Cisplatin-Related Hiccups: Male Predominance, Induction by Dexamethasone, and Protection Against Nausea and Vomiting

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1 Vol. 30 No. 4 October 2005 Journal of Pain and Symptom Management 359 Original Article Cisplatin-Related : Male Predominance, Induction by Dexamethasone, and Protection Against Nausea and Vomiting Chuang-Chi Liaw, MD, Cheng-Hsu Wang, MD, Hsien-Kun Chang, MD, Hung-Ming Wang, MD, Jen-Sheng Huang, MD, Yung-Chang Lin, MD, and Jen-Shi Chen, MD Division of Hematology-Oncology, Department of Internal Medicine, Chang-Gung Memorial Hospital and Chang-Gung University, Taipei, Taiwan, Republic of China Abstract Dexamethasone is likely to play a role in the etiology of hiccups in patients receiving cisplatinbased regimens. Two hundred seventy-seven patients received three doses of ondansetron 8 mg intravenously (IV) at 4 hour intervals plus dexamethasone 20 mg IV from the start of chemotherapy, followed by dexamethasone 5 mg IV every 12 hours, until chemotherapy was complete. were observed in 114 (41.2%) patients, of whom 97.4% were men. Nausea and vomiting showed inverse correlations with hiccups (P! and P , respectively). In 73 patients who experienced hiccups but lacked nausea/vomiting (H1N/V2), we discontinued dexamethasone in subsequent cycles. Sixty-six patients (90.4%) ceased hiccuping, but complete protection rates of nausea and vomiting decreased to 63% and 74%, respectively. For patients who experienced both hiccups and nausea/vomiting, the onset of nausea/vomiting usually was delayed to Day 3 or 4 and began after the cessation of hiccups. We conclude that cisplatin-related hiccups are predominant in males, dexamethasone-induced, and associated with protection against nausea/vomiting. J Pain Symptom Manage 2005;30: Ó 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Cisplatin, dexamethasone, ondansetron, hiccups, nausea, vomiting, gender Introduction The combination of 5-hydroxytryptamine (5-HT3) receptor antagonist and dexamethasone is recommended for cisplatin-induced emesis. 1 Although the complete protection Address reprint requests to: Chuang-Chi Liaw, MD, Division of Hematology-Oncology, Department of Internal Medicine, Chang-Gung Memorial Hospital, 199 Tung-Hwa North Road, 105, Taipei, Taiwan, ROC. Accepted for publication: April 5, Ó 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. rate for acute emesis is about 70%--90%, 1,2 delayed emesis remains an unsolved problem and only half the patients treated with cisplatin achieve complete control of emesis. 1,3--5 The use of dexamethasone may reduce the delayed symptoms, but this benefit may be balanced by adverse effects, one of which is hiccup. The incidence of hiccups varies from 3% to 61% in cancer patients using dexamethasonebased antiemetics for the prophylaxis of cisplatin-induced nausea/vomiting Although hiccups could be an effect of chemotherapy, /05/$--see front matter doi: /j.jpainsymman

2 360 Liaw et al. Vol. 30 No. 4 October 2005 they are not commonly seen after high doses of dexamethasone alone given in other settings Although the mechanism is not known, it has been proposed that corticosteroids reduce the synaptic transmission threshold in the midbrain and directly stimulate the hiccup reflex arc. 21,22 Our previous report suggested that both cisplatin and dexamethasone probably offer a synergistic effect to stimulate a hiccup reflex. 