A. The place of Olanzapine as an Antiemetic in palliative medicine
1. Efficacy
Each of the 13 articles included in this systematic review of the literature concluded that olanzapine is effective for the treatment of nausea and vomiting in patients with palliative disease, regardless of symptom aetiology. However, the differences in study methodologies and in the methods for evaluating symptoms prevent a rigorous comparison.
2. Applicability
In addition to its efficacy, several features make of olanzapine an interesting treatment option in the palliative care setting.
Olanzapine can be administered as a single, daily dose because of its long half-life that allows to cover a 24-hour period. This may facilitate patient compliance and reduce the risk of forgetfulness. In addition, it appears that, despite treatment for nausea and vomiting, rescue medications can be considered (6).
- Spectrum of effectiveness
In palliative situations, nausea and vomiting are often multifactorial. It is sometimes necessary to associate different symptomatic treatments, which can lead to drug interactions and side effects. Thus, a drug that acts on multiple receptors represents an interesting perspective (10).
Olanzapine exists in several galenic forms, allowing flexibility in administration. The orodispersible tablet formulation is particularly suitable for patients experiencing nausea or vomiting, and represents a safer and more flexible option than haloperidol in the outpatient setting. In fact, oral forms of haloperidol (35) include tablets at doses of 1 or 5 mg, while the usual antiemetic dose starts at 0.5 mg. The oral solution is dosed at 0.1 mg per drop, but drop count is a source of error.
In the case of the treatment of symptomatic intestinal obstruction on non-resectable peritoneal carcinomatosis, scientific and medical societies recommend using haloperidol as first-line antiemetic treatment (36). Oral intake in this context can be a source of discomfort for the patient, and the absorption of the drug is uncertain. In addition, in 2011, the National Agency for Drug Safety advised against the use of IV haloperidol due to cardiac risks (37,38). The Marketing Authorization (MA) for the injectable form of haloperidol relates exclusively to the intramuscular (IM) route, regardless of the indication.
Olanzapine exists as injectable form and its MA only applies to IM use. Studies on the IV or SC use for other indications, however, report a comparable efficacy and no significant side effects (19,20).
In addition, pharmacological studies suggest a part of transmucosal absorption with orodispersible tablets, even if the proportion and its impact on the overall bioavailability are unknown. Olanzapine is detectable earlier in the plasma of patients treated with orodispersible tablets than of those treated with standard tablets. This could prove to be an asset in case of occlusive syndrome (39-41). This hypothesis is supported by the results of the 2012 study by Kaneishi et al (27), which involved patients with nausea associated with malignant bowel obstruction. One study also investigated a form of reconstituted olanzapine as suppositories (42), which would provide an additional usable route of administration.
AAPs present a lower risk of adverse effects than first generation antipsychotics. Various explanations have been advanced, including the 5HT2A/D2 binding affinity ratio. The 5HT2A/D2 ratio is higher for AAPs than for first-generation antipsychotics (43), which explains the lower risk of extrapyramidal syndrome (44). In addition, olanzapine is predominantly metabolised via cytochrome P1A2, and not via the other CYP450 isoenzymes (10), which also limits the risk of drug interaction. Molecules such as carbamazepine (Tegretol®) or fluvoxamine (Floxyfral®) may, however, interact with CYP1A2. Similarly, enzyme inducer tobacco, can also modify the metabolism of olanzapine by interacting with cytochromes (11,44,45).
Finally, the antiemetic dose used, generally ranging from 5 to 10 mg/day, is lower than that used in psychiatry, which also explains the lower risk of adverse effects (10).
3. Adverse effects/Side effects
The treatment of CINV involves low doses of olanzapine over shorter periods of time, leading to few side effects. Most commonly reported event is drowsiness (26,27). However, this symptom remains difficult to assess in the palliative care context, where the causes can be multiple, mostly iatrogenic and disease progression. No other side effects of olanzapine have been reported in the studies included in this review of the literature.
In the psychiatric setting, olanzapine is used at higher doses and over longer periods of time. The extrapyramidal syndrome, consisting of acute dystonia, akathisia, parkinsonism and tardive dyskinesia (46), can occur at doses over 20 mg/day. However, the risk of developing a Parkinsonian syndrome or akathisia is, respectively, three times and twice lower than that with haloperidol at usual doses (44). Long-term use of olanzapine can lead to metabolic side effects such as increased appetite and weight gain, which may be beneficial in the palliative care setting (47). Lipid and glycaemic imbalances can also be observed during long-term treatment, which is why olanzapine is contraindicated in cases of diabetes in some countries (48). There is a risk of QT prolongation or of cardiac rhythm disturbances, but these effects are rare (17,49).
There is also a risk of decreasing the epileptogenic threshold and the neuroleptic malignant syndrome, but these are less common than with first-generation antipsychotics (10,44).
Other side effects have been reported in this setting, of varying frequency and intensity, such as headache, drowsiness, restlessness, insomnia, dry mouth, constipation, orthostatic hypotension (44,49). Finally, an asymptomatic elevation of transaminases (up to 3 times the normal level) has been reported in 2% of patients (44,49).
Contraindications to olanzapine are hypersensitivity to the active substance or to any of the excipients, and patients at risk of acute angle-closure glaucoma (AACG) (17). In a statement of March 9, 2004, the ANSM (French National Agency for Medicines) also recommended the utmost caution and advised against the use of olanzapine in elderly patients with dementia due to a threefold higher incidence of stroke (50).
B. Bias of the study
1. Intrinsic bias
The scarcity of published articles on the use of anti-emetic olanzapine in the palliative care setting is an obvious bias of this systematic review of the literature. In addition, the disparities in the methodology of the articles and the heterogeneity of outcomes used do not allow a rigorous analysis. Publication bias must also be considered, which may distort the effects of olanzapine. It is in order to limit this risk of bias that the gray literature has also been considered (51).
2. Bias of the analysed studies
Most of the articles included in this review have low statistical power. Case studies and series include, by definition, low numbers of patients and present a selection bias. In the studies included in this review, symptoms were not objectively and reproducibly evaluated, with investigators measuring treatment efficacy based on patient-reported relief and clinical examination.
Retrospective studies also have a selection bias by definition. Two of the included studies concerned a small number of patients and, the third, a 2016 study by Kaneishi et al (29), included a larger number of patients but did not mention the efficacy or tolerance of the treatment.
The evaluation of treatment efficacy among studies is not standardised. In the 2012 study by Kaneishi et al (27), the outcome was the degree of severity of symptoms on a scale, while in Atkinson's 2014 study (28), the evaluation of symptom improvement was subjective and the secondary outcomes were the use of treatment in situations of acute crisis and the daily cost of treatment.
The two prospective studies included in this review included few patients and neither were randomised nor did they include a control group. The evaluation of treatment efficacy in MacKintosch et al’s study was done using subjective criteria (26). The study by Passik et al (25) provided a more complete assessment of symptoms with subjective assessment and objective evaluation using quality of life scales. The three reviews of the literature included are not systematic and their methodology was non‑reproducible. Finally, only one study included an assessment of the quality of life of patients (25).