Ketamine's Efficiency in the Treatment of Chronic Pain: Kynurenin Pathway

Chronic Pain Clinical Trial

— KEKU1  

Official title:

Ketamine's Efficiency in the Treatment of Chronic Pain With an Added Inflammatory Component Exploring the Kynurenin Pathway. A Randomized, Double Blind, Placebo-controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03513822
• Other study ID #: REDAR
• Secondary ID: 2017-003930-10pr
• Status: Recruiting
• Phase: Phase 3
• Start date: February 16, 2018
• Est. completion date: November 2018

Study information

• Verified date: April 2018
• Source: Redar
• Contact: Cyril QUEMENEUR, Resident
• Phone: 0033681193981
• Email: c.quemeneur[@]gmx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The kynurenine pathway is involved in hyperalgesia. This pathway is activated by inflammation. Ketamine would interact with the kynurenine pathway and inflammation. Our working hypotheses are: the clinical effects of ketamine on neuropathic pain are greater in the presence of systemic inflammation and the mechanism of action involves an interaction on the kynurenine pathway.

Study design: Interventional randomized placebo-controlled clinical trial.

Main goals:

1. To show a better clinical efficacy of ketamine in chronic pain in patients with an inflammatory component.

2. Explore the anti-inflammatory activity of ketamine through the Kynurenine pathway.

Description:

The kynurenine pathway is involved in hyperalgesia. This pathway is activated by inflammation. Ketamine would interact with the kynurenine pathway and inflammation. Our working hypotheses are: the clinical effects of ketamine on neuropathic pain are greater in the presence of systemic inflammation and the mechanism of action involves an interaction on the kynurenine pathway.

Study design: Interventional randomized placebo-controlled clinical trial.

Main goals:

1. To show a better clinical efficacy of ketamine in chronic pain in patients with an inflammatory component.

2. Explore the anti-inflammatory activity of ketamine through the Kynurenine pathway.

Population Adult, medullary injured (BM), with chronic neuropathic pain (DN). 4 groups: BM with DN with bedsore Ketamine Group versus Placebo Group BM with DN without bedsore group Ketamine versus Placebo Group

Intervention Ketamine infusion 1 mg / kg IVSE over two hours versus Nacl perfusion 0.9%

 Primary judgment criterion Decrease by more than 30% the intensity of neuropathic pain evaluated at the moment on a numerical scale of 10 points between H0 and H4. Comparison of groups two by two.

Secondary judgment criterions:

NPSI score (Neuropathic pain symptom inventory) at H1, H4, D1, D4, J7 Sub score of NPSI; H1, H4, J1, J4, J7 Depression Scale HADS (Hospital Anxiety Depression Scale) J0, J1, J7 Plasma serotonin (5-HT) kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (KYN / TRP ratio), kynurenic acid ( KA) and quinolinic acid (QA), as well as 3 proinflammatory cytokines IL-1β, IL-6, and TNF-α before perfusion and H4 perfusion.

In parallel blood samples will be collected to study the activation of the kynurenine pathway in response to inflammation due to a pressure ulcer.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 48
• Est. completion date: November 2018
• Est. primary completion date: October 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adults speaking and understanding French

• presenting chronic neuropathic pain as defined by IASP

• Painful intensity> or = to 6/10 during the week preceding the inclusion - Medullary lesion, whatever the origin (traumatic, degenerative, tumoral, postoperative), responsible for paraplegia in a chronic state.

• Able to give informed consent, after clear, fair and appropriate information

• Having given their consent by a written consent signature.

Exclusion Criteria:

• Hypersensitivity to ketamine or any of its components

• Participation in another interventional trial, or participation in another trial.

• Patient unable to give consent.

• Pregnancy or breastfeeding

• Refusal to sign the consent

• Cardiovascular diseases associated in particular with disorders of rhythm and severe cardiac insufficiency, coronary insufficiency, discovered on examination, on ECG or by biological balance or known. - unstabilized HTA> 180/100 mmHg

• Severe hepatic and / or renal hepatic insufficiency.

Related Conditions & MeSH terms

• Chronic Pain
• Inflammation
• Neuralgia

Intervention

Drug:
• Ketamine 10 MG/ML
Ketamine infusion 1mg/kg with electric syringe during 2 hours.
• Placebos
Sodium chloride infusion with the same rate, electric syringe during 2 hours.
• Midazolam 1 MG/ML
Bolus of Midazolam 1mg before each perfusion.

Locations

Country	Name	City	State
France	Raymond Poincaré Hospital	Garches	Hauts De Seine

Sponsors (7)

Lead Sponsor	Collaborator
Redar	Fondation Apicil, Hopital Lariboisière, Hôpital Raymond Poincaré, Hospital Ambroise Paré Paris, Institut National de la Santé Et de la Recherche Médicale, France, Recherche Clinique Paris Descartes Necker Cochin Sainte Anne

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Numeric pain rating scale decrease between H0 and H4.	Numeric pain rating scale is a scale from 0 to 10. 0 is no pain, 10 is the worst pain we could imagine. The first outcome is decreasing the intensity of neuropathic pain evaluated at the moment on a numerical scale of 10 points at H4. Comparison of groups two by two.	4 hours after the end of infusion
Secondary	Paraclinical: Kynurenine pathway levels : SEROTONIN	Levels of SEROTONIN (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Paraclinical: Kynurenine pathway levels : KYNURENINE	Levels of KYNURENINE (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Paraclinical: Kynurenine pathway levels : IDO ACTIVITY	Levels of INDOLEAMINE DIOXYGENASE ACTIVITY (division Kynurenine/Tryptophane quote)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Paraclinical: Kynurenine pathway levels : KYNURENIC ACID	Levels of Kynurenic acid (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Paraclinical: Kynurenine pathway levels : QUINOLINIC ACID	Levels of Quinolinic acid (millimoles/liter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Paraclinical: Kynurenine pathway levels : IL1	Levels of Interleukin 1 (picograms/milliliter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Paraclinical: Kynurenine pathway levels : IL6	Levels of Interleukin 6 (picograms/milliliter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Paraclinical: Kynurenine pathway levels: TNF alpha	Levels of TNF alpha (picograms/milliliter)	Hour 0 and Hour 6 (4 hours after the ending of infusion)
Secondary	Clinical: Neuropathic pain symptom inventory	NPSI scoring: Neuropathic pain symptom inventory. A composite score composed by neuropathic pain components: Burning, Pressure, Squeezing, Electric shocks, Stabbing, Evoked by brushing, evoked by pressure, evoked by cold stimuli, pins and needles, tingling. Two questions about the time of pain for twenty four hours, and the numbers of crisis. Score from 0 to 100. 100 is the maximum.	Hour 0, Day 1, Day 4, Day 7
Secondary	Clinical: Pain timeline	Timeline of self assessment on a simple numeric scale of the pain three times a day during a week. Numeric pain rating scale is a scale from 0 to 10. 0 is no pain, 10 is the worst pain we could imagine.	Seven days
Secondary	Percentage overall improvement in pain over a week with self assessment	Self assessment of the global improvement in pain over the week after infusion	Between Hour 0 and Day 7
Secondary	Clinical: Subscore of Neuropathic pain symptom inventory	Subscore on NPSI scoring: NEUROPATHIC PAIN SYMPTOM INVENTORY, subscore are burning from 0 to 10, pressing (deep) spontaneous pain from 0 to 10, paroxysmal pain from 0 to 10, evoked pain from 0 to 10, paresthesia or dysesthesia from 0 to 10 (0 is the minimal, 10 is the maximal value for each of the component).	Hour 0, Day 1, Day 4, Day 7
Secondary	Clinical: Hospital anxiety and depression scale	Recording scoring on hospital anxiety and depression scale. HADS scale is a tool to detect anxiety and depressive disorders. It includes fourteen questions from 0 to 3 points each. Seven are related to anxiety. Seven are related to depressive mood. It permits to obtain 2 different scales with the maximum of each of 21.	Hour 0, Day 7.
Secondary	Percentage overall improvement in mood over a week with self assessment	Self assessment of the global improvement of the mood over the week after infusion	Between Hour 0 and day 7
Secondary	Clinical: Pain area on a body cartography	Evaluation of pain area on a body surface cartography	Hour 0, Day 1, Day 7.
Secondary	Clinical: Ketamine adverse effects	Recording ketamine adverse effects during and right after the infusion	Hour 0 to hour 4
Secondary	Paraclinical: Kynurenine pathway activation with ulcer pressure	Studying the levels of the kynurenine pathway elements between patients with inflammatory component (ulcer pressure) and without inflammatory component (without ulcer pressure)	Hour 0