- Email: [email protected]
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Journal of Pain and Symptom Management
Vol. 40 No. 1 July 2010
Palliative Care Rounds
Scopolamine for Cancer-Related Nausea and Vomiting Susan B. LeGrand, MD, FACP, and Declan Walsh, MSc, FRCP (Edin) Section of Palliative Medicine and Supportive Oncology, The Harry R. Horvitz Center for Palliative Medicine; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA
Abstract Nausea and vomiting is a common and troublesome symptom in advanced cancer. There have been different approaches described for the management of nausea and vomiting, specifically empirical and etiological. Scopolamine is listed in textbooks as a useful medication in management of nausea and vomiting in this setting, although there is no published data to support this recommendation. We present three cases that support the use of scopolamine in an etiologically based approach for management of nausea in advanced cancer. J Pain Symptom Manage 2010;40:136e141. Ó 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Antiemetics, cancer, nausea, scopolamine, vomiting
Introduction Nausea and vomiting are distressing symptoms and occur in 20%e98% of persons receiving palliative care.1e4 There has been little research on the best methods to control this symptom and also little published on the common medications used.3 There have been two general approaches. One is an empirical approach: start with one drug and, if unsuccessful, add or rotate to another.4,5 The
The authors have no financial conflicts of interest related to this article. The Harry R. Horvitz Center for Palliative Medicine is a World Health Organization Demonstration Project in Palliative Medicine and a European Society for Medical Oncology Designated Center of Integrated Oncology and Palliative Care. Address correspondence to: Susan B. LeGrand, MD, FACP, The Cleveland Clinic, 9500 Euclid Avenue, R35, Cleveland, OH 44195, USA. E-mail: legrans@ ccf.org Accepted for publication: December 2, 2009. Ó 2010 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
second approach is etiologically based and tailored to the suspected cause and likely receptors involved.6e9 There are reports that support each approach, but they have never been directly compared.
Pathophysiology Nausea and vomiting are controlled by four key elements in the central nervous center: the vomiting center, the chemoreceptor trigger zone, the cortex, and the vestibular nucleus. There are multiple receptors involved, which include the dopamine (D2), histamine (H1), serotonin (5HT3), neurokinin (NK-1), and muscarinic cholinergic (M1e5). Specific causes of nausea are believed by some to be related to particular receptors (Table 1).
Management Approaches The empirical approach was tested in two studies of specific medications. In the first, the value of a metoclopramide titration regimen was retrospectively reviewed.4 One hundred 0885-3924/$esee front matter doi:10.1016/j.jpainsymman.2009.12.008
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Table 1 Etiology of Nausea and Vomiting in Advanced Disease6e10 Cause
Location
Receptors
Gastrointestinal Gastroparesis Visceral
Vagal and sympathetic efferents
D2, 5HT3, NK-1
Chemical Medications Metabolic
Chemoreceptor trigger zone
D2, 5HT3, NK-1
Cranial Increased intracranial pressure CNS malignancy
CNS
H1
Cortical Pain Emotional factors
CNS
H1
Vestibular Final common pathway
Vestibular nucleus Vomiting center
M, H1 H1, M, 5HT3, NK-1
consecutive patients, 98% of whom had nausea or vomiting, were started on 10 mg of metoclopramide orally or subcutaneously (SQ) every four hours. Those with bowel obstruction were excluded. In Step 2, dexamethasone 10 mg twice daily, either orally or SQ, was added. Step 3 involved a change to a metoclopramide continuous SQ infusion plus continuation of the steroid. Step 4 was substitution of other antiemetics. Twenty-five of the 100 patients went ahead to Step 4. Eighteen of the 25 patients had bowel obstruction, three had toxicity, one had renal failure, and two had unknown pathology. Based on this study, metoclopramide might be considered universally effective, which is inconsistent with clinical experience. There was no clear definition of control, and nausea mean scores at Step 3 were 48 18 on a 100-mm visual analog scale. The second trial was a 280-patient randomized trial of tropisetron, metoclopramide, and chlorpromazine in patients with advanced cancer.5 The entry criteria eliminated many common causes of nausea and vomiting, specifically, bowel obstruction, medications, central nervous system (CNS) causes, and electrolyte and metabolic abnormalities. Ninetytwo percent of emesis and 87% of nausea were controlled with the combination of tropisetron, metoclopramide, and dexamethasonedthe most successful arm of the study. Continuous SQ metoclopramide was not tested, and results cannot be compared with the first study. There have been four reports on the etiological approach.6e9 The first6,7 prospectively observed 100 episodes in 85 patients. Seventy
percent were controlled within the first 24 hours based on the initial presumed cause. Within 48 hours, 10% were controlled with an increased dose, 12% with an additional antiemetic, and 1% with a change in antiemetic. Overall, 93% achieved control. In the second report, 40 episodes in 37 patients were prospectively reviewed.8 Reversible causes were managed appropriately. Eighty-two percent and 84% had complete resolution of their nausea and vomiting, respectively. The third report evaluated 121 patients, 50% of whom developed nausea and/or vomiting.9 Physicians were confident of the cause 75% of the time, although 26% changed their initial impression. At one week, 56% and 89% of nausea and vomiting, respectively, were controlled. Residual symptoms were generally mild. In all three studies, the predominant causes were gastrointestinal and chemical. There were no episodes of vestibular origin in two trials,8,9 and if any, they were presumably included in ‘‘other’’ in the first trial.7 We present three cases in which an etiological approach that used scopolamine may have decreased the suffering associated with prolonged uncontrolled nausea and vomiting and also decreased hospital length of stay.
