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

NCT ID: NCT03687970

Last Updated: 2021-05-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-17
• Study Completion Date: 2019-09-17

Brief Summary

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.

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.

Conditions

Chemotherapy-induced Peripheral Neuropathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Brief Pain Inventory

Intervention Type: OTHER

-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.

Hospital Anxiety and Depression Scale

Intervention Type: OTHER

• 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

Neuropathic Pain Symptom Inventory

Intervention Type: OTHER

-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

Diode Laser fiber type Selective Stimulator

Intervention Type: PROCEDURE

-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

Quantitative sensory testing

Intervention Type: PROCEDURE

• 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

Conditioned pain modulation efficiency

Intervention Type: PROCEDURE

-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.

Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS)

Intervention Type: OTHER

-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".

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

Group Type: ACTIVE_COMPARATOR

Brief Pain Inventory

Intervention Type: OTHER

-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.

Hospital Anxiety and Depression Scale

Intervention Type: OTHER

• 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

Neuropathic Pain Symptom Inventory

Intervention Type: OTHER

-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

Diode Laser fiber type Selective Stimulator

Intervention Type: PROCEDURE

-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

Quantitative sensory testing

Intervention Type: PROCEDURE

• 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

Conditioned pain modulation efficiency

Intervention Type: PROCEDURE

-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.

Spontaneous pain at baseline on 0-10 Numerical Rating Scale (NRS)

Intervention Type: OTHER

-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".

Interventions

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.

Intervention Type: 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

Intervention Type: 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

Intervention Type: OTHER

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

Intervention Type: 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

Intervention Type: 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.

Intervention Type: PROCEDURE

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".

Intervention Type: OTHER

Other Intervention Names

BPI; HADS; NPSI; DLss; QST; CPM

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Lasmed LLC

INDUSTRY

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Simon Haroutounian, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University School of Medicine

St Louis, Missouri, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34896646 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

http://www.siteman.wustl.edu

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

Other Identifiers

1R43CA206796-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

201807162

Identifier Type: -

Identifier Source: org_study_id