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  1. Regulatory Science in Action

Impact Story: Preclinical Research to Achieve Safer Prescribing of Psychoactive Therapeutics for Patients Who Use Opioids

Regulatory Science Impact Story

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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

Opioid deaths involving benzodiazepines. Annual deaths from 1999 to 2016 and proportion of deaths from opioids when benzodiazepines were taken concurrently (red). Both deaths from opioids alone, and deaths from opioids when benzodiazepines were taken concurrently rose significantly from 1999 to 2016. Data are from the Centers for Disease Control Opioid deaths involving benzodiazepines. Annual deaths from 1999 to 2016 and proportion of deaths from opioids when benzodiazepines were taken concurrently (red). Both deaths from opioids alone, and deaths from opioids when benzodiazepines were taken concurrently rose significantly from 1999 to 2016. Data are from the Centers for Disease Control.

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.

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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.

A model of respiratory depression in the presence of opioids. The graph shows the lowering of arterial oxygen levels in rates exposed to a benzodiazepine drug (Valium, blue line), the opioid drug oxycodone (gray), or both drugs (red). Respiratory depression or the extent to which oxygen is lowered in the presence of both drugs is more than what would be predicted by the action of each drug alone. Using a rat model they developed, CDER researchers are studying the respiratory effects of a wide and representative range of psychoactive sedative drugs (PSDs) in the presence or absence of oxycodone. The goal is to help develop more informed labeling and ultimately safer use and prescribing of PSDs in patients who are also being treated with opioids.</</ A model of respiratory depression in the presence of opioids. The graph shows the lowering of arterial oxygen levels in rates exposed to a benzodiazepine drug (Valium, blue line), the opioid drug oxycodone (gray), or both drugs (red). Respiratory depression or the extent to which oxygen is lowered in the presence of both drugs is more than what would be predicted by the action of each drug alone. Using a rat model they developed, CDER researchers are studying the respiratory effects of a wide and representative range of psychoactive sedative drugs (PSDs) in the presence or absence of oxycodone. The goal is to help develop more informed labeling and ultimately safer use and prescribing of PSDs in patients who are also being treated with opioids.

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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.

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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

How does this research advance the safety of patients being treated with opioids? The improved understanding of the interactions of commonly prescribed psychoactive drugs with opioids obtained in this research can inform improved labeling of these drugs so that dangerous and potentially fatal drug combinations are avoided.

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