Oxytocin Treatment of Alcohol Dependence
Oxytocin Treatment of Alcohol Dependence
This study will test in individuals who have alcohol dependence (alcohol addiction) the
 hypotheses 1) that intranasal oxytocin treatment will decrease withdrawal symptoms during
 medical detoxification and 2) that intranasal oxytocin treatment for 12 weeks in the
 outpatient setting will decrease drinking.
Study Design This is a randomized, double blind, placebo-controlled early phase II clinical
 trial.

 Recruitment: The study has 2 phases. The first is testing intranasal treatments (oxytocin
 [OT], placebo) on alcohol withdrawal (the inpatient phase) and the second is testing
 intranasal treatments on alcohol drinking, craving and anxiety over 12 weeks in the
 outpatient setting (the outpatient phase). Subjects for the inpatient phase will only be
 recruited from patients admitted to Freedom House (FRH, mental health center in Chapel Hill,
 NC) for medical detoxification from alcohol within the last 36 hours. Subjects for the
 outpatient phase of the study will be inpatients at FRH or the University of North Carolina
 (UNC) Hospitals who are near the end of their inpatient stay (medical detoxification has been
 or is nearly completed). Subjects in the inpatient phase of the study at FRH may continue
 into the outpatient phase after discharge. Subjects for the outpatient phase will also be
 heavy drinkers from the community who are screened during an initial outpatient clinic visit.

 Patients newly admitted to FRH to treat alcohol withdrawal will undergo a brief screening
 that includes: 1) a recent and past alcohol use interview (Time Line Follow Back, TLFB) and
 history of alcohol withdrawal interview; 2) a brief psychiatric interview; 3 ) a score on the
 10-item CIWA scale of alcohol withdrawal symptoms; 4) a review of potential medical exclusion
 criteria including a history of seizures or delirium tremens; 5) a spot urine pregnancy test
 on all prospective female subjects.

 Recruitment into the outpatient phase (treatment of outpatient drinking): Patients who
 undergo medical detoxification from alcohol will be recruited from FRH or from UNC Hospitals
 toward the end of their admission for participation in a trial to test the efficacy of
 intranasal OT vs. placebo treatment on alcohol drinking, alcohol craving and anxiety during a
 12-week outpatient treatment period. They will be screened to see if they meet study
 criteria. These individuals will read and sign the Breath Alcohol Policy that states that if
 their Breathalyzer reading at the beginning of an outpatient clinic visit is >.08 they will
 not be assessed at that visit and will not drive themselves home but rather will accept a
 ride from a family member, friend or a cab driver.

 Other individuals will be recruited from the community for participation in the outpatient
 phase of the study who have responded to a radio ad, a UNC listserve ad, a flyer, have been
 referred by local clinicians or have otherwise become aware of the study. These prospective
 subjects will undergo a telephone screening interview. If they appear to meet criteria over
 the phone, they will be further screened during an outpatient clinic visit. They must sign
 the Breath Alcohol Policy.

 Inpatient Treatment of Withdrawal Protocol and Measures: Subjects who enroll in the study
 shortly after being admitted to FRH will immediately complete the State portion of the
 Spielberger State-Trait Anxiety Inventory (SSTAI) and the Penn Alcohol Craving Scale (PACS).
 This will be followed by self-administration of their first intranasal test dose under
 supervision of research personnel. These subjects will self-administer additional intranasal
 test doses at 1 and 3 h after the initial dose and then on the evening of that first day of
 admission. On subsequent admission days at FRH, subjects will self-administer intranasal test
 doses 3 times per day. After the first intranasal test dose, blood (15 ml) and urine samples
 will be obtained from subjects at FRH by research personnel for complete blood count (CBC),
 electrolytes, blood urea nitrogen (BUN), creatinine, glucose, albumin, liver function tests,
 urinalysis and urine toxicology which will be transported to and run at the UNC Hospital
 laboratory.

