Clonidine for Relapse Prevention in Buprenorphine-Maintenance Patients

Background. Though buprenorphine effectively treats opioid dependence, some abstinent
patients relapse to maladaptive use of opioids during treatment. Relapse may be triggered by
stress. Rodent studies have demonstrated that stress can induce relapse to heroin and cocaine
use (Erb, et al., 1996; Shaham, et al., 1996; Shaham and Stewart, 1995). In a rodent model,
stress-induced relapse to heroin and cocaine seeking is blocked by the alpha-2 adrenergic
agonist clonidine. In this study, clonidine will be compared to placebo in preventing relapse
to opioid abuse in opioid maintained patients who have achieved abstinence while on
buprenorphine and contingency management.

Scientific goals. To determine whether clonidine, given to abstinent patients maintained on
buprenorphine, prevents relapse to opioid use more effectively than placebo.

Participant population. 300 opioid-dependent outpatients (120 evaluable). Target enrollment
will include 40 persent women and 60 percent minorities (mostly African-American).

Experimental design and methods. The study will be a randomized double-blind clinical trial.
Two treatment groups will be studied (60/group), one receiving clonidine and the other
receiving placebo. Assignment to treatment group will be randomized. All patients will
receive buprenorphine daily (8 mg to 24 mg SL) and individual counseling weekly throughout 28
weeks of treatment. In order to establish abstinence prior to clonidine induction, after one
week of stabilization on buprenorphine, they will receive contingent vouchers for
opioid-negative urine specimens for 8 weeks (weeks 1-8). Patients who are abstinent from
illicit opioids during weeks 5 and 6 will be randomized to receive clonidine (0.3 mg oral
dose) or clonidine placebo from weeks 9 through 20. Participants who are not abstinent will
be switched to methadone for four weeks (usual dose from 50 mg to 100 mg) followed by an
eight week methadone taper. Assignment to clonidine or placebo will be double-blind. Weeks 21
and 22 will include a clonidine taper to avoid rebound hypertension. From weeks 23-28,
participants will receive buprenorphine and counseling only, and then will be offered
assistance to transfer to another program; those who do not transfer will undergo an 8-week
buprenorphine taper. The primary outcome measures will be longest duration of opioid
abstinence, time to relapse, and the proportion of opioid-negative urine specimens over time
during the Intervention phase. In addition, fluctuations in drug use, drug craving, stress,
and HIV-risk behaviors such as injection drug use will be assessed via ecological momentary
assessment (EMA).

Benefits to participants and/or society. Participants will receive buprenorphine, drug
counseling, and contingency-management therapy. The buprenorphine and voucher interventions
are likely to reduce participants' use of opioids. Counseling will include reduction of HIV
risk behaviors.

Risks to participants. Participants may experience side effects from clonidine,
buprenorphine, or methadone and discomfort during withdrawal from each drug. In particular,
discontinuation of clonidine may cause rebound hypertension. The EMA component of the study
may generate some assessment burden.

- INCLUSION CRITERIA:

1. Age between 18 and 60

2. Evidence of physical dependence on opioids (self-report, urine screen, physical
exam)

3. Seeking treatment for opioid dependence

4. Able to attend treatment clinic 7 days/week

EXCLUSION CRITERIA:

General-

1. Poor venous access

2. Urologic conditions that would inhibit urine collection

3. Pregnancy or breastfeeding

4. Failure to agree to use a medically effective form of contraception while in the study
(in women who are sexually active with a male partner and able to get pregnant).
Acceptable forms of contraception for this study include: hormonal contraceptives
(birth control pills, injectable hormones, vaginal ring hormones), surgical sterility
(tubal ligation or hysterectomy); IUD; Diaphragm with spermicide; Condom with
spermicide

5. Current physical dependence on alcohol or sedative-hypnotics, e.g. benzodiazepines

Psychiatric-

1. Cognitive impairment severe enough to preclude informed consent or valid responses on
questionnaires (Shipley Institute of Living scale estimated full-scale IQ less than
80)

2. History of schizophrenia or any other DSM-IV psychotic disorder

3. History of bipolar disorder

4. Current Major Depressive Disorder

Medical-

1. Any active or untreated medical illness that in the view of the investigators would
compromise participation in research

2. Allergy or intolerance to either buprenorphine or clonidine

3. Cerebrovascular disease

4. Conduction disturbances (e.g., second-degree heart block, third-degree heart block,
atrial fibrillation, ventricular tachycardia) or arrhythmias

5. Myocardial infarction, or documented coronary artery disease

6. Congestive heart failure

7. Chronic renal failure, as estimated by Cr > 2.0

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

9. Marked, sustained bradycardia (HR < 45 bpm) on three separate occasions

10. Marked, sustained low blood pressure (SBP <95 or DBP < 40 mm Hg) over three separate
readings

11. Marked, sustained high blood pressure (SBP >160 mm Hg, DBP >100 mm Hg) over several
readings, without being on antihypertensive medications.

12. ECG changes suggestive of acute ischemia, clinical important arrhythmia, left bundle
branch block, or other changes that concerns the MRP will exclude the participant. If
accompanied by cardiovascular complaints such as chest pain or syncope, less specific
ECG findings will also exclude the patient. When in doubt, the ECG will be sent to
cardiology on a prn basis for a manual reading.

13. Orthostatic hypotension (upon standing for 3 minutes, there is a 20 mm Hg decrease in
systolic blood pressure or a 10 mmHg decrease in diastolic blood pressure accompanied
by an increase by 20 bpm in heart rate) on two separate readings.

Taking contraindicated medications-

1. Beta blockers

2. Tricyclic antidepressants

3. Antipsychotics

4. Mah huang

5. Yohimbe

6. Ephedra

7. Sildenafil citrate (Viagra). Sildenafil citrate doses > 25mg should not be taken
within 4 hours of taking an alpha blocker or it can produce significant and
symptomatic hypotension (Pfizer). Of note, Viagra, like buprenorphine, is metabolized
by cytochrome P450 3A4. Ingestion of buprenorphine could potentate the effects of
sildenafil citrate which could extent the period of safety to > 4 hrs from when an
alpha blocker could be taken after Viagra ingestion.

Family history of sudden cardiac death at age < 50

Lab Test and Lab Values:

WBC* < 1,500 > 13,000 #/CUMM

HCT < 33 > 49 Percent

Platelets < 100 > 500 K/CUMM

Sodium < 132 > 149 MEQ/L

Potassium < 3.5 > 5.2 MEQ/L

Calcium < 8.4 > 10.5 MG/DL

Magnesium < 1.3 > 3 MG/DL



BUN > 35 MG/DL

Cr > 2.0 MG/DL



Alk Phos > 200 U/L

AST > 200 U/L

ALT > 200 U/L

GGT > 400 U/L

Albumin < 3 GM/DL

Total bilirubin > 2.0 MG/DL

Direct bilirubin > 0.4 MG/DL

TSH < 0.27 > 4.2 UIU/ML



*Leukocytosis will prompt further investigation before clearance.