Background   Nonmotor symptoms likely affect overall quality of life in Parkinson Disease (PD) as much as motor symptoms (1).  Fast Fact #361 discussed the natural trajectory of PD.  This Fast Fact will focus on management strategies of common non-motor symptoms in PD patients.

Pain   Nearly 85% of PD patients report pain (2). Musculoskeletal pain from limitations in mobility is the most commonly reported pain type. While there are no comparative analgesic studies for PD, NSAIDs, acetaminophen, physical rehabilitation, and low dose opioids are commonly utilized analgesic strategies.  Dystonia is a prolonged involuntary muscle contraction which often leads to foot cramping, muscle spasms, and a sensation of muscles twisting. In addition to the analgesic strategies listed above, skeletal muscle relaxants and botulinum toxin injections may be warranted (see Fast Facts #340 & 324).  Neuropathic pain, which is often described as a shooting pain or a sensitivity to light touch within a dermatome, is a less common pain reported in PD.  Gabapentin, pregabalin, duloxetine, venlafaxine, and/or interventional strategies (e.g. spinal cord stimulator or a nerve block) are preferred over tricyclic antidepressants (TCAs) due to the risk for delirium and falls in PD patients. 

Neuropsychiatric Symptoms   As many as 40% of patients with advanced PD experience neuro-psychiatric symptoms, most commonly visual hallucinations (3)_.  The assessment and treatment is similar to delirium in general (see Fast Fact #1) with a few special considerations (3-10):

• Several PD medications are associated with psychosis: amantadine; monoamine oxidase type B (MAOB) inhibitors, catechol-O-methyl transferase inhibitors (e.g. entacapone); and dopamine agonists (e.g. pramipexole).  Before initiating new pharmacotherapies, reduce or discontinue offending medications as appropriate. Pharmacy and neurology input may be necessary.
• Common neuroleptics used to treat delirium such as haloperidol, risperidone, and olanzapine should be avoided as they may worsen motor symptoms by blocking dopamine and raise mortality risk.
• Quetiapine is the preferred pharmacologic treatment in PD because it seems to have the least effect on motor symptoms.  Because PD patients may be more prone to somnolence, many experts recommend initiating at a low dose such as 12.5 mg to 25 mg at bedtime or BID.  
• Clozapine has the most compelling evidence of all anti-psychotics for treating PD-related psychosis; however, its use is reserved to psychiatrists due to its association with agranulocytosis.  
• Pimavanserin is a FDA approved oral medication for PD-related hallucinations at a usual dose of 34 mg a day. Although randomized, placebo controlled trials show efficacy with little worsening of motor symptoms or other adverse effects (12-14), its use is limited by its cost which is >$80/day.

Daytime Sleepiness   Excessive daytime somnolence is common in PD.  Beyond best nocturnal sleep hygiene practices (see Fast Facts 101, 104 & 105), expert considerations include (15-17):

• AM intake of caffeine or a prescribed psychostimulant such as methylphenidate 5-10 mg twice a day or modafinil 100-200 mg per day.
• Screen for comorbid sleep disorders such as  rapid eye movement behavior sleep disorder, restless leg syndrome, and obstructive sleep apnea as roughly 85% of PD patients have a sleep disorder.  Refer to a sleep specialist when appropriate.
• Screen for sudden bouts of excessive daytime drowsiness or sleep (often referred as a “sleep attacks”) which can be common and hazardous in PD. If present, patients should avoid driving.

Depression   There is no clear consensus regarding the best antidepressant in PD.  Duloxetine, venlafaxine, buproprion, sertraline, and escitalopram are preferred by many experts over mirtazapine and TCAs which have higher anticholinergic activity. Clinicians should be cautious when combining any antidepressants with MAOB inhibitors to avoid serotonin syndrome (10,18,19).

Dementia   The only FDA-approved treatment for PD-related dementia is rivastigmine; however, its anticholinergic properties can worsen Parkinsonian symptoms and its efficacy in preventing progression of cognitive impairment is limited (10,20). Hence, many experts question its utility.

Orthostatic Hypotension   Nonpharmacologic interventions like increased fluid/salt intake and compression stockings are first-line treatments as are a reduction of antihypertensive medications if medically appropriate.  Fludrocortisone or midodrine can be added in refractory cases (5).  

Sialorrhea   Sialorrhea and drooling are common in PD because of the reduced oromotor control and autonomic dysfunction.  Chewing gum or hard candy may encourage swallowing and reduce drooling in mild cases (21). For moderate to severe symptoms, the use of glycopyrrolate 1-2 mg by mouth three times a day; sublingual atropine 1% ophthalmic solution 1-2 drops once to twice a day; ipratroprium spray, or botulinum toxin injections into salivary glands has been described (20-22) 

References

1. Giugni JC, Okun MS. Treatment of advanced Parkinson’s disease. Curr Opin Neurol. Aug 2014;27(4):450-460.

2. Geroin C, Gandolfi M, Bruno V, Smania N, Tinazzi M. Integrated Approach for Pain Management in Parkinson Disease. Curr Neurol Neurosci Rep. Apr 2016;16(4):28.

3. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol. Aug 2010;67(8):996-1001..

4. Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain. Apr 2000;123 ( Pt 4):733-745

5. Zesiewicz TA, Sullivan KL, Arnulf I, et al. Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Mar 16 2010;74(11):924-931.

6. Fernandez HH, Friedman JH, Jacques C, Rosenfeld M. Quetiapine for the treatment of drug-induced psychosis in Parkinson’s disease. Mov Disord. May 1999;14(3):484-487.

7. Morgante L, Epifanio A, Spina E, et al. Quetiapine versus clozapine: a preliminary report of comparative effects on dopaminergic psychosis in patients with Parkinson’s disease. Neurol Sci. Sep 2002;23 Suppl 2:S89-90.

8. Juncos JL, Roberts VJ, Evatt ML, et al. Quetiapine improves psychotic symptoms and cognition in Parkinson’s disease. Mov Disord. Jan 2004;19(1):29-35.

9. Pollak P, Tison F, Rascol O, et al. Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry. May 2004;75(5):689-695.

10. Miyasaki JM, Shannon K, Voon V, et al. Practice Parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Apr 11 2006;66(7):996-1002.

11. Weintraub D, Chiang C, Kim HM, et al. Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease. JAMA Neurol. May 1 2016;73(5):535-541.

12. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. Feb 8 2014;383(9916):533-540.

13. Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord. Oct 2011;26 Suppl 3:S42-80.

14. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311(16):1670-1683.

15. Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord. Mar 2003;18(3):287-293.

16. Gjerstad MD, Alves G, Wentzel-Larsen T, Aarsland D, Larsen JP. Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease? Neurology. Sep 12 2006;67(5):853-858.

17. Hobson DE, Lang AE, Martin WR, Razmy A, Rivest J, Fleming J. Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA; 2002: 287(4):455-463.

18. Menza M, Dobkin RD, Marin H, et al. A controlled trial of antidepressants in patients with Parkinson disease and depression. Neurology. Mar 10 2009;72(10):886-892.

19. Hauser RA, Zesiewicz TA. Sertraline for the treatment of depression in Parkinson’s disease. Mov Disord. Sep 1997;12(5):756-759.

20. Lee AH, Weintraub D. Psychosis in Parkinson’s disease without dementia: common and comorbid with other non-motor symptoms. Mov Disord. Jun 2012;27(7):858-863.

21. Srivanitchapoom P, Pandey S, Hallett M. Drooling in Parkinson’s disease: a review. Parkinsonism Relat Disord. Nov 2014;20(11):1109-1118.

22. Chou KL, Koeppe RA, Bohnen NI. Rhinorrhea: a common nondopaminergic feature of Parkinson’s disease. Mov Disord. Feb 1 2011;26(2):320-323.

23. Thomsen TR, Galpern WR, Asante A, Arenovich T, Fox SH. Ipratropium bromide spray as treatment for sialorrhea in Parkinson’s disease. Mov Disord. Nov 15 2007;22(15):2268-2273.

24. Hyson HC, Johnson AM, Jog MS. Sublingual atropine for sialorrhea secondary to parkinsonism: a pilot study. Mov Disord. Nov 2002;17(6):1318-1320.

Authors’ Affiliations: ¹Cleveland Clinic, Cleveland OH; ² Mayo Clinic College of Medicine, Rochester, MN.

Conflicts of Interest: None to reportVersion History: First electronically published in August 2018; originally edited by Sean Marks MD