Effectiveness and Safety of Methadone Versus Placebo for the Control of Neuropathic Pain in Different Etiologies

Study Overview
=================
Brief Summary
-----------------
Opioids are currently ranked as third-line agents for neuropathic pain (NP) treatment. The opioids more frequently tested for NP were tramadol, oxycodone and morphine. In the present study test the safety and effectiveness of methadone in patients with NP who remain symptomatic despite the use of first and second line drugs in a placebo-controlled randomized approach.

Detailed Description
-----------------
Background: neuropathic pain (NP) is highly refractory and it is estimated that about 40% of patients remain symptomatic despite the use of first and second line drugs. Opioids are currently ranked as third-line agents for NP treatment. The opioids more frequently tested for NP were tramadol, oxycodone and morphine. In the present study test the effectiveness and safety of methadone, an opioid agonist and glutamate n-methyl-d-aspartate (NMDA) receptor antagonist in patients with NP who remain symptomatic despite the use of first and second line drugs in a placebo-controlled randomized approach. Patients and Methods: this is a randomized, placebo controlled superiority trial including 80 subjects, aged between 18 and 85 years, with NP, that will be randomized to receive methadone or placebo in a 1:1 ratio. Enrollment will take place at the Pain Center of the University of São Paulo and it will include patients from primary care clinics from an area of 2 million people addressed to specialized care at a referral center. Expected results: the study hypothesis is that methadone is superior to placebo and it is safe to use that medication in patients with neuropathic pain. Recruitment time will be extended by 12 months due to dropouts related to the Covid pandemic. We have had dropouts due to a few patients developing covid and also due to patients having fear to become infected while attending hospital visits

Official Title
-----------------
A Randomized Controlled Trial Study to Assess the Effectiveness and Safety of Methadone Versus Placebo for the Control of Neuropathic Pain in Different Etiologies

Conditions
-----------------
Neuropathic Pain

Intervention / Treatment
-----------------
* Drug: methadone tablets
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Presence of an exclusive neuropathic pain (without other main pain syndrome occurring concomitantly at the same body area); Pain lasting at least 6 months (chronic) and being present most of the days; Pain fulfilling the current IASP (The International Association for the Study of Pain) criteria for defined Neuropathic Pain and with a score on the DN4 questionnaire (Douleur Neuropathique Pain 4 Questions) ≥ 4 (positive); The pain must be of at least moderate intensity (score on a visual analogue pain scale ≥ 40/100) despite the use of first and second line drugs in an adequate dosing. Exclusion Criteria: Patients under the age of 18 or over 85; Who has neuropathic pain duration less than 6 months; Who do not have an exclusive neuropathic pain (without other main pain syndrome occurring concomitantly at the same body area); Patients with neuropathic pain intensity less than 40 out of 100 on a visual analogue pain scale; Who scored less than 4 on the DN4 scale; Who wishes at any time to abandon the study; Patients with a previous allergic reaction to any of the drugs involved in the study (methadone) or placebo components; Patients in current use or in the last 14 days of medication (s) inhibitor (s) of monoamine oxidase (MAOI) or other medications with potential drug interaction with methadone; Patients in current continuous use of opioids (including methadone); Patients with a history of opioid abuse; Patients with a history of heavy/abusive alcohol consumption; Who is under judicial litigation, police custody or institutionalized for other reasons; Pregnant women, lactating women or women of childbearing age (without the use of an adequate contraceptive method); Patients with participation in another research protocol that implies the use of some medication during the 30 days preceding the inclusion in the project; Who uses illegal drugs; Patients unable to assess the risks and benefits of participating in the present study (eg, language barriers, psychiatric disorders or cognitive impairment); The presence of psychiatric disorders such as uncontrolled posttraumatic stress disorder, uncontrolled depression, uncontrolled anxiety disorder and suicidal ideation; Who has acute or chronic renal failure; Who has liver or heart failure; Who has a history of elevated cardiac QT interval, risk factors for elevated QT interval (including drugs that can prolong that interval), as well as cardiac arrhythmias/cardiac conduction abnormalities; Who has serious or intolerable adverse reactions to any component of the drugs involved in the study; Patients with a previous history of severe asthma or severe respiratory disease that may increase the risk of respiratory failure; Patients with active infectious gastrointestinal disease, active inflammatory gastrointestinal disease and obstruction of the gastrointestinal tract; Patients with history of recent traumatic brain injury (less than 7 days) or severe at any time interval; Who has moderate or severe obstructive sleep apnea-hypopnea syndrome; Who has uncontrolled hypothyroidism or hyperthyroidism; Patients with a history of uncontrolled epilepsy; Patients with current intracranial hypertension; Patients with grade III obesity (BMI ≥ 40 kg / m2).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: methadone<br>In this arm patients will take methadone 5mg | Drug: methadone tablets<br>* The intervention with the active drug (methadone) will start with the dose of 1 tablet (5 mg) twice a day (every 12 hours) and titrated on subsequent visits up to the maximum dose of 6 tablets a day (totaling 30 mg divided into 2 daily doses to facilitate therapeutic adherence).<br>* Other names: Mytedom;|
| Placebo Comparator: placebo<br>In this arm patients will take placebo tablets (the same number, color and physical aspects as the methadone tablets). | Drug: Placebo<br>* In this arm patients will take placebo tablets (the same number, color and physical aspects as the methadone tablets).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain intensity change from baseline, assessed by the visual analogue scale (VAS) | To evaluate the analgesic effect of methadone (number of patients with ≥ 30% pain intensity change from baseline) compared to placebo in patients with neuropathic pain (NP) of different etiologies. The impact on the average change in the intensity of NP (baseline) will be evaluated, with the main objective being a higher number of responders in the methadone at study completion compared to the placebo group. Responder is defined as pain intensity reduction greater than or equal to 30% compared to the baseline intensity of NP. It will be measured according to a visual analogue scale (VAS), 100 mm long, anchored by two verbal descriptors (0 mm being the total absence of pain and 100 mm being the worst imaginable pain). The measurement of the average change in the intensity of NP (baseline) will be performed by comparing the value on the first visit (day 0) with the value on the final visit (day 56). | 0 and 56 days | 
| Incidence of Serious Treatment-Emergent Adverse Events assessed by a questionnaire | The Incidence of Serious Treatment-Emergent Adverse Events will be assessed by measuring the number of participants who experience Serious Adverse Events with the use of methadone or placebo. The search for the adverse events will be done with a questionnaire containing the main adverse events previously described in the medical literature and in the manufacturer's label (methadone). In addition, unexpected adverse events will also be described in detail and reported to the responsible institution. The definition of a serious treatment adverse event will be made in accordance with the rules of the National System of Notifications for Health Surveillance-NOTIVISA. Each serious adverse event will be described in detail and notified to the responsible institution.The comparison between the incidence of Serious Treatment-Emergent Adverse Events will be made between the groups (methadone and placebo) at the end of the study. | 56 days | 
| Incidence of methadone addiction/misuse or withdrawal syndrome assessed by a prespecified questionnaire | The incidence of methadone addiction/misuse or withdrawal syndrome will be assessed by a prespecified questionnaire, containing eight clinical characteristics that may be related to the methadone addition/misuse or withdrawal syndromes. If one or more of those 8 characteristics listed in the questionnaire are present, an immediate communication will be made to the assistant physician (for diagnostic confirmation and referral to multidisciplinary treatment), as well as the exclusion of the individual from the study (after discussion with the research coordinators). | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of drop-outs due to Non-Serious Treatment-Emergent Adverse Events assessed by a questionnaire | The incidence of Non-Serious Treatment-Emergent Adverse Events will be assessed (at the end of the study) measuring the proportion of participants who experienced non-serious adverse events in each study group and the proportion of drop-out losses caused by such effects.The search for the adverse events will be done with a questionnaire containing the main adverse events previously described in the medical literature and in the manufacturer's label (methadone). In addition, unexpected adverse events will also be described in detail and reported to the responsible institution. | 56 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Methadone, Neuropathic Pain, Opioid, Pain