7 This prospective study attempts to clarify the relationships among cisplatin, dexamethasone, hiccups, and nausea/ vomiting. Methods Patients All patients in this study were scheduled to receive at least 50 mg/m 2 of cisplatin followed immediately by continuous infusion of 5-fluorouracil with or without other chemotherapeutic agents. Cisplatin was given on Day 1 and the other drugs on Day 1 and the following days. Eligibility criteria included the following characteristics: age at least 18 years, no prior experience with cisplatin-containing chemotherapy (CT), and an Eastern Cooperative Oncology Group performance status of Exclusion criteria included any other concurrent severe illness, nausea or vomiting within 24 hours before CT, other known causes of nausea or vomiting (e.g., central nervous system metastases, gastrointestinal obstruction, hypercalcemia), or concurrent therapy with corticosteroids or benzodiazepines (unless given for night sedation). All patients were hospitalized during CT administration. Antiemetic Therapy This was a single institution study. Each CT cycle consisted of cisplatin mg/m 2, dexamethasone 20 mg, and 20% mannitol ml administered in 500 ml of 5% dextrose in normal saline for 3 hours. Ondansetron (Zofran Ò ; GlaxoWellcome, Inc., Victoria, Australia), 8 mg in 100 ml dextrose, was given as a 15 minute intravenous (IV) infusion starting 30 minutes before cisplatin administration, and then every 4 hours for a total of three doses. In addition, all patients received dexamethasone 5 mg IV every 12 hours after cisplatin administration until the CT was complete. Intramuscular prochlorperazine was provided for antiemetic rescue. The rescue doses of prochlorperazine were 5 mg every 6 hours as needed. Oral chlorpromazine was also permitted to attenuate the hiccups as needed. For those who experienced hiccups but lacked nausea/vomiting during CT (H1N/ V2), we discontinued dexamethasone in the following cycles. If emesis followed the removal of dexamethasone, we readministered dexamethasone. For patients who experienced both hiccups and nausea/vomiting (H1N/V1), we added diphenhydramine 30 mg IV every 12 hours in the following cycles until the completion of CT. Response Assessment Data on vomiting, nausea, and hiccups were all prospectively evaluated daily by the investigators (medical doctors and nurse specialist) from the time of admission to the ward. Patients were requested to record their symptoms during the days after discharge. An emetic episode was defined as a vomit or a retch or any number of continuous vomits or retches (not separated by at least one minute). Efficacy of therapy against vomiting was defined as follows: 1) complete response, no emetic episodes; 2) major response, one to two emetic episodes; 3) minor response, three to five emetic episodes; and 4) failure, greater than five emetic episodes. The patients assessed the severity of nausea or hiccups with the following descriptions: 1) none; 2) mild, did not interfere with daily life; 3) moderate, interfered with daily life; and 4) severe, bedridden because of nausea or hiccups. Analysis of vomiting and nausea was performed separately for Day 1 (acute episodes) and Days 2--6 (delayed episodes). The severity of vomiting was based on the total number of emetic episodes recorded during the period. The intensity of delayed nausea was recorded as the worst nausea experienced during Days The intensity of hiccups was recorded as the worst hiccups experienced during Days Statistical Methods The Chi-squared test was used to detect the significance of differences between the groups. A P-value less than 0.05 was considered to indicate statistical significance.

3 Vol. 30 No. 4 October 2005 Cisplatin-Related 361 Results Two hundred seventy-seven patients were enrolled from October 2000 through October 2003 at Chang-Gung Memorial Hospital. The population consisted of 212 men and 65 women who ranged in age from 26 to 81 years (median, 66 years). Detailed characteristics of the patients are listed in Table 1. Efficacy and Adverse Events Vomiting and nausea were observed in 91 (32.9%) and 109 (39.4%) of 277 patients, respectively. Complete protection rates of acute nausea and vomiting were obtained in 95.3% and 96.4%, respectively. Complete protection rates of delayed nausea and vomiting were obtained in 60.6% and 67.1%, respectively. and constipation were the most common adverse events, observed in 110 (42.1%) and 94 (33.9%) patients, respectively. Dizziness, flushing, headache, and diarrhea were other adverse effects reported in 4.3%, 2.9%, 2.5%, and 1.4% of patients. Correlation of Clinical Factors with The relationships between hiccups and patient characteristics are listed in Tables 2 and 3. Among 114 patients with hiccups, 111 (97.4%) were males. Hiccup rates were 52.4% for male patients and 4.6% for female patients. Males had a significantly higher frequency of hiccups (P! ), while females had a significantly higher rate of nausea and vomiting (P! and P! , respectively). Nausea and vomiting showed inverse correlations with hiccups (P! and P , respectively). The severity of vomiting and the intensity of nausea through Days 1--6 were significantly less in hiccup patients (P! and P , respectively). More pronounced hiccups were found in patients receiving higher doses of cisplatin (P ). All patients receiving high-dose (100 or 75 mg) cisplatin were male, except one. No apparent associations were found with age and tumor type. Characteristic Table 1 Characteristics of Patients Patients (n 5 277) Sex Male 212 Female 65 Age group (y) Performance status 0, Previous non-cisplatin chemotherapy No 272 Yes 5 Primary tumor Head & Neck 68 Genitourinary 91 Gastrointestinal 97 Other 21 Chemotherapeutic regimen and dose [agent dose (mg) days] F 1000 D1--4,5/P F 1000 D1--4,5/P F 1000 D1--3/B 10 D2,3/P F 1000 D1--3/M 6/P 50 2 F 500 D1--3/L D1--3/P F 500 D1--2/L D1,2/Ep 30/P F 500 D1--2/L D1,2/M 6/P F 5 5-fluorouracil; P 5 cisplatin; B 5 bleomycin; M 5 mitomycin; Ep 5 epirubicin; L 5 leucovorin; D 5 Day. Table 2 Correlation of with Patients Characteristics Patients with Parameter Patients No. % P Total Gender! Male Female Age (y) Primary site 0.17 Head & Neck Genitourinary Gastrointestinal Other Cisplatin dose (mg/m 2 ) , Presence of vomiting during chemotherapy No Yes Presence of nausea! during chemotherapy No Yes

4 362 Liaw et al. Vol. 30 No. 4 October 2005 Emesis Time Table 3 Correlations Among Gender,, Nausea, and Vomiting Gender Men (n 5 212) Women (n 5 65) patients % patients % P Yes (n 5 114) No (n 5 163) patients % patients % P Nausea Day ! Days ! ! Days ! ! Vomiting Day ! Days ! Days ! ! Characteristics of usually began 24 hours after cisplatin administration. The onset of hiccups on Days 1, 2, and 3 was noted in 11 (9.6%), 101 (88.6%), and 2 (1.8%) patients, respectively. The hiccups persisted for 1 day in 25 patients (21.9%), 2 days in 73 patients (64.0%), 3 days in 15 patients (13.2%), and 4 days in one patient (0.9%). were mild in 38 patients (33.3%), moderate in 75 patients (65.8%), and severe in one patient (0.9%). Only a few patients needed oral chlorpromazine to attenuate the hiccups. H1N/V2 Patients after Discontinuation of Dexamethasone were experienced by 114 patients during the first cycle of CT. Eighty-five patients (74.6%) were H1N/V2, and 29 patients (25.4%) were H1N/V1. We discontinued dexamethasone in 73 of the 85 H1N/V2 patients entering the study. There were 26 (35.6%) with a mild degree and 47 (64.4%) with a moderate degree of hiccups. The causes of nonevaluation (n 5 12) were as follows: progression or death due to neoplasm (n 5 4), loss to follow-up (n 5 3), refusal of CT (n 5 2), and antiemetic treatment not given as scheduled (n 5 3). When dexamethasone was discontinued, most patients (90.4%) ceased hiccups except seven (9.6%) with very mild complaints. Complete protection rates of nausea and vomiting were decreased to 63.0% and 74.0% on Days 1--6, respectively (Table 4). Fifty-seven patients continued their third course of CT (Table 4). Forty-five achieved complete protection of nausea/vomiting in their second course of CT. Thirty-five continued without dexamethasone. Thirty-one patients (88.6%) did not complain of hiccups, except four (11.4%) with very mild symptoms. There was complete resolution of nausea and vomiting in 74.3% and 77.1% on Days 1--6, respectively. Twenty-two of 26 patients failed to maintain emesis