Naloxone, a life-saving drug that reverses the effects of an opioid overdose, is hoped by many in the drug abuse treatment field to be more widely available than it is. And joining those voices is Gil Kerlikowske, director of the Office of National Drug Control Policy. He went — on his own initiative — to a Project Lazarus naloxone symposium in Moravian Falls, North Carolina, on August 22 to promote naloxone as an overdose prevention strategy. Kerlikowkse has included a call for naloxone availability in every national drug strategy since 2010, as well.

In spite of the dramatic increase in opioid overdoses, access to this drug has been hampered by a variety of problems — most notably, market forces. The market is viewed as too small for pharmaceutical companies to invest in, and the drug is in short supply and costly. The Food and Drug Administration (FDA) cannot approve its use by nonprofessionals unless studies have been done, and for that a “sponsor” or pharmaceutical company is necessary. There are some federal grants, but private investors and pharmaceutical companies, including naloxone manufacturers, don’t seem interested.

In addition to regulatory problems, other problems with development are that naloxone is off-patent, and without market exclusivity, manufacturers don’t want to put any money into a product, according to Daniel Wermeling, Pharm.D., professor, University of Kentucky College of Pharmacy, and president and CEO, AntiOp, Inc., a panelist at the hearing. It’s not eligible for orphan drug designation for this indication, and there are reimbursement problems, he said. If it’s over the counter in an intranasal form — a product Wermeling is working on under a grant from the National Institute on Drug Abuse (NIDA) — neither insurance nor Medicare would pay for it, he said. If it’s by prescription as an injectable, the market is only $22 million — which is “very small,” he said, noting that development costs could easily exceed this amount. Wermeling is working on developing an intranasal product with the help of federal and state grants.

Injectable naloxone is typically used in emergency departments and hospitals to reverse overdoses, sometimes caused by anesthesia delivered during surgery. This is what it is approved for use — by a healthcare professional — and there is no labeling for use by nonprofessionals. Harm-reduction advocates and groups like Project Lazarus are making the drug available for “bystanders” and injecting drug users who are also trained in rescue breathing and use the drug to revive people who have overdosed.

A combination of a syringe filled with the drug, and a nasal atomizer is used to administer the drug intranasally, and while the FDA has approved the syringe and the atomizer, it has not approved the combination. Many people, even paramedics, do not want to risk injecting a drug user for fear of being contaminated with HIV or hepatitis C.

Shortage

This spring, the FDA, in conjunction with the Centers for Disease Control and Prevention (CDC) and the National Institute on Drug Abuse (NIDA), held a day-long public hearing on how naloxone can be used to prevent overdose deaths. Panelists such as Alexander Y. Walley, M.D., assistant professor of medicine at the Boston University School of Medicine and medical director of the Opioid Overdose Prevention Pilot with the Massachusetts Department of Public Health, showed how the drug is being used successfully in the state, and parents of children who died of overdoses asked — as they do, heartbreakingly, at every such meeting — why naloxone was not available to them. But FDA officials talked about the steps that need to be taken before it can be approved for use by consumers, including whether consumers can follow the directions or the labeling.

Nabarun Dasgupta, a co-founder of Project Lazarus, spoke at the public hearing as a member of the public about the “unreliability” of the main supplier of naloxone in the U.S., Hospira. “Some of the overdose prevention programs in this room are about to run out of or already have run out of naloxone,” he said. “ For what other disease condition would we allow the supply of the antidote to lapse in the middle of the epidemic that we heard about this morning? The FDA should be encouraged to take more aggressive action to address the shortage.” 

Last week, four months after the public hearing, we asked the FDA what it had done since then to make naloxone more available. According to a press spokeswoman, “the FDA sent letters to naloxone manufacturers expressing the agency’s interest in having them come to discuss the possibility of their developing a product for use by non-professionals.” This was the only information that the FDA would provide on steps taken to make naloxone more available. The FDA would not disclose the contents of the letter nor the companies it was sent to.

