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It’s been seven years since actor Heath Ledger (28) was found dead in his Manhattan home. The New York coroner’s office ruled that Ledger died of “poisoning” from six colds, sleeping pills, and anti-anxiety drugs.

Most drug overdoses are unintentional, says Barbara J. Turner, M.D., M.S.Ed., MACP, professor of medicine and director of the Center for Research to Advance Community Health. “People with chronic illnesses don’t try to end their lives,” he said. “But they take a lot of drugs with a big risk.”

These pain relievers include opioids such as hydrocodone, which are often prescribed with sedative-hypnotics such as alprazolam (Xanax) and zolpidem. Many patients are prescribed antidepressants to treat pain and negative emotions.

Two new studies, authored by Dr. Turner and Dr. Yuanyuan Liang, of the School of Medicine, found that daily morphine equivalent doses of 100 milligrams or more increase the risk of overdose and lower morphine levels. 50 to 99 milligrams per day is dangerous for a long time. Patients who have received small doses for more than 4 to 6 weeks have a higher risk. The findings are in a recent issue of The Journal of Pain.

Dr. Turner said, “If you take an average amount of opioids per day and your total dose is more than 1,800 milligrams, your risk of overdose is the same as that of someone who takes the drug multiple times per day,”.

Physicians should take into account how much opioid a person has been prescribed over a period of time, in addition to the daily dose, she said. The doctors also examined the increase in drug overdose risk for patients with mental health disorders who are taking opioids, hypnotic-sedatives, and antidepressants in combination—the type of cocktail that killed Ledger.

“We found that if a patient is taking benzodiazepines (one class of hypnotic-sedative) on top of the narcotics, the risk is multiplicative,” Dr. Turner said of the study published in The Journal of General Internal Medicine. “If you are at fourfold greater risk of overdose from higher-dose opioids, and then there is more than a twofold greater risk from being on benzodiazepines for 90 days or more, the risk of drug overdose using both together becomes eight times greater.”

In a new study, researchers from the Department of Drug Design and Pharmacology provide insight into the phenomenon using new technology.

Professor and Group Leader Stephan Pless said, “We know that this is sometimes caused by the malfunctioning of certain proteins in the cell membranes of heart cells. The proteins are called cardiac sodium channels and are responsible for making the heartbeat. But we don’t know why the protein suddenly stopped working properly after years of seemingly good work. In our study, we found that some cases of heart attack are not caused by the assumption that genes change in this membrane, but may require modification and quasi-phosphorylation”.

Phosphorylation is a process that can modify proteins and change their function. Stephan Pless explains that this happens all the time because all proteins are modified and unmodified by various drugs. For example, the process of phosphorylation can be triggered by stress or illness, and the group found that these changes also affect response to treatment. A combination of genetic and chemical changes can cause the protein to malfunction, leading to heart failure.