Evaluation of a Compliance Marker in Prescription Opioid Abusers With Chronic Pain

In a small, well-characterized sample of prescription opioid abusers (POAs) with chronic
pain and on buprenorphine therapy, this supplement study will investigate the utility and
feasibility of two novel tracer compounds, and in combination with a standard marker
(riboflavin), to monitor adherence to study drug prescription in the parent clinical trial
(NCT01821430).

1. We will examine the ability of two benign (in the doses used) medications, quinine
(80mg) and acetazolamide (15mg) to serve as valid and reliable markers of medication
use. The relative utility of each will be described for use with the study medication
(PGB 400mg/day), a drug dependent on primarily renal excretion. In that both PGB and
acetazolamide are eliminated unchanged in the urine, we will examine if the latter can
be used without altering the elimination rate of the former, or whether a maker with
both hepatic and renal modes of elimination (quinine) would serve as a better indicator
of adherence in the trial.

2. Being a standard in clinical trials, the medication adherence marker riboflavin is used
in the parent study (NCT01821430), as it can be readily detected in urine samples by
simple visual inspection. However, riboflavin is a relatively gross indicator of
medication use; it does not reside in the body for the time period typically required
in outpatient trials, can be affected by dietary riboflavin and has variable
absorption. Capitalizing on riboflavin's ease of detection, the second aim of this
supplement will be to examine whether riboflavin when combined with one of the new
candidate tracers, can provide a superior indicator of adherence, in that riboflavin
can be qualitatively observed immediately, and the other tracer being quantitatively
detected during subsequent urine toxicology analyses.

The cross over design of the study will allow us to address these aims in an efficient and
straightforward manner. Following examination of the pharmacokinetics (PK) of PGB alone,
it's PK will then be reexamined when compounded with acetazolamide, and again with both
acetazolamide and riboflavin present. Next, after a short washout period, the studies PGB PK
will be repeated with acetazolamide replaced by quinine. If the new tracers do not interfere
with the PK of PGB, one of them will be chosen to be formulated (along with riboflavin) with
PGB for use in the parent study, thereby providing both qualitative and quantitative
indicators of adherence.

Inclusion Criteria:

1. male and female English-speaking literate adults age 18- 50 years old,

2. have medically diagnosed chronic pain condition,

3. be on a stable dose of buprenorphine (clinic modal dose),

4. history of prescription opioid abuse,

5. adequate venous access,

6. if female, a negative pregnancy test. Individuals will not be accepted who are
unstable in buprenorphine treatment as evidence by continued illicit drug use and
irregular clinic attendance in the previous trial,

7. be otherwise in good physical health or in care of a physician who is wiling to take
responsibility for such treatment. The same conditions apply in cases of patients
with a psychiatric disorder needing ongoing treatment.

Exclusion Criteria:

1. physiologic drug dependence on benzodiazepines, barbiturates, and/or alcohol that
would require medical management,

2. significant ongoing medical problems (e.g., diabetes),

3. history of head injury or seizure,

4. serious psychiatric illness outside of drug use (e.g., schizophrenia),

5. recent use of any agent that inhibits or induces cytochrome P450 3A4 or 2D6,

6. 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 three months following
completion of the study,

7. have a cardiac conduction or blood clotting disorder,

8. blood donation within the past 30 days prior to screening,

9. clinically significant laboratory results (as judged by the
investigator/sub-investigator)

10. moderate to severe COPD,

11. renal impairment, and

12. severe renal hepatic impairment.