mystery of yawning
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal
Le bâillement, du réflexe à la pathologie
Le bâillement : de l'éthologie à la médecine clinique
Le bâillement : phylogenèse, éthologie, nosogénie
 Le bâillement : un comportement universel
La parakinésie brachiale oscitante
Yawning: its cycle, its role
Warum gähnen wir ?
Fetal yawning assessed by 3D and 4D sonography
Le bâillement foetal

mise à jour du
19 décembre 2011
Ann Pharmacother
Drug-induced yawning: a review
Edna Patatanian and Nancy Toedter Williams
College of Pharmacy, Southwestern Oklahoma State University, Weatherford, USA.


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.

Drug-induced yawning: A review of the french pharmacovigilance database
Sommet A, Desplas M, Lapeyre-Mestre M, Montastruc JL.
The French Network of Pharmacovigilance Centers. Drug Saf. 2007;30(4):327-331.
Le bâillement: de la physiologie à la iatrogénie.
Philibert C, Sauveplane K, Pinzani-Harter V et al.
La lettre du pneumologue. 2011;14(5):168-172
Drug-induced yawning: a review
Patatanian E, Williams NT.
Ann Pharmacother.

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).
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.
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