Investigational drugs for autonomic dysfunction in Parkinson’s disease

1. Drugs for autonomic dysfunction in Parkinson’s disease

Autonomic disturbances are common symptoms of Parkinson’s disease (PD),[1,2] with orthostatic hypotension affecting 20%–65% of patients,[3,4] sialorrhea about 75%,[5,6] sexual dysfunction 60% of men, urinary dysfunction up to 40%, and gastrointestinal motility disorders causing constipation up to 80%.[2] These symptoms can impair patients’ quality of life, worsen the burden of their caregivers, cause hospitalization and institutionalization, and increase the cost of care of patients with PD by four times.[1]

There are multiple factors contributing to autonomic dysfunction in PD. Deposition of Lewy bodies in the locus coeruleus, neuronal loss at the intermediolateral nucleus of the spinal cord, the ventrolateral medulla, and at the sympathetic ganglia have been implicated in the genesis of orthostatic hypotension.[7–9] Furthermore, exposure to dopamine agonists, alpha-adrenergic blockers used for prostatic hyperplasia, antihypertensives, and some antidepressants can also produce or aggravate orthostatic hypotension.[10] Reduced saliva deglutition appears to be main cause of sialorrhea.[6] Reduced bladder capacity, detrusor overactivity, and uninhibited external sphincter relaxation resulting from parasympathetic dysfunction are the hallmarks of urinary incontinence in PD.[11] Sexual dysfunction is mainly related to vascular autonomic malfunction, but some antidepressants may worsen it.[12] Finally, constipation might be related to the degeneration of autonomic innervation coming either from central autonomic nuclei or from the enteric nervous system within the colon itself.[13,14] Other secondary factors associated with constipation in PD might be poor bowel habits, reduced water intake, immobility, and drugs like antacids with aluminum, opioids, calcium channel blockers, anticholinergics, tricyclic antidepressants, antipsychotics, or amantadine.[15]

Management and treatment of autonomic dysfunction is a major unmet need in PD,[16] with poorly documented efficacy and safety for the majority of drugs currently used for this indication (Table 1).[17] A number of studies of variable quality have explored the efficacy and safety of experimental interventions for autonomic dysfunction in PD,[17–19] as summarized in Table 2. Brief discussions for the most important studies will be provided in the next paragraphs.

Table 1. Drugs currently used for autonomic dysfunction in PD.

Drug	Available evidence in PD	Practice implications^a	Approved for the indication by any Regulatory Agency?
Orthostatic hypotension
Midodrine	No	Investigational	Yes
Fludrocortisone	1 low-quality RCT	Investigational	No
Droxidopa	2 RCT	Not yet assessed	Yes
Sialorrhea
Botulinum toxin A or B	3 RCT	Clinically Useful	No
Urinary dysfunction
Tolterodine, Oxybutinin	No	Investigational	Yes
Sexual dysfunction
Sildenafil	1 low-quality RCT	Investigational	Yes
Constipation
Macrogol	1 RCT	Possibly useful	Yes
Lubiprostone	1 RCT	Investigational	Yes

RCT: randomized controlled trial.

^aAccording to the most recent Movement Disorders Society Evidence-Based Medicine Review [17] and its annual updates.

Table 2. Experimental treatments for autonomic dysfunction in PD.

