Use of a GLP-1 Agonist to Treat Opioid Use Disorder in Rats and Man

项目总结:

Project Summary: Opioid abuse, a disorder of chronic relapse, is a significant and escalating public health concern. In 2017, 70,237 people the United States died from a drug overdose; opioids were involved in 67.8% of these deaths. Despite having approved medications (methadone, buprenorphine/naloxone, naltrexone) and promising therapeutic interventions, the high rates of relapse (50% at 3 months, 65%-70% at one year) indicate a critical need for a better understanding of the factors that contribute to relapse to opioids, and for the development of new approaches to treatment. Several factors are known to contribute to the relapsing nature of this disease, including (but not limited to) craving, sleep disturbances, reduce stress tolerance, and negative affect. Sleep problems are a common – and undertreated – symptom in most substance use disorder syndromes, including opioid use disorders (OUD). Research shows that sleep problems are 8-9 times more prevalent among patients in early treatment for opioid use disorders (OUD) than the general population. However, the standard hypnotic medications used to treat sleep disorders cannot be used in OUD patients because of their addictive properties. Indeed, because they work on the opioid receptor system, the two most commonly used medications for OUD, methadone and buprenorphine, may disrupt sleep. However, a novel medication is being investigated that may allow the reduction of craving while improving sleep in OUD patients. In an ongoing clinical trial, the investigators are evaluating the potential to reduce craving in an OUD population by stimulating a glucagon-like peptide-1 receptor (GLP-1R) ‘satiety’ pathway. Activation of the GLP-1R pathway has been shown to inhibit not only the ingestion of palatable sweets, but also reduce responding for alcohol, nicotine, cocaine, and, now, from our laboratory, heroin, in rats and mice. The FDA-approved medication, liraglutide, is currently approved to treat Type II diabetes milletus and obesity in humans. The purpose of this supplemental study is to add polysomnography, the gold-standard for evaluating sleep architecture, to this ongoing study. Forty men and women in residential treatment for OUD will be recruited into a randomized, double blind, placebo-controlled study to determine whether once daily treatment with the GLP-1R agonist, liraglutide, can safely and effectively reduce craving and brain responses to drug cues, while improving their total sleep time and their percentage of slow wave sleep. All patients will be receiving programmatic counseling; patients will be allowed to elect to be on buprenorphine. Polysomnography tests will be conducted before they begin liraglutide, and again after 30 days of medication, when they are up to full dosage. Analyses will evaluate changes in total sleep and slow wave sleep, and whether improved sleep is associated with reduction of craving and brain responses to drug cues. If our hypotheses are supported, these data will show that treatment with GLP-1R agonists can safely and effectively reduce opioid craving, while also improving sleep, in humans, providing an indication for full multi-site, Phase III clinical trial.