Opiates have been used for thousands of years, with evidence of opium poppy (known as Hul Gil, “joy plant”) cultivation more than 5000 years ago among the Sumerians in the area of Mesopotamia, near modern day Iraq. Its use for rituals and mystical purposes is evidenced by poppy seed capsules discovered in burial sites in Neuchatel, Switzerland and the Cueva de los Murciélagos , Spain, which have been carbon-14 dated to 4200 BCE. As use spread throughout the Mediterranean, opium’s medicinal properties were recognized.
The Greek physician Galen may have been the first to record an opium overdose in around 140 CE, during which he reportedly treated the patient with an emetic made of sweet wine. In 1656, Christopher Wren experimented with intravenous administration (using animal bladders and goose quills) of opium to dogs and described overdose, and several years later, German scientists J.D. Major and J.S. Elsholtz performed similar experiments on humans with reported toxicity. A century and a half later, Friedrich Sertürner, the German pharmacist who isolated morphine from opium in the early 1800s, reported that he experimented with the alkaloid by administering it to himself, three boys, three dogs, and a mouse. One of the dogs reportedly died, and he described the effect that morphine had on himself and his three young “volunteers” as “near fatal.” The first recorded human fatality from a morphine overdose appears to be from the 1850s when Scottish physician Alexander Wood, one of the first to use and perfect the hypodermic needle and syringe, reportedly performed one of the first injections of morphine on his wife who subsequently died from respiratory depression, although others claim that this story is not true. Overdose is also discussed with regards to laudanum, a mixture of opium and alcohol, associated with overdose in mid-19th century. The Brooklyn (New York) Daily Eagle , January 10, 1861, reported two unrelated instances in a single day. Elizabeth Siddal an artist and wife of Dante Gabriel Rosetti, took laudanum for various illnesses and died of an overdose in February 1862.
The term “overdose” is used variably by the lay public, health professionals, and in the medical literature and generally refers to an “excessive amount” of a substance (the noun) or the act of taking such an amount (the verb). This excessive amount is dependent on an individual’s tolerance to the specific substance. Associated signs generally include the “opioid overdose triad” of constricted (“pinpoint”) pupils, altered level of consciousness, and respiratory depression (both rate and effort). Additional signs may include blue or ashen skin, nails and lips; gurgling or snore-like sounds (“death rattle”); decreased blood pressure and heart rate; and pulmonary edema ( Box 54.1 ).
Constricted (“pinpoint”) pupils
Altered level of consciousness
Respiratory depression (both rate and effort)
Blue or ashen skin, nails, and lips
Gurgling or snore-like sounds (“death rattle”)
Decreased blood pressure and heart rate
“Froth” from mouth (from pulmonary edema)
There are no consistent guidelines or cutoffs to distinguish overdose from intoxication or being under the influence. Some consider an overdose only if the individual has lost consciousness and is unarousable by external stimulation. Number of breaths per minute used to define overdose range from less than 12 per minute to less than 8 per minute. The term “opioid-induced respiratory depression” is sometimes used to describe the side effect of opioid used medically in an attempt to distinguish this effect from the term “overdose” with the associated negative connotation. Another term used to address the complexities of tolerance, co-ingestion, medical comorbidities, and environmental context is “opioid-related overdose.”
The term “overdose” is not recognized in standard medical diagnostic nomenclature such as the International Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM) and the Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5). What is commonly thought of as “overdose” can fall under one of two areas: “Poisoning” in the “Injury, Poisoning and Certain Other Consequences of External Causes” section or “Intoxication” in the “Mental, Behavioral and Neurodevelopmental Disorders” section.
International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM)
Injury, Poisoning, and Certain Other Consequences of External Causes
“Poisoning by, adverse effect of & under-dosing of drugs, medications & biological substances” (T26-50).
This category includes adverse effect of correct substance properly administered, poisoning by overdose of substance, poisoning by wrong substance given or taken in error, and underdosing by taking less substance than prescribed or instructed. The determination of poisoning versus adverse effect is based on how the substance was used. If the correct substance was administered as prescribed, the condition is classified as an adverse effect. Using the prescribed medication less frequently than prescribed, in smaller amounts, or not using the medication as instructed by the manufacturer is not coded as poisoning but as underdosing. When the condition is a poisoning, the poisoning code is sequenced first, followed by additional codes for all manifestations. If there is also a diagnosis of abuse or dependence on the substance, the abuse or dependence is also coded. The poisoning code is also used when a condition results from interaction of a therapeutic drug used correctly with a nonprescription drug and/or alcohol. All involved substances should be coded separately.
Poisoning by opioids is designated by the code T40. There are specific codes (first decimal place) for heroin (T40.1), other opioids (T40.2), methadone (T40.3), and other synthetic narcotics (T40.4). In addition, a determination is to be made (third decimal place) as to whether the poisoning was unintentional (.XX1), intentional self-harm (.XX2), assault (.XX3), or undetermined (.XX4). Additional codes specify initial encounter, subsequent encounter, and sequela (fourth decimal place) ( Box 54.2 ).
Mental, Behavioral and Neurodevelopmental Disorders: Mental and Behavioral Disorders Due to Psychoactive Substance Use
The diagnostic categories listed here are meant to designate the behavioral disorders of substance abuse and dependence. Although not meant to specifically designate the phenomenon of overdose, they are sometimes used interchangeably in studies, reports, and so on. They include Opioid use (F11.92), abuse (F11.12), or dependence (F11.22) with intoxication. Specifiers include uncomplicated (.XX0), with delirium (.XX1), with perceptual disturbance (.XX2), and unspecified (.XX9). There are not separate codes for the different types of opioid but the clinician is encouraged to add the name of the specific opioid (i.e., heroin, oxycodone, methadone) in addition to the numeric code.
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
The other major diagnostic coding system used for behavioral disorders in the United States is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Substance-Related and Addictive Disorders with Intoxication falls under the “Substance-Induced Disorder” category. With regard to Substance Use Disorders, the DSM-5 is similar to ICD-10-CM except it uses the term Opioid Use Disorder with the severity specifiers of Mild, Moderate, or Severe, whereas ICD-10-CM uses Abuse and Dependence codes (similar to the fourth edition [text revision] of the DSM [DSM-IV-TR]). With the DSM-5, a severity specifier of mild is the equivalent of ICD-10-CM abuse, whereas a severity specifier of moderate or severe is equivalent to ICD-10-CM dependence. The DSM-5 does not have a “Use” diagnostic category, although it does have an intoxication code for “Opioid Intoxication with no comorbid opioid use disorder.” There are four criteria for Opioid Intoxication:
Recent use of an opioid.
Clinically significant problematic behavioral or psychological changes (e.g., initial euphoria followed by apathy, dysphoria, psychomotor agitation or retardation, impaired judgment) that developed during, or shortly after, opioid use.
Pupillary constriction (or pupillary dilation due to anoxia from severe overdose) and one (or more) of the following signs or symptoms developing during, or shortly after, opioid use: (1) drowsiness or coma, (2) slurred speech, (3) impairment in attention or memory.
The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication with another substance.
The clinician can add a specifier “with or without perceptual disturbance.”
Unlike DSM-IV-TR, where the intoxication and use disorder (abuse or dependence) were listed individually, DSM-5 uses a code that combines the use disorder and intoxication (in order to distinguish it from intoxication in an individual who does not have a history of a use disorder).
Defining Fatal Overdose
Historically, there has been a great deal of inconsistency in the way that “poisoning” or intoxication-related deaths have been categorized. Because some states have a system based on a centralized medical examiner, whereas others use jurisdictional coroners, there is often a great deal of variability within and between states. Because the numbers reported have significant implications for public health surveillance and resultant prevention strategies, it is extremely important that these deaths be reported in a manner that is consistent as possible. The National Association of Medical Examiners along with American College of Medical Toxicology released guidelines for the investigation, diagnosis, and certification of deaths related to opioid drugs. These recommendations included a complete autopsy, a complete scene investigation (including reconciliation of prescription information and pill counts), and comprehensive toxicological testing (of blood, urine, and vitreous humor) to include opioid and benzodiazepine analytes as well as other depressants, stimulants, and antidepressants. All of these are to be used in conjunction with medical history to determine four key components of the death certificate: Cause of Death, Other Significant Conditions Contributing to Death, Manner of Death, and How Injury Occurred. For Cause of Death, all substances believed to have been responsible for the death, and present in sufficient concentrations, are listed (as opposed to vague statements such as “mixed drug intoxication”). The Other Significant Conditions section lists conditions that might have predisposed a person to death (such as sleep apnea) but were neither necessary nor sufficient to cause the death. The Manner of Death is classified as either accident, suicide, homicide, or undetermined. The recommendations encouraged the use of “accident” for all cases of misuse or abuse without any apparent intent of self-harm and stressed that the “undetermined” designation should be reserved only for those cases for which the evidence exists to support more than one possible determination (as opposed to the more common use when the manner is not absolutely certain). Finally, the How Injury Occurred section should include the information about medical history, route of administration, drug formulation (long-acting, extended release, or immediate-release), and source of drug (prescription, illicit, diverted).
The Substance Abuse and Mental Health Services Administration (SAMHSA) convened a consensus panel that addressed many of the same issues and added some additional case definitions: Drug-Caused Death, which refers to deaths that resulted from exposure to a substance regardless of the intent (accident, suicide, homicide) of the individual; and Drug-Detected Death, which refers to a death in which a drug is detected regardless of the drug’s role in causing the death. A subcategory of Drug-Caused Death is Drug Poisoning Death, which refers specifically to deaths caused by acute exposure. The US National Center for Health Statistics (NCHS), which releases the annual National Vital Statistics Report Deaths, Final Data , has also developed similar categories for drug-induced deaths; however, that classification also includes deaths involving adverse effects of drugs for therapeutic use.
The Centers for Disease Control and Prevention (CDC), based on the external-cause-of-injury matrix, recommends defining an overdose when the first-listed E-code is “drug poisoning” and the principal diagnosis is “injury.” Consensus recommendations from the Safe States Alliance’s Injury Surveillance Workgroup on Poisoning (ISW7) recommends two alternative case definitions: one in which an overdose is defined when either the first-listed E-code or principal diagnosis indicates drug poisoning” and the second when an overdose is defined when any E-code or diagnosis lists drug poisoning. One study looking at data from Kentucky found a 50% increase in overdose cases identified when using the second ISW7 definition as compared to the CDC recommended definition. In addition, in 1999, the ICD-10 replaced the previous revision of the ICD (ICD-9) as the classification system used by medical examiners in the determination of cause of death.
Reliable data on the epidemiology of the fatal overdose are variable and limited by the lack of consistency in case identification, coding, and reporting. The determination of the cause of death varies from country to country, within a given country and, often, within local jurisdictions. Toxicological verification is often not available, extremely limited, or imprecise. Many countries report on drug-related fatalities with some, in addition to drug overdoses, also including deaths due to HIV acquired through injecting drug use, suicide, and unintentional deaths and trauma due to illicit drug use. All of this makes comparisons between countries and regions difficult. With this understanding, the World Health Organization (WHO) estimates that there were 187,100 drug-related deaths in 2013, corresponding to a mortality rate of 40.8 drug-related deaths per million people 15–64 of age. By region, the estimated rates per million are: Africa, 61.9; North America, 136.8; Latin America and the Caribbean, 18.4; Asia, 28.2; West and Central Europe, 22.5; Eastern and Southeastern Europe, 41.5; and Oceania, 82.3. Although most countries report that opioids are the main drugs involved in these deaths, reliable numbers are not available for many countries. Other studies have looked at population-based crude and adjusted mortality rates in various areas and found a range of 0.04 to 46.6 per 100,000 person-years and 0.11–253.8 per 100,000 person-years, respectively. In addition, the largest systematic review of global deaths in people who inject drugs found that overdose is the leading cause in all areas of the world.
The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) monitors drug-use patterns in the European Union (EU) as well as Norway and Turkey. Despite large variability in case definition and reporting, the EMCDDA represents the best estimate of drug-related morbidity and mortality in Europe. According to their data, most EU countries have seen increases in overdose deaths from 2003 to 2009, at which time there was a leveling or decline for several years in some countries. Increases have been seen in a number of EU countries since 2012, with highest increases in Sweden, Spain, and Turkey as well as Ireland, Lithuania, and the United Kingdom (which saw a doubling of heroin-related overdoses between 2013 and 2015, the highest rates since the early 1990s). For most countries, between 2006 and 2014, overdose rates have increased in older adults and decreased in younger adults. Drug overdoses are estimated to account for 3.5% of all deaths among Europeans 15–39 years of age. In 2014, there were approximately 6800 overdose deaths reported in the EU, 82% of which involved an opioid and 78% in males. The overall rate for the EU is approximately 19.2 overdose fatalities per million population 15–64 years of age (18.3 in the EU plus Turkey and Norway), with individual national rates ranging from 2.4 per million in Romania to 113 per million in Estonia. Other countries with rates over 40 per million include Denmark, Finland, Ireland, Lithuania, Norway, Sweden, and the United Kingdom. Heroin or its metabolites were found in the majority of fatal overdoses, although other substances were often found in combination. Prescription opioids most commonly mentioned in toxicology reports are methadone, fentanyl, tramadol, and buprenorphine. Starting in around 2013, parts of Europe also began to see increases in overdoses related to illicitly manufactured fentanyl and other designer fentanyl analogs. Various areas of Canada have also seen substantial increases in overdose fatalities involving illicitly manufactured opioids.
Although fatalities related to opioid use are clearly tragic, nonfatal overdose is more common and exerts a huge cost, both economically and personally. Data on nonfatal overdoses are even more unreliable than data for fatal overdoses due to variability of definition, diagnosis, case identification, coding, and reporting. A number of studies from various parts of the world looking at individuals with histories of opioid misuse suggest that 16%–80% of those interviewed had experienced an overdose in their drug-using career, many of whom had experienced overdoses in the previous 6–12 months. a
a References 43, 46, 68, 140, 160, 178, 184, 261, 262, 299, 363, 436, 544, 589, 723.Other studies have estimated that 4%–5% of all overdose cases are fatal, with a cumulative risk of death increasing with each successive overdose.
Although not as variable as the majority of other countries, data on overdose within the United States do exhibit a fair amount of variability from state to state. On average, about 81% of all death certificates list the specific drug(s) contributing to the death, with some states reporting the specific drug(s) in less than 50% of their death certificates. In addition, there are issues with the manner in which coded diagnosis are used in gathering data: some are based on the external-cause-of-injury code (E-code) and others are based on the principal diagnosis.
The United States reports one of the highest drug-related mortality rates worldwide (at 4.6 times the global average) and accounts for approximately 20% of drug-related deaths globally. The higher mortality rate in North America likely, in part, reflects better monitoring and reporting. The relative contribution of opioids to all overdose deaths has risen from about 38% in 2004 to more than 63% in 2013. Prescription opioids account for approximately 75% of all prescription drug-related deaths.
Given that data before and after 1999 are not entirely comparable, it still appears that fatalities related to drug overdose have increased steadily since the early 1970s. In 1980, there were an estimated 6100 drug poisoning deaths, a rate of 4.8 per 100,000. During this period, the categorization of drug poisoning deaths did not allow easy distinction between deaths caused by prescription drugs and deaths caused by illicit drugs. Because the category of “opiates” did not distinguish between heroin and prescription opiates, it is difficult to determine how much of the change in opiate-related deaths was attributed to heroin and how much to prescription opioid analgesics.
Beginning in 1999, a new coding protocol was introduced that allowed researchers to better determine which drugs were involved in fatalities by allowing disaggregation of the “narcotics” category into the three largest components: heroin, cocaine, and opioid analgesics. Between 1999 and 2004, the number of annual deaths related to unintentional drug poisoning continued to rise to more than 20,000 in 2004. During this period, the gradual increase in cocaine-related mortality continued, whereas the number of deaths involving heroin stabilized. In contrast, the number of deaths involving prescription opioid analgesics increased from roughly 2900 in 1999 to 7500 in 2004, an increase of 160% in 5 years. By 2004, opioid painkiller deaths numbered more than the total of deaths involving heroin and cocaine combined. Overdose deaths involving prescription opioids quadrupled between 1999 and 2014, from a rate of 1.5 deaths per 100,000 persons to 5.9 deaths per 100,000 persons (more than 165,000 deaths over that period). The group with the highest risk for fatal prescription opioid–related poisoning was white, middle-aged men. As compared to the early 1990s, when overdose rates were lowest in the rural states, the highest mortality rates by 2004 were in New England, the Appalachian states, and the Southwest. In 2015, the four states with the highest drug overdose death rates per 100,000 population were West Virginia (41.5), New Hampshire (34.3), Kentucky (29.9), and Ohio (29.9).
In addition, there was a correlation between state drug poisoning rates and state sales of prescription opioids, with a nearly fourfold difference among states in their use of opioid analgesics. b
b References 97, 98, 436, 493, 521, 521, 666.The number of prescriptions for opioids written in the United States (which prescribes an estimated 80% of all opioids prescribed in the world) more than tripled between 1991 (76 million prescriptions) and 2012 (259 million prescriptions). The amount of opioid prescribed in the United States has been estimated to be the equivalent of 96 mg of morphine per person in 1997, 700 mg per person in 2007, 782 mg of morphine per person in 2010 (the peak), and decreasing gradually to 640 mg of morphine per person in 2015. Despite the decline between 2010 and 2015, the amount in 2015 is still three times as high as the 1999 number. In addition, there is a great deal of variability across the country, with significantly higher rates in counties with a larger percentage of non-Hispanic whites, higher rates of unemployment and Medicaid enrollment, higher prevalence of diabetes and arthritis, and micropolitan (10,000 to 50,000 population) status.
About 80% of individuals prescribed opioids receive less than 100 mg morphine equivalent per day from a single practitioner with another 10% receiving more than 100 mg morphine equivalents per day from a single provider. The remaining 10% of opioid prescription recipients tend to get higher doses (greater than 100 mg morphine equivalents per day) from multiple prescribers. c
c References 60, 98, 99, 229, 233, 320, 321, 340.
Since 2004, overall rates of fatal overdose have continued to rise, reaching a high of 52,404 in 2015. Of this total, 33,091 fatalities were associated with any opioid, 63% of the total drug overdose deaths in 2015. This represented a 6.5% increase from the age-adjusted rate of 13.8 per 100,000 in 2013 to 16.3 per 100,000 in 2015 ( Fig. 54.1 ). Rates of fatal overdose among non-Hispanic white persons has increased from 6.2 per 100,000 in 1999 to 21.1 per 100,000 in 2015. Increases for Hispanic and non-Hispanic black individuals have been much less dramatic. From 2010 to 2015, 30 states and the District of Columbia saw increased fatality rates.
The misuse of prescription opioids has continued to be a major public health problem, with an estimated 91.8 million persons 18 years of age or older (97.5 million including those 12 years of age or older) having used an opioid and 11.5 million (12.5 million including those 12 years of age or older; 4.7% of the US population over the age of 12) reporting nonmedical use in the past year. Of these, 59.9% reported using them without a prescription, with 40.8% reporting that they had obtained them from friends or relatives for free. Of those with a prescription, 22.2% used them in greater amounts than directed on their prescription, 14.6% used them more often than directed, and 13.1% used them longer than directed. Rates were higher in adults who were unemployed, uninsured, and with other behavioral health problems. Although troublingly high, these numbers represent a decrease from a high of 12.65 million in 2006, and a slight increase from 2014, which had seen the lowest number since 2002. Despite this, there were 22,598 fatalities involving opioid analgesics in 2015, up from a previous peak of 16,917 in 2011 ,and following declines in 2012 and 2013. The correlation between increased opioid prescribing and fatal overdose continued to be especially prevalent in rural areas including New England, Appalachia, and the southwest ( Fig. 54.2 ). d
d References 97, 98, 420, 459, 460, 562.
Another study of substance abuse treatment–seeking individuals found that, of individuals who had developed an opioid use disorder and reported that they were first exposed to an opioid through a legitimate opioid prescription, approximately 95% reported that they had used another psychoactive substance (including alcohol, 93%; nicotine, 90%; and marijuana, 87%) prior to or coincident with the initial opioid use. In addition, 78% had used licit or illicit stimulants and 60% had used benzodiazepines with respondents reporting an average of four to five different substances used prior to the initial opioid.
Unfortunately, the relative leveling off in prescription opioid misuse has been accompanied by a steady increase in the number of individuals reporting the use of heroin, with 914,000 reporting past year use in 2014 (approximately 0.3% of the population at or above the age of 12), up from a low of 310,000 in 2003 and a significant jump from 680,000 in 2013. Similar increases were found in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), with 0.33% of the adult population having used heroin in 2001 to 2002 and 1.6% in 2012 to 2013. The current heroin user tends to be slightly older, less urban, more often white, with a more even gender distribution than the typical heroin user of previous decades. The majority of the newer heroin users report being introduced to opioids through medical and nonmedical use of prescription opioids. This increase in heroin use has been accompanied by a fivefold increase in heroin-related fatal overdoses between 2000 (1842 deaths) and 2014 (10,574 deaths) ( Figs. 54.3 and 54.4 ) and an increase of 20.6% just between 2014 and 2015 (12,989 deaths).
Compared to other causes of unintentional injury deaths, poisoning has continued to increase over the past 15 years. In 2014, unintentional poisoning ranked in the top 10 causes of injury death in all age groups beginning at age 9, and was the leading cause for the age groups between 25- and 65-years-old. Further evidence of the huge impact of overdose (primarily opioid but alcohol and other substances as well) comes from an analysis of all-cause mortality in the United States from 1993 to 2013. The study found that, despite decades of steady decreases in mortality rates (by about 2% per year between 1978 and 1998) for all other age and demographic groups, there was an increase in overall mortality rates (by about 0.5% per year) in white non-Hispanics between 45- and 55-years-old. The majority of this increase was due to poisoning, although deaths from suicide and chronic liver disease also increased. This effect was sufficiently significant to lower the life expectancy for this age group of white non-Hispanics by 0.1 years between 2013 and 2014. A similar rise in mortality rates was not seen in other industrialized countries, including France, Germany, the United Kingdom, Canada, Australia, and Sweden.
Another indication of the growth of the problem related to poisoning fatalities can be seen in the comparison to fatalities related to car crashes. Once the leading cause of accidental fatalities, automobile crash fatalities have gradually declined since the 1970s. As overdose fatalities gradually increased, the numbers of related deaths intersected in 2008, at approximately 38,000 deaths, and have continued to move in opposite directions ever since ( Fig. 54.5 ). Complicating these statistics, however, a six-state study of fatally injured car drivers found that the prevalence of prescription opioids detected in postmortem toxicological testing increased from 1% in 1995 to 7.2% in 2015.
Several specific situations deserve special attention. Overdose involving methadone has had a unique epidemiology, which has been fairly closely tied to the use of methadone for the treatment of pain. Methadone-related overdose deaths increased 22.1% per year between 2002 and 2006, and then declined approximately 6.5% per year between 2007 and 2014 (39% total decline). The percentage of drug overdose deaths involving methadone also decreased from 12% in 2010 to 6% in 2015. This closely paralleled the amount of methadone prescribed, which increased by 25.1% per year between 2002 and 2006 and declined 3.2% per year from 2006 to 2013 ( Figs. 54.2 and 54.6 ) . These rates peaked between 2005 and 2007 in all age groups younger than 55 years, but continued to increase in 55- to 64-year-olds. The declines were seen in all racial/ethnic groups and in males and females, although the rate of decline was slower among females. The decline was also seen despite the fact that more than 100,000 individuals initiated methadone for the treatment of opioid use disorder during that period.
