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The Effects of Topical Treatment With Clonidine + Pentoxifylline in Patients With Neuropathic Pain (TTNP)

Primary Purpose

Neuralgia Peripheral

Status
Terminated
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Topical Solution
Placebos
Sponsored by
Terence J. Coderre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuralgia Peripheral

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Female or male patients, aged 18-70;
  2. An average spontaneous pain level of at least 4 on an 11-point numerical rating pain score (0= no pain, 10= worst pain possible) on at least 3 days during the week prior to the study;
  3. The existence of tactile allodynia, as a sign of chronic pain, following a traumatic peripheral nerve injury;
  4. Ability to communicate in English or in French;
  5. Willing and able to sign an informed consent;
  6. Stable pain disease with no anticipated change in treatment in the next 5 weeks.
  7. Female subjects of childbearing potential must agree to use effective method of contraception during the study period. Female subjects who utilize a hormonal contraceptive as one of their birth control methods must have consistently used the same method for at least three months prior to study drug dosing.

Exclusion Criteria:

  1. Diabetes mellitus necessitating antihyperglycemic treatment or any other endocrine disease;
  2. Any liver disease, resulting in aspartate aminotransferase (AST) levels greater than 3 times the normal values, or kidney disease, resulting in creatinine levels greater than 133 µmol/L;
  3. Hypertension or taking of anti-hypertensive medication;
  4. Malignant disease or taking of chemotherapeutic agents;
  5. Known diagnosis of angina pectoris, arrhythmias, congestive heart failure or peripheral arterial disease;
  6. Pregnancy or breast feeding. Female patients of child-bearing age must have a negative urine pregnancy test;
  7. Known allergic reaction to clonidine or pentoxifylline;
  8. Presence of major depression, bipolar affective disorder or schizophrenia;
  9. Presence of a severe medical condition, or condition known to affect peripheral circulation (intermittent claudication, peripheral arterial disease, Raynaud's syndrome);
  10. any medication that interacts with clonidine or pentoxifylline [e.g. cardiovascular drugs such as angiotensin converting enzyme (ACE) inhibitors, alpha blockers (prazosin, terazosin or doxazosin), beta blockers (atenolol, metoprolol, propranolol), neuroleptics (butyrophenones, phenothiazines, thioxanthenes), calcium channel blockers (verapamil, diltiazem) and non-cardiovascular drugs such as diuretics, thyroxine, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRIs), as well as vitamin K antagonists/blood thinners, such as warfarin];
  11. any medical condition that might be impacted by clonidine or pentoxifylline, such as cardiovascular disease, cardiac rhythm disorders (atrial-ventricular blockade or conduction abnormalities), orthostatic regulation disturbances, disorders of cerebral perfusion, chronic renal failure; sinus node dysfunction, or a recent cerebral and/or retinal haemorrhage.

Sites / Locations

  • McGill University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active drug group

Placebo group

Arm Description

Treatment with the topical solution of clonidine + pentoxifylline (0.1%/5%)

Treatment with placebo solution with out active drug ingredients

Outcomes

Primary Outcome Measures

Change in visual analogue scale (VAS) score of spontaneous pain intensity
This will be an evaluation of patients' daily spontaneous pain recorded on a pain diary. The visual analogue scale is a 100 millimetre line with the words "no pain" and "worst pain possible" on the left and right of it respectively. The patients will indicate their level of pain by marking on the line. The position of the mark on the line from the left end to the right will be measured in millimetres to obtain level of pain severity (The higher the VAS score the more severe the pain) . Change in VAS score will be obtained by comparing the difference between scores recorded on trial day 1 versus trial day 14 and trial day 21 versus trial day 35.
Change in visual analogue scale (VAS) score of dynamic mechanical allodynia (DMA)
The degree of dynamic mechanical allodynia will be determined by stroking the most painfully sensitive area of the skin three times over 5 seconds at a rate of 1-2 cm/s with a Somedic brush. The patient will indicate the amount of pain evoked on a 100-millimeter visual analogue scale (VAS) by marking on a 100 mm line with the words "no pain" and "worst pain possible" on the left and right of it respectively. The position of the mark on the line from the left end to the right will be measured in millimetres to obtain level of dynamic mechanical allodynia (The higher the VAS score the more severe the dynamic mechanical allodynia). The change in dynamic mechanical allodynia will be assessed by comparing the scores obtained on trial day 1 versus day 14 and scores obtained on day 21 versus day 35.

Secondary Outcome Measures

Analysis of pain relief
Pain relief measured on a 6-point categorical pain relief scale (0-worse pain to 5-complete pain relief). The higher the score the greater the pain relief.
Change in area of Punctate Hyperalgesia
Area of punctate hyperalgesia will be obtained by marking and calculating the area of sensitivity to punctate stimulation of the skin with a Neuropen. Change in area of punctate hyperalgesia will be obtained by comparing the areas measured on trial day 1 versus trial day 14 and trial day 21 versus trial day 35.

Full Information

First Posted
November 1, 2017
Last Updated
October 13, 2021
Sponsor
Terence J. Coderre
Collaborators
The Louise And Alan Edwards Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT03342950
Brief Title
The Effects of Topical Treatment With Clonidine + Pentoxifylline in Patients With Neuropathic Pain
Acronym
TTNP
Official Title
The Effects of Topical Treatment With Clonidine + Pentoxifylline in Patients With Neuropathic Pain
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Terminated
Why Stopped
Low recruitment due to the COVID-19 pandemic
Study Start Date
February 19, 2019 (Actual)
Primary Completion Date
October 12, 2021 (Actual)
Study Completion Date
October 12, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Terence J. Coderre
Collaborators
The Louise And Alan Edwards Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Microvascular dysfunction underlies pain in different animal models of neuropathic pain. Pentoxifylline is a phosphodiesterase inhibitor that reduces cyclic adenosine monophosphate (cAMP) hydrolysis, enhances blood flow and reduces platelet aggregation, decreases blood viscosity, and increases the flexibility of red blood cells, all of which relieve microvascular dysfunction. Clonidine is an α2-adrenergic receptor agonist that decreases sympathetic outflow from the brainstem, vascular reactivity and has direct peripheral vasodilatory action. Topical combination of pentoxifylline and clonidine produced significant antiallodynic effects in rat models of neuropathic pain with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. In healthy volunteers with an experimentally-induced surrogate for neuropathic pain: post-capsaicin tourniquet exposure, the topical combination reduced areas of dynamic allodynia and mechanical hyperalgesia, in addition to reducing post-capsaicin ischemic pain. This study will investigate if the same topical combination of clonidine + pentoxifylline will relieve pain in patients with neuropathic pain following traumatic injuries of peripheral nerves.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuralgia Peripheral

