Predicting Addiction: Could Your Initial Response to Painkillers Reveal Your Future Risk?

We’ve all heard stories about the opioid crisis, but one of the biggest mysteries remains: why can two people take the same dose of a painkiller, yet only one of them ends up struggling with addiction? While we know that individual risk varies wildly, identifying why one person transitions to dependency while another remains resilient is incredibly difficult because human lives are full of outside influences.

In our latest study published in Neuropsychopharmacology, we conducted a massive behavioral screening to find answers. By observing how different individuals react to oxycodone in a highly controlled environment, we are uncovering the behavioral patterns that reveal a higher risk of dependency.

Understanding Individual Vulnerability

To ensure our study truly captured the full spectrum of behavioral diversity, we phenotyped over 500 individuals. We chose such a large group to embrace the reality of individual vulnerability; by including all types of behavioral profiles, from the highly resilient to the highly vulnerable, we significantly increased the replication power and sensitivity of our design.

We allowed these individuals to self-administer oxycodone, tracking their behavior across several weeks. We didn't just look at how much they took; we measured a "syndrome" of behaviors to see how each individual differed:

• Escalation: We tracked how quickly each individual increased their drug intake when given long, 12-hour access sessions.

• Motivation: We measured how hard an individual would work to get just one more dose by progressively increasing the effort required.

• Tolerance: We tested how fast the drug’s pain-killing effects wore off over the course of the study.

• Withdrawal: We assessed how sensitive individuals became to pain, a condition called hyperalgesia once the drug was out of their system.

The Surprise: Pain Relief as a Red Flag

One of the most startling discoveries involved "analgesia", the drug's ability to block pain. You might think that an individual who doesn't feel much pain relief would be more likely to take more medication to compensate. However, we found the exact opposite.

We discovered that the individuals who experienced the highest initial pain relief from their very first doses were actually the ones most likely to develop severe addiction-like behaviors later on. This suggests that a high physiological sensitivity to the drug's effects, like intense pain relief, might be an early warning sign of a brain that is more vulnerable to getting hooked.

Our Key Findings on Individual Differences

• Sex Differences: We found that females escalated their drug use much faster and showed significantly higher motivation to seek out oxycodone than males.

• The Addiction Index: By combining all these behaviors into one score, we could clearly separate "resilient" individuals, who kept their use low, from "severe" ones, who showed robust addiction-like traits with high escalation, high motivation, high tolerance, high withdrawal-induced hyperalgesia.

Why This Matters for You

Our research is a major step toward understanding addiction as a complex syndrome rather than a single behavior. By identifying these distinct "vulnerability profiles," we can better understand why the transition from controlled use to addiction happens for some but not others.

Understanding that an "intense" first reaction to a painkiller might actually be a risk factor could change how we manage pain and screen for addiction vulnerability. It moves us toward a future where we can identify high-risk individuals early and provide safer, personalized care that prevents addiction before it even starts.

Reference: Kallupi, M., de Guglielmo, G., Carrette, L. L. G., et al. (2026). Large-scale behavioral characterization of oxycodone self-administration in heterogeneous stock rats reveals initial analgesic effects are associated with addiction-like behaviors. Neuropsychopharmacology. https://www.nature.com/articles/s41386-026-02348-8.pdf