Originally published by our sister publication Pain Medicine News
According to the latest data from the CDC, a record 108,279 Americans lost their lives to drug overdoses between March 2021 and March 2022. To address the growing crisis, the Reagan-Udall Foundation for the FDA—a nonprofit founded by Congress to help the FDA do its work more effectively—held an online conference focused on fatal overdoses.
“The conference underscored a development and advancement in how the FDA does its work. It is now a more patient-focused organization,” said Susan Winckler, RPh, Esq, the CEO of the Reagan-Udall Foundation. “A core part of the agency’s mission is understanding the needs of patients and making sure they have knowledge about, and access to, pharmaceutical innovation.”
Synthetic Opioids and Polysubstance Abuse
Provisional data from the CDC through July 2022 indicate that approximately 89.7% of overdose deaths involving opioids included synthetic opioids, in most cases illicitly manufactured fentanyl (IMF). Although IMF plays an outsized role in overdoses, combating the problem will require treating polysubstance use. This is due to two factors, according to Christopher M. Jones, PharmD, DrPH, MPH, the director of the National Center for Injury Prevention and Control at the CDC.
First, the increase in deaths caused by psychostimulants such as methamphetamine, both with or without opioid use, has grown in recent years. In fact, “over a quarter of opioid-involved overdose deaths involve psychostimulants or cocaine,” according to Jones.
“Furthermore, we also see the proliferation of counterfeit pills that look like commonly misused prescription medications, including stimulants and opioids, that have fentanyl or fentanyl analogs in bhthem,” Jones noted. Because people don’t actually know what they are using, there has been an increase in the lethality of drugs, he said.
Drug Testing
Several experts presenting at the conference stressed the importance of continuing to monitor what drugs are being used as a tool to help prevent overdoses.
“A national epidemiologic system for collecting and analyzing hospital patients’ urinalysis results, in order to monitor drug epidemics, should be established,” said Eric D. Wish, PhD, the former director of the Center for Substance Abuse Research, at the University of Maryland, in College Park, who briefed participants on the topic of drug testing. This system could aid healthcare professionals to stay ahead of the curve in their effort to keep treatments effective against the constantly evolving illicit drug landscape.
In particular, Wish stressed that “there is a need for most hospitals to add fentanyl to their standard urinalysis panels so that patients may be properly treated and informed of the drugs to which they are being exposed.”
Opioid-induced respiratory depression (OIRD) is the primary way opioids kill their user. Naloxone, a medication that displaces an opioid from its receptor on the respiratory neuron, restores breathing during an overdose and is key to saving lives. A major focus of the two-day conference was making sure that drug users and their communities have access to this lifesaving drug.
A single dose of naloxone is often not enough to reverse OIRD. “The higher the affinity of the opioids for the receptor, the more difficult is to displace the opioid from it—meaning greater quantities of naloxone in an initial dose may be required for drugs with high receptor affinity. The opioids that are most difficult to remove from a receptor are carfentanyl followed by buprenorphine, sufentanil, morphine and fentanyl itself,“ said Albert Dahan, MD, a professor of anesthesiology at Leiden University, in the Netherlands, in his presentation at the conference.
“Some drugs, especially fentanyl, accumulate in the body. That’s quite dangerous because naloxone has a very short elimination half-life, so it’s possible that initially there is a reversal of the fentanyl’s effect with respiratory depression recurring again later. For this reason, with fentanyl overdose, naloxone may need to be readministered several times,” Dahan said.
Are Naloxone Doses Adequate?
Intranasal naloxone is distributed widely in community settings in a two-dose packet. Administration of a single dose after overdose, with repeat doses every two to three minutes, is the approved dosing recommendation. Questions have been raised about whether current naloxone dosing guidelines are adequate due to the potency of illicitly manufactured fentanyl. A randomized clinical trial compared different intranasal naloxone dosing strategies (ClinicalTrials.gov Identifier: NCT04764630) in healthy participants and used a computer model to predict the effectiveness of the different naloxone dosing strategies in rescuing patients from fentanyl overdoses.
David Strauss, MD, PhD, the director of the Division of Applied Regulatory Science at the FDA, presented the results of the study and reported that “when administering one intranasal naloxone dose every 2.5 minutes, there was essentially no difference in displacement of fentanyl from the opioid receptor between administering two naloxone doses and four naloxone doses in the first 10 minutes. However, when administering two intranasal naloxone doses initially, there was a more rapid displacement of fentanyl from the opioid receptor.”
With respect to stopping cardiac arrest, the computer modeling suggested that the most important factor was the amount of the initial naloxone dose as opposed to the number of repeat doses. “Our team is continuing to assess how we can optimize intranasal naloxone dosing in the community setting to help save lives,” Strauss said.
Novel Approaches
“Naloxone is an incredibly effective but blunt instrument. The experts we brought together acknowledged the key role this drug plays in stopping overdose but also explored how methods might be more fine-tuned,” Winckler said.
Research into new avenues for helping opioid users include the development of wearable devices that could serve as an early warning system for overdose or have the ability to titrate opioid antagonists. (The FDA granted De Novo approval to the first, Masimo’s Opioid Halo system, in April.)
The pipeline for new pharmaceuticals was also discussed, including new mu-opioid receptor partial agonists and antagonists, drug sequestrants, and respiratory stimulants.
Until these tools are developed, the experts agreed that monitoring the illicit drug supply and making sure that naloxone is available and dosed adequately are the strongest tools that clinicians and the public have at their disposal to end the surge in overdose deaths.
—Myles Starr
Dahan, Jones, Strauss, Winckler and WIsh reported no relevant financial disclosures.
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