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. Author manuscript; available in PMC: 2018 Sep 1.
Published in final edited form as: Drug Alcohol Depend. 2017 Jul 4;178:501–511. doi: 10.1016/j.drugalcdep.2017.05.047

Increases from 2002 to 2015 in prescription opioid overdose deaths in combination with other substances*

Denise B Kandel 1,2,3, Mei-Chen Hu 1, Pamela Griesler 2, Melanie Wall 1,2,4
PMCID: PMC5568115  NIHMSID: NIHMS893356  PMID: 28719884

Abstract

Background

Prescription opioid (PO) overdose deaths increased sharply over the last decade. Changes in PO deaths in combination with other psychoactive substances may provide a partial explanation.

Methods

PO deaths from the National Multiple-Cause-of-Death Files for 2002–03 (N=15,973) and 2014–15 (N=41,491) were analyzed. We calculated (1) changes in proportions of deaths in combination with benzodiazepines, antidepressants, heroin, alcohol, cocaine between the two periods, and (2) proportions of increase in deaths attributable to each substance among PO and synthetic opioids other than methadone (SO-M) deaths, by age, gender, race/ethnicity.

Results

Between 2002–03 and 2014–15, PO deaths increased 2.6 times; SO-M deaths 5.6 times, especially for ages 18–34, males, African-Americans. For PO deaths, most frequent combinations at both periods were with benzodiazepines; for SO-M, benzodiazepines, antidepressants in 2002–03, heroin, benzodiazepines in 2014–15. The largest increases occurred in combination with heroin among all PO (4.6% to 15.4%, change ratio=3.3[95%CI=3.1–3.6]), but especially SO-M deaths (1.2% to 24.5%, change ratio=21.3[95%CI=15.0–30.3]). Deaths involving cocaine decreased among PO, increased among SO-M deaths. One-fifth of increased PO or SO-M deaths were attributable to any of the five substances. Increased PO deaths were equally attributable to benzodiazepines and heroin; deaths attributable to heroin were higher among ages 18–49, males, and non-Hispanic whites. Increased SO-M deaths were attributable mostly to heroin among all groups.

Conclusions

Increased PO overdose deaths over the last decade may be partially explained by increased deaths in combination with other psychoactive substances. Use of other substances should be considered in efforts toward reducing prescription opioid overdoses.

Keywords: Prescription opioids, Overdose deaths, Benzodiazepines, Heroin, Synthetic opioids other than methadone

1. Introduction

Mortality and morbidity associated with prescription opioid analgesics increased sharply over the last decade (Centers for Disease Control and Prevention, 2017; Compton et al., 2015; Franklin et al., 2015; Kolata and Cohen, 2016; National Institute on Drug Abuse, 2017; Paulozzi, 2012; Rudd et al., 2016a; The White House, 2016; Volkow et al., 2014), leading the Centers for Disease Control to declare drug overdose deaths to be an epidemic (Rudd et al., 2016b). Prescription opioid (PO) overdose deaths increased more than two and a half times between 2002 and 2015 (National Institute on Drug Abuse, 2017). Increases in deaths occurred in the context of decreased prevalence of PO use but increased rates of heavy use and disorder among users (Han et al., 2015). Issues related to prescription opioids are worldwide, affecting European countries, Australia, and Canada (Berecki-Gisolf et al., 2017; Berterame et al., 2016; Degenhardt et al., 2013; Dhalla et al., 2011; European Monitoring Centre for Drugs and Addiction, 2014; Fischer et al., 2014; Shei et al., 2015; United Nations).

Determining the factors contributing to increased PO mortality is needed for informing prevention and intervention efforts. The director of the National Institute on Drug Abuse emphasized that increased prescriptions, greater social acceptability for using medications, and aggressive marketing by pharmaceutical companies helped create the “environmental availability” of prescription opioids and likely contributed to the current prescription drug abuse problem (Volkow, 2014). Increases in number of PO users could potentially explain increases in PO deaths. Everything else constant, changes in number of deaths should parallel changes in number of users. However, a relationship between users and deaths cannot be directly established nationally. Records do not distinguish deaths related to medical or nonmedical prescription opioid (NMPO) use. Furthermore, trend data are only available for nonmedical PO use. Prevalence of NMPO use in the population declined (Frenk et al., 2015; Han et al., 2015) from 4.7% in 2002 to 3.9% in 2014 (Hu et al., 2017). The 8% increase in number of persons prescribed opioid analgesics from 75 million in 2002 to 81 million in 2014 (Hwang et al., 2016) paralleled the concurrent 10% increase in the US population size (288 million in 2002, 319 million in 2014). Consequently, the prevalence of individuals prescribed opioid analgesics remained flat, 26.0% in 2002, 25.4% in 2014. The evidence suggests that increased PO deaths did not result from an increased number of medical or nonmedical PO users.

