Oxytocin Treatment of Opioid Dependence

The purpose of this research study is to learn whether oxytocin treatment decreases use of
and cravings for opioids (narcotics) in people who have been using opioids heavily for long
periods and are unable to stop on their own. Oxytocin is made naturally and is released in
parts of the brain where it acts like a chemical signal from one cell to another. Oxytocin is
approved by the Food and Drug Administration for stimulating labor in pregnant women but is
not approved as a treatment for opioid dependence.

People who use large amounts of opioids every day or many days per week for weeks or months
undergo chemical changes in their brains. They continue to use opioids frequently and heavily
because, even though they may know opioid use is not good for their health, they have
unpleasant experiences if they stop or decrease the amount used. Those experiences can
include increased anxiety, difficulty sleeping, difficulty tolerating stress, and a craving
to use opioids, as well as physical symptoms of withdrawal such as feeling sweaty or having
chills, bone or joint aches, muscle cramps, nausea, diarrhea. Studies have shown that giving
oxytocin to opioid-addicted animals diminished opioid use after they had been denied access
to opioids for a while and reduced symptoms when they were put into opioid withdrawal.

This is a randomized, double-blind, Placebo-controlled trial in subjects with opioid
dependence that will test the efficacy of intranasal Oxytocin (OT) treatment vs. Placebo
(containing the same ingredients as the OT spray except OT) on:

1. reducing opioid withdrawal symptoms and

2. the total amount of standard, PRN medications required to control withdrawal symptoms
during medical opioid detoxification.

Treatment assignments will be random within each sex. Each treatment group will be composed
of up to 25 subjects. Essentially, this study involves adding daily OT or Placebo
administration on a fixed schedule onto standard symptom triggered treatment of opioid
withdrawal using non-opioid medications.

Subjects will be recruited from patients admitted to the Addictions Detoxification Unit (ADU)
at Wakebrook, the local mental health center for Wake County, NC for medical detoxification
from opioids. There will be no selection on the basis of gender, ethnicity or race. ADU
professional staff will be educated about inclusion and exclusion criteria for this study.
They will describe the study to newly-admitted opioid-dependent patients who appear to meet
criteria. If patients express interest in participation, ADU staff will either call the Study
Coordinator (at UNC Hospitals) as soon as possible or inform a member of the research team
who will visit the ADU each weekday morning. Also, research personnel will contact the ADU
each morning and afternoon to inquire about newly admitted patients. If the Study Coordinator
is contacted about a potential study candidate, the Coordinator will contact and inform the
member of the research team who will visit ADU that morning about the potential study
participant. As soon as possible after potential subjects are admitted to the ADU, research
personnel will obtain informed consent and conduct an initial brief assessment to determine
if subjects meet criteria for inclusion in the study.

The brief assessment includes completion of:

1. urine sample collection for rapid drug screen to confirm opioid use and to determine
other current substance use and, in women, to test for pregnancy;

2. a review of medical exclusion criteria;

3. vital sign (VS) measurements;

4. the M.I.N.I. psychiatric interview screening questions for psychotic disorders, severe
major depression, mania, and suicidality;

5. the Time Line Follow Back interview to quantify addictive substance consumption during
the preceding 3 months;

6. the SCID Substance Use Disorders Module to determine if prospective subjects meet
DSM-IV-R criteria for opioid dependence, currently meet criteria for opioid withdrawal,
and currently or in the past 3 months have met criteria for dependence on substances
that are exclusionary for this study;

7. draw a 5-ml blood sample for serum sodium concentration assay. Physical examinations are
completed by Wakebrook physicians within 24 hours after patients are admitted. Findings
on physical examinations will not be available until later the day of admission or the
following day, which will be after initiation of intranasal doses. If significant
physical exam abnormalities are identified, treatments and further subject participation
in the study will be stopped immediately. Vital signs are measured at regular intervals
on these patients. We will draw blood to assay serum sodium concentrations as a safety
measure for this study.

If need be, prospective subjects will receive PRN medications for withdrawal symptoms before
recruitment procedures are initiated or intranasal test treatments are begun. Treatment
Protocol and Measures: If subjects qualify for inclusion in the study, their withdrawal
symptoms will be immediately measured using the well-validated Clinical Opiate Withdrawal
Scale (COWS) and they will complete self-rating of opioid craving using a 100-mm visual
analog scale (VAS), Subjective Opioid Withdrawal Scale (SOWS) and a baseline Spielberger
State-Trait Anxiety Inventory (SSTAI). This will be followed by self-administration of their
first intranasal dose of the substance to which they have been randomized under supervision
of research personnel or ADU professional staff. The second dose on the first day of
admission will be given 2 hours after the first. A third dose will be given later on the
first day of admission (at least 4 hours after the second dose). On subsequent days of
admission, doses will be taken twice daily (shortly before breakfast or lunch and dinner).
All inpatient self-administration of intranasal test doses will be monitored by ADU or
research staff. Each dose will consist of 10 insufflations of Syntocinon Spray or placebo
(containing the same ingredients as Syntocinon Spray except for Oxytocin). Each insufflation
given 30 sec apart and alternating between nostrils. Oxytocin and Placebo doses are
administered from identical blind-labeled 60-ml spray bottles that deliver 0.1 ml of
aerosolized solution/spray per insufflation. Intranasal test treatments will be administered
for up to 5 days. After the first intranasal test dose, research personnel will complete the
rest of the M.I.N.I. psychiatric interview. During the first 2 inpatient days vital signs,
objective COWS and subjective SOWS subject self-rating of opioid craving will be obtained
every 4 hours or whenever subjects report or nurses observe the onset of withdrawal symptoms.
Subsequently, the COWS and SOWS measures will be obtained twice daily or whenever withdrawal
symptoms increase for at least 2 additional days and longer if subjects continue to exhibit
significant symptoms. Subjects will complete the VAS subjective rating of opioid craving and
the State portion of the SSTAI on each inpatient day starting on admission day 2
approximately 1 hour before their second intranasal test dose. In all subjects, per protocol,
multiple as-needed non-opioid medications will be available for symptoms of opioid
withdrawal.

Inclusion Criteria:

1. Age 21-45.

2. Regular opioid use (daily or nearly daily) for at least 6 months (subjective report).

3. Active DSM-IV diagnosis of opioid dependence.

Exclusion Criteria:

1. Meets DSM-IV criteria for dependence on psychoactive substances other than opioids,
caffeine or nicotine within 6 months prior to screening.

2. Treatment with naltrexone in the last month.

3. History of a significant psychiatric illness including: lifetime history of mania
requiring hospitalization, psychotic disorder, cognitive disorder; history during the
last two years of eating disorder. Standing or as needed non-exclusionary medications
for non-exclusionary psychiatric disorders will be permitted.

4. Unstable medical illness that could compromise consent to treatment, interfere with
evaluation of study medication, or present a safety concern (e.g. uncontrolled
diabetes mellitus, unstable hypertension, BMI <18 or >35, seizure disorder, traumatic
brain injury, Parkinson's disease, AIDS). Adequately controlled conditions (such as
diabetes mellitus, hypertension, asthma, HIV infection, and hepatitis C) will not be
exclusionary. Standing or or as needed medications for non-exclusionary medical
conditions will be permitted.

5. Serum sodium < 136 mEq/L (i.e., below the normal range) at the time of screening.

6. Significant abnormal findings on physical examination.

7. Women who are pregnant or breastfeeding.

8. In the judgment of the investigators, the individual would be considered a poor
candidate.