 Between the 1st and 3rd initial intranasal test doses, research personnel will complete a
 more detailed psychiatric interview. Subjects will also complete the University of Rhode
 Island Change Assessment Scale to assess their stage of motivation to stop or cut back on
 their drinking, the Drinker's Inventory of Consequences to assess the spectrum of
 consequences related to drinking, the Family History of Alcoholism Module to assess family
 history of alcohol problems, the Patient Health Questionnaire (PHQ) to assess symptoms of
 depression and a Demographic Questionnaire. During the first 2 inpatient days, vital signs
 and CIWA scores will be obtained (by FRH personnel) every 4 hours or whenever subjects report
 or nurses observe the onset of withdrawal symptoms. On the 3rd inpatient day, these measures
 will be obtained 3 times. And on subsequent inpatient days, these measures will be obtained
 once each day and whenever withdrawal symptoms increase. Subjects will complete the PACS and
 the SSTAI prior to administration of the 2nd test dose on each inpatient day starting the day
 after they enter the study. Blood will be drawn early on inpatient day 3 for electrolyte
 measurements.

 In all subjects participating in the inpatient phase of the study, lorazepam (2 mg), a
 standard medication to decrease withdrawal symptoms, will be administered by mouth (PO)
 whenever CIWA scores are ≥ 7. CIWA scores will be repeated 1 h after each lorazepam dose and
 another dose given if the CIWA score remains ≥ 7. Also, lorazepam (2 mg) will be administered
 if subjects are found to have any of the following elevated vital signs (even if CIWA scores
 remain low): pulse > 110; diastolic blood pressure > 100; systolic blood pressure > 160.
 Vital signs (as well as CIWA) will be repeated 1 h after each lorazepam dose and another dose
 will be given if any of the elevated measures persist. If a subject's CIWA score remains ≥ 7,
 pulse remains > 110 or diastolic blood pressure remains > 100 after 8 consecutive lorazepam
 doses, systolic blood pressure remains > 160 after 3 lorazepam doses, or CIWA scores steadily
 increase despite receiving 3 consecutive lorazepam doses or dangerous symptoms develop (e.g.,
 the onset of hallucinations), a more aggressive detoxification regimen will be initiated and
 the subject will be dropped from the study. All patients admitted to FRH for alcohol
 detoxification receive thiamine, folate and multivitamins supplementation.

 Initiating Outpatient Test Treatment: Subjects recruited into the outpatient phase of the
 study at the end of an inpatient admission for medical detoxification from alcohol will be
 randomized to a treatment group and begin intranasal test treatment during their first
 outpatient clinic visit after discharge from FRH or UNC Hospitals. Subjects recruited from
 the community will be randomized and begin intranasal test treatments at a outpatient clinic
 visit scheduled shortly after their screening clinic visit if assessments at the latter visit
 indicate they meet inclusion criteria and not exclusion criteria. Several measures will be
 obtained at the beginning of the clinic visit when subjects begin self-administration of test
 treatments: Breathalyzer reading, CIWA rating, TLFB interview assessment of recent alcohol
 consumption, self-ratings on the SSTAI and PACS. Research personnel will then instruct
 subjects in intranasal self-administration technique and then observe subjects take their
 first intranasal test dose. Subjects will be given written instructions on intranasal
 self-administration technique, cleaning the spray bottle nozzle after each dose, storing
 spray bottles between doses and contacting study personnel if they have question, difficulty
 with the self-administration procedure or may be experiencing side effects. At the end of the
 clinic visit, subjects will take home a 60 ml spray bottle (that ejects 0.1 ml metered dose
 per insufflation) containing 25 ml of test solution which they will use to self-administer
 test treatment doses twice daily (6 insufflations/dose).

 Outpatient clinic visits during the treatment period: Subjects will have follow-up outpatient
 clinic visits at weeks 1, 2, 3, 4, 6, 8, 10 and 12 after starting intranasal test treatments.
 Outpatient visits will take place in the Psychiatry Clinics in the UNC Neurosciences Hospital
 or the Alcohol and Substance Abuse Program (ASAP) clinic which is located off of the UNC
 campus on a bus line making it more convenient for participants to commute and park thereby
 facilitating their compliance with the outpatient portion of the study. To enhance
 continuity, the first visit will be 2-3 days after the clinic visit during which intranasal
 test treatments are started. At each clinic visit, a Breathalyzer reading, a CIWA score and
 vital signs will be obtained, a TLFB interview administered to quantify daily alcohol intake
 since the last clinic visit, and the SSTAI, PACS and PHQ questionnaires will be completed.
 Subjects will be given a fresh 60 ml intranasal spray bottle containing 25 ml of test
 substance at clinic visits every 2 weeks. At each clinic visit, subjects' spray bottles will
 be weighed to monitor compliance. Their intranasal self-administration technique will be
 reviewed and, if necessary, subjects will be reinstructed in proper technique. At 4, 8 and 12
 weeks, blood will be drawn for CBC, liver functions, electrolytes, BUN, creatinine, and a
 urine sample will be obtained for drug screening and pregnancy tests on all female subjects.

 During each clinic visit, 15 minutes of substance use counseling (Medical Management) will be
 provided.
Inclusion Criteria:

 -  Inclusion Criteria for the inpatient phase (alcohol withdrawal treatment) of the study

 1. Meeting criteria for DSM-IV (Diagnostic and Statistical Manual-IV-TR) alcohol
 dependence.

 *2. At least one prior episode of DSM-IV alcohol withdrawal as assessed by SCID
 Alcohol Dependence Module or scoring > 6 on the CIWA scale since admission to the
 inpatient unit, or having any of the following elevated vital signs since admission:
 pulse > 110; diastolic blood pressure > 100; systolic blood pressure > 160.

 3. At least 12 heavy drinking days in the 28 days prior to enrollment in the study. A
 heavy drinking day is defined as >5 standard drinks for men or >4 standard drinks for
 women.

 4. Women who are able to conceive children must be on an effective form of birth
 control such as oral contraceptives, intrauterine devices or the use of condoms with
 spermicide.

 5. Competency to give valid informed consent as indicated by a) a breathalyzer reading
 at the time the consent form is signed showing an estimated blood alcohol level (BAL)
 <.08 gm/dL (the consent process is repeated when the BAL level has dropped to 0.00
 gm/dL) and b) ability to understand the written informed consent form demonstrated by
 correctly answering questions about the contents of the form after reading the consent
 form without help (this will also determine whether prospective subjects can read and
 understand the study questionnaires).

 6. Ability to get to appointments either through personal or public transportation.

 -  Inclusion Criteria for the outpatient phase of the study (treatment of heavy drinking)
 for prospective subjects screened toward the end of their FRH or UNC inpatient stay
 The same criteria as those listed above for the inpatient phase of the study apply
 except for the criteria marked with an asterisk.

 -  Inclusion Criteria for the outpatient phase of the study for prospective subjects
 recruited from the community and screened during an initial outpatient clinic visit
 The same criteria as those listed above for the inpatient alcohol withdrawal treatment
 phase of the study apply except for having a previous history of alcohol withdrawal
 (inclusion criterion #2)

 Exclusion Criteria:

 -  Exclusion Criteria for the inpatient alcohol withdrawal treatment phase of the study

 -  1. History of alcohol withdrawal-related seizures, delirium tremens or
 hallucinations.

 2. Clinically significant medical disease that might interfere with the
 evaluation of the study medication or present a safety concern (e.g., renal
 insufficiency, cirrhosis, unstable hypertension, unstable diabetes mellitus,
 seizure disorder). Clinically significant psychiatric illnesses including any
 psychotic disorder, bipolar disorder, eating disorder, severe depression, or
 suicidal ideation.

 3. Other substance dependence disorder with the exceptions of nicotine or
 caffeine. Substance abuse disorders are not exclusionary.

 -  4. Chronic or subchronic ( >3 days in the week prior to admission or outpatient
 enrollment) treatment with/consumption of benzodiazepines, barbiturates,
 anticonvulsants or stimulants.

 -  5. Receipt of >6 mg of lorazepam or any dose of a long half-life benzodiazepine
 between admission for medical detoxification and beginning participation in the
 study (i.e., receiving the first intranasal dose of test treatment).

 6. AST or ALT (liver function tests) > 5 times ULN (upper level of normal),
 bilirubin (liver function test) > 1.5 X ULN, sodium < 132 or > 150 mMol/L,
 potassium < 3.2 or > 5.3 mMol/L.

 7. Women who are pregnant or breastfeeding. 8. Intent to participate in an
 additional alcohol treatment program other than Alcoholics Anonymous 9.
 Court-mandated participation in alcohol treatment or pending incarceration.

 -  Exclusion Criteria for the outpatient phase of the study (treatment of heavy drinking)
 for prospective subjects screened toward the end of their FRH or UNC inpatient stay
 The same criteria as those listed above for the inpatient phase of the study apply
 except for the criteria marked with an asterisk.