Gary Peltz, MD, PhD1Thomas C. Südhof, MD2

The health consequences of the opioid epidemic have led the United States to an inflection point at which its biomedical research–driven plan should be changed to effectively address this epidemic. To do so, 2 important changes in the focus for National Institutes of Health (NIH)–funded research are needed, which hopefully will develop actionable information and critically needed new treatments for opioid addiction. First, NIH-funded research currently focuses on the later stages of drug addiction1 that are associated with drug craving and relapse. However, because the opioid epidemic has a large iatrogenic component, prevention strategies that target the early stage of drug addiction should be developed. Second, a far deeper understanding of opioid neurobiology is required to change the focus. Instead of examining opiate-induced changes only at the neural circuit level or with brain imaging to identify involved brain regions, opiate-induced changes in synaptic signaling should be characterized.

An Iatrogenic Basis for the US Opioid Problem

More than 10 years ago, a change in the pattern of drug abuse in the United States became evident: prescription opioids had become a major driver of opioid abuse. Patients made an increased number of physician visits to obtain opioids (32 million per year), and physicians were prescribing high-potency opioids (hydrocodone, oxycodone) with a street value that far exceeded that of heroin.2 The increased number of opioid prescriptions was associated with increased rates of opioid misuse and fatal opioid overdose, and more people were misusing prescription opioids than all other illicit drugs combined.3 The increased number of prescriptions for potent opioids written by clinicians had significantly contributed to the growing opioid problem.

Three Stages of Opioid Addiction

Opioid addiction proceeds in a 3-stage cycle that worsens over time. Each stage results from drug-induced changes in multiple brain circuits.1 The first stage (binge/intoxication) involves opiate-induced reward sensations in the brain. The second stage (withdrawal/negative affect) is characterized by an elevation in the threshold for experiencing the reward sensation after drug use (ie, increased exposure to the drug is required) and a withdrawal state develops when the drug cannot be obtained. The third stage (preoccupation-relapse) is characterized by chronic relapse in drug use, often triggered by environmental and emotional cues. Chronic opioid use induces neurochemical changes that alter brain circuits, which reduces the reward sensation experienced during the initial stage and increases the stress and compulsivity associated with chronic drug addiction.1

A Better Direction for Research

Current research efforts are focused on understanding and treating the later stage of drug addiction, with the goal of developing therapies to reduce drug craving and relapse.1 Because of this approach to treatment, less emphasis is now placed on developing a preventive approach, which targets the first stage in the drug addiction cycle. To achieve prevention means developing methods that prevent a person who takes opioid analgesics for a short period from becoming a long-term opioid user. This is distinct from the common notion that prevention is achieved by restricting access to opioids. However, this common notion does not consider the central importance of opioid analgesics in medical practice and the lack of credible alternative analgesic medications. Moreover, it neglects the concept that treatments are more likely to fail when drug addiction has reached an advanced stage when many more brain circuits are involved.

Current research programs focus on identifying the neural circuits altered by opioid addiction. However, it is possible that a general opiate-induced maladaptation occurs in many brain circuits (perhaps hundreds). It seems likely that these maladaptive changes could be better understood when opiate-induced changes in molecular signaling are characterized, rather than when they are examined only at the neural circuit level. Moreover, drugs of abuse produce the addicted state by usurping mechanisms that the brain uses for learning and for storing memories. If the pathways that are affected in the early stage were better understood, new therapeutic approaches for the later stages could also be rationally developed.

Prevention Strategies Have Delivered Many Benefits

Although most US health care spending (and most research spending) targets treatment of diseases, preventive measures have substantially improved public health, such as immunization programs for infectious diseases, colonoscopy or Papanicolaou smears for cancer prevention, folic acid supplementation to prevent neural tube defects, and the use of car seats and seat belts in automobiles. Although there is an ongoing debate about where health care dollars are best spent, virtually all clinicians and public health experts agree that it is best if a disease can be prevented from developing, and a disease is more easily treated at early stages before it is fully developed. NIH-funded research on prevention has been essential for the establishment of community prevention programs that address substance misuse and other youth problems.4 These cost-effective programs are important to the public.

Would a Prevention Strategy Be Useful?

The benefits of a therapy that targets early stages of opioid addiction are suggested by data from a recent study that examined the probability of long-term opioid use (>1 year) after opioid-naive patients received an opioid prescription. If the initial period of opioid use was at least 1 day, a person had a 6% chance of becoming a chronic opioid user (one who continues using opioids 1 year later), and the probability increased to 13.5% if opioids were used for at least 8 days, which was the period covered by 30% of opioid prescriptions.5 Because US physicians wrote 66.5 opioid prescriptions for every 100 persons in 2016,6 the number of individuals at risk for chronic opioid abuse is substantial. Hence, a method that could prevent dependence from developing in opioid-naive individuals who are prescribed opioid pain relievers could substantially reduce the opioid epidemic in the United States.

Since only a minority of individuals taking an opioid analgesic will become addicted, people are differentially susceptible to opioid addiction. Across all classes of drugs of abuse, approximately 50% of addiction vulnerability has a genetic basis.7 However, even an individual with a relatively low genetic risk profile will become addicted after exposure to a sufficient dose of opioids for a sufficient period of time. This factor is particularly relevant because very potent opioids are prescribed.

Could a Prevention Strategy Be Developed?

The iatrogenic origin of much of the opioid problem favors implementation of approaches that could prevent addiction from occurring. Unlike illicit drug use, clinicians know when opioid-naive patients are initially exposed to opioids. There is evidence that it may be possible to develop methods to reduce the probability that opioid-naive individuals would become addicted after short-term opioid treatment. For example, it was recently demonstrated that a commonly used 5-HT3A receptor (5HT3AR) antagonist (ondansetron) had an unexpectedly profound effect on early-stage opioid responses; it substantially reduced the symptoms of experimentally induced opioid withdrawal in opioid-naive mice and humans.8 The major gaps in understanding the early-stage opioid response are illustrated by the fact that the ondansetron effect was unexpected, and its mechanism of action remains unexplained. Nevertheless, these early results with a commonly used and safe medication indicate that it may be possible to reduce the probability that an individual will become addicted to opioids following initial exposure. Similarly, new forms of opioid medications, which have a reduced tendency to produce dependence but retain the analgesic effects, can potentially be produced.9 These early results provide an indication that an improved research agenda that focuses resources on deeper understanding of opioid neurobiology and on prevention of opioid exposure among high-risk individuals will make it more likely that the clinical and public health response to the opioid epidemic could be effective.


It’s interesting that ondansetron can reduce withdrawal symptoms, there is so much yet to be learned about these drugs and the brain!

Dr. Raymond Oenbrink