Endogenous Opioid Dysfunction, Stress, and Risk for Smoking Relapse

Summary
Stress is one of the most commonly reported triggers of smoking relapse. It increases frequency of
smoking among chronic smokers and accelerates progression towards full relapse among abstinent
smokers. This relapse risk is particularly high in the presence of other negative affective states,
including anxiety, irritability, depression, and craving, especially in women. Our previous research has
demonstrated altered hypothalamic-pituitary-adrenocortical (HPA) axis and endogenous opioid
system (EOS) regulation of the stress response in smokers. We found that 1) smokers exhibit
enhanced basal HPA activity, 2) they exhibit decreased cortisol responses to multiple acute stress
procedures, and 3) early smoking relapse can be predicted by attenuated adrenocorticotropin (ACTH)
and cortisol responses to stress. Recent results using an opioid blockade challenge demonstrate
blunted opioid regulation of the HPA stress response in smokers relative to nonsmokers; and smoking
appears to acutely normalize opioid regulation of the stress response. The clinical significance of
altered opioid regulation of the stress response has not been tested in the clinical context of
smoking cessation and relapse. Building on previous findings, we plan in this new study to take a
novel approach in addiction relapse research by identifying indices of risk for relapse using opioid-
HPA stress response patterns. Our hypothesis is that smokers who exhibit blunted HPA stress
response to opioid blockade are more likely to relapse early in their cessation attempt. Blunted opioid
regulation contributes to inefficient stress response and may exacerbate stress effects on craving and
withdrawal symptoms. We will establish the link between altered endogenous opioid regulation of the
HPA stress response, withdrawal symptoms, and craving during smoking cessation. We will develop a
model to predict early smoking relapse using HPA responses to stress and HPA responses to
endogenous opioid blockade. Finally, we will examine sex differences in the HPA response to stress,
in the HPA response to opioid blockade, and in predictors of relapse. This research represents a step
forward in translating established preclinical neurobiological models of addiction and stress. It is
grounded in theory, builds on important preliminary results, and uses rigorous and reproducible
procedures. Demonstrating the utility of an opioid challenge in predicting relapse is a novel direction in
addiction relapse research that will enable indexing two important stress biological pathways,
providing both a novel mechanism of long-term effects of tobacco addiction and a marker of treatment
outcome and relapse probability. This will facilitate future efforts targeting those susceptible to effects
of stress on their risk for relapse with new or existing behavioral and pharmacological treatments.
Reducing relapse rates will reduce tobacco use and its devastating health effects.

Grant Number: 5R01DA016351-12
NIH Institute/Center: NIH
Principal Investigator: Mustafa al'Absi