FDA Reports Critical Drug Shortages

Delays put EMTs on alert for dextrose, naloxone, epinephrine.

It’s the kind of thing most people take for granted: You’re suddenly taken seriously ill—a heart attack, dehydration, asthma, shock, perhaps even a heroin overdose—and in the ambulance or the emergency room, medical professionals immediately go to work, using the right drugs and medications for the job.

Imagine lying in the back of an ambulance, in cardiac arrest, or experiencing an episode of acute schizophrenia, or turning blue from a heroin OD—and the EMTs and nurses and other medical staff have only a precariously minimal supply of what you need. You might expect such a thing in wartime, or in parts of the developing world.  But drug shortages already plague health care, and may worsen as drug suppliers run the risk of cutting back production too aggressively on vital drugs used in emergency medical procedures.

At present, according to the Food and Drug Administration (FDA), shortages exist for the following drugs, among others:

Injectable Dextrose 50%: unanticipated increased demand. Full recovery by mid-September. Used in IV solutions.

Injectable ephedrine: manufacturing delays, increased demand. Full recovery by late August. Used as a brochodilator.

Injectable epinephrine: Unanticipated increased demand. Recovery by late September. Used in the treatment of cardiac arrest, shock and anaphylaxis.

Injectable haloperidol decanoate: On back order from major suppliers, estimated recovery by November.  Used for schizophrenia.

Injectable naloxone: manufacturing delays. Recovery by mid-September. Used for heroin overdose.

Writing for the New England Journal of Medicine online, Valerie Jensen and Bob A. Rappaport demonstrate that shortages of certain drugs in sterile injectable form have been increasing. Data from the Drug Shortage Program at the FDA show that, while 35% of the drugs experiencing supply shortages in 2008 were sterile injectables, that number rose to 46% in 2009.  “Reduction in the supply of these drugs can have dramatic effects on medical practice,” they write, “ultimately keeping patients from receiving the level of care they deserve and have come to expect.”

How do these shortages happen? For perspective, the authors lay out the case history of the injectable drug propofol, a fast-acting sedative commonly used to induce and maintain sedation or anesthesia. In 2009, three pharmaceutical manufacturers serviced the market for propofol—Hospira, Teva, and APP. In October of 2009, Hospira recalled “multiple batches of its propofol owing to the presence of particulate matter in the vials.” A few weeks later, Teva issued a recall on several lots of propofol due to “possible microbial contamination.” In June of 2010, Hospira had still not returned to the market, and Teva had chosen to exit the market for good. That left a single company as sole supplier of propofol for the entire U.S.—“an unrealistic expectation, given anesthesiologists’ reliance on the drug.”

Drug shortages can occur in other ways. Producers often abandon older drugs for newer, higher margin offerings. Free market policies can and do lead to supply shortages, particularly in the case of complex injectable products with long manufacturing lead times. Such drugs are most efficiently manufactured in amounts that leave little excess supply in inventory channels. As a result, “a sudden change in either the supply of or the demand for the drug can have catastrophic clinical consequences,” the authors write.

The FDA, say the authors, “cannot require a company to start or to continue manufacturing a drug or dictate how much of a drug must be manufactured…” The free market paradox is always part of medicine: competition drives down the price of drugs, making them more affordable and accessible to patients. But if prices go too low, manufacturers may choose to stop producing a given drug, thereby limiting competition and making the drug vulnerable to supply shortages.

However, the FDA does have the authority to temporarily allow the importation of drugs certified to be of similar formulation and quality, if there is a serious shortage. In the case of propofol, the FDA allowed the importation of a similar but unapproved drug, Fresenius Propoven 1%, which is used in other countries.

Shortages of sterile injectable drugs like propofol create special hazards. For example, they are commonly used in ambulances and emergency rooms for treating shock and heart attack. We are not talking about a shortage of cotton swabs here. In addition, the FDA warns of numerous adverse effects resulting from “multiple entries into single-use vials of the drug,” a common method of dealing with shortages. The authors cite a case in a Nevada endoscopy clinic, where the practice of obtaining multiple doses from a single-dose vial “led to an outbreak of hepatitis C infection, and approximately 40,000 patients were advised to be tested for potential infection of hepatitis B, hepatitis C, and HIV.”

Jensen, V., & Rappaport, B. (2010). The Reality of Drug Shortages -- The Case of the Injectable Agent Propofol New England Journal of Medicine DOI: 10.1056/NEJMp1005849

Photo Credit: http://www.thaimedicalnews

Pill Head: Book Review

Desperately seeking Vicodin.

Recently, the Office of National Drug Control Policy, home of the nation’s “drug czar,” released a survey of the nation’s drug use, demonstrating that prescription drugs used non-medically have become the nation second most “abused” drug, after marijuana. In addition, the Substance Abuse and Mental Health Services Administration (SAMHSA) chipped in with a cheery report that painkiller drug abuse had increase by a staggering 400% from 1998 to 2008.