Changes in PO users’ behavior, including frequency of use, disorder, type of opioid used, prescription dosage, and concurrent use of other drugs, such as heroin or benzodiazepines, may account for increases in PO deaths (Compton et al., 2016; Drug Enforcement Administration, 2016; Hwang et al., 2016; Jones, 2012; 2013; Martins et al., 2017). High intensity NMPO use and disorder increased between 2002 and 2014 (Han et al., 2015; Hu et al., 2017; Jones, 2012). Prescription opioid dosage also increased since 1997 (Pain and Policy Studies Group/WHO Collaborating Center, 2015), and increased dosage is associated with increased morbidity and mortality (Bohnert et al., 2016; Dasgupta et al., 2016). Neither increasing intensity of use nor prescription dosage can be linked to population level PO overdose deaths because death records lack this information. Linkage can be implemented for one aspect of PO users’ behavior prior to death, use of other drugs, since death records list contributing drugs. Use of PO in combination with other substances, e.g., benzodiazepines, alcohol, fentanyl-mixed heroin or cocaine, has been associated with increased mortality from additive or synergistic adverse effects in the US (Babalonis and Walsh, 2015; Centers for Disease Control and Prevention, 2016; Jones et al., 2017; McCance-Katz et al., 2010; Oliver et al., 2007; Paone et al., 2016; Suzuki and El-Haddad, 2017), and Canada (Gomes et al., 2011), in part from pharmacokinetic and pharmacodynamic interactions resulting in respiratory depression and unintended rapid release of the opioid dose (Gudin et al., 2013; Jones et al., 2012; White and Irvine, 1999). Increased mortality associated with polydrug use involving opiates, cocaine, alcohol, or benzodiazepines in combination has been observed in New York City between 1990–98 (Coffin et al., 2003) and in Australia (Darke et al., 2010).

PO deaths involving other substances have been investigated at one time-point (Calcaterra et al., 2013; Dasgupta et al., 2016; Jann et al., 2014; Jones et al., 2013; 2014; Park et al., 2015; Saunders et al., 2012; Warner et al., 2016), but not over time, except for benzodiazepines (Chen et al., 2014; Jones and McAninch, 2015), which increased between 2004 and 2011 across age, gender and racial/ethnic groups (Jones and McAninch, 2015). Changes in overdose deaths from single substances, including heroin (Jones et al., 2015), psychostimulants (Calcaterra and Binswanger, 2013) and benzodiazepines (Bachhuber et al., 2016), have been examined separately up to 2009 or 2013. Using literal text analysis of information written on death certificates by medical certifiers (Trinidad et al., 2016; Warner et al., 2016), the National Center for Health Statistics and U.S. Food and Drug Administration recently identified specific drugs within classes of deaths in 2010–2014, and examined changes in all overdose deaths (not restricted to PO) for the ten most frequently mentioned specific drugs (Warner et al., 2016). Heroin deaths more than tripled; fentanyl deaths more than doubled.

The extent to which changes in PO deaths in combination with other substances contributed to the increase in PO deaths over the last decade and the relative contributions of different drug combinations to the increase remain to be specified.

We specify the extent to which changes in PO overdose deaths in combination with other substances contributed to increases in overall PO overdose deaths, and specifically synthetic opioids other than methadone (SO-M) overdose deaths which includes fentanyl, over the last twelve years in the population and in age, gender and race/ethnicity subgroups. We address three issues by analyzing national death records for 2002–03 and 2014–15 among all PO deaths, and among SO-M deaths, to capture indirectly changes related to fentanyl: (1) How has the proportion of PO deaths in combination with each of five central nervous system pharmaceutical or recreational psychoactive substances (benzodiazepines, antidepressants, heroin, alcohol, cocaine) changed in that interval? (2) What proportion of the increase in deaths is attributable to changes in deaths in combination with specific substances? (3) What are age, gender and racial/ethnic differences in these patterns?

2. Methods

2.1. Data

Data are from the Multiple-Cause-of-Death Files, National Vital Statistics System Wonder files (CDC, 2016) for PO overdose deaths for the years 2002–03 (N=15,973) and 2014–15 (N=41,491). One underlying cause-of-death, based on mechanism (e.g., overdose) and intent, and up to 20 contributing causes-of-deaths are recorded in death certificates (Slavova et al., 2015; Trinidad et al., 2016; Warner et al., 2016). Overdose/poisoning deaths involving PO are coded into three broad classes as per International Classification of Diseases-Tenth Edition (ICD-10) (National Center for Health Statistics, 2017): natural/semisynthetic opioids; methadone; synthetic opioids other than methadone (SO-M). Between 2002–2015, 17.0% to 28.9% of drug overdose death certificates lacked information about contributing drugs (Rudd et al., 2016a; Trinidad et al., 2016; Warner et al., 2009; 2016).

The following ICD-10 codes were used for selecting cases:

  1. Drug overdose deaths: underlying cause of death X40-X44 (unintentional), X60-X64 (suicide), X85 (assault), Y10-Y14 (undetermined intent).

  2. PO overdose deaths: (1) and one contributing cause-of-death code T40.2 (natural and semisynthetic opioids, e.g., morphine, oxycodone, hydrocodone), T40.3 (methadone), T40.4 (SO-M, e.g., fentanyl, tramadol, propoxyphene, meperidine).

  3. SO-M overdose deaths: (1) and code T40.4 (SO-M).

  4. Heroin-related overdose: (1) and T40.1 (heroin).

  5. Benzodiazepine-related overdose: (1) and T42.4 (benzodiazepine).

  6. Antidepressant-related overdose: (1) and T43.0-T43.2 (antidepressant).

  7. Cocaine-related overdose: (1) and T40.5 (cocaine).

  8. Alcohol poisoning-related overdose: (1) and T51.0 (toxic ethanol effect), T51.9 (toxic effect of unspecified alcohol).

