Clinical Abuse Potential Studies

EMBEDA has properties that are expected to reduce abuse via the oral and intranasal routes1

Overview

EMBEDA was studied in 3 randomized, single-dose, double-blind, placebo- and active-controlled, crossover studies in nondependent recreational opioid users1

A fourth study was conducted with IV administration of simulated crushed EMBEDA.1

  • It is unknown whether these results with simulated crushed EMBEDA predict a reduction in abuse by the IV route until additional postmarketing data are available.1

EMBEDA has properties that are expected to reduce abuse via the oral and intranasal routes as observed in studies measuring Drug Liking, Drug High, and Take Drug Again.1*

*Take Drug Again was only measured in the Oral ER (Study 2) and Intranasal (Study 3) studies.

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Study description

All studies had a randomized, double-blind, single-dose, placebo- and active-controlled, crossover design and were conducted in nondependent recreational opioid users. Drug Liking in Studies 1, 2, and 3 was measured on a bipolar 100-point VAS where 0 represents maximum disliking, 50 represents a neutral response (neither like nor dislike), and 100 represents maximum liking. Drug Liking in Study 4 and Drug High in all studies were measured on a unipolar 100-point VAS where 0 represents no response and 100 represents maximum response. Response to whether the subject would take the study drug again was also measured in 2 studies (Study 2, Study 3) on a bipolar 100-point VAS where 0 represents the strongest negative response (eg, "definitely would not"), 50 represents a neutral response, and 100 represents the strongest positive response (eg, "definitely would").1

Oral IR (Study 1)1
  • Compared EMBEDA to IR morphine sulfate.
  • 32 subjects received 4 treatments: 120 mg/4.8 mg as intact EMBEDA capsules, 120 mg/4.8 mg as crushed EMBEDA in solution, 120 mg IR morphine in solution, and placebo.
Oral ER (Study 2)1
  • Compared EMBEDA to ER morphine sulfate.
  • 36 subjects were randomized to receive 3 treatments in solution: 120 mg/4.8 mg as crushed EMBEDA capsules, 120 mg crushed ER morphine, and placebo.
Intranasal (Study 3)1
  • Compared intranasal administration of crushed EMBEDA to crushed ER morphine sulfate.
  • 33 subjects were randomized to receive 3 treatments: 30 mg/1.2 mg as crushed EMBEDA, 30 mg crushed ER morphine, and crushed placebo.
Simulated IV (Study 4)1
  • Compared 30 mg of IV morphine sulfate alone and 30 mg of IV morphine sulfate in combination with 1.2 mg of IV naltrexone HCl to simulate parenteral use of crushed EMBEDA in 28 subjects.
  • These doses were based on the assumption of the complete release of both morphine sulfate and naltrexone HCl upon crushing EMBEDA.
  • It is unknown whether these results with simulated crushed EMBEDA can predict a reduction in abuse by the IV route until additional postmarketing data are available.
ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Visual Analog Scale (VAS)

Drug Liking, Take Drug Again, and Drug High were measured on a 100-point VAS1

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.
 
REFERENCES

1. Embeda [prescribing information]. New York, NY: Pfizer Inc; December 2016. 2. Stauffer J, Setnik B, Sokolowska M, Romach M, Johnson F, Sellers E. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009;29(12):777-790. 3. Setnik B, Sommerville K, Goli V, Han L, Webster L. Assessment of pharmacodynamic effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users. Pain Med. 2013;14(8):1173-1186. 4. Setnik B, Goli V, Levy-Cooperman N, Mills C, Shram M, Smith I. Assessing the subjective and physiological effects of intranasally administered crushed extended-release morphine formulations with and without a sequestered naltrexone core in recreational opioid users. Pain Res Manag. 2013;18(4):e55-e62.

Oral IR (Study 1)

Drug Liking

Oral administration of crushed EMBEDA was associated with statistically significantly lower Drug Liking scores compared with IR morphine sulfate1-3

During each study treatment session, subjects underwent pharmacodynamic testing about 1 hour before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dosing. At these time points, subjects rated their perceptions of their subjective state and the effects of treatment.

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Drug High

Oral administration of crushed EMBEDA was associated with statistically significantly lower Drug High scores compared with IR morphine sulfate1-3

These are the subject-rated Drug High scores from 0.5 to 24 hours after dosing.

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Mean and median scores

Oral administration of crushed EMBEDA was associated with statistically significantly lower mean and median Drug Liking and Drug High VAS scores compared with IR morphine1

VAS SCALE (100 POINTS) MEAN Emax (SE) MEDIAN Emax (RANGE)
DRUG LIKING*
Crushed EMBEDA (120 mg/4.8 mg) 68.1 (3.1) 62 (50-100)
IR morphine (120 mg) 89.5 (2.2) 93 (57-100)
DRUG HIGH
Crushed EMBEDA (120 mg/4.8 mg) 54.7 (6.1) 64 (0-100)
IR morphine (120 mg) 90.2 (2.1) 97 (61-100)

Emax=maximal response; IR=immediate release; SE=standard error.