Another unique situation involves illicitly manufactured fentanyl (IMF), also known as nonpharmaceutical fentanyl (NPF), or its analogs (acetyl fentanyl, alpha-methylfentanyl, carfentanil, 3-methylfentanyl, and others) sold as heroin (often branded as more pure heroin under such names as China White, Tango & Cash, and TNT). Earlier epidemics were generally constrained to smaller areas starting in the late 1970s, with an outbreak (primarily in California) with at least 112 related deaths. Over the next decade, sporadic clusters of fentanyl-associated fatalities were encountered in the mid-Atlantic region, with 16 deaths associated with the use of heroin contaminated with 3-methylfentanyl, in Pittsburgh 1986–1988 and 20 deaths associated with illicit fentanyl use in Baltimore in 1992. From 2005 to 2007, a larger outbreak (more than 1000 fatalities) occurred over multiple metropolitan areas (Baltimore, Camden, Chicago, Detroit, Philadelphia, St. Louis, and Wilmington) as well as suburban and rural areas of Delaware, Illinois, Kentucky, Maine, Maryland, Massachusetts, Michigan, New Jersey, New Hampshire, Ohio, Pennsylvania, and Virginia. When the source of that NPF was traced to a single lab in Mexico, which was dismantled, the outbreak came to an end.
The largest epidemic of NPF began in late 2013 in Canada and various parts of the United States including the Midwest, Southeast, mid-Atlantic, and New England, and other parts of the world including Eastern Europe and Scandinavia, e
e References 22, 113, 220, 334, 608, 668.with significant increases in law enforcement confiscation of illicit fentanyl and related overdose fatalities f
f References 226, 276, 293, 484, 530, 608.( Figs. 54.4 and 54.7 ) . Between 2014 and 2015, the death rate from synthetic opioids other than methadone (primarily fentanyl and its analogues) increased 72%. Unlike the previous epidemics, this one saw both fentanyl-laced heroin as well as counterfeit pharmaceutical pills (oxycodone, Xanax, Norco), g
g References 222, 223, 265, 569, 631, 678.which contained NPF, often combined with a benzodiazepine, thereby increasing the potential lethality. Also new in this epidemic was the presence of carfentanil, an analogue 100 times more potent than fentanyl, which is used by large animal veterinarians. Concerns over the relative danger of these analogues have lead the US Drug Enforcement Administration (DEA) and many local jurisdictions to implement enhanced precautions for first responders interacting with individuals and crime scenes that may have been exposed to fentanyl analogues. In addition, this epidemic also saw the emergence of some novel opioids (AH-7921, MT-45, U-47700, and others) related to overdose fatalities in Canada, the United States, and Europe. h
h References 17, 34, 209, 225, 236, 359, 374, 463, 472, 561.
Numbers for nonfatal overdose are less reliable than those for fatalities. There is much more room for variability in coding. A heroin overdose may be coded as “respiratory depression” or “altered mental status” and “Heroin Use Disorder” and not detected as a “poisoning.” In addition, various databases may capture different components of the issue. The Drug Abuse Warning Network (DAWN), most recently overseen by SAMHSA and the Center for Behavioral Health Statistics and Quality (CBHSQ), collected information on substance-related emergency department (ED) admissions in various areas of the country from 1972, until it was discontinued in 2011. Based on their data, it can sometimes be difficult to ascertain how many visits were actually for an overdose, as they also captured “adverse reaction to a pharmaceutical” and other substance-related admissions. To add to the difficulty, the United States continued to use the ICD-9 for medical coding until October, 2015, when much of the rest of the world had been using ICD-10 for more than a decade.
Despite the limitations in data, unintentional poisoning ranks in the top 10 causes of nonfatal injury treated in an ED for ages 1–4 and all age groups over 15 years old in the United States. Earlier studies showed hospitalizations for heroin overdose increasing 69% between 1993 and 2006. In 2011, DAWN reported roughly 5 million total ED visits related to drugs (1626 visits/100,000 population) a 100% increase since 2004. Overall, medical emergencies related to nonmedical use of pharmaceuticals increased 132% in the period from 2004 to 2011 (1.2 million visits in 2011), with prescription opiate/opioid involvement rising 183% (approximately 348,000 visits in 2011). The specific drugs with the highest number of visits were oxycodone, hydrocodone, and methadone with 151,218, 82,480, and 66,870 visits, respectively. There were 258,482 visits related to heroin use, which constituted 83 visits/100,000 population, not a statistically significant rise from 2004. Studies using other data sources similarly found ED visits involving misuse/abuse of prescription opioids increased 153% between 2004 and 2011, and hospitalizations related to overdose on prescription opioid use increased as well.
Another large, national study used data from the Nationwide Inpatient Sample (NIS) Healthcare Cost Utilization Project (HCUP) in the Agency for Healthcare Research and Quality collected from 1993 to 2009. As these data only captured individuals who were admitted to the hospital, it is limited, in that it looks at only more severe cases. The authors looked at heroin-related overdoses (HODs) and prescription opioid–related overdoses (PODs) and found that PODs increased steadily over the study period. The highest increases were in white, middle-aged women, with rates of increase for whites more than double that for African Americans or Hispanics. Overall HODs increased from 1993 to 1999 but leveled off and decreased until they began to increase again around 2007. Since 1995, rates for African Americans and Hispanics decreased (with the exception of an uptick in 2009), whereas those for whites showed a gradual increase through most of the period with a significant increase beginning in 2007, surpassing African Americans for the first time in 2008. Yet another study using HCUP data found that the rate of hospital stays involving opioid overuse (which included treatment for opioid abuse and dependence in addition to overdose) among adults increased more than 150% between 1993 and 2012 when there were 709,500 opioid-related hospital stays representing a rate of 295.6 stays per 100,000 population.
Looking at hospitalizations related to prescription opioids versus heroin using the NIS between 2000 and 2014, one study found significant geographic variation with PODs highest in the South and lowest in the Northeast and heroin-related overdoses highest in the Northeast and Midwest. Between 2012 and 2014, POD hospitalizations decreased in all areas of the United States except New England, whereas heroin-related hospitalizations increased in all areas of the country.
The preponderance of ED substance-related visits for children 5 years of age or younger involve accidental ingestions (which were recorded separately by DAWN). On average, more than 3200 children younger than 5 years of age are seen in the ED each year due to accidental opioid overdose. In 2011, of a total of 113,634 visits, over 77,000 involved children in this age range. Pain relievers (including acetaminophen, aspirin, and nonsteroidal anti-inflammatories) were the most common class of drugs involved in accidental ingestion among children 5 years of age or younger, with 6.7% of visits related to opioids. Although overall visits for accidental ingestion by patients 5 years of age or younger were stable from 2004 to 2011, visits involving narcotic pain relievers increased 225% (from 1596 to 5187 per year).
As mentioned above, the hallmark of opioid overdose is constricted (“pinpoint”) pupils, altered level of consciousness, and respiratory depression. This triad has been found to have 92% sensitivity and 76% specificity for heroin overdose. The amount of a given opioid needed to produce these effects is dependent on tolerance, which is a complex interaction of single-cell and neuronal network-level alterations. Tolerance develops at different rates and to varied degrees to various clinical aspects of opioid intoxication, with that to respiratory depression developing slower and to a less complete extent than some other effects. Tolerance is also affected by nonpharmacological factors such as the environment in which the opioid is used. Animal studies and epidemiological data support the finding that fatal overdose is more likely when the opioid is used in a novel setting as compared to a setting in which the drug has previously been used.
The pupillary constriction, miosis, appears to be caused by parasympathetic excitation. This may not occur with overdose on meperidine, propoxyphene, and pentazocine. Altered mental status may vary from mild sedation to stupor and coma. Gag reflex may also be suppressed. In addition to the typical, centrally mediated respiratory depression (discussed below), severe opioid overdose can also produce noncardiogenic pulmonary edema (NCPE) and bronchospasm. This typically presents with frothy, pink secretions and rales. In nontolerant individuals, opioid use can also cause nausea and vomiting. Rarely, overdose may also produce a centrally mediated muscle rigidity of the chest and abdominal wall. Rhabdomyolysis may be seen as a result of prolonged motionlessness and compression of muscle, typically in the context of coma. Hypotension, acidosis and dehydration may further increase the risk of this. There are also reports of rhabdomyolysis occurring in the absence of coma suggesting that it may, rarely, be a direct toxic effect or allergic reaction to heroin or an adulterant.
Respiratory depression (decreased respiratory rate and effort, hypoxia, and hypercarbia) is the main cause of death due to opioid overdose, although cardiac arrest and arrhythmia induced by anoxia can also occur. The mechanisms through which μ-opioid agonists suppress respiration are complex and not yet fully understood in humans. Opioid receptors are found in various central and peripheral areas including the pons and ventrolateral medulla in the brainstem; the insula, thalamus, and anterior cingulate cortex higher in the brain; the carotid bodies and vagus nerve; as well as in the epithelial, submucosal, and muscular layers of the airways themselves. It appears that the strongest effect on respiration by μ-opioid receptor agonists is mediated through a decrease in ventilatory response to CO 2 through action on the respiratory centers in the brainstem. This results in a disruption of the respiratory pattern with prolongation of inspiration and, at higher opioid doses, changes in tidal volume.
The mechanism by which benzodiazepines might worsen respiratory depression associated with opioid use is not well described. Benzodiazepines bind to the γ2 subunit of the γ-aminobutyric acid A receptor (GABA A ) and have no activity at the μ-opioid receptor. There is some evidence that the GABAergic and opioidergic systems are coexpressed in several areas of the rat brain and that there is anatomical overlap in receptors in various brain regions. It has been postulated that benzodiazepines may also have effects on signal transduction and second messenger systems involved with μ-opioid receptor regulation. It is generally felt that any potential effect of benzodiazepines on the opioid system is not primarily pharmacodynamic in nature.
Certain opioids have specific physiological effects that may contribute to the clinical picture in overdoses. Methadone and the related l -alpha-acetylmethadol (LAAM; not currently commercially available) are fairly unique among opioids in their potential to cause QTc prolongation and resultant torsade de pointes. The true prevalence of this QTc prolongation and torsade de pointes associated with methadone and the implication for methadone-related overdose are not clear.
Seizures have rarely been reported with morphine, fentanyl, sufentanil, alfentanil, and meperidine. Most of these have been reported only in conjunction with general anesthesia and were not confirmed with simultaneous electroencephalography (EEG) readings. It is possible that, what appears to be seizure activity may actually be rigidity, myoclonic jerks, and other nonepileptic movements. i
i References 63, 89, 392, 462, 549, 570, 644.Meperidine, however, has been associated with seizures, primarily due to the metabolite normeperidine. The risk of this is increased in the presence of renal impairment (which reduces the clearance of normeperidine) or concomitant use of medications that induce microsomal liver enzymes (through increased conversion of meperidine to normeperidine). j
j References 294, 318, 338, 361, 437, 636.
Fentanyl and its analogs (e.g., acetylfentanyl, alfentanil, sufentanil) appear to be able to cause skeletal muscle rigidity (especially chest wall, sometimes referred to as “wooden chest”). It appears to be more common with rapid intravenous administration, although it is not dose dependent. Onset may be rapid and produce an inability to ventilate. It may be related to noradrenergic activation of spinal tracts associated with the locus coeruleus. Because the chest wall rigidity is not discernible after death, the role of this phenomenon in fatal overdose is not clear.
Buprenorphine, a partial μ-opioid agonist that has been associated with a significantly lower risk of overdose, needs special consideration when discussing opioid-induced respiratory effects. At lower doses, buprenorphine produces CNS and respiratory depression in a dose-dependent manner. However, as the dose is increased, a plateau is reached at which these effects no longer continue to increase, making respiratory depression less likely than with other opioids. The ceiling effect on respiratory depression may be more evident in habitual users than in opioid naïve individuals, in whom respiratory depression may occur before reaching the ceiling. k
k References 155, 164, 311, 445, 720, 721.Although the exact mechanism for this is not entirely clear, it appears that buprenorphine alone generally leads to mild decreases in PaO 2 with minimal increases in PaCO 2 as compared to the significant increase in PaCO 2 generally observed with full opioid agonists.
Increased respiratory depression associated with the combination of buprenorphine and benzodiazepines has been reported in the anesthesia and animal literature since the mid-1980s. This effect is generally found to be most pronounced for flunitrazepam, as compared to other benzodiazepines, with a relatively more pronounced effect on respiratory depression being observed when flunitrazepam is combined with buprenorphine as compared to some other opioids. In addition, buprenorphine’s main active N -dealkylated metabolite, norbuprenorphine, appears to produce considerably more potent respiratory depression than buprenorphine, and buprenorphine itself may act as a protectant against norbuprenorphine’s effects in rodents.
