Saturday, October 1, 2011

Naloxone: Still an Overlooked Overdose Solution

In The News Recent news and research articles have been decrying escalating trends in overdoses and deaths from opioid analgesics and heroin. Yet, rarely is mention made of the fact that there is an effective and safe antidote for such tragedies — naloxone. Isn’t it time to stop the complaining, and conducting pilot studies, and to start using naloxone on a broad scale to address the problems?

According to recent news reports, based on data from the United States and other countries, opioid overdoses and deaths are sharply on the rise, involving both analgesics prescribed for pain as well as illicit heroin. In the U.S., the latest statistics indicate that the number of drug-related overdose deaths climbed to nearly 37,500 in 2009; affecting about 1 person every 14 minutes and killing more people than automobile accidents [see, Los Angeles Times, 9/17/2011; Chicago Tribune, 9/26/2011]. In Europe, a lethal drug-related overdose occurs every hour. A further trend is that death tolls are highest among middle-aged males and increasingly among middle-class persons living in suburban and rural areas.

The trends are alarming and it is equally disturbing that government agencies at all levels seem so focused on collecting and reporting data, and seeking ways to curtail opioid analgesic prescribing and distribution — which ultimately negatively impacts persons with pain who legitimately need and benefit from the medications. Nowhere in the above newspaper reports or in directives from government agencies is mention made of naloxone, the opioid antagonist drug that is a life-saving antidote for overdose [previously discussed in an UPDATE here and in various resources here].

Writing recently in The New York Times [9/22/2011, also 9/27/2011] medical journalist Maia Szalavitz observes that, for many persons, life-saving naloxone is out of reach. Naloxone is currently available only by prescription, she notes, even though it is much safer than other drugs available without prescription. And, for the most part, naloxone is distributed primarily to opioid-addicted persons through needle-exchange programs or rehab centers in at least 16 states. Of 50,000 naloxone kits distributed by the year 2010 there were 10,000 reported overdose reversals — a 20% return on the investment in terms of lives saved.

Two news reports last August 2011 noted other successes of naloxone distribution programs…

  • Boston Public Health Commission officials reported on a local naloxone distribution program that is credited with reducing the opioid-related death rate by nearly a third [news article here]. Since 2006 the city has distributed intranasal naloxone kits to a little more than 2,000 people and officially recorded 215 cases in which overdoses were successfully reversed by the drug (actual numbers of rescues may be significantly higher, since not all are officially reported). In this case, distribution of naloxone was to known drug addicts, their family members, and interested police officers, and all received training on how to use the drug in an emergency. The program is being expanded in Massachusetts; however, its reach is limited, since community healthcare providers are still not prescribing naloxone for their patients.

  • A report from the UK — in the British Medical Journal [here] — notes that a pilot program providing family and friends of opioid users with naloxone (and training in its use) saved the lives of 18 persons who overdosed and were then administered the antidote. According to Paul Hayes — chief executive of the National Treatment Agency for Substance Misuse, a special health authority of the NHS — family members, partners, or other drug users are often first to find a user who has overdosed; “If they can be trained in how to manage such an emergency and keep the victim alive while waiting for the ambulance, potentially hundreds of lives could be saved in the UK every year.” As in the U.S. and many other countries, naloxone is a prescription-only drug in England but it is legal for it to be used by anyone for the purpose of saving a life in an emergency.

Naloxone also is used by emergency crews and in hospitals; however, most community pharmacies do not carry the drug, making it inaccessible even to patients with a prescription. In her NY Times article Szalavitz emphasizes, “That’s why making the drug available over-the-counter and campaigning to include it is first aid kits could make a big difference.”

Few programs have made a specific effort to distribute naloxone to patients with pain who are prescribed long-term opioid analgesics; in all cases, these were operating as research or demonstration projects. One of these, Project Lazarus in North Carolina, has been hugely successful and is being expanded state wide [see details in UPDATE here].

Naloxone has a highly favorable safety profile: generally, the drug itself cannot be overdosed and serious adverse effects of naloxone are very rare. Death from opioid overdose involves slowed and eventually stopped breathing, but this happens over the course of an hour or more so there is usually time to intervene. Naloxone can be life-saving because it quickly displaces opioids from receptors in the brain that depress breathing and the overdose victim is quickly revived. However, naloxone does nothing to reverse harmful effects of drugs other than opioids — such as benzodiazepines, alcohol, cocaine, etc. — so it is always essential that emergency help is summoned immediately.

Unfortunately, family members or friends of opioid users often are unaware of overdose signs and believe that, as with drunkenness, the person should just “sleep it off” — which can be fatal. An example, quoted by Szalavitz in her NY Times article, is provided by Sharon Stancliff, MD, medical director of the Harm Reduction Coalition:

“We constantly hear stories of a parent going to bed who heard her daughter snoring strangely. It was late at night; they didn’t realize what was going on or thought [the child was] sleeping something off. In the morning, the child is dead. That’s the kind of thing we hear about prescription opioid deaths.”

“So what can people do if they suddenly discover that a friend or family member they didn’t even suspect of drug [misuse] has turned blue, is snoring in an unusual way or seems to be slowly stopping breathing? That’s when having naloxone in a first aid kit matters.”

Why isn’t naloxone readily available to every patient prescribed opioids?

  • For one thing, naloxone — now a generic drug, and also under the brand names Narcan®, Nalone®, and Narcanti® — has been unduly tainted and stigmatized by its past associations with reversal of overdose in heroin addicts. Even its wider distribution to the public for take-home use has almost exclusively been to current or former injection-drug misusers through Harm Reduction organizations [eg, see BMJ editorial here]. Thus, the broader medical community often does not think of naloxone as being suitable (or necessary) for everyday patients prescribed opioid analgesics.