2.2. Variables

  • Gender: male, female.

  • Age: 0–17; 18–34; 35–49; 50 and older.

  • Race/ethnicity: non-Hispanic white; non-Hispanic African-American; Hispanic.

2.3. Analytical Strategy

We examined changes in proportions of PO deaths in combination with other substances between 2002–03 and 2014–15 for all PO deaths and for SO-M deaths. We calculated (1) changes in proportions of deaths in combination with benzodiazepines, antidepressants, heroin, alcohol, or cocaine between 2002–03 and 2014–15, and (2) the proportion of increase in deaths attributable to each substance in combination, as the difference between actual and expected number of deaths in combination with specific substances in 2014–15 divided by the total number of increased deaths between the two periods. Expected number of deaths was the 2014–15 number multiplied by the proportion of deaths in combination with other substances in 2002–03. Thus, in 2002–03, benzodiazepine-related deaths (N=2,682) constituted 16.791% of all PO deaths (N=15,973); in 2014–15, the expected number was 6,967=(16.791%×41,491 PO deaths). The difference between actual and expected numbers was 4,626=(11,593-6,967). Since PO deaths increased by 25,518 cases (41,491-15,973), the attributable proportion increase in PO-benzodiazepine deaths was 18.1%=(4,626/25,518).

For each substance, the attributable proportion of increase depends on the initial proportion among PO deaths in 2002–03, the percent change by 2014–15, and the increase in number of deaths between 2002–03 and 2014–15 for each group. Given the same percent change, the attributable proportions can be different, given differences in base number of deaths and the number of increased deaths for a particular group.

Statistical significance of differences in ratios of proportions and attributable proportions were evaluated by the log-linked Poisson model.

3. Results

3.1. Changes in PO Deaths by Opioid Class

Between 2002–03 and 2014–15, overall PO deaths increased 2.6 times (Table 1); methadone deaths increased 1.3 times; SO-M deaths increased 5.6 times. In 2002–03, 58.1% of PO deaths involved natural and semisynthetic opioids, 33.4% methadone, 16.9% SO-M versus 60.0%, 16.2%, 36.5%, respectively, in 2014–15.

Table 1.

Changes in proportions of prescription opioid deaths in combination with five other substances between 2002–03 and 2014–15 among all prescription opioid deaths and by class of prescription opioid deaths.

Deaths in Combination With: All Prescription Opioid Deaths Natural and Semi-Synthetic Opioid Deaths Methadone Deaths Synthetic Opioids Other than Methadone Deaths
2002–03
%		 2014–15
%		 Changes Between 2002–03 and 2014–15
Ratio (95%CI)a 		2002–03
%		 2014–15
%		 Changes Between 2002–03 and 2014–15
Ratio (95%CI)a 		2002–03
%		 2014–15
%		 Changes Between 2002–03 and 2014–15
Ratio (95%CI)a 		2002–03
%		 2014–15
%		 Changes Between 2002–03 and 2014–15
Ratio (95%CI)a
Benzodiazepines 16.8 27.9 1.7 (1.6–1.7) 18.3 33.7 1.8 (1.8–1.9)b 17.1 30.7 1.8 (1.7–1.9)b 17.5 20.0 1.1 (1.0–1.3)c
Antidepressants 13.2 12.9 1.0 (0.9–1.0) 13.0 15.2 1.2 (1.1–1.2)b 13.2 12.7 1.0 (0.9–1.1)c 17.4 10.1 0.6 (0.5–0.6)d
Heroin 4.6 15.4 3.3 (3.1–3.6) 6.9 10.6 1.5 (1.4–1.7)b 1.8 9.6 5.3 (4.3–6.6)c 1.2 24.5 21.3 (15.0–30.3)d
Alcohol 8.5 13.7 1.6 (1.5–1.7) 9.7 14.7 1.5 (1.4–1.6) 5.8 9.2 1.6 (1.4–1.8) 9.1 12.9 1.4 (1.3–1.6)
Cocaine 12.6 10.1 0.8 (0.8–0.8) 12.9 8.0 0.6 (0.6–0.7)b 14.5 8.7 0.6 (0.5–0.7)b 6.5 14.3 2.2 (1.9–2.6)c
Any of 5 substances 44.3 57.9 1.3 (1.3–1.3) 48.2 60.0 1.2 (1.2–1.3)b 41.9 52.3 1.2 (1.2–1.3)b 40.5 58.0 1.4 (1.4–1.5)c
Total Deaths (N) (15,973) (41,491) 2.6 (=41,491/15,973) (9,283) (24,886) 2.7 (=24,886/9,283) (5,330) (6,701) 1.3 (=6,701/5,330) (2,695) (15,124) 5.6 (=15,124/2,695)
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a

Standarderror[log(ratio)=(1/a)+(1/b)], where a and b equal the number of deaths in combination with other substances in 2002–03 and 2014–15.

b–d

For each substance-related death, different superscripts indicate statistically significant (p<0.05) differences between the classes of prescription opioids in change ratios.