protection, and we then readministered dexamethasone. recurred in 13 patients (59.1%), including 10 H1N/V2 and 3 H1N/V1. Complete protection rates of nausea/vomiting were increased to 54.5% and 72.7% on Days 1--6, respectively. H1N/V1 Patients after Addition of Diphenhydramine Of 29 H1N/V1 patients, we added diphenhydramine in 24 patients (Table 5). The causes of nonevaluation (n 5 5) were as follows: progression or death due to neoplasm (n 5 2), loss to follow-up (n 5 2), and refusal of CT (n 5 1). Complete protection from nausea and vomiting increased to 54.2% and 58.3% on Days 1--6, respectively. persisted in 12 patients (50.0%), including 7 H1N/ V2 and 5 H1N/V1. During the third cycle of CT, 19 patients continued with the addition of diphenhydramine. persisted in eight patients (42.2%), including five H1N/ V2 and three H1N/V1. Complete protection from nausea and vomiting was obtained in 52.9% and 52.9% on Days 1--6, respectively. Onset and Timing of Nausea and Vomiting Onset and timing of nausea/vomiting are listed in Table 6. The onset of nausea/vomiting in most H1N/V1 patients was delayed to

5 Vol. 30 No. 4 October 2005 Cisplatin-Related 363 Emesis Time Table 4 H1N/V2 a Patients after Discontinuation of Dexamethasone 2nd Cycle b 3rd Cycle b DEX2 (n 5 73) DEX2 (n 5 35) DEX1 c (n 5 22) Complete protection against nausea Day Days Days Complete protection against vomiting Day Days Days No Mild Moderate a Patients experienced hiccups but lacked nausea/vomiting during the first cycle of chemotherapy. b DEX2, dexamethasone not used; DEX1, dexamethasone used. c Dexamethasone was given again for patients with nausea/vomiting during the second cycle of chemotherapy. Day 3 or 4 and usually occurred after the cessation of hiccups. Five patients had nausea/vomiting alternated with hiccups. When hiccups started, nausea/vomiting ceased, and vice versa. In contrast to patients without hiccups, the onset of nausea/vomiting in those who discontinued dexamethasone was on Day 2, and the peak time of nausea/vomiting was on Days 2 and 3. Discussion were observed in 41.2% of our patients. Antiemetic regimens, including Emesis Time Table 5 H1N/V1 a Patients after Addition of Diphenhydramine 1st Cycle (n 5 29) 2nd Cycle (n 5 24) 3rd Cycle (n 5 19) Complete protection against nausea Day Days Days Complete protection against vomiting Day Days Days No Mild Moderate Severe a Patients experienced both hiccups and nausea/vomiting during the first cycle of chemotherapy. dexamethasone alone and dexamethasone combined with metoclopramide or serotonin antagonists, are all possibly hiccups inducers The diagnosis of drug-induced hiccups is difficult and often recognized only by a process of elimination. 23 The mechanism of hiccups is thought to be a result of the stimulation of one or more components of the hiccup reflex arc. 24 The afferent portion of the hiccup reflex arc comprises the phrenic and vagus nerves, and the sympathetic chain from thoracic segments T6--T12. The central connection for hiccups probably involves a nonspecific anatomic location between the cervical segments C3--C5 and the brain stem. The efferent portion of the arc consists of the phrenic nerve, the glottis, accessory respiratory muscles, and the complex interaction between the brain stem and midbrain areas, including the respiratory center, phrenic nerve nuclei, medullary reticular formation, and hypothalamus. 24 The cause of corticosteroid-induced hiccups is not known, but the etiology is complex. Dickerman et al. 25,26 suggested that numerous steroid receptors within the efferent limb hiccup reflex, including the medullary reticular formation, respiratory center, and hypothalamus, and stimulation of receptors within the hiccup reflex arc lead to hiccups. Dexamethasone poorly penetrates the brain. The brain penetration of this synthetic glucocorticoid is hampered by the mdr1a P-glycoprotein in the blood-brain barrier, and only an exceedingly high dose can activate receptors in the hippocampus

6 364 Liaw et al. Vol. 30 No. 4 October 2005 Table 6 Onset and Timing of Nausea and Vomiting Nausea Vomiting Patients with (n 5 29) Patients without (n 5 80) H1N/V2 a Patients after Discontinuing Dexamethasone (n 5 27) Patients with (n 5 24) Patients without (n 5 67) H1N/V2 Patients after Discontinuing Dexamethasone (n 5 19) Emesis Time Onset Day Day Day Day Days 5, Timing Day Day Day Day Days 5, a Patients experienced hiccups but lacked nausea/vomiting during the first cycle of chemotherapy. and hypothalamus. 27,28 Dexamethasone at 20 mg used for acute emesis prevention is a high dose and probably can enter the brain, and subsequently stimulate the steroid receptors within the efferent limb of the hiccup reflex arc, leading to hiccups. But dexamethasone alone may not fully explain the onset of hiccups. Cisplatin initiates the emetic reflex by the release of 5-HT3 from enterochromaffin cells and vagal afferents. 29 The vagus nerve is the afferent portion of the hiccup reflex arc, and both cisplatin and dexamethasone probably act synergistically to stimulate the hiccup reflex. Approximately 90% of patients ceased hiccuping after discontinuation of dexamethasone among H1N/V2 patients. Few patients remained with very mild hiccup attacks, and vagal afferents were thought to be the origin. More pronounced hiccups were found in the patients receiving higher doses of cisplatin. It is probable that higher doses of cisplatin elicit more vagal afferent activity. Besides cisplatin, the localization of tumor or a wide variety of pathologic conditions that can stimulate the limbs of the hiccup reflex arc 30 also likely cause the synergistic effects with dexamethasone. usually began 24 hours after cisplatin administration, especially during the second day of CT. The hiccups persisted for 1--3 days. Corticosteroid-induced hiccups are reported to begin as early as during the IV infusion to as late as 12 hours after the last dose and may persist for hours to days The synthetic derivatives, dexamethasone and prednisolone, have a longer half-life than cortisol. In the HeLa cell line study, dexamethasone reached the minimum level at 8 hours and remained suppressed for more than 24 hours. 31 Men had a significantly higher incidence of hiccups, while women had a significantly higher rate of nausea/vomiting. The cause of this gender difference is still unknown. Persistent hiccups (duration more than 48 hours) occur more frequently in men. 23,24 Drug-induced hiccups are also predominant in male patients. 23 Gender differences in the regulation of brain and pituitary corticosteroid receptors and their coactivators are probably the explanation. Steroid actions in the brain are exerted through their receptors that require steroid receptor coactivators (SRCs) for efficient transcription activity. 32 Karandrea and coworkers 33,34 found gender specificity in the regulation of brain and pituitary corticosteroid receptors of adult rats in response to restrained stress and forced swimming. Under basal conditions, nuclear SRC-1 is expressed at higher levels in the hippocampus and the pituitary of male rats, compared to female rats. 34 Stressed male animals exhibited a decrease in hippocampus glucocorticoid receptor SRC or

7 Vol. 30 No. 4 October 2005 Cisplatin-Related 365 immunoreactivity Similarly, hiccups have a tendency to attenuate in their following cycles once nausea/vomiting stress condition occurred. Inverse correlations between nausea/vomiting and hiccups were found among our patients. Hiccuping patients had a significantly more complete protection from nausea/vomiting during CT. The etiology is unknown. Glucocorticoid receptors probably play an important role in these settings. Ho et al. 36 found that dexamethasone exerted its central antiemetic action through the activation of the glucocorticoid receptors at the bilateral nuclei tractus solitarii in decerebrated cats. Among