Antidopaminergic therapy monitoring in patients with Parkinson’s disease

teaser

Unax Lertxundi
PharmD
Hospital Pharmacist

Javier Peral

Oihana Mora

Saioa Domingo-Echaburu

Ana de Juan ­Arroyo

Maria Jose ­Martínez-­Bengoechea
Servicio de Farmacia
Hospital de Galdacano
Galdacano, Vizcaya
Spain
E: [email protected]

Parkinson’s disease (PD) develops as a result of progressive loss of dopaminergic neurons in the substantia nigra and their fibres projecting into the neostritum and globus pallidus, together with a relative increase in acetylcholine. Drug therapy is aimed at correcting the imbalance between these neurotransmitters.

There are situations were antidopaminergic therapy is required, such as when psychotic symptoms are present. They consist of visual hallucinations, the belief of being persecuted, fears of personal endangerment or feelings of being followed, spied on or threatened. The prevalence of dopaminergic psychosis varies from 5% to 40%, depending on the methodology of the study and the symptoms taken into account.(1,2) Age, late-stage disease, institutionalisation, cognitive decline and depression appear to be major risk factors.(3)

Treatment of psychotic symptoms begins with the search for correctable infectious, toxic or metabolic aetiologies. If symptoms persist, antiparkinsonian drugs should be slowly reduced, which usually results in worsening of the parkinsonian features and is often poorly tolerated. It is recommended that anticholinergics, amantadine and selegiline be stopped in the first place,(4) followed if necessary by dopamine agonists and, finally, levodopa. When psychosis does not resolve, additional therapy is required. Older neuroleptics such as butyrophenones (ie, haloperidol) and phenothiazines (ie, perphenazine and chlorpromazine) block striatal dopamine D(2) receptors and may exacerbate parkinsonian symptoms.(5) Newer “atypical” ­antipsychotics have minimal activity at D(2) receptors and show promise in controlling symptoms without ­worsening parkinsonism.

The choice of the atypical antipsychotic to be used is based on ease of use, adverse effect profile and experience.(6,7) Currently there are six marketed atypical antipsychotic drugs in Spain: ­clozapine, ­risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole. Clozapine is the only atypical antipsychotic labelled to treat psychotic symptoms in PD patients in Spain and in the UK, but it lacks the indication in the USA. Several randomised placebo-controlled trials (RCT) have shown that the use of low-dosage clozapine can reduce psychotic symptoms in PD without exacerbating parkinsonism.(8–10) However, the use of clozapine requires intensive monitoring of the infrequent (1%) but potentially life-threatening complications of agranulocytosis, which make its use in clinical practice difficult.

None of the new antipsychotics has RCT ­supporting its use in PD psychosis.

The emergency treatment of psychotic symptoms in PD patients is a real challenge, since only olanzapine and ziprasidone have a parenteral presentation available, but they have not shown their efficacy and safety in RCT. There is a long-acting injectable formula for risperidone available, but it is not suitable for emergency use.

The other situation where dopamine antagonists are required in PD is the management of nausea and vomiting, which in turn are common side-effects of levodopa and dopamine agonists. Metoclopramide, an agent used to treat gastroparesis and nausea, can produce central dopamine blockade leading to a decreased levodopa effect. Domperidone, a peripheral D(2) antagonist, has antiemetic activity as a result of the blockade of dopamine receptors in the chemoreceptor trigger zone. It also provides short-term relief of symptoms in patients with dyspepsia or gastro-oesophageal reflux, prevents nausea and vomiting associated with emetogenic chemotherapy and prevents the gastrointestinal and emetic adverse effects of antiparkinsonian drugs. ­However, domperidone barely crosses the blood-brain ­barrier and the risk of developing extrapyramidal side-effects is minimal.(11) Some authors consider it the gold standard for treating gastrointestinal symptoms in PD patients.(12)

Therefore, antidopaminergic therapy in PD is needed in certain situations, and the selection of the best therapeutic option is complicated and requires a profound knowledge of the disease. As an approach to this problem, in this study we sought to investigate the incidence of potentially inappropriate antidopaminergic drug prescription in PD inpatients and to optimise this therapy by sending ­preformatted notes to the clinician in charge.

Methods
In our 400-bed general hospital, pharmacists transcribe written prescriptions into a computer program, and use that information for clinical pharmacy purposes. Computerised physician order entry is not yet available.

In order to monitor potentially inappropriate drug prescribing in our inpatient population, we designed a semiautomatic method using Access 97(®). First, a query detects all the patients with dopaminergic antiparkinson drugs from the N04B group of the Anatomical Therapeutic Chemical (ATC) classification system. Then a second query searches for ­propulsives (A03FA) and/or antipsychotics (N05A) prescriptions in these preselected patients.

Preformatted notes explaining the appropriate management of nausea/vomiting and psychotic symptoms in PD patients were written in collaboration with the neurology department. When metoclopramide was prescribed, change to domperidone was proposed. When typical antipsychotics were prescribed, a preformatted pharmacy intervention note about the management of psychotic symptoms in PD was sent when estimated necessary. All interventions were registered in the database for later statistical analysis.

All patients with prescriptions of dopaminergic antiparkinson drugs were added to the database in order to know the number of PD patients ­admitted during that period, as well as their sex, age, length of stay and service. PD patients not being treated with any of these drugs were not detected by the system. As both trihexyphenidil and biperiden (N04A drugs) are widely used for extrapyramidal symptoms in patients treated with neuroleptics, PD patients being treated with these drugs in monotherapy were not included.

Pharmacy interventions were just recommendations to clinicians, and no change was made in the patients’ therapy until a new medical prescription was received.

Descriptive statistical data (mean standard deviation, range for 95% confidence interval) were obtained for the variables sex, age, length of stay and service. Student’s t-test was used to compare means. The level of significance was set at p < 0.05.

Results
From December 2005 to June 2006 (211 days), the system registered a total of 75 hospital admissions of patients taking any dopaminergic antiparkinson drug for PD. One patient was admitted three times, four patients were admitted twice and 64 patients were admitted once (see Table 1). During the same period, a total of 9,443 different patients were ­admitted to the hospital, which means that 0.7% of the patients admitted were taking dopaminergic antiparkinson drugs for PD.

[[HPE32_table1_78]]

The mean age of the 69 patients admitted ­taking dopaminergic antiparkinson drugs for PD was 75 ± 11 years; 54% of the patients were male, and the ­average length of stay was 9 ± 6 days).

Seven patients were being treated with ­pramipexole (N04B drug) in monotherapy for restless legs syndrome (mainly associated with opioid withdrawal) and not for PD. This problem was discovered when the system was already running, so these patients were considered as false positives. They were not included in data analysis. Eighteen of 69 PD patients (26%) had a prescription for a neuroleptic drug; 21 antipsychotics were prescribed, 11 of which were atypical. In those cases, no advice was sent to the clinician in charge. The most frequently prescribed atypical antipsychotic was quetiapine (eight prescriptions), followed by risperidone (two prescriptions) and clozapine (one prescription). Only one PD patient with a prescription of domperidone was detected. No specific advice was considered in that case.

A total of 30 prescriptions of typical ­antipsychotics and metoclopramide were detected by the system (up to 35% of the PD patients, 31% of admissions). Staff pharmacists decided not to intervene seven times, twice because the drug was prescribed as needed (“pro re nata”), three times due to punctual doses and twice because of errors in drug ­transcription.

Physicians accepted our recommendation in 10 of the 23 interventions made (43%): 4/10 for typical antipsychotics and 6/13 for metoclopramide (see Table 2). Stopping the drug was the most frequent decision. Metoclopramide was switched to ­domperidone three times. Haloperidol was only once switched to risperidone. Antiparkinsonian drugs were never tapered down.

[[HPE32_table2_78]]

PD patients prescribed haloperidol tended to be older than PD patients who were not, but the difference was not statistically significant (79.5 vs 74.4 years; p = 0.238; 95% CI 3.47–13.69).

Discussion
As far as we know, this is the first study of the incidence of potentially inappropriate antidopaminergic (typical antipsychotic, metoclopramide) prescription in PD patients admitted to hospital. We found that these drugs were frequently used in our hospital despite not being recommended or even being contraindicated for this condition. The majority of admissions of PD patients occurred in services other than the neurology department, which could partly explain why metoclopramide and typical antipsychotics were prescribed so frequently.

The atypical antipsychotic more frequently used in PD patients was quetiapine, and only one patient was receiving clozapine. This is probably explained by the adverse-effect profile of each drug. Almost half of the neuroleptics prescribed in PD patients (10/21) were typical antipsychotics. The fact that haloperidol was so frequently stopped and not switched to an atypical antipsychotic could be explained because it is also used to treat other conditions rather than psychotic symptoms, such as agitation, pain or alcohol withdrawal.(13) Since age is a known risk factor for psychosis in PD patients, it is not surprising that PD patients with a haloperidol prescription tend to be older.

Some studies have reported a higher prevalence of PD in men, even though this issue is still controversial. In our inpatient population the proportion of men was slightly higher. Nonetheless, our sample size is far too small to draw any conclusion.

Chlorpromazine was prescribed for intractable hiccups on two occasions. The clinician was advised that its use in PD was contraindicated, but no alternative was offered. Even though many different drugs, such as baclofen, gabapentin, valproic acid or nifedipin,(14,15) have been tested to treat this problem there are no published studies about treatment of intractable hiccups in PD patients. Nevertheless, some authors recommend baclofen as a first-line alternative to haloperidol and chlorpromazine.(16)

The fact that domperidone is a relatively unknown drug and that it is not available for parenteral application in our country may have limited its use. Physicians did not support the pharmacist’s recommendation in seven cases where metoclopramide was prescribed. In five of these cases, the drug was ­prescribed for intravenous administration.

This semiautomatic method optimises time because little effort (a matter of seconds) is needed to monitor systematically inappropriate prescription of these drugs in all PD patients every day. In 211 days, only 23 interventions were made. Once a potentially inappropriate prescription is detected, it takes ­minutes to decide whether or not to ­intervene.

Because of the methodology used, not all PD patients were detected by the system. Untreated PD patients and PD patients receiving N04A drugs in monotherapy were not included. Nevertheless, the number of patients lost is expected to be very low. In a population-based study carried out in Norway, only 2% of PD patients were not taking antiparkinsonian drugs because they did not require symptomatic treatment or because of feared adverse effects.(4) In addition, and although anticholinergic drugs were the first pharmacological agents used in the treatment of PD, levodopa and other centrally acting dopaminergic agonists have largely supplanted their use.(17) Currently, anticholinergic drugs are restricted to early pharmacological therapy of the disease.(5)

Another limitation, which was discovered after the system had been put in place, relates to the false positives detected. Dopaminergic ­antiparkinson drugs are not only used for PD (pramipexole for restless legs syndrome, bromocriptine for hyperprolactinaemia, etc) and seven false positives had to be discarded. Nowadays, each time the system detects a patient treated with any dopaminergic antiparkinson drug, a pharmacist has to verify that it is indeed a PD patient, by checking the electronic medical record available via the intranet. It takes about five minutes to do so, and it happens about once every three days (75 admissions in 211 days).

Finally, this semiautomatic method has the potential to be used for checking many other drug-related problems, as all prescribing information is available.

Conclusions
Inappropriate prescription of antidopaminergics is a frequent drug-related problem, with one-third of PD inpatients receiving metoclopramide or/and a typical antipsychotic. This situation may be corrected with an automated system such as the one employed in this study. Further research is needed in order to optimise parenteral treatment of both psychotic symptoms and nausea/vomiting in PD patients; specifically, research is warranted about optimal treatment of intractable hiccups in PD patients. Even though clozapine is considered the gold standard for treatment of psychotic symptoms, it has rarely been used in our patient population, with quetiapine being the most used.

References

1. Cummings JL. Managing psychosis in patients with Parkinson’s disease. N Engl J Med 1999;340:801-3.
2. Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinson’s disease. Prevalence, phenomenology and risk factors. Brain 2000;123:733-45.
3. Aarsland D, Larsen JP, Cummins JL, Laake K. Prevalence and clinical correlates of psychotic symptoms in Parkinson disease: a community-based study. Arch Neurol 1999;56:595-601.
4. National Collaborating Centre for Chronic Conditions. Parkinson´s disease: national clinical guideline for ­diagnosis and management in primary and secondary care. London: Royal College of Physicians; 2006.
5. Juncos JL. Management of psychotic aspects of Parkinson’s disease. J Clin Psychiatry 1999;60 Suppl 8:42-53.
6. Fernandez HH, Trieschmann ME, Friedman JH. Treatment of psychosis in Parkinson’s disease: safety considerations. Drug Saf 2003;26:643-59.
7. Miyasaki JM, Shannon K, Voon V, et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:996-1002.
8. The Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 1999;340:757-63.
9. Pollak P, Tison F, Rascol O, et al. Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry 2004;75:689-95.
10. The French Clozapine Parkinson Study Group. Clozapine in drug-induced psychosis in Parkinson’s disease. Lancet 1999;12;353:2041-2.
11. Barone JA. Domperidone: a peripherally acting dopamine 2 receptor antagonist. Ann Pharmacother 1999;33:429-40.
12. Marti Masso JF, Poza JJ, Lopez de Munain A. Drug treatment of frequent disorders in patients with Parkinson’s disease. Neurologia 1996;11:109-15.
13. Battaglia J. Pharmacological management of acute agitation. Drugs 2005;65:1207-22.
14. Rosenberger J, Veseliny E, Bena L, Roland R. A renal transplant patient with intractable hiccups and review of the literature. Transpl Infect Dis 2005;7:86-8.
15. Friedman NL. Hiccups: a treatment review. Pharmacotherapy 1996;16:986-95.
16. Regnard C, Hockley J. Respiratory problems. In: A guide to symptom relief in palliative care. 5th ed. Oxford: Radcliffe Medical Press; 2004:131-8.
17. Brocks DR. Anticholinergic drugs used in Parkinson’s Disease: an overlooked class of drugs from a ­pharmacokinetic perspective. J Pharm Pharm Sci 1999;2:39-46.