Pain in Parkinson's Disease With Motor Fluctuations. (PAINinPD)

Spontaneous and Evoked Pain in Parkinson's Disease With Motor Fluctuations: an Observational, Prospective, Clinical and Neurophysiological Study in Patients Under L-dopa Add on Therapies.

Pain (spontaneous pain) is a fundamental non-motor symptom (NMS) of Parkinson's disease (PD) that is prevalent throughout the condition and often unrecognized and undertreated. The study of the scalp laser-evoked potentials (LEPs) (evoked pain) allows a non-invasive exploration of pain central pathways in humans. This technique proved useful in elucidating the physiopathology underlying different pain syndromes. This study has been conceived to study spontaneous pain (and/or evoked pain by laser stimulation) in PD patients (with or without pain) with motor fluctuations under drugs-on (Safinamide Metansolfonato or Rasagilina Mesilato).

Study Overview

• Status: Unknown
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: safinamide metansolfonato (12 weeks); Drug: rasagilina mesilato (12 weeks)

Detailed Description

Pain (spontaneous pain) is a fundamental non-motor symptom (NMS) of Parkinson's disease (PD) that is prevalent throughout the condition and often unrecognized and undertreated. Different types of pain have been described in association with PD including musculoskeletal, dystonic, central and neuropathic pain. Although musculoskeletal pain is the most commonly reported, a number of patients experience multiple types of pain which are more frequent and disabling in the intermediate phase of disease and which ultimately have a significant negative impact on the patient's quality of life. Despite its relevance, the pathophysiological mechanisms underlying pain in PD are yet to be fully understood. An abnormal nociceptive input processing in the central nervous system leading to hypersensitivity to evoked pain probably underlies all the different pain types experienced by PD patients and also intervene in pain-free PD patients. Additional factors including female gender, depression, disease duration, motor complications, postural abnormalities, medical conditions associated with painful symptoms (osteoporosis, rheumatic or degenerative joint disease,) probably contribute to the quality and distribution of spontaneous pain. Abnormalities in pain processing may be the consequence of decreased basal ganglia dopaminergic neurotransmission, as dopamine has been demonstrated to modulate pain perception in supraspinal regions involved in the pain pathways, including insula, anterior cingulate cortex, thalamus and periaqueductal grey. Furthermore, a neurodegeneration involving non-dopaminergic systems (such as g-aminobutyric acid, glutamate, noradrenaline, and serotonin) that modulate pain processing in other regions of the central nervous systems may also play a relevant role. The variegated pain dimension experienced by PD patients makes its therapeutic management a demanding challenge for clinicians.

The study of the scalp laser-evoked potentials (LEPs) (evoked pain) allows a non-invasive exploration of pain central pathways in humans. This technique proved useful in elucidating the physiopathology underlying different pain syndromes. Some data show that LEPs are altered in PD, in both pain-free PD patients and in PD patients with different kinds of pain, with amplitude reduction in N2/P2 component. Acute levodopa challenge had no effect in normalizing the decreased pain threshold/LEPs observed in PD patients in early Parkinson's disease while in PD patients with motor complications it partially increased pain threshold. This is consistent with the hypothesis that motor complications and pain may share common pathophysiological mechanisms which include not only dopaminergic but also non-dopaminergic systems dysfunction (25).This study has been conceived to study spontaneous pain (and/or evoked pain by laser stimulation) in PD patients (with or without pain) with motor fluctuations under drugs-on (Safinamide Metansolfonato or Rasagilina Mesilato).

• Study Type: Observational
• Enrollment (Anticipated): 48

Contacts and Locations

Study Locations

• Italy
  • Verona, Italy, 37126
    • Recruiting
    • Azienda Ospedaliera Universitaria Integrata Verona
    • Contact: Michele Tinazzi, MD, PhD; Phone Number: 0458027472; Email: michele.tinazzi@univr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Males or females patients with mid-to-late PD aged 30 to 80 years with or without chronic pain symptoms (duration >3 months) and motor fluctuations while receiving L-dopa alone or with other dopaminergic treatments.

Description

Inclusion Criteria:

• PD patients with or without pain willing to participate in this study and able to sign the written informed consent
• To be included in the PD with pain group, the patient's intensity of pain must be moderate to severe over the last month, as reported by a numerical rating scores (NRS≥4) despite the optimal dopaminergic treatment
• No modification of dopaminergic drugs and analgesic therapy with FANS during the 28 days before starting the enrollment in this study.
• Diagnosis of idiopathic PD of ≥3 years duration
• Hoehn and Yahr stage I-III during OFF time
• Motor fluctuations (>1.5 hours' OFF time/day)
• Patients who would have been treated with add-on therapy irrespective to the present protocol

Exclusion Criteria:

• Patients under (or with previous assumptions) monoamine oxidase inhibitor therapy.
• Late-stage PD experiencing severe, disabling peak-dose or biphasic dyskinesia, or unpredictable or widely swinging symptom fluctuations
• "de novo" patients, patients in early stage or non-fluctuating patients
• Evidence of dementia (MMSE <24)
• Sign and symptoms suggestive of atypical parkinsonism
• Major psychiatric illnesses
• Severe and progressive medical illnesses
• Concomitant diseases potentially causing acute or chronic pain (i.e., rheumatologic conditions, severe polyneuropathy, and spine injuries)
• Treatments with tri-tetracyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), opioids, neuroleptics, barbiturates and phenothiazines, pregabalin and gabapentin
• Any type of retinopathy

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
PD with PAIN; 12 patients will undergo add-on drugs therapy with safinamide metansolfonato.	Drug: safinamide metansolfonato (12 weeks); safinamide metansolfonato
PD without PAIN; 12 patients will undergo add-on drugs therapy with safinamide metansolfonato.	Drug: safinamide metansolfonato (12 weeks); safinamide metansolfonato
PD with PAIN rasagilina; 12 patients will undergo add-on drugs therapy with rasagilina mesilato.	Drug: rasagilina mesilato (12 weeks); rasagilina mesilato
PD without PAIN rasagilina; 12 patients will undergo add-on drugs therapy with rasagilina mesilato.	Drug: rasagilina mesilato (12 weeks); rasagilina mesilato

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Latency (ms) of N1/P1 complex.	Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group.	Change from baseline at 12 weeks
Latency (ms) of N2/P2 complex.	Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group.	Change from baseline at 12 weeks
Amplitude (microvolt) of N1/P1 complex.	Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group.	Change from baseline at 12 weeks
Amplitude (microvolt) of N2/P2 complex.	Laser-evoked potentials (LEPs) to explore the primary pain pathway will be assessed at each visit (V0 and V1). The technique of LEPs recording will be carried out as previously performed by our research group.	Change from baseline at 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body localization	The presence of pain (yes/no, dichotomous variable) in one or more body parts: head, upper limbs, lower limbs, shoulders, neck, trunk , lumbar back, pelvis, knees.	Change from baseline at 12 weeks
King's Pain Scale for Parkinson's Disease	(score)	Change from baseline at 12 weeks
Italian version of the brief pain inventory short form	(score)	Change from baseline at 12 weeks
Clinical global impression of change	(score)	Change from baseline at 12 weeks
The 39-Item Parkinson's Disease Questionnaire (PDQ-39)	(score)	Change from baseline at 12 weeks
Numeric Rating Scale (NRS)	(score)	Change from baseline at 12 weeks
Unified Parkinson's Disease Rating Scale	(score)	Change from baseline at 12 weeks
Total daily off time	Total daily off time will assessed by patient diaries reporting frequency and duration of the off periods (hours)	Change from baseline at 12 weeks
Off time following the first morning L-dopa dose	(hours)	Change from baseline at 12 weeks
Age	Age	One timepoint
Gender	(male/female)	One timepoint
Schooling	(years)	One timepoint
Job	type of job	One timepoint
Weight	(kg)	One timepoint
Disease duration	(years)	One timepoint
Age at PD onset	(years)	One timepoint
Laterality of PD symptom onset	(right, left, bilateral)	One timepoint
Most Affected Side	(right, left, bilateral)	One timepoint
Pain symptoms at PD onset	(yes, no)	One timepoint
Dominant phenotype	(Tremor, Bradikinetic/rigid, Mixed)	One timepoint
Modified H&Y	(score)	One timepoint
Pharmacologic therapy for PD	Pharmacologic therapy	One timepoint
Comorbilities	Comorbilities	One timepoint
Mini-Mental State Examination	(score)	One timepoint
Montreal Cognitive Assessment (MoCA)	(score)	One timepoint

Collaborators and Investigators

• Sponsor: Universita di Verona
• Collaborators: Azienda Ospedaliera Universitaria Integrata Verona
• Investigators: Principal Investigator: Michele Tinazzi, MD, PhD, Azienda Ospedaliera Universitaria Integrata Verona

Publications and helpful links

General Publications

• Defazio G, Berardelli A, Fabbrini G, Martino D, Fincati E, Fiaschi A, Moretto G, Abbruzzese G, Marchese R, Bonuccelli U, Del Dotto P, Barone P, De Vivo E, Albanese A, Antonini A, Canesi M, Lopiano L, Zibetti M, Nappi G, Martignoni E, Lamberti P, Tinazzi M. Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study. Arch Neurol. 2008 Sep;65(9):1191-4. doi: 10.1001/archneurol.2008.2.
• Tinazzi M, Recchia S, Simonetto S, Tamburin S, Defazio G, Fiaschi A, Moretto G, Valeriani M. Muscular pain in Parkinson's disease and nociceptive processing assessed with CO2 laser-evoked potentials. Mov Disord. 2010 Jan 30;25(2):213-20. doi: 10.1002/mds.22932.
• Tinazzi M, Recchia S, Simonetto S, Defazio G, Tamburin S, Moretto G, Fiaschi A, Miliucci R, Valeriani M. Hyperalgesia and laser evoked potentials alterations in hemiparkinson: evidence for an abnormal nociceptive processing. J Neurol Sci. 2009 Jan 15;276(1-2):153-8. doi: 10.1016/j.jns.2008.09.023. Epub 2008 Oct 26.
• Tinazzi M, Del Vesco C, Defazio G, Fincati E, Smania N, Moretto G, Fiaschi A, Le Pera D, Valeriani M. Abnormal processing of the nociceptive input in Parkinson's disease: a study with CO2 laser evoked potentials. Pain. 2008 May;136(1-2):117-24. doi: 10.1016/j.pain.2007.06.022. Epub 2007 Aug 31.
• Zambito-Marsala S, Erro R, Bacchin R, Fornasier A, Fabris F, Lo Cascio C, Ferracci F, Morgante F, Tinazzi M. Abnormal nociceptive processing occurs centrally and not peripherally in pain-free Parkinson disease patients: A study with laser-evoked potentials. Parkinsonism Relat Disord. 2017 Jan;34:43-48. doi: 10.1016/j.parkreldis.2016.10.019. Epub 2016 Oct 24.

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2018
• Primary Completion (Anticipated): March 28, 2019
• Study Completion (Anticipated): November 30, 2019

Study Registration Dates

• First Submitted: June 26, 2018
• First Submitted That Met QC Criteria: August 23, 2018
• First Posted (Actual): August 27, 2018

Study Record Updates

• Last Update Posted (Actual): August 27, 2018
• Last Update Submitted That Met QC Criteria: August 23, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Safinamide; Pain; Parkinson
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neuroprotective Agents; Protective Agents; Monoamine Oxidase Inhibitors; Rasagiline
• Other Study ID Numbers: 1470CESC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No