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

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.

Inclusion Criteria:

1. Be between the ages of 21 and 65 years of age.

2. 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.

3. 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.

4. Provide urine sample absent of any non-prescribed drugs of abuse at screening.

5. Screening cold-pressor pain tolerance < 70 seconds

6. Have chronic lower back pain or arthritis pain (duration six or more months).

7. 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.

8. Be agreeable to and capable of signing an informed consent.

Exclusion Criteria:

1. Have known sensitivity to pregabalin or gabapentin.

2. 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.

3. Currently be substance dependent on alcohol, benzodiazepine, methamphetamine, cocaine
or other drugs of abuse (except nicotine).

4. 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.

5. Be acutely psychotic, severely depressed and in need of inpatient treatment, or an
immediate suicide risk.

6. Have a neurological or psychiatric illness (i.e., schizophrenia, Raynaud's disease,
urticaria, stroke) that would affect pain responses.

7. Be currently taking opioid analgesic medication for a painful condition on a regular
basis.

8. 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.

9. 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.