Case 1 SN was a 19-year-old female with a Grade III, right frontoparietal anaplastic oligodendroglioma presenting with left hemiparesis and generalized tonic-clonic seizures. A craniotomy with total resection was followed by
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temozolomide (TemodarÒ; Schering Corporation, Kenilworth, NJ), with a plan for wholebrain radiation therapy on an experimental protocol. A second craniotomy with subtotal resection was performed when the tumor recurred within two months. Six weeks of radiation therapy (with concomitant temozolomide) was then delivered, with a subsequent dexamethasone taper. Postradiation, she was admitted to the hospital with continuous nausea, four to six episodes of vomiting daily, and postural dizziness. Oral medications before admission were carbamazepine 800 mg daily (divided three times a day: 200, 200, and 400 mg), dexamethasone 4 mg every morning and 2 mg every evening, esomeprazole 40 mg daily, granisetron 1 mg twice daily (begun five days before admission), hydrocodone/acetaminophen 5/500 mg every six hours as needed for headache, and levetiracetam 1,500 mg every 12 hours. On admission, she was given intravenous (IV) granisetron 1 mg every 24 hours as needed, an increased dexamethasone dose at 8 mg IV every eight hours, and famotidine 20 mg IV every 12 hours (esomeprazole was stopped). Other medications were unchanged. Twenty-four hours later, when symptoms continued, the dexamethasone dose was increased to 8 mg IV every six hours. Prochlorperazine 10 mg orally or IV every six hours, as needed, was added (she received only one dose). Progression of disease in the surgical cavity plus leptomeningeal involvement in the fourth ventricle were identified on magnetic resonance imaging (MRI) with gadolinium. This was thought to be the etiology of the symptoms. Radiation therapy to the fourth ventricle (3,000 cGy in 10 fractions) was begun. The following day, lorazepam 0.5 mg IV every six hours, as needed, was added for the nausea. It was given frequently, with some resultant sedation but minimal reduction in nausea. Ondansetron 8 mg orally three times daily was added without effect. A Palliative Medicine consultation was requested. Given a clear patient history of increased symptoms with head and body movement, transdermal scopolamine (TransScopÒ; Novartis Pharmaceuticals, New York, NY) was recommended. An antihistamine, hydroxyzine 25 mg orally every six hours, was also prescribed for breakthrough nausea. All
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other antiemetics were discontinued. Three days later, her nausea and vomiting had resolved. Hydroxyzine was an effective antinausea rescue medication (approximately two doses per day), but given the persistence of dizziness, meclizine was substituted. She felt that this increased her symptoms of nausea and dizziness, and therefore, hydroxyzine was resumed. The remainder of the admission focused on control of headache. She was discharged to an inpatient hospice on the following medications: dexamethasone 8 mg orally at 8 AM and noon; hydromorphone 4 mg orally, as needed, for headache; hydroxyzine 25 mg orally every six hours, as needed, for nausea; lorazepam 1 mg orally every six hours, as needed, for anxiety; and the scopolamine patch every 72 hours. Anticonvulsant therapy was not changed. She remained on the same scopolamine dose, with both nausea and vomiting well controlled until her death several months later.
Case 2 WB was a 61-year-old male with stage Ia IgG lambda myeloma. Initially, he was treated with melphalan and prednisone. This was complicated by a psychosis (presumably related to the corticosteroid). He developed a rash with thalidomide and could tolerate only small doses. Eighteen months after diagnosis, the therapy was changed to IV cyclophosphamide every three weeks. Three months later, he was admitted to the hospital for nausea and vomiting. Oral medications before admission were amlodipine 5 mg daily; esomeprazole 20 mg twice daily; loratidine 10 mg daily; and zolpidem 10 mg, as needed, at bedtime. A haloperidol IV continuous infusion of 5 mg/24 hours was begun. Metoclopramide was not used given a history of akisthisia. An abdominal radiograph showed extensive stool in the colon. This was thought to be a paralytic ilieus from chemotherapy and the probable cause of his symptoms. After a large bowel movement, nausea resolved, and the haloperidol infusion was stopped without recurrence of symptoms. At discharge, haloperidol 1 mg by mouth every four hours, as needed, for nausea, was added to his admission medications. Eight months later, he was readmitted with complaints of nausea, vomiting, dizziness, and
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Scopolamine for Cancer-Related Nausea and Vomiting
new onset diplopia. Admission medications were amlodipine 5 mg daily; esomeprazole 20 mg daily; transdermal fentanyl 50 mg over 72 hours (in use for five months); gabapentin 600 mg twice daily; loratidine 10 mg daily; propoxyphene/acetaminophen every 6 hours, as needed; and temazepam 15 mg at bedtime. Because he could not tolerate MRI, a computed tomography scan was done. A posterior fossa mass with surrounding edema was found, and it was deemed the cause of his symptoms. After a 20 mg IV bolus dose of dexamethasone, diplopia and vertigo improved, but nausea and vomiting persisted. The maximum tolerated daily dose of dexamethasone was 8 mg by mouth daily. A haloperidol IV continuous infusion of 5 mg/24 hours with 0.5 mg every six hours, as needed, for rescue, was prescribed, because it had been effective in the earlier admission. Whole-brain radiation therapy (2,250 cGy in five fractions) was given empirically without biopsy. Despite the dexamethasone and titration of haloperidol to 10 mg/24 hours, nausea and vomiting continued. Ondansetron 8 mg IV every eight hours, as needed, was ineffective. Given the complaint of dizziness and the cerebellar location of the tumor, he was started on a scopolamine patch. Vomiting resolved after one day, and nausea on the second day. Haloperidol was discontinued on Day 2. He was discharged on amlodipine 5 mg daily, dexamethasone 8 mg daily, fentanyl patch 50 mg every 72 hours, gabapentin 600 mg twice daily, sertraline 25 mg daily with plans for gradual increase, and one scopolamine patch every 72 hours. Symptoms remained controlled without any scopolamine increase until his final admission six months later for altered mental status and bilateral pneumonia. The scopolamine was stopped because of delirium (although hypoxemia secondary to bilateral pneumonia was the probable cause). Mild nausea returned at that time, managed with asneeded haloperidol. He died from pneumonia during that admission.
