Effectiveness of Ketamine Administered by Mesotherapy in Complex Regional Pain Syndrome Type 1 (CRPS1) (MESO-SDRC)

Pilot Study to Evaluate the Effectiveness of a Mixture of Ketamine / Lidocaine Administered by Mesotherapy in the Management of Neuropathic Pain in Complex Regional Pain Syndrome Type 1 (CRPS1). A Monocentric Randomized and Controlled Clinical Study

Complex Regional Pain Syndrome type 1 (CRPS1) is a disabling pain syndrome. Its definitive treatment has not been established and the results of current treatments are often unsatisfactory.

The prognosis is difficult to establish because the vast majority of CRPS regresses within a few weeks. However, some forms are hyperalgesic with a major chronic painful picture, very debilitating and responding poorly to treatments with possible permanent sequelae.

The management of CRPS remains difficult and unsatisfactory and is symptomatic, multidimensional and multidisciplinary involving medical, paramedical and socio-professional workers. The priority therapeutic objectives are analgesia, maintenance or gain of joint range and maintenance or restoration of motor functions. This treatment is not the subject of a consensus and its implementation is sometimes the responsibility of specialized centers such as "pain relief" centers or even Physical Medicine and Rehabilitation (MPR) structures.

Previous studies using ketamine as a treatment for CRPS1 show encouraging results with a decrease in neuropathic pain. Ketamine is a low dose pain reliever. Ketamine has been studied as an adjuvant for the treatment of chronic pain, particularly neuropathic pain. The results suggest that ketamine decreases pain intensity and reduces opioid reliance when used as an adjunct to chronic and acute pain. Ketamine is believed to have a greater analgesic effect in patients with CRPS1 compared to other chronic pain syndromes. In these studies, ketamine was used intravenously, subcutaneously, orally, intranasally, or topically.

Mesotherapy allows microdose local treatment to be carried out limiting side effects, ensuring compliance and easy to implement. The injected solutions often contain a local anesthetic (procaine or lidocaine). It allows better local tolerance from the start of treatment. In addition, through its vasodilator effect on the microcirculation, it increases the effectiveness and tolerance of other injected products.

There are no studies using ketamine administrated by mesotherapy. Based on the scientific literature, there are good reasons to believe that this treatment could be effective on the neuropathic pain of CRPS1 and well tolerated.

Study Overview

• Status: Completed
• Conditions: Neuropathic Pain; Complex Regional Pain Syndrome Type 1
• Intervention / Treatment: Drug: LIDOCAINE 20 mg; Drug: LIDOCAINE 20 mg + KETAMINE 20 mg; Drug: LIDOCAINE 20 mg + KETAMINE 40 mg

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69437
    • Department of orthopedic surgery and trauma emergencies of the lower limb, Edouard Herriot Hospital, Hospices Civils de Lyon

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male / female aged ≥18 years,
• Patient suffering from Complex Regional Pain Syndrome Type 1 (CRPS1), according to the Budapest criteria, with a neuropathic component limited to the lower or upper limbs diagnosed by the Neuropathic pain DN4 Questionnaire
• Patient having undergone a three-stage dynamic bone scan less than 3 months old : vascular, tissue, bone, showing diffuse and extensive hyperfixation in the area suspected of CRPS1,
• Negative urinary pregnancy test in women of childbearing age,
• VAS (Visual Analogue Scale) > 50mm (on a scale of 0 to 100 mm) at inclusion,
• Patients affiliated to the French social security system,
• Writing informed consent obtained.

Exclusion Criteria:

• Patient with the following medical history or ongoing pathologies: epilepsy, hypertension (> 180mm / 100mm Hg), unbalanced coronary artery disease, recent myocardial infarction (MDI) (less than 12 months), porphyria, hyperthyroidism, known Behçet's disease, known blood crass disorder or PT (Prothrombin Time) <20%, known psychiatric disorders, known septic osteoarticular disease,
• Patient with HIV ((Human Immunodeficiency Viruses) infection, immunosuppression and / or immunosuppressive treatment
• Severe heart failure,
• History of severe allergy (angioedema),
• Known allergies to Cr and Zn,
• Current skin infection,
• Skin lesion next to the injection area
• Phobia of injections,
• Known hypersensitivity to ketamine hydrochloride or chlorobutanol,
• Known hypersensitivity to lidocaine hydrochloride or to amide-linked local anesthetics,
• Pregnant or breastfeeding woman
• Patient under protective measure (safeguard measure, curatorship, guardianship) or deprived of liberty.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: LIDOCAINE 20 mg; 4 injections (on day 1, day 7, day 14, day 28) by mesotherapy of 20 mg Lidocaine (qsp 6 ml NaCl 0.9%).	Drug: LIDOCAINE 20 mg; 4 injections (on day 1, day 7, day 14, day 28) by mesotherapy of 20 mg Lidocaine (qsp 6 ml NaCl 0.9%). Each mesotherapy session includes 2 steps performed chronologically. It will be done within 2 or 3 minutes each one: 1st sequence: intra-epidermal injections of 3 ml by manual technique in crossed lines with a 13 mm x 0.30 needle,; 2nd sequence : superficial intradermal injections of 3 ml (between 1 and 2 mm) using a technique assisted by a Pistor Eliance injector at a frequency of 200 punctures per minute.
Experimental: LIDOCAINE 20 mg + KETAMINE 20 mg; 4 injections (on day 1, day 7, day 14, day 28) by mesotherapy of 20 mg Lidocaine + 20 mg Ketamine (qsp 6 ml NaCl 0.9%).	Drug: LIDOCAINE 20 mg + KETAMINE 20 mg; 4 injections (on day 1, day 7, day 14, day 28) by mesotherapy of 20 mg Lidocaine + 20 mg Ketamine (qsp 6 ml NaCl 0.9%). Each mesotherapy session includes 2 steps performed chronologically. It will be done within 2 or 3 minutes each one: 1st sequence: intra-epidermal injections of 3 ml by manual technique in crossed lines with a 13 mm x 0.30 needle,; 2nd sequence : superficial intradermal injections of 3 ml (between 1 and 2 mm) using a technique assisted by a Pistor Eliance injector at a frequency of 200 punctures per minute.
Experimental: LIDOCAINE 20 mg + KETAMINE 40 mg; 4 injections (on day 1, day 7, day 14, day 28) by mesotherapy of 20 mg Lidocaine + 40 mg Ketamine (qsp 6 ml NaCl 0.9%).	Drug: LIDOCAINE 20 mg + KETAMINE 40 mg; 4 injections (on day 1, day 7, day 14, day 28) by mesotherapy of 20 mg Lidocaine + 40 mg Ketamine (qsp 6 ml NaCl 0.9%). Each mesotherapy session includes 2 steps performed chronologically. It will be done within 2 or 3 minutes each one: 1st sequence: intra-epidermal injections of 3 ml by manual technique in crossed lines with a 13 mm x 0.30 needle,; 2nd sequence : superficial intradermal injections of 3 ml (between 1 and 2 mm) using a technique assisted by a Pistor Eliance injector at a frequency of 200 punctures per minute

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analogue Scale (VAS) score	Pain measured by VAS (Visual Analogue Scale)	On day 0 (inclusion) and day 56 (end of patient follow-up)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolution of the Visual Analogue Scale score	The VAS (Visual Analogue Scale) score will be assessed at inclusion, before each mesotherapy session, and at the end of the patient follow-up	On day 0 (inclusion), on day 1, day 7, day 14 and day 28 (mesotherapy sessions), and on day 56 (end of patient follow-up)
Neuropathic Pain Symptom Inventory (NPSI) self-questionnaire score	The Neuropathic pain will be assessed using the NPSI (Neuropathic Pain Symptom Inventory self-questionnaire) at inclusion, before each mesotherapy session, and at the patients withdrawal.	On day 0 (inclusion), on day 1, day 7, day 14 and day 28 (mesotherapy sessions), and on day 56 (end of the patient follow-up)
Brief Pain Inventory (BPI) self-questionnaire score	The main dimensions of pain (i.e. intensity, functional disability, social and family repercussions as well as the level of psychological distress) will be assessed using the BPI (Brief Pain Inventory self-questionnaire) at inclusion and at the patients withdrawal.	On day 0 (inclusion) and on day 56 (end of patient follouw-up)
Relevant adverse events	The relevant adverse events (AEs), as well as the average of the highest grades of the relevant adverse events, will be collected during the patient follow-up, in particular after each mesotherapy session. The physician will ask the patient at each of the visits and will report any adverse event (AE). The nature and intensity of the AE will be assessed according to the Common Terminology Criteria for Adverse Events grid (CTCAE version 5.0). Relevant adverse events (AEs at least possibly related to treatment or mesotherapy) will be considered.	Until day 56 (end of patient follow-up)
Concomitant consumption of analgesics	The consumption of other analgesics concomitant with the treatment will be recorded	Until day 56 (end of patient follow-up)
EQ-5D-5L (EuroQol health states) questionnaire score	The quality of life will be assessed using the EQ-5D-5L questionnaire (EuroQol health states)	On day 1 (inclusion) and on day 56 (end of patient follow-up)
Visual Analogue Scale and Adverse Events grades (Benefit / risk balance)	To simultaneously compare the VAS (Visual Analogue Scale) and the relevant adverse events (AE) grades between groups. This benefit-risk balance will be estimate in a hierarchical fashion using the method of pairwise comparisons. The VAS will be used as the first endpoint (benefit) and the highest grade of AE in a given patient as the second endpoint (risk). No clinical relevance threshold will be specified for the two criteria for the primary analysis, but they will then be added as a sensitivity analysis.	Until day 56 (end of patient follow-up)

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2021
• Primary Completion (Actual): January 12, 2024
• Study Completion (Actual): January 12, 2024

Study Registration Dates

• First Submitted: November 25, 2020
• First Submitted That Met QC Criteria: November 25, 2020
• First Posted (Actual): December 2, 2020

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Randomized clinical trial; Ketamine; Mesotherapy; Complex Regional Pain Syndrome Type 1; Lidocaïne
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Pain; Neurologic Manifestations; Disease; Neuromuscular Diseases; Peripheral Nervous System Diseases; Autonomic Nervous System Diseases; Syndrome; Neuralgia; Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy; Somatoform Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Ketamine; Lidocaine
• Other Study ID Numbers: 69HCL18_0996

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No