Modafinil and sleep architecture in an inpatient-outpatient treatment study of cocaine dependence

Abstract

Objective: To determine whether the increase in slow-wave sleep associated with modafinil treatment in chronic cocaine users mediates improved clinical outcomes.

Method: 57 cocaine dependent participants were randomized to receive modafinil 400mg or placebo daily during a period of inpatient treatment followed by six weeks of outpatient treatment. Participants underwent polysomnographic sleep recording during inpatient treatment prior to and after starting modafinil. Outpatient treatment consisted of weekly cognitive behavioral therapy. Contingency management was used to promote participation in treatment and research demands, including thrice weekly visits during the outpatient phase for urine toxicology screens and other assessments. The primary clinical outcome was the percent of urine toxicology screens that were negative for cocaine.

Results: Modafinil treatment was associated with a higher mean percentage (52% vs. 26%) of cocaine-free urine screens (p=0.02) and an increase in N3 sleep time (p=0.002). The change in N3 sleep time mediated the higher rate of cocaine-free urine screens. Modafinil treatment was also associated with more consecutive days abstinent during outpatient treatment, greater survival of abstinence, higher daily rates of abstinence, and less sleep degradation typically associated with abstinence from chronic cocaine use.

Conclusions: Morning-dosed modafinil improves slow-wave sleep in abstinent cocaine users in the inpatient setting, and this effect is a statistical mediator of improved clinical outcomes associated with continued modafinil treatment. The high rates of abstinence achieved in this trial suggest that promoting healthy sleep physiology in an inpatient setting may be important in the effective treatment of cocaine dependence.

Keywords: Cocaine; Modafinil; Sleep; Slow-wave sleep; Treatment.

Figure 1

Abstinence survival curve (left); *, p< 0.05 for difference in survival between groups. Day to day abstinence rates (right). Shaded boxes indicate the window in which the first 2-night inpatient readmission was scheduled. The second 2-night inpatient readmission occurred immediately after completion of outpatient treatment.

Figure 2

The relationship between clinical outcome and response of N3 sleep to abstinence. Greater increases in N3 sleep time from inpatient week 1 to week 2 correlate with consecutive days abstinent during the outpatient phase in the modafinil group (red squares), placebo group (blue diamonds) and the entire sample (trend line shown for entire sample).

Figure 3

Test for mediation of clinical effects of modafinil by N3 sleep time; a) modafinil increases N3 sleep time and cocaine free urines; increased N3 sleep time is associated with greater number of cocaine free urines; b) the effect of modafinil on cocaine free urines is not significant when controlled for change in N3 sleep time; c) the relationship between increases in N3 sleep time and cocaine free urines persists when controlled for modafinil treatment. Black arrows represent statistically significant relationships; grey arrow represents non-significant relationship.