Effects of Propranolol on Responses to Drug-Related Imagery Scripts

Background

Relapse to drug abuse or addiction is thought to result, in many cases, from exposure to cues
that elicit drug-related memories. The term memories is used here not in its everyday sense,
but in a sense that corresponds more closely to emotional associations for example, the
association between the sight of a crack pipe and a set of responses such as rapid heartbeat
and desire for cocaine. Studies in rodents and humans show that this type of memory is
reconsolidated (actively re-stored) each time it is reactivated, and that the reconsolidation
process can be disrupted by propranolol. Such disruption does not erase the autobiographical
memory of an event, but instead weakens the link between that memory and an emotional
response. Human studies are needed to determine whether propranolol disrupts reconsolidation
of drug-cued memories in addicted individuals; this would present a novel and exciting
therapeutic possibility for preventing craving and relapse.

Objective

To examine whether administration of propranolol interferes with reconsolidation of
cocaine-related memories and reduces cravings and drug use in substance abusers.

Study population

Up to 200 (60 evaluable) individuals maintained on methadone and using cocaine will be
recruited from local treatment programs. The target enrollment will include 40% women and 60%
minorities.

Experimental design and methods

Participants will be randomized to one of two groups: propranolol (40 mg, oral,
immediate-release formulation) or placebo. The study will include four laboratory sessions:
(1) An information-gathering session that includes an interview to obtain information for
development of a personalized drug script/cue set. (2) A two-hour intervention session in
which there will be baseline measures, drug administration (propranolol or placebo, double
blind), and, starting 60 min after drug administration, two script-guided imagery sets.
Cue-responsivity data will be collected, but the main purpose of the session is
interventional. This will be the only administration of propranolol during the study. (3, 4)
Two follow-up test sessions, 1 and 5 weeks after the intervention session; participants
responses to re-exposure to the personalized drug script/cue set will be measured. In
addition to attending the four laboratory sessions, participants will make brief visits to
our outpatient clinic for twice-weekly monitoring of ongoing drug use via urine screens and
self-report, starting 1 week before the intervention session and ending 5 weeks later.

Outcome measures

Outcome measures will include subjective ratings of drug craving, autonomic responses (heart
rate, blood pressure, galvanic skin response), and cocaine and heroin use (urine drug screens
and self-reported drug use).

- INCLUSION CRITERIA:

1. - Age between 18 and 55 years

2. - Evidence of current cocaine use (self-report)

3. - Minimum lifetime cocaine use of one year (self-report)

4. - Minimum use of cocaine of once in the past 30 days (self-report)

5. - Enrolled in methadone maintenance

EXCLUSION CRITERIA:

1. - Allergy or hypersensitivity to propranolol or other beta blockers.

2. - History of: schizophrenia (or of any other DSM-IV psychotic disorder), anxiety
disorders (e.g., panic disorder), or bipolar disorder.

3. - Current major depressive disorder.

4. - Current physical dependence on, or current abuse of, alcohol, benzodiazepines, or
other sedative-hypnotic drugs.

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

6. - Pregnant; breast feeding.

7. - Impaired hepatic function with AST or ALT greater than 5x the upper limit of normal.

8. - Medical conditions that would contraindicate administration of propranolol (e.g.,
uncompensated congestive heart failure; pulmonary edema; asthma; COPD; history of
severe allergic reactions (seasonal, environmental, food, medications, etc.); Raynaud
s disease; second- or third-degree atrioventricular block; arrhythmias other than
sinus arrhythmia; thyroid dysfunction; diabetes mellitus; renal impairment.

Per the American Thoracic Society (ATS), COPD Clinical assessment is based on medical
history and physical examination. Although a complete examination is indicated for all
patients, these two components are specifically important for patients with suspected
COPD. (ATS & ERS, 2004) Accordingly, if medical history and physical exam suggest
possible COPD the participant will be forwarded for spirometry/pulmonary function
tests to aid in the diagnosis.

9. - Bradycardia (heart rate < 60 bpm) on three consecutive readings.

10. - Systolic blood pressure < 100 mm Hg; diastolic blood pressure < 60 mm Hg; on three
consecutive readings.

11. - Medications that could interact with propranolol either pharmacodynamically or
pharmacokinetically to produce adverse effects. Such medication would include CNS
depressants (e.g., barbiturates, benzodiazepines, other sedatives), antihypertensive
medications (including nitrates), antiarrhythmic medications, antiseizure medications
(dilantin), acetylcholinesterase inhibitors (e.g., donepezil, galantamine),
aminoquinolines (antimalarial), antipsychotic medications, beta agonists, insulin,
MAOIs, NSAIDs, rifamycin derivatives, rizatriptan, SSRIs, sulfonylureas, theophylline,
pseudophedrine, phenylephrine, ephedrine, epinephrine, noriepinephrine, amphetamines,
and some herbal supplements.

12. - Current use of beta blockers for any medical condition.