Philip Seymour Hoffman’s death in 2014, from what media outlets are calling an apparent heroin overdose, was a tragedy by all accounts. It was also — like the fatal overdose of Cory Monteith — a shock. He was 46.

While Hoffman had been open about past struggles with addiction and even briefly checked into rehab last year, he told 60 Minutes in 2006 that he had been sober since he was 22.

If it seems like fatal heroin overdoses often happen during a relapse, it’s because they do.

The medical examiner has yet to release a report on Hoffman’s death, so we can’t know for sure whether the underlying cause was an excess of heroin, a dangerous new form of heroin, the combination of heroin with alcohol, or something else entirely.

But when addicts stop doing heroin for a while — for years or even just days — and then return to it, they are often killed by amounts they could previously withstand. The hypothesis is that their tolerance has diminished.

In 1998, a team of Italian researchers published a small but important study in The Lancet to investigate this question. People overdose with vastly different levels of heroin in their blood, and the researchers wanted to figure out why a dose of heroin is sometimes fatal and sometimes not.

Opioids like heroin linger in human hair for months after they’ve left the bloodstream, so the researchers analysed the hair of people who had died from a heroin overdose and compared it to the hair of current users, former addicts, and a control group.

Most fatal heroin overdoses, they found, occurred in people with lower levels of drugs in their hair than in that of current (living) users. Further, they added, “most individuals who died from heroin overdose had virtually abstained from heroin during the 4 months preceding death.“

Their conclusion? The risk of opioid overdose was higher after periods of sobriety, likely due to lowered tolerance or a lack of tolerance from irregular use. (Regular heroin use is obviously not safe either.)

Other studies have confirmed this result, finding that the risk of overdose is especially high soon after release from prison or from a detox program.

One reason a relapse involving heroin is especially risky is because of how heroin itself works — and why it can be fatal. The NIH explains:

When it enters the brain, heroin is converted back into morphine, which binds to molecules on cells known as opioid receptors. These receptors are located in many areas of the brain (and in the body), especially those involved in the perception of pain and in reward. Opioid receptors are also located in the brain stem, which controls automatic processes critical for life, such as blood pressure, arousal, and respiration. Heroin overdoses frequently involve a suppression of breathing, which can be fatal.

In long term users or people who have recently reduced their dosage, “the dose required to produce euphoria may approach the lethal dose,” notes a report from the National Drug and Alcohol Research Centre at the University of New South Wales.

Part of the problem is that people can maintain a high tolerance for the euphoric effects of heroin, even when their tolerance for the drug’s effect on breathing is diminished.

Previously heavy users who have quit and then relapsed may be especially at risk for misjudging how much is too much for their lowered tolerance. If they were once heavy users, relapsers may be accustomed to injecting an amount that is now fatal for them.

Drug overdose, including from prescription medications, is now the number one cause of injury death in the country, and heroin use has been rising sharply: There were 373,000 users in the U.S. in 2007 and 669,000 in 2012.

This surge in heroin use and overdose could be related to the increasing abuse of prescription medications like Oxycontin, which is an opioid. Changes the FDA has made to the drug make it harder to inhale and inject, which can lead addicts to experiment with other drugs to get the high they are used to. Other prescription opioid abusers turn to heroin because it is cheaper and sometimes more accessible.

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