Clinical trial NCT03342950: The Effects of Topical Treatment With Clonidine + Pentoxifylline in Patients With Neuropathic Pain
Official title: The Effects of Topical Treatment With Clonidine + Pentoxifylline in Patients With Neuropathic Pain
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Neuralgia Peripheral
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
Collaborators: name: The Louise And Alan Edwards Foundation
First posted: 2017-11-17
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in visual analogue scale (VAS) score of spontaneous pain intensity
timeFrame: Scores recorded on pain diary on trial day 1, day 14 , day 21 and day 35 will be used
measure: Change in visual analogue scale (VAS) score of dynamic mechanical allodynia (DMA)
timeFrame: Scores obtained from tests performed on trial day 1, day 14, day 21 and day 35 will be used.
Secondary outcomes:
measure: Analysis of pain relief
timeFrame: Scores will be obtained on trial day 14 and day 35.
measure: Change in area of Punctate Hyperalgesia
timeFrame: Measurements will be performed on trial day 1, day 14 , day 21 and day 35.
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: McGill University
state: Quebec
Study officials:
References:
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.
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.
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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.
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.
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.