Case 3 GC was a 51-year-old female diagnosed with a Stage III, high-grade malignant fibrous histiocytoma of the abdominal aorta. She presented with abdominal pain, nausea and vomiting, severe hypertension, and renal failure. Renal
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artery stenosis secondary to an infiltrating mass was diagnosed. Biopsy revealed a spindle cell sarcoma. She required ongoing hemodialysis. Nausea and vomiting resolved with resolution of her uremia. Two months after diagnosis, she underwent surgical resection of the tumor and grafting of the aorta. She did well postoperatively on a renal diet. Although nausea was not recorded in the chart at that time, antiemetics were prescribed. Discharge oral medications were aspirin 81 mg daily; hydrocodone/acetaminophen 5/500 mg every six hours, as needed; metoprolol extended release 200 mg a day; minoxidil 2.5 mg twice daily; and ondansetron 8 mg every eight hours, as needed. In addition, promethazine 25 mg suppository every six hours, as needed, was prescribed. Two days later (postoperative Day 8), she was readmitted with severe nausea and vomiting, food aversion since discharge, and new leftflank pain. Medication changes on admission included a change to IV promethazine 25 mg every six hours around the clock and IV dolasetron 12.5 mg every eight hours, as needed. Pain was managed with a 25 mg fentanyl patch, a medication she had tolerated postoperatively. Nausea and vomiting did not improve. On the eighth day of this admission, a nasogastric feeding tube was placed into the duodenum for nutritional support. This neither helped nor worsened her nausea and vomiting. Various antiemetics were tried, including dolasetron, lorazepam, metoclopramide (as needed), prochlorperazine, and promethazine. There was no intracranial abnormality on MRI. A nuclear medicine gastric emptying study suggested delayed emptying. Given this, metoclopramide was resumed at 10 mg IV every six hours around the clock and 10 mg IV every six hours, as needed. Symptoms did not improve. On the ninth hospital day, palliative medicine was consulted. An IV metoclopramide infusion was begun, first at 60 mg/24 hours and later increased to 120 mg/24 hours. This was replaced by a haloperidol IV continuous infusion 5 mg over 24 hours with little benefit. Her history was re-reviewed with specific enquiry about increased nausea with body movement, although she had never complained of dizziness. She felt that movement did worsen her symptoms, although the specific cause of
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motion-related nausea was unclear. Given this, a scopolamine patch was started (admission Day 15), with hydroxyzine as breakthrough. All other antiemetics were stopped. There was complete resolution of nausea and vomiting the next day. She required only one rescue dose of hydroxyzine, which was effective. She could tolerate her diet, the nasogastric feeding tube was removed, and she was discharged two days after scopolamine patch placement. She did not return after this admission.
Discussion All these cases illustrate how an etiological approach to management of nausea might have decreased distress and shortened hospital admission. What was done in these cases was the empirical approach, which started with a single drug, and then drugs were changed or added when response was not obtained. This approach was successful in two reports.4,5 An etiological approached these cases differently.6e9 When motion-related nausea was volunteered (SN) or noted in a detailed review of systems (WB and GC), it suggested a vestibular mechanism for the nausea and vomiting and suggested scopolamine as the drug of choice. Each individual had rapid resolution of his or her nausea once scopolamine was begun. All were able to stop combinations of antiemetics previously used. Symptom control was then maintained for months (SN and WB) without dosage adjustment. Muscarinic and histaminic receptors are believed to be the primary mediators of vestibular nausea and vomiting. Medications that impacted dopamine and 5HT3 receptors were ineffective. Although it is possible that other muscarinic inhibitors might have been effective as rescue medications, we empirically and successfully used the H1 receptor antagonist hydroxyzine for breakthrough nausea and vomiting.10 Scopolamine (L-hyoscine) is a naturally occurring belladonna alkaloid and a competitive inhibitor of muscarinic receptors. It has a short half-life after injection, which limited clinical utility until the transdermal patch was developed.11 The patch has 1.5 mg of scopolamine base; 1 mg is dispensed over three days with a 140 mg loading dose to facilitate onset. The preferred location for patch placement is the
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postauricular area, where the skin is thin and absorption is better.11 Although research has evaluated use in postoperative nausea and vomiting,12 opioid-induced nausea,13 bowel obstruction,14 and death rattle,15 the most common clinical use of the transdermal patch is in motion sickness.16 Although it is typically included among antiemetic agents recommended in palliative medicine practice,17,18 there are no case reports or specific trials of efficacy. Most side effects mimic atropine, but in contrast, scopolamine is a CNS depressant and can produce drowsiness and fatigue. Although the mechanism is unclear, excitation, restlessness, and delirium can occur with uncontrolled severe pain.11,19 Delirium may also occur in the elderly.19 Scopolamine has less impact on the cardiovascular system than atropine but may cause transient bradycardia at low dose and transient tachycardia at higher dose. It has a greater impact on salivary glands than atropine, with dry mouth in 67%. Urinary retention may occur. It is metabolized in the liver, with less than 10% urinary excretion of the parent compound or metabolites.11,19 We have described three cases that suggest a specific and important role for transdermal scopolamine in severe nausea and vomiting in cancer patients. The nausea and vomiting were associated with dizziness or physical movement (predominantly body). It is important to inquire specifically about these clinical characteristics. The nausea and vomiting were resistant to single or combination therapy with other widely prescribed and powerful antiemetics. In an etiological approach to cancerrelated nausea and vomiting, and in the presence of a suspected vestibular mechanism, scopolamine should be a first-line agent. Known posterior fossa or base of skull lesions associated with nausea and vomiting should also be considered the likely indications for first-line use. All three patients had long hospital admissions for intractable nausea and vomiting before patch application. Two (WB and GC) were discharged quickly thereafter. SN required additional management for headache. In conclusion, transdermal scopolamine was dramatically effective for severe drug-resistant nausea and vomiting in advanced cancer. It can be antiemetic sparing, because all other agents in these three patients were discontinued once the scopolamine was introduced. It
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Scopolamine for Cancer-Related Nausea and Vomiting
appears particularly appropriate for vestibular causes manifested by nausea and vomiting precipitated or exacerbated by head or body movement, with or without dizziness. These observations also support the concept of an etiological approach to the management of nausea and vomiting in advanced cancer.
References 1. Davis MP, Walsh D. Treatment of nausea and vomiting in advanced cancer. Support Care Cancer 2000;8:444e452. 2. Fainsinger R, Bruera D, Miller MJ, Hanson J, MacEachern T. Symptom control during the last week of life on a palliative care unit. J Palliat Care 1991;7:5e11. 3. Glare P, Pereira G, Kristjanson LJ, Stockler M, Tattersall M. Systematic review of the efficacy of antiemetics in the treatment of nausea in patients with far-advanced cancer. Support Care Cancer 2004;12: 432e440. 4. Bruera E, Seifert L, Watanabe S, et al. Chronic nausea in advanced cancer patients: a retrospective assessment of a metoclopramide-based antiemetic regimen. J Pain Symptom Manage 1996;11(3): 147e153. 5. Mystakidou K, Befon S, Liossi C, Vlachos L. Comparison of the efficacy and safety of tropisetron, metoclopramide and chlorpromazine in the treatment of emesis associated with far advanced cancer. Cancer 1998;83:1214e1223. 6. Lichter I. Forum: which antiemetic? J Palliat Care 1993;9(1):42e50. 7. Lichter I. Results of antiemetic management in terminal illness. J Palliat Care 1993;9(2):19e21. 8. Bentley A, Boyd K. Use of clinical pictures in the management of nausea and vomiting: a prospective audit. Palliat Med 2001;15(3):247e253. 9. Stephenson J, Davies A. An assessment of aetiology-based guidelines for the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer 2006;14:348e353.
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10. Snow JC. Hydroxyzine for postoperative nausea and vomiting following ophthalmologic surgery. Anesth Analg 1965;44(5):487e491. 11. Clissold SP, Heel RC. Transdermal hyoscine (scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1985;29:189e207. 12. Bailey PL, Streisand JB, Pace NL, et al. Transdermal scopolamine reduces nausea and vomiting after outpatient laparoscopy. Anesthesiology 1990;72: 977e980. 13. Ferris FD, Kerr IG, Sone M, Marcuzzi M. Transdermal scopolamine use in the control of narcotic-induced nausea. J Pain Symptom Manage 1991;6(6):389e393. 14. De Conno F, Caraceni A, Zecco E, et al. Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Manage 1991;6(8):484e486. 15. Wee B, Hillier R. Interventions for noisy breathing in patients near to death. Cochrane Database Syst Rev 2008;(1):CD005177. 16. Spinks AB, Wasiak J, Villanueva EV, Bernath V. Scopolamine (hyoscine) for preventing and treating motion sickness. Cochrane Database Syst Rev 2007; (3):CD002851. 17. Abraham JL, Fowler B, et al. Nausea, vomiting and early satiety. In: Walsh TD, Caraceni AT, Fainsinger R, eds. Palliative medicine. Philadelphia, PA: WB Saunders, 2009: 921e930. 18. Mannix KA. Gastrointestinal symptoms. In: Doyle D, Hanks GWC, Cherny N, Calman K, eds. Oxford textbook of palliative medicine, 3rd ed. Oxford, UK: Oxford Medical Publications, 2003: 489e498. 19. Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics, 11th ed. New York: The McGraw-Hill Companies, Inc., 2005: 183e200. Available from http://www.accessmedicine.com/ content.aspx?aID¼956720.
Journal of Pain and Symptom Management
Vol. 40 No. 1 July 2010
Palliative Care Rounds
Scopolamine for Cancer-Related Nausea and Vomiting Susan B. LeGrand, MD, FACP, and Declan Walsh, MSc, FRCP (Edin) Section of Palliative Medicine and Supportive Oncology, The Harry R. Horvitz Center for Palliative Medicine; and Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA
Abstract Nausea and vomiting is a common and troublesome symptom in advanced cancer. There have been different approaches described for the management of nausea and vomiting, specifically empirical and etiological. Scopolamine is listed in textbooks as a useful medication in management of nausea and vomiting in this setting, although there is no published data to support this recommendation. We present three cases that support the use of scopolamine in an etiologically based approach for management of nausea in advanced cancer. J Pain Symptom Manage 2010;40:136e141. Ó 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Antiemetics, cancer, nausea, scopolamine, vomiting
Introduction Nausea and vomiting are distressing symptoms and occur in 20%e98% of persons receiving palliative care.1e4 There has been little research on the best methods to control this symptom and also little published on the common medications used.3 There have been two general approaches. One is an empirical approach: start with one drug and, if unsuccessful, add or rotate to another.4,5 The
The authors have no financial conflicts of interest related to this article. The Harry R. Horvitz Center for Palliative Medicine is a World Health Organization Demonstration Project in Palliative Medicine and a European Society for Medical Oncology Designated Center of Integrated Oncology and Palliative Care. Address correspondence to: Susan B. LeGrand, MD, FACP, The Cleveland Clinic, 9500 Euclid Avenue, R35, Cleveland, OH 44195, USA. E-mail: legrans@ ccf.org Accepted for publication: December 2, 2009. Ó 2010 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
second approach is etiologically based and tailored to the suspected cause and likely receptors involved.6e9 There are reports that support each approach, but they have never been directly compared.
Pathophysiology Nausea and vomiting are controlled by four key elements in the central nervous center: the vomiting center, the chemoreceptor trigger zone, the cortex, and the vestibular nucleus. There are multiple receptors involved, which include the dopamine (D2), histamine (H1), serotonin (5HT3), neurokinin (NK-1), and muscarinic cholinergic (M1e5). Specific causes of nausea are believed by some to be related to particular receptors (Table 1).
Management Approaches The empirical approach was tested in two studies of specific medications. In the first, the value of a metoclopramide titration regimen was retrospectively reviewed.4 One hundred 0885-3924/$esee front matter doi:10.1016/j.jpainsymman.2009.12.008
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137
Table 1 Etiology of Nausea and Vomiting in Advanced Disease6e10 Cause
Location
Receptors
Gastrointestinal Gastroparesis Visceral
Vagal and sympathetic efferents
D2, 5HT3, NK-1
Chemical Medications Metabolic
Chemoreceptor trigger zone
D2, 5HT3, NK-1
Cranial Increased intracranial pressure CNS malignancy
CNS
H1
Cortical Pain Emotional factors
CNS
H1
Vestibular Final common pathway
Vestibular nucleus Vomiting center
M, H1 H1, M, 5HT3, NK-1
consecutive patients, 98% of whom had nausea or vomiting, were started on 10 mg of metoclopramide orally or subcutaneously (SQ) every four hours. Those with bowel obstruction were excluded. In Step 2, dexamethasone 10 mg twice daily, either orally or SQ, was added. Step 3 involved a change to a metoclopramide continuous SQ infusion plus continuation of the steroid. Step 4 was substitution of other antiemetics. Twenty-five of the 100 patients went ahead to Step 4. Eighteen of the 25 patients had bowel obstruction, three had toxicity, one had renal failure, and two had unknown pathology. Based on this study, metoclopramide might be considered universally effective, which is inconsistent with clinical experience. There was no clear definition of control, and nausea mean scores at Step 3 were 48 18 on a 100-mm visual analog scale. The second trial was a 280-patient randomized trial of tropisetron, metoclopramide, and chlorpromazine in patients with advanced cancer.5 The entry criteria eliminated many common causes of nausea and vomiting, specifically, bowel obstruction, medications, central nervous system (CNS) causes, and electrolyte and metabolic abnormalities. Ninetytwo percent of emesis and 87% of nausea were controlled with the combination of tropisetron, metoclopramide, and dexamethasonedthe most successful arm of the study. Continuous SQ metoclopramide was not tested, and results cannot be compared with the first study. There have been four reports on the etiological approach.6e9 The first6,7 prospectively observed 100 episodes in 85 patients. Seventy
percent were controlled within the first 24 hours based on the initial presumed cause. Within 48 hours, 10% were controlled with an increased dose, 12% with an additional antiemetic, and 1% with a change in antiemetic. Overall, 93% achieved control. In the second report, 40 episodes in 37 patients were prospectively reviewed.8 Reversible causes were managed appropriately. Eighty-two percent and 84% had complete resolution of their nausea and vomiting, respectively. The third report evaluated 121 patients, 50% of whom developed nausea and/or vomiting.9 Physicians were confident of the cause 75% of the time, although 26% changed their initial impression. At one week, 56% and 89% of nausea and vomiting, respectively, were controlled. Residual symptoms were generally mild. In all three studies, the predominant causes were gastrointestinal and chemical. There were no episodes of vestibular origin in two trials,8,9 and if any, they were presumably included in ‘‘other’’ in the first trial.7 We present three cases in which an etiological approach that used scopolamine may have decreased the suffering associated with prolonged uncontrolled nausea and vomiting and also decreased hospital length of stay.