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active drug group
Arm Type
Active Comparator
Arm Description
Treatment with the topical solution of clonidine + pentoxifylline (0.1%/5%)
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
Treatment with placebo solution with out active drug ingredients
Intervention Type
Drug
Intervention Name(s)
Topical Solution
Intervention Description
Topical Solution of Clonidine (0.01%) + Pentoxifylline (5%) in anhydrous ethanol (6.5%), polyethylene glycol 400 (20%), propylene glycol (53.5%), and oleyl alcohol (20%)
Intervention Type
Drug
Intervention Name(s)
Placebos
Intervention Description
Topical Solution of anhydrous ethanol (6.5%), polyethylene glycol 400 (20%), propylene glycol (53.5%), and oleyl alcohol (20%)
Primary Outcome Measure Information:
Title
Change in visual analogue scale (VAS) score of spontaneous pain intensity
Description
This will be an evaluation of patients' daily spontaneous pain recorded on a pain diary. The visual analogue scale is a 100 millimetre line with the words "no pain" and "worst pain possible" on the left and right of it respectively. The patients will indicate their level of pain by marking on the line. The position of the mark on the line from the left end to the right will be measured in millimetres to obtain level of pain severity (The higher the VAS score the more severe the pain) . Change in VAS score will be obtained by comparing the difference between scores recorded on trial day 1 versus trial day 14 and trial day 21 versus trial day 35.
Time Frame
Scores recorded on pain diary on trial day 1, day 14 , day 21 and day 35 will be used
Title
Change in visual analogue scale (VAS) score of dynamic mechanical allodynia (DMA)
Description
The degree of dynamic mechanical allodynia will be determined by stroking the most painfully sensitive area of the skin three times over 5 seconds at a rate of 1-2 cm/s with a Somedic brush. The patient will indicate the amount of pain evoked on a 100-millimeter visual analogue scale (VAS) by marking on a 100 mm line with the words "no pain" and "worst pain possible" on the left and right of it respectively. The position of the mark on the line from the left end to the right will be measured in millimetres to obtain level of dynamic mechanical allodynia (The higher the VAS score the more severe the dynamic mechanical allodynia). The change in dynamic mechanical allodynia will be assessed by comparing the scores obtained on trial day 1 versus day 14 and scores obtained on day 21 versus day 35.
Time Frame
Scores obtained from tests performed on trial day 1, day 14, day 21 and day 35 will be used.
Secondary Outcome Measure Information:
Title
Analysis of pain relief
Description
Pain relief measured on a 6-point categorical pain relief scale (0-worse pain to 5-complete pain relief). The higher the score the greater the pain relief.
Time Frame
Scores will be obtained on trial day 14 and day 35.
Title
Change in area of Punctate Hyperalgesia
Description
Area of punctate hyperalgesia will be obtained by marking and calculating the area of sensitivity to punctate stimulation of the skin with a Neuropen. Change in area of punctate hyperalgesia will be obtained by comparing the areas measured on trial day 1 versus trial day 14 and trial day 21 versus trial day 35.
Time Frame
Measurements will be performed on trial day 1, day 14 , day 21 and day 35.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Female or male patients, aged 18-70; An average spontaneous pain level of at least 4 on an 11-point numerical rating pain score (0= no pain, 10= worst pain possible) on at least 3 days during the week prior to the study; The existence of tactile allodynia, as a sign of chronic pain, following a traumatic peripheral nerve injury; Ability to communicate in English or in French; Willing and able to sign an informed consent; Stable pain disease with no anticipated change in treatment in the next 5 weeks. Female subjects of childbearing potential must agree to use effective method of contraception during the study period. Female subjects who utilize a hormonal contraceptive as one of their birth control methods must have consistently used the same method for at least three months prior to study drug dosing. Exclusion Criteria: Diabetes mellitus necessitating antihyperglycemic treatment or any other endocrine disease; Any liver disease, resulting in aspartate aminotransferase (AST) levels greater than 3 times the normal values, or kidney disease, resulting in creatinine levels greater than 133 µmol/L; Hypertension or taking of anti-hypertensive medication; Malignant disease or taking of chemotherapeutic agents; Known diagnosis of angina pectoris, arrhythmias, congestive heart failure or peripheral arterial disease; Pregnancy or breast feeding. Female patients of child-bearing age must have a negative urine pregnancy test; Known allergic reaction to clonidine or pentoxifylline; Presence of major depression, bipolar affective disorder or schizophrenia; Presence of a severe medical condition, or condition known to affect peripheral circulation (intermittent claudication, peripheral arterial disease, Raynaud's syndrome); any medication that interacts with clonidine or pentoxifylline [e.g. cardiovascular drugs such as angiotensin converting enzyme (ACE) inhibitors, alpha blockers (prazosin, terazosin or doxazosin), beta blockers (atenolol, metoprolol, propranolol), neuroleptics (butyrophenones, phenothiazines, thioxanthenes), calcium channel blockers (verapamil, diltiazem) and non-cardiovascular drugs such as diuretics, thyroxine, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRIs), as well as vitamin K antagonists/blood thinners, such as warfarin]; any medical condition that might be impacted by clonidine or pentoxifylline, such as cardiovascular disease, cardiac rhythm disorders (atrial-ventricular blockade or conduction abnormalities), orthostatic regulation disturbances, disorders of cerebral perfusion, chronic renal failure; sinus node dysfunction, or a recent cerebral and/or retinal haemorrhage.
Facility Information:
Facility Name
McGill University
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3G 1Y6
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
23273834
Citation
Ragavendran JV, Laferriere A, Xiao WH, Bennett GJ, Padi SS, Zhang J, Coderre TJ. Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain. J Pain. 2013 Jan;14(1):66-78. doi: 10.1016/j.jpain.2012.10.004.
Results Reference
background
PubMed Identifier
27385502
Citation
Ragavendran JV, Laferriere A, Bennett GJ, Ware MA, Gandhi W, Bley K, Schweinhardt P, Coderre TJ. Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study. Pain. 2016 Oct;157(10):2366-2374. doi: 10.1097/j.pain.0000000000000659.
Results Reference
background
PubMed Identifier
16556569
Citation
Brown MB, Martin GP, Jones SA, Akomeah FK. Dermal and transdermal drug delivery systems: current and future prospects. Drug Deliv. 2006 May-Jun;13(3):175-87. doi: 10.1080/10717540500455975.
Results Reference
background
PubMed Identifier
17721252
Citation
Li C, Sekiyama H, Hayashida M, Takeda K, Sumida T, Sawamura S, Yamada Y, Arita H, Hanaoka K. Effects of topical application of clonidine cream on pain behaviors and spinal Fos protein expression in rat models of neuropathic pain, postoperative pain, and inflammatory pain. Anesthesiology. 2007 Sep;107(3):486-94. doi: 10.1097/01.anes.0000278874.78715.1d.
Results Reference
background
PubMed Identifier
15504623
Citation
Palos GR, Mendoza TR, Cantor SB, Aday LA, Cleeland CS. Perceptions of analgesic use and side effects: what the public values in pain management. J Pain Symptom Manage. 2004 Nov;28(5):460-73. doi: 10.1016/j.jpainsymman.2004.02.016.
Results Reference
background
PubMed Identifier
33596969
Citation
Fulas OA, Laferriere A, Ware DMA, Shir Y, Coderre TJ. The effect of a topical combination of clonidine and pentoxifylline on post-traumatic neuropathic pain patients: study protocol for a randomized, double-blind placebo-controlled trial. Trials. 2021 Feb 17;22(1):149. doi: 10.1186/s13063-021-05088-w.
Results Reference
derived

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The Effects of Topical Treatment With Clonidine + Pentoxifylline in Patients With Neuropathic Pain

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