Update on Management of

t h e Or a l an d M a x i l l o f a c i a l
Surge ry Patient o n Selec t ive
S e ro t o n i n R e u p t a k e I n h i b i t o r s
Natasha Bhalla, DDSa,*, Michael H. Chan, DDSb,c

KEYWORDS
 SSRIs  Fentanyl  Serotonin syndrome  NSAIDs  Dental implants  GI bleed  Gastroprotection

KEY POINTS
 Selective serotonin reuptake inhibitors (SSRIs) emerged as the first line of antidepressant medica-
tions recommended by the 2011 American Psychiatric Association guidelines.
 SSRIs and fentanyl can precipitate serotonin syndrome—excessive serotonin activity in the central
nervous system. Serotonin syndrome presents as a triad of symptoms—mental status changes,
autonomic hyperactivity, and neuromuscular abnormalities. Early intervention can prevent
morbidity and mortality.
 Several studies have found that implant failure rates are higher in SSRI users versus nonusers. Cli-
nicians can inform patients of mild risk of implant failure in SSRI users.
 Increased gastrointestinal bleeds have been reported with SSRI users, and it doubles when com-
bined with nonsteroidal antiinflammatory drugs versus nonusers.
 Based on the current data, the authors recommend avoiding the combination of ibuprofen and
SSRIs. If both medications are deemed to be essential, synthetic prostaglandin, H2-blocker, or
PPI can provide gastroprotection.

Depression is a global prevalent disorder affecting
millions of people ranging from mild to major
forms. It is a medical condition associated with
low levels of circulating serotonin, norepinephrine,
and dopamine in major depressive disorder, which
can be linked with significant disability and
reduced quality of life. Antidepressants is a class
of medications aimed to treat this condition. His-
torically, monoamine oxidase inhibitors and tricy-
clics antidepressants have been used. However,
undesirable side effects have many physicians
divert to a newer second generation created in
the late 1980s namely the selective serotonin reup-
and less side effects than its predecessors, SSRIs
have emerged as the first line of antidepressant
medication recommended by the American Psy-
chiatric Association (APA) in their 2011 guide-
lines.1 Six of the top 200 prescribed medications
in the United States during 2018 were SSRIs with
some of the commercially available ones including
citalopram, escitalopram, fluoxetine, fluvoxamine,
paroxetine, and sertraline.1 Between 2015 and
2018, 13.2% of adults in the United States older
than 18 years used antidepressants in the past
30 days with women (17.7%) slightly doubled
that of men (8.4%).1 In addition to treatment of
oralmaxsurgery.theclinics.com

take inhibitor (SSRIs). Because of better tolerance depression, they are prescribed for anxiety,

a
Oral and Maxillofacial Surgery, The Brooklyn Hospital Center, 121 Dekalb Avenue, Brooklyn, NY 11201, USA;
b
Oral & Maxillofacial Surgery, Department of Veterans Affairs, New York Harbor Healthcare System (Brooklyn
Campus), 800 Poly Place (Bk-160), Brooklyn, NY 11209, USA; c Oral & Maxillofacial Surgery, Department of Oral
& Maxillofacial Surgery, The Brooklyn Hospital Center, 121 DeKalb Avenue (Box-187), Brooklyn, NY 11201, USA
* Corresponding author.
E-mail address: natashaa95@gmail.com

Oral Maxillofacial Surg Clin N Am 34 (2022) 127–134

https://doi.org/10.1016/j.coms.2021.08.009
1042-3699/22/Ó 2021 Elsevier Inc. All rights reserved.
128 Bhalla & Chan
bulimia nervosa, fibromyalgia, obsessive-
compulsive disorder, panic disorder, and post-
traumatic stress disorder. The purpose of this
chapter is to review pathophysiology, current
medications, adverse drug interactions, and man-
agement of common OMFS office–based proced-
ures when treating patients on SSRIs.
PATHOPHYSIOLOGY AND MECHANISM OF
ACTION OF SELECTIVE SEROTONIN
REUPTAKE INHIBITORS
Serotonin (5-hydroxytryptamine [5-HT]) receptors
are found in the nervous system, bones, and blood
platelets. Hence, SSRIs can have an effect on the
nervous, skeletal, and hematological system,
respectively.
In the nervous system, there is a wide projection
pattern of 5-HT receptors modulating physiologic
functions such as sleep, arousal, feeding, pain,
emotions, and cognition.2 Scientists have also
found serotonin to play a role in mood enhance-
ment, appetite suppressant, and sleep improve-
ment. The behavioral effects of 5-HT are
mediated by a family of 14 5-HT receptor sub-
types.2 The 5-HT1AR is one of the best studied
subtypes due to its implications in anxietylike be-
haviors and depression.2 The most common anti-
depressant, SSRIs, target the 5-HT1AR by
inhibiting serotonin reuptake from the synaptic
cleft into presynaptic nerve terminals, thereby
increasing the concentration of serotonin in the
synaptic cleft and enhancing serotonin available
for neurotransmission (Fig. 1).2
In addition, researchers have discovered sero-
tonin to regulate osteoclasts activation and differ-
entiation, as osteoclasts are derived from
hematopoietic cell precursors.3–6 Specifically, se-
rotonin transporters (SERT) and receptors are pre-
sent in bony microarchitecture.3–6 An in vivo study
has demonstrated significant reduction in osteo-
genic differentiation and mineralization with
concomitant reduction of osteoblast markers
including alkaline phosphatase, osterix, and
osteocalcin during SSRI administration.3–6 As a
result, SSRIs can have a negative influence on
bone mineral density.
The primary role of serotonin in response to
vascular injury is to promote vasoconstriction
and platelet aggregation for local hemostasis.7
SERT is responsible for the uptake of serotonin
into the platelets specifically into the granular cell
compartment. By blocking this site, platelets will
be devoid of serotonin rendering it useless from
its primary function12 (Fig. 2). Therefore, it may
be predicted SSRIs can ultimately reduce platelet
aggregation, clot formation, and increased risk of
bleeding.7 Literature reviews have demonstrated
a 90% reduction in platelet content of serotonin
just after a 2-week course of SSRIs, suggesting
clinicians should be aware of the relatively quick
onset.8–12
MEDICATION DOSAGES
Listed later (Table 1) are the starting doses of
common SSRI medications along with half-life.
This table also touches on the starting dose for
different psychiatric conditions.
ADVERSE REACTIONS/EVENTS OF SELECTIVE
SEROTONIN REUPTAKE INHIBITORS
SSRIs have only been available in the market for a
short period of time. And because of this, knowl-
edge about its adverse effects is emerging through
case reports and studies. There is no block box
warning label associated with sertraline, fluoxe-
tine, and paroxetine. Citalopram and escitalopram
are not approved for the pediatric population, with
escitalopram specifically not approved for those
younger than 12 years. Safety and efficacy of flu-
voxamine in patients younger than 8 years have
not been established.
Selective Serotonin Reuptake Inhibitors and
Nonsteroidal Antiinflammatory Drugs
Ibuprofen has been ranked as the 34th medication
most prescribed in the United States according to
the national data from 2018.13 In addition to pre-
scription sales, ibuprofen is also a commonly pur-
chased over-the-counter (OTC) medicine for
treatment of inflammation and pain.1 Data from
the National Consumer League of 2002 showed,
of the 4263 individuals that were interviewed,
83% reported OTC analgesic use in the past
year.1 Of these individuals, 15% reported using
analgesics daily and 29% reported taking them
several times per week, making ibuprofen the
most widely used nonnarcotic analgesia only
behind acetaminophen.1
As a nonselective cyclooxygenase (Cox) 1 and 2
inhibitor, ibuprofen is known to increase the risk of
bleeding by causing topical injury to the gastric
mucosa by blocking Cox 1 pathway, thus prevent-
ing prostaglandin production. By blocking prosta-
glandin production, the gastric mucosa cannot
produce mucous lining and is vulnerable for
increased risk in gastrointestinal (GI) bleed.14 In
addition, Cox 1 inhibitor prevents thromboxane
A2 production for vasoconstriction and platelet
aggregation. Furthermore, these platelets are
depleted of serotonin and lack any hemostatic
properties seen in normal platelets (see Fig. 2).
 Update on Management of the OMFS Patient on SSRIs
Fig. 1. SSRI blocks the reuptake of serotonin into the
presynaptic nerve terminal.
Not all patients will have the same risk of devel-
oping GI complications. These risk factors include
advanced age (>60 years), existing cardiovascular
disease (CV), and concurrent use of other nonste-
roidal antiinflammatory drugs (NSAIDs), antiplate-
let, or anticoagulant medications. Many of these
patients are already taking low-dose aspirin
(81 mg Aspirin [ASA]) for prevention of CV events.
129
And with the addition of ibuprofen, the risk of GI
bleed gets elevated to high risk.14 Also, elderly pa-
tients taking SSRIs with concomitant use of
ibuprofen have been reported to have a high rate
of perioperative GI bleed. One study reported a
3-fold increased risk of GI bleed with a combina-
tion of SSRI and ibuprofen when compared with
ibuprofen use alone.1 Other studies have also sug-
gested a similar outcome. There is a 60% risk of a
GI bleed with the combination of SSRIs and
NSAIDs against non-NSAID/non-SSRI users and
a drastic reduction to 30% when SSRI is
compared with non-NSAID/non-SSRI users.1 The
risk is doubled by administering NSAIDs to SSRI
users.
Anesthesia Case Report of Adverse Drug
Interaction Between Selective Serotonin
Reuptake Inhibitors and Nonsteroidal
Antiinflammatory Drugs
Anesthesia reported a case of a 53-year-old man
who underwent a resection of the mandible for treat-
ment of his carcinoma in situ.15 The surgeon per-
formed primary closure and had established
hemostasis at the surgical site.15 An hour later, in
the recovery room, he developed severe dyspnea
secondary to hematoma formation from the floor
of the mouth.15 Reintubation was not deemed
Fig. 2. SSRI blocks SERT site and pro-
hibits uptake of serotonin causing
depletion.
130 Bhalla & Chan

Table 1
Dosages, indications and half-life of common selective serotonin reuptake inhibitors

Indication Starting Dose Half-Life

Sertraline (Zoloft) Adults 26 h (range 22–36 h)
Mood depressive disorder (MDD)/ 50 mg
obsessive compulsive disorder
(OCD)
Panic disorder, posttraumatic 25 mg
stress disorder, seasonal
affective disorder (PD, PTSD,
SAD)
Pediatric Patients
OCD (age 6–12 y) 25 mg
OCD (age 13–17 y) 50 mg
Fluoxetine (Prozac) Adults 1–3 d
Depression/OCD/pervasive 20 mg
developmental disorders (PDD)
Bulimia 60 mg
PD 10 mg
Pediatric Patients
Depression (8–18 y)/depression 10–20 mg
(lower weight children)/OCD
(7–17 y)
OCD (lower weight children) 10 mg
Paroxetine (Paxil) Adults 21 h
Depression/SAD/OCD/PTSD/ 20 mg
generalized anxiety disorder
(GAD)
PD 10 mg
PDD 12.5 mg
Geriatric Dose
OCD/PTSD/SAD/GAD/depression 10 mg
Citalopram (Celexa) Adults 36 h
Depression 20 mg
Geriatric patients
Depression 20 mg
Escitalopram (Lexapro) Adults 27–32 h
GAD/depression 10 mg
Geriatric Patients
Depression 10 mg
Pediatric Patients
Depression 10 mg
Fluvoxamine (Luvox) Adults 58 h
OCD 50 mg
Pediatrics
OCD (8–11 y) 25 mg
OCD (11–17 y) 25 mg
Data from Refs.20–24

possible, and he had to undergo an emergency tra-
cheostomy. Ibuprofen was immediately discontin-
ued, and acetaminophen with codeine was
replaced for pain control.15 On further probing into
the patient’s surgical history, similar episodes of
postoperative bleeding have occurred with proced-
ures such as tooth extraction, correction of deviated
nasal septum, and biopsy from the retromolar pad
region.15 Further workup revealed his blood work
had significant decreased serotonin levels particu-
larly in his thrombocytes, demonstrating serotonin
depleted platelets.15 SSRIs such as fluvoxamine,
paroxetine, and sertraline are inhibitors of cyto-
chrome P-450 and will prevent the metabolism of
certain NSAIDs, resulting in NSAID accumulation
and the potential increased risk of bleeding.15
 Update on Management of the OMFS Patient on SSRIs
Selective Serotonin Reuptake Inhibitors and
Fentanyl
Fentanyl is a widely used potent analgesic in both
inpatient and outpatient settings with its short half-
life, making it an appealing choice for many OMFS
and anesthesiologists. The interaction between
fentanyl, a direct serotonin agonist, and SSRIs
could potentially result in an adverse outcome
called serotonin syndrome. An excessive seroto-
nin activity in the central nervous system (CNS),
typically in the setting of multiple drugs, can result
in an overdrive of serotonin
neurotransmission.16–18
Classically, it presents as a triad of symptoms—
mental status changes, autonomic hyperactivity,
and neuromuscular abnormalities.16–18 Clinical
manifestations can be rapid or delayed up to
6 hours and is characterized based on severity of
the condition: mild (ie, mild hypertension, tachy-
cardia, diaphoresis, myoclonus, tremor), moder-
ate (ie, agitation, clonus, myoclonus, altered
mental status), or severe (ie, delirium, seizures,
neuromuscular rigidity, hyperthermia, and
possible coma leading to death).17 Diagnosis of
serotonin syndrome is based on signs and symp-
toms, and serum serotonin levels do not correlate
with clinical findings.16–18 Treatment of serotonin
syndrome includes early stabilization of vital signs,
administration of oxygen, intravenous (IV) fluids,
and continuous cardiac monitoring.17 Patients
are typically hospitalized for observation and treat-
ment rendered based on symptoms.17 Many
cases tend to resolve within 24 hours after initia-
tion of supportive care and discontinuation of the
offending serotonergic medications.17
Management of Serotonin Syndrome
1. Benzodiazepines are given to treat agitation
and/or seizures.17
2. Serotonergic medication can be flushed out by
increasing IV hydration and to protect the kid-
neys from getting damaged
(rhabdomyolysis).17
3. In severe cases, cyproheptadine (Periactin) can
be used to block serotonin.17
4. Cooling blankets can be used for
hyperthermia.17
5. Hyperthermia may also require immediate
sedation and intubation by using a nondepola-
rizing neuromuscular blocking agent.17
Selective Serotonin Reuptake Inhibitors and
Local Anesthesia Containing Epinephrine
As per the investigative research, there is currently
no contraindications of administering local
131
anesthesia containing epinephrine to patients tak-
ing SSRIs.
Selective Serotonin Reuptake Inhibitors and
Dental Extractions
There are no case reports of adverse outcomes
with this drug and procedure.
Selective Serotonin Reuptake Inhibitors and
Dental Implants
Given the interaction among SSRIs, osteoblasts
and osteoclasts, several studies have been con-
ducted on SSRIs and osseointegration after dental
implant placement.8–10 In 2014, Wu and col-
leagues demonstrated implant failure rates were
4.6% for SSRI nonusers and 10.6% for SSRI
users.9 Their study showed failures mostly
occurred between 4 and 14 months after implant
placement, suggesting implant failure by SSRIs
was from the mechanical loading of the implants
and not from initial osseointegration.9 They
concluded careful surgical and prosthetic treat-
ment planning were necessary to circumvent
these issues.9 In addition, in 2017, Chrcanovic
and colleagues found implant failure rates were
12.5% for SSRI users and 3.3% for nonusers18
without any statistical differences.18 Lastly, in
2018, Altay and colleagues discovered implant
failure rates for SSRIs users were 5.6% and
1.85% for nonusers.10 Although the differences
between the 2 groups were not statistically signif-
icant,10 patients using SSRIs were found to be 3
times more likely to experience early implant fail-
ure than nonusers.10 The investigators concluded
SSRIs may lead to osseointegration failure.10
Selective Serotonin Reuptake Inhibitors and
Medication-Related Osteonecrosis of Jaw
Case Reports
There are currently no case reports of SSRI asso-
ciated with medication-related osteonecrosis of
jaw.
MANAGEMENT OF THE ORAL AND
MAXILLOFACIAL SURGERY PATIENTS ON
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Perioperative Management for Intravenous
Sedation
Practitioners should weigh the risks, benefits, and
alternatives before administering fentanyl to SSRI
users. Even though the occurrence is very low,
0.09% in patients who received both fentanyl
and a serotonergic agent,19 the potential of precip-
itating an iatrogenic serotonin syndrome is real,
132 Bhalla & Chan
Box 1
General rules for perioperative management
for pain control on selective serotonin reuptake
inhibitors
 Use of the lowest effective dose of NSAIDs for
the shortest period of time
 Avoid concomitant therapy with corticoste-
roids, anticoagulants, low-dose ASA (81 mg),
or antiplatelet agents.
 Ibuprofen is considered a “safer” NSAID
option.
 Eradicate Helicobacter pylori infection in pa-
tients with prior ulcer therapy.
Prevention Strategies
 No cardiovascular (CV) risk factors and (not
on low-dose ASA)
 No GI risk factors: can use ibuprofen
 One or more GI risk factors (advanced age,
alcohol intake, selective serotonin reup-
take inhibitors, corticosteroid, use of an-
tithrombotic drugs and anticoagulants,
and a history of complicated peptic ulcer
disease): use coxib (standard dose) or
ibuprofen 1 PPI or misoprostol
 If history of ulcer bleeding: use coxib 1 PPI.
Need to eradicate H pylori
 On low dose ASA
 One or more GI risk factor: use
naproxen 1 PPI or coxib 1 PPI
 Avoid combining with ibuprofen since it
will increase risk of bleeding with low-
dose ASA
Data from Al-Saeed A. Gastrointestinal and Cardiovas-
cular Risk of Nonsteroidal Anti-inflammatory Drugs.
Oman Med J. 2011 Nov;26(6):385-91.
and early recognition and intervention can prevent
morbidity and mortality. The authors also advise
clinicians to be aware of the increasing use of
SSRIs, especially in the teenage population
requiring removal of wisdom teeth under sedation.
Perioperative Management for Dental Implant
Surgery
Several studies have demonstrated, although
without statistical difference, an increase in failure
rate in dental implants performed on patients tak-
ing SSRIs. Clinicians can inform these patients of
the slight increased risk of implant failure when
compared with non-SSRI users, and this does
not preclude them from getting the surgery. Future
studies are recommended to understand the exact
association between SSRIs and the negative influ-
ence on dental implants.
Further studies are also needed to investigate the
cause of higher implant failure in SSRI users—
osseointegration, prosthetic, or both.
Perioperative Management for Pain Control
The authors recommend avoiding the combination
of ibuprofen and SSRIs when possible, to avoid
the risk of an upper GI bleed. Alternatively, acet-
aminophen with or without an additional narcotic
can be used. If ibuprofen is deemed to be essen-
tial, prevention strategies for GI toxicity should
be followed; this is demonstrated on Box 1 and
based on presence of cardiovascular risk factors.
If there are no cardiovascular risk factors and if
not on daily low-dose ASA, patients can take
NSAIDs at normally prescribed dose.14 When
one or more GI risk factors are present, the use
of a selective Cox 2 inhibitor (ie, celecoxib) alone
or ibuprofen plus a proton pump inhibitor (PPI) or
misoprostol can provide gastroprotection.14 Nor-
mally, prostaglandin is produced by both Cox 1
and 2 enzymes, with Cox 1 found in gastric lining
and blood platelets. They promote gastric protec-
tion and platelets aggregation, respectively. Cox 2