3.2. Changes in PO Deaths in Combination with Other Substances

The proportion of all PO deaths in combination with any of the five psychoactive substances increased 1.3 times (95% CI=1.3–1.3), from 44.3% in 2002–03 to 57.9% in 2014–15 (Table 1). PO deaths in combination with specific substances increased for all drugs, except cocaine, which decreased (10.1%), and antidepressants, which remained the same. Extent of change varied by combination substance. Heroin-related deaths more than tripled (change ratio=3.3 [95% CI=3.1–3.6]). Benzodiazepine and alcohol-related deaths increased by factors of 1.7 (95% CI = 1.6–1.7) and 1.6 (95% CI = 1.5–1.7), respectively. Cocaine-related deaths decreased (0.8 [95% CI = 0.8–0.8]) (Table 1).

The proportion of specific drug combinations varied substantially by class of PO deaths (Table 1). At both periods, the most frequent combination was with benzodiazepines: 16.8% in 2002–03, 27.9% in 2014–15. Antidepressants (13.2%) and cocaine (12.6%) were next in 2002–03, heroin (15.4%) and alcohol (13.7%) in 2014–15. In 2014–15, among (1) natural and semisynthetic opioids and (2) methadone deaths, benzodiazepines ranked first (27.9%), heroin was next but a third as prevalent (15.4%). Among SO-M deaths, heroin was first (24.5%) and benzodiazepines a close second (20.0%). Although heroin-related deaths increased more than any other drug combination among all three PO classes, the change ratio for heroin was strikingly higher among SO-M (21.3 [95% CI = 15.0–30.3]) than natural/semisynthetic opioids (1.5 [95% CI = 1.4–1.7]) and methadone (5.3 [95% CI = 4.3–6.6]) deaths. Cocaine-related deaths decreased among natural/semisynthetic opioids (0.6 [95% CI = 0.6–0.7]) and methadone (0.6 [95% CI = 0.5–0.7]) deaths, but doubled (2.2 [95% CI = 1.9–2.6]) among SO-M deaths.

3.2.1. Increases in PO Deaths Attributable to Other Substances

The proportions of increased deaths in 2014–15 attributable to combinations with each psychoactive substance exceeding those expected based on their proportions in 2002–03 were calculated.

Of the increases in deaths, 22.1% (95% CI = 21.6%–22.6%) among all PO deaths and 21.3% (95% CI = 20.6%–22.0%) among SO-M deaths were attributable to deaths involving any of the five substances (Figure 1, Supplementary Table 11). Among all PO deaths, the largest increases were attributable to benzodiazepines and heroin (18.1% [95% CI = 17.7%–18.6%]; 17.5% [95% CI = 17.0%–18.0%]), followed by alcohol (8.5% [95% CI = 8.2%–8.8%]). Cocaine was associated with a 3.9% (95% CI = −4.2%–−3.7%) decrease in deaths and antidepressants with a −0.5% (95% CI = −0.6%–−0.4%) decrease. Among SO-M deaths, the largest increase was attributable to heroin (28.5% [95% CI = 27.7%–29.3%]); cocaine was second (9.6% [95% CI = 9.1%–10.1%]). Only 3% (95% CI = 2.7%–3.3%) of the increase was attributable to benzodiazepines.

Figure 1.

Figure 1

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Attributable proportions of increases in prescription opioid (PO) deaths in combination with five other substances between 2002–03 and 2014–15 among (A) all prescription opioid (PO) deaths, and (B) synthetic opioids other than methadone (SO-M) deaths.

Because of multiple substance combinations, the increase in deaths attributable to each substance included a component uniquely attributable to that substance and one attributable to additional substances. Thus, in 2014–15, 67.0% of PO deaths in combination with one of the five psychoactive substances involved one substance, 28.0% a second substance, 4.6% a third one. Proportions attributable uniquely to one substance varied across type of PO death and substance. Among all PO deaths, the proportional increase attributable to only one substance in combination varied from 48.0% for benzodiazepines, 45.6% for heroin, to 26.7% for alcohol. Among SO-M deaths, these percentages were 54.3% for heroin, 5.9% for alcohol, 22.5% for cocaine (Supplementary Table 11).

3.3 PO Deaths by Age

3.3.1. Changes in PO Deaths in Combination with Other Substances by Age

Overall PO deaths increased most at ages 50 and older; SO-M deaths increased most at ages 18–34. Changes in deaths involving PO in combination with other substances were similar at all ages, with several exceptions (Table 2). Among all PO deaths, heroin-related deaths increased most at ages 18–34; alcohol-related deaths increased most at ages 50 and older. Among SO-M deaths, cocaine-related deaths increased more at ages 35 and older than ages 18–34.

Table 2.

Changes in proportions of prescription opioid deaths in combination with five other substances between 2002–03 and 2014–15 among all prescription opioid deaths and synthetic opioids other than methadone deaths, by age, gender and race/ethnicity.