 Radio entertainer Rush Limbaugh’s 2006 bust put prescription drug abuse on the public radar. Limbaugh surrendered to authorities on a charge of prescription fraud involving pain pills, the result of a three-year investigation into Limbaugh’s addiction to oxycontin—an addiction that may have cost him his hearing.  (Earlier, in 2001, Winona Ryder was arrested for shoplifting and found to have collected 37 prescriptions for painkillers from a total of 20 different doctors.)

Joshua Lyon, the young author of Pill Head: The Secret Life of a Painkiller Addict, can tell you exactly how people have pulled that off: Steal a prescription pad. “Doctor shop” with a list of hard-to-disprove physical ailments. (Migraine is a favorite.) Impersonate a physician and call a pharmacy if you have his or her Drug Enforcement Agency (DEA) number. Perhaps connect with a corrupt pharmacy employee, or with an organized ring of truck thieves. Another favorite is stealing pills from old people. Or you can suck it up and try buying them in bars or on the street. For a while, Joshua Lyon found a workable shortcut: “I just posted a bulletin on my MySpace page, asking if anyone had any Vicodin they wanted to sell. By the next day I had three different offers.” Users have learned to easily circumvent the time-release formulations by crushing the pills and snorting the powder, like Edie Falco’s Nurse Jackie. Corrupt doctors don’t appear to play a major role in much of this, even though they are a favorite DEA whipping boy.

Lyon’s pain pill odyssey began in 2003 when, as a 27-year-old reporter for Jane magazine, he was assigned a story about the “no prescription needed” Internet pill farms that were stuffing everyone’s email inbox with spam about cheap drugs. The author placed his orders, and in a few days, received Fed Ex boxes containing Xanax, Valium, and Vicodin. In only one case was he required to talk to a prescribing doctor over the phone. The "doctor" briefly asked him why he wanted painkillers, and then simply asked him how many pills he wanted.

No stranger to drug use, and a frequent habitué of the gay club scene in New York City, Lyon quickly discovered that prescription opioids were his drugs of choice. “The media,” he writes, “hadn’t dubbed us ‘Generation Rx’ for nothing.” A DEA official told Lyon: People taking Vicodin or hydrocodone, which is probably the most popular pharmaceutical drug in the United States, get the same rush as they would taking heroin, but you’re taking something that people perceive to be safe.”

There is at least a partial answer to prescription drug abuse: digital prescription databases. Unlike other addictive drugs, opioid medications begin life as legal compounds, licensed and produced under specific federal guidelines. The implementation of an electronic prescription drug reporting system, something several states have already undertaken, is a first step, but is obviously limited by the lack of a federal clearinghouse. And privacy concerns have hampered attempts to systemize the collection of prescription records from different doctors.

A health worker in a Lower East Side naloxone program told Lyon that if he called the ambulance about an OD, “don’t tell them that it’s an overdose. Tell them your friend has stopped breathing. They’ll come faster that way.”

All of this makes the ready availability of naloxone, the anti-overdose drug, an ethical imperative. See my posts on overdose kits for opioid addicts HERE and HERE.

Graphics Credit: http://blog.makezine.com/

Heroin Overdose Kits: The Debate Goes On

More states back naloxone programs, but Feds aren’t convinced.

Since the first trial run in Chicago several years ago, efforts to provide heroin addicts with naloxone overdose kits has gained ground in Baltimore, New York, Boston, and several other cities and states. As reported here at Addiction Inbox last month, Dr. Peter Moyer, medical director of Boston’s fire, police and emergency services, applauded the recent Massachusetts decision to expand the Boston program to the entire state and offer Massachusetts heroin addicts the overdose reversal kit. Approved by the Food and Drug Administration (FDA) 35 years ago, Naloxone, or Narcan, is the standard emergency room treatment for heroin overdose. Naloxone instantly reverses life-threatening overdoses by crowding out heroin molecules at the brain receptor sites where they bind.

Predictably, the Office of National Drug Control Policy in the White House does not support the Massachusetts program. Drug Policy officials do not like the idea of addicts medically treating other addicts and have argued repeatedly against distribution of the naloxone kits, claiming that distributing the Narcan antidote will only encourage heroin use and delay treatment.

But the move among states and cities for direct naloxone distribution to addicts continues to gain momentum. In Baltimore, assistant commissioner of health Richard W. Matens maintains that the direct-to-addicts model had been “extremely successful” in his city. Death by heroin overdose reached its lowest level in a decade in 2005, and Matens says the naloxone distribution program played an important role in that reduction.

At the New York State Health Department, which oversees 20 naloxone distribution programs in New York City, Dan O’Connell told the New York Times (reg. required) that from a public health perspective, heroin overdose kits were “a no-brainer.” O’Connell, director of the department’s H.I.V. prevention division, said: “For someone who is experiencing an overdose, naloxone can be the difference between life and death.”

