A New Method for Identifying Sensory Changes in Painful Chemotherapy-induced Peripheral Neuropathy (CIPN)

A New Method for Identifying Sensory Changes in Painful Chemotherapy-induced Peripheral Neuropathy (CIPN): a Feasibility Study

The investigators propose that using the Diode Laser fiber type Selective Stimulator (DLss) in patients with chemotherapy-induced peripheral neuropathy (CIPN) will allow for the assessment of changes in small-fiber pain thresholds, to identify differences between subjects who received chemotherapy and developed painful CIPN, compared to subjects who received similar chemotherapy but did not develop painful CIPN (control group).

Additionally, the investigators would like to investigate whether the response to DLss correlates with pain severity in patients with persistent painful neuropathy.

The ultimate goal of this study is to develop a non-invasive, bedside quantitative test that is specific for painful CIPN. If the investigators' initial hypothesis is confirmed, the next step would be to design a prospective longitudinal study and assess changes in DLss early after initiation of chemotherapy, to determine whether this approach can help identify early predictive parameters of painful CIPN.

Study Overview

• Status: Completed
• Conditions: Chemotherapy-induced Peripheral Neuropathy
• Intervention / Treatment: Other: Brief Pain Inventory; Other: Hospital Anxiety and Depression Scale; Other: Neuropathic Pain Symptom Inventory; Procedure: Diode Laser fiber type Selective Stimulator; Procedure: Quantitative sensory testing; Procedure: Conditioned pain modulation efficiency; Other: Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS)

Detailed Description

Painful chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy, occurring in more than 60% of patients at some point during the course of cancer treatment with commonly used drugs such as taxanes and platinum compounds. It potentially may result in severely diminished quality of life and dose reduction or/and treatment delay, which may ultimately impact survival.

The mechanisms by which chemotherapy-induced nerve damage ultimately leads to pain are poorly understood, because virtually no structural or functional differences in nerve fibers between painless and painful peripheral neuropathy have been identified. As a result, there is no reliable way to predict which patients will develop persistent painful chemotherapy-induced peripheral neuropathy.

The ultimate goal of this study is to develop a non-invasive, bedside quantitative test that is specific for painful CIPN. If our initial hypothesis is confirmed, the next step would be to design a prospective longitudinal study and assess changes in DLss early after initiation of chemotherapy, to determine whether this approach can help identify early predictive parameters of painful CIPN.

In this other interventional study, we will test the utility of the Diode Laser fiber type Selective Stimulator (DLss) to identify sensory changes that are unique to patients with painful chemotherapy induced peripheral neuropathy (CIPN) vs. controls.

Painful symptoms of CIPN develop in patients with differential nerve damage to Aδ vs C-type peripheral nerve fibers. We hypothesize that Aδ:C fiber threshold ratio, as measured by the DLss, will be different between patients with painful CIPN compared to control patients who received a similar regimen of chemotherapy, but did not develop painful CIPN. The confirmation of hypothesis may lead to a novel approach for early detection of CIPN.

Subjects: 20 evaluable patients with painful CIPN following treatment with oxaliplatin, cisplatin, paclitaxel, docetaxel (or any combination of above) will be included in painful CIPN group, and 20 controls matched by the type of chemotherapy received, who did not develop painful CIPN.

The study procedure will include a one-time visit for sensory assessments including:

1. Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS);
2. Assessment of pain symptoms on Neuropathic pain Symptom Inventory (NPSI) and Brief Pain Inventory (BPI).
3. Assessment of mood on hospital anxiety and depression scale (HADS)
4. Quantitative sensory testing (QST): thermal detection and pain thresholds, mechanical detection threshold, temporal summation (TS), and conditioned pain modulation (CPM).

The primary outcome is the comparison of Aδ:C fiber threshold ratio between patients who have developed painful CIPN, and the control subjects.

In secondary analyses, we will generate Spearman correlation coefficient between the "Aδ:C fiber threshold ratio" and the severity of painful CIPN on NPSI scale.

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

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

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:

Group A: Painful CIPN group

• Age >18
• Distal symmetric pain distribution (both feet, with or without pain in hands).
• The pain appeared during or up to 12 weeks after treatment with oxaliplatin, cisplatin, paclitaxel, docetaxel or any combination of these.
• Score of 4 or more on Douleur Neuropathique 4 (DN4) neuropathic pain questionnaire
• Pain duration > 2 months.
• Patient report of average daily pain intensity in the last week ≥3 on 0-10 Numerical Rating Scale (NRS).
• Able and willing to sign an Institutional Review Board (IRB)-approved written informed consent.

Group B: Control group:

• Age >18
• History of cancer diagnosis, previously treated with at least 8 infusions of chemotherapy regimen that included oxaliplatin or at least 6 infusions of chemotherapy regimen that included cisplatin, paclitaxel, docetaxel, or any combination of these.
• No ongoing pain in distal symmetric distribution (subjects with symptoms and signs such as mild numbness, or vibration sensation loss are eligible to be included in the control group).
• Able and willing to sign an IRB-approved written informed consent. * Subjects in the control group will be matched by the type of previous chemotherapy to the subjects in the Painful CIPN group. An additional attempt will be made to match controls by sex, age, cancer diagnosis, and cumulative neurotoxic chemotherapy dose.

Exclusion Criteria:

• History of pre-existing painful distal symmetric polyneuropathy prior to chemotherapy.
• Alternative etiology exists for the distal painful symptoms.
• Current or previous treatment with a vinca alkaloid (e.g. vincristine, vinblastine), bortezomib, or another agent which may cause major peripheral neurotoxicity.
• Pregnant
• Concomitant medication as follows:
• Patients receiving chronic daily opioids, topical lidocaine or topical capsaicin will be excluded.
• Patients receiving as needed (PRN) analgesics, including acetaminophen, NSAIDs or short-acting opioids, will be required not to take them 48h before testing, at for at least five half-lives of the specific analgesic, at the discretion of the investigators.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Painful CIPN Group; -Performed at baseline: NPSI, BPI, HADS, Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS), QST, CPM, and DLss	Other: Brief Pain Inventory; -A self-administered questionnaire used to evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The patient is asked to rate their worst, least, average, and current pain intensity (4 items which generate the PAIN SEVERITY score), list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life (7 items which generate the PAIN INTERFERENCE score) on a 10 point scale.; Other Names: BPI; Other: Hospital Anxiety and Depression Scale; 14 item scale with even of the items relating to anxiety and seven relating to depression; Each item on the questionnaire is scored from 0-3 and this means that a patient can score between 0 and 21 for either anxiety or depression; Other Names: HADS; Other: Neuropathic Pain Symptom Inventory; -The NPSI questionnaire utilized in this study includes eight parameters (i.e., burning pain, squeezing pain, pressure pain, electric shock pain, stabbing pain, tingling pain, pins and needles pain and allodynia [pain provoked by light touch]). Each of the parameters includes recall of the past 24 hours; Other Names: NPSI; Procedure: Diode Laser fiber type Selective Stimulator; -Each patient will have an A and C fiber stimulation. Stimulation will be performed on the dorsum of the foot using stimulation previously published parameters to elicit "burning pain," which is from activation of C-fibers and "pinprick" pain from A-fibers; Other Names: DLss; Procedure: Quantitative sensory testing; Quantitative sensory testing will be performed on the dorsal mid-foot and the ipsilateral shoulder will serve as control area; Cold and warm detection thresholds, cold and heat pain thresholds, mechanical detection thresholds, and wind-up ratio; Other Names: QST; Procedure: Conditioned pain modulation efficiency; -Immersion of a hand up to the wrist to a thermostat-controlled water bath maintained at 12 degrees Celsius, and the application of a heat stimulus on the contralateral forearm.; Other Names: CPM; Other: Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS); -The subjects are asked to rate the intensity of their current pain on a 0-10 scale - 0 denoting "no pain" and 10 denoting "worst imaginable pain".
Active Comparator: Group B: Control Group; -Performed at baseline: NPSI, BPI, HADS, Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS), QST, CPM, and DLss	Other: Brief Pain Inventory; -A self-administered questionnaire used to evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The patient is asked to rate their worst, least, average, and current pain intensity (4 items which generate the PAIN SEVERITY score), list current treatments and their perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life (7 items which generate the PAIN INTERFERENCE score) on a 10 point scale.; Other Names: BPI; Other: Hospital Anxiety and Depression Scale; 14 item scale with even of the items relating to anxiety and seven relating to depression; Each item on the questionnaire is scored from 0-3 and this means that a patient can score between 0 and 21 for either anxiety or depression; Other Names: HADS; Other: Neuropathic Pain Symptom Inventory; -The NPSI questionnaire utilized in this study includes eight parameters (i.e., burning pain, squeezing pain, pressure pain, electric shock pain, stabbing pain, tingling pain, pins and needles pain and allodynia [pain provoked by light touch]). Each of the parameters includes recall of the past 24 hours; Other Names: NPSI; Procedure: Diode Laser fiber type Selective Stimulator; -Each patient will have an A and C fiber stimulation. Stimulation will be performed on the dorsum of the foot using stimulation previously published parameters to elicit "burning pain," which is from activation of C-fibers and "pinprick" pain from A-fibers; Other Names: DLss; Procedure: Quantitative sensory testing; Quantitative sensory testing will be performed on the dorsal mid-foot and the ipsilateral shoulder will serve as control area; Cold and warm detection thresholds, cold and heat pain thresholds, mechanical detection thresholds, and wind-up ratio; Other Names: QST; Procedure: Conditioned pain modulation efficiency; -Immersion of a hand up to the wrist to a thermostat-controlled water bath maintained at 12 degrees Celsius, and the application of a heat stimulus on the contralateral forearm.; Other Names: CPM; Other: Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS); -The subjects are asked to rate the intensity of their current pain on a 0-10 scale - 0 denoting "no pain" and 10 denoting "worst imaginable pain".

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aδ:C Fiber Detection Threshold Ratio	Comparison of the Aδ:C fiber detection threshold ratio (as measured by the DLss) between patients with painful neuropathy and patients who did not develop painful neuropathy following similar cancer chemotherapy	At the time of the DLss (day 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Aδ:C Pain Threshold Ratio	Aδ:C pain threshold shows Aδ fiber threshold divided by C fiber threshold measured by DLss detection and pain threshold protocols.	At the time of the DLss (day 1)
The Severity of Neuropathy on NPSI Scale.	The severity of painful CIPN on Neuropathic Pain Symptom Inventory (NPSI) scale. Increased NPSI (0-100) score indicates more severe neuropathic pain.	At the time of the DLss (day 1)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH); LasMed LLC
• Investigators: Principal Investigator: Simon Haroutounian, Ph.D., Washington University School of Medicine

Publications and helpful links

General Publications

• Nemenov MI, Alaverdyan H, Burk C, Roles K, Frey K, Yan Y, Kazinets G, Haroutounian S. Characterization of Patients With and Without Painful Peripheral Neuropathy After Receiving Neurotoxic Chemotherapy: Traditional Quantitative Sensory Testing vs C-Fiber and Adelta-Fiber Selective Diode Laser Stimulation. J Pain. 2022 May;23(5):796-809. doi: 10.1016/j.jpain.2021.11.011. Epub 2021 Dec 9.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2018
• Primary Completion (Actual): September 17, 2019
• Study Completion (Actual): September 17, 2019

Study Registration Dates

• First Submitted: September 25, 2018
• First Submitted That Met QC Criteria: September 25, 2018
• First Posted (Actual): September 27, 2018

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Neuropathic pain; Peripheral neuropathy; CIPN; DLss
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases
• Other Study ID Numbers: 201807162; 1R43CA206796-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: In accordance with the recent proposal from the International Committee of Medical Journal Editors, patient-level data will be made available within 6 months after publication of the primary manuscript. Data will be provided to researchers who submit a methodologically sound research proposal including a protocol and statistical analysis plan. No patient-identifying fields (including dates) will be included in the shared dataset. Certain technical data related to the intellectual property rights of LasMed LLC may not be available for sharing.
• IPD Sharing Time Frame: Patient-level data will be made available within 6 months after publication of the primary manuscript.
• IPD Sharing Access Criteria: Data will be provided to researchers who submit a methodologically sound research proposal including a protocol and statistical analysis plan. No patient-identifying fields (including dates) will be included in the shared dataset. Certain technical data related to the intellectual property rights of LasMed LLC may not be available for sharing.
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF)

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