Over the past several decades, multiple studies have attempted to determine risk factors for overdose, both nonfatal and fatal. l
l References 24, 171, 174, 175, 178, 179, 566, 731.Although there is some variation over time and across different areas of the world, there is a fair amount of consistency in many of these factors ( Box 54.3 ).
Substance Usage Factors
Prior nonfatal overdose
Recent reduction of tolerance
Concomitant use of opioids with CNS depressant substances
Use in a novel environment or alone
Higher or variable heroin purity
Medical History Factors
Significant medical problems (especially hepatic and respiratory)
Significant mental health problems (especially depression and anxiety)
History of other substance use disorder
Prescription of opioids for pain (especially higher doses and longer-acting formulations)
Risk Related to Substance Use Factors
A history of prior overdose m
m References 46, 59, 93, 139, 145, 174, 177, 178, 253, 254, 261, 375, 594, 619, 723.is one of the strongest predictors of subsequent overdose. In addition, the risk of fatality appears to increase with each prior nonfatal overdose.
A history of opioid dependence with reduced tolerance following medical detoxification, n
n References 323, 422, 423, 450, 506, 541, 550, 584, 623, 637, 704, 707, 724, 731.release from incarceration (especially in the first 1–2 weeks), o
o References 15, 49, 50, 53, 52, 54, 139, 196, 252, 253, 302, 350, 364, 384, 450, 464, 559, 586, 597, 617, 714.cessation of treatment (especially in the first month), p
p References 136, 151, 152, 154, 176, 192, 197, 248, 300, 301.or self-imposed abstinence is also a very strong predictor of overdose. One study found that a total of 36 of 276 patients died after discharge from residential substance abuse treatment during the 8-year study period. Two-thirds of these deaths were classified as opiate overdose deaths, with six of these occurring within the first 4 weeks following discharge from the program, yielding an unadjusted excess mortality of 15.7 (rate ratio) in this period. There was no significant association between time in treatment and mortality after discharge, and no baseline characteristics correlated significantly with elevated mortality shortly after discharge. Another study looking at more than 32,000 patients in California seeking methadone maintenance treatment over a 5-year period, found that the highest mortality risk occurred during the 2 weeks immediately following discontinuation of treatment, with a rate approximately 30 times that expected in the general population. Yet another study found that victims of fatal overdose had significantly lower concentrations of morphine in hair samples compared to active heroin users, although their morphine levels were not significantly different than those in former heroin users who had been abstaining for several months prior to the study.
Another highly correlated factor is the concomitant use of opioids with CNS depressant substances , especially alcohol, benzodiazepines, and barbiturates. q
q References 15, 33, 52, 53,116, 117, 118, 139, 149, 228, 305, 320, 322, 327, 329, 358, 422, 424, 490, 526, 565, 614, 653, 688, 690, 691, 692, 711, 731, 728, 734.The relationship with alcohol use is not entirely straight forward, with some studies of fatalities showing higher alcohol levels correlated with lower morphine and 6-monoacetylmorphine (6-MAM) blood levels but others finding no significant correlation. One study actually found that complete abstinence from alcohol was a risk factor for opioid overdose fatality, possibly because individuals in that study who were not using alcohol tended to have higher rates of daily heroin use. Studies looking at blood levels of sedatives and opioids in fatal overdoses have not demonstrated a clear relationship.
Another important factor is use in a novel environment, r
r References 172, 178, 289, 313, 329, 600, 602, 603.likely related to a decrease in tolerance, which appears to be classically conditioned through environmental cues. This has also been reported in non–substance-abusing individuals who use opioids. Related to this, being homeless and using alone in secluded areas, often abandoned buildings, increases the risk of overdose and fatal overdose. At least part of the increased risk can be explained by the lack of others to directly administer or seek medical assistance. Possibly related, several studies have shown that rushing the use of heroin, because of fear of being caught, may also raise the risk for overdose.
Higher or variable heroin purity or “cut” is another important risk factor. Darke et al. measured the range and average heroin purity over a 2-year period and found that both were independent predictors of fatal overdoses and accounted for approximately 40% of the total variance. Related to the purity of heroin, the cost of a gram of pure heroin (which, in the United States has decreased from $2690 in 1982 to $1237 in 1992, and to $552 in 2002 and $465 in 2012) has also been shown to be correlated with overdose, with a 2.9% increase in the number of hospitalizations for overdose for every $100 decrease in the per gram price. In addition, heroin adulterated/substituted with other opioids , especially fentanyl (or its analogs: acetyl fentanyl, alpha-methylfentanyl, carfentanil, 3-methylfentanyl, and others) also appears to raise the risk for nonfatal and fatal overdose. s
s References 4, 57, 111, 113, 220, 257, 336, 385, 561, 562, 712.
Some studies have shown a higher risk for overdose with intravenous route of administration of opioids, whereas others have not found a significant correlation.
Risk Related to Medical History Factors
The presence of other significant medical conditions (HIV, liver, or lung disease) t
t References 305, 307, 641, 675, 685, 690, 691, 731, 734.appears to increase the risk for overdose and fatality. Respiratory compromise related to conditions such as sleep apnea may convey a particularly increased risk .
Opioid users with other psychiatric conditions (especially depression and anxiety) u
u References 29, 82, 120, 229, 422, 604, 605, 630, 651, 690, 691, 693, 707, 726.appear to be at higher risk for accidental overdose. Prior suicide attempts have also been associated with accidental overdose in some but not all studies. One study found that benzodiazepine users who did not initially use opioids were more likely than nonusers of benzodiazepines to later use opioids.
A history of other substance use disorder is generally associated with prescription opioid overdose deaths—as is poor compliance with or difficulty entering substance abuse treatment , v
v References 168, 169, 171, 179, 248, 690, 691, 730.although in a 5-year study of 155,434 patients treated with opioids in the United States by the Veterans Health Administration (VA), 60% of opioid-induced fatalities occurred in patients who did not have a history of a diagnosis of a substance use disorder.
People who are prescribed prescription opioids for pain , in particular those on higher doses, on long-acting preparations, and with higher reports of pain, appear to have an increased risk for overdose. w
w References 60, 61, 229, 228, 282, 357, 393, 455, 527, 552, 707, 709.The study by Dunn et al. found that, as prescription opioid dose escalates, the risk of prescription opioid overdose increases. Compared to persons taking opioid doses from 1–19 mg morphine-equivalent daily dose (MEDD), those persons taking 20–49 MEDD, 50–99 MEDD, and >100 MEDD had a 1.2-, 3-, and 11-fold increased risk of prescription opioid overdose, respectively. However, various studies have also found that many individuals who overdose are not chronic, daily opioid users and are not on higher doses (more than 100 mg morphine equivalents/day). Another study found that 10%–20% of people prescribed opioids received less than 100 mg MEDD from a single provider, 40% received more than 100 mg MEDD from a single provider, and 40% received more than 100 mg MEDD from multiple providers, but that 60% of all overdose fatalities from prescription opioids occurred in the 90% of the population who obtained their opioids from a single provider who was prescribing within guidelines.
Risk Related to Demographic Factors
Certain demographic factors have been associated with overdose, although these factors vary in different parts of the world and over time. Males have higher rates of overdose in most studies, x
x References 24,130, 357, 521, 521, 562, 690.although there is evidence that rates in women have been increasing at a relatively faster rate. Although all age groups beginning in adolescence are significantly impacted, higher rates have been reported in middle-age (variously defined but generally 35–54 years of age). y
y References 237, 282, 521, 521, 562, 658.Lower levels of education are also associated with overdose with higher rates in individuals who did not graduate high school.
Racial/ethnic characteristics appear to vary considerably over time and geography and are related to local heroin and prescription opioid use patterns in a given area. In the United States, through the 1980s and 1990s, heroin use tended to be concentrated in inner city neighborhoods with minority populations. During this period, overdose deaths were more common among African Americans and other minority groups. Various studies have reported increased risk in minorities: aboriginal individuals in Australia ; First Nations individuals in Canada ; non-Hispanic blacks and Hispanics in New York City ; and American Indian/Alaska Natives in the United States. However, non-Hispanic whites have consistently had higher rates of overdose from prescription opioids and, as misuse of prescription opioids ,began to rise in the mid- to late-1990s, the proportion of opioid-related overdoses in non-Hispanic whites also rose. Beginning around 2010, as rates of heroin use began to increase in areas previously associated with prescription opioid use, the rates of heroin-related overdose began to rise significantly in non-Hispanic whites.
Although heroin use and related overdose has been traditionally associated with urban settings, increasingly, rural areas in the United States (especially the Appalachian region, Great Lakes, Southwest and New England) and other countries have seen a marked increase in overdose, initially related to an increase in prescription opioid use from the late 1999s to around 2010, with a switch to increased overdose related to heroin. z
z References 76, 130, 234, 237, 320, 322, 327, 436, 460, 523, 560, 616, 718.Whether urban or rural overdose rates, a common finding is an association of poverty with increased overdose rates. In a study of fatal overdose in New York City in 1996, deaths were more likely to occur in neighborhoods in the top decile of income inequality than in more equitable neighborhoods. This relationship seemed to be partially explained by the level of disorder in the environment. Another study in New York City found that, compared with other unintentional, nonoverdose deaths, prescription opioid overdose deaths were more likely to occur in lower-income and fragmented neighborhoods, but when compared with heroin fatalities, they were more likely to occur in higher-income, less-fragmented neighborhoods. Similarly, in rural Kentucky, fatality rates from prescription opioid overdose increased with the amount of poverty in the decedent’s county of residence. A similar pattern has been seen in other countries as well.
Other risk factors for overdose that have been reported but with lower levels of support in the literature include: household members with a prescription for opioids, higher levels of dependence, witnessing a family member overdose, nicotine use, and presence of tattoos.
There have also been a few studies that have looked at the A118G single nucleotide polymorphism (SNP) of the mu-opioid receptor gene ( OPRM1 ), which is found in about 5%–30% of the general population and is associated with variability in nociception and opioid sensitivity. It appears that this allele is associated with worse clinical severity in overdose.
Risk Factors for Iatrogenic Overdose
Although opioid-induced respiratory depression is uncommon in the typical perioperative patient, there are several patient groups that are at higher risk: patients with sleep apnea, the morbidly obese, premature babies, the elderly, and the otherwise very ill. There may also be some increased risk with patient-controlled analgesia (PCA), where studies have shown significant respiratory depression in 0.5%–2% of patients. The use of very high-potency opioids such as remifentanil may also increase this risk. A study looking at adverse events related to opioids in the ED setting found that errors included lack of attention to chronic health conditions that could predispose an individual to an opioid-related adverse event, failure to adjust opioid dosing in the elderly and for hepatic or renal impairment, concurrent use of multiple doses and routes of administration of opioids, coadministration of opioids with other sedating medications, and systems-based problems with patient handoffs and pharmacy oversight.
Other data from MEDMARX (a national medication error reporting database) found that medical provider mistakes contributed significantly to opioid overdoses within the hospital. These overdoses occurred most often with hydromorphone, meperidine, fentanyl, and oxycodone. These errors include the interchanging of oral or intramuscular and intravenous formulations, interchanging of immediate release and extended release formulations, the incorrect administration time for intravenous drips (daily morphine dose being administered over 1 hour instead of 24 hours), and error in PCA settings. Other studies have shown significant adverse events related to improper use of opioid conversion tables, limitations in these tables themselves and prescription guidelines that are not consistent on opioid rotation procedures.
Methadone prescribed for pain has been found to be particularly associated with fatal overdose. In addition to patient behaviors (such as concomitant use of sedative-hypnotics or nonmedical use of the prescribed drug), practitioner errors can contribute to this. These errors include overreliance on published equianalgesic conversion tables when converting from another opioid to methadone, initiation of methadone at too high a dose, titration of dose too rapidly, unfamiliarity with the unique pharmacokinetics and pharmacodynamics of methadone, inadequate identification and monitoring of patients at risk for substance misuse, failure to appreciate the incomplete tolerance to respiratory depression associated with chronic use of other opioids, and lack of education related to risk of QT interval prolongation and sleep apnea. aa
aa References 14, 16, 266, 280, 377, 415, 692, 700.
Methadone dispensed for the treatment of opioid use disorder has also been associated with nonfatal and fatal overdose, bb
bb References 32, 85–87, 136, 232, 369, 461, 529, 613, 729, 730.with many of the deaths occurring in the first 1–4 weeks of treatment. cc
cc References 151, 152, 154, 192, 197, 248, 369.Although many of these involve the use of concomitant substances, it also appears that a good number of the deaths are related to the methadone dose being escalated too rapidly, typically as a result of an underappreciation of methadone’s long elimination half-life, extensive bioavailability, tendency to accumulate with continuous dosing, and reduced elimination, as well as the role of underlying sleep apnea, QT-prolongation, and other substance use. dd
dd References 85, 86, 151, 152, 613, 711.One Australian study of patients on methadone maintenance treatment (MMT) found that 238 patients died between 1990 and 1995, 21% in the first week of treatment. Eighty-eight percent of these patients had other substances in their system. Only 10% of the patients who died in the first week of MMT tested positive for methadone alone. There is also evidence that this may vary by setting, with lower rates in certain settings such as Norway, where all induction is done in specialty clinics, as compared to higher overdose rates in the United Kingdom and Australia, where induction is often done in the primary care setting.
Induction of patients onto buprenorphine or buprenorphine/naloxone appears to be much safer with significantly reduced risk for overdose compared to methadone. One study of more than 19 million prescriptions over a 6-year period in the United Kingdom determined that buprenorphine is six times safer than methadone in terms of overdose risk.
As with many public health issues, prevention of overdose can be thought of in terms of (1) Primary prevention , focused on the reduction of use or misuse of opioids; (2) Secondary prevention , focused on the reduction of overdose; and (3) Tertiary prevention , focused on the reduction of deaths from overdose. Across these categories, there are efforts focused both on the individual patient and entire populations.
There is significant evidence that increased availability of prescription opioids has led to increased misuse and resultant overdose. In addition, a relatively small number of patients appear to account for a disproportionate share of prescriptions. Similarly, some research shows that a relatively small number of physicians are responsible for disproportionate numbers of opioid prescriptions. As a result of these factors, a number of efforts have focused on reducing the prescribing, obtaining, use, and misuse of these medications. Although some efforts have been in existence for decades, there has been a significant increase in local, state, and federal efforts since the early to mid-2000s, with even further increase in 2014–2016. ee
ee References 18, 200, 279, 485, 486, 497, 499, 669.In 2011, The Office of National Drug Control Policy released Epidemic: Responding To America’s Prescription Drug Abuse Crisis , which outlined a plan to reduce nonmedical use through: (1) Education, (2) Tracking and Monitoring, (3) Proper Medication Disposal, and (4) Enforcement. Despite these various efforts, it is difficult to attribute any observed benefits to a given intervention as, in many cases, multiple interventions were in effect simultaneously. ff
ff References 108, 110, 211, 212, 279, 349, 352, 406, 631.Reductions in overdose deaths related to methadone provide an example of the impact of multiple prevention efforts ( Box 54.4 ; see Fig. 54.6 )
2005—SAMHSA released Treatment Improvement Protocol (TIP) 43 “Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs.” Provided guidance on the safe use of methadone for the treatment of opioid use disorder
2006—FDA alert – “Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat.” Warned about the risks of death, overdose, and cardiac arrhythmias when prescribing methadone for pain; revised the recommended dosing interval from every 3–4 hours to every 8–12 hours
2007—SAMHSA released “Guidelines for the Accreditation of Opioid Treatment Programs.” Provided further recommendations for ensuring safe use of methadone in treatment programs mid-2000s (ongoing). Physician/Practitioner Clinical Support System (PCSS), funded by SAMHSA; coordinated by AAAP, AOAAM, APA, and ASAM, provided mentoring and continuing medical education focused on the use of medication-assisted treatment (initially buprenorphine but later including methadone) and the use of opioids in the management of pain (with a strong focus on methadone)
Late 2000s (ongoing)—Opioid Treatment Program Clinical Staff Education, funded by SAMHSA, provided in-person trainings across the country on the safe use of methadone through best practices; provided technical assistance to programs providing methadone treatment
2008—Restriction of 40 mg methadone formulation to opioid use disorder treatment programs; coordinated effort of DEA and methadone manufacturers, attempted to better determine the source of diverted methadone, and attempted to control the availability and diversion of higher dosage form
2009—Recommendations for substantial reduction of the calculated dose on conventional equianalgesic conversion tables when switching from another opioid to methadone.
2011—SAMHSA issued a document requesting that OTPs check prescription drug monitoring databases; increased importance because federal confidentiality law 42-CFR Part 2 prohibits the recording of methadone dispensed from an OTP into a state’s PDMP
2012—REMS for methadone required by FDA
2013—States began removing methadone from preferred drug list for treatment of pain ; approximately one-third had done so by late 2016
2013—ASAM released a consensus statement on safe methadone induction and stabilization
2014—APS issued a clinical practice guideline on the use of methadone for pain
2014—AAPM recommended against methadone as a preferred analgesic
2015—SAMHSA released a revision of their “Federal Guidelines for Opioid Treatment Programs”; provided further recommendations on improving safety when dispensing methadone
2016—CDC published “CDC Guideline for Prescribing Opioids for Chronic Pain” ; recommended that methadone not be the first choice for a long-acting opioid and recommended that only clinicians who are familiar with methadone’s unique risk profile and are prepared to educate and closely monitor their patients consider prescribing methadone for pain
2016—CMS issued recommendations on best practices for addressing prescription opioid addiction and overdose ; focused on steps insurers can take to reduce harms associated with methadone use for pain
AAAP, American Academy of Addiction Psychiatry; AAPM, American Academy of Pain Medicine; AOAAM, American Osteopathic Academy of Addiction Medicine; APA, American Psychiatric Association; APS, American Pain Society; ASAM, American Society of Addiction Medicine; CDC, Centers for Disease Control and Prevention; CMS, Centers for Medicare & Medicaid Services; FDA, US Food and Drug Administration; OTP, Opioid Treatment Program; REMS, Risk Evaluation and Mitigation Strategies; SAMHSA, Substance Abuse and Mental Health Services Administration.
It is also important to point out that the success of many primary prevention initiatives in reducing the availability and misuse of prescription opioids may have played a role in the increased use of heroin and related overdose seen in the United States beginning around 2010, gg
gg References 127, 130, 146, 147, 149, 180, 407.although this is far from a universally held belief. hh
hh References 92, 146, 147, 211, 212, 326, 353, 357.Similarly, it is not clear how many chronic pain patients are negatively affected by these same efforts as they have increased difficulty accessing opioids for appropriate use.
Various initiatives to educate physicians and other health care providers have focused on education about evidence-based pain management, prescribing of controlled substances, and identification of substance misuse and use disorders. Although generally believed to be effective at increasing knowledge, the evidence as to whether or not there are actual improvements in pain treatment or prescribing practices with provider education is limited. ii
ii References 153, 158, 235, 317, 360, 413, 417, 656, 664, 727.Some states require such education as part of the medical license renewal process, and there have been recommendations to include such education as a part of DEA registration renewal.
Providers across the spectrum of medical practice continue to endorse insufficient education in pain or pain management. The Office of National Drug Control Policy recognized the need for evidence-based education for providers to identify, prevent, and treat substance use disorders and safe prescribing for pain. Partnered with National Institute on Drug Abuse (NIDA), the federal government released NIDAMED continuing medical education (CME) modules on opioid use disorders and pain management in 2012. In the 2 years after its debut, more than 90,000 providers had accessed and completed these modules. At the state level as of 2017, 23 states and D.C. have developed requirements by statute, regulation, or board guidelines mandating continuing education in prescribing controlled substances, pain management, and identifying substance use disorders. The 2011 Prescription Drug Abuse Prevention plan called for congressional amendment of federal law to require prescribers requesting DEA registration to participate in mandatory training on responsible opioid prescribing practices as a precondition to receiving a DEA number but, as of 2017, participation in continuing education remains voluntary.
In 2009, the Food and D.ug Administration (FDA) announced a Risk Evaluation and Mitigation Strategy (REMS) for extended-release (ER) and long-acting (LA) opioid medications. This action required the producers of opioid medications to self-fund CME programming to prescribers at little or no cost based on a predetermined educational blueprint developed by the FDA ( Box 54.5 )
General information for safe opioid prescribing
Patient selection and assessment
Determine goal of therapy
Assessment of the risk of abuse, including history of substance abuse and serious mental illness
When relevant, determining if patient is opioid tolerant
Considerations when prescribing opioids
Pharmacokinetics and potential for overdose
Addiction, abuse, and misuse
Intentional abuse by patient or household contacts
Interactions with other medications/substances
Managing patients taking opioids
Establishing goals for treatment and evaluating pain control
Use of Patient Provider Agreements (PPAs)
Adherence to a treatment plan
Recognizing aberrant behavior
Managing adverse events
Initiating and modifying dosing of opioids for chronic pain
As first opioid
Converting from one opioid to another
Converting from immediate-release to extended-release and long-acting products
Converting from one extended-release and long-acting product to another
How to deal with missed doses
Reassessment over time
Monitoring patients for misuse and abuse
Utilization of prescription monitoring programs to identify potential abuse
Understanding the role of drug testing
Screening and referral for substance abuse treatment
How to discontinue opioid therapy when it is not needed any longer
Patient counseling a.Information about prescribed opioid
How to take opioid properly
Adherence to dosing regimen
Risk from breaking, chewing, crushing certain products
Symptoms of overdose
Reporting adverse effects
Concomitant use of other CNS depressants, alcohol, or illegal drugs
Discontinuation of opioid
Risks associated with sharing, i.e., overdose prevention
Proper storage in the household
Avoiding accidental exposure
Avoiding unsafe exposure by preventing theft and proper disposal
Purpose and content of PPA
ER/LA, Extended-release and long-acting; FDA, US Food and Drug Administration; REMS, Risk Evaluation and Mitigation Strategy.
Education about pain management in American medical schools has traditionally been very limited, with an average of less than 10 hours dedicated to the topic. In 2016, the Association of American Medical Colleges (AAMC) released a statement committing to continued curriculum development and research efforts to elucidate addiction, pain, the brain, and behavior. More than 70 medical schools signed this statement in solidarity.
In March of 2016, the CDC released official guidelines for prescribing opioids for chronic pain, targeting primary care providers in the outpatient setting who treat patients with chronic, noncancer pain. Existing guidelines developed by various professional associations and federal agencies shared common components such as dosing thresholds and risk mitigation strategies. The guidelines were designed to assist with (1) determining when to initiate or continue opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care; (2) opioid selection, dosage, duration, follow-up, and discontinuation; and (3) assessment of risk and addressing harms of opioid use.
In the summer of 2016, as a part of his “Turn The TideRx” initiative, the Surgeon General mailed a letter to over 2.3 million health care professionals urging them to pledge to (1) educate themselves on how to treat pain safely and effectively, (2) screen their patients for opioid use disorders (and refer for evidence-based treatment if present), and (3) talk about and treat addiction as a chronic illness, not a moral failing. A companion website was created with various resources: turnthetiderx.org/
Implementation of prescribing guidelines is another means by which inappropriate prescribing of opioids can be reduced. National medical specialty organizations (such as the American College of Emergency Physicians and American Pain Society), large health care systems (such as the Veterans Administration/Department of Defense), health insurance companies, local and state health care agencies (New York City; Washington State) and hospitals have all issued clinical practice guidelines to improve quality of care and reduce negative outcomes through use of evidence-based practices. This has been done for specific drugs as well as for the prescribing of all opioids. Prescribing guidelines typically include limits on medications and formulations, initiation and titration of dose, maximum dose, drug switching, screening tools to assess risk for misuse, written treatment agreements, urine drug testing, and pill counts.
Evidence that these recommendations can impact prescribing patterns is somewhat limited, but some studies have shown reductions in number of patients managed with high-dose opioids, reductions in daily doses of prescribed opioids, increased percentages of providers reporting that they avoid using long-acting opioids for acute pain or in combination with benzodiazepines, and increases in use of drug screening by physicians. jj
jj References 138, 275, 277, 278, 342, 382, 468, 471, 493, 540, 587.Effects on actual overdoses are difficult to determine but several studies have reported decreased deaths related to the use of prescribing guidelines.
Prescription Drug Monitoring Programs
A prescription drug monitoring program (PDMP) is a state-run, statewide electronic database that collects information on prescribed/dispensed controlled substances (and, in a few cases, other drugs of concern) and makes that information available to authorized users. Similar programs exist in Canada, Australia, and other European countries. California was the first state to establish such a (nonelectronic) monitoring program in 1939. In 2005, Congress passed the National All Schedules Prescription Electronic Reporting (NASPER) Act, authorizing federal funding and support for PDMPs. As of 2015, 49 states had active PDMPs in place. Specifics of these programs vary considerably from state to state, with some focused more on improved clinical care and others focused more on law enforcement and diversion prevention. Programs differ as to whether they proactively report prescribing patterns to licensing boards, law enforcement, or insurance providers; whether prescribers/dispensers are required to register; whether clinicians must check the PDMP before prescribing; and if the PDMP is integrated with electronic health records. Twenty-nine states have mandatory access provisions in which regulation requires prescribers to query the PDMP for certain circumstances, such as in worker’s compensation cases or prior to prescribing in a pain management clinic. The DEA does not play a role in the management of PDMPs.
These programs are generally believed to be helpful in identifying major sources of “doctor shopping” and prescription drug diversion as well as improper prescribing and dispensing. kk
kk References 56, 306, 308, 317, 388, 470, 554, 655, 686, 717.Clinician acceptability, use, and actual impact on prescribing practices are variable. A multicenter survey of emergency room physicians revealed that only 59% of respondents were registered for access to their respective state PDMP. In a pre- and postevaluation of the implementation of Florida’s PDMP and “pill mill laws,” there was a small decrease in opioid prescriptions and morphine milligram equivalents prescribed. This was limited to prescribers and patients with the highest baseline opioid prescribing and use. Another study of medical providers in Ohio emergency departments found that 41% of those given PDMP data altered their prescribing for patients found to be receiving multiple simultaneous controlled substance prescriptions.
The state of Wyoming found that, when physicians and pharmacists received unsolicited PDMP reports concerning likely doctor shoppers, the number of patients meeting the criterion for doctor shopping dropped markedly, suggesting that PDMP reports prompted prescribers to reduce the availability of controlled substances to patients appearing to engage in doctor shopping. In British Columbia, within 6 months of the inception of their PDMP, medically inappropriate prescriptions for opioids fell by 33% and for benzodiazepines by 49%. Another study from Canada, however, found no difference in opioid prescribing between provinces with and without a PDMP. Another study looking at disabled patients in the United States receiving Medicare found no correlation of PDMPs with reductions in opioid prescribing. A study in France found a significant decrease in doctor shopping for buprenorphine with no effect on availability of the medication for treatment.
Fewer studies have attempted to correlate the presence of a PDMP with reductions in overdose. One study in Florida found a 25% decrease in oxycodone-caused deaths after implementation of that state’s PDMP in 2011. Another study found no difference in the incidence of opioid overdose mortality between states with and without PDMPs, whereas another study looking at states with PDMPs as of 2008 found wide variability across the United States, with some states recording increases in overdose fatalities and others, decreases. A more recent study looked at 35 states that implemented a PDMP between 1999 and 2013 and found that a state’s implementation of a program was associated with an average reduction of 1.12 opioid-related overdose deaths per 100,000 population in the year after implementation and that programs with more robust characteristics (such as monitoring for a greater numbers of drugs and weekly updating of data) had greater reductions in deaths, compared with states whose programs did not have these characteristics.
Insurance Company Monitoring, Pill Limits, and Care Coordination
Insurance companies and pharmacy benefit managers (PBMs) have access to medical and pharmacy claims data that can be used to identify inappropriate prescribing practices and potential misuse of controlled substances by patients. Various programs such as Patient Review and Restriction (PRR) programs (which limit “high utilizers” to single prescribers/pharmacies) and Drug Utilization Review (DUR) programs (which notify prescribers of patients with potential problematic use based on claims data) may help reduce misuse/diversion of controlled substances. Similarly, requirements for prior authorization and limits on medication quantity may also reduce misuse and diversion.
Although these interventions certainly make sense as useful interventions to decrease misuse and diversion of controlled substance, actual studies to support this are fairly limited. Studies from individual state Medicaid and commercial insurance programs have found decreases in individual patient medication utilization as well as overall numbers of controlled substance prescriptions when PRR and DUR programs are used ll
ll References 104, 182, 297, 339, 640, 733.but some have not found a difference. Similarly, studies looking at prior authorization requirements and quantity limits and patient care coordination have found reductions in amount of controlled substances prescribed and patient-level reductions in use. One study found that the inclusion of methadone on the preferred drug lists (PDLs) of two states was associated with higher rates of fatal and nonfatal methadone overdose compared to a nearby state that did not include methadone on their PDL.
FDA Changes in Scheduling and Postmarketing Surveillance of Opioids
Once the most widely prescribed medication in the United States (with over 137 million prescriptions per year), hydrocodone was moved from Schedule III to Schedule II by the DEA in 2014. One study found that the rescheduling resulted in an overall reduction of 26.3 million hydrocodone prescriptions (22% decrease form the year before the change), and 1.1 billion fewer hydrocodone tablets dispensed (16% decrease in the 12 months after rescheduling). The study was not able to analyze the actual impact on overdoses.
In early 2016, the FDA also revised the requirements for extended-release and long-acting (or ER/LA) opioids to include additional postmarketing observational studies and clinical trials to assess the known serious risks of misuse, abuse, addiction, overdose, and death.
Prescription Drug Identification Laws
Twenty-five states have laws either mandating or allowing pharmacists to request identification before dispensing prescription drugs. Most of the mandatory identification laws require a dispensing pharmacist to ask for identification if the person picking up the prescription is unknown to him or her. Five states have discretionary identification laws that allow the dispenser to demand patient identification rather than mandating that he or she do so.
Electronic Prescriptions for Controlled Substances (EPCS)
Another attempt to reduce the diversion of controlled substances (as well as potential dosing mistakes due to illegible handwriting) is through the use of electronic prescribing. In 2010, the DEA published Interim Final Rule for Electronic Prescriptions for Controlled Substances , which allowed for Schedule II, III, and IV medications to be prescribed through electronic means as long as the prescriber uses a software application that conforms to regulatory standards and two-factor authentication. The use of EPCS can also increase the likelihood that prescribers will check the PDMP prior to prescribing. Several states have passed legislation mandating the use of EPCS for controlled substances. No studies have yet demonstrated an impact on availability or misuse of controlled substances.
Laws Against Pill Mills and Doctor Shopping
In the first decade of the 21st century, a growing amount of attention was directed to the role of medical providers in the availability of misused opioids. Political and public concern over this issue led to, in early 2016, for the first time in the United States, a physician being convicted of murder for inappropriately prescribing opioids to patients who subsequently died of overdose. As a result of such concerns, various states have attempted to strengthen laws to decrease the ability of physicians to inappropriately prescribe opioids through underregulated facilities (pill mill laws) and identify/report patients who appear to be obtaining opioids inappropriately from multiple providers (doctor shopping laws; multiple provider laws). Pill mill laws typically require that a pain clinic be owned by a physician, that it not dispense opioids directly from the clinic, that it be registered with the DEA, that it agree to inspection, and that all prescriptions be reported to a state agency. Doctor shopping laws typically grant legal immunity to prescribers for reporting patients suspected of inappropriate prescription seeking. About one-fourth of US states have specific pill mill laws and about one-third have doctor shopping laws.
Some studies have shown a decrease in actual numbers of clinics and opioid prescriptions as well as overdoses related to these laws. DEA and state law enforcement raids of pill mills (through Operation Pill Nation and Operation Oxy Alley) also contributed to the 27% decline in opioid deaths in Florida between 2010 and 2012. In addition, in July of 2011, Florida instituted a law prohibiting physicians from dispensing Schedule II and III medications from their offices. Overdose deaths in the state attributed to hydrocodone product decrease from 315 in the year prior to the change to 245 in the year following the change (a 22.2% decline), whereas the prescribing rate of hydrocodone products per 100,000 population declined 9.7%. During the same period, overdose deaths attributed to oxycodone products declined 51.5% (from 1516 to 735), and the prescribing rate of oxycodone per 100,000 population declined 24%.
Screening Pain Patients for Substance Misuse Risk
Universal screening of potential opioid recipients for risk of opioid misuse is another important measure in reducing opioid misuse. Various screening tools have been validated for this purpose including the Opioid Risk Tool (ORT); the Diagnosis, Intractability, Risk, and Efficacy inventory (DIRE); and the Screener and Opioid Assessment for Patients With Pain (SOAPP). Similarly, once opioid treatment has been initiated, patients can be monitored on an ongoing basis with tools like the Current Opioid Misuse Measure. For patients with a history of opioid or other substance use disorder, further assessment is necessary and increased care should be taken to reduce the risk of opioid misuse if the use of an opioid is determined to be necessary for pain management. Potential measures include enlistment of family members to monitor medication at home, increased “call-backs” and “pill counts,” and prescriptions for smaller amounts of medication with more frequent follow-up visits. The impact of such measures on overdose has not been studied.
Public education has been a mainstay of prevention efforts to reduce substance use and misuse for many decades. From the Partnership For A Drug-Free America’s 1987 “This Is Your Brain On Drugs” public service announcement (and its 1997 and 2016 updates) to their “Mind Your Meds” campaign (launched in 2013 and continuing through 2016), multi-media messages, often aimed at adolescents, have attempted to portray the risks of substance use and decrease the social acceptability of use. Although often felt to be helpful (or, at least, not harmful), it is generally difficult to truly measure effects on actual substance use/misuse. However, examples of randomized trials of educational interventions (Iowa Strengthening Families Program; PROSPER) aimed at youth and/or families have shown effects on reducing prescription and illicit drug use in young adulthood.
In another attempt to educate the general public about addiction as a whole, in November 2016, the US Surgeon General released the office’s first ever report on the topic, Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health . Another source of public education around the safe use, storage, and disposal of ER/LA opioids is through the REMS program (mentioned previously), which also requires drug manufacturers to produce medication guides and patient counseling documents for distribution by prescribers and pharmacies ( Box 54.6 ; see Box 54.5 ).
|Patient Counseling Document on Extended-Release/Long-Acting Opioid Analgesics|
|For additional information on your medicine go to dailymed.nlm.nih.gov|
|Patient Counseling Document on Extended-Release/Long-Acting Opioid Analgesics|
Efforts focused on educating the public about safe storage and disposal of controlled substances have shown promise. One example is the “Use Only as Directed” campaign in Utah targeted at adults through television and radio public service announcements, posters, patient information cards, bookmarks, and a website. This campaign promoted storage of medications in a safe place and disposal of unused or expired medications. In follow-up, 18% of respondents reported that they disposed of controlled substances as a result of the campaign and that they were also less likely to take a prescription medication that was not prescribed to them by a physician after the campaign. The actual impact of such initiatives on overdose is not clear.
Prescription Medication Disposal and “Take-Back”
Another way to help reduce misuse of prescription opioids is to provide a safe means by which individuals can dispose of unused/expired medications in an environmentally safe manner. The Office of National Drug Control Policy (ONDCP) and FDA published guidelines on the safe disposal of unused medications, and in 2010, The Secure and Responsible Drug Disposal Act was passed to amend the Controlled Substances Act to allow a patient to deliver controlled substances to an entity that is authorized by federal law to dispose of them. DEA-sponsored National Prescription Drug Take-Back Day began in 2010 and has been held one or two times per year since then. The DEA has reported that the program has been successful, having collected almost 6.5 million pounds over the first 11 events, although it does not differentiate controlled substances from others. As of 2014, the DEA also permitted manufacturers, distributors, law enforcement officials, treatment programs, pharmacies, and health care facilities to become authorized collectors of prescription medications. Many jurisdictions have installed permanent drug drop boxes in law enforcement and health care facilities. Although these local efforts have been reported to be successful in removing controlled substances from the community, the impact of these efforts on overdose is difficult to determine.
A related program called the fentanyl “Patch 4 Patch” Return program has been implemented in a number of jurisdictions in Canada beginning in 2013. In it, a patient who is prescribed fentanyl patches for pain management must return the used patches in order to get new ones. Several of the jurisdictions have seen significant decreases in fentanyl-related overdoses since implementing the program.
Many individuals who misuse prescription opioids for nontherapeutic or recreational reasons often do so by chewing the pill to release the drug quickly, crushing it for increased ease of insufflation, or solubilizing it for intravenous injection. The goal of most abuse-deterrent formulations (ADFs) is to impose mechanical or chemical (such as gelling agents) barriers that make crushing or chewing the pill difficult. Other strategies include combination of an opioid antagonist with an agonist (used with Suboxone) that largely blocks the μ-opioid effects when the medication is injected ; the addition of a substance which would cause aversion if the formulation is altered (such as a nasal mucosa irritant); delivery systems that are difficult to manipulate (such as depot injections or subcutaneous implants); and prodrugs that require enzymatic activation in the body. A novel form of abuse deterrence currently under development, known as XpiRx (pronounced “expire”), uses technology that “deactivates” the opioid in a tablet after a certain amount of time.
Abuse-deterrent formulations FDA-approved in the United States include OxyContin, an ER oxycodone tablet formulated to be more difficult to crush, break, or dissolve, and when dissolved, forms a viscous gel that is difficult to inject; Embeda, an ER morphine capsule formulated from pellets that contain a sequestered core of naltrexone (if the pellets are crushed, chewed, or dissolved, naltrexone is released, blocking morphine-induced euphoria); Hysingla, an ER hydrocodone tablet formulation that, when dissolved, forms a viscous gel that is difficult to inject through a hypodermic needle; Xtampza, an ER oxycodone capsule that contains microspheres formulated in such a way that is difficult to manipulate; Arymo, an ER morphine product tablet formulated with a polymer matrix that, when dissolved, forms a viscous gel that is difficult to inject through a hypodermic needle; Zohydro, an ER hydrocodone capsule formulation that incorporates excipients that form a viscous gel when the capsules are crushed and dissolved; and Targiniq, an opioid agonist/antagonist combination containing ER oxycodone and naloxone.
A number of studies have shown that the reformulation of Oxycontin has led to a significant reduction in misuse and related overdose. mm
mm References 81, 92, 129, 150, 328, 591, 592, 593.A study of opioid users entering substance abuse treatment found a significant reduction in self-reported misuse of reformulated Oxycontin following its release in 2010, although one-third of those who had used the pre- and post-reformulation products reported that they had successfully defeated the ADF mechanism and continued to inhale or inject the Oxycontin, and another significant number continued to misuse it orally. In addition, that study found a significant rise in the initial use of heroin following the introduction of reformulated Oxycontin, although the authors stress that causality is difficult to establish. Another study found an increase in heroin and immediate-release oxycodone misuse associated with the decreased Oxycontin use. Yet another study using national opioid prescription insurance claims found that the estimated prescription opioid overdose rate was 20% lower 2 years after introduction of the new formulation, but the estimated heroin overdose rate increased by 23%. Other studies, however, have not found an increase in heroin use associated with a decrease in Oxycontin misuse. More research is needed to better understand the true impact of these products on opioid use and overdose as a whole.
Medication development efforts continue attempts to develop opioid medications that provide the same amount of analgesia as typical opioid agonists without reinforcement or respiratory depression. One example is BU08028, a novel opioid compound that acts as an agonist at mixed μ-opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptors, and appears to have no tolerance, addiction potential, or respiratory depression.
Possibly related to this, there are several studies that have shown an association between states with medical marijuana laws and decreased urine positivity for opioids in individuals involved in fatal car crashes and decreases in treatment admissions for opioid use disorder and opioid-related overdose deaths. The authors hypothesize that individuals in these areas are more likely to use marijuana for pain management. It is not possible to determine any causal relationship from these studies.
Increased Law Enforcement Interdiction
For decades, law enforcement interdiction, primarily focused on illicit drugs such as cocaine and heroin, had been a major component of the US War on Drugs. The High Intensity Drug Trafficking Areas (HIDTA) program was created as part of the Anti-Drug Abuse Act of 1988 with the purpose of providing assistance to federal, state, local, and tribal law enforcement agencies operating in areas determined to be critical drug-trafficking regions of the United States. The 28 HIDTAs, located in 48 states, Puerto Rico, the US Virgin Islands, and the District of Columbia cover approximately 17.6% of all counties in the United States and 63.5% of the US population. A program known as the Drug Market Intervention (DMI) began in 2004 as an effort to bring together drug dealers, their families, law enforcement officials, drug treatment and other social service providers, and community leaders to help eliminate “open-air” drug markets.
Beginning in the late 1990s, more focus was placed on diversion of controlled prescription medications. Since 2008, the DEA has partnered with various federal, state, and local law enforcement agencies to increase the number of Tactical Diversion Squads (TDS) targeting prescription opioid diversion. The DEA has also increased surveillance of DEA registrants with more diversion investigators. Operation Pill Nation and Operation Oxy Alley (mentioned above) are examples of initiatives of the Organized Crime Drug Enforcement Task Force (OCDETF) targeting the illicit distribution of prescription opioids. Prescription Drug Monitoring Programs (or PDMPs) are also used in some states by law enforcement to look for providers who are overprescribing. The actual effect of law enforcement interdiction on medication misuse and overdose is not clear.
Over the past 15–20 years, a growing amount of effort has been put into reducing/preventing opioid overdose and increasing help for those already addicted to opioids. Many of these interventions can be thought of as being both secondary and tertiary prevention, focused on reducing overdose and reducing related fatalities.
In addition to education aimed at reducing misuse and diversion of controlled substances mentioned earlier, some prescriber education has focused specifically on measures to reduce overdose. The risk evaluation and mitigation strategy (or REMS) for extended-release (ER) and long-acting (LA) opioid drugs specifically addresses the issue of minimizing risk for overdose. Consensus recommendations on the use of methadone for pain have also encouraged substantial reduction in calculated equianalgesic doses when converting from other opioids to methadone. Another effort to increase prescriber awareness of the risk of combining opioids and benzodiazepines occurred in the fall of 2016 when the FDA added a Black Box Warning to all opioids and benzodiazepines highlighting the increased risk for overdose if taken in combination. As with primary prevention efforts, actual impact on overdose is difficult to determine.
Public/Opioid User Awareness/Education
Along with general information about substance misuse/abuse/use disorders, a growing amount of effort has been put into educating drug users and the general public about measures that can specifically help prevent overdose. Often provided through syringe exchange and other outreach programs, this messaging includes encouragement of practices such as “never use alone,” “make an overdose prevention plan with your partner,” “don’t combine opioids with sedatives or alcohol,” and “use a much lower amount if you have not used opioids for a while.” Other efforts such as REMS (mentioned above) have specific messaging focused on preventing overdose (see Boxes 54.1 and 54.5 ). The actual impact of these efforts on overdose is difficult to determine.
Local Overdose Fatality Review Teams
Fatality review teams began in the late 1970s as a way to attempt to reduce future pediatric deaths by reviewing child fatality cases using a multidisciplinary team. Overdose Fatality Review Teams (OFRT) use the same concept by gathering representatives from various agencies such as medical examiner’s office, emergency medical services, drug treatment, social services, law enforcement, medical treatment, mental health treatment, and public health to review fatality cases to determine if there were things that might have helped prevent the death. The information is then used to inform policy and programmatic changes that might help prevent future overdoses. Although there have been no studies that have looked at the specific impact of these programs on overdose rates, the feeling that they help increase interagency communication and collaboration and resultant prevention efforts has been reported.
Increased Drug Treatment
A great deal of evidence shows that proper treatment of opioid use disorders helps reduce opioid misuse and reduces opioid-related overdose. Medication-assisted treatment (MAT), opioid maintenance treatment (OMT), or opioid substitution therapy are common terms used to refer to the use of methadone or buprenorphine for ongoing treatment. Although their use has been hampered by various federal and local policies/regulations, as well as negative attitudes held by the general public, patients, medical providers, and many clinicians who work in the substance abuse treatment field, the support of various government agencies (CDC, ONDCP) and reforms in insurance coverage (Affordable Care Act; state Medicaid expansion) appear to be helping increase their availability.
Various studies in multiple countries have looked at reduced nonfatal and fatal overdose in patients receiving treatment, nn
nn References 72, 86, 135, 136, 152, 170, 176, 193, 208, 292, 395, 609, 643, 689.whereas others have looked at decreased rates across a larger population as treatment is introduced or expanded. A large prospective cohort study of 10,545 heroin users entering treatment in Italy looked at standardized mortality ratio (SMR) estimates of excess mortality risk for heroin users in and out of treatment compared to the general population. It found that retention in any treatment was associated with decreased overdose compared to out of treatment (hazard ratio 0.09) with 10 overdose deaths in patients while in treatment versus 31 while out of treatment. Another study followed a cohort of 296 Australian heroin users admitted to methadone maintenance over 15 years and found that patients were one-fourth as likely to die (included overdose and suicide) while receiving methadone maintenance as those not in treatment. Another Australian study, however, found that fatal overdose rates were higher in the first 28 days in patients receiving methadone versus buprenorphine or naltrexone implant and that, after 28 days, buprenorphine seemed to be the most protective against nonfatal overdose. A meta-analysis of 19 treatment cohorts (including 122,885 individuals treated with methadone and 15,831 treated with buprenorphine) found that all cause rates of mortality were 11.3 per 1000 person years for those in methadone treatment versus 36.1 per 1000 person years for those out of treatment. Similarly, all-cause mortality was 4.3 per 1000 person years for those in buprenorphine treatment and 9.5 per 1000 person years for those out of treatment. Overdose mortality was similarly affected, with rates of 2.6 and 12.7 per 1000 person years for those in and out of methadone treatment, respectively, and 1.4 and 4.6 per 1000 person years for those in and out of buprenorphine treatment.
In France, methadone maintenance was expanded and buprenorphine treatment introduced in 1995. In parallel with these actions, the number of lethal overdoses fell from 564 in 1994 to 393 in 1996 and 143 in 1998 (a 74.6% decrease in 4 years). Another study in Baltimore, Maryland found a reduction in fatal heroin overdoses (from a high of 312 in 1999 to a low of 106 in 2008) related to the city’s expansion of publicly funded methadone (in 2000) and buprenorphine (in 2003 and 2006) treatment. Both studies caution that it is difficult to rule out other social and public health factors from contributing to some of these results.
Oral naltrexone, monthly ER injectable naltrexone (Vivitrol) and subcutaneous naltrexone implants (available in Russia and other countries) are also used. In addition, there are reports of increased overdose rates in patients taking oral naltrexone related to the total loss of tolerance that occurs when taking a μ-opioid agonist. Outcome studies on Vivitrol/naltrexone implant are limited but have not shown increased rates of overdose so far and one study with Vivitrol reported no overdoses compared to seven in the treatment as usual group after 18 months. Another study from Australia found decreased rates of overdose in patients who had received a sustained release naltrexone implant, with significantly less overdoses compared to patients receiving the oral naltrexone.
Although difficult to substantiate, there are some who have raised the possibility that diverted maintenance medications (primarily buprenorphine) are largely used for self-management of opioid withdrawal and may help reduce overdose in those individuals using the medication illicitly.
Safe Injection Facilities
Safe injection facilities (SIFs; variously referred to as Supervised Injecting/Consumption Centers/Rooms/Facilities, Drug Consumption Rooms, or Supervised Injection Services) are legally sanctioned facilities where individuals who use intravenous drugs can inject drugs under medical supervision (although a growing number of facilities target drug use via other routes of administration such as smoking). Such programs began more than three decades ago in Europe. As of 2016, more than 100 such facilities existed in 66 cities in Canada, Australia, and seven European countries (Switzerland, Germany, The Netherlands, Norway, Luxembourg, Spain, and Denmark). SIFs are designed to reduce the health and societal problems associated with injection drug use. Various studies have reported a reduction in opioid overdoses related to SIFs. oo
oo References 198, 240, 241, 245, 431, 456, 457, 541, 542, 572, 576, 588, 618, 671.One study examined population-based overdose mortality rates for the several-year period before and after Sept 21, 2003, when the Vancouver SIF opened. The fatal overdose rate in the area 500 meters surrounding the SIF decreased by 35% after the opening of the SIF, from 253 to 165 deaths per 100,000 person-years ( P = 0.048). By contrast, during the same period, the fatal overdose rate in the rest of the city decreased by only 9%, from 7.6 to 6.9 deaths per 100,000 person-years ( P = 0.490). It has been estimated that the facility has helped avert between 2 and 12 fatal overdoses per year.
