Symptoms of Medication Withdrawal in Parkinson’s Disease: Considerations for Informed Consent in patient-oriented Research

Abstract

Introduction:

Dopamine medication withdrawal in Parkinson’s Disease is commonly employed in clinical practice and can be required for participation in research studies. When asked to withdraw from medications, participants often enquire as to what symptoms they should expect.

Objectives:

This study sought to improve the informed consent process by identifying patient-reported symptoms when withholding from dopamine treatment. We also sought to provide clinical guidance regarding the extent of these symptoms and consider participant willingness to undergo these assessments.

Methods:

Participants were recruited from community-based PD programs and support groups in Nashville, Tennessee. A patient-based questionnaire determined the frequency and severity of motor and nonmotor symptoms. The questionnaire also assessed if patients would be willing to withhold from medication at a future date and for what purpose.

Results:

A total of 31/90 participants reported withdrawing from dopaminergic medications for clinical or research purposes. Tremor, walking, and balance was the most common motor symptom that worsened during this time. Sleep dysfunction, constipation, and tremor were noted as the most severe symptoms. Of note, 10% of the participants indicated that they would not be willing to go off medications again, suggesting that to a minority of patients this can be most discomforting. When prompted for a reason that participants would be willing to come off of their medications again, “clinical” purposes were the most selected.

Conclusions:

Study teams should list these symptoms in the applications to their institutional review board and in the informed consent to provide guidance for participants.

1. Introduction

Dopamine medication withdrawal is commonly employed in clinical practice to estimate disease severity in the off-medication state [1], quantify the benefit of dopamine medication effect in participants by determining the difference between on and off states, and can be required for participation in certain clinical research studies [2–6]. Having a washout period that is too short can result in residual dopamine drug effects, but too long withdrawal period can result in adverse experiences for patients [7]. The most common off-symptoms described by patients are characterized by worsening motor severity, but non-motor symptoms have been well characterized and are often described [8–10].

One of the more common questions patients ask when instructed to hold their medications is what to expect symptomatically. In this study, we assessed patient-reported perceptions of medication withdrawal in a cohort of individuals who were instructed to withhold medication for clinical-research purposes and compared these responses to participants who had not participated in these studies. Our main goal was to identify and describe patient reported symptoms in order to provide clinical guidance to patients who will withhold from medication and improve informed consent for research purposes. We designed a patient-based questionnaire to determine the frequency and severity of motor and nonmotor symptoms, and also determine if patients would be willing to withhold from medication at a future date.

2. Methods

2.1. Sample

This sample was recruited between January 2018 - January 2020 from the Vanderbilt University Medical Center Movement Disorders Clinic in Nashville, Tennessee. The Vanderbilt University Medical Center Human Research Protection Program reviewed and approved this study as minimal risk to participants as the information was voluntarily collected through an online system and was kept separately from the survey so as to de-identify the data. All participants reviewed and signed an informed consent form. The data were collected through RedCap, the Research Electronic Data Capture, an online data management platform using the survey distribution tool [11]. Surveys were collected through a survey address link (see supplementary information). In order to avoid only capturing Parkinson’s Disease (PD) patient profiles who are often involved in research, recruitment took place at local community-based PD programs in Nashville, TN. Eligibility criteria for this study included being aged 50–85 years, having a diagnosis of PD and taking at least one dopaminergic medication (i.e. levodopa, or a dopamine agonist).

2.2. Measures

For this questionnaire, participants first identified if they had a diagnosis of PD, which dopamine medications they were taking, if they ever experienced off symptoms, and if they ever purposefully went off their PD medications for a period of time for clinical or research purposes. Afterwards, they were asked to identify off symptoms they experienced from a predefined list based on clinical experience. Once identified, they were prompted to rate the severity of the symptom. The severity was rated from 1–5, with 1 defined as low, 3 as moderate, and 5 as severe. Participants had the opportunity to list any adverse event they experienced from being off of medications. Questions also asked participants how likely they would be willing to go off of their medications again. This question had a rating scale of 1–5, with 1 being low, 3 being moderate, and 5 being very willing. Using the same rating scale, they were then asked to rate how likely they would go off their medications in general, for a clinical reason, or as a benefit to science.

2.3. Statistical Analysis

Reports of medication use and willingness to withdraw from medications in general, for clinical purposes, or as a benefit to science will be based on the sample as a whole (n=90). Further statistical analysis will be based on the 31 participants who indicated they purposefully withdrew from dopaminergic medications for research or clinical purposes. In order to assess medication withdrawal symptoms in this sample, frequency, percentages, and two-sided proportion tests were used. To assess severity among individuals who experience off symptoms, percentage and average severity scores are reported. For individuals who indicated they would be willing withdraw off their PD medications again, percentages and severity scales are reported.

3. Results

While 90 participants completed the survey, only 31 indicated they purposefully went through withdrawal of their dopamine medications for clinical or research purposes. For demographic information, please see table 1. Most (91%) of participants were taking levodopa, while 31% were taking Ropinirole, 7% were taking Pramipexole, 3% were taking Rotigitine, and 13% were taking another dopaminergic PD medication (e.g. amantadine, entacapone). Regarding experiencing “off symptoms”, 52 out of 90, or 58%, selected “yes”, indicating they experience off symptoms.

Table 1.

Demographics^a

Demographics
Male (%)	20 (50)
Female (%)	20 (50)
Average Age (range)	65 (46–82)

^a.Table 1 summarizes the demographic information provided by those who reported it in the questionnaire.

Of the 31 participants who responded that they had purposefully withheld from dopaminergic medications for either a research or clinical purpose, all reported that they had experienced at least one off symptom, with tremor, walking and balance problems the most prevalent symptoms reported. Additional off symptoms, including sleep dysfunction, constipation, and tremor were noted as the most severe symptoms experienced by patients. The symptom count, percentage, and severity from being off the medication are listed in Table 2.

Table 2.

“Off” Symptoms Frequency and Severity^b

Symptom	% (number)	% Severity level 1	% Severity level 2	% Severity level 3	% Severity level 4	% Severity level 5	Average Score
Sleep Problems	38.7 (12)	16.7	8.3	16.7	25	33.3	3.5
Urinary Problems	19.4 (6)	0	33.3	66.7	0	0	2.7
Constipation Problems	16.1 (5)	0	20	20	40	20	3.6
Light Headedness	16.1 (5)	20	20	20	40	0	2.8
Speech Problems	16.1 (5)	20	40	20	20	0	2.4
Tremor	74.2 (23)	0	17.4	30.4	34.8	19.4	3.5
Saliva and Drooling Problems	9.7 (3)	0	0	100	0	0	3.0
Motor Control Problems (Rigidity and Dexterity)	48.4 (15)	6.7	13.3	60	20	0	2.9
Eating Problems (Chewing and Swallowing)	12.9 (4)	25	0	25	25	0	2.0
Walking and Balance Problems	61.3 (19)	5.3	26.3	26.3	26.3	15.8	3.2
Freezing Problems	29.0 (9)	0	33.3	22.2	22.2	22.2	3.0
Slowing Thinking or Focusing Problems	32.3 (10)	10	60	10	10 %	0	2.3
Vision Problems	3.2 (1)	0	0	0.03	0 %	0	3.0
Emotional Discomfort (Sadness, Apathy, etc…)	22.6 (7)	M	M	M	M	M	M
Other	6.5 (2)	M	M	M	M	M	M

^b.Table 2 summarizes the frequency and severity of “off” symptoms among participants who have purposefully gone off of their PD medications. The percentage of the severity is in terms of people who have experienced the symptom, so the denominator will be the frequency of participants indicating they had experienced the symptom. A severity of 1 was defined as “Low”, a severity of 3 was defined as “Moderate”, and a 5 was defined as “Severe”. M = missing as individuals who selected this symptom did not provide a rating of severity.

Participants also indicated if they would be willing to go off of their dopaminergic medications, and for what purpose they would be willing to do so (Table 3). Of those who had gone off previously, 13% indicated they would be “very willing” and only 10% indicated they would be “not at all willing” to go off their medications again. Of these participants (3/31), all were taking carbidopa-levodopa, 2 dopamine agonists, and 2 amantadine and entacapone. . Furthermore, of the three provided reasons to undergo medication withdrawal, “clinical” purposes were the most likely reason individuals would be willing to go off their medications.

Table 3.

Willingness to Go Off of PD Medication^c

Willingness to go off medication
	1	2	3	4	5	Average
*Again	9.7	19.4	38.7	19.4	12.9	3.1
General	14.4	5.6	10.0	24.4	10.0	2.0
Clinical	5.6	5.6	11.1	5.6	35.6	2.5
As a Benefit to Science	12.2	18.9	11.1	18.9	15.6	2.1

^c.Table 3 summarizes the percent of individuals willing to go off of their medications again, in general, for clinical reasons, and as a benefit to science.

^*“again” is calculated with the denominator as the number of individuals who indicated they had gone off of their medications previously (n=31). “General”, “Clinical”, and “As a Benefit to Science” was calculated as the denominator being the total dataset (n=90). 1 was listed as “not at all willing” while 5 was listed as “very willing”.

4. Discussion

Results for this study indicate that the main symptoms experienced by patients who undergo medication withdrawal are worsening tremor, difficulties with walking, and poor balance. These symptoms align well with common motor symptoms of PD, [12] and would be expected from a patient withdrawing from dopamine therapies. The most severely rated motor symptom was tremor, and the most severely rated non-motor symptoms were constipation and sleep dysfunction. Here, it is important to note that two of the most severely rated symptoms were non-motor. Furthermore, in this study we had a community-based cohort of patients and an overall 34% have come off dopaminergic medications for research or clinical purposes, indicating that medication withdrawal in PD is more commonplace in a community setting close to an academic medical center.

The finding of worse constipation in medication washout was not expected. Constipation is a well-described symptom of PD [13], and almost 50% of peripheral dopamine is produced in the gastrointestinal tract [14]. The pathophysiology of worsening constipation in response to dopaminergic medication withdrawal, however, does not appear to be a straightforward relationship. We suspect that in the off state, there is a reduced gastrointestinal motility, exacerbated by a lack of mobility due to off symptoms [10]. Also, changes to hydration and oral intake may also contribute to this symptom. When asking participants to undergo medication withdrawal, physicians should prepare patients who have a history of constipation for this possibility, and suggest increasing water and fiber intake to offset this symptom in advance.

Sleep-dysfunction has been well-characterized as a symptom of PD [15], however, it was unanticipated for this to be rated as a severe symptom of dopaminergic medication withdrawal, reported as a more severe symptom over other motor and non-motor symptoms. Greater sleep-fragmentation from being off medications [16], worse motor symptoms preventing sleep initiation, and the possibility that patients also stopped other medications often prescribed for sleep (e.g. melatonin or clonazepam) may contribute to this finding. We emphasize the importance of effective patient-physician communication and providing a list of which medications to withdrawal from can be useful.

One should note that, despite medication withdrawal being safe and well-tolerated for most patients, 10% of this cohort indicated they would not be willing to go through withdrawal again, emphasizing that a sizable proportion of participants found this to be a discomforting experience. While our sample was too small to discern withdrawal effects from certain dopamine therapies, previous studies suggest that certain dopamine treatments can result in specific medication washout symptoms. For instance, dopamine agonist withdrawal syndrome is a symptom related to dopamine agonists[17]. Future studies may further analyze the symptoms associated with withdrawal from particular dopaminergic medications. The limitations of this study include having a small cohort of participants and being limited to a geographical region, but we note that the community based recruitment strategy allows for us to sample a population in a select region.

5. Conclusions

The symptoms we have indicated here need to be listed clearly in the informed consent for studies involving medication withdrawal. Additionally, they can be useful to list in applications to institutional review boards as committees should take these symptoms into consideration when reviewing study protocols.

Key Points:

• Persons with Parkinson’s Disease often decide to undergo medication withdrawal. This study improves the informed consent by clearly listing symptoms participants should expect from when participating in dopamine medication withdrawal.

• Tremor, walking, and balance were the most common symptoms reported, however, tremor, sleep dysfunction, and constipation were rated as the most severe. 10% of participants indicated they would be unwilling to undergo dopamine medication withdrawal again.