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

Acute Amnestic Syndrome Associated with Fentanyl Overdose

To the Editor: Between 2012 and 2016, a total
of 14 patients in Massachusetts with a history of
substance use had an acute anterograde amnes-
tic syndrome that lasted for months (or longer in
some patients); this amnestic syndrome was char-
acterized by a hyperintense signal involving both
hippocampi on magnetic resonance imaging dif-
fusion-weighted sequences.1 The patients were
also variably observed to have deficits in other
cognitive domains, including orientation and at-
tention. Thirteen of these 14 patients had a posi-
tive toxicologic test for opioids or had a history of
opioid use, but none underwent testing for syn-
thetic opioids such as fentanyl. Although synthetic
opioids are currently often combined with heroin,
they are not typically identified on routine assays
for morphine, heroin metabolites, or oxycodone.2
This amnestic syndrome also occurred in a
patient who overdosed in Maryland and was ul-
timately transferred to a tertiary care center in
West Virginia, where the case was reported; this
patient had a history of heroin use and tested
positive for norfentanyl and cocaine.3 We report
four additional cases in patients (age range, 28
to 37 years) who had a history of heroin use and
presented with this acute amnestic syndrome in
Massachusetts in 2017. Confirmatory toxicologic
tests in all four patients were positive for fentanyl
and its metabolite norfentanyl in either urine (three
patients; range of fentanyl level, 1.8 to >200 ng per
milliliter) or serum (one patient; fentanyl level,
1.87 ng per milliliter). These patients were not
known to have used fentanyl. The results of the
toxicologic analysis are summarized in the Sup-
plementary Appendix, available with the full text
of this letter at NEJM.org. Routine screening im-
munoassays for opiates in the urine were negative
in three patients, but an immunoassay was posi-
tive in the fourth after the patient received mor-
phine in the hospital. The urine immunoassay for
the heroin metabolite 6-monoacetylmorphine was
negative in this fourth patient. In one patient, a
routine urine toxicologic screening test was also
positive for cocaine, benzodiazepines, and am-
phetamines, and a confirmatory urine test was
positive for a metabolite of buprenorphine. How-
ever, expanded confirmatory testing panels for
fentanyl analogues (synthetic opioids structur-
ally similar to fentanyl) and “designer” opioids
in the urine and serum of this patient were nega-
tive (the results of tests for additional drugs are
provided in the Supplementary Appendix).
Interpretation of the cause of the amnestic
syndrome was limited by the drugs for which
testing was performed. Another unidentified drug,
adulterant, or contaminant cannot be excluded
as a cause of the amnestic syndrome; however,
the presence of fentanyl in the four additional
patients described here strengthens an associa-
tion of fentanyl with this syndrome, and fentanyl
this week’s letters
1157 Acute Amnestic Syndrome Associated with
Fentanyl Overdose
1158 Hazards of Hazard Ratios — Deviations from
Model Assumptions in Immunotherapy
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1161 Thrombectomy 6 to 24 Hours after Stroke
1162 Acute Pyelonephritis in Adults
1163 Adverse Events Associated with Immune
Checkpoint Blockade

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The New England Journal of Medicine

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 The n e w e ng l a n d j o u r na l
was the only drug detected in two of the four pa-
tients. We may be observing this syndrome now
because of the increasing presence of fentanyl in
the supply of illicit drugs and because fentanyl has
a higher potency than other opioids.
Potential mechanisms of fentanyl-related hip-
pocampal injury include cerebral ischemia1 or hy-
poxemia as a result of overdose4 or excitotoxicity,
since fentanyl and its analogues have been shown
to induce neuronal hypermetabolism and acute
neuronal damage in the hippocampus of rats.5
Expanded toxicologic screening for fentanyl and
its analogues should be considered in patients with
a history of substance use who present with this
amnestic syndrome.
Jed A. Barash, M.D.
Soldiers’ Home
Chelsea, MA
Michael Ganetsky, M.D.
Katherine L. Boyle, M.D.
Vinod Raman, M.D.
Beth Israel Deaconess Medical Center
Boston, MA
Michael S. Toce, M.D.
Boston Children’s Hospital
Boston, MA
Hazards of Hazard Ratios — Deviations from Model
Assumptions in Immunotherapy
To the Editor: Summary statistics, such as
hazard ratios, that are based on models may be
difficult to interpret if there are substantial de-
partures from key assumptions, including the
assumption of proportionality of hazard func-
tions. Recent cancer immunotherapy trials pro-
vide a contemporary example.
In immunotherapy trials, progression-free sur-
vival (or overall survival) curves often separate at
later times, rather than as a constant process. We
recreated progression-free and overall survival
curves1 from recent articles on immunotherapy
trials in the Journal to check the proportional-
hazards assumption (Table 1, and the Supple-
mentary Appendix, available with the full text of
this letter at NEJM.org). All progression-free
survival (and some overall survival) effects devi-
ated from proportional hazards in our analysis.
When results deviated from proportional haz-
ards, an elementary non–proportional-hazards
analysis (excluding 20% of early events) gener-
ally resulted in more significant P values and
n engl j med 378;12 nejm.org  March 22, 2018
The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
Scott Kaplan, M.D.
Harvard Vanguard Medical Associates
Boston, MA
Michael H. Lev, M.D.
Jonathan L. Worth, M.D.
Massachusetts General Hospital
Boston, MA
Alfred DeMaria, Jr., M.D.
Massachusetts Department of Public Health
Jamaica Plain, MA
alfred.demaria@massmail.state.ma.us
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
1. Barash JA, Somerville N, DeMaria A Jr. Cluster of an unusual
amnestic syndrome — Massachusetts, 2012–2016. MMWR Morb
Mortal Wkly Rep 2017;​66:​76-9.
2. Massachusetts Department of Public Health. An assessment
of opioid-related deaths in Massachusetts (2013-2014). Septem-
ber 2016 (http://www​.mass​.gov/​eohhs/​docs/​dph/​stop-addiction/​
chapter-55-opioid-overdose-study-data-brief-9-15-2016​.pdf).
3. Duru UB, Pawar G, Barash JA, Miller LE, Thiruselvam IK,
Haut MW. An unusual amnestic syndrome associated with com-
bined fentanyl and cocaine use. Ann Intern Med 2018 January 30
(Epub ahead of print).
4. Bhattacharyya S, Gholipour T, Colorado RA, Klein JP. Bilat-
eral hippocampal restricted diffusion: same picture many
causes. J Neuroimaging 2017;​27:​300-5.
5. Kofke WA, Garman RH, Stiller RL, Rose ME, Garman R.
Opioid neurotoxicity: fentanyl dose-response effects in rats.
Anesth Analg 1996;​83:​1298-306.
DOI: 10.1056/NEJMc1716355
more pronounced estimates of the treatment
effect (Table 1).
Are there relevant implications of these ob-
servations? In clinical trials in which modeling
assumptions that are selected at the design stage
are violated, the results are questionable. Post hoc
confirmatory analyses and evaluations of robust-
ness of the statistical plan can be used; however,
prespecified analyses are critical to reproducibility
in trials that are meant to be practice-changing.
Expected deviations from proportional-hazards
assumptions for a drug or therapeutic class can,
however, guide future trial design.
Statistical analyses that account for likely pro-
portional-hazards deviations could result in small-
er trials and interim analyses that are consistent
with current knowledge. A variety of methods
for avoiding or relaxing proportional-hazards as-
sumptions can be found in the literature — for
example, restricted mean survival methods3 and
models for delayed treatment effects4 (see the
Supplementary Appendix).