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During 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	Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours
Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During 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	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.
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During 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	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.