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

NCT03342950 | Terminated Phase 2

• 1 other identifier: A03-M45-15B
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuralgia Peripheral

Outcome Measures

Primary Outcomes (2)

• 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.

  Scores recorded on pain diary on trial day 1, day 14 , day 21 and day 35 will be used

• 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.

  Scores obtained from tests performed on trial day 1, day 14, day 21 and day 35 will be used.

Secondary Outcomes (2)

• Analysis of pain relief

  Scores will be obtained on trial day 14 and day 35.

• Change in area of Punctate Hyperalgesia

  Measurements will be performed on trial day 1, day 14 , day 21 and day 35.

Study Arms (2)

Active drug group

ACTIVE COMPARATOR

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

Drug: Topical Solution

Placebo group

PLACEBO COMPARATOR

Treatment with placebo solution with out active drug ingredients

Drug: Placebos

Interventions

Topical Solution DRUG

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%)

Active drug group

Placebos DRUG

Topical Solution of anhydrous ethanol (6.5%), polyethylene glycol 400 (20%), propylene glycol (53.5%), and oleyl alcohol (20%)

Placebo group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Terence J. Coderre: lead
• The Louise And Alan Edwards Foundation: collaborator

Study Sites (1)

McGill University

Montreal, Quebec, H3G 1Y6, Canada

Location

Related Publications (6)

• 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.

  PMID: 23273834 BACKGROUND

• 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.

  PMID: 27385502 BACKGROUND

• 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.

  PMID: 16556569 BACKGROUND

• 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.

  PMID: 17721252 BACKGROUND

• 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.

  PMID: 15504623 BACKGROUND

• 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.

  PMID: 33596969 DERIVED

MeSH Terms

Interventions

Solutions

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 1, 2017
• First Posted: November 17, 2017
• Study Start: February 19, 2019
• Primary Completion: October 12, 2021
• Study Completion: October 12, 2021
• Last Updated: October 21, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)