  • With but a few exceptions, distribution of naloxone for take-home use has been for injection — requiring assembly of a sterile needled syringe, filling the syringe with the drug, and intramuscular injection. While such a procedure might be familiar to persons who are injection-drug users, it certainly could be daunting, impractical, and perhaps hazardous for typical patients and their families or friends.

    The easy and more practical solution is intranasal naloxone, which uses an atomizer tip attached to a pre-filled syringe of naloxone to spray the drug into nasal passages; thus making it safe and easy to administer to an adult, or even to a child or family pet that has accidentally consumed an opioid. (Note: in the U.S., naloxone has not been officially FDA-approved for intranasal administration; most likely because nobody has applied for such approval. An interesting short video on intranasal naloxone is available [here].)

    Another solution could be a naloxone-filled autoinjector, similar to the well-known EpiPen used to ward off severe allergic reactions. However, development, testing, and approval of such a naloxone device is probably years away, if ever.

  • Opponents of widespread naloxone distribution have claimed that having easy access to the antidote might incur a false sense of security that encourages opioid overuse and/or misuse. However, all pertinent research evidence to date has consistently found that this is NOT the case.

    An alternative hypothesis might be that providing naloxone, along with instructions for why and how it is used, would serve a preventive or deterrent role by heightening awareness of the potential dangers of opioid misuse; this might actually discourage opioid overuse and/or use with interacting drugs or alcohol, especially by patients with pain, as well as greater diligence by their family/friends. However, these possibilities have not been explored in the research.

  • Some medical practitioners have argued that naloxone only temporarily suspends respiratory depression (which might allow a recurrence of life-threatening distress within a short time) and its use is not entirely without risks. However, significant adverse effects of naloxone rarely have been reported in the literature and, since there is the prospect of imminent death without it, the potential benefits of naloxone certainly outweigh any risks. The simple answer to naloxone’s temporary effects is that users — patients, family, friends — should be instructed to also always call for emergency assistance.

  • Another aspect that has not been adequately researched is that, when opioids are combined with other drugs such as benzodiazepines or alcohol that foster respiratory depression and hasten death, reversing at least the opioid-induced component of such distress with naloxone might be sufficient to forestall death while awaiting emergency help.

  • There have been calls for a number of initiatives, such as better education of the public regarding opioid safety and the need for laws protecting drug addicts from prosecution if they call for emergency help when friends overdose. These actions could be important and helpful, but they are not life-sustaining measures, as is naloxone, for persons who are in the throes of respiratory depression due to opioid overdose.

  • Finally, there has been some support for over-the-counter (OTC) access to naloxone [eg, see Salavitz article here], and the U.S. FDA will be conducting a hearing on expanding access to the drug, but not until next May 2012. The opioid antagonist drug has been available OTC from pharmacies in Italy since 1995. However, perhaps in the U.S. and many other countries such open access would be too much of a leap forward; the most immediate question is, since naloxone is available by prescription today, why isn’t it being ordered for all patients taking opioid analgesics on a daily basis?

There seems to be abundant and compelling evidence, from studies worldwide, that the provision of naloxone to the public is feasible, without significant adverse consequences. Another very recent news item in the New York Times [here] reports that groups in Eastern Europe and Asia have been distributing naloxone-containing “overdose rescue kits” to drug addicts and their families. Each kit also contains instructions, sterile gloves, and a face shield for use during mouth-to-mouth resuscitation. Again, however, the emphasis is on distribution among drug-addicted persons.

The NY Times article notes that an injectable rescue dose of naloxone costs about $6 in the U.S., but in most other countries the cost is below $2 and can be as little as 25 cents. Increasing global availability of naloxone as a nasal spray should make the approach more practical and without added expense.

It is curious that, while U.S. government agencies have acknowledged awareness of naloxone and its use in reversing opioid overdose, they have expressed no interest in supporting and promoting widespread distribution of overdose rescue kits containing naloxone. For example, throughout the FDA’s REMS (Risk Evaluation and Mitigation Strategies) development process for opioid analgesics, agency personnel have rarely mentioned naloxone even though it certainly qualifies as a reasonable harm mitigation measure.

One would think that, if federal and state government agencies in the U.S. were serious about quelling their self-proclaimed “epidemic” of opioid overdoses and deaths, they would fast-track FDA approval of intranasal naloxone and strongly support its take-home distribution (with appropriate instruction) to all patients given prescriptions for more than a few days worth of opioid analgesics. Furthermore, not only should public and private healthcare insurers be willing to cover the costs of overdose rescue kits, but one might question why they have not been eagerly insisting on the distribution of naloxone kits as a patient safety, public health, and, ultimately, a cost-containment measure.

The vital importance of take-home naloxone overdose-rescue kits is best summarized by Professor John Strang from King’s College, London, who comments [in article here]:

“We are approaching a time when a clinician might be considered negligent if he or she did not tell the family of [an opioid] user how to manage an overdose, particularly if the user later overdosed and was initially found alive, but then died because the family didn’t know what to do.  . . . .  Some people may think that providing families with naloxone gives out a mixed message, but it is surely better for family and friends to know how to deal with an overdose emergency, even though you do everything possible to avoid it happening.  . . . .  Empowering families [with naloxone] feels alien; it’s similar to when EpiPens (adrenaline autoinjectors) became available for people with allergies. But we must get over this: we can hardly allow deaths to occur once we establish that they could be avoided [emphasis added].”