Orlova Y, Rizzoli P, Loder E. Association of Coprescription
of Triptan Antimigraine Drugs and Selective Serotonin Reuptake
Inhibitor or Selective Norepinephrine Reuptake Inhibitor Antidepressants With
Serotonin Syndrome. JAMA Neurol. 2018 Feb 26. doi: 10.1001/jamaneurol.2017.5144.
[Epub ahead of print]
Abstract
IMPORTANCE:
In 2006, the US Food and Drug Administration (FDA) issued an
advisory warning on the risk of serotonin syndrome with concomitant use of
triptans and selective serotonin reuptake inhibitor (SSRI) or selective
norepinephrine reuptake inhibitor (SNRI) antidepressants, but the true risk of
serotonin syndrome in these patients remains unknown.
OBJECTIVE:
To assess the risk of serotonin syndrome with concomitant
use of triptans and SSRI or SNRI antidepressants.
DESIGN, SETTING, AND PARTICIPANTS:
This study used electronic health record data from the
Partners Research Data Registry (RPDR) to identify patients who had received an
International Classification of Diseases, Ninth Revision diagnosis compatible
with serotonin syndrome who had been coprescribed triptans and SSRI or SNRI
antidepressants in the Greater Boston, Massachusetts, area from January 1,
2001, through December 31, 2014 (14 years). Clinical information was extracted
to determine whether the case met formal diagnostic criteria and had
coprescription within a calendar year. Both conservative and broad case
definitions were used to better characterize the spectrum of risk. Data
analysis was performed from November 23, 2016, to July 15, 2017.
MAIN OUTCOMES AND MEASURES:
Incidence of serotonin syndrome.
RESULTS:
The RPDR search revealed 47 968 (±3) unique patients who
were prescribed triptans during the 14-year period of the study. A total of
19 017 (±3) patients were coprescribed triptans and antidepressants during the
study, with a total of 30 928 person-years of exposure. Serotonin syndrome was
suspected in 17 patients. Only 2 patients were classified as having definite
serotonin syndrome (incidence rate, 0.6 cases per 10 000 person-years of
exposure; 95% CI, 0.0-1.5). Five patients were classified as having possible
serotonin syndrome (incidence rate with these 5 cases added to the 2 definite
cases, 2.3 cases per 10 000 person-years of exposure; 95% CI, 0.6-3.9). The
proportion of patients with triptan prescriptions who were coprescribed an SSRI
or SNRI antidepressant was relatively stable during the study, ranging from 21%
to 29%.
CONCLUSIONS AND RELEVANCE:
The risk of serotonin syndrome associated with concomitant
use of triptans and SSRIs or SNRIs was low. Coprescription of these drugs is
common and did not decrease after the 2006 FDA advisory. Our results cast doubt
on the validity of the FDA advisory and suggest that it should be reconsidered.
______________________________________________________________________________
Since its publication in 2006, the US Food and Drug
Administration (FDA) advisory against coprescription of triptans and selective
serotonin reuptake inhibitors (SSRI) or selective norepinephrine reuptake
inhibitors (SNRI) because of elevated risk of serotonin syndrome has been met
with resistance from headache specialists. In 2010, the American Headache
Society even released a position paper finding insufficient evidence (Level U)
for the advisory and urging the FDA to reconsider its statement.
But a new study published online first in the February 26
issue of JAMA Neurology, which reviewed registry data of nearly 48,000 patients
prescribed triptans, bolsters the argument against the advisory. It found a low
risk of serotonin syndrome in the patients with concomitant use of these
medications. (Serotonin syndrome, which is believed to occur because of
elevated levels of serotonin, varies in severity from mild to fatal and can
cause a constellation of symptoms, including diarrhea, tachycardia, unstable
blood pressure, and hyperthermia.)…
During the 14-year study period, about 47,968 unique
patients were prescribed triptans and a total of about 19,017 patients were
coprescribed triptans and antidepressants, resulting in a total of 30,928
person-years of exposure. The percentage of patients receiving both
prescriptions ranged from 21 to 29 percent during the study.
Although serotonin syndrome was suspected in 17 patients,
only four met both the Sternbach and Hunter criteria for serotonin syndrome,
while two met Sternbach criteria only and one met Hunter criteria only. The
definite serotonin syndrome incidence rate was 0.6 cases per 10,000
person-years of exposure (95% CI, 0.0-1.5) and the possible serotonin syndrome
incidence rate (including cases meeting any criteria) was 2.3 cases per 10,000
person-years of exposure (95% CI, 0.6-3.9)….
Fifteen years ago, Stewart J. Tepper, MD, professor of
neurology at the Geisel School of Medicine at Dartmouth College, and colleagues
reviewed coprescriptions in patients taking triptans using a Merck-Medco
database of more than 240,000 patients and found a similar rate to the current
paper by Orlova et al. — about 20 percent of patients on triptans were also
prescribed SSRIs. There is a “bidirectional comorbidity” with migraine and
depression or anxiety, he explained. “It's not that depression or anxiety cause
migraine or the reverse, but they clearly co-occur and with such regularity and
at such a high frequency that there is a clinical importance to being able to
prescribe triptans and SSRIs or SNRIs in the same patient.”…
Dr. Tepper, who was one of the authors of the 2010 AHS
position paper, said the AHS has requested meetings with the FDA on multiple
occasions to review the warning data and talk about rescinding the advisory
with no success. “Whenever headache specialists teach, we are always asked,
‘Why can't we prescribe SSRIs and SSNRIs with triptans. What's the serotonin
syndrome risk?’” The AHS position paper, he continued, is even truer now that
we have the Orlova study…
When his patients go to the pharmacy to pick up a
prescription, Dr. Tepper warns them: “Someone is going to go on the speaker and
say, ‘Dr. Tepper is trying to kill this patient by prescribing fluoxetine and
sumatriptan,’ and I'm telling you in advance, that the AHS position is that
there is not a reason to not co-prescribe if you need both kinds of drugs.” If
the pharmacist has concerns, he offers to send both the patient and the
pharmacist the AHS position paper. “The electronic medical record fortunately
has a choice of ‘inappropriate alert’ which is what I choose” for this drug
interaction, he said.
Medication side effects are a major concern for patients and
their parents, and the FDA warning often exacerbates anxiety and may interfere
with treatment if parents feel they are putting their child's life in danger,
Dr. Bickel said. “This study will certainly help to dampen those fears.”
https://journals.lww.com/neurotodayonline/Fulltext/2018/04050/In_the_Clinic_Migraine__New_Data_Refutes_FDA.14.aspx
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