Linaclotide and Prucalopride for Management of Constipation in Patients with Parkinsonism

Constipation is a common condition in patients with neurodegenerative parkinsonism, including Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP).1, 2 Multiple mechanisms of pathogenesis have been proposed, such as accumulation of α‐synuclein in the gastrointestinal system, dysautonomia, and medication side effects.1 Chronic constipation negatively impacts quality of life and decreases the absorption of antiparkinsonian drugs.3 Conventional management, including adequate fiber and fluid intake and over‐the‐counter laxatives are generally ineffective.4

Linaclotide (guanylate cyclase C agonist) and prucalopride (selective 5‐HT₄ receptor agonist) are emerging effective drugs for the management of chronic idiopathic constipation (CIC).5, 6 To date, these drugs have not been tested in controlled trials in patients with parkinsonism and therefore their efficacy is unknown in this population.

With the approval of a local ethics committee, we searched our patient database for patients diagnosed with neurodegenerative parkinsonism and constipation who had received linaclotide or prucalopride. Constipation was defined by Rome III criteria and one of the symptoms must include fewer than three bowel movements (BM) per week.7 Patients who had undergone previous small or large bowel surgery were excluded, except for percutaneous endoscopic gastrostomy placement. Demographics, treatment characteristics, BM frequency, and side effects were captured from medical records. Objective improvement was defined as post‐treatment BM frequency of three or more per week. Subjective improvement was assessed by clinical or telephone interview, and the patient's satisfaction level was defined as either “agreement” or “strong agreement” with the studied drug treating the constipation symptoms. The results were captured in a five‐point Likert scale. Continuous variables were expressed as median (range) or mean ± SD. Wilcoxon signed‐rank or Fisher's exact test were used as appropriate.

Among the 30 patients identified, 13 received linaclotide only, 11 received prucalopride only, and six individuals used both drugs, but not simultaneously (Table 1). Mean treatment duration with linaclotide (145 or 290 μg) was 10 ± 8 months and with prucalopride (1–4 mg) was 19 ± 18 months. The number of BM per week significantly increased after treatment with either linaclotide (1.5[1–3] vs. 3[2–7]; P < 0.01) or prucalopride (1[1–2] vs. 5[1–7]; P < 0.05). In patients who did not respond to prucalopride, 67% reported improvement after switching to linaclotide. Subjective satisfaction for treating their constipation symptoms was greater for patients who received linaclotide than prucalopride (69% vs. 47%). Proportion of objective and subjective improvement was not significantly different between PD and non‐PD patients (Table 1). There was no difference in the use of over‐the‐counter laxative before starting the treatment in both groups. Side effects were only reported in one patient who discontinued prucalopride due to headache.

Table 1.

Results of Treatment With Linaclotide and Prucalopride

Demographics
24 PD – duration: 13 ± 7 years; UPDRS range: 7–60 6 non‐PD parkinsonism: 2 MSA‐ duration: 4 ± 1 years; 4 PSP – duration: 7 ± 5 years Total: 30 patients (age 67 ± 9 years; 50% female) 6 patients used both medications (linaclotide and prucalopride)*

	Linaclotide (n = 19)			Prucalopride (n = 17)
Treatment duration (months)		10 ± 8			19 ± 18
Dosage		145 μg: n = 11 290 μg: n = 4 Missing data: n = 4			1 mg: n = 4 2 mg: n = 8 4 mg: n = 2 Missing data: n = 3
Patients refractory to over‐the‐counter laxatives before starting linaclotide or prucalopride		70%			89%
	All patients (n = 19)	PD (n = 16)	Non‐PD (n = 3)	All patients (n = 17)	PD (n = 13):	Non‐PD (n = 4)
Bowel movement frequency (per week)
Pre‐treatment	1.5 (1–3; n = 10)	1 (1–3; n = 8)	2 (2–2; n = 2)	1 (1–2; n = 11)	1 (1–2; n = 9)	1.5 (1–2; n = 2)
Post‐treatment	3 (2–7; n = 11)**	3 (2–7; n = 9)***	7 (7–7; n = 2)	5 (1–7; n = 9)***	5 (1–7; n = 7)**	7 (7–7; n = 2)
Objective improvement
Yes	n = 8 (42%)	n = 6	n = 2	n = 8 (47%)	n = 6	n = 2
No	n = 3 (16%)	n = 3	n = 0	n = 1 (6%)	n = 1	n = 0
Missing data	n = 8 (42%)	n = 7	n = 1	n = 8 (47%)	n = 6	n = 2
Subjective improvement
Yes	n = 13 (69%)	n = 10	n = 3	n = 8 (47%)	n = 6	n = 2
No	n = 4 (21%)	n = 4	n = 0	n = 6 (35%)	n = 5	n = 1
Missing data	n = 2 (10%)	n = 2	n = 0	n = 3 (18%)	n = 2	n = 1

Missing data: information not documented in medical records and patient could not answer the telephone interview. One patient with SPG11 (Spastic Paraplegia 11) was initially identified but not included in the final analysis.

*Six patients in the prucalopride group were switched to linaclotide: 5 patients because of lack of efficacy and 1 due to significant headache. Among these 6 patients, 4 (67%) reported improvement with linaclotide, 1 reported no improvement and in 1 patient, data was not available. Data on bowel movement frequency are median (range).

**P < 0.01 and ***P < 0.05 (Wilcoxon signed‐rank test). Objective and subjective improvement were not significantly different between PD and non‐PD patients (P > 0.05, Fisher's exact test).

Abbreviations: MSA, Multiple System Atrophy; PD, Parkinson's disease; PSP, Progressive Supranuclear Palsy (MSA, PD, and PSP based on clinical criteria); UPDRS, Unified Parkinson's disease rating scale.

Linaclotide and prucalopride are effective, safe and well tolerated in patients with CIC.6 Both drugs improved the BM frequency in our patients with neurodegenerative parkinsonism who had failed initial constipation management. Interestingly, a higher proportion of patients reported subjective satisfaction in controlling their constipation symptoms with the use of linaclotide as compared to prucalopride. Although recall bias and missing data in this retrospective study limit our ability to make a definite recommendation, our preliminary results suggest potential benefits of these medications, and thus we encourage further well‐designed controlled trials to advance the standard of care of constipation in patients with parkinsonism.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

M.E.F: 1B, 1C, 2A, 2B, 2C, 3A, 3B

A.A.: 1A, 1B, 1C, 3B

A.E.L.: 1A, 1B, 1C, 2C, 3B

L.W.C.L.: 1A, 1B, 1C, 2C, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The authors declare no conflicts of interest.

Financial disclosures from previous 12 months: Maria Eliza Freitas, none; Abdullah Alqaraawi, none; Anthony E. Lang, none; Louis WC Liu, speaker at: AbbVie, Allergan Canada, Covidien/Medtronic; Advisory: AbbVie, Allergan Canada, Lupin Pharma Canada; Consultant: AbbVie, Allergan Canada, Covidien/Medtronic.