Feb. 6, 2008 -- Doctors say the cocktail of drugs that killed Health Ledger — a deadly mix of powerful prescription painkillers, anxiety drugs and a sleeping pill — was not a combination that any single physician could have reasonably prescribed.
According to a statement issued by the New York City medical examiner's spokeswoman, Ellen Borakove, Ledger "died as the result of acute intoxication by the combined effects of oxycodone, hydrocodone, diazepam, temazepam, alprazolam and doxylamine."
A statement later issued by Ledger's family suggests that all of the drugs found in the actor's body were in therapeutic levels, contributing to the notion that it was no single medication that directly caused his death.
Both oxycodone and hydrocodone (known by the trade names Oxycontin and Vicodin) are powerful opioid pain medications. Diazepam (Valium), temazepam (Restoril) and alprazolam (Xanax) are prescribed to treat anxiety. And doxylamine (Unisom) is a sleep aid.
But considering the powerful nature of the drugs in the mix, say doctors, it's little surprise that the drug combination turned out to be fatal.
"Any one of these drugs, in the right amount, could be dangerous or fatal," says Dr. Vatsal Thakkar, clinical assistant professor of psychiatry at New York University Medical Center.
"The fact that he was taking a number of them at the same time makes them even more dangerous," Thakkar says. "When you add in a number of classes [of drugs] that all have a sedative effect, you increase the chances of 'quieting down' the brain to the point that the victim stops breathing."
"Certainly, there is no need to be taking two opiates, the oxycodone and the hydrocodone, at the same time," adds Lynn Willis, professor emeritus in the department of pharmacology and toxicology at the Indiana University School of Medicine. "Similarly, there is no justification for taking more than one benzodiazepine — diazepam, temazepam and alprazolam — at the same time, unless under a physician's direction."
Ledger's death may even serve as a warning sign for those who take prescription medications regularly for both pain relief and anxiety.
"The interesting aspect of this combination of drugs, prescribed for pain and anxiety, is that people develop tolerance to them," says Dr. Donna Seger, associate professor of medicine and emergency medicine at Vanderbilt University Medical Center in Nashville. "If one takes these drugs chronically, the drugs will cause minimal depressant effect. To continue to have effect, doses have to be increased."
And as these dosages increase, so too does the potential health risk, Thakkar says.
"I don't know whether the findings speak to whether his death was accidental or intentional," he notes. "But people can get into a situation where they need a higher and higher dose for pain relief and end up in an accidental death scenario."
A Killer Combination
Despite the potential for danger, it is not uncommon for a doctor to prescribe both a painkiller and an anti-anxiety medication to a single patient.
"A person in acute pain who is prescribed an opioid — for example, hydrocodone — might have an anxiety disorder and so might be already be taking a benzodiazepine," says James Zacny of the University of Chicago's Department of Anesthesia and Critical Care. "So opioids and benzos are not necessarily odd combinations."
But Zacny adds that finding multiple drugs of each type is a red flag for improper use.
"What is odd and points to abuse is that he had three different benzos in his system and two opioids," he says. "No doctor would prescribe that cocktail."
Thakkar agrees. "I can't see any appropriate clinical situation where all of these medications should have been given to one person at the same time."
The combination would have had what is known as an additive effect. In short, this means that the depressive effects of each of these medications would have piggy-backed on each other.
Hydrocodone and oxycodone, for example, can depress activity in the area of the brain that tells you to breathe, Zacny says. Diazepam, temazepam and alprazolam in high or combined doses can decrease respiration. On top of this, the sleeping pill Ledger took could have further depressed the systems in his body that kept him breathing.
But how could Ledger have gotten access to all these medications? Fairly easily, Thakkar notes. They may have come through different doctors, or Ledger could have obtained them through illegitimate means.
"People do share or obtain prescription medications illegally or inappropriately," adds Thakkar. "This highlights the point that these medications are not to be taken lightly."
Amid Tragedy, a Lesson
In the shadow of Ledger's death, doctors note that the circumstances of his death may serve as an important warning to those who may not be monitoring their medicines as closely as they should.
"The public health angle is the big story here," says Dr. Alan Ducatman, professor and chair of community medicine at the West Virginia University School of Medicine, in Morgantown. "One man — and not the first such celebrity, and definitely not the only American — has raised questions about how we prescribe, monitor, are affected by prescription drugs in our society."
And the impacts of these questions could be widespread. Thakkar says that there are likely millions of people in the United States taking at least one of the medications that contributed to Ledger's death.
"This shouldn't be a loud warning to anyone who is taking these medicines under a doctor's supervision," he says. "But people need to understand that the more they are taking different medications for a single indication, the more they need to be carefully supervised."
Willis agrees. "The message is that this case isn't about pain relief, it's about drug abuse. Where pain is concerned, let your physician be the judge of which drugs to prescribe."