Clinical trial NCT05235191: Effectiveness and Safety of Methadone Versus Placebo for the Control of Neuropathic Pain in Different Etiologies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neuropathic Pain
Keywords: Methadone
Neuropathic Pain
Opioid
Pain
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
First posted: 2022-02-11
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: Inclusion Criteria:

1. Presence of an exclusive neuropathic pain (without other main pain syndrome occurring concomitantly at the same body area);
2. Pain lasting at least 6 months (chronic) and being present most of the days;
3. 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);
4. 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).

Primary outcomes:
measure: Pain intensity change from baseline, assessed by the visual analogue scale (VAS)
timeFrame: 0 and 56 days
measure: Incidence of Serious Treatment-Emergent Adverse Events assessed by a questionnaire
timeFrame: 56 days
measure: Incidence of methadone addiction/misuse or withdrawal syndrome assessed by a prespecified questionnaire
timeFrame: 56 days
Secondary outcomes:
measure: Incidence of drop-outs due to Non-Serious Treatment-Emergent Adverse Events assessed by a questionnaire
timeFrame: 56 days
Other outcomes:
measure: Improvement in sleep quality, assessed by The Medical Outcomes Study Sleep Problem Index II (SPI II)
timeFrame: 56 days
measure: Improvement in mood and anxiety symptoms, assessed by The Hospital Anxiety and Depression Scale (HADS)
timeFrame: 56 days
measure: Improvement in quality of life, assessed by The Short-Form 6 dimensions Questionnaire (SF-6D)
timeFrame: 56 days
Locations:
city: São Paulo
country: Brazil
facility: University of São Paulo
Study officials:
affiliation: University of Sao Paulo
name: Daniel C. de Andrade, PhD
role: STUDY_CHAIR
References: