Clonidine for Relapse Prevention in Buprenorphine-Maintenance Patients
Clonidine for Relapse Prevention in Buprenorphine-Maintenance Patients
Background:

 -  Though the drug buprenorphine effectively treats dependence on opioids like heroin, some
 abstinent patients relapse to use during treatment. This relapse may be triggered by
 stress or stressful situations, and buprenorphine probably has no specific protective
 effect in these situations. Buprenorphine probably also has no specific effect on
 relapse to cocaine use.

 -  Research has shown that clonidine, a drug originally prescribed to treat high blood
 pressure and some symptoms of opioid withdrawal, can help block stress-induced relapse
 to heroin and cocaine seeking in rats. Researchers are interested in studying whether a
 combination of clonidine and buprenorphine may be more effective in preventing drug
 relapse than administering one of the medications alone.

 Objectives:

 - To determine whether clonidine, given to abstinent patients maintained on buprenorphine, is
 more effective than placebo in preventing relapse to heroin or cocaine use.

 Eligibility:

 - Individuals between 18 and 50 years of age who are current cocaine or heroin users seeking
 treatment.

 Design:

 -  The study will last up to 36 weeks, with four phases of treatment and a follow-up
 evaluation. Three times a week, participants will be asked to report illicit drug use
 and provide urine and breath samples. Throughout the study, participants will receive
 individual counseling in weekly 40 60 minute sessions. Other samples and tests will be
 scheduled as required by the study researchers.

 -  Patients will be stabilized on daily buprenorphine over the first 14 days of the study.

 -  Weeks 1 8: Participants will receive vouchers for regular substance-free urine samples.
 Those who successfully complete this phase will continue to the next part of the study.

 -  Weeks 7 9: Participants will receive either clonidine or placebo along with the
 buprenorphine. The dose of clonidine will be stabilized during this time.

 -  Weeks 9 22: Participants will continue to receive either clonidine or placebo along with
 the buprenorphine. During this part of the study, participants will keep electronic
 diaries to record drug use or craving and to record data on mood, stress levels, and
 activity.

 -  Weeks 23 28: Participants will stop taking the clonidine or placebo, but will continue
 the buprenorphine treatment. Participants will continue to keep electronic diaries.

 -  Weeks 29 36: Participants will have the choice of transferring to a community clinic
 transfer or gradually reducing doses of buprenorphine to end the study.

 -  Participants will return for a follow-up visit and urine sample 6 months after the end
 of the study.
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

 <TAB>

 BUN > 35 MG/DL

 Cr<TAB> > 2.0 MG/DL

 <TAB>

 Alk Phos<TAB> > 200 U/L

 AST<TAB> > 200 U/L

 ALT<TAB> > 200 U/L

 GGT<TAB> > 400 U/L

 Albumin<TAB> < 3 GM/DL

 Total bilirubin > 2.0 MG/DL

 Direct bilirubin > 0.4 MG/DL

 TSH<TAB> < 0.27 > 4.2 UIU/ML

 <TAB>

 *Leukocytosis will prompt further investigation before clearance.<TAB>