Journal of Pain & Palliative Care Pharmacotherapy. 2015;29:148–152. Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2015.1035831
CASE REPORT
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Olanzapine in the Treatment of Refractory Nausea and Vomiting: A Case Report and Review of the Literature Michael Langley-DeGroot, Joseph D. Ma, Jeremy Hirst, and Eric J. Roeland AB STRACT The role of olanzapine in chemotherapy-induced nausea and vomiting (CINV) is supported from randomized controlled trials and national consensus guidelines such as the National Comprehensive Cancer Network. In contrast, the role of olanzapine in refractory non-CINV is limited to case reports/series, retrospective studies, one pilot study, and one randomized controlled trial in patients with major depressive disorder. We present a case of a 36-year-old man with dyskeratosis congenita and refractory non-CINV over several years in which low-dose olanzapine was effective and tolerable. We aim to contribute to the growing evidence supporting the use of olanzapine for refractory non-CINV. Furthermore, we review and summarize the literature regarding olanzapine in the CINV and non-CINV settings. KEYWORDS non–chemotherapy-induced nausea vomiting, olanzapine, refractory
Overlapping combinations of metoclopramide, promethazine, ondansetron, dronabinol, and lorazepam were attempted. The duration of use for these medications, as well as others, are summarized in Table 1. Medication dispensation was managed by the patient’s mother who observed medication consumption by the patient. Unfortunately, his NV was not controlled and the patient was admitted to the hospital 18 times from 2011 to 2014 for these symptoms. Mounting frustration due to poor control of his symptoms led the patient to also try medicinal marijuana in the form of a lozenge in addition to domperidone, a drug not available in the United States given the cardiac risk associated with QTc prolongation.2 All pharmacologic approaches in multiple combinations failed to improve his symptoms. Nonpharmacologic interventions including endoscopic evaluation with balloon dilation of the pylorus on November 16, 2012, behavioral interventions, and trials of ginger tea and essential oils were also ineffective. Given the prospective data in chemotherapy-induced nausea and vomiting (CINV) and case reports in nonCINV, the risks and benefits of olanzapine to treat refractory non-CINV were discussed with the patient, and he selected to initiate oral olanzapine. Non-CINV was assessed with a numerical rating scale (NRS) and the Scored Patient-Generated
CASE PRESENTATION A 36-year-old man with a history of dyskeratosis congenita was receiving outpatient palliative care for refractory nausea and vomiting (NV) that had been escalating over several years. Dyskeratosis congenita is a rare, inherited disorder characterized by progressive bone marrow failure and anomalies of the integumentary system, including finger and toenail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Dyskeratosis congenita patients also have a high predisposition to develop secondary cancers and fatal pulmonary complications.1 Despite multiple endoscopic, radiologic, and laboratory evaluations to determine the etiology of his symptoms, no singular cause could be identified. Additionally, evaluations by the palliative psychiatry service revealed that an occult, underlyling psychotic, mood, or anxiety disorder was unlikely to be a significant causative factor in the patient’s NV. Michael Langley-DeGroot, BA, Joseph D. Ma, PharmD, Jeremy Hirst, MD, and Eric J. Roeland, MD, are with the Doris A. Howell Palliative Care Service, University of California San Diego (UC San Diego) Moores Cancer Center, La Jolla, California, USA. Address correspondence to: Eric J. Roeland, MD, FAAHPM, Doris A. Howell Palliative Care Service, University of California San Diego Moores Cancer Center, La Jolla, CA 92093. Tel: 858-534-7079. (E-mail: [email protected])
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M. Langley-DeGroot et al. TABLE 1.
Current and previously tried antiemetics to treat refractory non-CINV in this patient prior to olanzapine initiation
Time interval (month/year)
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1/11–present (current medication) 1/12–present (current medication) 12/12–present (current medication) 1/11–7/14 6/12–7/12 7/12–11/13 3/13–7/14
Antiemetic
Patient dose, route, and frequency
Ondansetron Lorazepam Marijuana lozenge Metoclopramide Dronabinol Promethazine Domperidone
8 mg IV twice daily as needed 1 mg by mouth twice daily as needed One to two by mouth per day as needed 10 mg by mouth four times daily 2.5 mg by mouth twice daily before meals 25 mg by mouth every 6 hours as needed 10 mg by mouth twice daily
Subjective Global Assessment (PG-SGA). The PG-SGA assesses self-reported domains, including “weight loss,” “food intake,” “symptoms,” and “activities and function.”3 Prior to olanzapine therapy, the patient endorsed a weight loss of 14 pounds over the course of 1 month. His food intake was described as “less than usual” for the same time period. He endorsed symptoms including NV, stomach pain, early satiety, and aversion to certain smells and described his functional level as “able to do little activity and spend most of the day in bed or chair.” The total PG-SGA score was 20 at this time, indicating “a critical need for improved symptom management and/or nutrient intervention options.” Additionally, the patient rated his current NV as an 8 out of 10 on the NRS. Prior to olanzapine initiation on July 8, 2014, the patient’s NV regimen included metoclopramide 10 mg by mouth four times per day, lorazepam 1 mg by mouth twice daily as needed, intravenous (IV) ondansetron 8 mg twice daily as needed, medicinal marijuana lozenges by mouth as needed, and domperidone 10 mg by mouth twice daily (obtained from Mexico). Intravenous ondansetron was given through an indwelling PORT-a-cath along with IV hydration. On treatment day 1, domperidone was discontinued and oral olanzapine 5 mg at night was initiated. A telephone encounter was conducted approximately 48 hours later. After 2 days of olanzapine in addition to metoclopramide, lorazepam, ondansetron, and medicinal marijuana lozenges, the patient reported significant improvement of NV with no usage of breakthrough ondansetron (prior usage was typically one to two 8 mg doses daily). At this time, scheduled metoclopramide was also discontinued and his olanzapine dose was increased to 10 mg daily at night. The patient returned to clinic on treatment day 22. He endorsed continued improvement of NV in the typical day; however, he noted worsening of his nausea on the car trip to clinic and subsequently ranked current NV as an 8 out of 10 on the NRS. The followup PG-SGA revealed that the patient had gained 3 pounds since treatment day 1. His food intake was noted to be “more than usual,” and although he con C
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tinued to endorse nausea, he no longer complained of vomiting, stomach pain, early satiety, or aversion to certain smells. His functional level had improved to “not my normal self, but able to be up and about with fairly normal activities.” The PG-SGA total score after 22 days on olanzapine had decreased to 7. Overall, the patient reported an improved quality of life since the initiation of olanzapine therapy and denied any adverse effects related to the medication.
DISCUSSION Nausea and vomiting are symptoms commonly experienced by patients in the palliative care setting. Although treatment with the combination of standard antiemetics of different classes is often effective, some patients experience NV that fails to respond. Because NV can significantly detract from the quality of life of patients, it is important to consider pharmacologic alternatives when NV is refractory to standard treatment.4 For the purposes of this case report, we define refractory NV as the persistence of symptoms despite an appropriate duration of use (e.g., achievement of steady-state concentrations) of at least two scheduled antiemetic agents with different mechanisms of action. Olanzapine is an atypical antipsychotic medication indicated for the treatment of schizophrenia and bipolar disorder. Olanzapine antagonizes the following neurotransmitter receptors with high affinity: serotonin (5HT)2A/2C , 5HT6 , dopamine (D)1–4 , histamine (H)1 , and α 1 -adrenergic receptors. It is an antagonist with moderate affinity binding for 5HT3 and muscarinic (M)1–5 and binds weakly to γ aminobutyric acid (GABA)A , benzodiazepine (BZD), and β-adrenergic receptors.5 The association of D2, 5HT2A , 5HT2C , and 5HT3 receptors with the emetic pathway makes olanzapine an intriguing potential antiemetic agent.6 There is evidence supporting olanzapine in the prevention and treatment of CINV. Table 2 summarizes the results of prospective studies investigating the use of olanzapine as an antiemetic in this
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TABLE 2.
Summary of prospective studies investigating the use of olanzapine for the treatment of CINV Study phase
N
Passik et al. (2004)7
I
15
Olanzapine in addition to standard antiemetics
Delayed emesis in cancer patients receiving MEC/HEC
Navari et al. (2005)8
II
30
Olanzapine in addition to granisetron and dexamethasone
Acute and delayed CINV in cancer patients receiving MEC/HEC
Navari et al. (2007)9
II
40
Olanzapine in addition to palonosetron and dexamethasone
Acute and delayed CINV in cancer patients receiving MEC/HEC
Tan et al. (2009)10
III
229
Azasetron and dexamethasone versus Olanzapine, azasetron, and dexamethasone
Acute and delayed CINV in cancer patients receiving MEC/HEC
Navari et al. (2011)11
III
241
Olanzapine, palonosetron, and dexamethasone versus Aprepitant, palonosteron, and dexamethasone
Acute and delayed emesis and nausea in patients receiving HEC
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Author (year)
Interventions
Primary end point
Results MEC cohort: 4/6 patients with no episodes of delayed emesis HEC cohort: 9/9 patients with no episodes of delayed emesis MEC cohort: 20/20 patients with no acute emesis, 17/20 patients with no delayed emesis, and 13/20 with no nausea HEC cohort: 10/10 patients with no acute emesis, 8/10 patients with no delayed emesis, and 10/10 patients with no nausea MEC cohort: 31/32 patients with no acute emesis, 24/32 patients with no delayed emesis, and 25/32 patients with no nausea HEC cohort: 8/8 patients with no acute emesis, 6/8 patients with no delayed emesis, and 4/8 patients with no nausea MEC cohort: Patients in the olanzapine group experienced less delayed nausea (25.01% reduction) and vomiting (13.43% reduction), P < .05. HEC cohort: Patients in the olanzapine group experienced less delayed nausea (39.21% reduction) and vomiting (22.05% reduction), P < .05. Of the 121 patients in the olanzapine group, 77% had no episodes of emesis and 69% of patients denied nausea. Complete response rate was not significantly different compared with the aprepitant group (120 patients). Percent of patients experiencing no nausea was significantly higher in the olanzapine group (69% vs. 38%).
Grade 3/4 adverse effects No grade 4 toxicities observed. 3 subjects with grade 3 toxicity of depressed level of consciousness None
None
None
None
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Journal of Pain & Palliative Care Pharmacotherapy
M. Langley-DeGroot et al. TABLE 2. Author (year)
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Navari et al. (2013)12
Mizukami et al. (2014)13
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Summary of prospective studies investigating the use of olanzapine for the treatment of CINV(Continued) Study phase
N
Interventions
III
108
Olanzapine versus metoclopramide for CINV refractory to a standard antiemetic regimen
Breakthrough nausea and vomiting in patients receiving HEC
N/A
44
Olanzapine added to standard antiemetic regimen
Acute and delayed CINV in patients receiving chemotherapy
Primary end point
Results 39/56 patients receiving olanzapine versus 16/52 patients receiving metoclopramide experienced no emesis (P < .01). 38/56 patients receiving olanzapine versus 12/52 patients receiving metoclopramide reported no nausea (P < .01). 86% and 64% of patients receiving olanzapine had no episodes of emesis in the acute and delayed phases of treatment, respectively, compared with only 55% (P = .045) and 23% (P = .014) of patients in the control group.
Grade 3/4 adverse effects None
None
Note. HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy.
setting.7–13 Two phase III studies by Navari and colleagues provide some of the most compelling evidence for the use of olanzapine to treat and prevent CINV. The first study compared olanzapine with aprepitant in the prevention of both acute (24 hours post chemotherapy) and delayed (2 to 5 days post chemotherapy) CINV. Patients receiving highly emetogenic chemotherapy were randomized to receive either oral olanzapine or aprepitant in combination with IV palonosetron and dexamethasone. Complete response rate (no emesis or rescue medications) was 97% in the acute period and 77% in the delayed period for patients receiving 10 mg olanzapine in addition to palonosetron and dexamethasone. Complete response rates were comparable in the aprepitant group, although the number of patients who experienced no nausea (69% in the olanzapine group vs. 38% in the aprepitant group) was significantly lower (P < .01). No grade 3 or 4 toxicities were reported.11 The second phase III study compared olanzapine 10 mg daily with metoclopramide 10 mg three times daily over a 3-day treatment period for patients experiencing breakthrough CINV despite standard antiemetics. During the 72-hour observation period, 70% of patients receiving olanzapine had no emesis versus 31% receiving metoclopramide (P < .01). Nausea was also better controlled in the olanzapine group (68% vs. 23%; P < .01). There were no grade 3 or 4 toxicities.12 C
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In marked contrast, the evidence for the use of olanzapine to treat NV in patients who are not receiving chemotherapy is limited. Three case reports have been published describing patients who experienced symptomatic improvement of non-CINV following treatment with olanzapine.14–16 Additionally, one case series details the treatment and clinical course of six patients whose non-CINV responded to olanzapine.17 A small retrospective study of four cancer patients with non-CINV found that the initiation of olanzapine improved symptoms and reduced the need for additional scheduled and rescue antiemetics.18 Another retrospective study of 20 cancer patients with NV associated with incomplete bowel obstruction found that olanzapine therapy significantly reduced the intensity of nausea and frequency of vomiting.19 Prospective studies investigating the role of olanzapine in the treatment of non-CINV have been published.20,21 An open label pilot study of 15 cancer patients with non-CINV found that olanzapine significantly reduced symptoms at doses of 2.5, 5, and 10 mg daily.20 In a randomized controlled trial, 268 subjects with major depressive disorder were given either duloxetine alone, duloxetine plus 1.25 mg olanzapine, or duloxetine plus 2.5 mg olanzapine. Subjects taking both medications experienced less NV than patients taking duloxetine alone, and the antiemetic effect was higher in the group receiving 2.5 mg of olanzapine.21
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We believe this case report is unique to the nonCINV literature given the duration of symptoms over a course of years and the number of antiemetics and home therapies failed by the patient. Additionally, the majority of the prior non-CINV studies/reports have investigated the use of olanzapine for refractory NV in end-of-life care, particularly in patients with advanced cancer. The remaining studies/reports have examined olanzapine as an adjuvant for a known, reversible cause of non-CINV. This patient is not a terminal patient, and the etiology of his refractory non-CINV, despite multiple imaging modalities and endoscopic evaluation, remains unknown. This case report and review of the CINV and nonCINV literature suggests that olanzapine may be an alternative antiemetic in the non-CINV setting and supports existing case reports.14–16 Of note, in our case as in previous studies, the required effective olanzapine dose was low, symptom improvement occurred within days, and the medication was well tolerated. We hypothesize that olanzapine’s role in the treatment of refractory non-CINV may be due in part to the promiscuous antagonism of multiple dopamine and serotonin receptors in contrast to the selective antagonism of antiemetic drugs available currently. We believe that olanzapine may be an effective antiemetic for the treatment of refractory non-CINV. Additional double-blind, placebo-controlled studies are needed to further assess olanzapine’s efficacy in the refractory non-CINV setting. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES [1] Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol. 2000;110:768–779. [2] van Noord C, Dieleman JP, van Herpen G, Verhamme K, Sturkenboom MC. Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in The Netherlands. Drug Saf. 2010;33:1003–1014. [3] Bauer J, Capra S, Ferguson M. Use of the scored PatientGenerated Subjective Global Assessment (PG-SGA) as a nutrition assessment tool in patients with cancer. Eur J Clin Nutr. 2002;56:779–785. [4] Pirri C, Bayliss E, Trotter J, et al. Nausea still the poor relation in antiemetic therapy? The impact on cancer patients’ quality of life and psychological adjustment of nausea, vomiting and appetite loss, individually and concurrently as part of a symptom cluster. Support Care Cancer. 2013;21:735–748. [5] Eli Lilly and Company. Available at: http://pi.lilly.com/ us/zyprexa-pi.pdf, updated December 2014. Accessed January 2, 2015.
