The risk of death from opioid use can be greatly increased when patients are taking other, non-opioid psychoactive therapeutics with sedative properties. To support safer labeling and prescribing of these non-opioid therapeutics, CDER scientists are developing the capability to screen them for potentially dangerous interactions with opioid drugs.
Prescription opioid analgesics are pain-reducing medications that can provide great benefits to patients. Yet each fresh news cycle seems to underscore the devastating effects that these medications can have if used inappropriately. In its most recent report, the Centers for Disease Control and Prevention estimated that in 2016, 46 people in the United States died from prescription opioid overdoses each day. FDA is addressing this crisis on multiple fronts—by advancing strategies to prevent addiction, improving the quality of treatments for opioid use disorder, fostering development of abuse-deterrent formulations, and improving enforcement activities. Recently, CDER scientists initiated research to help achieve a regulatory outcome central to this overall effort: improved labeling to support safer prescribing for patients being treated with opioids in combination with other psychoactive drugs with sedative properties.
Interaction With Other Psychoactive Medications
Opioids cause respiratory depression by direct action on the respiratory centers of the brain. Respiratory depression leading to death can occur with too high a dose of an opioid or when opioids are taken along with other drugs that may have similar respiratory effects. In fact, more than 30 percent of deaths from opioids involve use of benzodiazepines, which are commonly used to treat anxiety or insomnia. Thus, it is essential to reduce or prevent the unnecessary use of drugs and other substances such as alcohol that might worsen the respiratory effects of opioids in patients being treated for pain. To achieve this goal, FDA recently required addition of Boxed Warnings to the drug labeling of opioids and benzodiazepines to address the risks of concomitant use, as well as revisions to the Warnings and Precautions, Drug Interactions, and Patient Counseling Information sections of the labeling. The agency also issued a Drug Safety Communication that calls on health care professionals to prescribe opioid pain medicines with benzodiazepines or other CNS depressants only to patients for whom alternative treatment options are inadequate.
Gaps in the Evidence Needed to Support Safer Prescribing
CDER investigators and reviewers realized that there were many other marketed psychoactive drugs with sedative properties that could have additive or synergistic effects on respiratory depression caused by opioids. For safe prescribing in millions of patients taking psychoactive drugs who are also being treated for pain, health care professionals would need reliable information not only on these drugs’ effects on respiration when taken alone but also on how they interact with widely used opioids
CDER scientists began by carefully reviewing the data (for example, from previous animal and clinical studies, drug utilization data to see how often products are used, and the FDA Adverse Event Reporting System) that could be hazardous when used with an opioid. Based on their review, the investigators recommended that additional studies be performed on some psychoactive sedative drugs, including widely used classes of drugs.
Developing a Preclinical Model to Help Fill the Gaps
The investigators then developed a preclinical animal model to study and help predict the interaction of psychoactive sedative drugs and opioids. Rats were exposed to a psychoactive drug with or without the opioid oxycodone to determine both the respiratory effect of the test drug itself and how it influences opioid-induced respiratory depression. The researchers measured oxygen and carbon dioxide levels in arterial blood to quantify respiratory depression. They used diazepam, a benzodiazepine drug with known synergistic effects on respiratory depression caused by opioids, as the positive control to ensure the model’s reliability and sensitivity. In preliminary experiments, the researchers carefully measured the achieved blood concentrations for each of multiple test drugs at a range of doses over time to determine how to administer the drugs so that the tested drug and the opioid reach peak levels simultaneously.
Translation of the Preclinical Findings
As the researchers accumulate data for each of the selected drugs, CDER clinical pharmacologists and clinicians will assess the findings’ relevance to patient care, consider other available data and make recommendations as to whether the data are sufficient to support changes in the drug labels or whether additional studies are needed