Effect of Clonidine on Responses to Imagery Scripts

Background. Stress and exposure to drug-related cues (environmental stimuli previously
associated with drug availability) are considered factors that increase the risk of relapse
to heroin and/or cocaine use. The two factors may act through different neural mechanisms.
Alpha-2 adrenergic agonists, such as clonidine, have been shown to block stress-induced
relapse, but not cue-induced relapse, to heroin and cocaine self-administration in rodents.
The ability of clonidine to attenuate stress- or cue-induced heroin and cocaine craving in
drug abusers has not been tested. It is important to determine, in humans, whether clonidine
blocks the acute effects of only one putative class of relapse precipitants, or whether its
effects are more general.

Scientific goal. To compare the ability of clonidine to reduce stress-induced and cue-induced
cocaine and heroin craving in drug abusers.

Participant population. A total of up to 160 drug abusers using cocaine, heroin, or both will
be enrolled. Target enrollment will include 40% women and 60% minorities (mostly
African-American).

Experimental design and methods. Participants will be randomized to one of three groups
receiving clonidine 0.1 mg, clonidine 0.2 mg, or placebo orally under double-blind
conditions. The study will consist of a single 5-6 hr experimental session in which there
will be baseline measures, drug administration, and four script-guided imagery sets, each
followed by a period of data collection. Three hours after dosing (when peak plasma clonidine
concentrations are reached), participants will be exposed to four scripts: one
stress-inducing, one describing drug cues, and two with neutral content. The standardized
script-guided imagery procedure has previously been shown to reliably induce negative
affective states (stress scripts) and/or craving (stress and drug-cue scripts) compared to
the neutral scripts and to have internal and external validity (Tiffany and Drobes, 1990;
Maude-Griffin and Tiffany, 1996; Taylor et al., 2000; Sinha et al., 1999, 2000, 2003;
Singleton et al., 2003; Tiffany and Haekeneworth, 1991; Elash et al., 1995; Drobes and
Tiffany, 1997; Taylor et al., 2000; Singleton et al., 2003). Outcome measures will include
subjective ratings of drug craving and mood, autonomic response (galvanic skin response
[GSR]), and endocrine responses (salivary cortisol and salivary ?-amylase, a measure of
endogenous adrenergic activity during stress (Chatterton et al., 1996; Nater et al., 2005;
van Stegeren et al., 2005)).

Benefits to participants and/or society. There are no direct benefits to participants.
However, if clonidine is effective in blocking stress-induced and/or cue-induced craving,
then the results will be used as a basis for designing a treatment trial, and drug abusers
and society may benefit from the eventual use of clonidine or other alpha agonists for
prevention of relapse in cocaine and heroin users. In addition, this research will provide
information on the clinical relevance of a preclinical model of relapse, possibly
strengthening arguments for its use in medication development.

Risks to participants. Participants may experience side effects from clonidine such as
sedation and are expected to experience brief, mild psychological stress and drug craving
from the laboratory script procedures. Prior to leaving the session, participants will be
assessed for the presence of continued drug effects. If participants are experiencing any
stress or craving at the end of the session, they will undergo a 10-minute guided relaxation
session, which will be repeated until feelings of stress or craving dissipate, before being
released from the laboratory. Participants may be kept longer than the planned session
length, up to and including staying overnight on the inpatient ward, because of continued
side effects or elevated stress or craving. If the MRP deems it medically necessary,
participants will be sent to JHBMC emergency department for further evaluation and treatment.

- INCLUSION CRITERIA:

1. Age between 18 and 55;

2. Evidence of current cocaine and/or heroin use (by self-report) with a minimum
lifetime drug-use duration of 1 year and a minimum current drug use of once in
the last 30 days;

EXCLUSION CRITERIA:

1. Hypersensitivity to clonidine or any component of the formulation

2. Schizophrenia or any other DSM-IV psychotic disorder; history of anxiety
disorder, panic disorder, bipolar disorder; current Major Depressive Disorder

3. Current physical dependence on opioids, cocaine, alcohol, benzodiazepines or
other sedative-hypnotic; this is an exclusion criterion because we want to
evaluate the ability of clonidine to affect stress- and cue-induced drug craving
independent of its effects on drug withdrawal

4. Cognitive impairment severe enough to preclude informed consent or valid
responses on questionnaires

5. Pregnancy or breast feeding

6. Severely impaired hepatic function

7. Severely impaired renal function, with CLcr < 10 ml/minute

8. Medical conditions that contraindicate or that could complicate clonidine
administration:

1. hypotension (SBP <95 or DBP < 40 mm Hg) over several readings

2. hypertension(SBP >160 mm Hg, DBP >95 mm Hg) over several readings

3. orthostatic hypotension over several readings or as a consequence of any
underlying medical disorder (e.g., autonomic insufficiency)

4. bradycardia (heart rate < 50 bpm) over several readings

5. cerebrovascular disease or any history of CVA or transient ischemic attack
(TIA)

6. documented coronary disease

7. serious arrhythmia or conduction defect (e.g., second or third degree heart
block, atrial fibrillation)

8. sinus node dysfunction, severe bradycardia or symptomatic bradycardia

9. congestive heart failure

9. Medications that could interact adversely with clonidine: antipsychotics;
antihypertensives (e.g., beta blockers); antiepileptics; CNS depressants (e.g.
barbiturates, benzodiazepines, narcotic analgesics, alcohol, or other sedatives);
cyclosporine; oral hypoglycemic agents or insulin; levodopa; tricyclic
antidepressants; herbals such as dong quai, ephedra, yohimbe, ginseng, valerian,
St. John s wort, kava kava, gotu kola

10. Women who are able to get pregnant and are not abstinent from sexual activity
must agree to use a medically effective form of contraception while in the study.
Those include:

1. Hormonal contraceptives (birth control pills, injectable hormones, vaginal ring
hormones),

2. Surgical sterility (tubal ligation or hysterectomy)

3. IUD

4. Diaphragm with spermicide

5. Condom with spermicide

Women who do not agree to use these medically effective forms of contraception while in the
study will be excluded.