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Journal of Studies on Alcohol and Drugs logoLink to Journal of Studies on Alcohol and Drugs
. 2023 Feb 19;84(1):171–179. doi: 10.15288/jsad.22-00049

Characterization of Unintentional Deaths Among Buprenorphine Users

Zheng Dai a,,*, George N Limen b, Marie A Abate b, James C Kraner c, Allen R Mock c, Gordon S Smith d
PMCID: PMC9948141  PMID: 36799687

Abstract

Objective:

Medications used to treat opioid use disorder (OUD) reduce drug overdose risk. Buprenorphine is often the preferred treatment for OUD because of its high safety profile. Given expanding buprenorphine use, this study sought to examine buprenorphine-involved deaths (BIDs) and compare them with other drug-related deaths.

Method:

West Virginia drug-related deaths from 2005 to early 2020 were identified. Study data included decedent demographics, toxicology, autopsy findings, and medical and prescription histories. Characteristics of BIDs compared with other drug-related deaths were statistically analyzed.

Results:

Among 11,764 drug-related deaths, only 564 (4.8%) involved buprenorphine. Buprenorphine alone was present in 32 deaths, of which 20 were considered the direct cause of death (0.2% of all drug-related deaths). Significantly more BIDs involved five or more drugs (23%) compared with other opioid deaths (14.9%). Co-intoxicants found most frequently in BIDs were benzodiazepines (47.3%), methamphetamine (27.1%), and fentanyl (22.9%). Cardiovascular and pulmonary comorbidities were identified in 43% and 21% of BIDs, respectively. Of the 564 BIDs, a current buprenorphine prescription was present in 132 deaths (23.4%).

Conclusions:

Despite increasing buprenorphine use, BIDs comprised less than 5% of overall West Virginia drug-related deaths. Seldom was it the only drug found, and most decedents did not have current prescriptions for buprenorphine. Although buprenorphine is effective, with a wide safety margin, clinicians and patients should be aware that buprenorphine can be involved in overdose deaths, especially when buprenorphine is taken in combination with drugs such as benzodiazepines, methamphetamine, or fentanyl, and in persons with underlying cardiovascular or pulmonary comorbidities.

Overdose death rates in the United States have almost tripled over the past two decades (Rudd et al., 2016), with West Virginia leading the nation in drug overdose mortality rates (Centers for Disease Control and Prevention, 2019). In 2019, 70.6% of U.S. overdose deaths involved an opioid (Mattson et al., 2021), with almost 2 million Americans suffering from opioid use disorder (OUD) (Substance Abuse and Mental Health Services Administration, 2021). Medications for opioid use disorder (MOUD) reduce overdose fatalities, and although use is increasing, the need to improve access to treatment is widely recognized (Haffajee et al., 2018; Li et al., 2016; McLean & Kavanaugh, 2019; Priest et al., 2020; Scholl et al., 2018; Woodruff et al., 2019; Wyse et al., 2022), especially with an increase in overdose deaths during the COVID-19 pandemic (Au-Yeung et al., 2021; Cochran et al., 2020; Davis & Samuels, 2021).

Although buprenorphine has been approved by the U.S. Food and Drug Administration to treat OUD (Volkow & Blanco, 2020), it remains underused in the United States, with access varying widely (Priest et al., 2020; Roehler et al., 2020; Wyse et al., 2022). As a partial agonist with a ceiling effect for respiratory depression, buprenorphine is generally a safer option than other opioids for OUD patients (Hickman et al., 2018; Mégarbane et al., 2006). Buprenorphine has become a key component of MOUD, especially in office-based settings, and efforts are under way to greatly expand access to it (Becerra, 2021; Substance Abuse and Mental Health Services Administration, 2021). However, although benefits generally substantially outweigh potential risks (Doernberg et al., 2019; Kriikku et al., 2018; Paone et al., 2015), buprenorphine has occasionally been identified as a primary or secondary cause of unintentional intoxication deaths (Bishop-Freeman et al., 2021; Mariottini et al., 2021; Pelissier-Alicot et al., 2010; Wightman et al., 2021), especially when combined with other central nervous system depressants (Bardy et al., 2015). The 2016–2018 U.S.