*Presented on bipolar 100-point Visual Analog Scales (VAS) (0=maximum negative response, 50=neutral response, 100=maximum positive response).

Presented on a unipolar 100-point VAS scale (0=no response, 100=maximum response).

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Responder rates

Approximate percentage of patients who had some reduction in Drug Liking and Drug High with crushed EMBEDA versus IR morphine1

VAS SCALE (100 POINTS) DRUG LIKING DRUG HIGH
Study 1 (Oral, n=32) SOME REDUCTION NO REDUCTION SOME REDUCTION NO REDUCTION
Crushed EMBEDA (120 mg/4.8 mg) compared with IR morphine (120 mg) 81% 19% 81% 19%
  • In Study 1, at least 30% and 50% reduction in Drug Liking with crushed EMBEDA compared with IR morphine was observed in 72% and 56% of subjects, respectively. At least a 30% and 50% reduction in Drug High with crushed EMBEDA was observed in 56% and 31% of subjects, respectively.1
ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.
 
Oral ER (Study 2)

Drug Liking

Oral administration of crushed EMBEDA was associated with statistically significantly lower Drug Liking scores compared with crushed ER morphine sulfate1,2,4

In this study, subjects rated their perceptions of their subjective state and the effects of treatment at predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing.

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Drug High

Oral administration of crushed EMBEDA was associated with statistically significantly lower Drug High scores compared with crushed ER morphine sulfate1,2,4

These are the subject-rated Drug High scores from 0.5 to 24 hours after dosing.

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Mean and median scores

Oral administration of crushed EMBEDA was associated with statistically significantly lower mean and median Drug Liking and Drug High VAS scores compared with crushed ER morphine1

VAS SCALE (100 POINTS) MEAN Emax (SE) MEDIAN Emax (RANGE)
DRUG LIKING*
Crushed EMBEDA (120 mg/4.8 mg) 65.2 (2.0) 65 (51-100)
Crushed ER morphine (120 mg) 80.6 (2.3) 81 (50-100)
DRUG HIGH
Crushed EMBEDA (120 mg/4.8 mg) 29.2 (3.6) 27 (0-78)
Crushed ER morphine (120 mg) 64.1 (3.3) 63 (28-100)

Emax=maximal response; IR=immediate release; SE=standard error.

*Presented on bipolar 100-point Visual Analog Scales (VAS) (0=maximum negative response, 50=neutral response, 100=maximum positive response).

Presented on a unipolar 100-point VAS scale (0=no response, 100=maximum response).

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Responder rates

Approximate percentage of patients who had some reduction in Drug Liking and Drug High with crushed EMBEDA versus ER morphine1

VAS SCALE (100 POINTS) DRUG LIKING DRUG HIGH
Study 2 (Oral, n=33) SOME REDUCTION NO REDUCTION SOME REDUCTION NO REDUCTION
Crushed EMBEDA (120 mg/4.8 mg) compared with crushed ER morphine (120 mg) 85% 15% 100% 0%
  • In Study 2, at least a 30% and 50% reduction in Drug Liking with crushed EMBEDA compared with crushed ER morphine was observed in 76% and 52% of subjects, respectively. At least a 30% and 50% reduction in Drug High with crushed EMBEDA was observed in 79% and 64% of subjects, respectively.1
ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Take Drug Again scores

Oral administration of crushed EMBEDA was associated with statistically significantly lower Take Drug Again mean and median scores compared with crushed ER morphine sulfate1

  MEAN Emax (SE) MEDIAN Emax (RANGE)
TAKE DRUG AGAIN*
Crushed EMBEDA (120 mg/4.8 mg) 58.0 (3.8) 58 (9-100)
Crushed ER morphine (120 mg) 70.6 (4.3) 75 (12-100)

Emax=maximal response; SE=standard error.

*Presented on bipolar 100-point Visual Analog Scales (VAS) (0=maximum negative response, 50=neutral response, 100=maximum positive response).

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.
 
REFERENCES

1. Embeda [prescribing information]. New York, NY: Pfizer Inc; December 2016. 2. Data on file. Pfizer Inc, New York, NY. 3. Stauffer J, Setnik B, Sokolowska M, Romach M, Johnson F, Sellers E. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009;29(12):777-790. 4. Setnik B, Sommerville K, Goli V, Han L, Webster L. Assessment of pharmacodynamic effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users. Pain Med. 2013;14(8):1173-1186.

Intranasal (Study 3)

Drug Liking

Intranasal administration of crushed EMBEDA was associated with statistically significantly lower Drug Liking scores compared with crushed ER morphine sulfate1-3

In this study, subjects rated their perceptions of their subjective state and the effects of treatment at predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dosing.

