Pioglitazone to Treat Opioid Withdrawal Symptoms

Background:

Some individuals successfully maintained on buprenorphine or methadone are appropriate
candidates for dose tapering and transition to medication-free follow-up care. For such
individuals, the physical discomfort of the dose taper can be a barrier to a successful
transition. Recent data suggest a novel approach: the FDA-approved diabetes medication
pioglitazone (Actos), which activates the gamma (g) subtype of
peroxisome-proliferator-activated receptors (PPARs). Pioglitazone acts not only in peripheral
tissue, but also in brain regions associated with drug tolerance and withdrawal. In animal
models, pioglitazone prevents signs of opioid withdrawal. In a small, preliminary open-label
clinical study, opioid-maintained outpatients given pioglitazone were remarkably successful
in transitioning comfortably to a medication-free state, after prior unsuccessful attempts
without pioglitazone. These initial data provide proof of principle and indicate that
pioglitazone merits evaluation in a randomized-controlled study.

Scientific goals:

(1) To determine whether, compared to placebo, pioglitazone increases successful completion
of an opioid agonist/antagonist taper in patients who are physically dependent on opioids.
(2) To determine the neural mechanisms by which such an effect may occur.

Participant population:

A total of up to 120 opioid-dependent participants (80 evaluable) will be enrolled. Evaluable
participants are defined as those who are randomized to one of the two main experimental
groups (pioglitazone or placebo). Target enrollment will include 25% women and 70% minorities
(mostly African-American).

Experimental design and methods:

The study will be a randomized, double-blind clinical trial with two treatment groups (40 per
group): pioglitazone (45 mg oral daily) and placebo. The study will last up to 10 weeks. All
participants will receive 27 days of buprenorphine/naloxone (referred to hereinafter as
buprenorphine) - 14 days of stabilization and a 13-day taper. Pioglitazone/placebo will be
initiated in week 2 and continue for 5 weeks (3 weeks concurrently with buprenorphine and 2
weeks without). Participants will have two follow-up assessments: a clinic visit (week 7 or
one week post-pioglitazone/placebo) and a phone follow-up (week 10 or 4 weeks
post-pioglitazone/placebo). Participation will be conducted as a combination of outpatient
and inpatient portions: first two weeks (pre-buprenorphine taper) as outpatients; 18 days on
an inpatient unit (JHBC CRU) during and for approximately 5 days after the buprenorphine
taper; and 10 daily visits and two follow-up visits outpatient. Throughout the study,
participants will receive weekly individual counseling, including case management to prepare
for post-study treatment. Data on opiate-withdrawal symptoms and craving will be collected
daily. Data on self-reported drug use, with urine specimens for drug testing, will be
collected three times weekly. A subset of participants will undergo functional
magnetic-resonance imaging (fMRI) and magnetic-resonance spectroscopy (MRS): one training
session in the mock scanner and two scanning sessions that will occur at the end of the first
week of buprenorphine and during the second week of the buprenorphine taper. Another subset
of participants (largely overlapping with the subset who undergo fMRI/MRS) will undergo one
lumbar puncture so that we can measure levels of neurotransmitters, metabolites, and
proinflammatory cytokines in cerebrospinal fluid (CSF). At the lumbar-puncture visit, blood
will also be drawn so that we can compare analyte levels in CSF and blood. At the end of the
study, all participants will be offered assistance to transfer to another treatment program,
either drug-free treatment or opioid-agonist treatment (OAT). The primary outcome measures
will be opioid-withdrawal severity as measured on the SOWs and COWs. Secondary outcome
measures will include overall proportions of opioid-negative urines, proportions of
participants needing adjunct medications, time to resumption of opioid use following
discharge from the residential unit, status at follow-up, and (in the subset of participants
who agree to undergo lumbar puncture) CSF levels (and corresponding blood levels) of
proinflammatory cytokines and other analytes, which we hypothesize will predict outcome and
thereby clarify pioglitazone s mechanism of action. In the subset of participants who agree
to undergo fMRI/MRS and lumbar puncture, we will attempt to determine the neural mediators of
pioglitazone s therapeutic effects, or (if pioglitazone is not effective) to determine
predictors of treatment outcome. Post-treatment outcome measures are expected to be affected
only indirectly by pioglitazone; we anticipate that pioglitazone will reduce withdrawal
symptoms, enhance initial abstinence during the buprenorphine taper, and address possible
protracted withdrawal.

