Serotonine-antagonists

Clinical question 2f:

What is the effect of serotonin antagonists in the treatment of nausea and/or vomiting in patients in the palliative phase of cancer, heart failure, COPD, MS, ALS or renal failure?

Recommendation

Treatment with serotonin antagonists is recommended for patients in the palliative phase:

• to prevent or treat nausea and vomiting as a result of chemotherapy, radiotherapy or postoperatively
• for nausea and/or vomiting that does not respond sufficiently to earlier treatment with metoclopramide, domperidone, haloperidol, dexamethasone and levomepromazine
• as first line treatment in patients with terminal renal failure with nausea and vomiting

Introduction

Serotonin (5HT3) antagonists, such as ondansetron, granisetron, tropisetron and palonosetron are the antiemetic of choice with moderately and strongly emetogenic chemotherapy, with nausea and vomiting after radiotherapy and with postoperative nausea and vomiting.
They are also applied in the case of nausea and vomiting due to other causes than chemotherapy, radiotherapy or surgery. However, they are not registered for this indication.

In the following text, the role of serotonin antagonists in the prevention and treatment of nausea and vomiting as a result of chemotherapy will not be discussed.

Literature discussion

During the literature research, a systematic review [Davis 2010], four randomised studies [Hardy 2002; Ljutic 2002; Mystakidou 1997; 1998a and 1998b], two retrospective studies [Currow 1997; Weschules 2006], a case series [Porcel 1998] and five case reports [Buchanan 2007; Cole 1998; Macleod 2000; Mercadante 1998; Pereira 1996] were found. Nine studies concerned ondansetron [Cole 1998; Currow 1997; Hardy 2002; Ljutic 2002; Macleod 2000; Mercadante 1998; Pereira 1996; Porcel 1998; Weschules 2006], two concerned tropisetron [Mystakidou 1997; 1998a and 1998b] and two concerned granisetron [Buchanan 2007; Porcel 1998]. Most studies were performed in patients with an advanced stage of cancer.

Mystakidou conducted a randomised study in 280 patients in an advanced stage of cancer with nausea and vomiting, who did not respond to treatment with metoclopramide [Mystakidou 1998a]. The patients were randomised between treatment for a duration of 14 days with 1) metoclopramide 10 mg four times daily + dexamethasone 2 mg once daily (n=40), 2) tropisetron 5 mg once daily (n=40), 3) metoclopramide 10 mg twice daily + tropisetron 5 mg once daily (n=40), 4) metoclopramide 10 mg twice daily + tropisetron 5 mg once daily + dexamethasone 2 mg once daily (n=40), 5) chlorpromazine 25 mg twice daily + dexamethasone 2 mg once daily (n=40), 6) chlorpromazine 25 mg twice daily + tropisetron 5 mg once daily (n=40), and 7) chlorpromazine 2dd 25 mg twice daily + tropisetron 5 mg once daily + dexamethasone 2 mg once daily (n=40) [Mystakidou 1998a]. In a second publication, the results of groups 2, 5, 6 and 7 were outlined further [Mystakidou 1998b]. The patients completed a diary, in which they recorded how many hours per day they suffered from nausea and how often they vomited. In all groups treated with tropisetron, a maximum effect on both nausea and vomiting was achieved after 3 days of treatment. Complete control of the nausea after 3 days was seen in 10% of cases (metoclopramide + dexamethasone), 30% (tropisetron), 35% (metoclopramide + tropisetron), 55% (metoclopramide + tropisetron + dexamethasone), 10% (chlorpromazine + dexamethasone), 42% (chlorpromazine + tropisetron) and 60% (chlorpromazine + tropisetron + dexamethasone), respectively. Complete control of vomiting after 3 days was seen in 9% of cases (metoclopramide + dexamethasone), 42% (tropisetron), 65% (metoclopramide + tropisetron), 75% (metoclopramide + tropisetron + dexamethasone), 8% (chlorpromazine + dexamethasone), 67% (chlorpromazine + tropisetron) and 77% (chlorpromazine + tropisetron + dexamethasone), respectively. Comparisons between subgroups suggest that the addition of dexamethasone to the combination of metoclopramide or chlorpromazine and tropisetron leads to a slightly better control of nausea and vomiting. No correction was made for multiple testing.

The results from the study by Mystakidou suggest that tropisetron is effective in the treatment of nausea and vomiting, but the statistical analysis is questionable due to the lack of correction for the large number of comparisons.
Two randomised studies researched the effect of ondansetron with opioid-induced nausea and vomiting in patients with cancer [Hardy 2002; Mystakidou 1997].

In a randomised, double-blind setting, Hardy compared 24 mg ondansetron orally once daily (n=29) with metoclopramide 10 mg three times daily(n=33) and placebo (n=30) in patients with cancer who had nausea and vomiting as a result of opioids [Hardy 2002 41]. The study was ended prematurely due to difficulty with inclusion of patients. No significant differences were seen between the groups in relation to complete control of nausea and vomiting after 24 hours of treatment. However, the power of the study to show a difference was limited due to small patient numbers.

Mystakidou conducted a randomised study in 120 patients in an advanced stage of cancer with nausea and vomiting, who did not respond to treatment with metoclopramide [Mystakidou 1997]. All patients used opioids. They were randomised between metoclopramide10 mg four times daily + dexamethasone 2 mg once daily (n=40), metoclopramide 10 mg twice daily + tropisetron 5 mg once daily (n=40) and metoclopramide 10 mg twice daily + dexamethasone 2 mg once daily + tropisetron 15 mg once daily (n=40). The patients completed a diary, in which they recorded how many hours per day they suffered from nausea and how often they vomited. Complete control of nausea after 14 days was seen in 18%, 74% and 87% of patients, respectively, and complete control of vomiting in 24%, 84% and 92% of patients, respectively. Side effects (weakness, dizziness and constipation occurred in 22 patients.

In a double-blind crossover study [Ljutic 2002], Ljutic compared a single dose of metoclopramide (10 mg i.v.) with ondansetron (8 mg i.v.) in 10 patients with complaints of nausea and vomiting with terminal renal failure. The effect of vomiting was scored on a scale of 1-3 by both the patient and the researcher. Nausea was scored by the patients on a scale of 1-5. High scores indicated a better effect. Ondansetron helped more than metoclopramide against nausea (average score 4.10 versus 2.10) and vomiting (average score 2.80 versus 1.40).

Weschules conducted a retrospective cohort study in patients in a home care programme in which the results of collaborative practice protocols for pain, sleeplessness and nausea and vomited were compared retrospectively with the results of treatment with new drugs [Weschules 2006]. Treatment with prochlorperazine (n=45) was compared with ondansetron (n=45) in relation to nausea and vomiting. All patients were in the palliative phase; patients who were treated with ondansetron more often had cancer than patients who were treated with prochlorperazine (44 versus 27). The number of complete responses (total disappearance of nausea and vomiting) after 1-2 weeks was higher in the prochlorperazine group (49% versus 27%).

In a retrospective study, Currow described the effect of treatment with ondansetron in a dose of 8-24 mg per day, divided over 2-3 doses with 16 patients (seven with cancer and nine with AIDS), who were admitted to a hospice [Currow 1997]. All patients were treated earlier with other antiemetics. The response after 48 hours was evaluated on the basis of scores for nausea and vomiting by the health care providers. Nausea improved in 12 out of 15 and vomiting in 10 out of 14 patients.

Porcel described the effect of ondansetron 8 mg s.c. three times daily (n=6) or 3 mg granisetron s.c. once daily (n=4) in patients with an advanced stage of cancer with nausea and vomiting, who had responded insufficiently to treatment with other antiemetics [Porcel 1998]. Nine patients experienced a clear and rapid improvement in vomiting.

Different case reports described favourable effects for granisetron s.c. in two patients with  metastatic breast cancer and a metastatic ovarian carcinoma respectively with therapy-resistant nausea and vomiting [Buchanan 2007] and for ondansetron in patients with cancer [Cole 1998; Mercadante 1998; Pereira 1996] and with two patients with multiple sclerosis [Macleod 2000]. The systematic review concluded that ondansetron is an effective antiemetic (based on cohort studies, retrospective studies, case series or case reports) [Davis 2010]. No conclusion was drawn about other serotonin antagonists.

There are indications that ondansetron, granisetron and tropisetron are effective antiemetics for nausea and vomiting in patients with an advanced stage of cancer, AIDS or multiple sclerosis, who have responded insufficiently to earlier antiemetics.
[Buchanan 2007; Cole 1998; Currow 1997; Macleod 2000; Mystakidou 1998-1 and 1998-2; Porcel 1998]

No statement can be made about the effectiveness of serotonin antagonists for nausea and vomiting as a result of opioids due to poor quality of research and conflicting results.
[Hardy 2002; Mystakidou 1997]

There are indications that ondansetron is more effective than metoclopramide for nausea and vomiting in patients with terminal renal failure.
[Ljutic 2002]

Given research and experience in patients experiencing nausea and vomiting due to chemotherapy [Bilio 2010], there is no reason to assume that there are differences in effectiveness or side effects between ondansetron, granisetron or tropisetron. No statement can be made as to which drug is preferable.

The side effects of serotonin antagonists have not been systematically researched and reported in the studies discussed. Experience in patients being treated with serotonin antagonists who suffer from nausea and vomiting due to chemotherapy shows that constipation is a common problem.

The costs of oral administration of serotonin antagonists amount to €10-14 per day (compared to metoclopramide €0.20-0.35 per day and domperidone €0.30-0.60 per day).