The UN Commission on Narcotic Drugs this year urged all member states to include ways to prevent and treat opioid overdose, something that Kerlikowske, as a representative, urged (see ADAW, March 15).

The CDC has found that the numbers of heroin overdoses have been increasing over the last two or three years, and that opioid overdoses in general have increased dramatically (see graph).

CSAT toolkit

At the April 12 public hearing, Nicholas Reuter, senior public health analyst with the Center for Substance Abuse Treatment (CSAT) at the Substance Abuse and Mental Health Services Administration (SAMHSA), was one of many panelists referring to a Morbidity and Mortality Weekly Report (MMWR) on successful community uses of naloxone to reverse overdoses (for that MMWR, go to www.cdc.gov/mmwr/preview/mmwrhtml/mm6106a1.htm). One recommendation from the MMWR was to expand public treatment programs. Another was to expand access to naloxone.

As of October 2010, there were 188 community-based programs, said Reuter. Between 1996 and 2010, these programs, operating in 15 states, provided naloxone to 53,000 people and reversed 10,000 overdoses. (Naloxone doesn’t work if the overdose is due to a substance other than opioids, such as benzodiazepines or alcohol, and it doesn’t work if the heart has already stopped beating.)

Reuter pointed out that one of the highest rates of opioid overdose is in West Virginia, where there is no naloxone distribution program.

SAMHSA is developing a toolkit for naloxone use, but it will include everything but the naloxone, Reuter said last April. “Instead, it's going to provide resources and information where people can get naloxone.” It will also provide information about rescue breathing, how to administer naloxone and how to link with treatment.

NIDA funding

Wilson M. Compton, M.D., director of NIDA’s Division of Epidemiology, Services, and Prevention Research, said the agency is funding the development of an intranasal formulation of naloxone “which is certainly much easier to administer and may be more widely available.” This is Wermeling’s grant. NIDA also is funding two randomized clinical trials looking at the use of naloxone for overdose prevention, he said.

We asked Wermeling why more isn’t being done by the FDA to get naloxone available, and why the FDA officials in charge are declining to discuss this. “It’s really difficult for them as regulators to talk about something that isn’t approved,” said Wermeling, adding it would be at least two or three years before his product had any chance of getting to market.

He believes that naloxone should be available by prescription, for the simple reason that insurance companies won’t cover it if it’s over the counter. “My hypothesis is there will be greater access if it’s available by prescription,” he said, noting that other drugs, once they become over the counter, are too expensive for many people to buy. “You can have the greatest drug on earth, but if people can’t get paid back, they won’t get it.”

In Massachusetts, there have been problems with reimbursement, Walley said at the hearing.  Medicaid used to pay for it but had recently dropped it, he said. In addition, private insurance doesn’t necessarily pay for it either.

Harm reduction

So the onus on using naloxone to save lives is still on the harm-reduction groups. What is significant is that Kerlikowske — hardly a proponent of “harm reduction” if that means legalizing marijuana or encouraging illicit drug use in any way — is embracing this movement. On August 22, he commended Project Lazarus for saving lives and noted that Wilkes County has had a disproportionate number of overdoses — four times the North Carolina state average in 2009 due to prescription opioid pain relievers.

“While my office is committed to reducing illicit drug use in America, we are equally committed to reducing the harmful consequences of drug use, too,” Kerlikowske said in his prepared speech. “Drug prevention — especially overdose prevention — is a critical piece of our mission.”

Fred Wells Brason II, chief executive of Project Lazarus, told ADAW that the opioid treatment program in Wilkes County — which Project Lazarus helped bring there three years ago — is dispensing naloxone to every new enrollee. The induction phase of methadone maintenance treatment is the most risky time for overdose in methadone treatment.

And while Brason questioned why the FDA has not put naloxone on a “fast track” because of the overdose epidemic, he said he “salutes” them for holding the public hearing. He also commended Kerlikowske, who, he said, attended the Project Lazarus symposium out of his own commitment to the group and its mission. “He asked to come,” said Brason.