Botulinum Toxin in Peripheral Neuropathic Pain

Randomized Double Blind Placebo Controlled Multicenter Study of the Efficacy and Safety of Repeated Administrations of Botulinum Toxin Type A (Botox) in the Treatment of Peripheral Neuropathic Pain

Pain due to peripheral nerve lesion remains extremely difficult to treat and current treatments have onl moderate efficacy and/or side effects. The investigators have previously demonstrated the long term efficacy of Botulinum toxin type A (BTX-A) in a small group of patients with post-traumatic/postherpetic neuralgia and allodynia. The present study aims to a/ confirm the efficacy of repeated applications of BTX-A in a larger group of patients with peripheral neuropathic pain with or without allodynia(primary outcome) ; b/ evaluate its mechanisms of action ; c/analyse the predictors of response ;d/analyse whether the second injection is associated with a therapeutic gain. This will be a randomized placebo controlled study. A total of 30 patients will be randomized to receive either BTX-A (subcutaneous injection in the painful area) or placebo. Each injection will be repeated within at least 3 months depending on the duration of efficacy. Skin punch biopsies will be performed before and 1 month after BTX-A administration. The investigators postulate that this study will confirm the clinical efficacy and good safety of repeated administrations of BTX-A in the treatment of peripheral neuropathic pain.

Study Overview

• Status: Completed
• Conditions: Postherpetic Neuralgia; Diabetic Polyneuropathies; Other Polyneuropathies
• Intervention / Treatment: Drug: botulinum toxin type A

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil
    • Divisão de Clínica Neurológica do Hospital das Clínicas da FMUSP
• France
  • Boulogne-Billancourt, France, 92100
    • Hôpital Ambroise Paré, APHP
  • Limoges, France
    • Hopital Dupuytren

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Men or women aged 18 to 85 years Spontaneous pain with a minimal intensity of 4/10 on numerical scle Pain present for at least 6 months Pain related to painful mononeuropathy or sensory polyneuropathy Able to understand the protocol and comply to the requirements of the study Written informed consent Painful area limited to a maximum of 240 cm2

Exclusion Criteria:

Facial pain Litigation (pending) Unstable condition responsible for neuropathic pain (ie, unstable immunological disease...) HIV or chemotherapy induced neuropathy Contraindications to BTX-A (neuromuscular disease, hypersensitivity, infection, coagulation disorder, pregnancy) Other pain more severe than neuropathic pain No compliance with the self diary Drug abuse or alcoholism Severe major depression Cognitive impairment Other research protocol within the last 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: botulinum toxin type A; botulinum toxin type A will be injected subcutaneously in the painful area (maximum 300 units)	Drug: botulinum toxin type A; BTX A : 5 units/0.2 ml, maximum 300 units will be injected subcutaneous in the painful area ; this will be performed after randomization and within a minimum of 3 months interval depending on the duration of efficacy (maximum 6 months) Saline will be injected in the same volume in the painful area within the same frequency; Other Names: botox
PLACEBO_COMPARATOR: sodium chloride 9 %; sodium chloride 9 % will be used as a neutral placebo	Drug: botulinum toxin type A; BTX A : 5 units/0.2 ml, maximum 300 units will be injected subcutaneous in the painful area ; this will be performed after randomization and within a minimum of 3 months interval depending on the duration of efficacy (maximum 6 months) Saline will be injected in the same volume in the painful area within the same frequency; Other Names: botox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average pain intensity on numerical scales in a self diary by the patient	Numerical scales (0-10)	every day from baseline for up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of treatment on neuropathic symptoms	Neuropathic Pain Symptom Inventory will be used to assess symptoms	at each visit
Quality of life VAS	This will be assessed using the EuroQol questionnaire	at each visit
Intensity of allodynia to brush	This will performed using a brush	at each visit
assessment of effects of BTX-A on substance P and CGRP	This will be performed using skin punch biopsies in the painful area	at baseline and 1 month after BTX-A or placebo
Side effects	side effects of BTX-A will be assessed	throughout the study and each each visit
Detection and pain thresholds to mechanical and thermal stimuli and responses to suprathreshold stimuli	this will use quantitative sensory testing (thermotest, Von Frey filaments)	at each visit
Predictors of the response	We will assess the predictors of the response to BTX-A based on baseline pain thresholds, presence and severity of allodynia, skin punch biopsy and catastrophizing	Up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the therapeutic gain of the second injection	Evaluate whether the second injection is associated with significant therapeutic gain on average pain intensity over 6 months	Throughout the study up to 6 months
Evaluate pain relief at 24 weeks	pain relief scale	24 weeks

Collaborators and Investigators

• Sponsor: Hospital Ambroise Paré Paris
• Investigators: Study Director: Nadine ATTAL, MD PhD, APHP and INSERM

Publications and helpful links

General Publications

• Attal N, de Andrade DC, Adam F, Ranoux D, Teixeira MJ, Galhardoni R, Raicher I, Uceyler N, Sommer C, Bouhassira D. Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2016 May;15(6):555-65. doi: 10.1016/S1474-4422(16)00017-X. Epub 2016 Mar 2.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): January 1, 2014
• Study Completion (ACTUAL): January 1, 2014

Study Registration Dates

• First Submitted: November 30, 2010
• First Submitted That Met QC Criteria: November 30, 2010
• First Posted (ESTIMATE): December 1, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): March 11, 2016
• Last Update Submitted That Met QC Criteria: March 10, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: NEUROPATHIC PAIN; RANDOMIZED CONTROLLED TRIAL; BOTULINUM TOXIN
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Polyneuropathies; Diabetic Neuropathies; Neuralgia, Postherpetic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: BOTNEP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO