- Email: [email protected]
Ondansetron in Nausea and Vomiting Induced by Spinal Morphine
Vol. 16 No. 4 October 1998
Journal of Pain and Symptom Management
259
Palliative Care Rounds
Ondansetron in Nausea and Vomiting Induced by Spinal Morphine Sebastiano Mercadante, MD, Monica Sapio, MD, and Roberto Serretta, MD Pain Relief and Palliative Care (S.M.), SAMOT, Palermo, Italy; and Department of Anesthesia and Intensive Care (S.M., M.S., R.S.), Buccheri La Ferla Fatebenefratelli Hospital, Palermo, Italy
Abstract Nausea and vomiting induced by opioids are relatively frequent in advanced cancer patients, although other factors may play a role. These effects, which tend to disappear after repeated dosing, can usually be controlled with antiemetic drugs, including metoclopramide, haloperidol, and phenothiazines. Occasionally, nausea and vomiting persist, in spite of the prolonged administration of the antiemetic treatment. We report a patient who had nausea and vomiting that was resistant to common antiemetic treatments, change in opioid drugs, and change in route of administration, and who had a complete and immediate response to parenteral or oral ondansetron. J Pain Symptom Manage 1998;16:259–262. © U.S. Cancer Pain Relief Committee, 1998. Key Words Nausea and vomiting, opioids, ondansetron, palliative care Nausea and vomiting are common symptoms in patients with advanced cancer. Different etiologies have been recognized and some patients may have more than one cause.1 Causes of nausea and vomiting include gastrointestinal motility disorders, metabolic derangement, raised intracranial pressure, chemotherapy and radiotherapy, psychosomatic factors, and drugs. The opioids, which are used extensively in advanced cancer patients with pain,2 may be an important cause in some patients. Opioids stimulate nausea and vomiting by an action on the chemoreceptor trigger zone in the area postrema, by increasing vestibular sensitivity, and delaying gastric emptying. The relative emetogenicity with chronic dosing of different opioids is unknown. Although there may well be a relationship between emesis and
dose or route of administration of opioids, possibly due to higher levels of morphine metabolites found when using the oral route.3 the literature on this is far from clear. After repeated dosing, tolerance to opioidinduced nausea and vomiting typically develops and these phenomena tend to disappear within a few days. When needed, treatment with antiemetic drugs, including metoclopramide, haloperidol, and phenothiazines, results in a high rate of success. Occasionally, nausea and vomiting persist, in spite of the prolonged administration of the antiemetic treatment. We report a patient who experienced nausea and vomiting resistant to common antiemetic treatments, change in opioid therapy, and change in route of administration, who had a complete response to ondansetron.
Address reprint requests to: Sebastiano Mercadante, M.D., Pain Relief and Palliative Care Program, SAMOT, via Libertà 191, 90143 Palermo, Italy. Accepted for publication: February 4, 1998.
Case Report
© U.S. Cancer Pain Relief Committee, 1998 Published by Elsevier, New York, New York
A 61-year-old woman was referred for lumbar pain radiating to the thigh. In 1994, she 0885-3924/98/$19.00 PII S0885-3924(98)00082-7
260
Mercadante et al.
