Oxytocin Treatment of Alcohol Withdrawal

Study Design: This will be a double-blind, placebo controlled comparison of the efficacy of
twice daily intranasal administration of oxytocin and placebo (saline) in reducing alcohol
withdrawal symptoms, the number of bouts of withdrawal during which symptoms are of
sufficient magnitude requiring prn lorazepam treatment (see definitions below) and the
amount of lorazepam required to resolve withdrawal bouts. Treatment group assignment will be
random within each sex. Subjects will be patients admitted to UNC Hospitals or the Dix CRU
for medical detoxification. Each treatment group will be composed of up to 40 subjects. Dr.
Hamer, the study statistician, will construct a randomization plan to randomize 80 subjects
to 2 groups of 40 subjects each with a blocksize of 4. This will be a permuted blocksize as
this is a blind study.

Procedures: Most patients who are admitted to the UNC Neuroscience Hospital Crisis
Stabilization Unit, UNC Hospitals Family Practice or Hospitalist Services, or the Dix CRU
for medical detoxification from alcohol will come in through the UNC Hospitals Emergency
Department or Dorothea Dix Screening and Admissions during the late evening or early
morning. Physical examination, medical and psychiatric history and lab tests (including CBC,
electrolytes including magnesium, Na, K, BUN, creatinine, glucose, albumin, ALT, AST, LDH,
GGT, TSH, B12, folate, urinalysis, urine toxicology screen and pregnancy test) are routinely
obtained by the ED/ Dorothea Dix Screening and Admissions and/or inpatient unit during the
admission process. Possibly in the UNC Hospitals ED/ Dorothea Dix Screening and Admissions
and definitely after admission to these units, patients will have their vital signs (VSs)
measured and their withdrawal symptoms quantified using the revised Clinical Institute
Withdrawal Assessment for Alcohol scale (CIWA-Ar scale, Sullivan et al 1989) on the schedule
in the standard alcohol detoxification order set in the UNC Hospital CPOE system. The CRU
at Dorothea Dix will use a hard copy version of the CIWA used in the CPOE at UNC Hospitals.

After consent is obtained, subjects will be randomly assigned to a treatment group (oxytocin
or placebo). Prior to receiving their first intranasal treatment, an ECG will be obtained
and blood drawn to obtain serum for assay of cytokine and allopregnanolone concentrations.
Subjects also will rate their symptoms using the Alcohol Withdrawal Symptom Checklist (AWSC,
Pittman et al 2007) prior to receiving their first test dose. These procedures will be
done/overseen by research nurses or physicians. Subjects will usually receive their first
intranasal test dose between 1000 and 1200 hours and will consist of 6 insufflations of
Syntocinon Spray (approximately 24 IU) or placebo, with each insufflation given 30 seconds
apart and alternating between nostrils. Test doses will be taken again at 1700 hr later that
day (Admission Day 1) and at 0900 and 1700 hr on Admission Days 2 and 3. Oxytocin test
treatments will be administered from 5 ml intranasal spray vials designed to deliver 0.1 ml
metered volume per insufflation. The placebo treatments will be administered from 60 ml
intranasal spray vials (each containing 30ml of solution) also designed to deliver 0.1ml
metered volume per insufflation. Vials containing oxytocin and placebo spray will be blind
labeled by the UNC Investigational Drug Service or the Dorothea Dix Hospital pharmacy.
Research nurses or physicians will oversee subject self-administration of all intranasal
test doses. After enrollment on admission day 1 and in the morning on admission days 2 and
3, subjects will be given multiple copies of the AWSC questionnaire and requested to
complete one each time the unit nurses do CIWA ratings. These questionnaires will be
retrieved by research staff the following morning. Shortly after the morning test dose on
admission days 2 and 3, subjects will complete the Alcohol Craving Visual Analog Scales
(ACVAS), the Penn Alcohol Craving Scale, and the Profile of Mood States (McNair et al,
1971). On these same admission days, research nurses will also draw (and subsequently
process) blood serum samples to assay cytokine and allopregnanolone concentrations shortly
after the morning test dose. Additional blood will be drawn after the morning test dose on
admission day 2 to obtain serum for tests to be run in McLendon Laboratories (magnesium, Cl,
Ca, Na, K, BUN, creatinine, and GGT). Another ECG will also be obtained shortly after the
morning test treatment on admission day 2. Research staff will retrieve on a daily basis
CIWA ratings and vital sign measurements obtained on each subject from their electronic
medical record.

In all subjects, PRN lorazepam doses will be administered PO or IV (if subjects cannot take
medication PO) whenever CIWA ratings are > 14 per the protocol in the standard alcohol
detoxification order set in the UNC Hospital CPOE system. Lorazepam doses (1 - 4 mg) and
frequency (q 2 -6 h) will be adjusted based on the severity of withdrawal symptoms. This
same order set will be employed at the Dorothea Dix CRU.