A few studies have not found a significant reduction in overdoses attributable to safe consumption facilities, and one found that overdoses, though none fatal, increased significantly within the facility. As with many of the other prevention initiatives covered, it is very difficult to attribute any reductions in overdose to one intervention as it is often the case that multiple interventions are instituted at roughly the same time.
Heroin-Assisted Treatment (HAT) [also referred to as poly-morphone-(or diamorphine or diacetylmorphine) Assisted Treatment or Supervised Injectable Heroin (SIH)] has been used in various countries at different times for over a century (including the United States in the early 1900s). It is currently part of standard medical practice for treatment-refractory heroin dependence in Canada, Switzerland, Germany, The Netherlands, and Denmark (as well as the United Kingdom where it can also be used for the treatment of pain). It is also approved in Belgium and Spain for use under research protocols. Several studies have reported a modest reduction in overdose correlated with the introduction of HAT. pp
pp References 258, 316, 429, 511, 528, 672, 673.
A related clinical trial in Vancouver compared intravenous diacetylmorphine to hydromorphone and found lower overdoses (11 vs. 3, respectively) during the 6-month period of the study. Reports on slow-release morphine, used as an alternative maintenance treatment in several European countries, have not reported on impact on overdose.
Drug testing/checking has been used for several decades primarily in settings where designer drugs such as 3,4-methylenedioxy-methamphetamin (MDMA) are commonly used. More recently, such programs have emerged in Europe and Canada to test samples for the presence of synthetic opioids including fentanyl and some of its analogues. The hope is that, if an individual knows that his/her drugs may contain a more potent, illicitly manufactured opioid, that individual might choose not to use the drug or to use a much smaller amount or use in a safe space like a safe consumption facility. Preliminary data from the Insite program in Vancouver, Canada have shown that the testing does influence the choices that the opioid user makes. Further research is needed to determine the actual impact on overdose.
As mentioned earlier, many initiatives focus on prevention of both overdose and fatalities due to overdose. Most studies or evaluation efforts are unable to distinguish the relative effects of the two.
As the number of opioid-related overdoses began to increase in the early 2000s, public awareness campaigns began to increase in the affected areas of the United States. As was mentioned under secondary prevention, many of the education efforts were focused on both preventing overdose and preventing fatalities. Many of the education efforts were also combined with the provision of naloxone (see below) so the relative benefit of one versus the other is difficult to determine. One study of intravenous drug users found that they had improved knowledge of recognizing and responding to an overdose after viewing posters and leaflets displayed in an addiction treatment program. A large event, International Overdose Awareness Day (August 31), originated in 2001with the aims “… to raise awareness of overdose and reduce the stigma of a drug-related death. It also acknowledges the grief felt by families and friends remembering those who have met death or permanent injury as a result of drug overdose.”
Naloxone Distribution to Illicit Opioid Users
Because one of the main risk factors for fatal opioid overdose is having experienced a prior nonfatal overdose and because many overdoses occur in settings where other opioid users are present, there is a strong argument for making naloxone widely available to illicit opioid users. Surveys of current or former illicit drug users have found that most are willing to administer naloxone to an individual who has overdosed. qq
qq References 21, 370, 394, 533, 583, 624, 682.
The provision of naloxone to heroin users was first discussed in the mid-1990s , , with small programs beginning distribution in around 1996. By 2010, approximately 188 overdose education and naloxone distribution (OEND) programs existed in the United States (in 15 states and the District of Columbia) with many more added in the following 6 years. Multiple professional societies and government agencies have also made naloxone distribution a key component to their recommendations for battling the opioid overdose epidemic, including the American Academy of Addiction Psychiatry, the American Heart Association (as part of the updated guidelines for cardiopulmonary resuscitation, the American Medical Association, the American Society of Addiction Medicine, the American Pharmacists Association, the American Psychiatric Association, the Centers for Disease Control and Prevention, the Office of National Drug Control Policy, the Substance Abuse and Mental Health Services Administration, the World Health Organization, and the United Nations Office on Drugs and Crime. Although naloxone is not classified as an over-the-counter medication by the FDA in the United States, a number of states have passed legislation for it to be distributed directly from a pharmacy under a blanket standing order. Programs also exist in more than 15 other countries in Europe, Asia, and Australia, rr
rr References 202, 319, 324, 404, 439, 622, 657.with more programs being added as the World Health Organization has encouraged the use of naloxone.
A survey of the 188 programs in the United States in 2010 found that they had distributed naloxone to over 50,000 individuals and had received reports of over 10,000 administrations of naloxone. By 2014, these numbers had increased dramatically, with over 150,000 laypersons having received training and naloxone and program participants reporting reversal of more than 26,000 overdoses. Various other studies have now shown that distribution of naloxone to opioid users can be done fairly easily and that a significant number of recipients use the naloxone to reverse an overdose. ss
ss References 2, 44, 45, 132, 206, 238, 335, 396, 401, 441, 473, 532, 533, 585, 650, 657, 725.Although the majority of these studies are based on participant self-report of individuals trained in a single program, several have prospectively followed patient cohorts and found positive results. A systematic review of 17 more rigorous studies found that 20 deaths occurred versus 2336 episodes of naloxone administration, or approximately one death per 123 administrations. In some of the deaths, it is not clear if the victim was still alive when the naloxone was administered.
Several studies have attempted to look at outcomes at a larger, population level. Following the implementation of OEND in various areas of Massachusetts in 2007, an analysis looked at areas with no OEND implementation versus those with low implementation (1–100 people trained per 100,000 population) and high implementation (greater than 100 people trained per 100,000 population). After adjusting for community level demographic and substance use factors, they found 27% and 46% reductions in opioid overdose mortality rates, respectively. Naloxone distribution was also believed to play a major role in the dramatic reduction in heroin overdoses seen in San Francisco (from approximately 180 per year in the late 1990s to 10–11 per year from 2010–2012). Another randomized controlled trial of naloxone distribution to opioid users upon release from prisons (16 prisons; 1685 prisoners) in Scotland showed a significant reduction in overdose fatalities during the period in which naloxone was supplied, although the trial was terminated early because only one-third of the reported naloxone administrations was to the ex-prisoners.
One concern is the steadily rising cost of naloxone in the United States over the past 10–15 years. This is partially offset by the growing numbers of commercial and state Medicaid programs that cover the medication. Several studies have shown that OEND programs are cost effective, even if the full cost of the naloxone is absorbed by the program.
Naloxone Distribution to Third Parties
Because opioid overdose often occurs when the victim is at home or with friends, family members and other acquaintances are often the best situated to act to administer naloxone. However, unlike the instances of prescribing to illicit opioid users or co-prescribing to individuals taking prescribed opioids chronically, in this case, the person to whom the naloxone is dispensed/prescribed is not the ultimate intended recipient of the medication, thus it does not neatly fall under the typical practice of medicine. To address this, most states have created or amended laws to allow for the legitimate prescription to a third party (as well as some immunity from prosecution for the prescriber). Since 2001 when New Mexico first enacted such legislation, all 50 states and the District of Columbia have passed some type of law intended to increase prescribing and/or provide immunity to medical professionals who prescribe or dispense naloxone. The majority of these laws were passed between 2010 and 2015 and promote the use of naloxone in addition to training and education on recognizing and preventing overdoses.
There are fewer publications available looking specifically at naloxone distribution to nonopioid using third parties, but available evidence suggests that the programs are easy to implement and that trainees retain information even 12 months following the training, and that these programs also contribute to a reduction in overdose fatalities.
Naloxone Co-Prescribing to Patients Taking Opioids
Although not traditionally done by most prescribers and not always accepted by some, the co-prescribing of naloxone with opioids (prescribed/dispensed either for pain or the treatment of opioid use disorder) has been encouraged increasingly through various initiatives including guidelines from the US Department of Veterans Affairs and the CDC. Along with this are recommendations for opioid prescribers to assess all patients for risk of misuse and risk of overdose, and to educate patients and significant others about factors that can increase the risk of overdose (such as concurrent alcohol or sedative use) as well as safe storage of opioids. Several studies have shown that this practice is feasible, generally well-accepted by patients, and associated with clinical benefits. The NOSE (Naloxone for Opioid Safety Evaluation) study found that, in a chronic pain population, patients who had been prescribed naloxone had fewer opioid-related emergency department visits than those who were not prescribed naloxone.
Naloxone With Law Enforcement and Other First Responders
In many areas, law enforcement personnel are likely to arrive at an overdose scene prior to emergency medical personnel. Traditionally, officers might be taught cardiopulmonary resuscitation but would not carry or administer any medications. As many areas have initiated and expanded distribution and prescribing of naloxone to opioid users and third parties, efforts have also been put in place to train law enforcement officers in recognizing and responding to overdose, including the use of naloxone. Studies have shown that law enforcement officers are generally in favor of naloxone distribution. The ONDCP and the Department of Justice (DOJ) have urged police departments to have officers carry naloxone and the DOJ released a Naloxone Toolkit to help facilitate the increased use of naloxone by law enforcement officers. As of late 2016, thousands of local and state police departments had implemented such programs.
Good Samaritan Laws
Related to the expansion of availability of naloxone to third parties is the issue of encouraging individuals to seek further medical assistance in the event of an overdose. Fear of arrest, either for drug possession, outstanding warrants, or for a possible bad outcome related to the overdose, has often been reported by bystanders as the main reason they do not call 911 in such an event. tt
tt References 21, 184, 394, 538, 595, 649, 654.In an effort to address this, many states have enacted or expanded existing Good Samaritan laws (sometimes known as “medical amnesty laws”) to provide legal protection to the overdose victim and/or the individual administering assistance. Between 2007 (when New Mexico became the first state) and 2016, over two-thirds of states and the District of Columbia had enacted such legislation. Although this clearly can help increase the likelihood that bystanders will intervene and seek further medical assistance, there is also evidence that law enforcement is not always aware of the laws.
There is also concern by some prescribers about legal consequences of prescribing naloxone. As of 2016, a total of 32 states had enacted specific legislation to provide full or partial civil immunity to medical professionals who prescribe naloxone as permitted by the law in their state.
States and local jurisdictions are increasingly looking for novel programs to enhance the tertiary prevention strategies mentioned here. Vancouver has instituted a Mobile Medical Unit in areas with high overdose rates in order to help provide additional rapid response medical capability to the already overwhelmed emergency medical system. States such as Rhode Island, Massachusetts, and Maryland have implemented outreach teams to try to engage overdose survivors and their social networks in order to offer prevention, education, treatment referrals and other social services. The Boston Healthcare for the Homeless program has established a Supportive Place for Observation and Treatment (SPOT) where an individual who has recently used a substance can come to be monitored by medical staff while acutely intoxicated. The staff are able to provide supportive medical care and naloxone, should the intoxication progress to overdose. Though these types of programs should be effective in reducing overdose fatalities, very little data exists in their effectiveness.
Use of Technology
Mobile and on-line technologies have also been used to help reduce overdose fatalities. Websites such as subreddit/r/opiates/wiki have been used to facilitate communication between drug users who post cautions such as areas where suspected fentanyl-laced heroin is being sold. A mobile phone app, Remote Egg Timer, allows an opioid user to program an emergency contact’s number and then set a timer (for 10 minutes or so) prior to injecting. If the user does not push a stop button when the timer goes off, a text message is automatically sent to the emergency contact. Although it can be customized, the default message reads: “This is an automated request for help. Unresponsive after using. Would you mind checking up on me?” In order that the emergency contact can send help, the message can be made to send the user’s GPS coordinates. Other mobile-phone apps (Trek Medics and OD Help) help connect potential opioid overdose victims with a crowd-sourced network of individuals who possess naloxone.
Although early in development, a vaccine has been developed which appears to attenuate some of the psychoactive effects and respiratory depression of fentanyl and many of its analogues. Similar vaccines have been developed which have demonstrated an attenuation of heroin’s effects.