had been diagnosed with uterine cancer and underwent hysterectomy followed by radiotherapy. Computerized tomography showed a retroperitoneal mass involving most lumbar vertebrae and infiltrating the left psoas muscle. The pain, which had a burning component, arose in her spine and shot down to the left thigh, both anteriorly and posteriorly. She also experienced left leg numbness. She was treated with a combination of codeine and paracetamol. Subsequently, diclofenac with ranitidine, amitriptyline up to 40 mg daily, and increasing doses of oral morphine (60–90 mg) were administered for her pain. The appearance of nausea and vomiting, resistant to adjuvant therapy, including steroids and haloperidol, limited further escalation. Pain was not well controlled. Morphine was switched to oral patient-controlled analgesia with methadone (about 15 mg daily, with 2–3 doses of 5 mg a day, using a patient-controlled analgesia regimen to optimize the analgesia–adverse effect balance), and intramuscular diclofenac was used just as a rescue drug. The patient was ambulant and cognitive function was normal. Laboratory investigations excluded any metabolic abnormality (hypercalcemia, electrolyte changes, or renal impairment) and there were no clinical signs of raised intracranial pressure. Constipation was controlled using a combination of laxatives. No signs of bowel obstruction were observed. Acceptable analgesia was not achieved and nausea and vomiting remained intractable despite substantial measures instituted for its control, including haloperidol up to 5 mg daily, metoclopramide 30–60 mg, and dexamethasone 8 mg daily. All antiemetics were administered by parenteral route, alone or in combination. Oral morphine was restored at a dose of 90 mg daily. However, the patient asked to decrease the doses to reduce the gastrointestinal symptoms, and pain control was not adequate. The change in the route of administration with 30–40 mg of morphine subcutaneously was unsuccessful in terms of analgesia–side effect balance. Haloperidol and steroids were continued but ineffectively. An intrathecal treatment was proposed and accepted by the patient. A continuous administration of bupivacaine 15 mg and morphine up to 2.5 mg daily was effective. However, when higher doses of morphine were required in the next few days (5 mg), nausea and vomiting re-
Vol. 16 No. 4 October 1998
appeared. No signs of catheter leak could be demonstrated. Ondansetron 4 mg intravenously immediately stopped the gastrointestinal symptoms. Two doses of 4 mg a day were effective. After 2 days, ondansetron was stopped and the patient was discharged home without nausea and vomiting. Spinal treatment continued with morphine 5 mg and bupivacaine 15 mg daily continuously administered by a pump. After some weeks nausea and vomiting symptoms occurred once again, possibly as a consequence of increased intrathecal morphine requirements (7.5 mg daily). Intramuscular ondansetron at dose of 4 mg twice a day was successfully. The treatment was continued with oral ondansetron (4 mg twice a day). When ondansetron was stopped, nausea and vomiting appeared again. After 4 months, the patient was on 12.5 mg of intrathecal morphine combined with 15 mg of bupivacaine daily. Analgesia was satisfactory and she could stay at home in a village about 40 km away, continuing her ondansetron medication for vomiting. The pain syndrome required increasing doses of morphine (up to 40 mg) and bupivacaine (up to 25 mg). Symptom control was maintained using ondansetron 4 mg twice a day until death, which occurred after passing peaceful holidays at home. Ondansetron was administered for 7 months without reporting specific adverse effects.
Discussion The area postrema includes a functional entity, called the chemoreceptor trigger zone, which receives input from the vestibular apparatus and the vagus. Its chemoreceptors can sample both blood and cerebrospinal fluid,2 and may be stimulated by several emetogenic substances. It contains a great concentration of 5HT3-receptors and dopaminergic receptors. Different drugs have been proposed to treat nausea and vomiting induced by opioids. Haloperidol, a potent narrow-spectrum drug with antidopaminergic activity, is frequently used before using more broad-spectrum drugs, such as methotrimeprazine.4 Haloperidol has been also proposed by epidural route to reduce nausea and vomiting from epidural opioids.5 However, the experience with spinal haloperidol is still limited and its efficacy by this route probably is a matter of dosage, because the high lipo-
Vol. 16 No. 4 October 1998
Ondansetron in Morphine-Induced Nausea and Vomiting
solubility of haloperidol may facilitate its passage into the spinal cord rather than brain, the chemotrigger zone is bathed by systemic circulation,2 and the extent of systemic absorption may limit the selective spinal effect. Parenteral preparations of most common phenothiazines, which are necessary for an aggressive approach to vomiting, are not available in most Southern European countries. Other drugs of this group with more intense sedative effects were not indicated in an ambulatory patient. Metoclopramide is an antidopaminergic drug and a weak antagonist of 5-HT3 receptors and a prokinetic activity due to an agonist activity at 5HT4 receptors in the intestinal tract. It is frequently used in chronic nausea in advanced cancer patients.6 Metoclopramide use, however, is often associated with distressing extrapyramidal reactions.7 Steroids also are frequently used in advanced cancer patients with nausea and vomiting, despite a mechanism of action that is not clear. The antidopaminergic agents, haloperidol and metoclopramide, and steroids were ineffective in the present case. Opioid rotation and change of route of administration, including a change to the spinal route, are known to widen the therapeutic window of opioids in some circumstances. These approaches did not resolve the clinical situation. Ondansetron was immediately effective in both the hospital and home settings. Both parenteral and oral ondansetron relieved the symptoms. The effect could not be attributed to opioid tolerance because nausea and vomiting occurred at the same dose of spinal opioid after stopping ondansetron. Ondansetron is a selective antagonist of 5-HT3 receptors introduced for the clinical management of emesis associated with chemotherapy and radiotherapy. The antiemetic activity of ondansetron is believed to be mediated through blockade of the 5-HT3 receptors found on vagal afferent terminals and located centrally in the area postrema. Ondansetron has been used for the prevention and treatment of postoperative nausea and vomiting, which has a complex etiology related to patient characteristics, type of surgery, type of anesthetic, and the drugs employed for pain management (such as opioids).8 The finding that ondansetron in doses of 4–16 mg may be effective in preventing opioid-induced emesis is consistent with results obtained in clinical studies.9-11
261
Little is known about the direct effectiveness of ondansetron in opioid-induced emesis in terminally ill patients. A high response rate to ondansetron was reported in a retrospective analysis of 16 advanced patients with HIV– AIDS and cancer who had nausea and vomiting and an inadequate response to therapeutic doses of standard antiemetics, used either singly or in combination. The treatment was well tolerated, onset of action was rapid, and the effect was sustained over time.12 Other cases suggest that combined blockade of dopamine or serotonin receptors with haloperidol and ondansetron is sometime required to relieve intractable nausea and vomiting induced by opioids,13 and that ondansetron can be useful in the management of intractable nausea probably due to opioids.14 Unlike the other antiemetics currently used, ondansetron does not appear to cause drowsiness or cognitive impairment or produce extrapyramidal side effects.15 Equivalent systemic availability of intramuscular and intravenous ondansetron has been demonstrated, and less pain compared with placebo was reported following intramuscular ondansetron.16 These findings make its administration by subcutaneous route (preferable in a palliative care setting) reliable, as confirmed by our experience in other patients. Moreover the average half-life of ondansetron is longer than that of haloperidol and a single 4-mg intravenous dose of ondansetron could effectively treat postoperative nausea and vomiting over a 24-hr period with a side effect profile similar to that of placebo.16 Even though the terminal plasma half-life of ondansetron is approximately 3 hr, the pharmacological duration of action exceeds the half-life of the drug. Cost is of concern with ondansetron. However, with reduction in inpatient bed stays, the total costs of ondansetron could be met while at the same time better supporting patients remaining in the community.12 Controlled prospective studies are necessary to further clarify the role of ondansetron in the different types of nausea and vomiting presenting in advanced cancer patients.
References 1. Regnard C, Comiskey M. Nausea and vomiting in advancer cancer—a flow diagram. Palliat Med 1992;6:146–151. 2. Allan SG. Nausea and vomiting. In: Doyle D,
262
Mercadante et al.
Hanks GW, MacDonald, eds. Oxford textbook of palliative medicine. Oxford: Oxford Medical Publications, 1993:282–290. 3. Peterson GM, Randall CTC, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 1990;38:121–124. 4. Twycross R, Barkby GD, Hallwood PM. The use of low dose levopromazine (methotrimeprazine) in the management of nausea and vomiting. Prog Palliat Care 1997;5:49–53. 5. Aldrete JA. Reduction of nausea and vomiting from epidural opioids by adding droperidol to the infusate in home-bound patients. J Pain Symptom Manage 1995;10:544–547. 6. Bruera E, Seifert L, Watanabe S, Babul N, Darke A, Harsany Z, Suarez-Almazor M. Chronic nausea in advanced cancer patients: a retrospective assessment of a metoclopramide-based antiemetic regimen. J Pain Symptom Manage 1996;11:147–153. 7. Avorn J, Gurwitz JH, Bohn RL, Mogun H, Monane M, Walker A. Incresed incidence of levodopa therapy following metoclopramide use. JAMA 1995; 274:1780–1782. 8. Watcha M, White P. Postoperative nausea and vomiting. Anesthesiology 1992;77:162–184. 9. Kock KL, Xu L, Bingman J, Summy-Long J, Seaton J, Stern RM, Joslyn A, William M. Effects of ondansetron on morphine-induced nausea, vasopressin and gastric myoelectrical activity. Gastroenterology 1993;104 (suppl):A535.
Vol. 16 No. 4 October 1998
10. McKenzie R, Kovac A, O’Connor T, Duncalf D, Angel J, Gratz I, Tolpin E, McLaskey C, Joslyn A. Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery. Anesthesiology 1993;78:21–28. 11. Rung GW, Claybon L, Hord A, Patel C, Kallgren M, Koppel J, Benedetti C, Creed M, Asgharian A, Bryson J. Intravenous ondansetron for postsurgical opioid-induced nausea and vomiting. Anesth Analg 1997;84:832–838. 12. Currow DC, Coughlan M, Fardell B, Cooney NJ. Use of ondansetron in palliative medicine. J Pain Symptom Manage 1997;13:302–307. 13. Cole RM, Robinson F, Harvey L, Trethowan K, Murdoch V. Successful control of intractable nausea and vomiting requiring combined ondansetron and haloperidol in a patient with advanced cancer. J Pain Symptom Manage 1994;9:48–50. 14. Pereira J, Bruera E. Successful management of intractable nausea with ondansetron: a case study. J Palliat Care 1996;12:47–50. 15. Marthy M, Pouillart P, Pcholl S, et al. Comparison of the 5-hydroxytryptamine (serotonin) antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990;322:816–821. 16. Claybon L. Single dose intravenous administration ondansetron for the 24-hour treatment of postoperative nausea and vomiting. Anesthesia 1994;49 (suppl):24–29.
Journal of Pain and Symptom Management
259
Palliative Care Rounds
Ondansetron in Nausea and Vomiting Induced by Spinal Morphine Sebastiano Mercadante, MD, Monica Sapio, MD, and Roberto Serretta, MD Pain Relief and Palliative Care (S.M.), SAMOT, Palermo, Italy; and Department of Anesthesia and Intensive Care (S.M., M.S., R.S.), Buccheri La Ferla Fatebenefratelli Hospital, Palermo, Italy
Abstract Nausea and vomiting induced by opioids are relatively frequent in advanced cancer patients, although other factors may play a role. These effects, which tend to disappear after repeated dosing, can usually be controlled with antiemetic drugs, including metoclopramide, haloperidol, and phenothiazines. Occasionally, nausea and vomiting persist, in spite of the prolonged administration of the antiemetic treatment. We report a patient who had nausea and vomiting that was resistant to common antiemetic treatments, change in opioid drugs, and change in route of administration, and who had a complete and immediate response to parenteral or oral ondansetron. J Pain Symptom Manage 1998;16:259–262. © U.S. Cancer Pain Relief Committee, 1998. Key Words Nausea and vomiting, opioids, ondansetron, palliative care Nausea and vomiting are common symptoms in patients with advanced cancer. Different etiologies have been recognized and some patients may have more than one cause.1 Causes of nausea and vomiting include gastrointestinal motility disorders, metabolic derangement, raised intracranial pressure, chemotherapy and radiotherapy, psychosomatic factors, and drugs. The opioids, which are used extensively in advanced cancer patients with pain,2 may be an important cause in some patients. Opioids stimulate nausea and vomiting by an action on the chemoreceptor trigger zone in the area postrema, by increasing vestibular sensitivity, and delaying gastric emptying. The relative emetogenicity with chronic dosing of different opioids is unknown. Although there may well be a relationship between emesis and
dose or route of administration of opioids, possibly due to higher levels of morphine metabolites found when using the oral route.3 the literature on this is far from clear. After repeated dosing, tolerance to opioidinduced nausea and vomiting typically develops and these phenomena tend to disappear within a few days. When needed, treatment with antiemetic drugs, including metoclopramide, haloperidol, and phenothiazines, results in a high rate of success. Occasionally, nausea and vomiting persist, in spite of the prolonged administration of the antiemetic treatment. We report a patient who experienced nausea and vomiting resistant to common antiemetic treatments, change in opioid therapy, and change in route of administration, who had a complete response to ondansetron.
Address reprint requests to: Sebastiano Mercadante, M.D., Pain Relief and Palliative Care Program, SAMOT, via Libertà 191, 90143 Palermo, Italy. Accepted for publication: February 4, 1998.
Case Report
© U.S. Cancer Pain Relief Committee, 1998 Published by Elsevier, New York, New York
A 61-year-old woman was referred for lumbar pain radiating to the thigh. In 1994, she 0885-3924/98/$19.00 PII S0885-3924(98)00082-7
260
Mercadante et al.
had been diagnosed with uterine cancer and underwent hysterectomy followed by radiotherapy. Computerized tomography showed a retroperitoneal mass involving most lumbar vertebrae and infiltrating the left psoas muscle. The pain, which had a burning component, arose in her spine and shot down to the left thigh, both anteriorly and posteriorly. She also experienced left leg numbness. She was treated with a combination of codeine and paracetamol. Subsequently, diclofenac with ranitidine, amitriptyline up to 40 mg daily, and increasing doses of oral morphine (60–90 mg) were administered for her pain. The appearance of nausea and vomiting, resistant to adjuvant therapy, including steroids and haloperidol, limited further escalation. Pain was not well controlled. Morphine was switched to oral patient-controlled analgesia with methadone (about 15 mg daily, with 2–3 doses of 5 mg a day, using a patient-controlled analgesia regimen to optimize the analgesia–adverse effect balance), and intramuscular diclofenac was used just as a rescue drug. The patient was ambulant and cognitive function was normal. Laboratory investigations excluded any metabolic abnormality (hypercalcemia, electrolyte changes, or renal impairment) and there were no clinical signs of raised intracranial pressure. Constipation was controlled using a combination of laxatives. No signs of bowel obstruction were observed. Acceptable analgesia was not achieved and nausea and vomiting remained intractable despite substantial measures instituted for its control, including haloperidol up to 5 mg daily, metoclopramide 30–60 mg, and dexamethasone 8 mg daily. All antiemetics were administered by parenteral route, alone or in combination. Oral morphine was restored at a dose of 90 mg daily. However, the patient asked to decrease the doses to reduce the gastrointestinal symptoms, and pain control was not adequate. The change in the route of administration with 30–40 mg of morphine subcutaneously was unsuccessful in terms of analgesia–side effect balance. Haloperidol and steroids were continued but ineffectively. An intrathecal treatment was proposed and accepted by the patient. A continuous administration of bupivacaine 15 mg and morphine up to 2.5 mg daily was effective. However, when higher doses of morphine were required in the next few days (5 mg), nausea and vomiting re-
Vol. 16 No. 4 October 1998
appeared. No signs of catheter leak could be demonstrated. Ondansetron 4 mg intravenously immediately stopped the gastrointestinal symptoms. Two doses of 4 mg a day were effective. After 2 days, ondansetron was stopped and the patient was discharged home without nausea and vomiting. Spinal treatment continued with morphine 5 mg and bupivacaine 15 mg daily continuously administered by a pump. After some weeks nausea and vomiting symptoms occurred once again, possibly as a consequence of increased intrathecal morphine requirements (7.5 mg daily). Intramuscular ondansetron at dose of 4 mg twice a day was successfully. The treatment was continued with oral ondansetron (4 mg twice a day). When ondansetron was stopped, nausea and vomiting appeared again. After 4 months, the patient was on 12.5 mg of intrathecal morphine combined with 15 mg of bupivacaine daily. Analgesia was satisfactory and she could stay at home in a village about 40 km away, continuing her ondansetron medication for vomiting. The pain syndrome required increasing doses of morphine (up to 40 mg) and bupivacaine (up to 25 mg). Symptom control was maintained using ondansetron 4 mg twice a day until death, which occurred after passing peaceful holidays at home. Ondansetron was administered for 7 months without reporting specific adverse effects.
Discussion The area postrema includes a functional entity, called the chemoreceptor trigger zone, which receives input from the vestibular apparatus and the vagus. Its chemoreceptors can sample both blood and cerebrospinal fluid,2 and may be stimulated by several emetogenic substances. It contains a great concentration of 5HT3-receptors and dopaminergic receptors. Different drugs have been proposed to treat nausea and vomiting induced by opioids. Haloperidol, a potent narrow-spectrum drug with antidopaminergic activity, is frequently used before using more broad-spectrum drugs, such as methotrimeprazine.4 Haloperidol has been also proposed by epidural route to reduce nausea and vomiting from epidural opioids.5 However, the experience with spinal haloperidol is still limited and its efficacy by this route probably is a matter of dosage, because the high lipo-
Vol. 16 No. 4 October 1998
Ondansetron in Morphine-Induced Nausea and Vomiting
solubility of haloperidol may facilitate its passage into the spinal cord rather than brain, the chemotrigger zone is bathed by systemic circulation,2 and the extent of systemic absorption may limit the selective spinal effect. Parenteral preparations of most common phenothiazines, which are necessary for an aggressive approach to vomiting, are not available in most Southern European countries. Other drugs of this group with more intense sedative effects were not indicated in an ambulatory patient. Metoclopramide is an antidopaminergic drug and a weak antagonist of 5-HT3 receptors and a prokinetic activity due to an agonist activity at 5HT4 receptors in the intestinal tract. It is frequently used in chronic nausea in advanced cancer patients.6 Metoclopramide use, however, is often associated with distressing extrapyramidal reactions.7 Steroids also are frequently used in advanced cancer patients with nausea and vomiting, despite a mechanism of action that is not clear. The antidopaminergic agents, haloperidol and metoclopramide, and steroids were ineffective in the present case. Opioid rotation and change of route of administration, including a change to the spinal route, are known to widen the therapeutic window of opioids in some circumstances. These approaches did not resolve the clinical situation. Ondansetron was immediately effective in both the hospital and home settings. Both parenteral and oral ondansetron relieved the symptoms. The effect could not be attributed to opioid tolerance because nausea and vomiting occurred at the same dose of spinal opioid after stopping ondansetron. Ondansetron is a selective antagonist of 5-HT3 receptors introduced for the clinical management of emesis associated with chemotherapy and radiotherapy. The antiemetic activity of ondansetron is believed to be mediated through blockade of the 5-HT3 receptors found on vagal afferent terminals and located centrally in the area postrema. Ondansetron has been used for the prevention and treatment of postoperative nausea and vomiting, which has a complex etiology related to patient characteristics, type of surgery, type of anesthetic, and the drugs employed for pain management (such as opioids).8 The finding that ondansetron in doses of 4–16 mg may be effective in preventing opioid-induced emesis is consistent with results obtained in clinical studies.9-11
261
Little is known about the direct effectiveness of ondansetron in opioid-induced emesis in terminally ill patients. A high response rate to ondansetron was reported in a retrospective analysis of 16 advanced patients with HIV– AIDS and cancer who had nausea and vomiting and an inadequate response to therapeutic doses of standard antiemetics, used either singly or in combination. The treatment was well tolerated, onset of action was rapid, and the effect was sustained over time.12 Other cases suggest that combined blockade of dopamine or serotonin receptors with haloperidol and ondansetron is sometime required to relieve intractable nausea and vomiting induced by opioids,13 and that ondansetron can be useful in the management of intractable nausea probably due to opioids.14 Unlike the other antiemetics currently used, ondansetron does not appear to cause drowsiness or cognitive impairment or produce extrapyramidal side effects.15 Equivalent systemic availability of intramuscular and intravenous ondansetron has been demonstrated, and less pain compared with placebo was reported following intramuscular ondansetron.16 These findings make its administration by subcutaneous route (preferable in a palliative care setting) reliable, as confirmed by our experience in other patients. Moreover the average half-life of ondansetron is longer than that of haloperidol and a single 4-mg intravenous dose of ondansetron could effectively treat postoperative nausea and vomiting over a 24-hr period with a side effect profile similar to that of placebo.16 Even though the terminal plasma half-life of ondansetron is approximately 3 hr, the pharmacological duration of action exceeds the half-life of the drug. Cost is of concern with ondansetron. However, with reduction in inpatient bed stays, the total costs of ondansetron could be met while at the same time better supporting patients remaining in the community.12 Controlled prospective studies are necessary to further clarify the role of ondansetron in the different types of nausea and vomiting presenting in advanced cancer patients.
References 1. Regnard C, Comiskey M. Nausea and vomiting in advancer cancer—a flow diagram. Palliat Med 1992;6:146–151. 2. Allan SG. Nausea and vomiting. In: Doyle D,
262
Mercadante et al.
Hanks GW, MacDonald, eds. Oxford textbook of palliative medicine. Oxford: Oxford Medical Publications, 1993:282–290. 3. Peterson GM, Randall CTC, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 1990;38:121–124. 4. Twycross R, Barkby GD, Hallwood PM. The use of low dose levopromazine (methotrimeprazine) in the management of nausea and vomiting. Prog Palliat Care 1997;5:49–53. 5. Aldrete JA. Reduction of nausea and vomiting from epidural opioids by adding droperidol to the infusate in home-bound patients. J Pain Symptom Manage 1995;10:544–547. 6. Bruera E, Seifert L, Watanabe S, Babul N, Darke A, Harsany Z, Suarez-Almazor M. Chronic nausea in advanced cancer patients: a retrospective assessment of a metoclopramide-based antiemetic regimen. J Pain Symptom Manage 1996;11:147–153. 7. Avorn J, Gurwitz JH, Bohn RL, Mogun H, Monane M, Walker A. Incresed incidence of levodopa therapy following metoclopramide use. JAMA 1995; 274:1780–1782. 8. Watcha M, White P. Postoperative nausea and vomiting. Anesthesiology 1992;77:162–184. 9. Kock KL, Xu L, Bingman J, Summy-Long J, Seaton J, Stern RM, Joslyn A, William M. Effects of ondansetron on morphine-induced nausea, vasopressin and gastric myoelectrical activity. Gastroenterology 1993;104 (suppl):A535.
Vol. 16 No. 4 October 1998
10. McKenzie R, Kovac A, O’Connor T, Duncalf D, Angel J, Gratz I, Tolpin E, McLaskey C, Joslyn A. Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery. Anesthesiology 1993;78:21–28. 11. Rung GW, Claybon L, Hord A, Patel C, Kallgren M, Koppel J, Benedetti C, Creed M, Asgharian A, Bryson J. Intravenous ondansetron for postsurgical opioid-induced nausea and vomiting. Anesth Analg 1997;84:832–838. 12. Currow DC, Coughlan M, Fardell B, Cooney NJ. Use of ondansetron in palliative medicine. J Pain Symptom Manage 1997;13:302–307. 13. Cole RM, Robinson F, Harvey L, Trethowan K, Murdoch V. Successful control of intractable nausea and vomiting requiring combined ondansetron and haloperidol in a patient with advanced cancer. J Pain Symptom Manage 1994;9:48–50. 14. Pereira J, Bruera E. Successful management of intractable nausea with ondansetron: a case study. J Palliat Care 1996;12:47–50. 15. Marthy M, Pouillart P, Pcholl S, et al. Comparison of the 5-hydroxytryptamine (serotonin) antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990;322:816–821. 16. Claybon L. Single dose intravenous administration ondansetron for the 24-hour treatment of postoperative nausea and vomiting. Anesthesia 1994;49 (suppl):24–29.