Naloxone for Community Opioid Overdose Reversal

The number of Americans lost to opioid overdose has been increasing for nearly two decades, in an epidemic that impacts people from all ages, races, and geographic areas (Rossen, Khan, & Warner, 2014; Chen, Hedegaard, & Warner, 2014). Fatal poisonings, most of which are caused by drug overdose, have increased by nearly 600 percent in the past three decades, and are now the leading cause of injury death in the United States (Warner et al., 2011). Although this increase has been driven mainly by opioid painkillers (Okie, 2010; Modarai et al., 2013), which took the lives of over 16,000 Americans in 2013, recent data show a marked increase in heroin-related deaths as well (Pollini et al., 2011; Jones, 2013; Rudd et al., 2014; Warner, 2015; Hedegaard, Chen, & Warner, 2015). Heroin-related fatalities rose to over 8,000 in 2013, a nearly four-fold increase since 2000, while prescription opioid-related deaths appear to have plateaued (Rudd et al., 2014; Hedegaard, Chen, & Warner, 2015). Evidence strongly suggests that the increase in heroin deaths is at least partly the result of prescription opioid users transitioning to heroin use (Rudd et al., 2014; Dasgupta et al., 2014; Peavy et al., 2012).

Opioid overdose causes decreased levels of consciousness and respiratory depression. It becomes life threatening when breathing is depressed to the point that insufficient oxygen is available to permit the brain and other organs to function effectively, a state called hypoxia (Bouillon, Bruhn, Roepcke, & Hoeft, 2003; Pattinson, 2008; White & Irvine, 1999). Early intervention is critical, as hypoxia can cause cell death within minutes, and the risk of irreversible damage increases with the amount of time the person remains hypoxic (Michiels, 2004). Because most people do not overdose alone, equipping people who use opioids and the friends and family members of those at risk of opioid overdose with the tools to quickly reverse it can reduce the risk of overdose death as well as damage to the brain and other organs (Galea et al., 2006).

Opioid overdose, whether caused by heroin or prescription painkillers, can typically be reversed by administering a medication called naloxone (Chamberlain & Klein, 1994). Naloxone, commonly known by the brand name Narcan, was approved by the Food and Drug Administration (FDA) in 1971. It is a prescription medicine but not a controlled substance, and it has no potential for abuse (Chamberlain & Klein, 1994). It displaces opioids from the brain receptors to which they attach, reversing their effects and restoring normal respiration (Chamberlain & Klein, 1994; Lewanowitsch & Irvine, 2002). It is stocked by nearly every hospital and has been used by paramedics for decades (Barton et al., 2002). While medical professionals typically inject it into a victim’s vein, most community groups provide the equipment to inject it into a muscle or to spray it into the nose of a person who is suffering an overdose (Doe-Simkins, Walley, Epstein, & Moyer, 2009). An easy-to-use auto-injector device (brand name Evzio) was approved in 2014 (Food and Drug Administration, 2014).

Because people who use drugs (PWUD) are already “on the scene” of an overdose, experts have suggested reducing time to naloxone administration by equipping them with naloxone for more than twenty years (Strang, Darke, Hall, Farrell, & Ali, 1996). By the mid-1990’s, naloxone was being distributed to heroin users in Italy (Simini, 1998), Germany, and the United Kingdom (Coffin et al., 2003). The first programs to dispense naloxone to PWUD in the United States were launched in the late 1990’s and early 2000’s, with the first documented programs operating in Chicago in 1996 and San Francisco in 2001 (Bigg & Maxwell, 2002; Seal et al., 2005; Centers for Disease Control and Prevention, 2012).

By the mid-2000s, community programs in several states including New Mexico, Massachusetts and New York had begun distributing naloxone and overdose rescue training to PWUD and the friends and family members of people at high risk of overdose (Galea et al., 2006; Doe-Simkins, Walley, Epstein, & Moyer, 2009; Maxwell, Bigg, Stanczykiewicz, & Carlberg-Racich, 2006; Clark, Wilder, & Winstainley, 2014; Piper et al., 2008). As of 2014, more than 150,000 laypeople have received training and naloxone kits, and participants reported reversing more than 26,000 overdoses (Wheeler, Jones, Gilbert & Davidson, 2015). Naloxone access initiatives have since expanded beyond PWUD, with many states taking action to encourage the provision of naloxone by physicians, pharmacists, and community organizations to anyone at risk of opioid overdose (Bailey & Wermeling, 2014; Zaller et al., 2013; Davis, Webb, & Burris, 2013). There is also increasing movement to equip non-medical first responders such as firefighters and law enforcement officers with naloxone, although evidence supporting the efficacy of this intervention is not yet available (Davis, Ruiz, Glynn, Picariello, & Walley, 2014).

