Opioids encompass a diverse array of prescription and illegal drugs, including codeine, morphine and heroin. In 2007, about 12.5 million Americans aged 12 and older used prescription pain medications for non-medical purposes, according to the National Survey on Drug Use and Health, administered by the federal government's Substance Abuse and Mental Health Services Administration.
"Opioid abuse is rising at a faster rate than any other type of illicit drug use, yet only about a quarter of those dependent on opioids seek treatment," said Larry F. Chu, MD, assistant professor of anesthesia at the School of Medicine and lead author of the study that will be published online Feb. 17 in the Journal of Pharmacogenetics and Genomics. "One barrier to treatment is that when you abruptly stop taking the drugs, there is a constellation of symptoms associated with withdrawal." Chu described opioid withdrawal as a "bad flu," characterized by agitation, insomnia, diarrhea, nausea and vomiting.
Current methods of treatment are not completely effective, according to Chu. One drug used for withdrawal, clonidine, requires close medical supervision as it can cause severe side effects, while two others, methadone and buprenorphine, don't provide a satisfactory solution because they act through the same mechanism as the abused drugs. "It's like replacing one drug with another," said co-investigator Gary Peltz, MD, PhD, professor of anesthesia.
"What we need is a magic bullet," said Chu. "Something that treats the symptoms of withdrawal, does not lead to addiction and can be taken at home."
The researchers' investigation led them to the drug ondansetron, after they determined that it would block certain receptors involved in withdrawal symptoms.
The scientists were able to make this connection thanks to their having a good animal model for opioid dependence. Mice given morphine for several days develop the mouse equivalent of addiction. Researchers then stop providing morphine to trigger withdrawal symptoms. Strikingly, these mice, when placed into a plastic cylinder, will start to jump into the air. One can measure how dependent these mice are by counting how many times they jump. Like humans, dependent mice also become very sensitive to pain when they stop receiving morphine.
But the responses vary among the laboratory animals. There are "different flavors of mice," explained Peltz. "Some strains of mice are more likely to become dependent on opioids." By comparing the withdrawal symptoms and genomes of these different strains, it's possible to figure out which genes play a major role in addiction.
To accomplish this feat, Peltz and his colleagues used a powerful computational "haplotype-based" genetic mapping method that he had recently developed, which can sample a large portion of the genome within just a few hours. This method pinpoints genes responsible for the variation in withdrawal symptoms across these strains of mice.
The analysis revealed an unambiguous result: One particular gene determined the severity of withdrawal. That gene codes for the 5-HT3 receptor, a protein that responds to the brain-signaling chemical serotonin.
To confirm these results, the researchers injected the dependent mice with ondansetron, a drug that specifically blocks 5-HT3 receptors. The drug significantly reduced the jumping behavior of mice as well as pain sensitivity — two signs of addiction.
The scientists were able to jump from "from mouse to man" by sheer luck: It turns out that ondansetron is already on the market for the treatment of pain and nausea. As a result, they were able to immediately use this drug, approved by the Food and Drug Administration, in eight healthy, non-opioid-dependent humans. In one session, they received only a single large dose of morphine, and in another session that was separated by at least week, they took ondansetron in combination with morphine. They were then given questionnaires to assess their withdrawal symptoms.
Similar to mice, humans treated with ondansetron before or while receiving morphine showed a significant reduction in withdrawal signs compared with when they received morphine but not ondansetron. "A major accomplishment of this study was to take lab findings and translate them to humans," said principal investigator J. David Clark, MD, PhD, professor of anesthesia at Stanford University School of Medicine and the Palo Alto Veterans Affairs Health Care System.
Chu plans on conducting a clinical study to confirm the effectiveness of another ondansetron-like drug in treating opioid withdrawal symptoms in a larger group of healthy humans. And the research team will continue to test the effectiveness of ondansetron in treating opioid addiction.
The scientists warned that ondansetron will not by itself resolve the problems that arise with continued use of these painkillers. Addiction is a long-term, complex process, involving both physical and psychological factors that lead to compulsive drug use. "This is not a cure for addiction," said Clark. "It's naïve to think that any one receptor is a panacea for treatment. Treating the withdrawal component is only one way of alleviating the suffering. With luck and determination, we can identify additional targets and put together a comprehensive treatment program."
Collaborators on this study included De-Yong Liang, PhD, the study's co-lead author, previously a research associate in the Department of Anesthesia and currently a research associate at the Palo Alto Institute for Research and Education; Xiangqi Li, MD, a life science research assistant in the department; Nicole D'Arcy, a medical student: Peyman Sahbaie, MD, a research associate at the institute; and Guochun Liao, PhD, of the pharmaceutical company Hoffman-La Roche. This work was supported by grants to Clark from the National Institutes of Health and the National Institute on Drug Abuse, and grants to Chu from the NIH and the National Institute of General Medical Sciences.
The researchers are working with the Stanford University Office of Technology Licensing to seek a patent for the use of ondansetron and related medicines in the treatment of drug addiction.
What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
06.12.2016 | Materials Sciences
06.12.2016 | Medical Engineering
06.12.2016 | Power and Electrical Engineering