Focus on Levomepromazine

Written By: Sam Savage

Published Date: February 25, 2005 Last Edited: February 25, 2005

Key words: Antipsychotic – Anxiolytic – Mcthotrimeprazine – Phenothiazines – Schizoaffective disorder – Schizophrenia

SUMMARY

This is a review of the uses of levomepromazine in psychiatry, based upon MEDLINE, PSYCLIT and EMBASE literature searches.

The main indications for this drug in psychiatry are schizophrenia and schizoaffective disorder. Levomepromazine’s sedative properties particularly fit it to use in psychiatric intensive care. There is also some evidence to suggest it has efficacy in drug-resistant psychosis, although this property of the drug does require further research.

In other areas of medicine levomepromazine has been used in: alleviating bronchoconstriction; as a preoperative sedative; in terminal pain control and postoperative analgesia; and in the control of nausea. Some antimycobacterial properties have been recorded.

The drug should not be prescribed to patients at high risk of accidental or suicidal overdose.

Introduction

In Canada, UK and most other European countries, levomepromazine (or methotrimeprazine) is marketed as Nozinan* (and in the US as Levoprome) and is available orally as levomepromazine maleate 25mg or as an intramuscular (IM) injection levomepromazine hydrochloride (a 2.5% isotonic solution in ampoules). The oral form of the drug is licensed for use in the UK for psychotic disorders, the intramuscular form is not. The intramuscular preparation is sometimes useful for rapid tranquillisation in severely disturbed patients with schizophrenia. Since the bioavailability of an intramuscular dose is higher than the bioavailability of an oral dose any initial IM dose should be in the order of 12.5 mg with a maximum IM dose of 50mg.

Levomepromazine was originally marketed by Rhne-Poulenc Rorer (Aventis) as an antipsychotic.

In psychiatry levomepromazine is used as a sedative and in the management of schizophrenia. Levomepromazine has been used in a variety of clinical areas – alleviating bronchoconstriction1, as a preoperative sedative2, in terminal pain control and postoperative analgesia3,4 and in the control of nausea5. Similar to some other phenothiazines, levomepromazine even has some antimycobacterial properties6.

This review considers the use of levomepromazine in psychiatry and is based on literature searches using MEDLINE, EMBASE and PSYCLIT.

Structure

Levomepromazine or methotrimeprazine is a phenothiazine aliphatic antipsychotic with the molecular formula C^sub 19^H^sub 25^N^sub 2^OS. Levomepromazine, therefore, belongs to the phenothiazine group of drugs, like chlorpromazine. Phenothiazines have a three-ring structure in which two benzene rings are linked by a sulphur and nitrogen atom. Levomepromazine’s chemical structure is (- )(dimethylamino-3 methyl-2 propyl)-10 methoxy-2 phenothiazine (Figure 1).

Pharmacokinetics and metabolism

Therapeutic levels of levomepromazine are achieved at serum concentrations between 0.02 mg/L and 0.14mg/L7.

Orally administered levomepromazine is subject to a first pass metabolism such that only 50% of the orally administered drug reaches the general circulation8. Plasma concentrations of levomepromazine reach their maximum levels 30 min-90 min after intramuscular injection, and 1 h-3 h after oral administration. The half-life of levomepromazine is 15 h-30 h. Levomepromazine has two major metabolites in man: the pharmacologically active N- monodesmethyl levomepromazine, which is almost as potent an antipsychotic as the parent drug; and levomepromazine sulphoxide, which is much less active. The metabolism is predominantly hepatic.

In different patients the half-life has been found to vary from 16.5 h to 77.8 h9. The individual variability in metabolising the drug may account for the variation in the therapeutic dose required in different individuals.

Pharmacology

The therapeutic actions of levomepromazine in schizophrenia and as an antipsychotic in general are largely ascribed to its dopamine blocking ability. However, it has been mooted that the drug may have some additional tendency to be useful in treatment-resistant schizophrenia and this has been linked to its receptor binding profile, which has been compared and contrasted to clozapine and chlorpromazine by Lal et al.10. In their study of the binding profile of levomepromazine in the human brain they found that levomepromazine showed significantly greater binding affinity for both alpha-1 and serotonin-2 binding sites than clozapine or chlorpromazine, which they thought significant. Levomepromazine has significantly greater binding to alpha-2 sites than chlorpromazine. The exact reasons why clozapine has a unique efficacy are perhaps more complex, however.

Figure 1. The molecular structure of levomepromazine

Early on in the literature, levomepromazine was referred to as an antidepressant neuroleptic. It seems to have acquired the term, antidepressant neuroleptic, because it is a potent serotonin 5-HT2 and alpha 1-adrenergic blocking agent and because it was noted that chronic administration affected the serotonin system in a manner similar to that produced by prolonged administration of antidepressants11. There is no substantial evidence to back the historical claims of antidepressant activity, and further research would be necessary in this regard.

The two major metabolites are N-monodesmethyl levomepromazine and levomepromazine sulphoxide. N-monodesmethyl levomepromazine may contribute to the antipsychotic effects of levomepromazine, but the sulphoxide metabolite lacks neuroleptic potency12. Both metabolites contribute to the autonomie side effects of the drug. N- monodesmethyl levomepromazine has a slightly higher potency than chlorpromazine on alpha-adrenergic binding, and a somewhat lower potency than chlorpromazine on dopamine receptor binding. Levomepromazine sulphoxide was relatively inactive in terms of dopamine receptor binding but seems much more active in the alpha- adrenergic receptor binding with a binding affinity similar to 7- hydroxy chlorpromazine.

Indications

The main indications in psychiatry are schizophrenia and schizoaffective disorder. Its sedative properties particularly fit it to use in psychiatric intensive care.

Efficacy

The relatively elderly nature of the compound means that recent drug trials often see the drug used as a standard comparator for novel agents. The wealth of research data now used to launch novel drugs is just not apparent with levomepromazine. An example of a trial in recent years employing levomepromazine as comparator is one where risperidone was compared with haloperidol and levomepromazine in 62 patients with schizophrenia randomised to receive one of the three antipsychotic drugs13.

Risperidone and haloperidol appeared to produce a 20% reduction in PANSS symptoms in a higher frequency of patients than with levomepromazine13. The 20% reduction in PANSS symptoms occurred with 81% of the risperidone patients, 60% of the haloperidol patients, and 52% of the levomepromazine patients. In terms of the Psychotic Anxiety Scale, improvements were significantly greater in the risperidone patients than the levomepromazine patients; but the difference between haloperidol and levomepromazine was not significant. Extrapyramidal side effects were more severe in the haloperidol group than with levomepromazine or risperidone, but there was little difference between risperidone and levomepromazine treated patients.

The binding profile of levomepromazine has led to speculation about its potential usefulness in treatmentresistant schizophrenia11. There is some tentative clinical evidence that there may indeed be some potential in using levomepromazine in treatment resistant schizophrenia. LaI and Nair found improvement in 16 of 23 chronic treatment-resistant schizophrenic patients who were treated with levomepromazine14. They had previously been hospitalised, in most cases for at least 2 years and had problems with positive symptoms, irritability, restlessness, hostility, uncooperativeness, poor concentration and aggressive behaviour. Discharge to less restrictive environments was possible in seven, placement on a waiting list for a foster home in four and improved behaviour and autonomy in five patients. There were, however, untoward adverse effects in a high proportion – five subjects developed seizures and one agranulocytosis.

A Norwegian study of elderly residents of nursing homes in 1992 found that levomepromazine with haloperidol was as effective as zuclopenthixol in managing elderly patients with symptoms of agitation and hostility/aggressiveness15.

Its use for agitation associated with acquired brain injury was described in a retrospective chart review of over 100 patients discharged from an acquired brain injury unit over a course of 2 years16.

Adverse effects

Table 1 lists the adverse reactions notified to the UK Medicine Control Agency from 1963 to 2004.

Table 1. Adverse reactions notified to UK Medicines Control Agency

Acute dystonias (spasms of eye, face, neck and back muscles), akathisia (motor restlessness), Parkinsonism-like syndrome (rigidity and tremor) can all occur. Levomepromazine’s potential to cause extrapyramidal side effects is less than haloperidol and similar to risperidone13. Levomepromazine is linked with tardive dyskinesia.

Other noted side effects include cholinergically mediated ones such as dry mouth, nasal stuffiness, difficulty in micturition, constipation a\nd blurring of vision.

Other adverse effects include tachycardia, hypotension, weight gain, impotence, galactorrhoea, hypothermia (a problem in the elderly), gynaecomastia, amenorrhoea, benign obstructive jaundice and dermatitis, ECG irregularities, drowsiness, lethargy, fatigue, epileptiform seizures.

Blood dyscrasias such as agranulocytosis and pancytopenia have been recognized as adverse effects for some time14,17,18.

Neuroleptic Malignant Syndrome (NMS) has been linked to levomepromazine used with olanzapine in one patient in a recent report19.

Phototoxicity is a noted problem with phenothiazines. Levomepromazine may have a reduced propensity to cause this problem compared to chlorpromazine20.

Fatal overdoses with levomepromazine are rare, but have been reported7. In the latter case report the blood drug concentration recorded was 4.1 mg/L, (whereas therapeutic levels are 0.02mg/L- 0.14mg/L).

The relative toxicities of different neuroleptics have been compared using f-values. The f-value is calculated by dividing the number of deaths caused by a specific neuroleptic into the number of defined daily doses prescribed in the observation period. The highest f-values for neuroleptics have been linked with low- potency, such as prothipendyl, chlorprothixene and levomepromazine21. The Schreinzer et al. study incorporated 85 fatal intoxications with neuroleptics in Vienna from 1991 to 199721. The authors concluded that careless use of low-potency neuroleptics should be avoided in patients with a potential risk of accidental or suicidal overdose. A Finnish study by Koski et al. looked at the interaction of alcohol and drugs in fatal poisonings. The study sounded a note of caution finding that some drugs seemed to be especially problematic in overdose with alcohol. They also found a relatively high fatal toxicity index (FTI) for levomepromazine (FTI = 47.3), similar to propoxyphene (FTI = 32.0) and amitriptyline (FTI = 12.2), but not as severe as promazine (FTI = 120.8)22.

Since levomepromazine has been noted to have analgesic properties a propensity for abuse could be predicted to be a potential problem. Levomepromazine’s analgesic effects have been studied in comparison to morphine. Levomepromazine does not compete with naloxone for binding sites in the brain and its analgesic effects are not antagonized by naloxone. Unlike morphine, tolerance does not develop to the analgesic effect of levomepromazine, in the short term anyway.

Interactions

Out of all the phenothiazines, levomepromazine exerts the most potent effects on cytochrome P-450 activity (as measured by caffeine oxidation in rat liver microsomes)23.

Levomepromazine inhibits CYP1A2, CYP3A2, CYP2D6 and other CYP isoenzymes. This would have implications for the metabolism of other drugs, which are metabolised by these isoenzymes, if co administered with levomepromazine.

Levomepromazine may interact with citalopram causing a 10%-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram24.

Cautions and contraindications

Contraindications include comatose states and bone marrow depression (except where levomepromazine is used in terminal care).

Cautions include cardiovascular disease, hepatic impairment, Parkinsonism, epilepsy, pregnancy and lactation.

Conclusions

The main indications for use of this drug in psychiatry are schizophrenia and schizoaffective disorder. The drug appears to be effective in psychosis and there is also some evidence to suggest it has efficacy in drug-resistant psychosis, although this property of the drug does require further research. Levomepromazine’s sedative properties particularly fit it to use in psychiatric intensive care. The drug should be avoided in patients at high risk of accidental or suicidal overdose.

A definitive formal controlled study of levomepromazine in treatment-resistant schizophrenia is warranted.

* Nozinan is a registered tradename of Rhne-Poulenc Rorer (Aventis Pharma)

References

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2. Costantini D, Trifogli R, Fiaschetti T. On the use of Nozinan (levomepromazine) in preanesthetic medication [Italian]. Acta Anaesthesiologica 1968:Suppl 8:277 and Dahl SG, Hall H. Binding affinity of levomepromazine and two of its major metabolites of central dopamine and alpha-adrenergic receptors in the rat. Psychopharmacology 1981;74(2):101-4

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9. Dahl SG, Strandjord RE, Sigfusson S. Pharmacokinetics and relative bioavailability of levomepromazine after repeated administration of tablets and syrup. Eur J Clin Pharmacol 1977;11(4):305-10

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15. Nygaard HA, Fuglum E, Eigen K. Zuclopenthixol, melperone and haloperidol/levomepromazine in the elderly. Meta-analysis of two double-blind trials at 15 nursing homes in Norway. Curr Med Res Opin 1992;12(10):615-22

16. Maryniak O, Manchanda R, Velani A. Methotrimeprazine in the treatment of agitation in acquired brain injury patients. Brain Injury 2001;15(2):167-74

17. Garzotto N, Burti L, Tansella M. A fatal case of pancytopenia due to levomepromazine. Br J Psychiatry 1976; 129:443-5

18. Ananth JY Lehmann HE, Ban TA. Agranulocytosis associated with methotrimeprazine (Nozinan) administration: a report of three cases. Can Med Assoc J 1970;102(12):1286-7

19. Jarventausta K, Leinonen E. Neuroleptic malignant syndrome during olanzapine and levomepromazine treatment. Acta Psychiatr Scand 2000;102(3):231-3

20. Eberlein-Konig B, Bindl A, Przybilla B. Phototoxic properties of neuroleptic drugs. Dermatology 1997; 194(2):131-5

21. Schreinzer D, Frey R, Stimpfl T, Vycudilik W Berzlanovich A, Kasper S. Different fatal toxicity of neuroleptics identified by autopsy. Eur Neuropsychopharmacol 2001;11(2): 117-24

22. Koski, A, Ojanpera I, Vuori E. Interaction of alcohol and drugs in fatal poisonings. Hum Experimental Toxicol 2003;22(5):281- 7

23. Daniel WA, Syrek M, Rylko Z, Kot M. Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver. Pol J Pharmacol 2001;53(6):61 5-21

24. Gram LF, Hansen MG, Sindrup SH, et al. Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 1993;15(1):18-24

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