Since the early 2000s, the antiemetic efficacy of olanzapine, a drug conventionally used as an antipsychotic, has been suggested (1). Numerous studies and literature reviews have been conducted on its efficacy and safety profile for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) (2-4).
In three recent systematic reviews the most frequently reported adverse event was drowsiness, which was mostly well tolerated by patients (5-7). No severe side effects were described.
Some studies concluded on a greater efficacy of olanzapine as a crisis medication for CINV despite standard prophylaxis, over standard crisis medication (metoclopramide - Primpéran®).
The Multinational Association for Supportive Care in Cancer (MASCC) and the National Comprehensive Cancer Network (NCCN) recommend olanzapine for treating refractory CINV in addition to appropriate preventive treatment. NCCN also recommends its use in combination with a selective antagonist of the 5HT3 receptor and corticosteroids, or with corticosteroids alone, for the prevention of CINV (8,9).
Our primary objective was to investigate whether these results could be generalized to the prevention and treatment of nausea and vomiting not induced by chemotherapy in a palliative care setting. We also aimed at supplementing and updating the non-systematic review published by Fonte et al. in 2015 (10), which focused mainly on the use of olanzapine in chemotherapy-induced nausea and vomiting.
First, we describe the characteristics of olanzapine, including its tolerance profile and receptor-binding ability, which is of interest in the palliative care setting. Secondly, the findings of a systematic literature review of olanzapine used in this indication are presented to provide an update on current knowledge. Finally, we propose a therapeutic schema adapted to the palliative setting.
I.Olanzapine, an atypical antipsychotic
A. Overview on atypical antipsychotics
The efficacy of antipsychotics drugs stems from their action on the dopaminergic system, which plays a role in the regulation of emotional life, motivation control, modulation of perceptions and organization of adaptive behaviors. According to their side effects, antipsychotics can be classified as first-generation, which are frequently associated with extrapyramidal effects, and second-generation, which are atypical and better tolerated (11).
Atypical antipsychotics (AAPs) are those meeting the following criteria (12):
have low or no risk of triggering extrapyramidal effects at doses at which an antipsychotic effect is achieved,
do not increase prolactin levels, or do it minimally,
significantly reduce the positive and negative symptoms of schizophrenia, and
have mood stabilizer properties.
They also have an atypical binding profile to brain receptors. Atypical agents have a greater in vitro affinity for serotoninergic 5HT2 and dopaminergic D2 receptors than first-generation antipsychotics (12). The main representatives of second-generation antipsychotics are: olanzapine (Zyprexa®), clozapine (Leponex®), risperidone (Risperdal®), quetiapine (Xeroquel®), sertindole, ziprasidone (Zeldox®), aripiprazole (Abilify®), paliperidone (Xeplion®), lurasidone (Latuda®), asenapine (Sycrest®).
Olanzapine is a thienobenzodiazepine derivative and has a structure close to that of clozapine (11). It binds to many types of dopaminergic (D1, D2, D3, D4, D5) and serotoninergic (5HT2A / 2C, 5HT3, 5HT6 and 5HT7) receptors, but its affinity for 5HT2 receptors - in particular 5HT2A – is higher than that for dopaminergic receptors. Olanzapine is also an antagonist of the muscarinic M1, M2, M3, M4, M5 (contributing to reduce the risk of extrapyramidal effects), α1-adrenergic and histamine H1 receptors. Its affinity for α2-adrenergic, 5HT1, GABA (Gamma-AminoButyric Acid), β-adrenergic and benzodiazepine receptors is lower. Olanzapine also has a low antagonistic effect on N-Methyl-D Aspartate (NMDA) receptors (13,14).
Olanzapine is an antipsychotic agent, an antimanic and mood stabilizer indicated in the management of manic episodes, schizophrenia, and bipolar disorder (15). It has also been indicated for delirium especially in palliative care (16,17). The usual dose ranges between 2.5 and 30 mg once daily, but some studies report the use of the maximum dose of 60 mg per day depending on the symptomatology, the treatment response and the tolerance (15,18).
The bioavailability of oral olanzapine is 80 to 90%, and the peak serum concentration is reached approximately 6 hours after administration. After intramuscular administration, olanzapine is rapidly absorbed and the time to peak serum concentration is less than 45 min. While a few studies have focused on the intravenous (IV) and subcutaneous (SC) routes, no pharmacokinetic data have been reported (19,20). The plasma protein binding rate is about 90%. The elimination half-life of olanzapine is approximately 30 hours, ranging from 20 to 70 hours (13,15). Plasma equilibrium is reached within 5 to 7 days. Hepatic first-pass effect is important, with 40% of the administered dose metabolized before it enters the systemic circulation (13). Olanzapine is mainly metabolized in the liver by conjugation and oxidation and the main metabolites, 10-N-glucuronide and 42-N-desmethyl olanzapine, have no known pharmacological activity. The main route of olanzapine elimination is the oxidative metabolism by CYP1A2, while CYP2D6 and CYP2D19 are minor pathways (12,15). The metabolites are then eliminated through urine (60%) and feces (30%) (13).
Antiemetic treatments act by blocking receptors that are specific to neurotransmitters involved in transmitting the emetic signal to the vomiting center. The main treatments can be classified according to the targeted receptors (21-23):
- Prokinetics: these stimulate the motility of the upper digestive tract through several mechanisms of action:
o By activating 5HT4 serotonin receptors
o By blocking 5HT3 serotonin receptors
o By activating motilin receptors
o By inhibiting the dopamine system
- Dopamine antagonists: certain antipsychotic agents block dopamine D2 receptors located in the CTZ. All of these, except for haloperidol, have a broad spectrum of activity and also act on histamine, muscarinic, serotonin and/or alpha adrenergic receptors.
- Serotonin antagonists (5HT3): the 5HT3 receptors are located on the vagus nerve which sends signals to the vomiting center, on the enterochromaffin cells of the digestive tract, in the nucleus of the solitary tract and in the CTZ.
- Anticholinergic antihistamines: the first histamine receptor antagonists, known as piperazines, block H1 receptors in the vomiting center, in the vestibular nucleus and in the CTZ. Antimuscarinic activity also reduces mucous secretion.
- Anticholinergics: their ability to block muscarinic receptors relaxes the smooth muscles and reduces gastrointestinal secretion. They are particularly indicated in cases of malignant bowel obstruction.
- Neurokinin-1 receptor antagonists: their mechanism of action is based on their ability to inhibit the binding of substance P to the NK1 receptors in the digestive tract and in the vomiting center of the brain. The inhibitory action of olanzapine, in particular on the serotonin receptors 5HT2 and 5HT3 and the dopamine receptor D2, explains its antiemetic activity.
The inhibitory action of olanzapine, in particular on the serotonin receptors 5HT2 and 5HT3 and the dopamine receptor D2, explains its antiemetic activity. To a lesser extent, olanzapine is also a histamine and muscarinic receptor antagonist (13). However, the mechanisms involved are not fully understood. The benefit of olanzapine, the only atypical antipsychotic to have antiemetic properties, is that it acts on a large number of receptors, while nausea and vomiting in a palliative situation are very often caused by multiple factors and may require the combination of several treatments, which increases the risk of drug interactions.