[6] Glare P, Miller J, Nikolova T, Tickoo R. Treating nausea and vomiting in palliative care: a review. Clin Interv Aging. 2011;6:243–259. [7] Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine (Zyprexa) for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group study. Cancer Invest. 2004;22:383–388. [8] Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer. 2005;13:529–534. [9] Navari R, Einhorn L, Loehrer P, et al. A phase II trial of olanzapine for the prevention of chemotherapy induced nausea and vomiting (CINV). J Clin Oncol (Meeting Abstracts). 2004;2004:8046. [10] Tan L, Liu J, Liu X, et al. Clinical research of Olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res. 2009;28:131. [11] Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol. 2011;9:188–195. [12] Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21:1655–1663. [13] Mizukami N, Yamauchi M, Koike K, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: a randomized, double-blind, placebo-controlled study. J Pain Symptom Manage. 2014;47:542–550. [14] Yoshida K, Higuchi H, Ozaki N. Successful treatment of severe antidepressant-induced nausea with a combination of milnacipran and olanzapine. Pharmacopsychiatry. 2007;40:84–85. [15] Murakami N, Tanabe K, Yamatani K, et al. Use of orally disintegrating olanzapine tablet for patients with cancerous peritonitis and postoperative gastric cancer receiving home palliative care. Gan to Kagaku Ryoho. 2012;39:649–652. [16] Suzuki M, Komuro K, Ohara K. Olanzapine and betamethasone are effective for the treatment of nausea and vomiting due to metastatic brain tumors of rectal cancer. Case Rep Gastroenterol. 2014;8:13–17. [17] Jackson WC, Tavernier L. Olanzapine for intractable nausea in palliative care patients. J Palliat Med. 2003;6:251–255. [18] Atkinson SR. Olanzapine for intractable nausea and vomiting in palliative care patients not receiving chemotherapy. J Palliat Med. 2014;17:503–504. [19] Kaneishi K, Kawabata M, Morita T. Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manage. 2012;44:604–607. [20] Passik SD, Lundberg J, Kirsh KL, et al. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage. 2002;23:526–532. [21] Zhong Z, Zhang Y, Han H, et al. Effects of low-dose olanzapine on duloxetine-related nausea and vomiting for the treatment of major depressive disorder. J Clin Psychopharmacol. 2014;34:495–498.
RECEIVED: 5 January 2015 REVISED: 10 March 2015 ACCEPTED: 27 March 2015
Journal of Pain & Palliative Care Pharmacotherapy
CASE REPORT
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Nyu Medical Center on 07/05/15 For personal use only.
Olanzapine in the Treatment of Refractory Nausea and Vomiting: A Case Report and Review of the Literature Michael Langley-DeGroot, Joseph D. Ma, Jeremy Hirst, and Eric J. Roeland AB STRACT The role of olanzapine in chemotherapy-induced nausea and vomiting (CINV) is supported from randomized controlled trials and national consensus guidelines such as the National Comprehensive Cancer Network. In contrast, the role of olanzapine in refractory non-CINV is limited to case reports/series, retrospective studies, one pilot study, and one randomized controlled trial in patients with major depressive disorder. We present a case of a 36-year-old man with dyskeratosis congenita and refractory non-CINV over several years in which low-dose olanzapine was effective and tolerable. We aim to contribute to the growing evidence supporting the use of olanzapine for refractory non-CINV. Furthermore, we review and summarize the literature regarding olanzapine in the CINV and non-CINV settings. KEYWORDS non–chemotherapy-induced nausea vomiting, olanzapine, refractory
Overlapping combinations of metoclopramide, promethazine, ondansetron, dronabinol, and lorazepam were attempted. The duration of use for these medications, as well as others, are summarized in Table 1. Medication dispensation was managed by the patient’s mother who observed medication consumption by the patient. Unfortunately, his NV was not controlled and the patient was admitted to the hospital 18 times from 2011 to 2014 for these symptoms. Mounting frustration due to poor control of his symptoms led the patient to also try medicinal marijuana in the form of a lozenge in addition to domperidone, a drug not available in the United States given the cardiac risk associated with QTc prolongation.2 All pharmacologic approaches in multiple combinations failed to improve his symptoms. Nonpharmacologic interventions including endoscopic evaluation with balloon dilation of the pylorus on November 16, 2012, behavioral interventions, and trials of ginger tea and essential oils were also ineffective. Given the prospective data in chemotherapy-induced nausea and vomiting (CINV) and case reports in nonCINV, the risks and benefits of olanzapine to treat refractory non-CINV were discussed with the patient, and he selected to initiate oral olanzapine. Non-CINV was assessed with a numerical rating scale (NRS) and the Scored Patient-Generated
CASE PRESENTATION A 36-year-old man with a history of dyskeratosis congenita was receiving outpatient palliative care for refractory nausea and vomiting (NV) that had been escalating over several years. Dyskeratosis congenita is a rare, inherited disorder characterized by progressive bone marrow failure and anomalies of the integumentary system, including finger and toenail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Dyskeratosis congenita patients also have a high predisposition to develop secondary cancers and fatal pulmonary complications.1 Despite multiple endoscopic, radiologic, and laboratory evaluations to determine the etiology of his symptoms, no singular cause could be identified. Additionally, evaluations by the palliative psychiatry service revealed that an occult, underlyling psychotic, mood, or anxiety disorder was unlikely to be a significant causative factor in the patient’s NV. Michael Langley-DeGroot, BA, Joseph D. Ma, PharmD, Jeremy Hirst, MD, and Eric J. Roeland, MD, are with the Doris A. Howell Palliative Care Service, University of California San Diego (UC San Diego) Moores Cancer Center, La Jolla, California, USA. Address correspondence to: Eric J. Roeland, MD, FAAHPM, Doris A. Howell Palliative Care Service, University of California San Diego Moores Cancer Center, La Jolla, CA 92093. Tel: 858-534-7079. (E-mail: [email protected])
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M. Langley-DeGroot et al. TABLE 1.
Current and previously tried antiemetics to treat refractory non-CINV in this patient prior to olanzapine initiation
Time interval (month/year)
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1/11–present (current medication) 1/12–present (current medication) 12/12–present (current medication) 1/11–7/14 6/12–7/12 7/12–11/13 3/13–7/14
Antiemetic
Patient dose, route, and frequency
Ondansetron Lorazepam Marijuana lozenge Metoclopramide Dronabinol Promethazine Domperidone
8 mg IV twice daily as needed 1 mg by mouth twice daily as needed One to two by mouth per day as needed 10 mg by mouth four times daily 2.5 mg by mouth twice daily before meals 25 mg by mouth every 6 hours as needed 10 mg by mouth twice daily
Subjective Global Assessment (PG-SGA). The PG-SGA assesses self-reported domains, including “weight loss,” “food intake,” “symptoms,” and “activities and function.”3 Prior to olanzapine therapy, the patient endorsed a weight loss of 14 pounds over the course of 1 month. His food intake was described as “less than usual” for the same time period. He endorsed symptoms including NV, stomach pain, early satiety, and aversion to certain smells and described his functional level as “able to do little activity and spend most of the day in bed or chair.” The total PG-SGA score was 20 at this time, indicating “a critical need for improved symptom management and/or nutrient intervention options.” Additionally, the patient rated his current NV as an 8 out of 10 on the NRS. Prior to olanzapine initiation on July 8, 2014, the patient’s NV regimen included metoclopramide 10 mg by mouth four times per day, lorazepam 1 mg by mouth twice daily as needed, intravenous (IV) ondansetron 8 mg twice daily as needed, medicinal marijuana lozenges by mouth as needed, and domperidone 10 mg by mouth twice daily (obtained from Mexico). Intravenous ondansetron was given through an indwelling PORT-a-cath along with IV hydration. On treatment day 1, domperidone was discontinued and oral olanzapine 5 mg at night was initiated. A telephone encounter was conducted approximately 48 hours later. After 2 days of olanzapine in addition to metoclopramide, lorazepam, ondansetron, and medicinal marijuana lozenges, the patient reported significant improvement of NV with no usage of breakthrough ondansetron (prior usage was typically one to two 8 mg doses daily). At this time, scheduled metoclopramide was also discontinued and his olanzapine dose was increased to 10 mg daily at night. The patient returned to clinic on treatment day 22. He endorsed continued improvement of NV in the typical day; however, he noted worsening of his nausea on the car trip to clinic and subsequently ranked current NV as an 8 out of 10 on the NRS. The followup PG-SGA revealed that the patient had gained 3 pounds since treatment day 1. His food intake was noted to be “more than usual,” and although he con C
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tinued to endorse nausea, he no longer complained of vomiting, stomach pain, early satiety, or aversion to certain smells. His functional level had improved to “not my normal self, but able to be up and about with fairly normal activities.” The PG-SGA total score after 22 days on olanzapine had decreased to 7. Overall, the patient reported an improved quality of life since the initiation of olanzapine therapy and denied any adverse effects related to the medication.
