Clinical trial NCT01380093: Abuse Potential of Orally Administered Crushed Embeda Compared to Crushed Controlled-Release Morphine and Placebo in Non-Dependent Recreational Opioid Users
Official title: A Randomized, Double-Blind, Placebo- and Active-Controlled, 3-Way Crossover Study to Determine the Abuse Potential of Oral Administration of Crushed EMBEDA Relative to Crushed Controlled-Release Morphine Sulfate and Placebo in Non Dependent, Recreational Opioid Users
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Nondependent Opioid Abuse, Episodic
Keywords: abuse potential
abuse liability
recreational opioid use
morphine
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2011-06-27
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The primary purpose of this study is to determine the abuse potential of EMBEDA compared to controlled release morphine when crushed and taken orally by non-dependent recreational opioid users; secondary purposes include to determine the abuse potential of crushed EMBEDA relative to placebo and and to compare the pharmacokinetics and safety of crushed EMBEDA with crushed controlled-release morphine and crushed placebo.


Eligibility criteria: Inclusion Criteria:

* Subject is a recreational opioid user who is NOT physically dependent on opioids based on Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision (DSM-IV-TR) criteria, and the Naloxone Challenge. A recreational opioid user is defined as recreationally abusing opioids for non-therapeutic purposes (i.e., for psychoactive effects) on at least 10 occasions within the last year and at least once in the 12 weeks prior to Visit 1.
* Subject is in generally good health as determined by medical history, physical examination, vital signs, clinical laboratory tests, and 12-lead electrocardiogram (ECG).

Exclusion Criteria:

* Has a history or current diagnosis of substance dependence (excluding caffeine and nicotine), as assessed by the Investigator using the DSM IV-TR criteria.
* Has participated in, is currently participating in, or is seeking treatment for substance- and/or alcohol-related disorders (excluding nicotine and caffeine).
* History or presence of any clinically significant illness (e.g., cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, musculoskeletal, or psychiatric) or any other condition, which in the opinion of the Investigator would jeopardize the safety of the subject or the validity of the study results.
* Has a known allergy or history of hypersensitivity to morphine sulfate, opioids in general, naltrexone hydrochloride (HCl) or similar compounds and/or the known excipients in the investigational drug products.
* Has any condition in which an opioid is contraindicated (e.g., significant respiratory depression, acute or severe bronchial asthma or hypercarbia, or is suspected of having paralytic ileus).
* Females who are pregnant, lactating, or are planning to become pregnant during the course of the study. Females with a positive serum pregnancy test at Visit 1 or at any subsequent study visit will be excluded from participating in the study.

Primary outcomes:
measure: Drug Liking: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: Drug Liking: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: High: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: High: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
Secondary outcomes:
measure: Drug Liking: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: Drug Liking: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Drug Liking: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Drug Liking: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Drug Liking: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Drug Liking: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: High: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: High: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: High: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: High: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: High: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: High: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Good Effects: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: Good Effects: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: Good Effects: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Good Effects: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Good Effects: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Good Effects: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Good Effects: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Good Effects: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Any Effects: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: Any Effects: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: Any Effects: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Any Effects: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Any Effects: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Any Effects: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Any Effects: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Any Effects: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Bad Effects: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: Bad Effects: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: Bad Effects: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Bad Effects: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Bad Effects: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Bad Effects: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Bad Effects: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Bad Effects: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Nausea: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: Pre-dose, 0.5 and 1 hrs post-dose
measure: Nausea: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5 and 2 hrs post-dose
measure: Nausea: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Nausea: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Nausea: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Nausea: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Nausea: Peak Effect (Emax)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Nausea: Time to Maximum (Peak) Effect (TEmax)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Feel Sick: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: Feel Sick: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: Feel Sick: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Feel Sick: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Feel Sick: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Feel Sick: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Feel Sick: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Feel Sick: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Sleepy: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: Sleepy: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: Sleepy: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Sleepy: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Sleepy: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Sleepy: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Sleepy: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Sleepy: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Dizzy: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: 0.5 and 1 hrs post-dose
measure: Dizzy: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: 0.5, 1, 1.5 and 2 hrs post-dose
measure: Dizzy: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Dizzy: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Dizzy: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Dizzy: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Dizzy: Peak Effect (Emax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Dizzy: Time to Maximum (Peak) Effect (TEmax)
timeFrame: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Overall Drug Liking Effect at 24 Hours
timeFrame: 24 hrs post dose
measure: Take Drug Again Effect at 24 Hours
timeFrame: 24 hrs post dose
measure: Pupillometry: Area Under Effect Curve (AUE) From 0-1 Hour
timeFrame: Pre-dose, 0.5 and 1 hrs post-dose
measure: Pupillometry: Area Under Effect Curve (AUE) From 0-2 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5 and 2 hrs post-dose
measure: Pupillometry: Area Under Effect Curve (AUE) From 0-4 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Pupillometry: Area Under Effect Curve (AUE) From 0-8 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Pupillometry: Area Under Effect Curve (AUE) From 0-12 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Pupillometry: Area Under Effect Curve (AUE) From 0-24 Hours
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Pupillometry: Peak Effect (Emax)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Pupillometry: Time to Maximum (Peak) Effect (TEmax)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-1)] of Morphine
timeFrame: Pre-dose, 0.5 and 1 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-2)] of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5 and 2 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-4)] of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-8)] of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-12)] of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of Morphine
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-1)] of Naltrexone
timeFrame: Pre-dose, 0.5 and 1 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-2)] of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5 and 2 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-4)] of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-8)] of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-12)] of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of Naltrexone
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-1)] of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5 and 1 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-2)] of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5 and 2 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-4)] of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3 and 4 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-8)] of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-12)] of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hrs post-dose
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of Naltrexone Metabolite (6-beta-naltrexol)
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hrs post-dose
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: Lifetree Clinical Research
state: Utah
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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 Aug;14(8):1173-86. doi: 10.1111/pme.12148. Epub 2013 Jun 7.