Digestive Disorders in Parkinson’s Disease

Parkinson’s disease (PD) affects nerves throughout the gastrointestinal (GI) tract and can cause profound gastrointestinal (GI) dysfunction leading to poor outcomes for patients.

Common gastrointestinal disorders in patients with PD include gastroparesis (GP), constipation, and small intestine bacterial overgrowth syndrome (SIBO).

In particular, GP is difficult to treat due to the limited options available and precautions, contraindications and adverse effects associated with approved treatments. Additionally, some commonly used medications can worsen pre-existing PD.

Our review will focus on treatment options for GP and SIBO with motilin agonists, dopamine receptor antagonists, ghrelin agonists, muscarinic agonists, 5-HT4 receptor agonists, antibiotics, probiotics, and herbal formulation such as iberogast.

Constipation occurs in the majority of PD patients, and fortunately, many treatments are now available. Our review is based on original documents or reviews selected from the PUBMED search and Cochrane reviews.

Constipation is defined as difficulty defecating or having fewer than three bowel movements per week. It is associated with straining, incomplete evacuation, and hard stools. The most recent consensus for the diagnosis of constipation is based on the ROME III criteria.

The prevalence of constipation in PD varies from 52 to 65%. According to data from the National Emergency Department Sample, emergency room visits for constipation have increased by 41.5% in the US between 2006 and 2011. These emergency room visits translated into a cost of $1.6 billion in 2011.

Constipation rates are higher in PD patients than in the general population (odds ratio [OR] = 2.48; 95% confidence interval [CI]: 1.49 - 4.11, p = 0.0005) [17]. In some PD patients, constipation could precede the development of motor PD symptoms by up to two decades.

Although the diagnosis of constipation is clinical , to rule out neuromuscular dysfunction of the rectum or slow transit constipation, additional testing is often performed using anorectal manometry, wireless motility capsule, or Sitz marker studies used as colonic transit tests.

The latter two methods have been used to document slow-transit constipation where colonic dysmotility may exist, while anorectal manometry is performed in patients with a neurological cause of constipation, such as in PD or dyssynergic defecation, which is also seen. often in patients with PD.

Gastroparesis (GP) is a chronic gastrointestinal condition affecting the stomach and is defined as delayed gastric emptying in the absence of mechanical obstruction. Symptoms of GP include nausea, vomiting, early satiety, fullness, bloating, and upper abdominal pain. Common causes of gastroparesis are idiopathic, some of which may be due to previous viral infection or bacterial infection (called post-infectious gastroparesis or dyspepsia), diabetes, and post-gastric surgery.

The standard diagnostic test to rule out gastric motor dysfunction in GP is gastric emptying scan. An abnormal test requires that more than 10% of the contents of a radiolabeled meal be retained in the stomach after 4 h. Additional diagnostic studies are available, such as breath testing, recently approved by the FDA in the US, and wireless mobility capsule (Smartpill) testing. These studies can be performed in the outpatient setting and eliminate the risk of radiation exposure.

The exact prevalence of GP in patients with PD is unknown, but delayed emptying is reported in 70% to 100% of patients, although not all patients are symptomatic. PD itself represents 7.5% of GP cases and is a common cause of this dysfunction in all neurological diseases.

Gastroparesis has been shown to contribute to fluctuations in response to levadopa therapy, used to treat PD. These fluctuations may affect the amount of bioavailable levadopa concentrations leading to fluctuations in motor symptoms or inconsistent response to medications. Therefore, treating delayed gastric emptying may improve these fluctuations and therefore your motor symptoms.

SIBO is associated with increased numbers of bacteria in the small intestine. Often, this overgrowth reflects the bacteria found in the colon, which is commonly composed of anaerobic methane-producing bacteria.

As the current standard, SIBO is diagnosed by endoscopic jejunal aspiration by identification of >105 colony-forming units/ml of organisms or breath tests with identification of hydrogen- or methane-producing bacteria.

Symptoms associated with SIBO include not only bloating, abdominal pain, weight loss, diarrhea, and occasionally constipation and bloating. The exact prevalence of SIBO in the general population is unknown and differs depending on the diagnostic tool used.

Lifestyle modifications, such as increasing fiber, water, and physical activity intake, are frequently recommended. These lifestyle modifications may be beneficial in the general population, but it is unknown whether they will be effective in patients with PD. Before selecting a treatment option, secondary causes of constipation should be evaluated and treated.

The most common secondary causes of constipation are mechanical obstruction, endocrine or metabolic disorders, and medications such as narcotics.

There are multiple approaches to treating constipation in PD, including over-the-counter (OTC) medications and prescription medications, such as bisacodyl, milk of magnesia, lactulose, and senna products. Although there are multiple medications available to treat constipation, our review will focus only on therapies that have been studied in patients with PD and constipation.

> Bulk laxatives

First-line options for the treatment of constipation in the general population are bulk-forming laxatives that are available without a prescription and contain psyllium, polycarbophil, wheat dextrin, methylcellulose, and soluble dietary fiber. Fiber supplements work by increasing fluid absorption in the gastrointestinal tract, which promotes peristalsis, increases stool volume, softness, and intraluminal pressure.

> Osmotic laxatives - PEG

The osmotic laxative PEG, also available as an OTC product, leads to water retention in the colon, which increases stool frequency. PEG is used as a first-line agent in the treatment of constipation in the general population. PEG has also been studied in patients with PD and constipation.

> Chloride channel activator - lubiprostone

Lubiprostone is an FDA-approved medication for the treatment of chronic constipation and irritable bowel syndrome (IBS). It activates chloride channels in the intestinal lumen and increases intestinal fluid secretion, which improves motility. It has also been shown to improve symptoms of bloating, constipation, pain, and straining. Lubiprostone has also been used in patients with PD and constipation.

> Guanylate cyclase c receptor peptide agonist - linaclotide

Linaclotide is another FDA-approved medication for the treatment of chronic constipation and IBS with constipation ; however, it has not been studied in patients with PD. This newer drug promotes the generation of cyclic guanosine monophosphate that secretes chloride and bicarbonate into the intestinal lumen, increasing luminal fluid secretion and accelerating intestinal transit.

In two combined double-blind RCTs evaluating 1276 patients, linaclotide 145 or 290 mcg/day administered for 12 weeks resulted in more complete spontaneous bowel movements (SBM) per week compared to placebo.

Diarrhea was the most common adverse event observed with linaclotide use compared to placebo (14.2 - 16.0% with linaclotide versus 4.7% with placebo). Although linaclotide has not been tested in PD, it has been shown to be effective in treating constipation and may be used in PD if other options have not been successful. Additionally, linaclotide also directly inhibits pain by acting on C fibers in the colon and may be beneficial in patients with abdominal pain.

> Serotonin 5-HT4 receptor agonists - mosapride and prucalopride

The gastrointestinal tract houses 95% of the body’s serotonin and activation of these receptors stimulates the peristaltic reflex, improves intestinal secretions and reduces visceral hypersensitivity, all of which can help treat constipation.

Mosapride and prucalopride are both 5-HT4 receptor agonists used to treat chronic constipation; however, they are not yet approved by the FDA. Mosapride is available in Asia and South America and prucalopride is available in Canada and Europe.

> IBAT: elobixibat

Elobixibat is a novel new medication used to treat constipation that works as a modulator of the ileal sodium/bile acid transporter (IBAT). It is a minimally absorbable IBAT that partially inhibits the ileal bile acid transporter, leading to increased fluid secretion and motility by increased bile acid delivery to the colon.

Overall, therapeutic options for GP are limited, and the lack of existing well-designed trials is also evident in the PD literature. In this review, we discuss the current evidence supporting the treatment of GP in PD and will cover FDA-approved (only one), unapproved, prescription-based, OTC, and herbal medications that treat delayed gastric emptying in GP.

Identification of GP is important in PD as it can lead to fluctuations in levodopa levels and a delay in levodopa peaks. Appropriate GP treatment can help address delays in the onset of medications used to treat the motor symptoms of PD]. As there are no completely safe and effective standard treatments to treat GP in PD, patient-specific considerations must be taken into account.

Additionally, the risks, many of which are neurological, and their benefits must be examined. The first management consideration in patients with GP includes dietary recommendations that can help reduce symptoms and improve nutritional deficiencies. These include eating small, frequent meals, a low-fiber and low-fat diet with predominantly liquids, and protein supplements.

Consideration should be given to identifying and correcting nutritional deficiencies, including zinc, iron, selenium, folic acid, B12, vitamin C, and vitamins A, D, K, and E. For more severe GP, a liquid diet, a jejunal feeding tube, Gastric electrical stimulation, total parenteral nutrition or other approaches may be necessary.

In addition to improving gastric lag in GP, ​​the goal of GP management also includes control of symptoms that may or may not follow improved gastric emptying. Of these symptoms, nausea and vomiting are the most debilitating, and various antiemetics can be used to treat these symptoms in PD patients.

Some commonly used antiemetics include, but are not limited to, promethazine, chlorpromazine, prochlorperazine, and metoclopramide. The latter medication may precipitate acute parkinsonism or worsen pre-existing PD as it is a dopamine receptor antagonist and crosses the blood-brain barrier and should therefore be avoided in patients with PD.

> Peripheral dopaminergic blockers: domperidone and metoclopramide.

Blocking peripheral dopamine receptors present in the upper gastrointestinal tract ultimately improves motility and accelerates gastric emptying, relieving nausea, vomiting, and bloating caused by GP.

The two most commonly used agents are metoclopramide and domperidone . Although domperidone is not approved by the FDA and is not available in the United States, it is available as a prescription around the world and even over the counter in many other countries.

An important difference between domperidone and metoclopramide (the only drug approved by the FDA for use in GP in the US) is that metoclopramide readily crosses the blood-brain barrier and has central dopaminergic activity. Since PD is worsened by blocking CNS dopamine, metoclopramide is contraindicated in patients with PD .

> Macrolides: azithromycin and erythromycin.

Erythromycin and azithromycin are antibiotics and motilin agonists that increase gastric antral contractions and have been shown to improve gastric emptying in patients with gastroparesis. Erythromycin is the most potent prokinetic available and azithromycin improves gastric and small intestinal motility.

Although current evidence supports use of both medications as prokinetics, they are not approved by the FDA for the treatment of GP. Furthermore, evidence for its use has not been established in PD. There are differences between erythromycin and azithromycin in the duration of action.

The half-life of azithromycin is 68 to 72 h and is administered once daily, while the half-life of erythromycin is 2 h and must be administered 4 times daily. Erythromycin inhibits CYP450-3A4 which can cause drug interactions, while azithromycin does not affect this enzyme, resulting in fewer drug interactions. Additionally, tachyphylaxis has been demonstrated with erythromycin due to downregulation of the motilin receptor.

There is controversy and growing concern with the use of azithromycin and erythromycin leading to cardiac arrhythmias and sudden cardiac death due to data from observational studies. However, a recent meta-analysis of RCTs did not show an increased risk of mortality or cardiovascular events associated with azithromycin.

> Histamine H2 blocker: nizatidine

This selective histamine-2 receptor blocker inhibits gastric acid secretion and is thought to stimulate gastric motility by non-competitively inhibiting acetylcholinesterase. Doi and her colleagues evaluated nizatidine 150 mg twice daily in an open-label study in 20 PD patients administered for 3 months and found no significant difference in gastric emptying compared to baseline.

They performed a secondary analysis that revealed that nizatidine shortened gastric emptying time in all 9 patients with delayed gastric emptying compared to their baseline values ​​(p < 0.05). Improvements in symptoms were noted, although it was not reported which symptoms improved.

Furthermore, nizatidine was well tolerated and no side effects were noted. Nizatidine has also been shown to improve gastric emptying in patients with functional dyspepsia [68], an upper gastrointestinal disorder similar to GP. Nizatidine is available over the counter and may be a safe option for treating GP.

> Ghrelin agonists: TZP-101, TZP-102 and RM-131

Ghrelin is an amino acid that binds to the growth hormone secretagogue receptor. It is produced in the gastric mucosa and exerts its prokinetic effects through the acceleration of gastric emptying in the GP. Oral ghrelin receptor agonists, TZP-101, TZP-102, and RM-131 have been studied in patients with diabetic gastroparesis. TZP-101 and RM-131 improved gastric emptying time and TZP-101 and TZP-102 improved Gastroparesis Cardinal Symptom Index scores. However, evidence of its effectiveness in PD is lacking.

> Serotonin 5-HT4 receptor agonists

There are multiple 5-HT4 receptor agonists in addition to the mosapride and prucalopride mentioned above in this category, used primarily for the treatment of constipation. These other agents are naropride, renzapride, celopride, and velusetrag.

These medications have not been studied in patients with GP of PD, but it is thought that they may help patients with GP due to previous evidence of other similar 5-HT4 receptor agonists (cisapride and tegaserod) used to treat GP in the EP . The FDA removed these medications due to the risk of cardiac toxicity.

> Combination of herbal extracts - STW5 / iberogast

STW5/Iberogast is a fixed combination of nine hydroethanolic herbal extracts not available in the US but available over the counter in other countries. Although it has an unknown mechanism of action, it is believed to increase gastric and intestinal secretions, improve gastrointestinal transit and constipation.

Treatment of SIBO generally involves correcting secondary causes and reducing intestinal bacterial content as well as gas production. In addition to antibiotics traditionally used to treat SIBO, other options under investigation are probiotics as discussed below.

Treatment of SIBO and GP can improve the motor symptoms of PD. However, the treatment of SIBO is challenging due to the absence of well-designed clinical trials in patients with or without PD and SIBO. The lack of consensus on the exact definition of SIBO and specific diagnostic criteria also complicates its treatment.

> Rifaximin

Rifaximin is a broad-spectrum antibiotic that covers gram-negative and positive aerobic and anaerobic bacteria; therefore, it is likely to be effective in treating SIBO.

It binds to bacterial DNA-dependent RNA polymerase that inhibits bacterial RNA synthesis. It has low resistance rates and is poorly absorbed, with less than 0.4% absorbed from the gastrointestinal tract after oral administration; therefore, it is associated with minimal adverse effects.

Phase III randomized placebo-controlled clinical trials showed that a 2-week treatment of rifaximin showed relief of IBS symptoms, bloating, abdominal pain, and loose/watery stools in IBS patients without constipation.

Additionally, rifaximin is the only FDA-approved antibiotic for the treatment of diarrhea-predominant IBS and the most studied antibiotic for the treatment of SIBO. Unfortunately, it is very expensive compared to other antibiotics and is often not covered by third-party payers. The use of rifaximin for the treatment of SIBO in patients with PD is unknown at this time.

> Probiotics and prebiotics.

Probiotics are live bacteria and yeast that may be beneficial in treating SIBO by repopulating the small intestine with normal flora and inhibiting pathogenic methane-producing anaerobic bacteria that cause SIBO symptoms.

Probiotics have been shown to improve sensory responses and signaling in the intestinal epithelium, nutrition and the immune system by decreasing inflammatory responses at the mucosal level and therefore improving motility. They are generally well tolerated with low rates of adverse effects. The use of lactobacillus strands specifically leads to improvement of symptoms in patients with SIBO.

Motility disorders of the gastrointestinal tract are frequently found in patients with PD, and treatment of the underlying gastrointestinal disorders caused by PD with various prokinetics and laxatives is essential to achieve improvements in the patient’s motor function.

Various prokinetics and laxatives are now available to provide some relief from gastrointestinal morbidity caused by PD leading to even better absorption of even PD treatments.