A 1999 survey of heroin injectors reported that 89 percent said that they would have used naloxone at the last overdose they witnessed if they’d had it available (Strang et al., 1999). Since then, tens of thousands of lay people have been trained in recognizing and responding to overdose, including administering naloxone (Wheeler, Jones, Gilbert & Davidson, 2015; Clark, Wilder, & Winstanley, 2014). Recent data show that PWUD who received naloxone from one such program were highly likely to administer it during an overdose (Rowe et al., 2015).

Overdose prevention programs typically train people receiving naloxone kits to reduce overdose risk as well as recognize and appropriately respond to overdose (Clark, Wilder, & Winstanley, 2014). Although the level of evidence is relatively low, most reviews report that people who receive naloxone training increase their level of relevant knowledge (Haegerich, Paulozzi, Manns, & Jones, 2014). A study of mostly homeless people who inject drugs in Los Angeles found that a single training session significantly increased knowledge of appropriate overdose response (Wagner et al., 2010), and a study of people trained in overdose response at six sites in the United States reported that they were significantly more likely to recognize and respond to overdose (Green, Heimer, & Grau, 2008). Recent evidence suggests that a very brief education session is sufficient (Behar, Santos, Wheeler, Rowe, & Coffin, 2015), and a recent study found no significant difference in rescue behaviors or reversal rates between naloxone administered by people who had received formal training versus those who had not (Doe-Simkins et al., 2014).

No medication is completely safe. However, naloxone has a low risk of serious side effects. The most common stem from the withdrawal symptoms the medication can cause, and include shivering, sweating, and aggressiveness (Buajordet, Naess, Jacobson, & Brors, 2004; Kelly et al., 2005). While these can be uncomfortable, they are generally not life-threatening (Wermeling, 2015). While there are some reports of life-threatening injuries post-naloxone administration, they are rare (Osterwalder, 1996; Enteen et al., 2010; Yokell et al., 2011) and almost always reported in medically complex, post-operative settings where naloxone is administered in amounts higher than those typically used in the community (Boajordet, Naess, Jacobson, & Brors, 2004; Kelly et al., 2005). It is not clear whether these adverse effects, which have included acute lung injury (pulmonary edema), are the result of naloxone administration or events related to the overdose itself (Kelly et al., 2005; Osterwalder, 1996).

Additionally, it appears that individuals who receive naloxone but do not receive additional medical care are not at increased risk of negative outcomes. A 2003 study of 5 years of data in San Diego found no deaths in the 12 hours after patients who were administered naloxone by EMS refused transport to the hospital (n=998) (Vilke, Sloane, Smith, & Chan, 2003). A 2005 study from Finland found no life-threatening events in the 12 hours after overdose patients (n=84) were treated pre-hospital and refused further treatment, which lead the authors to conclude that permitting “presumed heroin overdose patients to sign out after pre-hospital care with naloxone is safe” (Boyd et al., 2006). Likewise, a 2011 retroactive study of 20 months of data from San Antonio found no evidence that any patients who had been administered naloxone and refused transport died in the next 48 hours (n=542) (Wampler et al., 2011).

A number of laws and regulations hamper access to naloxone. Because it is a prescription medication, it can be dispensed only on the order of a medical professional authorized to issue prescriptions (Davis, Webb, & Burris, 2013). Further, state medical practice laws typically discourage or prohibit the prescription or distribution of medications to a person other than the person to whom they are to be administered (a process referred to as third-party prescription) or to a person the physician has not examined (Davis, Webb, & Burris, 2013). These restrictions have often prevented naloxone from being available when and where it is needed outside of the medical setting.

Additionally, some prescribers may refrain from prescribing naloxone because of concerns that it might increase their risk of civil liability, although there is no evidence that these concerns are justified (Beletsky et al., 2007; Burris et al., 2009). Similarly, people present at the scene of an overdose may be afraid to call 911 because of fear of being charged with a crime, particularly where they are using illegal drugs or using prescribed medication other than as prescribed (Enteen et al., 2010; Tobin, Davey, & Latkin, 2005; Sherman et al., 2008).

