html xmlns=”http://www.w3.org/1999/xhtml” xmlns:mml=”http://www.w3.org/1998/Math/MathML” xmlns:epub=”http://www.idpf.org/2007/ops”>
Chapter 10 Management of autonomic dysfunction in Parkinson’s disease
Introduction
Autonomic dysfunction can occur many years before a diagnosis of Parkinson’s disease (PD) is made [1], and symptoms are prevalent in patients with newly diagnosed, untreated PD [2]. Some studies reported that the most common nonmotor symptoms in PD are autonomic, and these correlate strongly with health-related quality of life [3]. Some of these symptoms, particularly persistent orthostatic hypotension, may also be a predictor of shorter survival [4]. Recognition of autonomic impairment is important, and physicians should actively investigate and treat these problems as an integral part of treating PD, since symptomatic treatment is frequently effective and may have an impact on the overall function and quality of life in PD (e.g. alleviating orthostatic hypotension could reduce the risk of falls).
Unlike the motor manifestations of PD, autonomic dysfunction is usually nonresponsive to dopaminergic medications. In fact, some autonomic problems, such as orthostatic hypotension, can be exacerbated by dopaminergic therapy. Physicians also need to bear in mind that drugs for autonomic problems may treat one symptom while potentially worsening another at the same time (e.g. anticholinergics for overactive bladder may aggravate constipation). Nonpharmacological measures should usually be administered in the first instance [5]. As for the management of other aspects of PD, an interdisciplinary approach can be of great benefit [6].
In this chapter, we review management strategies for the more common features of autonomic dysfunction. Less commonly recognized entities such as rhinorrhea or dry mouth will not be discussed. Details of epidemiology, assessment, pathophysiology and the impact of deep-brain stimulation surgery are also beyond the scope of this chapter and have been covered elsewhere [7–9]. It should be noted that in the recently published Movement Disorder Society Evidence-Based Medicine Review for the treatment of nonmotor symptoms in PD, which reviewed randomized controlled trials (RCTs) (i.e. level I studies), the only drugs for autonomic dysfunction receiving a designation of “efficacious” were botulinum toxin injections and glycopyrrolate (for sialorrhea) [10]. Macrogol and lubiprostone (for constipation) and domperidone (for anorexia, nausea and vomiting associated with dopaminergic therapy) were designated “likely efficacious” [10]. All other treatments for autonomic dysfunction in PD were designated as having “insufficient evidence,” indicating that most of the management recommendations discussed below are based on a lower level of evidence.
Orthostatic hypotension
Orthostatic hypotension occurs in up to 58% of PD patients (but may be symptomatic in only 20%) [6, 7]. Orthostatic hypotension is defined as a reduction in systolic blood pressure of ≥20mmHg or diastolic blood pressure ≥10mmHg within 3min of standing or head-up tilt to at least 60° on a tilt table (in some patients, however, 3min of postural challenge may be insufficiently sensitive) [11]. Although the characteristic symptoms are light-headedness or syncope when upright, patients are frequently asymptomatic [11], or symptoms may be nonspecific (e.g. blurred vision, nausea, vertigo, disequilibrium, leg buckling, falls, impaired cognition, fatigue/tiredness, weakness or pain [e.g. in the head, posterior cervical or shoulder region]) [12–15]. Tilt-table testing or 24h ambulatory blood pressure recording should be performed to confirm a diagnosis of suspected orthostatic hypotension when bedside sphygmomanometry is nondiagnostic [11, 16]. Nonneurogenic causes of orthostatic hypotension should also be considered, such as reduced cardiac output from aortic stenosis or cardiomyopathy [13, 17].
Orthostatic hypotension can be caused by antiparkinsonian medications (dopamine agonists, selegiline and amantadine more so than levodopa [l-DOPA]) [5, 7]. Antihypertensive (e.g. diuretics), antidepressant (e.g. tricyclics) and antipsychotic medications are other common causes of orthostatic hypotension [5, 18]. In one study, polypharmacy (defined as intake of five or more medicines) was an independent risk factor for orthostatic hypotension in PD patients, with an odds ratio of 3.6 [18]. Discontinuation, dose change or substitution of these drugs should be considered. Doses of antihypertensive medication, if needed, should be shifted to the afternoon or evening, as orthostatic hypotension is often worst in the morning. Patients should maintain a blood pressure diary to record measurements and note accompanying symptoms (e.g. sitting and standing up on awakening, before lunch and 1h after lunch, and supine before retiring) [13, 14]. In individuals with advanced disease and disabling orthostatic symptoms, a pragmatic approach may need to be adopted, for instance, aiming for systolic blood pressure of >80 and <180mmHg when supine, in conjunction with improvement of symptoms [14].
Nonpharmacological interventions
Nonpharmacological interventions should be the first line of therapy and are summarized in Table 10.1 [7, 13, 14, 19]. However, PD patients may also have difficulty adopting some of these measures (e.g. increasing fluid intake can worsen urinary symptoms), and in one study the overall compliance with nonpharmacological management was 78% over a 3-week period (patients were least compliant with compression stockings) [20].
Nonpharmacological management of orthostatic hypotension
| Ensure sufficient fluid intake (2–3 l/day). Intermittent water boluses (e.g. two glasses or 500 ml of water ingested rapidly) raises blood pressure within 5–15 min, for 1–2 h (e.g. this can be done in the morning, when orthostatic hypotension is usually worse) |
| Liberal addition of salt to the diet (up to 10 g/day) |
| Move from a lying to a standing position in gradual stages (e.g. sit on the side of the bed for 30 s before standing; wait for several seconds before starting to walk) |
| Avoid standing still for long periods |
| Avoid Valsalva maneuvers (straining). Constipation, urinary hesitancy or cough, if present, should be treated |
| Avoid large carbohydrate meals (instead, take small meals throughout the day) |
| Avoid alcohol consumption |
| Avoid exposure to hot environments (e.g. hot baths) |
| Avoid overly vigorous physical exercise (instead, exercise at a moderate level and/or in a recumbent or seated position) |
| Adopt physical countermaneuvers when symptoms occur (e.g. squatting, marching in place, toe raise [standing on tiptoes] or sitting with the legs crossed) |
| Wear tight waist-high stockings or a corset/abdominal binder |
| Raise the head of the bed while sleeping at night by 10–30°/10–30 cm |
Pharmacological interventions
Pharmacological interventions may be warranted if significant symptoms persist despite the above measures (Table 10.2). These are targeted at volume expansion and vasoconstriction. The drugs most commonly used are fludrocortisone and midodrine, either as monotherapy or combined. Droxidopa has recently received US Food and Drug Administration (FDA) approval for treatment of neurogenic orthostatic hypotension [21]. It is debatable whether patients with asymptomatic orthostatic hypotension should be treated pharmacologically [5]. Supine hypertension (see p. 97) can be caused or exacerbated by many of these agents.
Pharmacological agents commonly used to treat autonomic dysfunction in Parkinson’s disease
| Autonomic problem | Pharmacological agent, suggested doses and remarks |
|---|---|
| Orthostatic hypotension | Fludrocortisone (Florinef®): starting dose 0.05 or 0.1 mg, uptitrated by 0.05 mg weekly according to response to 0.3 mg daily (doses up to 1 mg daily have been used) Use cautiously in patients with heart disease (may precipitate heart failure) |
Midodrine (Amatine®, Gutron®): starting dose 2.5 mg bid or tid (before meals), and uptitrated according to response (e.g. by weekly increments of 2.5 mg) to 10 mg two to four times daily The last dose should be given no later than 4 h before recumbency/bedtime (e.g. at 5 or 6 pm) | |
| Domperidone (Motilium®): 10–20 mg orally tid (e.g. 30–60 min before dopamine agonist dosing) | |
| Droxidopa (Northera®): 100 mg orally tid, titrating in increments of 100 mg tid every 24–48 h (maximum dose, 600 mg tid) | |
| Gastroparesis | Domperidone (Motilium®): 10–20 mg orally 30 min before meals |
| Constipation | Supplemental fiber/bulk-forming laxative: e.g. Psyllium (Fybogel® or Metamucil®, one sachet bid with breakfast and dinner) |
Osmotic laxative: e.g. Macrogol/polyethylene glycol (PEG) (Macrogol 3350/Movicol®, one sachet every 3 days to two sachets/day, or Macrogol 4000/Forlax®, one to two sachets/day) Lactulose (Duphalac® 10 ml/day, up to 40 ml bid) | |
| Stimulant laxative: e.g. Bisacodyl (Dulcolax®) 5–15 mg at bedtime | |
| Prokinetic agent: e.g. Prucalopride (Resolor®) 2 or 4 mg daily | |
| Rectal laxatives: e.g. Dulcolax® 10 mg, or glycerin, one suppository as needed | |
| Sialorrhea | Glycopyrrolate (Robinul®, Cuvposa®): 1–2 mg tid |
| Sublingual atropine: 1% ophthalmic drops, one drop (0.5 mg) bid | |
| The following are usually used for other primary indications, but may reduce sialorrhea as a side effect: Trihexyphenidyl (Artane®, Apo-Trihex®) Amitriptyline (e.g. Endep®, Elavil®) Amantadine (Symmetrel®, PK Merz®) | |
Botulinum toxin injections Parotid gland (dose given for each side; each parotid injected in two sites): Botox® 15–50 units Dysport® 75–150 units Neurobloc®/Myobloc® 500–4000 units Submandibular gland (dose given for each side; injected in one site): Botox® 10–15 units Dysport® 25–80 units Neurobloc®/Myobloc® 250 units | |
| “Irritative” urinary symptoms (urgency, frequency, nocturia) | Oxybutynin: immediate release (Ditropan®) 2.5–5 mg two to four times daily, or extended release (Gelnique®) 5–30 mg once daily, or patch (Oxytrol®) one application twice a week |
| Tolterodine/detrusitol (Detrol®): immediate release 1 or 2 mg bid or tid, or extended release 2–4 mg once daily | |
| Trospium (Sanctura®, Spasmolyt®): 20 mg once daily or bid | |
| Solifenacin (Vesicare®): 5–10 mg once daily | |
| Erectile dysfunction | Sildenafil (Viagra®): starting dose 50 mg, which can be titrated up to 100 mg (or down to 25 mg) as required Usually taken 1 h before sexual activity, but in some PD patients the onset of action may be delayed up to 4 h; efficacy is optimal when taken on an empty stomach Orthostatic hypotension may occur, and sildenafil is contraindicated if blood pressure is below 90/50 mmHg, or in patients receiving nitrate therapy (co-administration can produce life-threatening hypotension) |
bid, Twice daily; tid, three times daily.
