Clue to What Drives Addiction Opioid Addiction and Genetics

Highlights from clinical trials on opioid research RESEARCH ROUND-UP By Neil Savage

BIOCHEMISTRY nucleus accumbens — part increase drug consumption were being treated for heroin of the brain’s reward system and might lead to addiction. addiction, 163 people who Clue to what that produces pleasure-giving Int. J. Neuropsychoph. 22, had taken illicit opioids but drives addiction dopamine in response to 383–393 (2019) had not become addicted, and STOLLE DANIEL certain stimuli. They then 153 healthy volunteers who Rats that have too many copies taught that group of rats and a GENOMICS had never used illicit opioids. of a microRNA in their brains control group to press a lever All study participants were of might have a higher chance of to receive an injection of the Opioid addiction Dutch ancestry. becoming addicted to opioids. opioid oxycodone. and genetics The researchers found MicroRNAs are short At first, there was no 20 variants in 6 genes that snippets of RNA molecules difference between the two Genes might play a part in seemed to be associated with that don’t create proteins groups. But over several days, making some people more opioid addiction. In particular, themselves but can control the rats with the extra copies of vulnerable to opioid addiction they found that a combination how much genes are expressed. miR-9 began to press the lever than others. Matthew Randesi of three single-nucleotide Scientists already knew that more frequently and wait less at the Rockefeller University changes in a specific gene one, miR-9, was affected by time between injections. When in New York City is seeking had a significant association giving mice either cocaine the researchers looked at the clues as to why only 25–33% with such an addiction. The or morphine. Elena Chartoff animals’ brains, they found of people who take drugs such gene in question encodes and her colleagues at Harvard that rats with extra miR-9 as heroin become addicted the protein SLC18A2, also Medical School in Boston, had increased expression of a to them. known as VMAT2, which Massachusetts, wondered dopamine receptor protein and He and his colleagues packs neurotransmitters such whether overexpression decreased levels of a protein at Rockefeller and in the as dopamine and serotonin of miR-9 would produce that suppresses gene expression Netherlands investigated into structures called vesicles, addictive behaviour in rats. The at times that coincided with whether there are genetic ready for secretion. The next researchers used an adeno- self-injection by the rats. The differences between people step, the researchers say, will associated virus, a common study shows that exposure to with an opioid addiction and be to clarify how these gene tool for gene therapy, to inject opioids leads to molecular those without. They took DNA variants contribute to the extra copies of miR-9 into the changes in the brain that samples from 281 people who development of an addiction.