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Drug High

Intranasal administration of crushed EMBEDA was associated with statistically significantly lower Drug High scores compared with crushed ER morphine sulfate1-3

These are the subject-rated Drug High scores from 0.5 to 24 hours after dosing.

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Mean and median scores

Intranasal administration of crushed EMBEDA was associated with significantly lower mean and median Drug Liking and Drug High VAS scores compared with crushed ER morphine1

VAS SCALE (100 POINTS) MEAN Emax (SE) MEDIAN Emax (RANGE)
DRUG LIKING*
Crushed EMBEDA (30 mg/1.2 mg) 69.0 (3.5) 66 (50-100)
Crushed ER morphine (30 mg) 88.4 (3.2) 100 (51-100)
DRUG HIGH
Crushed EMBEDA (30 mg/1.2 mg) 48.6 (7.8) 51 (-39-100)
Crushed ER morphine (30 mg) 84.4 (3.8) 100 (42-100)

Emax=maximal response; ER=extended release; SE=standard error.

*Presented on bipolar 100-point Visual Analog Scales (VAS) (0=maximum negative response, 50=neutral response, 100=maximum positive response).

Presented on a unipolar 100-point VAS scale (0=no response, 100=maximum response).

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Responder rates

Approximate percentage of patients who had some reduction in Drug Liking and Drug High with crushed EMBEDA versus ER morphine1

VAS SCALE (100 POINTS) DRUG LIKING DRUG HIGH
Study 3 (Intranasal, n=27) SOME REDUCTION NO REDUCTION SOME REDUCTION NO REDUCTION
Crushed EMBEDA (30/1.2 mg) compared with crushed ER morphine (30 mg) 78% 22% 70% 30%
  • In study 3, at least a 30% and 50% reduction in Drug Liking with crushed EMBEDA compared with crushed ER morphine was observed in 63% and 59% of subjects, respectively. At least a 30% and 50% reduction in Drug High with crushed EMBEDA was observed in 59% and 37% of subjects, respectively.1
ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.

Take Drug Again scores

Intranasal administration of crushed EMBEDA was associated with statistically significantly lower Take Drug Again mean and median scores compared with crushed ER morphine sulfate1

  MEAN Emax(SE) MEDIAN Emax(RANGE)
TAKE DRUG AGAIN*
Crushed EMBEDA (30 mg/1.2 mg) 59.1 (5.4) 56 (0-100)
Crushed ER morphine (30 mg) 87.0 (4.0) 100 (12-100)

Emax=maximal response; SE=standard error.

*Presented on bipolar 100-point Visual Analog Scales (VAS) (0=maximum negative response, 50=neutral response, 100=maximum positive response).

ABUSE OF EMBEDA IS STILL POSSIBLE THROUGH ORAL, INTRANASAL, AND INTRAVENOUS ROUTES. DATA FROM LABORATORY AND CLINICAL STUDIES MAY NOT FULLY PREDICT ABUSE POTENTIAL.
 
REFERENCES

1. Embeda [prescribing information]. New York, NY: Pfizer Inc; December 2016. 2. Data on file. Pfizer Inc, New York, NY. 3. Setnik B, Goli V, Levy-Cooperman N, Mills C, Shram M, Smith I. Assessing the subjective and physiological effects of intranasally administered crushed extended-release morphine formulations with and without a sequestered naltrexone core in recreational opioid users. Pain Res Manag. 2013;18(4):e55-e62.

Clinical abuse potential study of simulated IV EMBEDA

IT IS UNKNOWN WHETHER THESE RESULTS WITH SIMULATED CRUSHED EMBEDA PREDICT A REDUCTION IN ABUSE BY THE IV ROUTE UNTIL ADDITIONAL POSTMARKETING DATA ARE AVAILABLE.1
  • Intravenous administration of combination morphine sulfate and naltrexone HCl was associated with statistically significantly lower median Drug Liking and Drug High scores vs morphine sulfate alone.1
  • This study was performed using 30 mg of IV morphine sulfate in combination with 1.2 mg of IV naltrexone HCl (to simulate parenteral use of crushed EMBEDA and 30 mg of IV morphine sulfate alone.1
    • These doses were based on the assumption of the complete release of both morphine sulfate and naltrexone HCl upon crushing EMBEDA.
  • Drug Liking and Drug High scores were measured on a 100-point unipolar VAS (0=no response, 100=maximum response).1
    • Median Drug Liking scores were 86 for morphine sulfate vs 34 for simulated crushed EMBEDA.
    • Median Drug High scores were 89 for morphine sulfate vs 23 for simulated crushed EMBEDA.
  • Three of the 26 subjects who completed the study had no reduction in Drug Liking and all the subjects showed some reduction in Drug High.1
  • Intravenous injection of crushed EMBEDA may result in serious injury and death due to a morphine overdose and may precipitate a severe withdrawal syndrome in opioid-dependent patients.1
REFERENCE

1. Embeda [prescribing information]. New York, NY: Pfizer Inc; December 2016.