The n e w e ng l a n d j o u r na l of m e dic i n e

C or r e sp ondence

Fentanyl-Associated Overdose Deaths Outside the Hospital

To the Editor: In March 2022, 12-month drug-
overdose fatalities reached their highest record-
ed level in the United States, with an estimated
110,360 deaths.1 Changes in the illicit drug sup-
ply during the pandemic have resulted in more
fentanyl-associated overdose deaths.2 The potency
of fentanyl and the rapidity of onset of its effect
have the potential to increase overdose mortality,
especially among people who are unable to re-
ceive timely medical care.
We used cause-of-death data from the Na-
tional Center for Health Statistics3 to evaluate
drug-overdose deaths that occurred outside the
hospital before the Covid-19 pandemic as com-
pared with deaths that occurred during the early
years of the pandemic (2016 through 2021). Over-
dose deaths were categorized according to wheth-
er they involved a synthetic opioid other than
methadone (primarily fentanyl),4 another opioid
without fentanyl, or no opioid. The place of death
was categorized as outside a hospital or in a hos-
pital or other medical setting, and we calculated
the annual incidence of death per million U.S.
population. Poisson regression models were used
to calculate changes in mortality. We used Join-
point statistical software to perform regression
analysis to identify changes in trends in the
percentage of out-of-hospital overdose deaths in
each drug category.5 Details regarding the meth-
ods and data analysis used in the study are avail-
able in the Supplementary Appendix, available
with the full text of this letter at NEJM.org.
We found that overdose deaths increased dur-
ing the early pandemic period and were driven
primarily by out-of-hospital deaths that were as-
sociated with fentanyl, which increased from 46.6
per million in 2016 to 178.0 per million in 2021,
a 282% increase (95% confidence interval [CI],
275 to 289) (Fig. 1). In 2016, 74.1% of all over-
dose deaths occurred outside the hospital, a
percentage that increased to 78.0% in 2020 and
78.6% in 2021. Deaths occurred outside the hos-
pital in 83.0% of fentanyl overdoses in 2021, as
compared with 76.1% of opioid-overdose deaths
without fentanyl involvement and 67.8% of over-
dose deaths that did not include opioids. The pro-
portion of out-of-hospital deaths increased for
fentanyl overdoses (annual percent change, 1.6%;
95% CI, 1.1 to 2.0) at the same time that the
proportions remained similar for other opioid
overdoses (annual percent change, 0.1%; 95% CI,
−0.2 to 0.3) and nonopioid overdoses (annual
percent change, −0.3%; 95% CI, −1.1 to 0.5). Ad-
ditional data regarding yearly overdose deaths,
changes in incidence, and place of death are
provided in Tables S1 through S4 in the Supple-
mentary Appendix.
Joinpoint regression analysis identified chang-
es in trend in the proportion of overdose deaths
that occurred outside the hospital for each drug
category during the first and second years of the
pandemic. The increase in out-of-hospital over-
this week’s letters
87 Fentanyl-Associated Overdose Deaths Outside
the Hospital
88 Endovascular Thrombectomy for Acute Large
Ischemic Strokes
90 Fifteen-Year Outcomes of the ProtecT Trial
for Localized Prostate Cancer
92 Screening for Prostate Cancer
94 Case 11-2023: A Man with Mantle-Cell
Lymphoma and Hypoxemia

n engl j med 389;1 nejm.org July 6, 2023 87

The New England Journal of Medicine
Downloaded from nejm.org on August 7, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

180 Fentanyl: out-of-hospital

170
160
150

Deaths (no. per million population)

140
130
120
110
100
90
80
70
60
Nonopioid: out-of-hospital
50
40 Fentanyl: hospital
30 Nonopioid: hospital
20 Other opioid: out-of-hospital
10 Other opioid: hospital
0
2016 2017 2018 2019 2020 2021

Figure 1. Trends in Drug-Overdose Deaths, According to Location and Drug Type.

Shown are the number of deaths from drug overdoses per 1 million U.S. population from 2016 through 2021, a peri-
od that encompassed the years immediately before and after the start of the Covid-19 pandemic.

dose deaths during the early years of the Covid-19 Disclosure forms provided by the authors are available with
pandemic suggests that drug overdoses had in- the full text of this letter at NEJM.org.

creased in severity because of the increasing in- This letter was published on June 21, 2023, at NEJM.org.
volvement of fentanyl. 1. Ahmad FB, Cisewski JA, Rossen LM, Sutton P. Provisional
Molly M. Jeffery, Ph.D., M.P.P. drug overdose death counts. Atlanta:​Centers for Disease Con-
trol and Prevention, 2023 (https://www​.­cdc​.­gov/​­nchs/​­nvss/​­vsrr/​
Maria Stevens, M.A., M.P.H. ­drug​-­overdose​-­data​.­htm).
Mayo Clinic 2. Centers for Disease Control and Prevention. Increase in fatal
Rochester, MN drug overdoses across the United States driven by synthetic opi-
jeffery​.­molly@​­mayo​.­edu oids before and during the COVID-19 pandemic. December 17,
2020 (https://emergency​.­cdc​.­gov/​­han/​­2020/​­han00438​.­asp).
Gail D’Onofrio, M.D. 3. National Center for Health Statistics. Public use data file
Edward R. Melnick, M.D., M.H.S. documentation: mortality multiple cause-of-death. Atlanta:​
Yale University Centers for Disease Control and Prevention, December 22, 2022
New Haven, CT (https://www​.­cdc​.­gov/​­nchs/​­nvss/​­mortality_public_use_data​.­htm).
The content of this letter is solely the responsibility of the 4. Han B, Einstein EB, Jones CM, Cotto J, Compton WM,
authors and does not necessarily represent the official views of Volkow ND. Racial and ethnic disparities in drug overdose
the National Institutes of Health. deaths in the US during the COVID-19 pandemic. JAMA Netw
Supported by the National Institutes of Health (NIH) Com- Open 2022;​5(9):​e2232314.
mon Fund of the NIH Health Care Systems Research Collabora- 5. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests
tory through a cooperative agreement (U24AT009676) with the for joinpoint regression with applications to cancer rates. Stat
Office of Strategic Coordination and by a cooperative agreement Med 2000;​19:​335-51.
(UH3DA047003) with the National Institute on Drug Abuse. DOI: 10.1056/NEJMc2304991

Endovascular Thrombectomy for Acute Large Ischemic Strokes

To the Editor: SELECT2 (Randomized Con- that supports the use of thrombectomy for large
trolled Trial to Optimize Patient’s Selection for ischemic strokes. The protocol mentions an as-
Endovascular Treatment in Acute Ischemic Stroke) sessment of collateral vessels at baseline,2 but the
by Sarraj et al. (April 6 issue)1 provides evidence authors do not provide this information. In a

88 n engl j med 389;1 nejm.org July 6, 2023

The New England Journal of Medicine

Downloaded from nejm.org on August 7, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.