National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance data found that transmucosal buprenorphine products were involved in more than a third of emergency department visits involving any nonmedical injection of prescription opioids (Tanwar et al., 2020). However, identifying the relative importance of buprenorphine in adverse events is difficult because interpreting buprenorphine drug concentrations can be problematic, since postmortem peripheral blood concentrations have overlapped with antemortem therapeutic plasma concentrations for OUD patients receiving sublingual buprenorphine maintenance therapy (Bishop-Freeman et al., 2021).

When access to MOUD was expanded in Sweden, beneficial health and social outcomes such as reduced opioid mortality and hospitalizations were accompanied by an increase in buprenorphine deaths (Romelsjö et al., 2010). Two recent reports from Australia and Finland found that the risk of a fatal outcome from buprenorphine was associated with older age, concurrent drug use (especially central nervous system depressants), and a history of cardiovascular disease (Darke et al., 2021; Mariottini et al., 2021). Although another drug was present in most of these buprenorphine-involved deaths (BIDs), in a small proportion buprenorphine was the only substance found, which is similar to other recent reports (Bishop-Freeman et al., 2021; Wightman et al., 2021).

Given the lack of an established toxic blood concentration range for buprenorphine, the buprenorphine (parent drug):norbuprenorphine metabolite blood concentration ratio (B:N) has been proposed as a diagnostic tool to identify buprenorphine toxicity, with a B:N > 1 indicating potentially fatal buprenorphine intoxication (Häkkinen et al., 2012; Kronstrand et al., 2003; Seldén et al., 2012).

Although expanding buprenorphine prescribing for MOUD is a key element to mitigate the opioid crisis, it is important to examine buprenorphine involvement in drug-related deaths to determine its prevalence and possible contributing factors. The aims of this study were to characterize West Virginia BIDs, including source (prescribed vs. nonprescribed), common co-intoxicants, and concentrations present, and to compare the characteristics of BIDs with those of other opioids and non-opioid drug-related deaths.

Method

Data sources

In 2005, a forensic drug database was developed in collaboration with the West Virginia Office of the Chief Medical Examiner (WVOCME) to compile data from all West Virginia drug-related deaths (Dai et al., 2022). Drug-related death data were available from 2005 through 2020, with about 24% of 2019 deaths and 38% of 2020 deaths still being processed at the time of this study. The deaths included those in which overdose was the direct cause of death or a transportation-related injury, other injury, or medical condition was the direct cause of death but drugs were determined to be significant contributors. Toxicological testing is routinely performed in deaths investigated by the WVOCME, with confirmatory tests conducted for most positive screens. The forensic drug database cases include demographics (e.g., age, sex, race), cause and manner of death, toxicology findings (e.g., drugs identified, concentrations, postmortem interval), whether a prescription was present within the past 30 days for controlled substances, autopsy findings, and medical history. Data were obtained from the death certificate, autopsy report, external examination and investigator reports, medical records, police and toxicology reports, and the WV Controlled Substances Monitoring Program (WVCSMP). Medical history information was from county medical examiner records, scene investigations, prescription records, autopsy reports, and medical records when available. Comorbidities were identified through autopsy reports and decedent file information (Supplemental Table 1). The number of drugs with a valid prescription (a prescription present within 30 days before death) and buprenorphine MOUD use were determined through use of the WVCSMP and decedent records. Exemption was obtained by the West Virginia University Institutional Review Board for use of decedent de-identified records.

Toxicological testing

Blood, urine, and/or tissue samples are screened for volatile compounds using gas chromatography with flame ionization detection and drugs using automated enzyme immunoassay. Positive immunoassay screens are followed by confirmatory testing and quantitative measurement in a peripheral blood sample. Heroin was considered present when the drug or its metabolite 6-monoacetylmorphine (6-MAM) were identified in any sample tested. Deaths involving buprenorphine were confirmed by postmortem toxicology testing and identified by the medical examiner as a direct cause of or contributor to death.

Buprenorphine and norbuprenorphine concentrations were determined using liquid chromatography with tandem mass spectrometry following solid supported liquid extraction. Limits of quantitation were 0.5 ng/ml and 1.0 ng/ml for buprenorphine and norbuprenorphine, respectively. Femoral or subclavian blood samples were used for concentration analyses and to calculate parent drug (buprenorphine) to metabolite (norbuprenorphine) concentration ratios.