Drug or intervention	Mechanism of action	Quality of evidence	Efficacy results	Safety results
Orthostatic hypotension
Droxidopa	Norepinephrine prodrug	I	Reduced frequency of dizziness and improved pressor response to orthostatism (short term)	Headache, supine hypertension
Midodrine	Alpha1-adrenoreceptor agonist	II	Reduced orthostatic blood pressure drop	Hypertension
Fludrocortisone	Mineralocorticoid	II	Reduced orthostasis symptoms	No major issues
Pyridostigmine	Cholinesterase enzyme inhibitor	II	No results available	No results available
Fipamezole	Alpha2-adrenoreceptor antagonist	II	Reduced levodopa-induced BP fall	No major issues
Partial weight supported treadmill gait training	Physical therapy	II	Increased baroreflex sensitivity	No major issues
Entacapone	Inhibitor of the COMT enzyme	III	Orthostatic hypotension was less frequent in patients exposed to entacapone	Not explored
Yohimbine	Alpha2-adrenoreceptor antagonist	II	Improved standing diastolic blood pressure	No data available
Sialorrhea
Tropicamide	Muscarinic antagonist	II	Tropicamide 1 mg reduced buccal saliva levels. A confirmatory RCT in underway	No major issues
Clonidine	Alpha2-adrenoreceptor agonist	II	Patients on clonidine had to dry their mouth less frequently	Somnolence, dizziness
Radiotherapy	Salivary gland ablation	III	Sialorrhea improved after radiotherapy	Loss of taste, dry mouth
Urinary dysfunction
Botulinum toxin A	Cholinergic blocker	III	Increased bladder capacity and reduced incontinence episodes	Post-void residue
Behavioral therapy	Behavioral modification	III	Reduced incontinence episodes	No major issues
Solifenacin	Muscarinic antagonist	I	No significant reductions in micturition episodes per 24-hour period	No major issues
Fesoterodine	Muscarinic antagonist	I	No results available	No results available
Transcutaneous tibial nerve stimulation	Stimulation of the sacral nerve plexus	II	Significant reductions in the number of urgency and nocturia episodes	No major issues
Sexual dysfunction
Sildenafil	PDE-5 enzyme inhibitor	II	Improved erectile function	No major issues
Constipation
Mosapride	5-HT4 agonist	III	Nonsignificant improvements in colonic transit	No major issues
Neurotrophin 3	Neurotrophic factor	II	Nonsignificant increments in stool frequency	Diarrhea, abdominal cramps
Probiotics	Restoration of colonic flora	III	Less frequent bloating, abdominal pain, tenesmus	No major issues
Biofeedback therapy	Behavioral modification	III	No results available	No results available
Relamorelin	Ghrelin peptide agonist	I	No results available	No results available

I = double blind, randomized, prospective, controlled studies with more than 20 patients and lasting for more than 12 weeks; II = nonrandomized and/or open-label, prospective, controlled studies or level I studies with insufficient sample size, mixed populations, or short follow-up; III = noncontrolled, retrospective, or cross-sectional studies.

Droxidopa showed positive results in two recent double-blind, randomized, placebo-controlled trials including patients with neurogenic orthostatic hypotension due to PD, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy.[19] In another double-blind, randomized, placebo-controlled trial involving 171 PD patients, droxidopa significantly improved dizziness (item no. 1 of the Orthostatic Hypotension Questionnaire) and significantly increased the pressor response to orthostatism, at day 7.[20] The FDA recently granted Northera® (droxidopa capsules) marketing authorization based on these short-term efficacy results, but additional long-term efficacy studies were requested.

A double-blind, randomized, controlled trial with midodrine for orthostatic hypotension is going on (NCT02365012), but follow-up will probably be insufficient to allow firm conclusions on the long-term efficacy of the drug. Fludrocortisone, fipamezole and yohimbine showed significant results in low-quality studies. There appears to be no further studies on their way for these drugs. Partial weight–supported treadmill gait training increased baroreflex sensitivity in an open-label, controlled trial, but it is uncertain if this may translate into reductions in blood pressure fall after orthostatism. A cross-sectional study found that orthostatism was less frequent with entacapone, but randomized clinical trials are needed to confirm these findings. A small double-blind randomized trial with pyridostigmine is also under way (NCT01993680).

Reductions in buccal saliva levels were observed with tropicamide and clonidine in small and/or low-quality studies. A double-blind, crossover trial with tropicamide is under way and results are expected soon (NCT01844648). Improvements in sialorrhea were also seen with radiotherapy in an uncontrolled study, but results have not been replicated and the risk/benefit ratio of this irreversible intervention is not clear.

Low-quality studies showed promising results for botulinum toxin A, behavioral therapy, and transcutaneous tibial nerve stimulation in the treatment of urinary dysfunction, which have not been replicated. Behavioral therapy may be an interesting option since it is related to virtually no side effects. Results from a small randomized controlled study with solifenacin showed negative results. A randomized study with fesoterodine, which efficacy is documented in the general population, is going on and results are awaited (NCT02385500).

Results of a low-quality study showed significant results with sildenafil for erectile dysfunction, but results have not been replicated. There are no other studies under way for this indication.

Mosapride and neurotrophin 3 induced nonsignificant improvements in constipation in low-quality pilot trials. Conversely, improvements with probiotics were significant, but the uncontrolled nature of the study precludes obtaining firm conclusions. A well-designed, randomized, controlled study with relamorelin is under way (NCT01955616).

2. Conclusion

There is a paucity of well-designed clinical trials assessing the efficacy and safety of treatments for autonomic dysfunction in PD. Furthermore, only few of the most recent trials provided high-quality evidence to support the use of new experimental therapies.

3. Expert opinion

Well-designed, double-blind, randomized, controlled studies are the hallmark of evidence-based medicine.[21] Without such trials, management decisions are based on personal experience, opinions from experts, or potentially biased studies, thus frequently resulting in suboptimal health care. It is therefore essential that high-quality evidence is produced to support the efficacy and safety of interventions for autonomic dysfunction in PD.

High-quality evidence about drug efficacy can only come from randomized, double-blind, controlled trials,[21] as it minimizes the risk of selection and observation bias.[22] Ideally, trials for autonomic dysfunction in PD should last for at least 12 weeks and include at least 20 subjects.[17] Primary outcomes should be measures of autonomic dysfunction specifically validated for use in PD. For example, studies about orthostatic hypotension might use the extent of orthostatic blood pressure fall or questionnaires assessing orthostatism symptoms, such as the SCOPA-AUT or COMPASS scales, as primary outcome measures.[18] The Drooling Severity and Frequency Scale, the Drooling Rating Scale, or the Sialorrhea Clinical Scale for PD have been suggested for sialorrhea evaluation in PD, but only the latter has been validated. Urinary dysfunction may be assessed by Likert scales exploring patients’ feelings or treatment benefices, but there are no validation studies in PD. The International Index of Erectile Function or the Sexual Health Inventory Scale-M version can be used for the evaluation of sexual function. Constipation can be evaluated by patient-reported assessments of the frequency of bowel movements. It should be mentioned that outcomes measurement tools have not been validated for use in PD in urinary, sexual dysfunctions, or constipation.

Study populations should be appropriately defined. Studies on orthostatic hypotension should use the internationally validated diagnostic criteria (i.e. the sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 min of standing or head-up tilt to at least 60° on a tilt table). It has been suggested that patients with mean standing blood pressure < 75 mmHg may be the most beneficiated ones by pharmacological treatment for orthostatic hypotension,[23] and thus are probably very good candidates for clinical trials. Patients with sialorrhea can be identified by the Unified PD Rating Scale Part II (Activities of daily living). PD patients to be included in studies on sexual dysfunction should not be affected by mood disorders. Patients participating in constipation studies should fulfill ROME III criteria. In all cases, secondary causes of autonomic dysfunction, including drug treatments, should be ruled out before inclusion in trials.

Safety issues should also be assessed in clinical trials. Besides general assessments, some events need to be specifically monitored.[18] This is the case of supine hypertension with pressor drugs for orthostatic hypotension. Dry mouth and dysphagia are frequently observed with interventions for sialorrhea and thus also need special attention. Hypotension is a common adverse event of those drugs for erectile dysfunction acting on genital blood vessels and thus should be specifically monitored if the drug in study acts via a similar mechanism. Finally, post-void residue and diarrhea are common adverse reactions to drugs for urinary dysfunction and constipation, respectively.

In summary, management of autonomic dysfunction is a major unmet need in PD and there is a paucity of well-designed clinical trials to support the efficacy and safety of many of the most commonly used agents. Furthermore, only few of the most recent trials provided level I evidence to support the efficacy of experimental therapies. In this context, practitioners can seldom take evidence-based treatment decisions, frequently exposing patients to suboptimal care. Therefore, investments from the medical research community and the drug/device-selling companies are needed to overcome this gap in the evidence. The fact that high-quality clinical trials with some drugs are under way or have been recently finished is encouraging and will mark the path for future trials with other interventions. The importance of having high-quality evidence cannot be overemphasized and hopefully, in the near future, practitioners will be able to rely on solid evidence coming from well-designed trials for managing autonomic dysfunction in PD patients.

Financial and competing interests disclosure

S Perez-Lloret is supported by the Institute of Cardiology Research of the National Scientific and Research Council (ININCA-CONICET), Argentina. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed