Exploration by NMR Spectroscopy of the Choline Concentrations in the Insular Cortex of Patients Suffering of Neuropathic Pain Induced by Oxaliplatin (INSULOX)

Neurotoxic chemotherapy, including oxaliplatin, are responsible for very disabling neuropathic pain that can last for months or even years after the end of chemotherapy. Currently, there is no effective neuroprotective treatment to prevent or relieve this pain. The only strategy is the reduction of oxaliplatin doses or premature discontinuation of therapy, with the risk of burdening the prognosis for remission. Thus, a better understanding of the pathophysiology of these iatrogenic neuropathies appears necessary in order to discover new potential therapeutic targets.

Preclinical works were able to demonstrate important metabolic changes in certain brain structures in an animal model of oxaliplatin-induced neuropathy. A significant increase of choline concentration has been found in the posterior insular cortex of neuropathic animals compared with control animals. Furthermore, the concentrations of choline were positively correlated to nociceptive thresholds. Thus, neuropathic pain induced by oxaliplatin would involve the posterior insular cortex and would be associated with an increase in choline concentration at this level. Clinical translation of these preclinical results is feasible in practice since choline concentration can be determined in the brain by non-invasive magnetic resonance spectroscopy.

Study Overview

• Status: Completed
• Conditions: Neuropathy; Painful
• Intervention / Treatment: Procedure: NMR Spectroscopy

Detailed Description

The objective of this study is to demonstrate a significant increase in choline concentration in the insular cortex of patients with an oxaliplatin induced neuropathy. Other objectives will assess the correlation between metabolite concentrations in the insular cortex and frequency / intensity of pain and neuropathic symptoms, cold and heat-induced pain and comorbidities (anxiety, pain, quality of life).

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63003
    • CHU de Clermont-Ferrand

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Oxaliplatin treated patient and suffering from neuropathic pain

  • Chemotherapy (oxaliplatin based) ended
  • Pain VAS ≥ 3/10, 1 month after the chemotherapy end
  • DN4 interview score ≥ 3/7, 1 month after the chemotherapy end

• Oxaliplatin treated patient without neuropathic pain

  • Chemotherapy (oxaliplatin based) ended
  • Pain VAS < 3/10, 1 month after the chemotherapy end
  • DN4 interview score < 3/7, 1 month after the chemotherapy end

• All patients

  • right-handed
  • No contrindication to MRI
  • Free, written and informed consent
  • Affiliated to the french health system
  • Effective contraception for male or female of childbearing age
  • Performance score (WHO) ≤ 2

Exclusion Criteria:

• Age < 18
• Left-handed
• BMI > 30 kg/m²
• Amputees of all or part of an upper limb
• Diabetic patient
• Painful events scheduled after enrollment (eg. surgical resection)
• Neurological diseases (eg Parkinson's disease, stroke, migraine, fibromyalgia ...)
• Chronic pain history before chemotherapy
• Analgesic treatment being other than paracetamol and weak opioids
• Alcohol consumption >3 units/day (30 g/day) for men and >2 units/day (20 g/day) for women
• Any unbalanced progressive disease (hepatic failure, renal impairment (creatinine clearance <30 mL/min), respiratory failure, congestive heart failure, myocardial infarction within the past 6 months ...)
• All active cancer
• Patient with a pacemaker, a cochlear implant, metal implants, or any other magnetic element
• Claustrophobia
• Pregnant or lactation
• Legal incapacity (person deprived of liberty or guardianship)
• Psychological, social, family or geographical reasons incompatible with the study
• Already included in another clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oxaliplatin and neuropathic pain; The objective of this study is to demonstrate a significant increase in choline concentration in the insular cortex of patients with an oxaliplatin induced neuropathy. Other objectives will assess the correlation between metabolite concentrations in the insular cortex and frequency / intensity of pain and neuropathic symptoms, cold and heat-induced pain and comorbidities (anxiety, pain, quality of life).	Procedure: NMR Spectroscopy
Other: Oxaliplatin without neuropathic pain; The objective of this study is to demonstrate a significant increase in choline concentration in the insular cortex of patients with an oxaliplatin induced neuropathy. Other objectives will assess the correlation between metabolite concentrations in the insular cortex and frequency / intensity of pain and neuropathic symptoms, cold and heat-induced pain and comorbidities (anxiety, pain, quality of life).	Procedure: NMR Spectroscopy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Choline concentration assessed by NMR spectroscopy in the posterior insula	1 month after chemotherapy end

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolite concentrations assessed by NMR spectroscopy in the posterior insula	Metabolite (choline, myo-inositol, N-acétylaspartate, créatine, glutamate/glutamine, lactate and taurine)	1 month and 6 months after chemotherapy end
Pain intensity (VAS and BPI questionnaire)	(VAS and BPI questionnaire)	1 month and 6 months after chemotherapy end
Neuropathic pain diagnostic 9DN4 interview questionnaire)		1 month and 6 months after chemotherapy end
Neuropathic pain intensity (NPSI questionnaire)	NPSI questionnaire	1 month and 6 months after chemotherapy end
BPI questionnaire		1 month and 6 months after chemotherapy end
Quantitative sensory threshold (cold, heat, vibration)		1 month and 6 months after chemotherapy end
Neuropathy grade		1 month and 6 months after chemotherapy end
Anxiety and depression symptoms (HADS questionnaire)	HADS questionnaire	1 month and 6 months after chemotherapy end
Intensity of chemotherapy-induced peripheral neuropathy (CIPN20 questionnaire)	CIPN20 questionnaire	1 month and 6 months after chemotherapy end
Health related quality of life (QLQ-C30 questionnaire)	(QLQ-C30 questionnaire	at 1 month and 6 months after chemotherapy end

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2014
• Primary Completion (Actual): February 4, 2021
• Study Completion (Actual): August 27, 2021

Study Registration Dates

• First Submitted: January 8, 2015
• First Submitted That Met QC Criteria: January 15, 2015
• First Posted (Estimate): January 16, 2015

Study Record Updates

• Last Update Posted (Actual): January 14, 2022
• Last Update Submitted That Met QC Criteria: December 30, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Neuropathy; Oxaliplatin; choline; Insula
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia
• Other Study ID Numbers: CHU-0217; 2013-A01588-37 (Registry Identifier: 2013-A01588-37)