Data analyses

Descriptive analyses were used to characterize the demographics, number of concomitant drugs, and comorbidities present in BIDs, deaths involving other opioids, and deaths involving non-opioid substances. Kruskal–Wallis tests and chi-square tests were used for continuous and categorical data comparisons, respectively, among the three groups. Age-adjusted mortality rates were calculated for each group using the direct method by controlling for age distributions of a “standard” population. Standard West Virginia population weights for age standardization from the 2000 U.S. census were used (https://www.infoplease.com/us/census/west-virginia/demographic-statistics). Among BIDs in which a valid buprenorphine prescription was present, the extent to which buprenorphine was documented to have been used as part of MOUD, along with the number of days prescribed (when available), were determined. The BID co-intoxicants and their prescription status were also examined based on whether the buprenorphine was prescribed versus nonprescribed. Because of skewed distributions, Kruskal–Wallis tests were used to compare buprenorphine and norbuprenorphine concentrations based on the number of drugs identified in the deaths. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC). A p value of less than .05 was considered statistically significant.

Results

Most of the 11,764 drug-related deaths from January 2005 to December 2020 were associated with opioids; 564 (4.8%) were BIDs and 68.6% involved other opioids (Table 1). No opioids were present (non-opioid group) in only 26.6% of deaths. Approximately 68% overall were male, with the mean age slightly but statistically significantly higher in the non-opioid group (~45 years old) compared with the other groups (~41 years old). The West Virginia decedent ages ranged up to 75 years old; about 15% of decedents were 55 years of age or older. Roughly a third of decedents overall were obese (mean body mass index across groups of 28–29 kg/m2). A greater percentage of BIDs (96%) were unintentional compared with the other groups (p < .0001), with most resulting from overdose. Significantly more drugs were identified in the BIDs (p < .0001), particularly when compared with the non-opioid group (means of 3.5 vs. 1.8 drugs, respectively). Almost 45% of BIDs had four or more substances identified, compared with about 32% of other opioid-related deaths and only 11% of non-opioid deaths. Female decedents, regardless of subgroup, had a slightly higher mean number of co-intoxicants present compared with males.

Table 1.

Characteristics of drug-related deaths by opioid and buprenorphine involvement in West Virginia, 2005 to 2020 (n = 11,764)

graphic file with name jsad.22-00049.tbl1.jpg

Characteristics Total, n (%) Buprenorphine, n (%) opioid(s)an (%) Non-opioidbn (%) p c
Total 11,764 564 (4.8%) 8,075 (68.6%) 3,125 (26.6%) N.A.
Age, M (SD) 42.0 (12.1) 41.5 (1.8) 41.1 (11.7) 44.6 (13.0)* <.0001
Male 7,973 (67.8%) 382 (67.7%) 5,395 (66.8%) 2,196 (70.3%)* .0019
Race <.0001
 White 11,265 (95.8%) 553 (98.0%)* 7,765 (96.2%) 2,947 (94.3%)
 Black 453 (3.9%) 9 (1.6%) 287 (3.6%) 157 (5.0%)
 Other 46 (0.4%) 2 (0.4%) 23 (0.3%) 21 (0.7%)
Weight distribution <.0001
 Overweight 3,416 (29.0%) 149 (26.4%) 2,382 (29.5%) 885 (28.3%)
 Obese 4,105 (34.9%) 201 (35.6%) 2,954 (36.6%) 950 (30.4%)*
BMI, M (SD) 28.6 (7.8) 28.3 (8.0) 29.0 (7.9) 27.7 (7.5) .0743
Manner of death <.0001
 Unintentional 10,456 (88.9%) 543 (96.3%) 7,554 (93.5%) 2,359 (75.5%)*
 Suicide 711 (6.0%) 4 (0.7%) 232 (2.9%) 475 (15.2%)
 Other (could not be determined, homicide) 597 (5.1%) 17 (3.0%) 289 (3.6%) 291 (9.3%)
Cause of death <.0001
 Overdose 10,432 (88.7%) 525 (93.1%) 7,804 (96.6%) 2,103 (67.3%)*
 Transportation 680 (5.8%) 25 (4.4%) 126 (1.6%) 529 (16.9%)
 Other injury (e.g., drowning, fire, etc.) 652 (5.5%) 14 (2.5%) 145 (1.8%) 493 (15.8%)
Number of drugs identified, M (SD) 2.7 (1.5) 3.5 (1.5) 3.0 (1.5) 1.8 (1.3)* <.0001
 Male 2.6 (1.4) 3.4 (1.4) 2.9 (1.4%) 1.6 (1.0%)* <.0001
 Female 3.1 (1.7) 3.7 (1.7) 3.3 (1.6%) 2.3 (1.6%)* <.0001
Concomitant drugs identified <.0001
 Single drug 2,757 (23.4%) 32 (5.7%)* 929 (11.5%) 1,796 (57.5%)
 Two drugs 3,156 (26.8%) 120 (21.3%) 2,380 (29.5%) 656 (21.0%)
 Three drugs 2,694 (22.9%) 161 (28.5%) 2,196 (27.2%) 337 (10.8%)
 Four or more drugs 3,157 (26.8%) 251 (44.6%) 2,570 (31.8%) 336 (10.8%)
Comorbidities
 Cardiovascular 4,622 (39.3%) 244 (43.3%)* 3,251 (40.3%) 1,127 (36.1%) <.0001
 Pulmonary 2,375 (20.2%) 119 (21.1%) 1,649 (20.4%) 607 (19.4%) .4285
 History of substance use disorder 7,919 (67.3%) 494 (87.6%)* 5,447 (67.5%) 1,978 (63.3%) <.0001
 Psychiatric 2,302 (19.6%) 134 (23.8%)* 1,497 (18.5%) 671 (21.5%) <.0001
 Hepatic 1043 (8.9%) 66 (11.7%)* 738 (9.1%) 239 (7.6%) .0024
 Pain 840 (7.1%) 45 (8.0%) 658 (8.1%) 137 (4.4%)* <.0001
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Notes: N.A. = not applicable; BMI = body mass index.