Fludrocortisone
Fludrocortisone (9-α-fluorohydrocortisone) is a synthetic mineralocorticoid. It increases plasma volume by promoting renal sodium retention and enhances the sensitivity of blood vessels to circulating catecholamines [13]. Fludrocortisone has a prolonged duration of action and the pressor effect requires several days to be apparent [13]. The starting dose is 0.05 or 0.1mg, which can be uptitrated by 0.05mg weekly according to response to 0.3mg daily (although doses up to 1mg daily have been used) [7, 13, 22]. This agent should be used cautiously in patients with heart disease because of the possibility of precipitating congestive heart failure. Peripheral edema, supine hypertension and headache are potential adverse effects; higher doses can cause hypokalemia, and potassium supplementation may be necessary.
Midodrine
Midodrine is a prodrug with an active metabolite, desglymidodrine, that is an α1-adrenoreceptor agonist that constricts arterioles and veins and increases total peripheral resistance. Midodrine should be started at 2.5mg two or three times daily (before meals), and uptitrated according to response (e.g. by weekly increments of 2.5mg) to 10mg two to four times daily [12, 13, 23]. Most patients respond best to 10mg [14]. The peak effect is at 1h, and the duration of action of a single dose is approximately 4h. Supine hypertension is a common side effect, but because midodrine has a short blood-pressure-raising effect, it can be withheld in the later part of the day (the last dose should be given no later than 4h before recumbency/bedtime, e.g. at 5 or 6 pm) [12, 13]. Other potential side effects are piloerection (goosebumps), itch, paresthesias (especially of the scalp; these symptoms are due to its α-adrenergic effects on the skin and skin appendages) and urinary retention [12, 23]. It should be noted that the multicenter double-blinded placebo-controlled randomized studies reported by Jankovic et al. [23] and Low et al. [12] evaluating midodrine for neurogenic orthostatic hypotension (n = 97 and 171 subjects, respectively) included a total of only 41 PD patients. In the study by Jankovic et al. [23], the mean increase in standing blood pressure with midodrine (10mg twice daily) was 22mmHg for systolic and 15mmHg for diastolic readings, and in the study by Low et al. [12] this was 19.5–22.4mmHg for systolic and 11.1–13.3mmHg for diastolic readings. These blood pressure changes were associated with improvement in orthostatic symptoms.
Domperidone
Domperidone is a peripheral dopamine D2 receptor antagonist that does not cross the blood–brain barrier. Its mechanism of action has been proposed to be via inhibition of presynaptic dopamine receptors on sympathetic nerve endings, thereby enhancing norepinephrine release [20]. It is often used to treat and prevent orthostatic hypotension induced by dopamine agonist therapy [20, 24, 25]. The dosage is 10–20mg 30–60min orally before dopamine agonist dosing. In one small double-blinded crossover RCT (n = 13 PD patients with symptomatic orthostasis in the drug treatment phase) comparing domperidone 10mg three times daily versus fludrocortisone 0.1mg daily, both treatments resulted in improvement of orthostatic symptoms and a trend toward reduced orthostatic drop on tilt-table testing (with domperidone having a greater effect than fludrocortisone for the latter endpoint) [20]. In this study, all patients were on levodopa therapy and 24% received dopamine agonist treatment, suggesting that the efficacy of domperidone is not limited to patients on dopamine agonists (or only to orthostatic hypotension in PD, since efficacy has also been reported in diabetic orthostatic hypotension). The efficacy of domperidone for orthostatic hypotension in PD requires further study [19]. This agent does not appear to induce supine hypertension [20].
Droxidopa
Droxidopa (l-threo-3,4,-dihydroxyphenylserine or l-threo-DOPS or l-DOPS), a norepinephrine precursor, was tested in randomized placebo-controlled phase 3 clinical trial in PD and other patients with neurogenic orthostatic hypotension and showed that oral administration of droxidopa three times daily (study NOH301) increased blood pressure and improved symptoms of postural light-headedness [21]. Supine systolic BP of >180mmHg was observed in 5% of droxidopa and 2.5% of placebo recipients, but no patients registered >200mmHg. Interestingly, in a parallel study, droxidopa recipients reported fewer total falls than placebo recipients (79 vs 192) (50% fewer falls per patient in the droxidopa group; P = 0.16) [26], and this independent effect is being directly examined in further studies.
