Abuse Liability of Pregabalin and Its Effects on Benzodiazepine Withdrawal Symptoms

Study Overview
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Brief Summary
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The purpose of this study is to determine if a single dose of pregabalin 300mg in patients receiving medications for sedative-hypnotic withdrawal symptoms will produce meaningful differences in measures of drug liking and drug high as compared to placebo.

Detailed Description
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Pregabalin is currently being explored as a pharmacotherapy for substance use disorders. Open-labeled, uncontrolled studies indicate modest efficacy of pregabalin in benzodiazepine withdrawal symptom management and as a long-term benzodiazepine dependence treatment. Concurrently, there is increasing information from case reports and adverse drug event registries regarding pregabalin abuse in patients with substance use disorders. Given that the abuse liability of pregabalin has not been clearly established, nor its effects on benzodiazepine withdrawal symptoms in inpatients, this study is a randomized, double-blind, placebo-controlled, cross-over, abuse liability study of a single dose of pregabalin 300mg, nested within a randomized,double-blind placebo-controlled, feasibility study evaluating pregabalin's effects on withdrawal symptoms in inpatients undergoing medically-assisted withdrawal from benzodiazepine, zopiclone or zolpidem.

Official Title
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Evaluation of Pregabalin's Abuse Liability and Its Effects on Benzodiazepine Withdrawal Symptoms in Inpatients Undergoing Medically Assisted Benzodiazepine Withdrawal

Conditions
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Substance-Related Disorders

Intervention / Treatment
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* Drug: Pregabalin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admitted to the Medical Withdrawal Unit at the Centre for Addiction and Mental Health for medically assisted withdrawal from benzodiazepines, zopiclone and/or zolpidem Willing and capable to give written informed consent Exclusion Criteria: Patients who are hypersensitive to pregabalin or to any ingredient in the formulation or component of the container. Pregnant or nursing women Renal impairment (creatinine clearance less than 60ml/min) History of angioedema, or taking drugs associated with angioedema (e.g., ACE-inhibitors). Currently taking pregabalin or gabapentin Currently taking thiazolidinedione antidiabetic agents (e.g., rosiglitazone, pioglitazone) Previous history of pregabalin or gabapentin abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pregabalin<br>Pregabalin titrated up to, and tapered from, 225mg/day in divided doses for 10 days | Drug: Pregabalin<br>* In replacement of their morning 75mg pregabalin or placebo dose on Days 6 and 8, all participants will receive either a single dose of 300mg of pregabalin or placebo, in a randomized, double-blind, crossover manner. This is when steady state concentrations of pregabalin occur.<br>* Other names: Lyrica;Drug: Placebo<br>* In replacement of their morning 75mg pregabalin or placebo dose on Days 6 and 8, all participants will receive either a single dose of 300mg of pregabalin or placebo, in a randomized, double-blind, crossover manner. This is when steady state concentrations of pregabalin occur.<br>|
| Placebo Comparator: Placebo<br>Placebo for 10 days | Drug: Pregabalin<br>* In replacement of their morning 75mg pregabalin or placebo dose on Days 6 and 8, all participants will receive either a single dose of 300mg of pregabalin or placebo, in a randomized, double-blind, crossover manner. This is when steady state concentrations of pregabalin occur.<br>* Other names: Lyrica;Drug: Placebo<br>* In replacement of their morning 75mg pregabalin or placebo dose on Days 6 and 8, all participants will receive either a single dose of 300mg of pregabalin or placebo, in a randomized, double-blind, crossover manner. This is when steady state concentrations of pregabalin occur.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline on Visual Analogue Scale for Drug Liking over 5 hours post-dose administration |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Profile of Mood States (POMS) |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Psychomotor Performance (Digit Symbol Substitution Test (DSST) | Digit Symbol Substitution Test (DSST) | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Take Drug Again |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Any Drug Effects |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Good Effects |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Bad Effects |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Feel Sick |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Nausea |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Sleepy |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Visual Analogue Scale for Dizzy |  | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Sedation (Addiction Research Center Inventory (ARCI) | Addiction Research Center Inventory (ARCI) | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Euphoria (Addiction Research Center Inventory (ARCI) | Addiction Research Center Inventory (ARCI) | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Dysphoric Changes (Addiction Research Center Inventory (ARCI) | Addiction Research Center Inventory (ARCI) | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Psychotomimetic Changes (Addiction Research Center Inventory (ARCI) | Addiction Research Center Inventory (ARCI) | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Somatic Disturbances (Addiction Research Center Inventory (ARCI) | Addiction Research Center Inventory (ARCI) | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Sensory Disturbances (Addiction Research Center Inventory (ARCI) | Addiction Research Center Inventory (ARCI) | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose | 
| Tmax Estimated peak plasma pregabalin concentration | Estimated peak plasma pregabalin concentration | On Days 6 and 8 only: obtained 1 hour post-dose | 
| Change from baseline on Visual Analogue Scale for Drug High over 5 hours | Additional Primary Outcome | On Days 6 and 8 only: Baseline (0), and at 1, 2, 2.5, 3, 4, 5 hours post-dose |