Abuse Potential of Hydrocodone in Human Studies

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1 Abuse Potential of Hydrocodone in Human Studies Sharon L. Walsh, Ph.D. Center on Drug and Alcohol Research University of Kentucky Report to the Drug Safety and Risk Management Advisory Committee January 24-25, 13

2 Outline Abuse potential vs. abuse liability Human laboratory approach Populations and methods Results from published studies Normal volunteers Opioid abusers Summary of results 2

3 Abuse Potential vs. Abuse Liability Abuse Potential Characterizes the ability of a CNS-active drug to produce positive psychoactive effects may include sedation, euphoria, perceptual and other cognitive distortions, hallucinations and mood changes. These effects are viewed as correlated with or predictive of the risk of abuse and/or addiction 3

4 Abuse Potential vs. Abuse Liability Abuse Liability Is similar and sometimes used interchangeably Includes abuse potential Captures other factors, including ease of synthesis and drug abuse/diversion history Describes abuse potential in a social and public health context 4

5 How Are They Measured? 5

6 Human Abuse Potential Studies: General Methods Enroll adult volunteers with appropriate drug use histories (preferably as inpatients) opioid abuse histories (but without physical dependence) Include tests of the appropriate control (positive and negative if available) agents for comparison with the test drug of interest Control condition(s) full mu opioid agonist Double-blind testing is employed 6

7 Human Abuse Potential Studies: General Methods Collect a comprehensive array of outcomes Physiological Respiratory, cardiovascular, pupil diameter Subjective measures Visual analog questionnaires Adjective scales Street value estimates Observer-rated effects Cognitive/psychomotor tasks Assess impairment 7

8 Contemporary Studies of Hydrocodone Available for Review Six human abuse potential studies of hydrocodone [published between 3 to ] Five of oral hydrocodone Hydrocodone/homatropine (Hycodan ) (n=1) Hydrocodone/acetaminophen (n=3) Hydrocodone alone (n=1) One of intravenous hydrocodone alone All studies employed within-subject, crossover designs Conducted in healthy non-drug-abusing volunteers 8

9 Hydrocodone/Homatropine: Hycodan Healthy Volunteers Pupil Diameter How Much Do You LIKE the Drug? 6.5 Trough Diameter (mm) Mean Peak Score Positive Negative 5 (1.5) (3) (6) Hydrocodone (Homatropine, mg) 4 2 Morphine Lorazepam 5 (1.5) (3) (6) Hydrocodone (Homatropine, mg) 4 2 Morphine Lorazepam Zacny J.P. (3) Psychopharmacology, 165:

10 Hydrocodone/Acetaminophen Healthy Volunteers Pupil Diameter How Much Do You LIKE the Drug? 6.5 Trough Diameter (mm) Mean Peak Score Positive Negative 5 (5) (5) () Hydrocodone (Acetaminophen, mg) 4 Morphine Acetaminophen 5 (5) (5) () Hydrocodone (Acetaminophen, mg) 4 Morphine Acetaminophen Zacny, Gutierrez & Bolbolan (5) Drug and Alcohol Dependence: 78:

11 Hydrocodone/ACET & Oxycodone/ACET Healthy Volunteers 6.5 Pupil Diameter How Much Do You LIKE the Drug? 7 Trough Pupil Size (mm) Mean Peak Score (487) (975) 15 (487) 3 (975) (487) (975) 15 (487) 3 (975) Oxycodone (Acetaminophen, mg) Hydrocodone (Acetaminophen, mg) Oxycodone (Acetaminophen, mg) Hydrocodone (Acetaminophen, mg) Zacny & Gutierrez (9) Drug and Alcohol Dependence, 1:

12 Hydrocodone/ACET & Oxycodone/ACET Healthy Volunteers Coasting Nauseated 5 4 Mean Peak Score 4 3 Mean Peak Score 3 (487) (975) 15 (487) 3 (975) (487) (975) 15 (487) 3 (975) Oxycodone (Acetaminophen, mg) Hydrocodone (Acetaminophen, mg) Oxycodone (Acetaminophen, mg) Hydrocodone (Acetaminophen, mg) Zacny & Gutierrez (9) Drug and Alcohol Dependence, 1:

13 Oxycodone, Hydrocodone & Hydromorphone Prescription Opioid Abusers How Much Do You LIKE the Drug? Oxycodone Hydrocodone Hydromorphone Visual Analog Scale (mm) mg mg mg 4 mg BL mg 15 mg 3 mg 45 mg mg mg 17.5 mg 25 mg 6 BL BL Time (hour) Time (hour) Time (hour) Walsh, Nuzzo, Lofwall & Holtman (8) Drug and Alcohol Dependence, 98:

14 Oxycodone, Hydrocodone & Hydromorphone Prescription Opioid Abusers Pupil Diameter Respiratory Rate Placebo Oxycodone 14 Diameter (mm) Hydromorphone Hydrocodone Breaths/minute Dose Dose Walsh, Nuzzo, Lofwall & Holtman (8) Drug and Alcohol Dependence, 98:

15 Oxycodone, Hydrocodone & Hydromorphone Prescription Opioid Abusers Agonist Scale - Subject Agonist Scale - Observer Score 15 Score Placebo Oxycodone Hydromorphone Hydrocodone Dose Dose Walsh, Nuzzo, Lofwall & Holtman (8) Drug and Alcohol Dependence, 98:

16 Relative Potency Estimates Only variables meeting the criteria for a valid bioassay were included (Finney, 1964) Mean relative potency estimates across outcomes Oxycodone : Hydrocodone =.93 mg : 1 mg Finney D.J. (1964) Statistical Method in Biological Assay, 2 nd Ed. Hafner, NY. 16

17 Intravenous Morphine, Oxycodone & Hydrocodone Prescription Opioid Abusers How Much Do You LIKE the Drug? Morphine Oxycodone Hydrocodone 6 Visual Analog Scale (mm) mg 5 mg mg mg mg 5 mg mg mg mg 5 mg mg mg BL BL BL Time (min) Time (min) Time (min) Stoops, Hatton, Lofwall, Nuzzo & Walsh () Psychopharmacology, 212:

18 Intravenous Morphine, Oxycodone & Hydrocodone Prescription Opioid Abusers Pupil Diameter Expired End-Tidal CO 2 Trough Diameter (mm) mmhg Morphine (mg, i.v.) Oxycodone (mg, i.v.) Hydrocodone (mg, i.v.) Morphine (mg, i.v.) Oxycodone (mg, i.v.) Hydrocodone (mg, i.v.) Stoops, Hatton, Lofwall, Nuzzo & Walsh () Psychopharmacology, 212:

19 Intravenous Morphine, Oxycodone & Hydrocodone Prescription Opioid Abusers 5 Street Value U.S. Dollars Morphine (mg, i.v.) Oxycodone (mg, i.v.) Hydrocodone (mg, i.v.) Stoops, Hatton, Lofwall, Nuzzo & Walsh () Psychopharmacology, 212:

20 Summary: Studies in Healthy Volunteers Hydrocodone (in combination with homatropine or acetaminophen) produces dose dependent euphorigenic effects These effects are similar to those of morphine and oxycodone Hydrocodone mg ~ Morphine 4 mg Hydrocodone 3 mg ~ Oxycodone mg ACET produces no discernible effects alone Unpleasant effects (e.g., nausea, dizziness) occurred at the upper end of the hydrocodone dose range (as with other opioids)

21 Summary: Studies in Prescription Opioid Abusers Hydrocodone produces dose dependent increases on ratings of positive subjective reports, including ratings of liking, good effects and endorsements of street value There is little to no evidence that hydrocodone produces reports of negative or unpleasant symptoms Hydrocodone is only slightly less potent than oxycodone on subjective effects related to abuse potential The profile of hydrocodone is similar to comparator opioids, including morphine, hydromorphone and oxycodone 21

A HISTORICAL PERSPECTIVE ON HUMAN ABUSE LIABILITY STUDIES. Donald R Jasinski, MD

A HISTORICAL PERSPECTIVE ON HUMAN ABUSE LIABILITY STUDIES Donald R Jasinski, MD Origin of methods Modify morphine molecule Develop a selective analgesic lacking abuse potential Reduce public health and