Key Guidelines and Evidence

Fox Shet al.  Movement Disorder Society Evidence-Based Medicine Committee. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord. 2018 Aug;33(8):1248-1266

Early PD:

1. To prevent/delay disease progression:
   • Clinically useful: None to date.
   • Not useful: Pramipexole; Coenzyme Q10; Creatine.
   • Investigational: Selegiline, rasagiline, ropinirole, vitamin D, exercise.
2. Early PD requiring symptomatic therapy:
   • Clinically useful: Non-ergot dopamine agonists (DA) such as piribedil, pramipexole (both immediate-release [IR] and extended-release [ER]), ropinirole IR, rotigotine; Ergot DA (cabergoline, pergolide); Levodopa preparations (IR, CR, ER); Monoamine oxidase B inhibitors (MAO-B inhibitors like selegiline and rasagiline); anticholinergics.
   • Possibly useful: Non-ergot DA (ropinirole prolonged release [PR]), Ergot DA (bromocriptine); amantadine.
3. Early PD requiring symptomatic therapy:
   • Clinically useful: Non-ergot dopamine agonists (DA) such as piribedil, pramipexole (both immediate-release [IR] and extended-release [ER]), ropinirole IR, rotigotine; Ergot DA (cabergoline, pergolide); Levodopa preparations (IR, CR, ER); Monoamine oxidase B inhibitors (MAO-B inhibitors like selegiline and rasagiline); anticholinergics.
   • Possibly useful: Non-ergot DA (ropinirole prolonged release [PR]), Ergot DA (bromocriptine); amantadine.

Treated PD Optimized on Oral Levodopa:

1. Treating motor fluctuations:
2. Clinically useful: Non-ergot DA (pramipexole, ropinirole, rotigotine, apomorphine intermittent injections, pergolide); Catechol-O-methyltransferase (COMT) inhibitors (entacapone, opicapone); MAO-B inhibitors (rasagiline, selegiline); zonisamide; Levodopa-carbidopa intestinal gel (LCIG); bilateral DBS surgery (STN or Globus pallidus internus [GPi]).
3. Possibly useful: Ergot DA (bromocriptine, cabergoline); istradefylline; tolcapone; Non-ergot DA (apomorphine infusion).
4. Treating dyskinesia:
   1. Clinically useful: Amantadine; clozapine; LCIG; bilateral DBS surgery (STN or GPi); unilateral pallidotomy.
5. Treating specific/general motor symptoms:
   1. Clinically useful: Physiotherapy.
   1. Possibly useful: Rivastigmine (gait and balance); Exercise-based movement strategy training (gait and balance); formalized patterned exercises (gait and balance); speech therapy (speech and swallowing); occupational therapy; thalamic surgery (DBS or thalamotomy).
   1. Investigational: Donepezil (gait and balance); methylphenidate (gait and balance); memantine (gait and balance) cannabidiol; technology-based movement strategies; acupuncture; rTMS; tDCS.

These recommendations highlight various pharmacological and non-pharmacological interventions to manage early and advanced stages of PD, each with their respective clinical usefulness and investigational status.

Levodopa/Carbidopa Combination: The gold standard for symptomatic treatment of Parkinson’s disease is Levodopa, often combined with Carbidopa. A significant study, the LEAP (Levodopa in Early Parkinson’s Disease) trial, investigated whether this combination had disease-modifying effects. This randomized, double-blind, placebo-controlled, delayed-start trial involved 445 patients with early Parkinson’s disease. They were either given Levodopa (100 mg three times per day) with Carbidopa (25 mg three times per day) for 80 weeks or a placebo for 40 weeks, followed by Levodopa and Carbidopa for another 40 weeks. The primary outcome measured was the change from baseline to week 80 in the Unified Parkinson’s Disease Rating Scale (UPDRS) score. Results showed that at week 80, there was no significant difference between the early-start and delayed-start groups in the change of UPDRS score, indicating that Levodopa/Carbidopa does not have a disease-modifying effect, but is effective in symptom management

• Verschuur CV, Suwijn SR, Post B, Dijkgraaf M, Bloem BR, van Hilten JJ, van Laar T, Tissingh G, Deuschl G, Lang AE, de Haan RJ, de Bie RM. Protocol of a randomised delayed-start double-blind placebo-controlled multi-centre trial for Levodopa in EArly Parkinson’s disease: the LEAP-study. BMC Neurol. 2015 Nov 19;15:236. doi: 10.1186/s12883-015-0491-1. PMID: 26584951; PMCID: PMC4653886.

Rotigotine: The RECOVER study, a double-blind, placebo-controlled trial, evaluated Rotigotine transdermal system in patients with Parkinson’s disease who were experiencing early-morning motor dysfunction. The study involved 287 patients, with outcomes measured using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (motor examination) score. Patients receiving Rotigotine showed a significant improvement in early morning motor function and sleep disturbance compared to placebo. This study supports the efficacy of Rotigotine in managing early morning motor symptoms and sleep disturbances Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, Dioszeghy P, Hill D,

• Anderson T, Myllyla V, Kassubek J, Steiger M, Zucconi M, Tolosa E, Poewe W, Surmann E, Whitesides J, Boroojerdi B, Chaudhuri KR; Recover Study Group. Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord. 2011 Jan;26(1):90-9. doi: 10.1002/mds.23441. Epub 2010 Nov 18. PMID: 21322021; PMCID: PMC3072524. in Parkinson’s disease.