a

Includes oxycodone, hydrocodone, heroin, etc.;

b

includes stimulants, benzodiazepines, alcohol, etc.;

c

comparison among the three subgroups, chi-square or Kruskal–Wallis tests as appropriate.

*

Significantly different from other two subgroups. Chi-square tests (with Tukey multiple comparisons following overall significant difference) and Kruskal–Wallis test (with Dunn–Bonferroni post hoc tests following overall significant difference) were used as appropriate.

Buprenorphine was identified as a single drug in only 32 unintentional BIDs (Table 1). The route of administration in most was unknown (20 cases), with injection reported in 8 cases, oral administration in 3 cases, and nasal insufflation in 1 case. In 12 of the 32 cases, the direct cause of death was transportation/mechanical injuries or an underlying medical condition, with buprenorphine considered a contributor to death. In the remaining 20 cases, buprenorphine was the direct cause of death, but medical conditions including cardiovascular disease in 5 cases (ischemic heart disease, atherosclerotic coronary artery disease, heart failure) and pulmonary disease (2 cases) were contributors. A recent prescription was documented in just 5 of the 32 buprenorphine-alone deaths.

A history of substance use disorder was documented in a greater percentage (~88%) of BIDs compared with the other subgroups (p < .0001; Table 1). Of the comorbidities analyzed, cardiovascular disorders were present in almost 40% of decedents overall (43% of BIDs vs. 36% of non-opioid deaths and 40% of other opioid-related deaths; p < .0001). Pulmonary disease or a documented psychiatric condition were each present in approximately 20% of decedents overall, followed by hepatic disease; BIDs had statistically significantly higher percentages of the latter two comorbidi-ties compared with the other subgroups.

Figure 1 shows the proportion of BIDs, other opioid-related deaths, and non-opioid deaths over time. The BIDs remained fairly low (<40 cases/year) through 2015, with a 127% increase occurring from 2015 (37 deaths) to 2016 (84 deaths), followed by fairly stable numbers and proportions afterward. This leveling of BIDs from 2016 to 2018 (~7%–8% of the total drug-related deaths per year) was observed even though the total number of prescribed buprenorphine doses in West Virginia steadily increased over time from 3.5 million doses in 2011 to 8.7 million doses in 2018. The highest annual age-adjusted mortality rate for BIDs (4.7 per 100,000) occurred in 2018, compared with death rates that year of 59.9 per 100,000 for total overdose deaths, 37.8 per 100,000 for other opioid deaths, and 17.5 per 100,000 for non-opioid drug-related deaths. Although data entry for 2019 and 2020 were incomplete, the number and proportion of BIDs using the available data for those years showed that the BIDs remained low (69 BIDs representing 7% of overall drug-related deaths in 2019 and 70 BIDs representing 8.4% of overall deaths in 2020).

Figure 1.

Figure 1.

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Buprenorphine, other opioid, non-opioid-related deaths, N(% total), West Virginia, 2011–2018. The three lines denote the number of buprenorphine, other opioid, and non–opioid-related deaths in West Virginia by year, 2011–2018; N (percentage of total drug deaths) shown for every other year.

Examination of prescription data found that of the total 564 BIDs, a valid prescription for buprenorphine was present in only 132 (23%), with most (108 [82%]) of those documented to be enrolled in an MOUD program (19% of total BIDs). The numbers of BIDs with no buprenorphine prescription were similar from 2016 to 2018 (55–57 deaths per year). Although there was much overlap among cases, the number of days buprenorphine was prescribed before death was considerably longer in decedents who received buprenorphine as part of MOUD versus not part of MOUD or unknown (M = 482 and 180 days, respectively).

Table 2 shows the number of deaths with specific substances present in the total unintentional deaths and for BIDs, based on the number of BID co-intoxicants identified. Overall, benzodiazepines were most frequently present in BIDs (47.3%), followed by other opioids (42.2%) and stimulants (40.9%). Although fentanyl was most frequently identified in the total drug-induced deaths, alprazolam was the most common co-intoxicant present overall in BIDs (29.5%), followed by methamphetamine (27.4%) and fentanyl (23.6%). Stimulants were most frequently identified in BIDs when only one co-intoxicant was present (50% of cases), with methamphetamine being most common (42.2%), followed by ethanol (16.4%) and cocaine (6.9%). As the number of co-intoxicants increased, alprazolam, diazepam, clonazepam, and most of the other substances shown in Table 2 (with the exception of hydrocodone, methamphetamine, and ethanol) were found with increasing frequency.

Table 2.

Substances in unintentional total and buprenorphine-involved deaths (BIDs)

graphic file with name jsad.22-00049.tbl2.jpg

Substance Total deaths n (%)a Total BIDs n (%)b Substances present n (%) by number of co-intoxicants in BIDs
One (n = 116) Two (n =158) Three (n = 112) Four (n = 126)
Opioids 8,097 (77.4) 229 (42.2%)c 15 (12.9) 64 (40.5) 63 (56.3) 87 (69.0)
 Fentanyl 2,884 (27.6) 128 (23.6) 6 (5.2) 38 (24.1) 33 (29.5) 51 (40.5)
 Oxycodone 2,081 (19.9) 50 (9.2) 2 (1.7) 40 (7.6) 15 (13.4) 21 (16.7)
 Heroin 1,614 (15.4) 48 (8.8) 1 (0.8) 11 (7.0) 12 (10.7) 24 (19.0)
 Hydrocodone 1,447 (13.8) 49 (9.0) 3 (2.6) 13 (8.2) 17 (15.2) 16 (12.7)
Benzodiazepines 3,997 (38.2) 257 (47.3) 11 (9.5) 74 (46.8) 77 (68.8) 95 (75.4)
 Alprazolam 2,296 (22.0) 160 (29.5) 7 (6.0) 45 (28.5) 49 (43.8) 59 (46.8)
 Diazepam 1,787 (17.1) 104 (19.2) 2 (1.7) 28 (17.7) 32 (28.6) 42 (33.3)
 Clonazepam 675 (6.5) 68 (12.5) 2 (1.7) 6 (3.8) 23 (20.5) 37 (29.4)
Stimulants 3,159 (30.2) 222 (40.9) 58 (50.0) 63 (39.9) 40 (35.7) 61 (48.4)
 Methamphetamine 1,592 (15.2) 149 (27.4) 49 (42.2) 41 (25.9) 23 (20.5) 36 (28.6)
 Cocaine 1,573 (15.0) 75 (13.8) 8 (6.9) 22 (13.9) 20 (17.9) 25 (19.8)
Ethanol 2,386 (22.8) 83 (15.3) 19 (16.4) 20 (12.5) 22 (19.6) 22 (17.5)
Gabapentin 648 (6.2) 90 (16.6) 4 (3.4) 23 (14.6) 23 (20.5) 40 (31.7)
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Notes: Bold indicates top three individual substances present in column.

a

Denominator = total unintentional drug-related deaths (N = 10,456);

b

denominator = total number of unintentional buprenorphine deaths (n = 543);

c

opioids other than buprenorphine.