While making naloxone available over the counter would likely solve many of these access problems, only the FDA has the authority to make that change. However, states have taken a number of steps to increase access to naloxone, beginning with New Mexico in 2001. As of May 2015, 30 other states and the District of Columbia have also modified law to make it easier for lay people to access naloxone. These changes vary, but most permit individuals otherwise authorized to prescribe naloxone to prescribe it not only to their own patients, but also to family members, caregivers, and others (Davis, Webb, & Burris, 2013). Many states also permit naloxone to be prescribed via a standing order, in which one prescriber issues a prescription for naloxone to be provided to any person who meets certain criteria, as opposed to a named individual. Nearly all of these laws provide limited immunity to medical professionals who prescribe naloxone and lay people who administer it in an overdose (Davis, 2015). An increasing number also authorize law enforcement officers and other non-medical first responders such as firefighters to carry naloxone and administer it in an overdose (Davis, et al., 2014; Davis, Ruiz, Glynn, Picariello, & Walley, 2014).

New Mexico was also the first state, in 2007, to amend its laws to encourage overdose witnesses to summon aid in the event of an overdose by providing limited criminal immunity to overdose witnesses who summon emergency help for an overdose victim. As of May 2015, 22 other states and the District of Columbia have also passed such laws (Davis, 2015). These laws, which are often referred to as “Good Samaritan” laws, provide limited criminal immunity (typically from minor drug-related crimes) for both the overdose victim and the person who calls for help, although some of the more recent laws expand the protection to offenses such as probation and parole violations.

Although data are limited, access to naloxone does not appear to encourage risky behavior, likely because naloxone overdose reversal removes the user’s “high” and, depending on the opioid that was taken and the amount of naloxone administered, can put the victim into withdrawal, an extremely unpleasant experience. A study in England reported that 94 percent of heroin users said that having access to naloxone would not increase the dose of drugs that they used (Stran et al., 1999). A small study from San Francisco found that heroin users who received naloxone and overdose education reported a statistically significant decrease in heroin injection six months after the intervention (Seal et al., 2005), and a study in Los Angeles noted that a majority of individuals trained in overdose prevention reported that their drug use decreased three months after the training (Wagner et al., 2010).

Researchers evaluating the Massachusetts Overdose Education and Naloxone Distribution program found that “training active substance users in overdose management and distributing naloxone rescue kits does not lead opioid users to increase their overall opioid use” (Doe-Simkins et al., 2014). According to a recent systematic review, two studies reported that participants in opioid overdose prevention programs reported a decrease in calling 911, while two reported an increase and one found no change (Clark, Wilder, & Winstanley, 2014).

Evidence of the effectiveness of naloxone access programs in reducing fatal overdose and overdose-related morbidity is limited, but existing data point to a positive effect (Clark, Wilder, & Winstanley, 2014). The best evidence comes from a study in Massachusetts, which showed that communities with higher access to naloxone and overdose training had significantly lower opioid overdose death rates than those did not (Walley et al., 2013). A systematic review of published literature found that 11 of 18 studies reported a survival rate of 100 percent after naloxone was administered in the community setting; the others reported a range of 83-96 percent (Clark, Wilder, & Winstanley, 2014).

Initial evidence from a comprehensive overdose prevention program (Project Lazarus) in one county in North Carolina found a striking decrease in overdose deaths in that county after the program was initiated (Albert et al., 2011). Researchers have suggested that reduction in heroin deaths in Chicago may be partly attributable to a naloxone distribution program in that city, although that finding is merely observational (Maxwell, Bigg, Stanczykiewicz, Carlberg-Racich, 2006).

Naloxone is available in a number of different formulations, with widely varying costs. Evzio, the recently approved auto-injector, retails for $450-$600 (Beletsky, 2015). According to the manufacturer, the majority of state Medicaid programs provide coverage for Evzio, co-pay assistance is available to bring the out-of-pocket cost to less than $30 for most commercially insured patients, and programs are available to provide Evzio at no cost to individuals without drug coverage and qualifying harm reduction and law enforcement agencies (communication with kaleo, June 19, 2015). Community overdose programs reported costs in the range of $15 per kit of injectable naloxone, and $30 per kit of intranasal naloxone in 2013 (Coffin & Sullivan, 2013). The price of the medication has recently increased by as much as a factor of 2 to 3, reducing the ability of some community organizations to distribute the medication and prompting protests from government officials in several states (Goodman, 2014).

Emergency department visits are expensive, as is follow-up care for patients with lasting damage caused by hypoxia. In a 2013 study, the provision of naloxone kits to heroin users was found to be robustly cost-effective even under extremely conservative assumptions (Coffin & Sullivan, 2013). A separate study noted that the cost of treating people who had overdosed in Rhode Island hospitals could have paid for more than 61,000 naloxone kits at the then-current cost of $15 (Yokell et al., 2011).

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