enzyme focuses primarily on inflammation and
pain production. By specifically targeting these in-
flammatory sites by blocking Cox 2, undesirable
gastric and bleeding from dysfunctional platelets’
adverse effects can be avoided.
Managing Gastrointestinal Toxicity
Patients with GI risk factors, who require nonse-
lective NSAIDs, should receive a gastroprotec-
tant.14 Misoprostol is a synthetic prostaglandin
that stimulates mucous secretion in the upper GI
tract.14 One study showed misoprostol, 200 mg,
used 4 times a day orally significantly reduced
symptomatic ulcers.14 However, misoprostol use
in clinical practice is limited by its poor tolera-
bility.14 The required dosing schedule of 4 times
per day makes it inconvenient for patients, thereby
adversely affecting treatment compliance and
outcome.14 In addition, women of child-bearing
age are contraindicated in using this medication
due to the increased risk of abortion.14
H2-receptor antagonists are gastroprotectants
by reversibility interference and blocking histamine
receptors in the parietal cell, which reduces acid
secretion.14 High-dose famotidine has been
shown to prevent both gastric and duodenal ulcers
associated with NSAID use.14
Proton pump inhibitors (PPIs) block gastric acid
secretion by inhibiting the H1/K 1 ATPase and are
significantly more effective than H2-receptor
 Update on Management of the OMFS Patient on SSRIs
antagonists for treatment and prevention of acid-
related diseases.14 Studies have confirmed omep-
razole (PPI), 20 mg/d, was more effective than ra-
nitidine (H2—antagonist) and low-dose
misoprostol in the primary or secondary preven-
tion of gastric and duodenal ulcers in ibuprofen
users.14
On occasion, clinicians may need to prescribe a
lengthy course of NSAIDs for treatment of tempo-
romandibular/myofascial pain; the addition of a
gastroprotectant such as misoprostol, histamine-
2 receptor antagonist, or a PPI would be
recommended.14
SUMMARY
With the increasing use of SSRIs in all age groups,
the Oral and Maxillofacial Surgeon should be
aware of the mechanism of action, medication
dosages, and adverse interactions with other
common medications.
SSRIs increase the risk of bleeding when used
with ibuprofen. Hence, the authors recommend
avoiding this combination. Alternatively, acetamin-
ophen with or without an additional narcotic can
be used. If ibuprofen use is required, prevention
strategies for GI toxicity should be followed. The
interaction between fentanyl and SSRIs could
result in serotonin syndrome. Early recognition of
symptoms and intervention can prevent morbidity
and mortality. Last, several studies have demon-
strated an increased risk in dental implant failures
in those taking SSRIs. Clinicians should inform
these patients of the slight increased risk. Whether
dental implant failure is due to initial osseointegra-
tion or after prosthetic loading, further investiga-
tions via randomized controlled trials are needed
to elucidate the exact cause.
In conclusion, SSRIs are beneficial to the medi-
cal management of patients. Knowledge about the
medication will result in appropriate management
of patients.
CLINICS CARE POINTS
 Based on the current data, the authors
recommend avoiding the combination of
ibuprofen and SSRIs. If both medications are
deemed to be essential, misoprostol, H2-
blocker, or PPI can provide gastroprotection.
 Alternatively, acetaminophen  narcotic can
be used instead of ibuprofen alone for pain
control.
133
 Even though the occurrence of serotonin syn-
drome is very low, 0.09% in patients who
received both fentanyl and a serotonergic
agent, the authors advise clinicians to be
aware of the increasing use of SSRIs, espe-
cially in the teenage population requiring
removal of wisdom teeth under sedation.
 Several studies have demonstrated, although
without statistical difference, an increase in
failure rate in dental implants performed on
patients taking SSRIs.
ACKNOWLEDGMENT
The authors want to extend a very special thank
you to Ms. Maya Nunez for her brilliant illustrations
for Figs. 1 and 2.
DISCLOSURE
The authors have nothing to disclose.
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