Treatments not commonly used currently in PD patients
Pyridostigmine, by inhibiting acetylcholinesterase, enhances sympathetic ganglionic neurotransmission (as preganglionic sympathetic neurons are cholinergic), primarily in the upright position. This agent is started at a dose of 30mg twice daily, and increased gradually to the target dose of 60mg three times daily [14, 27]. Singer et al. [28] reported in an RCT (n = 58, but none of the subjects had PD) that pyridostigmine 60mg modestly reduced the fall in standing diastolic blood pressure (fall of 27.6 versus 34.0mmHg with placebo; P = 0.04), with an improvement in orthostatic symptoms, without aggravating supine hypertension [13, 14]. However, in a recently published RCT (31 patients with severe orthostatic hypotension, including six patients with PD), pyridostigmine 60mg did not increase standing diastolic blood pressure nor improve symptoms [29]. The difference observed between the two studies could be due to the greater severity of dysfunction in the cohort of Shibao et al. [29] (with a mean drop in standing systolic blood pressure of 67mmHg). Potential adverse effects include excessive salivation, abdominal colic and diarrhea [13].
Indomethacin is a prostaglandin synthetase inhibitor and its effect may be due to an inhibition of vasodilatory prostaglandins [17]. Indomethacin improved orthostatic hypotension in a small, double-blinded placebo-controlled RCT involving 12 PD subjects. In this study, oral indomethacin reduced the fall in mean blood pressure on standing from 34.8 to 17.3mmHg (while placebo had no noticeable effect), with a reduction in orthostatic symptoms. The dosage used is 25–50mg three times daily [17, 19]. However, gastrointestinal toxicity is a limiting factor.
Desmopressin (DDAVP®) is a vasopressin analog that acts on the collecting ducts of renal tubules to reduce nocturnal diuresis [7, 13, 15, 19]. The usual dosage is 5–40μg at bedtime by nasal spray [13]. However, in the only study involving patients with PD (n = 8, all with orthostatic hypotension), desmopressin produced no significant changes in blood pressure [30]. Water intoxication with hyponatremia is a potential side effect.
Erythropoietin increases the production of red blood cells and may also have may have direct or indirect effects on vascular walls [7, 13]. It was shown to increase upright blood pressure and improved postural symptoms in patients with neurogenic orthostatic hypotension; however, none of the published studies included patients with PD [13].
Octreotide is a somatostatin analog that inhibits the release of gastrointestinal peptides (some of which have vasodilatory properties) and causes splanchnic vasoconstriction [31]. This agent was shown in small studies to be effective for orthostatic and post-prandial hypotension, without causing supine hypertension; however, none of the published studies included PD patients [17, 31]. The method of administration (by daily subcutaneous injection) and expense limit more widespread use of this agent [17, 32].
Cardiac pacing to increase cardiac output by increasing heart rate was suggested in several case reports as a treatment for severe orthostatic hypotension, but in one RCT by Sahul et al. [33] involving six patients (two with PD) and tilt-table testing, dual chamber pacing at 90 and 110 beats/min did not produce any benefits.
Supine hypertension
Many patients with PD, particularly those with orthostatic hypotension, demonstrate nondipping (i.e. <10% blood pressure decrease during the night) or have supine hypertension, even before treatment of hypotension is initiated [16]. This raises concerns regarding hypertensive end-organ damage (such as cerebrovascular disease, cardiomyopathy, nephropathy and retinopathy), which has to be taken into consideration when treating orthostatic hypotension (although the incidence of these complications has not been studied prospectively in patients with neurogenic orthostatic hypotension) [13, 17]. During the day, patients should avoid the supine posture (e.g. should sit in a reclining chair with the feet on the floor), and at night the head of the bed should be raised 10–30° [13, 32]. Antihypotensive medications such as midodrine should be taken no later than 4h before recumbency/bedtime, e.g. at 5 or 6 pm. Alternative antihypotensive agents that do not aggravate supine hypertension, such as pyridostigmine or octreotide, may be considered [17, 27]. Short-acting antihypertensive agents in the evening (so that their effects have waned by the next morning) may be considered in patients with severe sustained supine hypertension. These include nifedipine (30mg), nitroglycerin transdermally (0.1–0.2mg/h) and clonidine 0.1mg [7, 13, 32]. Twenty-four-hour ambulatory blood pressure monitoring is recommended in this setting to evaluate therapeutic efficacy.
Gastroparesis
Gastroparesis is characterized by impaired gastric emptying in the absence of mechanical outlet obstruction, and can be associated with nausea, early satiety, bloating, heartburn, vomiting, abdominal pain (“dyspepsia” symptoms) and weight loss [6, 34, 35]. Gastroparesis occurs in untreated patients with early PD and is exacerbated by levodopa or dopamine agonist treatment [32, 36]. Gastroparesis can alter the bioavailability of levodopa (since levodopa must reach the small intestine to be absorbed) and contribute to the development of response fluctuations such as delayed “on” and even dose failures (due to gastric conversion of levodopa into dopamine, which prevents its absorption and transport to the brain) [6].
Patients should be encouraged to take small but frequent low-fat meals (fat empties from the stomach slowly) [32, 34, 35]. Dietitian referral may be beneficial to help correct malnutrition, if present. Domperidone is a peripheral dopamine D2 receptor antagonist that is relatively impermeable to the blood–brain barrier [32, 35, 36]. It antagonizes dopamine’s inhibitory effects on gastric motility and is the preferred prokinetic drug in PD [37, 38]. Domperidone also has antiemetic activity as a result of blockade of dopamine receptors in the chemoreceptor trigger zone, located outside the blood–brain barrier, and of gastric dopamine receptors [36]. The dosage is 10–20mg, 30min before meals as required. Some studies have used up to 120mg daily in PD patients without adverse effects [36, 37, 39], but recently concerns have been raised about potential cardiotoxicity (prolongation of the QT interval and ventricular arrhythmias), especially at higher dosages (>30mg daily), when combined with other QT-prolonging drugs (e.g. erythromycin, citalopram, escitalopram and tricyclic antidepressants), or in patients with cardiac disease [40]. Nevertheless, there is currently limited evidence relating drug-induced QT prolongation to morbidity and mortality specifically in PD patients [40]. Domperidone-induced worsening of parkinsonian symptoms is rare [36, 37, 39], but has been reported [37]. Metoclopramide, another D2 receptor antagonist, also improves gastric emptying but is contraindicated in PD because it crosses the blood–brain barrier and worsens parkinsonism [36].
Treatments not commonly used currently in PD patients
Erythromycin (50–250mg orally two or four times daily) is a potent prokinetic but has not been studied specifically in patients with PD (note that this antibiotic, like domperidone, also prolongs the QT interval) [32, 35].
The serotonergic 5-HT4 agonists mosapride and prucalopride accelerate gastric emptying and colonic transit (activation of 5-HT4 receptors on cholinergic nerve endings throughout the gastrointestinal tract enhances the release of acetylcholine from motor neurons, thereby stimulating gastrointestinal motility) [35, 41].
Mosapride prolonged “on” time in a small open-label study (n = 5 PD patients) by Asai et al. [42]; there are no studies as yet on prucalopride in PD patients. The nonselective 5-HT4 agonists cisapride and tegaserod have been withdrawn from the market because of potential cardiovascular side effects [41].
Botulinum toxin injections into the pyloric sphincter (to reduce the resistance of the pyloric sphincter, thereby facilitating gastric emptying) improved gastric emptying in two PD patients, but further study is needed [6, 35]. This technique is invasive and endoscopic expertise is needed.
Gastric electrical stimulation (with electrodes surgically inserted into the stomach by laparotomy or laparoscopy, and the stimulator placed subcutaneously in the abdomen) is an emerging treatment for refractory gastroparesis but has not been studied specifically in PD [6, 35].
Constipation
Constipation, generally defined as fewer than three bowel movements per week, can be due to slow colonic transit or outlet obstruction (see below). Up to 80% of PD patients have slowed colonic transit [43]. However, a colonoscopy or barium enema to exclude organic obstruction by neoplasm or inflammatory disease should be performed in patients with a recent alteration in bowel habit if there is unexplained weight loss (although this is also common in patients with PD), rectal bleeding, anemia or a positive family history of colorectal or ovarian cancer [44].
Treatment should begin with simple measures (increasing fiber and fluid intake, and physical activity) [34, 43–45]. An open-label study of a high-fiber diet in 19 PD patients (mean daily fiber intake of 28g/day) by Astarloa et al. [46] showed significant improvement of constipation severity in all patients (accompanied by improved levodopa bioavailability and motor function). It is thought that fiber increases stool bulk, distending the colon and promoting propulsive activity. Psyllium powder is obtained from the outer coat of the psyllium seed from the plant Plantago ovata. A small RCT by Ashraf et al. [47] (n = 7 PD patients) (three received 5.1g of psyllium twice daily vs four receiving placebo) showed that stool frequency increased significantly after 8 weeks of treatment (on average, three additional bowel movements per week) [43]. One study in non-PD subjects found psyllium to be superior to different pharmacological agents such as lactulose in the treatment of constipation, with a lower incidence of adverse events [48]. Another study of frail elderly patients by Sturtzel et al. [49] reported that increased dietary fiber allowed discontinuation of laxatives in a majority of patients and, in contrast to laxative treatment, was not associated with weight loss. Bloating, abdominal pain and flatulence are potential side effects of increased fiber [45]. Regardless of the source (dietary vs supplemental), combining fiber with adequate fluid intake (e.g. 1.5–2 l/day) is important [45]. Medications that can exacerbate constipation should be replaced if possible (e.g. opioids, anticholinergics, tricyclic antidepressants, antihistamines, calcium-channel antagonists, diuretics and nonsteroidal anti-inflammatory drugs) [44, 45]. An association between dopaminergic medications and constipation remains debated [44, 50].
Osmotic laxatives
These agents produce an osmotic gradient and retain fluid in the colonic lumen, leading to softer stools and improved propulsion. A small open-label study of macrogol/polyethylene glycol (PEG) 3350 (PEG with a molecular mass of 3350) plus electrolytes (Movicol®) in severely constipated patients by Eichhorn et al. [51] (n = 8 PD and 2 multiple-system atrophy [MSA]patients) found this agent to be effective in improving stool frequency and ease of defecation in all patients studied (leading to the withdrawal of all concomitant laxatives). The maintenance dose ranged from two sachets daily to one sachet every 3 days. A larger RCT by Zangaglia et al. [52] (29 PD patients received PEG 7.3g plus electrolytes, one to three sachets daily; 28 received placebo) provided level I evidence that PEG is effective and well-tolerated in the treatment of constipation in PD patients. One systematic review of drug trials for constipation concluded that PEG is modestly more effective than lactulose [48]. Adverse effects are few, but nausea, vomiting, diarrhea, flatulence and abdominal pain can occur [45, 48, 52]. Lactulose is commonly used, but there are no studies in patients with PD. Nausea, bloating, flatulence and loose stools are potential side effects [48]. Although lactulose is a nonabsorbable disaccharide, lactulose syrup may contain small amounts of absorbable sugars, and has rarely been reported to worsen glycemic control in diabetic patients, as reported by Kirkman et al. [53].
Stimulant/“irritant” laxatives
These agents simulate the colonic myenteric plexus. Bisacodyl and senna are commonly used examples. One study found these laxatives to be less effective than lactulose [48]. Tolerance may develop but appears to be uncommon [54]. The suggestion that chronic use of stimulant laxatives can damage intestinal smooth muscle or the myenteric plexus and cause “cathartic colon” is poorly documented. The prevailing opinion, supported by more recent investigations, is that stimulant laxatives used at the recommended doses are unlikely to be harmful to the colon [45, 48, 54].
Prokinetic agents
5-HT4 agonists accelerate colonic transit by facilitating acetylcholine release from enteric cholinergic neurons. The nonselective 5-HT4 agonists cisapride and tegaserod have been withdrawn from the market because of potential cardiovascular side effects [41]. A small open-label study by Liu et al. [55] (n = 7 patients with PD, 7 with MSA) showed that mosapride 15mg daily augmented lower gastrointestinal tract motility with improvement in bowel frequency and difficult defecation. Prucalopride is a highly selective 5-HT4 receptor agonist and has not been reported to be associated with cardiovascular side effects [41]. Camilleri et al. [56] randomized 620 subjects with severe idiopathic constipation to receive prucalopride 2mg, prucalopride 4mg or placebo once daily over 12 weeks. The proportion of patients with three or more spontaneous, complete bowel movements per week was higher in the prucalopride groups (2mg, 30.9%; 4mg, 28.4%) compared with placebo (12%, P < 0.01). Headache, nausea, abdominal pain and diarrhea are potential side effects [56]. Prucalopride has not been studied specifically in PD patients.
Stool softeners
The evidence for the effectiveness of these agents is weak [45]. Docusate has modest efficacy only [48]. Liquid paraffin has been associated with reduced absorption of fat-soluble vitamins, and lipoid pneumonia after aspiration [45].
Rectal laxatives
Glycerin (or glycerol) and bisacodyl suppositories are commonly used, with an onset of action occurring within minutes [45]. Anorectal irritation is a potential side effect.
Treatments not commonly used currently in PD patients
Probiotics have been suggested to have favorable effects on gastrointestinal function by suppressing the growth of pathogenic bacteria (which may contribute to gastrointestinal dysmotility), and they have become popular in treating a spectrum of gastrointestinal disorders. Cassani et al. [57] studied the use of Lactobacillus casei strain Shirota daily for 5 weeks in PD patients (n = 40) and found improvement in stool consistency and symptoms such as bloating, abdominal pain and the sensation of incomplete emptying.
Lubiprostone is a chloride channel activator that enhances fluid secretion into the intestinal lumen and intestinal motility, without altering serum concentrations of sodium and potassium [58]. Systemic absorption of the drug is negligible. In a 4-week double-blinded study, PD patients with significant constipation (n = 54) were randomly assigned to lubiprostone (uptitrated to 24μg twice daily) or placebo [58]. A marked or very marked clinical global improvement was reported by 64% of subjects receiving lubiprostone versus 19% of the placebo group. The constipation rating scale, visual analog scale for change in constipation and number of daily stools by diary also improved significantly with lubiprostone. Adverse events were mild, most commonly intermittent loose stools, which did not result in study withdrawals. The agent was otherwise very well tolerated.
Sandyk et al. [59] reported that colchicine, frequently used for the treatment of gout, was effective in treating refractory constipation in three PD patients without adverse effects (0.3–0.6mg). The mechanism of action is unclear, but the efficacy of colchicine (0.6mg three times daily) was subsequently shown in a small 4-week, placebo-controlled RCT involving 16 patients with refractory idiopathic chronic constipation (0.6mg three times daily) [45]. There was a mild increase in abdominal pain scores during treatment with colchicine, but this decreased by the fourth week of therapy.
An anecdotal report by Sadjadpour suggested that pyridostigmine, a cholinesterase inhibitor used in the treatment of myasthenia gravis, was effective in PD patients with refractory constipation (60mg one to three times daily).
A small open-label study by Sakakibara et al. [60] (n = 6 PD patients, 4 MSA patients) suggested that Dai-Kenchu-To (a dietary herb extract) improved bowel movement frequency and difficult defecation, with no adverse effects. Objective measures of lower gastrointestinal tract motility also improved.
The efficacy of neutrophin-3 injections was reported by Pfeiffer et al. [61], but this agent has been abandoned.
In one study of 16 PD patients, magnetic stimulation (with the coil placed over the T9 and L3 spinal processes for 20min twice daily, over 3 weeks) significantly improved colonic transit time and symptoms including frequency of bowel movement and stool consistency [62]. Treatment also improved pelvic floor descent and anorectal angle during defecation. The beneficial effects persisted at the 3-month follow-up [62].
Defecatory dysfunction
In one study, 13% of PD patients with chronic constipation had isolated or prominent outlet-type constipation [63]. This is caused by a failure of relaxation of the puborectalis muscles and the external anal sphincter during defecation [44]. Symptoms include anal pain with defecation, excessive straining and incomplete evacuation [64]. Anorectal manometry and fluoroscopic defecography are useful for evaluating anorectal dysfunction but may not always be readily available [64]. Treatment is often very challenging.
Albanese et al. [63] showed in a prospective study of ten PD patients that botulinum toxin injections into the puborectalis muscles resulted in objective improvements (reduced anorectal tone and increased anorectal angle, during straining); however, the effect on patients’ symptoms was not reported. In another open-label study using a similar design (n = 18 PD patients, injected with 100 units of Botox® into the puborectalis under transrectal ultrasound guidance) [64], symptomatic improvement was noted at the 1- and 2-month follow-ups in eight (44%) and ten (56%) patients, respectively, accompanied by objective improvements similar to those reported by Albanese et al. [63]. The eight patients who did not respond to the initial treatment were retreated with 200 units of Botox®, resulting in symptomatic and objective improvements in four of them. No significant side effects were reported. There are anecdotal reports in a small number of PD patients that intermittent subcutaneous apomorphine injections can ameliorate symptoms of outlet constipation, with objective improvements documented by defecography and anorectal manometry [65, 66]. Biofeedback has been reported to benefit many patients with obstructed defecation, but no studies have been conducted in PD patients.
Sialorrhea
Sialorrhea (excessive build-up of saliva in the mouth) and drooling (involuntary spillage of saliva from the mouth) in PD are mainly due to dysphagia with decreased swallowing frequency or less efficient swallowing, and are often compounded by a tendency to keep the mouth open (facial hypomimia) and stooped posture. Although common in advanced PD, one recent study reported a high prevalence of increased saliva or drooling in patients with newly diagnosed and untreated PD (42 vs 6% of nonparkinsonian controls) [2]. Some drugs used frequently in advanced PD, such as clozapine and cholinesterase inhibitors, can increase salivary gland excretion. Sialorrhea can also be caused by factors other than PD (e.g. badly fitting dentures). Many patients experience only drooling on the pillow at night; however, in some patients, drooling causes social embarrassment and isolation, skin maceration, and speech and feeding may be disturbed.
Chewing gum or sucking on hard candy (preferably sugarless) may provide temporary improvement by serving as a cue to swallow more frequently [6]. In an acute experimental study, gum chewing increased swallow frequency and decreased the interval between swallows [67]. This may be an effective self-managed approach for saliva management without reducing salivary flow. In this study, patients performed gum chewing for only 5min; therefore, the long-term efficacy of this approach requires further study. Behavior modification approaches, e.g. regular reminders to consciously swallow saliva using a beep-emitting brooch, may be effective in motivated patients but has been studied in only a small number of PD subjects (n = 6).
Better control of parkinsonian motor symptoms, including motor fluctuations (sialorrhea is more prominent during “off” periods) can improve sialorrhea; however, the response is usually only partial [68].