Benefits to participants and/or society:

Participants will receive buprenorphine taper and drug counseling. There may be incidental
benefits from the buprenorphine and counseling, because they are likely to reduce
participants' use of opioids and risk of infectious diseases such as HIV or hepatitis B and
C.

Risks to participants:

Participants may experience side effects from pioglitazone and/or buprenorphine/naloxone and
are likely to experience some discomfort from opioid withdrawal. The subset of participants
who agree to undergo lumbar puncture and fMRI/MRS may experience side effects from those
procedures.

- INCLUSION CRITERIA:

1. Age between 18 and 65

2. Evidence of physical dependence on opioids (determined by a combination of
self-report, urine screen, and/or physical exam)

3. Seeking detoxification treatment for opioid dependence

4. Able to attend the clinic 7 days/week and undergo an 18-day residential stay

5. For women:

1. post-menopausal or surgically sterile (tubal ligation or hysterectomy) or

2. if sexually active with a male partner and able to get pregnant, documented
agreement to use an IRB-approved form of birth control. Acceptable forms of
contraception for this study include: hormonal contraceptives (birth-control
pills, injectable hormones, vaginal-ring hormones); IUD; diaphragm with
spermicide; condom with spermicide.

EXCLUSION CRITERIA:

1. Any medical illness that in the view of the investigators would compromise
participation in research (determined by Medical History; Physical Examination; Blood
and Urine Laboratory tests; see details under Screening measures below), including,
but not limited to:

- Diabetes mellitus Type I or Type II

- Past or current diagnosis of congestive heart failure

- Signs and symptoms consistent with congestive heart failure including but not
limited to fatigue, exercise intolerance, decreased peripheral perfusion,
orthopnea, dyspnea on exertion, paroxysmal nocturnal dyspnea, peripheral edema,
elevated jugular-venous pressure, pleural and pericardial effusions, hepatic
congestion, ascites, elevated BUN and creatinine, hyponatremia, and elevated
serum levels of hepatic enzymes.

- Cardiovascular disease (e.g., history of congenital heart defect, heart disease,
symptomatic coronary-artery disease, heart attack, irregular heartbeat, etc.)

- Cerebrovascular disease

- Unexplained history of syncope

- History of seizures, except for febrile seizures at childhood

- History of head injury with loss of consciousness of more than 30 minutes or with
postconcussive sequelae lasting more than two days, regardless of loss of
consciousness

- Chronic renal failure as estimated by glomerular filtration rate (GFR) <60
mL/min/1.73 m(2)

- CD4 < 200 or evidence of severely compromised immune system /AIDS

- Active bladder cancer or history of bladder cancer

2. Allergy, hypersensitivity, or intolerance to buprenorphine, pioglitazone, other TZDs,
or the metabolites of any of those drugs (determined by Medical History)

3. Pregnancy or breastfeeding (Urine Pregnancy Test; self-report)

4. Diabetes medications (e.g., sulfonylureas, metformin, insulin, etc.)

5. Contraindicated medications (Medical History): Gemfibrozil (inhibitor of CYP2C8) and
Rifampin (inducer of CYP2C8), atorvastatin, ketoconazole, nifedipine, topiramate, and
diazepam.

6. Psychiatric history:

A) Cognitive impairment severe enough to preclude informed consent or valid responses
on questionnaires

B) Current diagnosis of: schizophrenia or any other DSM-IV psychotic disorder, bipolar
disorder, or Major Depressive Disorder (Self-Report; SCID Screen Patient Questionnaire

- Extended (SSPQ-X))

7. Current physical dependence on alcohol or sedative-hypnotics, e.g. benzodiazepines
(self-report; ASI; alcohol CAGE questions; and pattern of positive drug screens or BAL
for alcohol)

8. Body Mass Index (BMI) of 40 or higher

Additional Exclusion Criteria for the fMRI portion of the Study:

Exclusion from the MRI component of the study will be based on the criteria outlined below.
Participants who do not qualify or who do not agree to participate in the fMRI portion of
the study will not be excluded from the main study. Exclusion criteria will be assessed
during screening under NIDA-IRP screening protocol 06-DA-N415. Participants will be
excluded from the fMRI portion of the study if they:

1. are left handed. Justification: Some of the neural processes assessed in this protocol
may be lateralized in the brain. In order to reduce potential variance, participants
will be required to be right-handed. Assessment tool(s): Edinburgh Handedness
Inventory.

2. over the age of 55 years. Justification: Many cognitive processes change with age. In
addition, the likelihood of difficult-to-detect medical abnormalities such as silent
cerebral infarcts increases with age. Therefore, older individuals, defined as those
over 55, will be

excluded from the present study.

3. have certain implanted devices (cardiac pacemaker or neurostimulator, some artificial
joints, metal pins, surgical clips or other implanted metal parts), body morphology,
or claustrophobia. Justification: Implanted devices may increase the risk of MRI
scanning and/or adversely affect the quality of the data; body morphology may prevent
optimal positioning in the scanner and thus affect the quality of the data;
participants with claustrophobia may find the MRI scan too unpleasant and may exhibit
excess movement that will adversely affect the quality of the data. Assessment
tool(s): Prospective participants will fill out an MRI screening questionnaire and
undergo an interview with an MR technologist. Questions concerning suitability for
scanning will be referred to the MR Medical Advisory Investigator. Prospective
participants will be questioned about symptoms of claustrophobia and placed in the
mock scanner during their first visit to assess for possible difficulty tolerating the
confinement of the scanner and for ability to fit into the scanner.

4. have conditions restricting their ability to lie flat for several hours (such as
coagulopathies, superficial or deep vein thrombosis, or musculoskeletal
abnormalities). Justification: MR scanning sessions require participants to lie flat
on their backs and remain perfectly still for approximately two hours. Therefore,
conditions that would make that difficult (e.g. chronic back pain, significant
scoliosis) or dangerous (e.g. familial hypercoagulability syndrome, history of
thrombosis) will be exclusionary. Assessment tool(s): History and physical examination
by a qualified IRP clinician, supplemented with a trial of lying in the mock scanner
to assess comfort.

5. are cognitively impaired or learning disabled. Justification: Cognitive impairment and
learning disabilities may be associated with altered brain functioning in regions
recruited during laboratory task performance. Assessment tool(s): History of placement
in special education classes as a consequence of serious learning problems and not
solely as a consequence of behavioral problems, assessed during the History and
Physical screening assessment.

6. have HIV or Syphilis. Justification: HIV and syphilis can each have CNS sequelae,
introducing unnecessary variability into the data. Assessment tool(s): Oral HIV
followed by blood test if oral test is + and Syphilis Treponemal Test (STT) without
history of adequate treatment.

7. regularly use any medications that would alter CNS function, cardiovascular function,
or neuronal-vascular coupling. This includes prescription medications (e.g.,
antidepressants, benzodiazepines, antipsychotics, anticonvulsants, barbiturates),
over-the-counter medications (e.g., cold medicine), or herbal medications (e.g., Kava,
Gingko biloba, St. John s wort). The only exceptions are the study medications.
Justification: The use of these substances may alter the fMRI signal and/or neural
functions of interest. Assessment tool(s): History and comprehensive urine drug
screening to detect antidepressants, benzodiazepines, antipsychotics, anticonvulsants,
and barbiturates.

8. have any current or prior neurological illnesses including, but not limited to, those
listed in the main exclusion criteria. Justification: Neurological diseases alter CNS
function and, possibly, the neuronal-vascular coupling that forms the basis of the
fMRI signal. Assessment tool(s): History and physical examination by a qualified IRP
clinician, adult ADHD Self-Report Scale, urine drug screening for anticonvulsants not
disclosed by history.

9. have any other major medical condition that in the view of the investigators would
compromise the integrity of the data. Justification: Many illness not explicitly
covered here may alter important outcome measures. Assessment tool(s): History and
physical examination by a qualified IRP clinician and CBC, urinalysis, NIDA chemistry
panel (liver function tests, electrolytes, kidney function). Determination of
exclusionary status will be based on laboratory values outlined in Table I for the
main study, but the MAI will retain discretion to exclude participants from the
fMRI/MRS secondary study based on less extreme lab results. After the screening
process has been completed, the MAI will take into account all data collected in order
to decide if there is an existing medical illness that would compromise participation
in this research.

Additional Exclusion Criteria for the lumbar-puncture portion of the study

1. Bleeding diathesis/coagulopathy

2. Platelet count <50,000 and INR (International Normalized Ratio) greater than or equal
to 1.5, or on Warfarin (coumadin)

3. Evidence of intracerebral mass based on history, neurologic exam, or papilledema on
fundoscopic exam

4. Clinically significant lumbar spine disease by history, e.g. degenerative disk
disease, ankylosing spondylitis or previous lumbar surgery

5. History of abnormal cranial CT scan or MRI scan, suggesting the possibility of
increased intracranial pressure