Wisconsin, Minnesota, Connecticut, New Mexico, Rhode Island, and several other states are also embarking on naloxone distribution programs. Thousands of lives are likely to be saved if the idea continues to gain ground.

So what could be the worm in the apple?

“It is not based on good scientific data,” contends Dr. Bertha Madras, deputy director with the White House Office of National Drug Control Policy, which continues its steadfast opposition to such programs. “It’s based on what some people would consider the right thing to do. But the studies supporting it are so sparse it’s painful.” As evidence, Madras and other federal substance abuse officials point to a survey of San Francisco drug addicts done in 2003, the year San Francisco first began funding naloxone distribution. About one-third of the addicts in the survey said they might use more heroin if they had naloxone to protect against overdose. “In the absence of scientific evidence,” Madras told the Times, “we don’t engage in policies that would bring more harm than benefit.”

However, a more recent survey of San Francisco addicts casts major doubt on those findings. In 2005, when the city began a trial program giving out two free needles loaded with naloxone, local officials claimed that fatal overdoses began to fall markedly, and city officials were soon claiming that heroin overdose deaths were at their lowest mark in ten years. California programs train addicts in the use and administration of naloxone. “I’m glad they’re showing us this stuff,” one addict said. “I don’t want to just sit there if someone ends up in a bad situation.”

According to figures reported by the Harm Reduction Coalition, 3,691 California drug users died of overdose in 2003, the latest year of official records. This represents an increase of 42 per cent since 1998, resulting in an annual death rate greater than that from firearms, homicides, and A.I.D.S.

But so far, states are on their own, as Federal drug policy officials continue to maintain that naloxone should only be prescribed and administered by doctors. And yet, many doctors refuse to treat heroin addicts, on the grounds that there is nothing that can be done for them, or that they are recalcitrant patients.

Dan Bigg, director of the Chicago Recovery Alliance, told the New York Times he has seen firsthand that such overdose kits are effective. “What we have here is an antidote to the problem [of heroin overdose],” Bigg said. “Now we just have to convince people it’s worth it.”

Naloxone and “Receptorology”

The power of the opiates revealed

The breakthrough that laid the groundwork for the first truly scientific understanding of addictive drugs took place in 1972, when researchers discovered the existence of specific receptor sites in the brain for the opium molecule.

At roughly the same time, emergency room doctors were baffled to discover that timely injections of a drug called naloxone completely reversed the effects of heroin intoxication. Minutes after an injection of naloxone, heroin addicts were awake, fully recovered, and instantly into the rigors of heroin withdrawal. Naloxone, and a similar drug called naltrexone, rescued O.D. victims from respiratory failure. Like a magic bullet, naloxone--trade name Narcan-- blocked the effects of heroin.

At Johns Hopkins University School of Medicine in Baltimore, Dr. Solomon Snyder and a young doctoral candidate named Candace Pert devised a method for testing this theory. By making molecules of naloxone radioactive, and following the course of the molecules with the aid of a radiation counter, Snyder and Pert were able to show that naloxone attached itself very specifically to certain neurons in certain parts of the brain. If naloxone molecules were capable of locking into specific sites, then presumably these were the same sites in the brain where the opiates did their work.

The sites in question were mean for naturally occurring painkillers called endorphins. The only reason opium worked so dramatically to relieve pain was because a part of the opium molecule was similar in shape to the naturally occurring endorphins. Heroin “fooled” the receptors designed for the shape of an endorphin molecule. Not only that, but heroin and the other opiates stimulated these receptors just as effectively as the natural endorphins did.

The stunning power of the opiates had been revealed as an architectural quirk of nature.

Naloxone was a heroin antagonist—it blocked the effect of the drug at specific sites on nerve cells in the brain. (If the drug fits the receptor and elicits a response, it is called an agonist. If it simply blocks the receptor site without stimulating a response, it is an antagonist.)

The naloxone molecule also bore an uncanny resemblance to the shape of natural endorphin molecules, and when doctors gave an O.D. victim a shot of naloxone, the naloxone molecules knocked the opium molecules right off their receptors. Then they bound themselves to the endorphin sites even more tightly than the heroin molecules did. Naloxone was capable of snapping onto the receptor sites without triggering the release of endorphin.

The brain scans developed for studying this chemical activity were produced by introducing radioactive atoms into naloxone. Wherever naloxone stuck to a receptor site in the brain of a rat, the “hot” connection lit up on special film. These maps of receptor geography in the brain led Dr. Pert and her colleagues to christen the new science “receptorology.” Likening these snapshots to “tiny sparkling grains in a sea of colorfully stained brain tissue,” Pert was helping to invent a new field of study.

“Receptorology” came to be known as neuroscience, or neuropharmacology, and operated under a deceptively simple premise: If it is a drug, and if it has an effect on the brain, then it must have a brain receptor site to which it binds. Find its site of action, and you find out what it is, what it does, and where it does it.