Analyses of prescription data for the controlled substances involved in total drug-related deaths and BIDs found that decedents did not have a prescription for most substances present. For example, of the 2,296 total unintentional deaths involving alprazolam (seen in Table 2), only 930 (40.5%) had a recent prescription in the WVCSMP. Of the 160 BIDs in which alprazolam was identified, alprazolam was prescribed in only about 9.5% of cases; the percentages were similar regardless of whether buprenorphine was prescribed or not prescribed. When fentanyl, oxycodone, hydrocodone, diazepam, or clonazepam were identified in the BIDs, a prescription was found to be present for less than 5% of each.

The buprenorphine and norbuprenorphine (metabolite) concentrations varied significantly (generally lower) as the number of drugs involved increased (Table 3) from single buprenorphine presence to three or four or more drugs present (p < .0001 for buprenorphine, p = .0008 for norbuprenorphine). The highest concentrations were present in single buprenorphine deaths. Although not shown in the table, the median buprenorphine concentration was found to be significantly higher in decedents documented to be in an MOUD program (0.0030 µg/ml) compared with the nonprescribed buprenorphine group (0.0022 µg/ml) (p = .03).

Table 3.

Buprenorphine and norbuprenorphine concentrations in unintentional deaths by number of drugs present

graphic file with name jsad.22-00049.tbl3.jpg

Drug or metabolite, gg/ml n M (SD) Mdn [min., max.] p a
Buprenorphine 378 0.0073 (0.0257) 0.0026 [0.0004, 0.3800] <.0001
 Single drug 27 0.0154 (0.0357) 0.0074 [0.0012, 0.1910]
 Two drugs 83 0.0097 (0.0276) 0.0025 [0.0005, 0.1720]
 Three drugs 106 0.0052 (0.0076) 0.0025 [0.0005, 0.0460]
 Four or more drugs 162 0.0061 (0.0300) 0.0023 [0.0004, 0.3800]
Norbuprenorphine 364 0.0060 (0.0134) 0.0027 [0.0003, 0.1900] .0008
 Single drug 27 0.0148 (0.0355) 0.0074 [0.0005, 0.1900]
 Two drugs 76 0.0071 (0.0151) 0.0027 [0.0003, 0.1190]
 Three drugs 94 0.0042 (0.0044) 0.0025 [0.0005, 0.0212]
 Four or more drugs 163 0.0050 (0.0080) 0.0024 [0.0005, 0.0561]
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Notes: Min. = minimum; max. = maximum.

a

Kruskal–Wallis tests were used to compare the concentrations by number of concomitant drugs.

The B:N ratio was determined in 27 of the 32 buprenorphine-only deaths for which subclavian or femoral blood concentrations were available (Supplemental Table 2). When the cause of death was identified as direct buprenorphine toxicity, the mean and median B:N ratios in the direct toxicity subgroup (2.02 and 1.21) were larger than those in the subgroup in which buprenorphine was ruled a contributor to death (1.05 and 0.91). The B:N ratios exceeded 1 in 11 of 17 direct toxicity cases (64.7%) and in 5/10 cases (50%) when buprenorphine contributed to death.

Discussion

The number of BIDs in West Virginia was low, with less than 1 in 20 total drug-related deaths involving buprenorphine. Despite continual increases in prescribed buprenorphine doses, the buprenorphine-involved mortality rate remained low over time compared with the total drug overdose and opioid-related death rates. About two thirds of BIDs in this study were male, slightly lower than the 72%–83% reported in the literature (Darke et al., 2021; Kintz, 2001; Mariottini et al., 2021; Uosukainen et al., 2013). The mean age of BIDs in this report (41.5 years) was older than the mean ages (27–34 years) found in other studies (Cicero et al., 2014; Häkkinen et al., 2012; Seldén et al., 2012). The proportion of obese decedents across all subgroups was high but consistent with the 37.7% prevalence of obesity in West Virginia (Simonsen et al., 2020).

Although buprenorphine is unlikely to cause respiratory depression in the absence of other depressant drugs, small numbers of deaths involving buprenorphine alone have been reported (Darke et al., 2021; Kriikku et al., 2018; Mariottini et al., 2021; Seldén et al., 2012). Buprenorphine was the only drug present in a small number of drug-related deaths in our study. Cardiovascular or pulmonary disease were present in 50% and 25%, respectively, of these deaths and could have been contributing factors. Only 20 of the buprenorphine-only deaths resulted from direct toxicity (<0.2% of all drug-related deaths). In contrast, buprenorphine has been shown to reduce overdose death rates by more than a third (National Institutes of Health, 2018), which can be of substantial benefit to the estimated 2 million OUD patients in American (Substance Abuse and Mental Health Services Administration, 2021).

The greater prevalence of reported substance use disorder among BIDs was expected given buprenorphine's role as an MOUD. Both cardiovascular and pulmonary diseases were relatively frequent in the West Virginia BIDs (43% and 21%, respectively), which were significantly greater proportions than seen in the other opioid or non-opioid–related deaths. It should be noted that these BID rates were also higher than the prevalence of cardiovascular disease (14.6% of population) and chronic obstructive pulmonary disease (13.9%) in the general West Virginia population (West Virginia Department of Health and Human Resources, 2018). Australia reported cardiovascular and pulmonary diseases in their buprenorphine-related deaths in proportions similar to those observed in the West Virginia BIDs, with cardiovascular pathology observed in 43% and pulmonary disease (emphysema and/or asthma) identified in 24% of Australian buprenorphine-related fatalities (Darke et al., 2021). Thus, underlying cardiovascular or pulmonary conditions may be risk factors for adverse outcomes with buprenorphine, especially when combined with other substances.

Most BIDs in this analysis resulted from unintentional buprenorphine overdose without the presence of a buprenorphine prescription. Only 23% of decedents had a buprenorphine prescription in the WVCSMP within 30 days before death, a much smaller proportion than the 75% prescription rate reported from Australia (Darke et al., 2021). In West Virginia, all buprenorphine dispensed by health care providers, including opioid treatment programs, must be entered into the WVCSMP within 24 hours. As a schedule III controlled substance, buprenorphine is subject to the prescribing limitations of other such medications in West Virginia (i.e., not filled or refilled more than 6 months after the date issued, and if authorized to be refilled may not be refilled more than five times) (West Virginia Code, 2022). The lack of documented buprenorphine prescriptions in our data set can reflect illicit use of the drug or out-of-state prescribing and/ or dispensing from an opioid treatment program in another state or from a veterans’ health care facility not tracked by the WVCSMP. Although buprenorphine prescribing has been increasing in West Virginia, it is unknown how increases in prescribed buprenorphine might affect its diversion or illicit use. Current studies suggest that most nonprescribed buprenorphine is used to self-treat and control withdrawal and craving symptoms from other opioids (National Institute on Drug Abuse, 2021), and that higher frequency of nonprescribed buprenorphine use is associated with a decreased overdose risk (Carlson et al., 2020). Increased prescribed buprenorphine to treat OUD would also be expected to reduce overall drug overdose rates.

Most West Virginia BIDs involved multiple co-intoxicants, most commonly benzodiazepines (e.g., alprazolam), opioids (e.g., fentanyl), or stimulants (e.g., methamphetamine), similar to prior studies (Häkkinen et al., 2012; Mariottini et al., 2021; Simonsen et al., 2020; Winstanley et al., 2020). Our study identified a benzodiazepine in a higher proportion of BIDs compared with drug-related deaths overall (47% vs. 38%, respectively), which increased to about three quarters with more than four co-intoxicants present. This differed from other studies outside the United States that identified benzodiazepines in a much greater proportion (82%–94%) of BIDs (Häkkinen et al., 2012; Mariottini et al., 2021). Many OUD patients can have concomitant anxiety disorders, insomnia, or agitation for which a benzodiazepine is indicated (Bounds & Nelson, 2021). It is unclear if the risks of intoxication/death with concomitant buprenorphine and benzodiazepine ingestion might vary depending on the specific benzodiazepine involved. Similar to our findings, two other studies identified alprazolam as the top benzodiazepine present among BIDs (Häkkinen et al., 2012; Seldén et al., 2012); another report found the same top three benzodiazepines as in our study but at differing frequencies (Mariottini et al., 2021). Seldén et al. (2012) speculated that there might be enhanced toxicity from the alprazolam combination given the prevalence of alprazolam (41%) in their buprenorphine intoxication deaths. However, differences in specific benzodiazepine frequencies among BIDs could simply represent drug availability (prescription, street/illicit) or prescriber preferences in different countries or geographic areas. The presence of benzodiazepines, fentanyl, or alcohol is consistent with the fact that buprenorphine's ceiling effect can be overcome by other psychoactive drugs (Häkkinen et al., 2012). Even among deaths in which buprenorphine was prescribed, illicit benzodiazepines and multiple substance ingestion can be an important cause of fatal overdosage (Mariottini et al., 2021; Park et al., 2020).