Deaths in Combination With: All Prescription Opioid Deaths Synthetic Opioids Other than Methadone Deaths
2002–03
%		 2014–15
%		 Changes Between 2002–03 and 2014–15
Ratio (95%CI)a 		2002–03
%		 2014–15
%		 Changes Between 2002–03 and 2014–15
Ratio (95%CI)a
AGEb
18–34
Benzodiazepines 17.0 26.5 1.6 (1.4–1.7) 18.8 17.7 0.9 (0.8–1.1)c
Antidepressants 7.9 6.9 0.9 (0.8–1.0) 12.4 5.0 0.4 (0.3–0.5)c
Heroin 4.6 23.1 5.0 (4.3–5.7)c 1.0 30.3 31.4 (14.1–69.7)
Alcohol 8.6 12.3 1.4 (1.3–1.6)c 8.0 10.7 1.3 (1.0–1.8)
Cocaine 15.5 11.8 0.8 (0.7–0.8)c 9.0 14.1 1.6 (1.2–2.0)c
Any of 5 substances 43.5 58.4 1.3 (1.3–1.4) 38.4 56.4 1.5 (1.3–1.6)
Total deaths (N) (4,234) (12,075) 2.9 (=12,075/4,234) (622) (5,845) 9.4 (=5,845/622)
35–49
Benzodiazepines 16.9 28.6 1.7 (1.6–1.8) 16.5 20.6 1.2 (1.1–1.4)d
Antidepressants 14.1 14.0 1.0 (0.9–1.1) 18.0 11.0 0.6 (0.5–0.7)d
Heroin 4.6 15.3 3.4 (3.0–3.7)d 1.2 23.9 19.8 (12.3–31.8)
Alcohol 9.2 14.8 1.6 (1.5–1.7)c 10.2 14.6 1.4 (1.2–1.7)
Cocaine 12.9 11.6 0.9 (0.8–1.0)d 6.4 16.6 2.6 (2.1–3.2)d
Any of 5 substances 45.6 59.9 1.3 (1.3–1.4) 41.3 60.7 1.5 (1.4–1.6)
Total deaths (N) (8,212) (14,412) 1.8 (=14,412/8,212) (1,406) (5,265) 3.7 (=5,265/1,406)
50 and older
Benzodiazepines 16.7 28.7 1.7 (1.6–1.9) 18.9 22.6 1.2 (1.0–1.4)c,d
Antidepressants 18.5 16.9 0.9 (0.8–1.0) 21.3 16.5 0.8 (0.7–0.9)e
Heroin 5.1 9.4 1.8 (1.6–2.1)e 1.3 17.1 13.7 (6.9–27.3)
Alcohol 7.0 14.0 2.0 (1.8–2.3)d 7.8 14.0 1.8 (1.4–2.4)
Cocaine 8.3 7.6 0.9 (0.8–1.0)d 4.1 11.9 2.9 (2.0–4.3)d
Any of 5 substances 43.6 56.1 1.3 (1.2–1.3) 41.6 57.2 1.4 (1.2–1.5)
Total deaths (N) (3,292) (14,726) 4.5 (=14,726/3,292) (639) (3,951) 6.2 (=3,951/639)
GENDER
Males
Benzodiazepines 16.6 25.7 1.6 (1.5–1.6)f 18.1 17.5 1.0 (0.8–1.1)f
Antidepressants 9.1 8.6 0.9 (0.9–1.0) 12.2 6.3 0.5 (0.4–0.6)f
Heroin 6.2 19.1 3.1 (2.8–3.3)f 1.6 27.6 17.3 (11.5–25.9)
Alcohol 10.4 16.5 1.6 (1.5–1.7)f 11.5 14.7 1.3 (1.1–1.5)
Cocaine 14.5 11.8 0.8 (0.8–0.9) 7.7 15.5 2.0 (1.7–2.4)
Any of 5 substances 45.2 58.9 1.3 (1.3–1.3) 39.1 58.4 1.5 (1.4–1.6)
Total deaths (N) (10,039) (24,781) 2.5 (=24,781/10,039) (1,438) (10,025) 7.0 (=10,025/1,438)
Females
Benzodiazepines 17.1 31.2 1.8 (1.7–2.0) 16.9 24.9 1.5 (1.3–1.7)
Antidepressants 20.3 19.3 1.0 (0.9–1.0) 23.3 17.7 0.8 (0.7–0.9)
Heroin 2.0 10.0 5.0 (4.2–6.0) 0.6 18.5 29.1 (14.6–58.2)
Alcohol 5.2 9.6 1.8 (1.6–2.1) 6.3 9.2 1.5 (1.2–1.9)
Cocaine 9.2 7.6 0.8 (0.8–0.9) 5.0 12.0 2.4 (1.9–3.1)
Any of 5 substances 42.8 56.4 1.3 (1.3–1.4) 42.2 57.2 1.4 (1.3–1.5)
Total deaths (N) (5,934) (16,710) 2.8 (=16,710/5,934) (1,257) (5,099) 4.1 (=5,099/1,257)
RACE/ETHNICITY
Whites
Benzodiazepines 17.8 29.2 1.6 (1.6–1.7)e 18.2 21.3 1.2 (1.1–1.3)
Antidepressants 13.5 13.3 1.0 (0.9–1.0) 17.3 10.5 0.6 (0.6–0.7)
Heroin 3.5 14.5 4.2 (3.8–4.6)g 0.9 23.5 24.8 (16.5–37.3)g
Alcohol 8.2 12.9 1.6 (1.5–1.7)g 8.6 11.7 1.4 (1.2–1.6)
Cocaine 10.9 8.9 0.8 (0.8–0.9) 5.8 12.8 2.2 (1.9–2.6)g
Any of 5 substances 42.7 57.3 1.3 (1.3–1.4)g 40.2 57.0 1.4 (1.3–1.5)
Total deaths (N) (13,710) (34,951) 2.5 (=34,951/13,710) (2,429) (12,680) 5.2 (12,680/2,429)
African-Americans
Benzodiazepines 8.6 17.4 2.0 (1.6–2.6)g,h 10.6 10.5 1.0 (0.5–1.8)
Antidepressants 12.5 10.4 0.8 (0.7–1.0) 18.6 7.0 0.4 (0.2–0.6)
Heroin 10.6 21.5 2.0 (1.7–2.5)h 3.5 32.5 9.2 (3.5–24.1) g,h
Alcohol 7.3 17.9 2.5 (1.9–3.2)h 11.5 20.5 1.8 (1.1–3.0)
Cocaine 30.1 21.7 0.7 (0.6–0.8) 21.2 26.0 1.2 (0.8–1.8)h
Any of 5 substances 53.6 62.3 1.2 (1.1–1.2)h 42.5 65.7 1.5 (1.2–1.9)
Total deaths (N) (879) (3,082) 3.5 (=3,082/879) (113) (1,332) 11.8 (=1,332/113)
Hispanics
Benzodiazepines 11.0 23.9 2.2 (1.8–2.6)h 13.0 16.8 1.3 (0.7–2.2)
Antidepressants 10.0 10.4 1.0 (0.8–1.3) 16.7 8.4 0.5 (0.3–0.8)
Heroin 14.7 20.9 1.4 (1.2–1.7)i 3.7 27.7 7.5 (2.8–19.7) i
Alcohol 11.1 18.3 1.6 (1.4–2.0)g 13.0 17.8 1.4 (0.8–2.3)
Cocaine 20.2 14.3 0.7 (0.6–0.8) 8.3 20.1 2.4 (1.3–4.6)g,h
Any of 5 substances 55.5 60.9 1.1 (1.0–1.2)h 46.3 62.1 1.3 (1.1–1.7)
Total deaths (N) (1,072) (2,492) 2.3 (=2,492/1,072) (108) (826) 7.6 (=826/108)
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a