OPIOIDS OUTLOOK

Pharmacogenomics 20, 331–341 tested whether pretreating which leads researchers to DRUG DEVELOPMENT (2019). mice with the opioid-receptor think that it might have a blocker, or antagonist, lower potential for abuse. Dual receptor DRUG MISUSE naltrindole could alter the Conventionally, there has activation effects of oxycodone. Over not been a satisfactory way Finding ways to the course of eight days, the to assess a drug for its abuse An opioid drug that targets two prevent addiction team injected one group potential. But now, Analgesic types of pain receptor shows of mice with naltrindole, Solutions, a company in strong pain-reduction effects One way in which drug followed 30 minutes later by Wayland, Massachusetts, but little potential for causing addiction spreads is when a an injection of oxycodone. that seeks to improve the addiction in monkeys. drug user introduces a non- Another group received a design of clinical trials, Stephen Husbands at the user to the act of injecting saline injection first, and then has developed a system University of Bath, UK, and drugs — a phenomenon known oxycodone. A further group called MADDERS (Misuse, Mei-Chuan Ko at Wake as social communicability. But received naltrindole followed Abuse, and Diversion Forest School of Medicine treating people who are already by a saline solution, and a Drug Event Reporting in Winston-Salem, North addicted to and injecting control group received only System). MADDERS creates Carolina, and their colleagues opioid drugs might make the saline. standardized definitions tested a new analgesic drug them less likely to pass on that At the end of the study, to help classify drug abuse called BU10038 in rhesus addiction to others. the researchers stopped the during clinical trials. macaques (Macaca mulatta). Dan Werb at the University treatments and looked for To test the system, Ryan The drug has promise as a of California, San Diego, signs of opioid withdrawal. Lanier at Analgesic Solutions painkiller because it is a partial and his colleagues tested Mice that had been treated and his colleagues applied activator of the μ-opioid the concept of ‘treatment with the antagonist before MADDERS to data from two receptor and the nociceptin as prevention’ for addiction receiving oxycodone receptor — both of which seem by looking at data that had showed fewer symptoms of “Conventionally, to play a part in pain reduction. been gathered from injecting withdrawal than did those there has Monkeys were fitted with drug users in Vancouver, who had been given only not been a catheters that enabled them to Canada, in 2014–17. Of oxycodone, suggesting satisfactory way self-administer BU10038. The 1,740 participants, 80 people that they had become less to assess a drug researchers found that the drug said that they had within physically dependent on the for its abuse delivered potent, long-lasting the past six months initiated drug. A conditioning test potential.” pain reduction by interacting new users by helping them to found that the pretreated mice with both types of receptor. perform their first injection. did not try to regain access consecutive clinical trials of However, it produced none Almost half of the study to oxycodone after it was no NKTR-181 to determine how of the behaviour-reinforcing participants were being longer being administered. many ‘negative events’ had effects that can lead to opioid treated for addiction with Pretreatment also did not been reported. addiction, even at a dose opioid substitutes such as seem to decrease the opioid’s The team looked at ten times that needed for methadone or buprenorphine, painkilling effects. SUMMIT-07, a 12-week treating pain. and those who were actively A common side effect double-blind, randomized The team also gave the drug participating in such therapy of taking oxycodone is trial of the drug in people to monkeys by injecting it were 48% less likely to help constipation. The pretreated with lower-back pain, and into their spinal columns, a another person to deliver their mice, however, had much SUMMIT-LTS, a 52-week common way to provide pain first injection. Researchers lower levels of constipation open-label follow-on study. relief for people undergoing hope that this treatment-as- than did their untreated Of 1,189 participants in the surgery. When the potent prevention approach will counterparts. Slowed SUMMIT-07 trial, 79 people opioid morphine is used, work well, in a similar way to breathing, an often lethal side (6.6%) experienced a total the procedure causes itching how antiretroviral drugs have effect of opioid overdose, of 86 negative events. In the that can continue even after slowed the spread of HIV. was not affected by the use of SUMMIT-LTS trial, 51 of drug administration has been Drug Alcohol Depend. 197, naltrindole. the 683 participants (8%) stopped. BU10038 given in 354–360 (2019) Eur. J. Pharmacol. 852, 265–273 experienced 59 negative this way produced no itching. (2019) events. The researchers And repeated administration ADDICTION described the number of of the drug, unlike morphine, ANALGESICS events as low for this type did not seem to induce physical Blocking of trial. dependence or tolerance — addiction in mice Discovering safer Most of the events that factors that promote addiction. painkillers MADDERS identified could BU10038 and other drugs Giving patients a drug that be categorized as symptoms that target both types of can block the function of A new opioid painkiller of drug withdrawal, receptor might open the door opioid receptors before represents a lower risk for unintentional overuse or to painkillers that do not lead to administering an opioid might abuse and addiction than deliberate overuse to derive addiction, the researchers say. help to prevent addiction, do existing drugs. The drug, a therapeutic benefit. The Br. J. Anaesth. 122, e146–e156 and could also reduce some NKTR-181, developed by researchers noted that (2019) of opioids’ unpleasant side Nektar Therapeutics in San the overall incidence of effects. Francisco, California, enters withdrawal symptoms for NATURE.COM Pao-Luh Tao at the National the central nervous system NKTR-181 was low. For the latest Research Highlights Defense Medical Center in slowly and is also slow to Curr. Med. Res. Opin. 35, published by Nature Research visit: Taipei and her colleagues activate opioid receptors, 1513–1522 (2019) http://go.nature.com/2xyawlx