Pharmacotherapeutic management of Parkinson’s disease inpatients: how about asking hospital pharmacists?

Abstract

Introduction

Parkinson’s disease (PD) is considered to be the fastest growing neurological disorder in the world. Patients with PD are hospitalised more frequently, have longer admissions and experience more complications during hospitalisation than age-matched control groups. The incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs are the most important risk factors for motor function deterioration during hospital admission, and have been associated with longer hospital stays and even increased mortality. Despite their crucial role in pharmacotherapy, little attention has been paid to the perspective of hospital pharmacists. The objective of this study was to identify key issues in the pharmacotherapeutic management of inpatients with PD by the implementation of a national Spanish survey specifically designed to analyse the perspective of hospital pharmacists.

Methods

An internet-based questionnaire covering the following areas was designed: hospital and participant characteristics, drug formulary, medication compliance and reconciliation, protocols and contraindicated drugs and areas for improvement.

Results

A total of 76 pharmacists from 59 hospitals answered the survey. Some weaknesses were identified in the availability of drugs: (1) pharmacy services closed at certain times (86.4%); (2) low variety of antiparkinsonian drugs (18.4% store >21 different drugs); (3) delay in antiparkinsonian drug administration if unavailable (>12 hours in 39.5% of cases); (4) lack of flexibility in administration times; (5) low availability of transdermal rotigotine and subcutaneous apomorphine (<50%). The participants ranked highly the designing of specific protocols for patients with PD and implementation of concrete actions to optimise PD inpatient pharmacotherapy.

Conclusions

The participants detected some improvement opportunities and proposed realistic and applicable recommendations and strategies aiming to enhance the safety of patients with PD. Protocols for antiparkinsonian drug interchange, administration timing and nil by mouth status, medication reconciliation, and handling nausea/vomiting or psychotic symptoms are considered the main improvement areas.

Introduction

Parkinson's disease (PD) is a highly prevalent, complex, age-related, neurodegenerative disease influenced by many environmental and genetic factors. The estimated prevalence of PD is 0.3% in the general population and higher in older people (1% and 3% in people aged >60 and >80 years, respectively). PD is now considered as the fastest growing neurological disorder in the world, leading some authors to speak about a true pandemic. From 1990 to 2015 the number of patients with PD doubled to over 6 million. Due to ageing, this number is expected to double again to over 12 million by 2040.¹

Patients with PD are hospitalised more frequently, have longer admissions and experience more complications during hospitalisation than age-matched control groups.² The treatment of patients with PD during hospital stay is challenging and requires the cooperation of multidisciplinary teams. Consideration of the patient’s symptoms, comorbidities, medication and patient resources and vital signs is crucial for effective and safe treatment.³ The incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs are the most important risk factors for motor function deterioration during hospital admission. These factors have been associated with longer hospital stays^{4 5} and even increased mortality,⁵ although the available evidence is inconclusive.⁶ Therefore, some recommendations have been suggested for improving safety in patients with PD including: (1) identifying potentially inadequate and contraindicated drugs from prescriptions; (2) evaluating potential drug–drug interactions; (3) developing and using recommendation lists specifically for PD patients; and (4) revising the timing of levodopa administration.^{3 5} Moreover, surveys carried out with patients⁷ and professionals from several areas involved in the care of patients with PD including neurologists, nurse specialists and geriatricians^{8 9} have shown an urgent need for improvement in PD inpatient pharmacotherapeutic management. Accordingly, some prestigious bodies in the field of patient safety such as the Institute for Safe Medication Practices (ISMP) have published specific recommendations for healthcare providers to improve the medication management of hospitalised patients with PD.¹⁰

Nonetheless, there are two issues that call for special attention: (1) the implementation of recommendations and strategies to improve the quality of the pharmacotherapeutic management of hospitalised patients with PD is not widespread; (2) despite their crucial role in pharmacotherapy, little attention has been paid to the perspective of hospital pharmacists. Therefore, further improvements in this regard are needed.

Based on these considerations, the main objective of this study was to identify key issues in the pharmacotherapeutic management of PD inpatients from the perspective of hospital pharmacists, with the purpose of recommending potential improvement actions. In Spain, pharmacists are, among other duties, responsible for the medications available at hospitals and are able to review the prescriptions made by clinicians. Therefore, evaluation of their opinion about the management of pharmacotherapy in a specific group of patients is undoubtedly of great value in order to identify weaknesses and strengths, which could lead to the implementation of improvement strategies or plans and consequently to a reduction in the clinically relevant drug-related problems. Nowadays, a legally defined specialisation programme (Especialidad en Farmacia Hospitalaria) is required to work as a hospital pharmacist in Spain, in addition to a 5-year University Degree in Pharmacy. The 4-year programme is conducted at the hospital where all the training is provided.¹¹

With this goal in mind, a national survey was carried out in the public Spanish hospital pharmacy services and information was collected about medication compliance and reconciliation, protocols, use of contraindicated drugs and areas for improvement.

Methods

Study sample

All hospital pharmacists working in any hospital with more than 100 beds in Spain were invited to participate. Pharmacists were contacted by email, where a link to the online questionnaire was provided along with an informational text about the study. To that end, the mailing list of the Spanish Society of Hospital Pharmacists (listasefh) was used. In addition, a reminder was sent via Twitter using the Spanish Neuropsychiatric Task Force account using the Spanish National Catalogue of Hospitals.¹²

Survey design

To conduct this study, an internet-based questionnaire was developed using Google forms. The survey consisted of a list of 40 questions, which took approximately 15 min to answer and was posted for 8 weeks.

The questionnaire was divided into six sections: (1) hospital characteristics; (2) participant information; (3) pharmacy service and treatment guidelines; (4) compliance with dosing interval during levodopa treatment and medication reconciliation in patients with antiparkinsonian treatment; (5) contraindicated medication and specific treatment protocols; and (6) improvement plans and actions. Responders were instructed to reflect the usual clinical practice in their pharmacy service and level of knowledge of their colleagues rather than their personal opinions. We also asked some open-ended questions about possible ideas to improve care. The full questionnaire is available in online supplemental appendix 1.

Statistical analysis

A descriptive analysis was performed using absolute and relative frequencies for qualitative variables and mean and SD for quantitative variables. The Student’s t-test and the χ² test were used to compare quantitative and qualitative variables, respectively.

Statistical analyses were performed using SPSS Statistics for Windows, Version 23.0 (IBM Corp, Armonk, New York, USA).

Results

The main results from the survey are presented in table 1 and are detailed below.

Table 1.

Main results of the survey

A. Hospital characteristics and participant information, n/number of hospitals (%)
Medium sized hospitals (200–1000 beds)		30/59 (50.8%)
Hospitals with neurology ward		42/59 (71.2%)
Hospitals which regularly have inpatients with PD		45/59 (81.3%)
Electronic prescribing		54/59 (91.5%)
B. Pharmacy service and hospital drug formulary, n/number of hospitals (%)
Pharmacy service opening hours	24 hours, 7 days	8/59 (13.5%)
	Closed at night	51/59 (86.4%)
	Closed in the afternoon and night	18/59 (30.5%)
	Restricted opening hours during weekends	21/59 (35.6%)
C. Antiparkinsonian drug compliance and reconciliation, n/number of respondent pharmacists (%)
Usually taken actions when an unavailable antiparkinsonian drug is prescribed	Request the drug from a pharmaceutical wholesaler	66/76 (86.8%)
	Encourage relatives to bring the drug	62/76 (81.5%)
	Proposal of pharmacotherapeutic substitution by the pharmacist	17/76 (22.3%)
	Availability of a protocol for antiparkinsonian drug interchange	6/76 (7.8%)
Delay of >12 hours a patient might spend without receiving the prescribed drug, considering drug availability in their setting		30/76 (39.5%)
Nil by mouth patients: estimation of complete omission of dopaminergic drugs until the patient could tolerate orally		22/76 (28.9%)
Availability of antiparkinsonian drug extra stock on neurology wards		12/76 (15.8%)
Medication reconciliation on admission		63/76 (82.8%)
Medication reconciliation at discharge		6/76 (7.8%)
Perception that patients/caregivers are interviewed during the reconciliation process		28/76 (36.8%)
Timing of levodopa administration	Patient/caregiver asked about the exact timing	37/76 (48.6%)
	Adjusted to fit 'normal' administration schedules/ standardised frequencies	38/76 (50%)
Patients are asked to bring in and manage their treatment		26/76 (34.2%)
Electronic prescribing software allowing precise levodopa prescription (ie, adequate timing of levodopa doses)		73/76 (96.1%)
D. Treatment protocols and contraindicated drugs, n/number of respondent pharmacists (%)
Most common intervention when a contraindicated drug is prescribed	Warnings from pharmacists to prescribers	60/76 (78.9%)
	Automatic electronic alert	15/76 (19.7%)
	Use of pimavanserin, a drug not on the market in Spain but which could be imported on demand by the Spanish Government	0/76 (0%)
	Availability of specific guidelines to manage agitation in PD patients	19/76 (25%)
	Direct prescription of haloperidol	11/76 (14.5%)
Nausea and vomiting	Availability of specific guidelines to manage nausea and vomiting in PD patients	18/76 (23.7%)
Drugs most frequently used to treat hiccups	Chlorpromazine	14/76 (18.4%)
	Baclofen	4/76 (5.3%)
	Omeprazole	2/76 (2.6%)
	Other drugs mentioned	Levomepromazine, metoclopramide, domperidone

Hospital characteristics and participant information

A total of 76 pharmacists from 59 different hospitals answered the survey. The estimated response rate was 12.9% (59/456). Electronic prescribing was available in almost all hospitals, and it allowed levodopa to be prescribed in detail, respecting the tailored regimens for each patient. Most responders worked at hospitals that had a neurology ward and regularly had inpatients with PD. More than half of the hospitals were medium sized (200–1000 beds).

At least one answer from all autonomous regions was obtained except for Castilla y Leon, Castilla-La Mancha, Extremadura, and the autonomous cities of Ceuta and Melilla. These regions and cities together only account for around 12.1% of Spain’s total population.¹³ Figure 1 shows additional information about the responders and their hospitals.

Figure 1.

Characteristics and place of work of responders to the survey.

Pharmacy service and hospital drug formulary

Pharmacy service opening hours

The pharmacy service was open 24 hours a day, 7 days a week in only eight hospitals. In all other cases this service was closed at night (later than 22:00 hours). Nearly a third closed at some point in the afternoon (mostly later than 20:00 hours) and just over a third had more restricted opening hours at the weekend.

Hospital drug formulary

Box 1 shows information about the availability of the different antiparkinsonian drugs in the hospital formulary. Rotigotine and apomorphine were available in 44.7% and 42.1% of cases, according to survey responders. Only one responder answered that no antiparkinsonian drug at all was available in their place of work.

Box 1. Drugs included in the hospital drug formulary, N (%).

L-DOPA

• L-DOPA + decarboxylase inhibitor, 75 (98.7)

• L-DOPA + decarboxylase inhibitor RETARD, 74 (97.4)

• L-DOPA + decarboxylase inhibitor + COMT inhibitor, 40 (52.6)

• Other formulations (gel…), 32 (42.1)

• None, 1 (1.3)

Dopamine agonists

• Pramipexol, 42 (55.3)

• Rotigotine, 34 (44.7)

• Ropinirole, 32 (42.1)

• Apomorphine, 32 (42.1)

• None, 23 (30.3)

MAO-B inhibitors

• Rasagiline, 35 (46.1)

• Selegiline, 31 (40.8)

• Safinamide, 7 (9.2)

• None, 28 (36.8)

Anticholinergics

• Biperiden, 74 (97.4)

• Trihexyphenidyl, 45 (59.2)

Number of different antiparkinsonian drugs (brands)

• 0–10, 35 (46.1)

• 11–20, 27 (35.5)

• 21–40, 10 (13.2)

• >40, 4 (5.3)

Domperidone

• Available, 69 (90.8)

• Not available, 3 (3.9)

• Ordered in exceptional circumstances, 4 (5.3)

Antiparkinsonian drug compliance and reconciliation

When an unavailable antiparkinsonian drug was prescribed, 66 responders reported that it was requested from a pharmaceutical wholesaler. In this case, relatives are often encouraged to bring the patient’s medication to the hospital. Only 17 responders proposed some type of pharmacotherapeutic substitution, and just six responders reported having a formal protocol for antiparkinsonian drug interchange.

Hospital pharmacists estimated how much time a patient might spend without receiving the prescribed drug, considering drug availability in their setting. In 30 of the 76 cases the predicted time until the drug was administered was >12 hours. No differences in the delay until the patient received the prescribed drug were found according to the pharmacy opening hours (p>0.05). In the case of nil by mouth patients, 22 of the pharmacists considered that dopaminergic drugs would be completely omitted until the patient could tolerate drugs orally. No extra stock of antiparkinsonian drugs was available on neurology wards according to the majority of responders.

When performed, medication reconciliation in patients with PD is mainly done on admission whereas it is rarely carried out at discharge. Only 28 of the 76 responders believed that patients/caregivers were interviewed during the medication reconciliation process. Figure 2A shows the confidence level of the responders to the questions containing a quantitative scale response. As can be seen in figure 2A, the confidence about medication reconciliation being systematically completed was one of the questions for which the confidence values were the lowest. No differences were found in any of the three questions between survey responders working in hospitals that did and did not have a neurology ward (p>0.05)

Figure 2.

Hospital pharmacists’ perception of the level of knowledge of colleagues about (A) medication compliance and reconciliation, (B) treatment protocols and contraindicated drugs and (C) improvement plans and actions.

When questioned about respecting the exact timing for each levodopa administration, fewer than half of the responders believed the patient or caregiver was asked. As many as half of the responders believed that administration was adjusted to fit 'normal' administration schedules or standardised drug frequencies.

Only 26 pharmacists answered that patients are asked to bring in and manage their antiparkinsonian treatment while admitted.

In general, survey responders believe that their colleagues correctly identify antiparkinsonian drug omission as a potential cause of motor function deterioration in patients with PD, with a score of 7.5/10. The level of knowledge about campaigns such as 'Get It On Time' and 'Aware in Care' were lower (4.3/10) (figure 2). The vast majority of responders reported that their electronic prescribing software allowed for precise levodopa prescription (ie, adequate timing of levodopa doses).

Treatment protocols and contraindicated drugs

The most common intervention when a contraindicated drug was prescribed to a PD inpatient was warning the prescriber. Only 15 survey responders explained that an automatic electronic alert warned clinicians about this issue.

Psychotic symptoms

Responders believed that hospital pharmacists generally identify organic factors (dehydration, infections, drugs, etc) as potential causes of delirium in patients with PD. Both quetiapine and clozapine were generally known to be the best choice to treat psychotic symptoms in these patients (6.7/10). So far, no hospital has used pimavanserin, a drug which is not on the market in Spain. Nevertheless, it could be imported on demand by the Spanish Government.

No specific guidelines to manage agitation in patients with PD were available according to 57 responders. Eleven responders said that haloperidol was directly prescribed in this situation.

Nausea and vomiting

The level of awareness that domperidone is the gold standard to treat nausea and vomiting was high among responders, with a score of 8/10 (figure 2B). On the other hand, most acknowledged that there were no specific guidelines for the management of these symptoms in their hospitals.

Hiccups

Fourteen survey responders stated that chlorpromazine was the drug most frequently used to treat hiccups in patients with PD, followed by baclofen (4/76) and omeprazole (2/76). Other drugs mentioned were levomepromazine, metoclopramide and domperidone.

Again, no differences were found in any of the three questions between survey responders working in hospitals that did and did not have a neurology ward (p>0.05).

Improvement plans and actions

Survey responders ranked highly both the designing of specific protocols for patients with PD and the implementation of concrete actions to optimise PD inpatient pharmacotherapy (8.0/10 and 8.1/10, respectively) (figure 2C). Once again, no differences were found in either of the two questions between survey responders working in hospitals that did and did not have a neurology ward (p>0.05).

Discussion

To our knowledge, this is the first study that provides data on the perspective of hospital pharmacists concerning key elements of pharmacotherapeutic management of inpatients with PD.

One crucial aspect of PD inpatient pharmacotherapy is guaranteeing that levodopa doses are administered on time, which can be difficult.¹⁴ In relation to this, it has even been suggested that PD medications should be considered as important as insulin for diabetics.¹⁵ One of the reported reasons for omitting or delaying levodopa administration has been the medication being unavailable on time where needed—that is, on the medical wards where patients are admitted.⁵ The ISMP¹⁰ and 'Get It On Time',¹⁶ among others,¹⁷ suggest that all commercially available antiparkinsonian drugs should be available in all hospital wards without delay (on time). The results of our survey suggest that it is unfeasible to achieve this in practice. First, the number of different antiparkinsonian drugs included in drug formularies of many hospitals is very likely insufficient, only 18.4% of responders stating that their service had >21 different drugs when a previous study estimated at least 25 different brands would be necessary.¹⁸ Second, the majority of pharmacy services close at certain times. Although in this study we found no differences among responders from hospitals with different opening hours concerning access to antiparkinsonian drugs, we believe this issue should be studied in depth.

More than a third of the hospital pharmacists acknowledged that, in the case of a patient needing an antiparkinsonian drug that is not available, significant delays of >12 hours may occur. Moreover, approximately two-thirds of responders acknowledged that patients are not encouraged to manage their own treatment while admitted, although this is a recommended practice,^{16 18} and less than half of responders (48.6%) believed patients/caregivers were asked about the exact timing for levodopa administration. Further, the majority of pharmacists believed that, although the prescribing software generally allowed a detailed prescription, antiparkinsonian drugs are prescribed at fixed hospital drug administration times rather than according to patient needs or following their home regimen. Therefore, we believe hospital pharmacists could help clarifying timing of medications during their reconciliation processes and encouraging prescribers to adjust hospital prescriptions accordingly.

In addition, more than half of drug formularies include neither rotigotine nor apomorphine. This is in line with the findings of our previous study⁵ where, in 88% of the admissions where a dopaminergic drug was not administered because of oral intolerance or nil by mouth status, neither transdermal rotigotine nor subcutaneous apormophine was used. This shows that there is substantial room for improvement in the implementation of published recommendations, such as those for optimising the management of PD during surgery.¹⁹ It should be kept in mind that antiparkinsonian drug omission has been associated with longer hospital stays and higher mortality rates in previous studies.^{4 5} Therefore, hospital pharmacies could be encouraged to ensure non-oral options (ie, rotigotine or apomorphine) are available on their formulary.

Even in a specialist unit with an augmented stock of antiparkinsonian drugs, it was stated that: ‘‘The available stock was not used as flexibly as we had hoped: eg, doses of modified release medications were omitted rather than a temporary switch to available standard release drugs”.²⁰ Perhaps we should consider implementing new more realistic strategies such as protocols for drug substitution in which the unavailable PD drug is first converted to the equivalent levodopa dose.²¹

Expedited medication reconciliation is another key element for safe drug use in hospitalised patients with PD.¹⁰ According to survey responders, this procedure is not performed systematically so it is likely that the problem of omission and delays of antiparkinsonian drug administration is underestimated, since there is no guarantee that the hospital prescription is actually the same as the outpatient prescription.

Another key element of the pharmacotherapeutic management of inpatients with PD is avoiding centrally acting antidopaminergics which are used to treat common comorbidities of the disease. Hospitalised patients with PD are at high risk of developing delirium. Indeed, it is likely that many agitated patients treated with haloperidol may well be suffering from an undiagnosed acute confusional state. We believe specific guidelines to identify and treat delirium in PD are of special interest since many recommended drugs such as haloperidol are contraindicated and can have deleterious effects.²²

The level of awareness that quetiapine and clozapine is the treatment of choice for psychotic symptoms in patients with PD seems to be high among the hospital pharmacists surveyed. Domperidone was also identified as the gold standard for nausea and vomiting. Nonetheless, chlorpromazine, although not recommended because of its liability to worsen motor features of the disease,²³ seems to be the most frequently used drug to treat hiccups in hospitalised patients with PD.

On the other hand, computerised warnings to alert prescribers are little used. Despite there being no specific protocols for the management of psychotic symptoms or nausea/vomiting in many hospitals, the pharmacists surveyed seem to believe that having them should be a priority. Guidelines to improve the pharmacotherapy in patients with PD are also required, including protocols for antiparkinsonian drug interchange and medication reconciliation or for the management of antiparkinsonian drug timing and nil by mouth status. In essence, all these protocols and guides should be available in all hospitals, and the accessibility to required medication should be guaranteed throughout the day. Broadening hospital formularies and increasing pharmacy service hours might be considered.

Limitations and strengths

Only pharmacists from around 12% of the hospitals in Spain with a pharmacy service answered the survey. Nonetheless, we received at least one answer from autonomous regions that account for around 87.9% of Spain’s total population.

On the other hand, survey responders may be more motivated in this area of healthcare and provide better services than average. Moreover, survey results represent experiences of individuals and not necessarily all pharmacists at each hospital. So there is a significant potential for bias, since the findings represent only opinion and perception without any way of knowing the accuracy of the pharmacist survey responses.

Conclusion

The pharmacotherapeutic management of patients with PD admitted to hospital needs to be improved with the active involvement of hospital pharmacists in the decision-making processes. In the national survey developed in Spanish pharmacy services, the participant pharmacists detected some improvement opportunities. Moreover, realistic and applicable recommendations and strategies were proposed aiming to enhance the safety of patients with PD. The main suggested improvement areas include the development of protocols for antiparkinsonian drug interchange, for the management of antiparkinsonian drug timing and nil by mouth status, for medication reconciliation and for handling nausea/vomiting or psychotic symptoms.

What this paper adds.

What is already known about this subject

• Patients with PD are hospitalised more frequently, have longer admissions and experience more complications during hospitalisation than age-matched control groups.

• The incorrect timing of levodopa administration and prescription of contraindicated antidopaminergic drugs lead to longer hospital stays and increased mortality.

• Despite their crucial role in pharmacotherapy, so far little attention has been paid to the perspective of hospital pharmacists.

What this study adds

• The implementation of a national survey specifically designed to analyse the perspective of hospital pharmacists identified key issues in the pharmacotherapeutic management of inpatients with PD.

• Protocols for antiparkinsonian drug interchange, administration timing and nil by mouth status, medication reconciliation and handling nausea/vomiting or psychotic symptoms are considered the main areas for improvement.

• Realistic and applicable recommendations and strategies aiming to enhance the safety of patients with PD are proposed.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Not required.