H1N/V2 patients, hiccups ceased after discontinuation of dexamethasone, but nausea/vomiting rates increased. In failed patients, hiccups recurred after they were given dexamethasone again, and inversely, nausea/ vomiting rates decreased. These results suggest that the activation of glucocorticoid receptors by dexamethasone may be causally linked to both hiccups and nausea/vomiting protection. Among most H1N/V1 patients, nausea/ vomiting was delayed to Day 3 or 4 and began after the cessation of hiccups. Some patients had nausea/vomiting alternated with hiccups. It is likely that hiccups have a protective action against nausea/vomiting. The mechanism is unknown. Glucocorticoid receptors and neurotransmitters such as serotonin may be involved. Dexamethasone is reported to downregulate coactivators of glucocorticoid receptor. 37 Delayed emesis is known to be related to neurotransmitters. 3 Neurotransmitters such as serotonin regulate brain corticosteroid receptors in a complex pathway. 38 When diphenhydramine was added for H1N/V1 patients, rates of nausea/vomiting decreased. Diphenhydramine is an inexpensive antiemetic with an efficacy in the prophylaxis of postoperative nausea/vomiting. 39 Its antiemetic effect is mild but may have a small role if it is given in addition to standard antiemetics due to different neurotransmitters. 3 In summary, the involvement of cisplatin-related hiccups are male predominant, dexamethasone induced, and involved in the protection against nausea/vomiting. Discontinuation of dexamethasone prevents hiccups, but nausea/vomiting rates increase. The high frequency of hiccups suggests that dexamethasone acts in synergy with cisplatin or other factors to stimulate the hiccup reflex arc. Glucocorticoid receptors activated by dexamethasone probably link with mechanisms that induce hiccups and protect against nausea/vomiting. Men may express higher levels of SRCs in the brain compared to women. This hypothetical explanation awaits confirmation, and several unresolved questions wait for investigation. Acknowledgments The authors thank Professor Jacqueline Whang-Peng for her helpful suggestions on this manuscript. References 1. Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 1999;17: De Mulder PHM, Verweij J. Prevention of acute cisplatin-induced nausea and vomiting. In: Tonato M, ed. Antiemetics in the supportive care of cancer patients. New York: Springer Verlag, 1996: Herrstedt J. Nausea and emesis: still an unsolved problem in cancer patients. Support Care Cancer 2002;10: Roila F, Donati D, Tamberi S, Margutti G. Delayed emesis: incidence, pattern, prognostic factors and optimal treatment. Support Care Cancer 2002;10: Tavorath R, Hesketh PJ. Drug treatment of chemotherapy-induced delayed emesis. Drugs 1996;52: Liaw CC, Wang CH, Chang HK, et al. Gender discrepancy observed between chemotherapy-induced emesis and hiccups. Support Care Cancer 2001;9: Sekine I, Nishiwaki Y, Kakinuma R, et al. Phase II study of high-dose dexamethasone-based association in acute and delayed high-dose cisplatin-induced emesis: JCOG study Br J Cancer 1997; 78: Kris MG, Gralla RJ, Tyson LB, et al. Controlling delayed vomiting: double-blind randomized trial comparing placebo, dexamethasone alone and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 1989;7: Nicolai N, Mangiarotti B, Salvioni R, et al. Dexamethasone plus ondansetron versus dexamethasone plus alizapride in the prevention of emesis induced by cisplatin-containing chemotherapies for urological cancers. Eur Urol 1993;23:

8 366 Liaw et al. Vol. 30 No. 4 October Italian Group for Antiemetic Research. Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Ann Oncol 1995;6: Italian Group for Antiemetic Research. Cisplatininduced delayed emesis: pattern and prognostic factors during three subsequent cycles. Ann Oncol 1994;5: Italian Group for Antiemetic Research. Ondansetron versus metoclopramide, both combined with dexamethasone, in the prevention of cisplatin-induced delayed emesis. J Clin Oncol 1997;15: Goedhals L, Heron JF, Kleisbauer JP, Pagani O, Sessa C. Control of delayed nausea and vomiting with granisetron plus dexamethasone or dexamethasone alone in patients receiving highly emetogenic chemotherapy: a double-blind, placebo-controlled, comparative study. Ann Oncol 1998;9: Gralla RJ, Rittenberg C, Peralta M, Lettow L, Cronin M. Cisplatin and emesis: aspects of treatment and a new trial for delayed emesis using oral dexamethasone plus ondansetron beginning at 16 h after cisplatin. Oncology 1996;53(Suppl 1): Takiguchi Y, Watanabe R, Nagao K, Kuriyama T. as an adverse reaction to cancer chemotherapy. J Natl Cancer Inst 2002;94: Cersosimo RJ, Brophy MT. with high dose dexamethasone administration: a case report. Cancer 1998;82: Baethge BA, Lidsky MD. Intractable hiccups associated with high-dose intravenous methylprednisolone therapy. Ann Intern Med 1986;104: Kanwar AJ, Kaur S, Dhar S, Ghosh S. : a side-effect of pulse therapy. Dermatology 1993; 187: Ross J, Eledrisi M, Casner P. Persistent hiccups induced by dexamethasone. West J Med 1999;170: Jain R, Kumar B. Immediate and delayed complications of dexamethasone cyclophosphamide pulse (DCP) therapy. J Dermatol 2003;30: Newsom-Davis J. An experimental study of hiccups. Brain 1970;93: Feldman S, Todt JC, Porter RW. Effect of adrenocortical hormones on evoked potentials in the brain stem. Neurology 1961;11: Bagheri H, Cismondo S, Monstastruc JL. Druginduced hiccup: a review of the France pharmacologic vigilance database. Therapie 1999;54: Kolodzik PW, Eilers MA. (singultus): review and approach to management. Ann Emerg Med 1995;88: Dickerman RD, Jaikumar S. The hiccups reflex arc and persistent hiccups with high-dose anabolic steroids: is the brainstem the steroid-responsive locus? Clin Neuropharmacol 2001;24: Dickerman RD, Overby C, Eisenberg M, Hollis P, Levine M. The steroid-responsive hiccup reflex arc: competitive binding to the corticosteroid-receptor? Neuroendocrinol Lett 2003;24: De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19: Miller AH, Spencer RL, Pulera M, et al. Adrenal steroid receptor activation in rat and brain pituitary following dexamethasone: implications for the dexamethasone suppression test. Biol Psychiatry 1992;32: Grunbero SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329: Launois S, Bizec JL, Whitelaw WA, Cabane J, Derenne JP. Hiccup in adults: an overview. Eur Respir J 1993;6: Shimojo M, Hiroi N, Yakushiji F, et al. Differences in down-regulation of glucocorticoid receptor mrna by cortisol, prednisolone and dexamethasone in HeLa cells. Endocr J 1995;42: Meijer OC. Coregulator proteins and corticosteroid action in the brain. J Neuroendocrinol 2002; 14: Karandrea D, Kittas C, Kitraki E. Forced swimming differentially affects male and female brain corticosteroid receptors. Neuroendocrinology 2002;75: Bousios S, Karandrea D, Kittas C, Kitraki E. Effects of gender and stress on the regulation of steroid receptor coactivator-1 expression in rat brain and pituitary. J Steroid Biochem Mol Biol 2001;78: Kitraki E, Kremmyda O, Youlatos D, Alexis MN, Kittas C. Gender-dependent alterations in corticosteroid receptor status and spatial performance following 21 days of restraint stress. Neuroscience 2004;125: Ho CM, Ho ST, Wang JJ, Tsai SK, Chai CY. Dexamethasone has a central antiemetic mechanism in decerebrated cats. Anesth Analg 2004;99: Kurihara I, Shibata H, Suzuki T, et al. Expression and regulation of nuclear receptor coactivators in glucocorticoid action. Mol Cell Endocrinol 2002; 189: Semont A, Fache M, Ouafik L, et al. Effect of serotonin inhibition on glucocorticoid and mineralcorticoid expression in various brain structures. Neuroendocrinology 1999;69: Kranke P, Morin AM, Roewer N, Eberhart LH. Dimenhydrinate for prophylaxis of postoperative nausea and vomiting: a meta-analysis of randomized controlled trials. Acta Anaesthesiol Scand 2002;46: