College of Pharmacy,
Southwestern Oklahoma State University,
Weatherford, USA.
Abstract
OBJECTIVE: To review the current
literature on drug-induced yawning.
DATA SOURCES: Literature was accessed
through MEDLINE/PubMed (1996-July 2011),
International Pharmaceutical Abstracts
(1997-July 2011), and EMBASE, using the search
terms yawning, drug-induced yawning, and adverse
drug reactions.
STUDY SELECTION AND DATA EXTRACTION:
Relevant clinical trials and case reports were
selected and included to present background
information. Bibliographies of all relevant
articles were reviewed for additional
citations.
DATA SYNTHESIS: Yawning is a common
stereotype behavior with unknown physiologic
function that occurs in most vertebrates and
humans as early as 15 weeks of intrauterine
life. Yawning is under the control of several
neurotransmitters and neuropeptides, including
dopamine, serotonin, oxytocin, and
acetylcholine. Among drugs, antidepressants,
opioids, dopaminergic agents, benzodiazepines,
and induction agents are the main pharmacologic
classes associated with yawning.
CONCLUSIONS: Yawning is rarely a
serious adverse reaction and is not frequently
listed in the drug summary. Most available data
are based on case reports, small studies, and
older literature. Clinicians should be aware of
the agents commonly triggering this
behavior.
OBJECTIF: Revoir la
littérature actuelle sur le
bâillement induit par le
médicament
SOURCES DE DONNÉES: Une
recherche dans la littérature a
été effectuée dans
MEDLINE/PubMed (1996-juillet 2011),
International Pharmaceutique
Résumé (1997-juillet 2011), et
EMBASE en utilisant des termes de recherche:
yawning, drug-induced yawning et adverse drug
reactions.
SÉLECTION DES ÉTUDES ET
EXTRACTION DES DONNÉES: Les essais
cliniques pertinents et les rapports de cas ont
été sélectionnés. La
bibliographie de tous les articles pertinents a
été examinée pour des
citations supplémentaires.
SYNTHÈSE DES DONNÉES:
Le bâillement est un comportement
stéréotypé commun dont le
fonctionnement physiologique est inconnu, mais
qui se manifeste dans la plupart des
vertébrés et, chez l'homme,
à partir de 15 semaines de vie
intra-utérine. Le bâillement est
sous le contrôle de plusieurs
neurotransmetteurs et neuropeptides, notamment
la dopamine, la sérotonine, l'ocytocine,
et l'acétylcholine. Parmi les
médicaments, les antidépresseurs,
les opioïdes, les agents dopaminergiques,
les benzodiazépines et les agents
d'induction de l'ovulation sont les principales
classes pharmacologiques associées au
bâillement.
CONCLUSIONS: Le bâillement est
rarement une réaction indésirable
grave et n'est pas souvent mentionné dans
les monographies des produits. La plupart des
données disponibles sont basées
sur des rapports de cas, de petites
études et des publications beaucoup moins
récentes. Les cliniciens doivent
être conscients des agents pouvant
déclencher ce comportement.
Yawning has been defined as a common
physiologic event that may present as early as
15 weeks of intrauterine life.1 It is
characterized by a single deep inhalation
followed by a short expiration and is often
accompanied by stretching the muscles of the jaw
and trunk, tears or shivering, lacrimation, and
penile erection. The average duration of yawn is
about 6 seconds; it is more frequent at bedtime,
upon awakening, and in boring situations.
Yawning is a poorly understood phenomenon
that is rarely discussed in pharmacologic
textbooks and receives little coverage in
medical schools. A number of theories have been
proposed to explain the mechanism of yawning.
The paraventricular nucleus (PVN) of the
hypothalamus, also referred to as the yawning
center of the brain, contains a number of
chemical messengers that can induce yawning.
Yawning is under the control of several
neurotransmitters and neuropeptides. Of these
substances, dopamine, excitatory amino acids,
acetylcholine, serotonin, nitric oxide,
adrenocorticotropic hormone (ACTH),
melanocyte-stimulating hormone (MSH), and
oxytocin are the best known facilitators of
yawning, while opioid peptides, g-aminobutyric
acid (GABA), dopamine antagonists, and
luteinizing hormonereleasing hormone inhibit
this behavioral response.4 Some investigators
suggest that yawning may even be precipitated by
hormonal imbalance involving MSH and ACTH.
