Randomized Controlled Trial of Efficacy and Safety of Local Anesthetics and Steroids for Chronic Peripheral Post-traumatic Neuropathic Pain (RESPERIST)

A Multi-center Randomized Controlled Trial of Efficacy and Safety of Perineural Local Anesthetics and Steroids for Chronic Peripheral Post-traumatic Neuropathic Pain: The Resperist Study

The purpose of this study is to evaluate three different injectable solutions used to block ankle nerves to manage ankle pain. The current standard of medical care is to inject a combination of local anesthetics and steroids around injured nerves. There is evidence that injection of local anesthetic (without the steroid) can calm the injured nerve and provide pain relief from a few days up to a few months. Injection of sterile salt water also has the potential to provide pain relief by breaking scar tissue around the nerve thereby relieving compression. Injections of local anesthetic and steroids around injured nerves have been used for many years to provide relief of pain but the specific reason is not well known for this benefit.

There are three possibilities: 1) Steroids can reduce inflammation and calm the nerves, 2) local anesthetics can have similar actions but with shorter duration (few days), and 3) injection of any solution can break scarring around an injured/compressed nerve.

The study will compare pain relief and possible adverse effects from these three different solutions. This study will help provide definitive answers regarding pain relief and possible adverse effects of the three solutions. This, in turn, will determine the best possible option for injection in patients with nerve-related injury pain.

Study Overview

• Status: Completed
• Conditions: Neuralgia; Peripheral Neuropathic Pain
• Intervention / Treatment: Drug: Bupivacaine; Drug: Lidocaine; Drug: Depo-Medrol Injectable Product; Other: Saline (Sodium Chloride) solution

Detailed Description

This project is a randomized controlled trial with the aim of comparing efficacy of image (ultrasound)-guided administration of perineural combination of steroids and local anesthetic (current standard of care) against perineural local anesthetic (LA) or saline in providing sustained analgesic benefit in people with chronic neuropathic pain (NP) of the foot and ankle.

The study design will be multi-center, prospective, concealed, blinded, parallel group trial with three groups, block randomization (blocks of six participants) and allocation in a 2:2:2 ratio. Study participants and outcome evaluators will be blinded to treatment assignments.

Participants will be randomly assigned to one of the three groups to receive two US-guided injections (at an interval of one to two weeks) of one of the following around one or more of the five nerves innervating the foot and ankle:

The initial procedure will be repeated after one to two weeks unless clinical circumstances dictate otherwise (that is, the patient declined a second injection because of increase in pain or satisfaction with pain relief). The rationale for the repeat procedure is to allow possible benefit from a cumulative effect of the procedures and/or the injectates. Between the first injection and first follow-up visit, no patient will be allowed any additional therapeutic interventions. Nerves to be targeted by the injection will be decided by the treating physician based on area of the foot and ankle that displays features of neuropathic pain. Each injection of study medications will be preceded by subcutaneous injections of 1 mLs of LA (2% lidocaine) at each of the injection sites. This will reduce discomfort of the study participants from the injections. The subcutaneous LA will also cause numbness of the skin and this will ensure blinding of participants to their group allocation. Two ultrasound-guided procedures will be performed at weekly intervals over two weeks. The US-guided technique for performing these procedures has been described in previous studies from our center.22 Conservative measures (oral analgesics, physiotherapy) will continue during the study. Fasting blood glucose will be measured at baseline and at one month following the interventions. Systolic and diastolic blood pressure (with participant sitting for at least 5 minutes prior to the measurement) values will be recoded as a mean of three consecutive readings at baseline and at one month following the interventions. Cross-sectional area (CSA) of tibial nerve at 3 cm proximal to cephalad edge of medial malleolus will also be measured prior to the first procedure and prior to the second procedure in participants with pain in distribution of the tibial nerve. Change in CSA (if any) will be correlated with analgesic response to perineural injections because decrease in CSA may indicate reduction in edema of the nerve.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pain in foot in neuro-anatomically congruent location following trauma (including surgery) for more than three months
2. Physician-reported DN4 scoring confirming neuropathic pain (score >3/10)
3. Average intensity of pain more than 3/10 on numerical rating score
4. Failed trial of appropriate doses of first line medications for neuropathic pain (anticonvulsants and/or antidepressants) for six weeks

Exclusion Criteria:

1. Age < 18 or Age > 80 years
2. Perineural or intra-articular steroid injections in the last 6 months
3. Allergy to local anesthetics or steroids
4. Ongoing litigation issues related to the patient's pain
5. Pregnancy
6. Coagulopathy or systemic infection
7. Peripheral neuropathy or myopathy, central neuropathic pain (e.g. post-stroke pain)
8. Infection in the ankle or foot
9. An unstable medical or psychiatric condition
10. Significant catastrophizing as indicated by pain catastrophizing scale (PCS) score equal to or more than 30/52.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Local Anesthetic; Injection of 2-6 cc of LA (0.25% bupivacaine) per nerve to a maximum of 20 cc	Drug: Bupivacaine; Other Names: Marcaine; Drug: Lidocaine; Each injection of study medications will be preceded by subcutaneous injections of 1 mLs of 2% lidocaine at each injection site to reduce discomfort of the study participants from the injections
ACTIVE_COMPARATOR: Local Anesthetic with steroids; Injection of 2-6 cc of LA (0.25% bupivacaine) per nerve containing steroids (methylprednisolone (Depo-Medrol) 4 mg per cc) to a maximum of 20 cc	Drug: Bupivacaine; Other Names: Marcaine; Drug: Lidocaine; Each injection of study medications will be preceded by subcutaneous injections of 1 mLs of 2% lidocaine at each injection site to reduce discomfort of the study participants from the injections; Drug: Depo-Medrol Injectable Product; Other Names: Methylprednisone
PLACEBO_COMPARATOR: Saline; Injection of 2-6 cc of saline (0.9% sodium chloride) per nerve to a maximum of 20 cc	Drug: Lidocaine; Each injection of study medications will be preceded by subcutaneous injections of 1 mLs of 2% lidocaine at each injection site to reduce discomfort of the study participants from the injections; Other: Saline (Sodium Chloride) solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Determination of Numerical Rating Scores (NRS) (range 0-10) for foot and ankle pain	One month after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measuring NRS (range 0-10) for foot and ankle pain		Three months after intervention compared to pre-intervention
Measuring changes in the PCS (Pain Catastrophizing Scale) Questionnaire		One month and three months after intervention compared to pre-intervention
Measuring changes in the Douleur Neuropathique (DN4) Questionnaire		One month and three months after intervention compared to pre-intervention
Measuring change in the NPSI (Neuropathic Pain Symptom Inventory) Questionnaire		One month and three months after intervention compared to pre-intervention
Measuring change in the Anxiety and Depression component scores on the Hospital Anxiety and Depression Scale (HADS)		One month and three months after intervention compared to pre-intervention
Measuring change in Depression scores on the Patient Health Questionnaire (PHQ-9)		One month and three months after intervention compared to pre-intervention
Measuring change in Brief Pain Inventory interference with activities (BPI-I) score		One month and three months after intervention compared to pre-intervention
Measuring change in Short Form-12 (SF-12) score		One month and three months after intervention compared to pre-intervention
Measuring change in Lower Extremity Function Score (LEFS)		One month and three months after intervention compared to pre-intervention
Measuring change in pain (cold pain and heat pain) thresholds as determined by quantitative sensory testing (QST)		One month and three months after intervention compared to pre-intervention
Measuring change in sensory (cold and hot detection) thresholds as determined by quantitative sensory testing (QST)		One month and three months after intervention compared to pre-intervention
Measurement of the cross-sectional area of tibial nerve for neural edema between interventions		One month and three months after intervention compared to pre-intervention
Measuring incidence of adverse effects	Hyperglycemia (change in blood glucose levels) and hypertension (change in blood pressure levels); Infections at the injection site, skin discolouration or atrophy at the injection site, fractures, and evidence of myopathy	One month and three months after intervention compared to pre-intervention

Collaborators and Investigators

• Sponsor: University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (ACTUAL): March 1, 2018
• Study Completion (ACTUAL): June 1, 2019

Study Registration Dates

• First Submitted: December 28, 2016
• First Submitted That Met QC Criteria: December 30, 2016
• First Posted (ESTIMATE): January 4, 2017

Study Record Updates

• Last Update Posted (ACTUAL): March 24, 2020
• Last Update Submitted That Met QC Criteria: March 23, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Lidocaine; Bupivacaine
• Other Study ID Numbers: 16-5927

Plan for Individual participant data (IPD)

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