Standarderror[log(ratio)=(1/a)+(1/b)], where a and b equal the number of deaths in combination with other substances in 2002–03 and 2014–15.

b

Aged <18 are not shown.

c–e

For each substance-related death, different superscripts indicate statistically significant (p<.05) differences between age groups in change ratios among all prescription opioid and synthetic opioids other than methadone deaths.

f

For each substance-related death, superscript indicates statistically significant (p<.05) differences by gender in change ratios among all prescription opioid and synthetic opioids other than methadone deaths.

g–i

For each substance-related death, different superscripts indicate statistically significant (p<.05) differences between race/ethnicity groups in change ratios among all prescription opioid and synthetic opioids other than methadone deaths.

3.3.2. Increases in PO Deaths Attributable to Other Substances by Age

Proportional increases in PO deaths attributable to specific substance combinations varied by age (Figure 2, Supplementary Table 22). Among all PO deaths, those in combination with heroin contributed most to increased deaths at ages 18–34 (28.5% [95% CI = 27.5%–29.5%]) and 35–49 (25.0% [95% CI = 24.0%–26.1%]). Benzodiazepines did so at ages 35–49 (27.1% [95% CI = 26.0%–28.2%). There was a reversal with increasing age in the relative increases in deaths attributable to heroin and benzodiazepines. At ages 18–34, increases attributable to heroin (28.5%) contributed 1.9 times as much as benzodiazepines (14.6% [95% CI=13.8%–15.4%]); at ages 35–49, both drugs contributed equally; at ages 50+, increases attributable to benzodiazepines (15.5% [95% CI=14.8%–16.1%]) were almost three times higher than heroin (5.5% [95% CI=5.1%–5.9%]). Among all PO deaths, the largest increases attributable to alcohol occurred at ages 35–49; the largest decrease associated with cocaine occurred at ages 18–34. Among SO-M deaths, the largest proportion of increased deaths was attributable to heroin at all ages, but especially ages 18–49. The proportion of increased deaths attributable to cocaine was highest at ages 35–49.

Figure 2.

Figure 2

Open in a new tab

Attributable proportions of increases in prescription opioid (PO) deaths in combination with five other substances between 2002–03 and 2014–15 among (A) all prescription opioid (PO) deaths, and (B) synthetic opioids other than methadone (SO-M) deaths, by age.

3.4. PO Deaths by Gender

3.4.1. Changes in PO Deaths in Combination with Other Substances by Gender

While increases in number of overall PO deaths from 2002–03 to 2014–15 did not differ by gender, the increases in number of SO-M deaths were 70% higher among males (increased 7 times) than females (increased 4.1 times) (Table 2). Increases in proportions of deaths involving all PO and SO-M in combination with any of the five psychoactive substances were similar for males and females (change ratios=1.3–1.5). However, among PO and SO-M deaths, deaths in combination with benzodiazepines increased more for females than males (Table 2).

3.4.2. Increases in PO Deaths Attributable to Other Substances by Gender

The largest proportion of increased overall PO deaths was attributable to heroin among males, benzodiazepines among females. The largest proportion of increased SO-M deaths was attributable to heroin among both genders, but especially males (Figure 3, Supplementary Table 23).

Figure 3.

Figure 3

Open in a new tab

Attributable proportions of increases in prescription opioid (PO) deaths in combination with five other substances between 2002–03 and 2014–15 among (A) all prescription opioid (PO) deaths, and (B) synthetic opioids other than methadone (SO-M) deaths, by gender.

3.5. PO Deaths by Race/Ethnicity

3.5.1. Changes in PO Deaths in Combination with Other Substances by Race/Ethnicity

Increases in overall PO deaths, those in combination with other substances, and patterns of change differed by race/ethnicity. PO deaths, especially SO-M deaths, increased more among African-Americans (3.5 times all PO deaths, 11.8 times SO-M deaths) than whites or Hispanics (Table 2). The proportion of PO deaths in combination with any of five psychoactive substances in 2002–03 was higher among minorities than whites (Table 2). By 2014–15, PO deaths involving other substances had increased among all groups, and racial/ethnic differences were attenuated.

Among all PO deaths in 2002–03, the proportions of benzodiazepine-related deaths were higher than other combinations among whites, cocaine-related deaths were higher among minorities. By 2014–15, the proportions of heroin-related deaths had increased more among whites than minorities: change ratio=4.2 (95% CI = 3.8–4.6) among whites, 2.0 (95% CI = 1.7–2.5) among African-Americans, 1.4 (95% CI = 1.2–1.7) among Hispanics. Proportions of benzodiazepine-related deaths increased more among Hispanics than whites; alcohol-related deaths increased the most among African-Americans. In 2014–15, PO deaths in combination with benzodiazepines were most prevalent among whites, those involving heroin and cocaine among African-Americans, those involving heroin and benzodiazepines among Hispanics.

Among SO-M deaths, the proportions of heroin-related deaths increased more among whites (change ratio=24.8 [95% CI =16.5–37.3]) than African-Americans (9.2 [95% CI = 3.5–24.1]) and Hispanics (7.5 [95% CI = 2.8–19.7]). The proportions of cocaine-related deaths increased more among whites than African-Americans (Table 2). In 2014–15, the most prevalent combination was with heroin across race/ethnicity groups.

3.5.2. Increases in PO Deaths Attributable to Other Substances by Race/Ethnicity

The proportional increase in all PO deaths attributable to any of the five psychoactive substances was much higher for whites (24.0% [95% CI = 23.3%–24.5%] than African-Americans (12.2% [95% CI = 10.3%–13.0%]) or Hispanics (9.6% [95% CI = 8.1%–11.1%]). Among SO-M deaths, the increase attributable to substances in combination was highest among African-Americans (Figure 4, Supplementary Table 24).

Figure 4.

Figure 4

Figure 4

Open in a new tab

Attributable proportions of increases in prescription opioid (PO) deaths in combination with five other substances between 2002–03 and 2014–15 among (A) all prescription opioid (PO) deaths, and (B) synthetic opioids other than methadone (SO-M) deaths, by race/ethnicity.

Among all PO deaths, the increase attributable to heroin was higher among whites (18.1% [95% CI = 17.6%–18.6%]) than African-Americans (15.3% [95% CI = 13.7%–16.7%]) and Hispanics (10.8% [95% CI = 9.2%–12.4%]). The decrease in deaths attributable to cocaine was highest among minorities. Among SO-M deaths, the increase attributable to heroin was similar for all racial/ethnic groups; the increase attributable to cocaine was highest among Hispanics.

4. Discussion

Between 2002–03 and 2014–15, overall PO overdose deaths more than doubled; those involving SO-M increased over five times. To provide some insight into these increases, we implemented a novel analysis in which we examined concomitantly five psychoactive substances (benzodiazepines, antidepressants, heroin, alcohol, cocaine) listed in death records as contributing to PO deaths. We estimated the proportions of increase in overdose deaths over a twelve-year period attributable to increases in combination with specific substances. SO-M deaths were examined separately to capture indirectly the consequences of changing patterns of fentanyl deaths included in these deaths, since only broad drug classes, but not specific drugs, are identified in the Multiple-Cause-of-Death Files. Using this approach, we found that increases of almost one-fifth of all PO and SO-M deaths were attributable to substances in combination.

In 2014–15, 57.9% of all PO deaths involved one of five other psychoactive substances versus 44.3% in 2002–03. Benzodiazepines and heroin each contributed similar increases to all PO deaths, while heroin contributed to a much larger proportion of increased SO-M deaths than benzodiazepines (28.5% vs. 3.0%). However, cocaine-related deaths decreased among all PO deaths, but increased among SO-M deaths, and tempered the overall increase in all PO deaths. Cocaine was next in importance to heroin in its association with increased SO-M deaths. There were age, gender and racial/ethnic differences. At ages 50 and over, PO deaths in combination with benzodiazepines contributed more to all PO deaths than heroin. Heroin contributed more to increased deaths at ages 18–49 and among males than females for all PO and SO-M deaths. The proportion of heroin-related deaths was consistently lower among whites than minorities but increased substantially among whites. Despite the small number of heroin users in the population, increases in heroin-related deaths contributed markedly to the overall increase in PO deaths. Recent reports document that the increase in SO-M deaths is from increases in illicit fentanyl in combination with heroin (Gladden et al., 2016; Peterson et al., 2016) and cocaine (Tomassoni et al., 2017).

Increases in PO deaths involving other substances might be partially explained by increases in intensive nonmedical prescription use, since heavy users are more likely to use other substances (Han et al., 2015; Jones, 2013). Whether this is also the case for medical users cannot be ascertained, since trend data are unavailable. Our analyses of national 2015 data from the National Survey on Drug Use and Health (SAMHSA, 2016) indicate that past-year nonmedical benzodiazepine, cocaine and heroin use by exclusive medical users was only slightly higher than among non-PO users and much lower than among NMPO users (Supplementary Table 35). Thus, deaths in combination with other substances may be less prevalent among medical than nonmedical PO deaths. However, the respective proportions of PO deaths due to medical or nonmedical use are unknown. Many causes of increased PO mortality, besides deaths in combination with other substances, remain to be understood. These factors include increases in specific opioids used, intensity of use, opioid use disorder, medical, psychiatric or drug-disorder co-morbidities (Bohnert et al., 2016; Han et al., 2015), drug strength and purity (Pain and Policy Studies Group/WHO Collaborating Center, 2015), addition of toxic compounds, such as illicit fentanyl in heroin and cocaine (CDC, 2016, 2017; DEA, 2016; Gladden et al., 2016; Paone et al., 2016; Suzuki and El-Haddad, 2017). Number of prescriptions (Hwang et al., 2016; Volkow, 2014), variations in prescribing across states (CDC, 2014), changes in drug market, availability, and price may have also contributed to changing mortality patterns, as have broader societal changes, such as economic downturns (Carpenter et al., 2016). Except for combinations with other substances, these factors cannot be linked to death records, and their contributions to increased PO deaths cannot be evaluated.

Understanding the causes of PO deaths would be enhanced if medical and nonmedical PO users could be compared and if deaths could be linked to users’ behaviors prior to death, such as patterns of opioid use, use of other substances, or mental and physical health status. Longitudinal data from large cohorts sampled at different historical periods necessary to establish these linkages are unavailable.

Death records have limitations that may have affected our conclusions, including variations in the determination of causes of deaths, in testing or reporting, drug misidentification, missing data on specific drugs in different parts of the United States and at different periods, and the undercount of Hispanics (Arias et al., 2016; Hedegaard et al., 2014; Rudd et al., 2016a; Warner et al., 2009; 2016). The quality and completeness of reporting of specific substances involved in drug overdose deaths have varied substantially across time, as noted under Methods. Thus, increased PO overdose deaths may be due to improved post-mortem testing and overdose certification practices (Davis, 2014; Goldberger et al., 2013; Warner et al., 2016), as well as to increased use of other substances.

The findings highlight that one-fifth of the increase in PO overdose deaths over the last decade involved other substances in combination, particularly benzodiazepines and heroin, that a lower percentage among overall PO deaths involved cocaine, counterbalancing the increase among SO-M deaths, and that combinations with other substances vary among different age, gender and racial/ethnic groups. The greatest increases in heroin-related deaths occurred at ages 18–49 and for males among all PO and SO-M deaths.

Different groups of prescription opioid users will require different approaches to reduce morbidity and mortality. For populations in treatment for chronic pain, recommendations issued by the CDC for primary care physicians (Dowell et al., 2016) include reducing concurrent prescribing of opioids and benzodiazepines; educating patients regarding the risk of respiratory depression and overdose when prescription opioids are taken with benzodiazepines, alcohol, or illicit drugs, including heroin; addressing substance use, mental health and other comorbidities that increase the risk for polysubstance use; and drug testing to monitor the use of controlled and illicit substances. From public health and developmental perspectives, preventing polysubstance use may reduce morbidity and mortality associated with PO. Prevention and intervention efforts targeted toward reducing mortality associated with PO needs to take into account the type of opioid used, the frequency of opioid use and disorder, and use of other substances in different groups in the population.

Supplementary Material

1

Highlights.

  • 22% of increased prescription opioid (PO) deaths are attributable to 5 other drugs.

  • Benzodiazepines and heroin contribute equally to increased PO deaths.

  • Heroin contributes most to increased PO deaths at ages 18–49, among males, whites.

  • Increased non-methadone synthetic opioid deaths are mostly attributable to heroin.

Acknowledgments

Role of Funding Source

This research was supported by grant R01 DA036748 from the National Institute on Drug Abuse (D. Kandel, PI). Support was also provided by the New York State Psychiatric Institute (Griesler). The funding agency had no part in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

We thank the reviewers for their insightful comments. We would also like to acknowledge Benjamin Jenkins’ assistance in the preparation of the manuscript.

Footnotes

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Contributors

D. Kandel conceptualized the analysis. M. Hu conducted the data analysis. M. Wall provided statistical consultation. All of the authors contributed to the design of the analysis, reviewed the analysis, and participated in the writing of the manuscript.

Conflicts of Interest

The authors report no conflicts of interest.

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