Yawning can occur under different
physiologic (sedation, hunger, hypoglycemia) and
pathologic (gastric or biliary disease, motion
sickness, Eustachian tube disorder, infection)
circumstances.1-3 Yawning has been reported in
individuals with various neurologic and
psychiatric illnesses, such as brain tumors,
encephalitis, cerebral hypoxia, schizophrenia,
headaches, and depression
Yawning has rare complications and is
generally considered of little clinical
significance. Occasionally, people may report
myofacial pain and locking of the jaw after
yawning.7 Yawning is socially unacceptable and
may be taken as a display of disrespect,
criticism, or impolite behavior. 8 In this
article, we report the observations of yawning
as an adverse drug reaction (ADR).
LITERATURE REVIEW
The literature review included a search of
MEDLINE/ PubMed (1996-July 2011), International
Pharmaceutical Abstracts (1997-July 2011), and
EMBASE, using Englishlanguage literature. Search
terms were yawning, drug-induced yawning, and
adverse drug reactions. Bibliographies of all
relevant articles were also reviewed for
additional citations. Drug-induced yawning has
been reported in both animal and human models in
the medical literature. Animal studies9- 16 that
included rats, mice, dogs, cats, and monkeys
reported that oxytocin, the dopamine receptor
agonist apomorphine (Apo), ACTH, MSH, nitric
oxide, and GABA were the most common agents
triggering yawning behavior. Although animal
data are relevant, the rest of the review will
focus on data available on humans. There are
numerous cases in which drugs have been
implicated as the primary etiology of yawning in
humans (Table 1). In these case reports,
induction agents (propofol and thiopental),
selective serotonin reuptake inhibitors
([SSRIs] duloxetine and paroxetine), and
Apo are the drugs most frequently associated
with yawning.17-25 Most of the presumed
drug-induced yawning cases were reversible and
resolved upon dose reduction or discontinuation
of the suspected causative agent.
In general, yawning is not a serious ADR;
however, some potential complications could
occur. Three cases17-19 reported dislocation of
the temporomandibular joint (TMJ) due to
excessive yawning. These were confirmed by
X-rays and symptoms. In the first case,17 the
patient began yawning forcefully after propofol
administration, leading to TMJ dislocation. No
other medications were reported with this case,
and the author concluded that forceful yawning
should be avoided during propofol induction. The
second case18 involved fluoxetine monotherapy.
The patient reported yawning starting on day 5,
with a frequency of 5-10 times/day and mild
intensity. On day 42, the patient sought out a
dentist, complaining of pain and movement
disorder in both TMJ locations due to excessive
yawning. Fluoxetine was discontinued, and the
frequency and intensity of yawning lessened.
Yawning was resolved on day 17 after medication
discontinuation. Similar to the first case17 of
TMJ dislocation with propofol induction, the
patient in the third case19 experienced yawning
and TMJ dislocation after induction with
propofol along with fentanyl. However, in this
instance, the patient had a previous history of
jaw dislocation. Therefore, the authors
concluded that patients with preexisting TMJ
dislocation may be at an increased risk of
another dislocation if yawning occurs during
anesthesia induction. Two cases22 reported
excessive yawning induced by duloxetine. This
was not accompanied by drowsiness but was
reported by the patients to be disabling in
their jobs. In both instances, the excessive
yawning resolved after discontinuation of
duloxetine treatment. To our knowledge, neither
patient was on any other medication besides
duloxetine therapy.
Some cases have suggested that yawning
behavior might be dose-dependent. Pae et al.
reported that yawn of the 20-mg/day dose but was
more intense and frequent with the increased
dose (40 mg/day). With the 2 case reports20
involving paroxetine, yawning occurred more
frequently in the morning and improved as the
dose was reduced. Interestingly, yawning was not
accompanied by drowsiness and sedation. Similar
to both fluoxetine and paroxetine, which
demonstrated dose-dependent effects, Goldberg23
reported that yawning induced by imipramine
worsened as the dose was increased and decreased
in frequency upon dose reduction. Of the 4
dose-dependent yawning case reports, 3 described
resolution of yawning after discontinuation of
the offending agents. Although therapy was not
stopped in 1 patient, excessive yawning resolved
upon dose reduction of paroxetine to 10 mg/day.
Two cases24,25 described yawning as a
complication of drug withdrawal. Biswas et al.24
described yawning secondary to fentanyl and
midazolam withdrawal. In this case report, a
premature infant on chronic ventilatory support
became dependent on opioids and benzodiazepines
following multiple surgical procedures. She
developed yawning and other symptoms, including
agitation, tachycardia, hypertension, and loose
stools 5 days following Nissen fundoplication
and gastrostomy tube insertion. The infant's
course was further complicated by a
nonfunctioning central venous catheter,
resulting in interrupted medication delivery and
subsequent withdrawal. Yawning and most of the
other symptoms resolved once the catheter was
replaced and medications (fentanyl and
midazolam) were resumed. In the other case
report,25 a 68-year-old female with a
long-standing history of recurrent depression
and depressive delusions developed excessive
yawning after electroconvulsive therapy (ECT).
The patient was receiving antidepressant
(trazodone) as well as antipsychotic
(thiothixene) therapy concurrent with ECT. The
antipsychotic medication was tapered and
discontinued. After her final ECT session, the
patient developed excessive yawning during which
her mouth stayed open for several hours. The
authors could not fully determine whether the
yawning was associated with the ECT or the
antipsychotic regimen withdrawal.
In addition to the case reports, yawning has
been reported in multiple small studies in
association with various other drugs. Kasuya and
colleagues26 hypothesized that yawning is
associated with a transient arousal shift during
general anesthesia induction. In that study, 60
patients scheduled for elective surgery received
intravenous induction with a single dose of
either thiopental 4 mg/kg (n = 30) or propofol 2
mg/kg (n = 30). Yawning was assessed
continuously for 1 minute as the only endpoint.
A yawning response was observed in 18 (60%)
patients in the thiopental group and 14 (47%) in
the propofol group. Limitations of this study
include small sample size, uncontrolled design,
and no report of yawning frequency. Additional
medications (atropine sulfate and hydroxyzine
hydrochloride) were administered prior to
anesthesia induction, which could have served as
a confounding factor.
A larger study by Oshima et al.27 also
validated the yawning response following
intravenous thiopental administration. Data from
1322 patients undergoing elective surgery were
analyzed to examine the association of
independent predictors for thiopental-induced
yawning. Data collected included age, sex, and
smoking history, as well as other demographic
findings. Preanesthesia medications, per
institution protocol (ie, benzodiazepines,
clonidine, hydroxyzine, atropine, lidocaine,
vecuronium, and fentanyl), were also noted. A
total of 461 (35%) patients demonstrated a
yawning response, described by authors as
"opening of the mouth," after thiopental
injection (3.8 ± 1 mg/kg). The probability
of thiopental-induced yawning response was
reduced with prior administration of fentanyl
and clonidine, as well as female sex. Therefore,
the findings from this study suggest that
premedication with clonidine combined with
intravenous fentanyl may prevent the incidence
of thiopental-induced yawning. Although this was
a somewhat larger and more recent study, several
weaknesses deserve discussion. It was hard to
interpret the thiopental dose (mean vs median),
and the yawning response was not clearly
defined. While these 2 studies26,27 reported
that thiopental induction may elicit a yawning
response, this agent is no longer commercially
available in the US, and it is unknown whether
methohexital will cause a similar ADR. Five
trials28-32 described the association between
Apo and yawning response. Szechtman and
colleagues28 investigated Apo-induced yawning in
5 healthy male university students (aged 21-30
years). These subjects received subcutaneous Apo
0.0107 mg/kg in the morning after a 12- hour
fasting period. All subjects received a total of
12 injections, given every 2 weeks. The
incidence of yawning was monitored both through
videotaping and the attending nurse's
documentation of each yawn. Although the
participants were aware of the videotaping, they
were not informed that yawning was being
monitored. The onset of the first yawn, mean
number of yawns, and frequency of yawning were
measured. Repeated injections resulted in an
earlier peak and onset of yawning, but the total
number of yawns was unaffected. Interestingly,
no yawning was observed beyond 45 minutes after
Apo injection. Although this was a small study,
it demonstrated that a yawning response was
observed with Apo injections. However, the
number of yawns was listed only in figure format
and not in the text, which made data
interpretation difficult. A second study, by
Dewey et al.,29 evaluated the safety and
efficacy of Apo for parkinsonian off-state
(reduced motor function) periods. Twenty-nine
patients with advanced Parkinson disease were
evaluated in both inpatient and outpatient
settings. Patients received titrated doses of
subcutaneous Apo (2-10 mg, n = 20) or placebo (n
= 9). Of the numerous adverse effects associated
with Apo, only yawning frequency was noted to be
statistically significant, reported by 40% (n =
8) of Apo-treated subjects and none in the
placebo group. Although this was a small trial
and the number of yawns per patient was not
reported, it was randomized, double-blind, and
placebo-controlled and included both inpatients
and outpatients.
Lal et al. described yawning effects of Apo
in multiple trials.30-32 In 1 study,30 6 healthy
male volunteers (aged 21-38 years) received
subcutaneous Apo 0.5 mg. Within 10-20 minutes of
injection, yawning was observed in 3 (50%)
subjects. In another study,31 6 male volunteers
(age not specified) received subcutaneous Apo
0.75 mg. In contrast to the prior study, in
which yawning was observed in only half of the
subjects, all participants in the second study
experienced yawning behavior within 10 minutes
of Apo injection. The results of these 2 small
trials further illustrate the dose-dependent
yawning effect with Apo. Similar to the Dewey29
trial, the number of yawns per patient was not
specified. A third study by Lal et al.32
investigated the relationship of yawning
behavior to varying doses of Apo. Five subjects
(aged 19-29 years) received subcutaneous Apo
(3.5, 5, 7, and 10.5 ?g/kg) and placebo on 5
occasions. The number of yawns was recorded over
the 60-minute period after administration of
drug or placebo. The yawning response was
significantly higher than placebo only in the 7
?g/kg dosage regimen. The number of yawns (mean
± SD) was 25.4 ± 12.9 in the 7 ?g/kg
Apo regimen versus 15.6 ± 9.2 in the
placebo group (p < 0.05). Based on the
results of this dose-response study, the authors
further investigated the effect of age on
Apo-induced yawning, using the 7-?g/kg dose.
This somewhat larger study32 involved both young
(<30 years, n = 16) and older (>60 years,
n = 12) volunteers. After Apo injection, the
yawning response was observed more frequently in
the younger group versus the elderly subjects
(15 of 16 vs 6 of 12, respectively). The number
of yawns was 21.3 ± 14.7 in young subjects
versus 2.5 ± 3.3 in older subjects (p <
0.0001). The authors concluded that there is a
strong age effect for spontaneous yawning with
Apo. Unlike the previous trials, this study32
clearly reported the number of yawns per
patient.
Several limitations should be noted with
this review of drug-induced yawning. The
articles cited were mostly case reports, small
studies, and not current. Clinical trials were
generally poorly designed and uncontrolled. The
frequency of the yawning response was often not
quantified, and only stated as excessive. In
relation to the causative agent, the timing of
yawning was usually not reported. Furthermore,
the articles generally did not address whether
any other confounding factors could have
contributed to this drug-induced behavior.
Although the literature search included
MEDLINE/PubMed, EMBASE, and International
Pharmaceutical Abstracts, some studies/case
reports may have been missed if they were not
indexed properly or did not use similar key
words. Summary Drug-induced yawning is a
potential ADR occurring with certain
medications. Agents most frequently reported as
being associated with this physiologic response
include SSRIs (duloxetine, paroxetine,
fluoxetine), induction agents (thiopental,
propofol), drugs that have been withdrawn
(fentanyl, midazolam), and Apo. Treatment
generally involves dose reduction or withdrawal
of the suspected causative agent. Although
yawning behavior has few complications,
pharmacists should be aware of this potential
ADR and the offending agents.
References
1. Shalini A, Sreedharan S. A complex,
contagious, evolutionary habit. Ann Acad Med
Singapore 2006;35:433- 4.
2. Askenasy
JJ Is yawning an arousal defense reflex? J
Psychol 1989;123(6):609-621
4. Argiolas
A, Melis MR The neuropharmacology of yawning
Eur Pharmacol 1998;343(1):1-16
5. Jacome D
Primary yawning headache.Cephalalgia
2001;21(6):697-699.
6. Jacome D
Compulsive yawning as migraine premonitory
symptom. Cephalalgia 2001;21(5):623-5
7. Tesfaye
Y, Lal S Hazard of yawning Canadian Med
Assoc J 1990;142(1):15 et 1991;145(12):1560
8. Schiller
F Yawning ? Journal of the History of the
Neurosciences 2002;11(4): 392-401
9. Melis MR, Argiolas A, Gessa GL.
Oxytocin-induced penile erection and yawning:
site of action in the brain. Brain Res
1986;398:259-65.
10. Melis MR,
Argiolas A, Gessa Apomorphine-induced penile
erection and Yawning : site of action in brain
Brain Research 1987; 415; 98-104
11. Melis
MR , A.Argiolas. Reduction of drug-induced
yawning and penile erection and of noncontact
erections in male rats by the activation of
GABAA receptors in the paraventricular nucleus:
involvement of nitric oxide Eur J Neurosci 2002;
15; 5; 852-60
12. Gower
J, Berendsen H et al. Yawning-penile
erection syndrome as a model for putative
dopamine autoreceptor activity Eur J Pharmcol
1984;103:81-89
14. Berendsen
HG, Gower AJ Opiate-androgen interactions in
drug-induced yawning and penile erections in the
rats Neuroendocrinology 1986;42:185-1901
15. Bertolini A, Gessa GL. Behavioral
effects of ACTH and MSH peptides. J Endocrinol
Invest 1981;4:241-51.
16. Sato-Suzuki
I, Kita I, Oguri M, Arita H Stereotyped
yawning responses induced by electrical and
chemical stimulation of paraventricular nucleus
of the rat Journal of Neurophysiology,
1998;80(5)2765-2775
17. Avidan
A Dislocation of the temporomandibular joint
due to forceful yawning during induction with
propofol J Clin Anesth; 2002;14:159
18. Pae CU,
JJ Kim et al Injured temporomandibular joint
associated with fluoxetine-monotherapy-induced
repeated yawning Gen Hosp Psychiatry
2003;25(3):217-8
19. Unnikrishnan
KP, Sinha PK, Rao S. Mandibular dislocation
from yawning during induction of anesthesia. Can
J Anaesth. 2006;53(11):1164-5
20. Harada KI.
Paroxetine-induced excessive yawning Psychiatry
Clinical Neurosciences 2006;60:260.
21. Goren;
Friedmann Yawning : an aura for an L Dopa
induced "off" in Parkinson diesease Neurologie
1998;50(3):823
22. De Las
Cuevas C, Sanz EJ Duloxetine-induced
excessive disturbing and disabling yawning. J
Clin Psychopharmacol. 2007;27(1):106-107.
23. Goldberg
RL Sustained yawning as a side effect of
imipramine Int J Psychiatry Med
1983-84;13(4):277-80
24. Biswas AK, Feldman BL, Davis DH, Zintz
EA. Myocardial ischemia as a result of severe
benzodiazepine and opioid withdrawal. Clin
Toxicol 2005;43:207-9.
25. D'Mello,
Vincent, Lerner Yawning as complication of
electroconvulsive therapy and concurrent
neuroleptic withdrawal. The Journal of Nervous
and Mental Disease; 1988;176(3):188-189
26. Kasuya
Y, Murakami T, et al. Does yawning represent
a transient arousal-shift during intravenous
induction of general anesthesia? Anesth Analg
2005;101(2):382-384
27. Oshima
T et al. Inhibitory effects of landiolol and
nicardipine on thiopental-induced yawning in
humans J Anesth 2010;24(2):168-172
28. Szechtman
H et al Sensitization and tolerance to
apomorphine in men: yawning, growth hormone,
nausea, and hyperthermia Psychiatry Research
1988, 23, 245-255
29. Dewey
RB Jr, Hutton JT, LeWitt PA, Factor SA A
randomized; double-blind; placebo-controlled
trial of subcutaneously injected apomorphine for
parkinsonian off-state events.Arch Neurol
2001;58(9)1385-1392
30. Lal S, Nair NPV, Iskandar HL, et al.
Effect of domperidone on apomorphine- induced
growth hormone secretion in normal men. J Neural
Transm 1982;54:75-84.
31. Lal S, Guyda H, Bikadoroff S. Effect of
methysergide and pimozide on apomorphine-induced
growth hormone secretion in men. J Clin
Endocrinol Metab 1977;44:766-70.
32. Lal S,
Tesfaye Y et al Apomorphine: clinical
studies on erectile impotence and yawning. Prog
Neuropsychopharmacol Biol Psychiatry
1989;13(3-4):329-39
