Increased Sensitivity to Pain Caused by Opioids in People Who Have Abused Prescription Opioids

Study Overview
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Brief Summary
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Managing pain in patients who abuse prescription opioids presents many challenges, including the development of opioid-induced hyperalgesia (OIH). Hyperalgesia is a condition in which something that usually feels slightly painful is perceived as something very painful. The proposed study will test the efficacy of the well-known neurological medication pregabalin to diminish OIH and chronic pain in persons who are in Suboxone (buprenorphine) or methadone treatment for prescription drug abuse.

Detailed Description
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The clinical management of pain in prescription opioid abusers presents a challenge to the health care professional. Investigators have novel pilot data showing that the GABA-agonist gabapentin (GPN) significantly decreases opioid-induced hyperalgesia (OIH) in methadone patients (Compton et al., 2009), providing the first empirical evidence of a pharmacotherapy for OIH in opioid abusers. The work of Gore and colleagues (2011) showed that pregabalin (PGB), a GABA analogue succeeding GPN, was shown to decrease opioid use in patients with neuropathic pain in patients, suggesting an anti-hyperalgesia effect not observed in the matched cohort receiving GPN. The proposed research will comprehensively evaluate the efficacy of PGB in treating opioid-induced hyperalgesia (OIH) in a well-described population of prescription opioid abusers (POAs) with chronic pain and on Suboxone (buprenorphine) or methadone therapy. A pressing need for such investigation is presented by the rising number of POAs presenting for treatment (SAMHSA, 2010; 2011), and for whom, chronic pain is a common co-morbidity. The proposed work is anticipated to provide vital and timely information on the efficacy of PGB in the treatment of OIH in prescription opioid abusers on Suboxone or methadone therapy. Following recruitment and screening, 75 subjects assigned to the active medication group will receive pregabalin 400 mg/day, a dose well-within published guidelines of 300-600 mg/day for the treatment of neuropathic pain (http://www.pfizerpro.com/hcp/lyrica/phndosing). During the first week of treatment, subjects will be quickly titrated up to the assigned daily PGB dose of 400 mg/day PO (50mg BID x 2 days; 100mg BID x 2 days; 150mg BID x 2 days, with full dosage of 400mg administered on day 7 ), or maximum dose tolerated) for six weeks. 75 subjects will be assigned to receive matched and undergo identical titration and study activities under double-blind conditions. Study staff will evaluate subjects daily by phone during titration; thereafter they will be seen weekly at study sessions. Tapering of medication will begin at the end of week 6. The severity of chronic pain will be measured at each time point using two standardized self report tools which report on pain severity (McGill Pain Questionnaire) and pain-related disability (Brief Pain Inventory). Opioid-induced hyperalgesia will be measured at each time point using a standardized cold pressor trial, and performance at baseline will be compared to performance following PGB/placebo administration over time.

Official Title
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Opioid-Induced Hyperalgesia in Prescription Opioid Abusers: Effects of Pregabalin

Conditions
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Chronic Pain

Intervention / Treatment
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* Drug: Pregabalin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between the ages of 21 and 65 years of age. Have a DSM-IVR diagnosis (used through 10/1/2014) of prescription opioid abuse or dependence disorder or a DSM-5 diagnosis of opioid use disorder. Be enrolled and compliant in Suboxone or methadone treatment and on a stable dose [Suboxone (6-24mg/day); of methadone (60-120mg/day)] x at least 10 days. Provide urine sample absent of any non-prescribed drugs of abuse at screening. Screening cold-pressor pain tolerance < 70 seconds Have chronic lower back pain or arthritis pain (duration six or more months). Be otherwise in good physical health, or in the case of a medical condition needing ongoing treatment, be in the care of a physician who is willing to take responsibility for such treatment. The same conditions apply in cases of patients with a psychiatric disorder needing ongoing treatment. Be agreeable to and capable of signing an informed consent. Exclusion Criteria: Have known sensitivity to pregabalin or gabapentin. Potential participants must not be taking the following medications: pregabalin or gabapentin, tiagabine, vigabatrin, valproate, phenobarbital or primidone for the treatment of epilepsy; SNRI or TCA antidepressants; baclofen; or carbamazepine, oxycarbazepine or lamotrigine for the treatment of chronic pain. Currently be substance dependent on alcohol, benzodiazepine, methamphetamine, cocaine or other drugs of abuse (except nicotine). Have any acute medical condition that would make participation medically hazardous, (e.g., acute hepatitis, unstable cardiovascular disease, liver or renal disease) or have liver enzyme values (AST or ALT) greater than 5 times normal range. Be acutely psychotic, severely depressed and in need of inpatient treatment, or an immediate suicide risk. Have a neurological or psychiatric illness (i.e., schizophrenia, Raynaud's disease, urticaria, stroke) that would affect pain responses. Be currently taking opioid analgesic medication for a painful condition on a regular basis. Be a nursing or pregnant female, or a female or male who does not agree to not become pregnant or father a child during the course of, and six months following completion of the study. If a subject becomes pregnant or fathers a child during the study, they must immediately notify the study investigator. Have a history of heart disease, stroke, liver or kidney disease, epilepsy or acute hepatitis, or currently have a pacemaker or uncontrolled high blood pressure.

Ages Eligible for Study
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Minimum Age: 21 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: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregabalin<br>Pregabalin 400mg / Day | Drug: Pregabalin<br>* Titration of intervention will begin with 50mg PO BID x 2 days, then 100mg PO BID x 2 days, then 150mg PO BID X 2 days, then on day 7 full dose of Pregabalin 400mg PO QD for six weeks<br>* Other names: Lyrica;|
| Placebo Comparator: Placebo Control<br>Placebo Tablet | Drug: Placebo<br>* Placebo group will follow the same titration as the pregabalin group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improved Pain Response, threshold and tolerance | To test the efficacy of PGB, compared to placebo, to diminish OIH, as evidenced by improved pain responses (threshold and tolerance) to experimentally induced cold-pressor pain, in a well-described sample of POA patients with chronic pain and on buprenorphine or methadone therapy. Pain Threshold: On the CP assay, pain threshold is operationalized as the number of seconds after the onset of the painful stimulus when a painful sensation is first detected. Subjects will indicate threshold by saying Pain. Pain Tolerance: On the CP assay, pain tolerance is operationalized as the number of seconds after the onset of the painful stimulus when the painful sensation is subjectively intolerable. Subjects will indicate tolerance by removing their arm from the ice bath. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in pain severity and daily functionality | To test the efficacy of PGB, compared to placebo, to diminish chronic pain, as evidenced by improvements in pain severity and functionality in a well-described sample of POA patients with chronic pain and on buprenorphine or methadone therapy. Pain Severity will be measured with The McGill Pain Questionnaire. Daily Functionality will be measured with the Brief Pain Inventory | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Pain, Narcotic Abuse, Opioid related disorders, Opiate substitution treatment, Buprenorphrine, Pregabalin, Methadone