Case 1 SN was a 19-year-old female with a Grade III, right frontoparietal anaplastic oligodendroglioma presenting with left hemiparesis and generalized tonic-clonic seizures. A craniotomy with total resection was followed by
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temozolomide (TemodarÒ; Schering Corporation, Kenilworth, NJ), with a plan for wholebrain radiation therapy on an experimental protocol. A second craniotomy with subtotal resection was performed when the tumor recurred within two months. Six weeks of radiation therapy (with concomitant temozolomide) was then delivered, with a subsequent dexamethasone taper. Postradiation, she was admitted to the hospital with continuous nausea, four to six episodes of vomiting daily, and postural dizziness. Oral medications before admission were carbamazepine 800 mg daily (divided three times a day: 200, 200, and 400 mg), dexamethasone 4 mg every morning and 2 mg every evening, esomeprazole 40 mg daily, granisetron 1 mg twice daily (begun five days before admission), hydrocodone/acetaminophen 5/500 mg every six hours as needed for headache, and levetiracetam 1,500 mg every 12 hours. On admission, she was given intravenous (IV) granisetron 1 mg every 24 hours as needed, an increased dexamethasone dose at 8 mg IV every eight hours, and famotidine 20 mg IV every 12 hours (esomeprazole was stopped). Other medications were unchanged. Twenty-four hours later, when symptoms continued, the dexamethasone dose was increased to 8 mg IV every six hours. Prochlorperazine 10 mg orally or IV every six hours, as needed, was added (she received only one dose). Progression of disease in the surgical cavity plus leptomeningeal involvement in the fourth ventricle were identified on magnetic resonance imaging (MRI) with gadolinium. This was thought to be the etiology of the symptoms. Radiation therapy to the fourth ventricle (3,000 cGy in 10 fractions) was begun. The following day, lorazepam 0.5 mg IV every six hours, as needed, was added for the nausea. It was given frequently, with some resultant sedation but minimal reduction in nausea. Ondansetron 8 mg orally three times daily was added without effect. A Palliative Medicine consultation was requested. Given a clear patient history of increased symptoms with head and body movement, transdermal scopolamine (TransScopÒ; Novartis Pharmaceuticals, New York, NY) was recommended. An antihistamine, hydroxyzine 25 mg orally every six hours, was also prescribed for breakthrough nausea. All
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other antiemetics were discontinued. Three days later, her nausea and vomiting had resolved. Hydroxyzine was an effective antinausea rescue medication (approximately two doses per day), but given the persistence of dizziness, meclizine was substituted. She felt that this increased her symptoms of nausea and dizziness, and therefore, hydroxyzine was resumed. The remainder of the admission focused on control of headache. She was discharged to an inpatient hospice on the following medications: dexamethasone 8 mg orally at 8 AM and noon; hydromorphone 4 mg orally, as needed, for headache; hydroxyzine 25 mg orally every six hours, as needed, for nausea; lorazepam 1 mg orally every six hours, as needed, for anxiety; and the scopolamine patch every 72 hours. Anticonvulsant therapy was not changed. She remained on the same scopolamine dose, with both nausea and vomiting well controlled until her death several months later.
Case 2 WB was a 61-year-old male with stage Ia IgG lambda myeloma. Initially, he was treated with melphalan and prednisone. This was complicated by a psychosis (presumably related to the corticosteroid). He developed a rash with thalidomide and could tolerate only small doses. Eighteen months after diagnosis, the therapy was changed to IV cyclophosphamide every three weeks. Three months later, he was admitted to the hospital for nausea and vomiting. Oral medications before admission were amlodipine 5 mg daily; esomeprazole 20 mg twice daily; loratidine 10 mg daily; and zolpidem 10 mg, as needed, at bedtime. A haloperidol IV continuous infusion of 5 mg/24 hours was begun. Metoclopramide was not used given a history of akisthisia. An abdominal radiograph showed extensive stool in the colon. This was thought to be a paralytic ilieus from chemotherapy and the probable cause of his symptoms. After a large bowel movement, nausea resolved, and the haloperidol infusion was stopped without recurrence of symptoms. At discharge, haloperidol 1 mg by mouth every four hours, as needed, for nausea, was added to his admission medications. Eight months later, he was readmitted with complaints of nausea, vomiting, dizziness, and
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new onset diplopia. Admission medications were amlodipine 5 mg daily; esomeprazole 20 mg daily; transdermal fentanyl 50 mg over 72 hours (in use for five months); gabapentin 600 mg twice daily; loratidine 10 mg daily; propoxyphene/acetaminophen every 6 hours, as needed; and temazepam 15 mg at bedtime. Because he could not tolerate MRI, a computed tomography scan was done. A posterior fossa mass with surrounding edema was found, and it was deemed the cause of his symptoms. After a 20 mg IV bolus dose of dexamethasone, diplopia and vertigo improved, but nausea and vomiting persisted. The maximum tolerated daily dose of dexamethasone was 8 mg by mouth daily. A haloperidol IV continuous infusion of 5 mg/24 hours with 0.5 mg every six hours, as needed, for rescue, was prescribed, because it had been effective in the earlier admission. Whole-brain radiation therapy (2,250 cGy in five fractions) was given empirically without biopsy. Despite the dexamethasone and titration of haloperidol to 10 mg/24 hours, nausea and vomiting continued. Ondansetron 8 mg IV every eight hours, as needed, was ineffective. Given the complaint of dizziness and the cerebellar location of the tumor, he was started on a scopolamine patch. Vomiting resolved after one day, and nausea on the second day. Haloperidol was discontinued on Day 2. He was discharged on amlodipine 5 mg daily, dexamethasone 8 mg daily, fentanyl patch 50 mg every 72 hours, gabapentin 600 mg twice daily, sertraline 25 mg daily with plans for gradual increase, and one scopolamine patch every 72 hours. Symptoms remained controlled without any scopolamine increase until his final admission six months later for altered mental status and bilateral pneumonia. The scopolamine was stopped because of delirium (although hypoxemia secondary to bilateral pneumonia was the probable cause). Mild nausea returned at that time, managed with asneeded haloperidol. He died from pneumonia during that admission.
Case 3 GC was a 51-year-old female diagnosed with a Stage III, high-grade malignant fibrous histiocytoma of the abdominal aorta. She presented with abdominal pain, nausea and vomiting, severe hypertension, and renal failure. Renal
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artery stenosis secondary to an infiltrating mass was diagnosed. Biopsy revealed a spindle cell sarcoma. She required ongoing hemodialysis. Nausea and vomiting resolved with resolution of her uremia. Two months after diagnosis, she underwent surgical resection of the tumor and grafting of the aorta. She did well postoperatively on a renal diet. Although nausea was not recorded in the chart at that time, antiemetics were prescribed. Discharge oral medications were aspirin 81 mg daily; hydrocodone/acetaminophen 5/500 mg every six hours, as needed; metoprolol extended release 200 mg a day; minoxidil 2.5 mg twice daily; and ondansetron 8 mg every eight hours, as needed. In addition, promethazine 25 mg suppository every six hours, as needed, was prescribed. Two days later (postoperative Day 8), she was readmitted with severe nausea and vomiting, food aversion since discharge, and new leftflank pain. Medication changes on admission included a change to IV promethazine 25 mg every six hours around the clock and IV dolasetron 12.5 mg every eight hours, as needed. Pain was managed with a 25 mg fentanyl patch, a medication she had tolerated postoperatively. Nausea and vomiting did not improve. On the eighth day of this admission, a nasogastric feeding tube was placed into the duodenum for nutritional support. This neither helped nor worsened her nausea and vomiting. Various antiemetics were tried, including dolasetron, lorazepam, metoclopramide (as needed), prochlorperazine, and promethazine. There was no intracranial abnormality on MRI. A nuclear medicine gastric emptying study suggested delayed emptying. Given this, metoclopramide was resumed at 10 mg IV every six hours around the clock and 10 mg IV every six hours, as needed. Symptoms did not improve. On the ninth hospital day, palliative medicine was consulted. An IV metoclopramide infusion was begun, first at 60 mg/24 hours and later increased to 120 mg/24 hours. This was replaced by a haloperidol IV continuous infusion 5 mg over 24 hours with little benefit. Her history was re-reviewed with specific enquiry about increased nausea with body movement, although she had never complained of dizziness. She felt that movement did worsen her symptoms, although the specific cause of
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motion-related nausea was unclear. Given this, a scopolamine patch was started (admission Day 15), with hydroxyzine as breakthrough. All other antiemetics were stopped. There was complete resolution of nausea and vomiting the next day. She required only one rescue dose of hydroxyzine, which was effective. She could tolerate her diet, the nasogastric feeding tube was removed, and she was discharged two days after scopolamine patch placement. She did not return after this admission.
Discussion All these cases illustrate how an etiological approach to management of nausea might have decreased distress and shortened hospital admission. What was done in these cases was the empirical approach, which started with a single drug, and then drugs were changed or added when response was not obtained. This approach was successful in two reports.4,5 An etiological approached these cases differently.6e9 When motion-related nausea was volunteered (SN) or noted in a detailed review of systems (WB and GC), it suggested a vestibular mechanism for the nausea and vomiting and suggested scopolamine as the drug of choice. Each individual had rapid resolution of his or her nausea once scopolamine was begun. All were able to stop combinations of antiemetics previously used. Symptom control was then maintained for months (SN and WB) without dosage adjustment. Muscarinic and histaminic receptors are believed to be the primary mediators of vestibular nausea and vomiting. Medications that impacted dopamine and 5HT3 receptors were ineffective. Although it is possible that other muscarinic inhibitors might have been effective as rescue medications, we empirically and successfully used the H1 receptor antagonist hydroxyzine for breakthrough nausea and vomiting.10 Scopolamine (L-hyoscine) is a naturally occurring belladonna alkaloid and a competitive inhibitor of muscarinic receptors. It has a short half-life after injection, which limited clinical utility until the transdermal patch was developed.11 The patch has 1.5 mg of scopolamine base; 1 mg is dispensed over three days with a 140 mg loading dose to facilitate onset. The preferred location for patch placement is the
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postauricular area, where the skin is thin and absorption is better.11 Although research has evaluated use in postoperative nausea and vomiting,12 opioid-induced nausea,13 bowel obstruction,14 and death rattle,15 the most common clinical use of the transdermal patch is in motion sickness.16 Although it is typically included among antiemetic agents recommended in palliative medicine practice,17,18 there are no case reports or specific trials of efficacy. Most side effects mimic atropine, but in contrast, scopolamine is a CNS depressant and can produce drowsiness and fatigue. Although the mechanism is unclear, excitation, restlessness, and delirium can occur with uncontrolled severe pain.11,19 Delirium may also occur in the elderly.19 Scopolamine has less impact on the cardiovascular system than atropine but may cause transient bradycardia at low dose and transient tachycardia at higher dose. It has a greater impact on salivary glands than atropine, with dry mouth in 67%. Urinary retention may occur. It is metabolized in the liver, with less than 10% urinary excretion of the parent compound or metabolites.11,19 We have described three cases that suggest a specific and important role for transdermal scopolamine in severe nausea and vomiting in cancer patients. The nausea and vomiting were associated with dizziness or physical movement (predominantly body). It is important to inquire specifically about these clinical characteristics. The nausea and vomiting were resistant to single or combination therapy with other widely prescribed and powerful antiemetics. In an etiological approach to cancerrelated nausea and vomiting, and in the presence of a suspected vestibular mechanism, scopolamine should be a first-line agent. Known posterior fossa or base of skull lesions associated with nausea and vomiting should also be considered the likely indications for first-line use. All three patients had long hospital admissions for intractable nausea and vomiting before patch application. Two (WB and GC) were discharged quickly thereafter. SN required additional management for headache. In conclusion, transdermal scopolamine was dramatically effective for severe drug-resistant nausea and vomiting in advanced cancer. It can be antiemetic sparing, because all other agents in these three patients were discontinued once the scopolamine was introduced. It
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appears particularly appropriate for vestibular causes manifested by nausea and vomiting precipitated or exacerbated by head or body movement, with or without dizziness. These observations also support the concept of an etiological approach to the management of nausea and vomiting in advanced cancer.
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10. Snow JC. Hydroxyzine for postoperative nausea and vomiting following ophthalmologic surgery. Anesth Analg 1965;44(5):487e491. 11. Clissold SP, Heel RC. Transdermal hyoscine (scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1985;29:189e207. 12. Bailey PL, Streisand JB, Pace NL, et al. Transdermal scopolamine reduces nausea and vomiting after outpatient laparoscopy. Anesthesiology 1990;72: 977e980. 13. Ferris FD, Kerr IG, Sone M, Marcuzzi M. Transdermal scopolamine use in the control of narcotic-induced nausea. J Pain Symptom Manage 1991;6(6):389e393. 14. De Conno F, Caraceni A, Zecco E, et al. Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Manage 1991;6(8):484e486. 15. Wee B, Hillier R. Interventions for noisy breathing in patients near to death. Cochrane Database Syst Rev 2008;(1):CD005177. 16. Spinks AB, Wasiak J, Villanueva EV, Bernath V. Scopolamine (hyoscine) for preventing and treating motion sickness. Cochrane Database Syst Rev 2007; (3):CD002851. 17. Abraham JL, Fowler B, et al. Nausea, vomiting and early satiety. In: Walsh TD, Caraceni AT, Fainsinger R, eds. Palliative medicine. Philadelphia, PA: WB Saunders, 2009: 921e930. 18. Mannix KA. Gastrointestinal symptoms. In: Doyle D, Hanks GWC, Cherny N, Calman K, eds. Oxford textbook of palliative medicine, 3rd ed. Oxford, UK: Oxford Medical Publications, 2003: 489e498. 19. Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics, 11th ed. New York: The McGraw-Hill Companies, Inc., 2005: 183e200. Available from http://www.accessmedicine.com/ content.aspx?aID¼956720.