Salivation is mediated primarily through parasympathetic (cholinergic) innervation of the salivary glands, and anticholinergic agents are the first-line pharmacological therapy for sialorrhea [68]. Trihexyphenidyl is an anticholinergic commonly prescribed for tremor in PD. Dryness of the mouth is a very common side effect, but there has been no formal study of this agent as a treatment for sialorrhea in PD. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug that does not cross the blood–brain barrier in considerable amounts and therefore exhibits minimal central side effects. One double-blinded RCT (n = 23 PD patients) showed that 39% of patients taking oral glycopyrrolate (1mg three times daily) had a clinically relevant improvement (≥30% in mean sialorrhea score) versus only one patient (4%) in the placebo group (P = 0.021) [69]. The mean improvement in sialorrhea score with glycopyrrolate compared with placebo was 0.8 points (on a 9-point scale, P = 0.011). There were no significant adverse events with glycopyrrolate. The maximum recommended dose is 8mg/day [69]. Sublingual atropine (1% ophthalmic drops; one drop [0.5mg] twice daily) was effective in a small open-label study (n = 6 PD patients) by Hyson et al. [70], both in terms of self-reported drooling severity and objectively measured saliva production [56]. Although two patients experienced worsening of hallucinations in this study, this treatment appears to be relatively safe in clinical practice [71]. Sublingual application of ipratropium bromide spray (an anticholinergic that does not cross the blood–brain barrier; one to two sprays four times/day as needed [21μg of ipratropium bromide per metered dose spray]) was evaluated by Thomsen et al. [72] in a double-blinded RCT (n = 15 patients completing the study). Treatment had no effect on the weight of saliva produced (the primary outcome measure), but there was a mild effect on subjective measures of sialorrhea. The treatment was well tolerated without any anticholinergic side effects. Amitriptyline (e.g. to treat depression, insomnia or pain) or amantadine (most often used for levodopa-induced dyskinesias) also have anticholinergic properties and may have the useful side effect of reducing sialorrhea [68].
Botulinum toxin blocks acetylcholine release at the cholinergic neurosecretory junction of the salivary glands, thereby reducing saliva production. Ninety percent of saliva production originates (in equal amounts) from the parotid and submandibular glands (the other salivary glands contributing the remaining 10%); these glands can be injected (bilaterally) using anatomical landmarks [68, 73]. Some authors reported superior efficacy with combined injections (of both the parotid and submandibular glands) or with ultrasound guidance, but there is no consensus on this issue [68]. Botulinum toxin type B may have a preferential action on autonomic neurons and could potentially be more effective for sialorrhea. However, one pilot study by Guidubaldi et al. [74] found no significant difference in the mean duration of benefit for botulinum toxin A (Dysport® 250 units) and botulinum toxin B (Neurobloc® 2500 units); this study was limited by a small sample size (n = 7 PD patients only completing the study). There is a risk of transiently exacerbating dysphagia and chewing difficulties, due to toxin diffusion into the pharyngeal, masseter and temporalis muscles. A large, multicenter, placebo-controlled trial with botulinum toxin type B (Myobloc® 2500 units) is ongoing in the USA (National Institutes of Health clinical trials registry [clinicaltrials.gov] NCT01994109).
Treatments not commonly used currently in PD patients
Tropicamide (slowly-dissolving, intraoral thin film) was evaluated in a pilot study (n = 19 PD patients) [5]. The primary efficacy outcome was negative, but some antisialorrhea effects were observed, without adverse events; a larger study of this agent is ongoing (clinicaltrials.gov identifier NCT01844648).
Other treatments that have been used for sialorrhea include clonidine, modafanil, and β-blockers, but there is only limited evidence currently to support their use in PD patients [5, 68].
Radiotherapy to the parotid and submandibular glands (dose of 12 gray) was shown in one study to be effective and safe in patients with parkinsonism (n = 28, 22 with PD) [75]. A treatment effect was seen within days in most patients, and lasted more than a year (with some patients still experiencing considerable improvement of drooling at the 5-year follow-up). One or more persistent adverse effects occurred in one-third of patients, including loss of taste, dry mouth and increased viscosity of saliva. Nevertheless, patients reported significantly improved quality of life, and clinical global impression scores at the final follow-up showed that 80% of patients were either satisfied or very satisfied. There can be up to a 40-fold increased risk of developing salivary gland tumors many years after radiotherapy, but patients with PD and severe drooling generally have advanced disease (and often also advanced age) with a limited life expectancy, which probably alters the risk:benefit ratio [68, 75].
Surgical treatments (e.g. submandibular duct relocation or neurectomy [sectioning the chorda tympani nerves]) are invasive and there are no published reports on these procedures in PD patients [68].
Related posts:
Oral dopamine agonists in the management of Parkinson’s disease
Management of disease-related behavioral disturbances in Parkinson’s disease
Emerging targets and other stimulation-related procedures in the management of Parkinson’s disease
Functional imaging markers as outcome measures in clinical trials for Parkinson’s disease
Lessons and challenges of trials for other nonmotor complications of Parkinson’s disease
Lessons and challenges of trials involving ancillary therapies for the management of Parkinson’s disease
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