Methamphetamine was a frequent co-intoxicant in our BIDs and was more commonly identified than in the total drug-related deaths. It was the most frequent substance present when only one additional drug was identified with buprenorphine. In contrast, methamphetamine was present in just slightly over a quarter of buprenorphine overdose cases in prior studies (Darke et al., 2021; Simonsen et al., 2020). Whether a methamphetamine–buprenorphine combination might have a greater risk potential compared with other single drug–buprenorphine combinations is unknown and should be studied further.

Considerable variability in buprenorphine concentrations has been observed in BIDs, with reported concentrations ranging from 0.0001 to 0.076 µg/ml (Kintz, 2001). Our analyses found 5 of 378 (1.3%) BIDs with buprenorphine concentrations greater than 0.076 µg/ml. The significant decrease in median buprenorphine and norbuprenorphine concentrations seen in our data as the number of potential respiratory co-intoxicants increased is consistent with a reduction in or loss of buprenorphine's ceiling effect. There was a higher calculated B:N ratio in our single-drug BIDs in which buprenorphine toxicity was considered the direct cause of death versus the deaths in which buprenorphine was a contributing factor. Although there was variability among the B:N ratios with values of both less than and greater than 1 observed, the larger B:N values in our study were consistent with prior reports of B:N ratios greater than 1 with buprenorphine poisoning (Häkkinen et al., 2012; Kronstrand et al., 2003; Seldén et al., 2012).

Strengths of this study included the long period studied, inclusion of buprenorphine prescribing information, and comparisons with other opioid and non-opioid decedent groups. The use of a comprehensive database that did not rely primarily on death certificate information provided a broad range of data for analyses. Study limitations included that it was not possible to determine the extent to which buprenorphine was obtained illicitly in decedents without a prescription for the drug. About 14.5% of BIDs, a fairly small number, were excluded from the concentration analyses because of missing femoral or subclavian drug concentrations. Interpreting postmortem drug concentrations can be difficult due to potential postmortem redistribution. To minimize variability attributable to redistribution, only femoral or subclavian blood samples were used to determine buprenorphine and norbuprenorphine concentrations. Although efforts were made to identify all comorbidities (e.g., cardiovascular, respiratory, psychiatric disease), medical records were not available for all cases, so some relevant preexisting conditions were likely missed. Data were incomplete for drug-related deaths in 2019 and 2020. Finally, it was not possible to determine the specific mortality rate associated with buprenorphine use for MOUD since an accurate number of patients receiving buprenorphine therapy as part of MOUD statewide could not be determined. Additionally, it was not known if any decedents had recently stopped MOUD, since abstinence from buprenorphine for a short time might increase the fatal intoxication risk resulting from loss of opioid tolerance (Seldén et al., 2012).

Conclusions

Compared with other opioids, buprenorphine was involved in a relatively small number of West Virginia deaths since 2005. Although the number of BIDs increased in recent years, the proportion of buprenorphine involvement in total drug-related deaths was stable despite steady increases in buprenorphine prescribing. A documented prescription was not present for most buprenorphine involved in the deaths. Polydrug use, particularly involving fentanyl, benzodiazepines, and stimulants, was very common. Buprenorphine as a single drug was involved in a very small number of fatalities. Comorbid cardiovascular or respiratory disease was prevalent in a greater-than-expected percentage of BIDs and could be risk factors for toxicity development, especially when multiple drugs are combined. Buprenorphine plays an important role in the evidence-based treatment of OUD. However, clinicians and patients should be knowledgeable about the potential risks of mixing other drugs with buprenorphine, particularly in the presence of underlying comorbidities.

Conflict-of-Interest Statement

Gordon S. Smith has testified for West Virginia in opioid litigation. No other conflicts are declared.

Footnotes

This work was supported by the following awards: National Institute of General Medical Sciences (2U54GM104942-02) and National Institute on DrugAbuse (R21DA040187 and 1UG3DA044825).The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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