DISCUSSION Nausea and vomiting are symptoms commonly experienced by patients in the palliative care setting. Although treatment with the combination of standard antiemetics of different classes is often effective, some patients experience NV that fails to respond. Because NV can significantly detract from the quality of life of patients, it is important to consider pharmacologic alternatives when NV is refractory to standard treatment.4 For the purposes of this case report, we define refractory NV as the persistence of symptoms despite an appropriate duration of use (e.g., achievement of steady-state concentrations) of at least two scheduled antiemetic agents with different mechanisms of action. Olanzapine is an atypical antipsychotic medication indicated for the treatment of schizophrenia and bipolar disorder. Olanzapine antagonizes the following neurotransmitter receptors with high affinity: serotonin (5HT)2A/2C , 5HT6 , dopamine (D)1–4 , histamine (H)1 , and α 1 -adrenergic receptors. It is an antagonist with moderate affinity binding for 5HT3 and muscarinic (M)1–5 and binds weakly to γ aminobutyric acid (GABA)A , benzodiazepine (BZD), and β-adrenergic receptors.5 The association of D2, 5HT2A , 5HT2C , and 5HT3 receptors with the emetic pathway makes olanzapine an intriguing potential antiemetic agent.6 There is evidence supporting olanzapine in the prevention and treatment of CINV. Table 2 summarizes the results of prospective studies investigating the use of olanzapine as an antiemetic in this
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TABLE 2.
Summary of prospective studies investigating the use of olanzapine for the treatment of CINV Study phase
N
Passik et al. (2004)7
I
15
Olanzapine in addition to standard antiemetics
Delayed emesis in cancer patients receiving MEC/HEC
Navari et al. (2005)8
II
30
Olanzapine in addition to granisetron and dexamethasone
Acute and delayed CINV in cancer patients receiving MEC/HEC
Navari et al. (2007)9
II
40
Olanzapine in addition to palonosetron and dexamethasone
Acute and delayed CINV in cancer patients receiving MEC/HEC
Tan et al. (2009)10
III
229
Azasetron and dexamethasone versus Olanzapine, azasetron, and dexamethasone
Acute and delayed CINV in cancer patients receiving MEC/HEC
Navari et al. (2011)11
III
241
Olanzapine, palonosetron, and dexamethasone versus Aprepitant, palonosteron, and dexamethasone
Acute and delayed emesis and nausea in patients receiving HEC
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Nyu Medical Center on 07/05/15 For personal use only.
Author (year)
Interventions
Primary end point
Results MEC cohort: 4/6 patients with no episodes of delayed emesis HEC cohort: 9/9 patients with no episodes of delayed emesis MEC cohort: 20/20 patients with no acute emesis, 17/20 patients with no delayed emesis, and 13/20 with no nausea HEC cohort: 10/10 patients with no acute emesis, 8/10 patients with no delayed emesis, and 10/10 patients with no nausea MEC cohort: 31/32 patients with no acute emesis, 24/32 patients with no delayed emesis, and 25/32 patients with no nausea HEC cohort: 8/8 patients with no acute emesis, 6/8 patients with no delayed emesis, and 4/8 patients with no nausea MEC cohort: Patients in the olanzapine group experienced less delayed nausea (25.01% reduction) and vomiting (13.43% reduction), P < .05. HEC cohort: Patients in the olanzapine group experienced less delayed nausea (39.21% reduction) and vomiting (22.05% reduction), P < .05. Of the 121 patients in the olanzapine group, 77% had no episodes of emesis and 69% of patients denied nausea. Complete response rate was not significantly different compared with the aprepitant group (120 patients). Percent of patients experiencing no nausea was significantly higher in the olanzapine group (69% vs. 38%).
Grade 3/4 adverse effects No grade 4 toxicities observed. 3 subjects with grade 3 toxicity of depressed level of consciousness None
None
None
None
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Journal of Pain & Palliative Care Pharmacotherapy
M. Langley-DeGroot et al. TABLE 2. Author (year)
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Navari et al. (2013)12
Mizukami et al. (2014)13
151
Summary of prospective studies investigating the use of olanzapine for the treatment of CINV(Continued) Study phase
N
Interventions
III
108
Olanzapine versus metoclopramide for CINV refractory to a standard antiemetic regimen
Breakthrough nausea and vomiting in patients receiving HEC
N/A
44
Olanzapine added to standard antiemetic regimen
Acute and delayed CINV in patients receiving chemotherapy
Primary end point
Results 39/56 patients receiving olanzapine versus 16/52 patients receiving metoclopramide experienced no emesis (P < .01). 38/56 patients receiving olanzapine versus 12/52 patients receiving metoclopramide reported no nausea (P < .01). 86% and 64% of patients receiving olanzapine had no episodes of emesis in the acute and delayed phases of treatment, respectively, compared with only 55% (P = .045) and 23% (P = .014) of patients in the control group.
Grade 3/4 adverse effects None
None
Note. HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy.
setting.7–13 Two phase III studies by Navari and colleagues provide some of the most compelling evidence for the use of olanzapine to treat and prevent CINV. The first study compared olanzapine with aprepitant in the prevention of both acute (24 hours post chemotherapy) and delayed (2 to 5 days post chemotherapy) CINV. Patients receiving highly emetogenic chemotherapy were randomized to receive either oral olanzapine or aprepitant in combination with IV palonosetron and dexamethasone. Complete response rate (no emesis or rescue medications) was 97% in the acute period and 77% in the delayed period for patients receiving 10 mg olanzapine in addition to palonosetron and dexamethasone. Complete response rates were comparable in the aprepitant group, although the number of patients who experienced no nausea (69% in the olanzapine group vs. 38% in the aprepitant group) was significantly lower (P < .01). No grade 3 or 4 toxicities were reported.11 The second phase III study compared olanzapine 10 mg daily with metoclopramide 10 mg three times daily over a 3-day treatment period for patients experiencing breakthrough CINV despite standard antiemetics. During the 72-hour observation period, 70% of patients receiving olanzapine had no emesis versus 31% receiving metoclopramide (P < .01). Nausea was also better controlled in the olanzapine group (68% vs. 23%; P < .01). There were no grade 3 or 4 toxicities.12 C
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In marked contrast, the evidence for the use of olanzapine to treat NV in patients who are not receiving chemotherapy is limited. Three case reports have been published describing patients who experienced symptomatic improvement of non-CINV following treatment with olanzapine.14–16 Additionally, one case series details the treatment and clinical course of six patients whose non-CINV responded to olanzapine.17 A small retrospective study of four cancer patients with non-CINV found that the initiation of olanzapine improved symptoms and reduced the need for additional scheduled and rescue antiemetics.18 Another retrospective study of 20 cancer patients with NV associated with incomplete bowel obstruction found that olanzapine therapy significantly reduced the intensity of nausea and frequency of vomiting.19 Prospective studies investigating the role of olanzapine in the treatment of non-CINV have been published.20,21 An open label pilot study of 15 cancer patients with non-CINV found that olanzapine significantly reduced symptoms at doses of 2.5, 5, and 10 mg daily.20 In a randomized controlled trial, 268 subjects with major depressive disorder were given either duloxetine alone, duloxetine plus 1.25 mg olanzapine, or duloxetine plus 2.5 mg olanzapine. Subjects taking both medications experienced less NV than patients taking duloxetine alone, and the antiemetic effect was higher in the group receiving 2.5 mg of olanzapine.21
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We believe this case report is unique to the nonCINV literature given the duration of symptoms over a course of years and the number of antiemetics and home therapies failed by the patient. Additionally, the majority of the prior non-CINV studies/reports have investigated the use of olanzapine for refractory NV in end-of-life care, particularly in patients with advanced cancer. The remaining studies/reports have examined olanzapine as an adjuvant for a known, reversible cause of non-CINV. This patient is not a terminal patient, and the etiology of his refractory non-CINV, despite multiple imaging modalities and endoscopic evaluation, remains unknown. This case report and review of the CINV and nonCINV literature suggests that olanzapine may be an alternative antiemetic in the non-CINV setting and supports existing case reports.14–16 Of note, in our case as in previous studies, the required effective olanzapine dose was low, symptom improvement occurred within days, and the medication was well tolerated. We hypothesize that olanzapine’s role in the treatment of refractory non-CINV may be due in part to the promiscuous antagonism of multiple dopamine and serotonin receptors in contrast to the selective antagonism of antiemetic drugs available currently. We believe that olanzapine may be an effective antiemetic for the treatment of refractory non-CINV. Additional double-blind, placebo-controlled studies are needed to further assess olanzapine’s efficacy in the refractory non-CINV setting. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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RECEIVED: 5 January 2015 REVISED: 10 March 2015 ACCEPTED: 27 March 2015
Journal of Pain & Palliative Care Pharmacotherapy
