Clinical trial NCT02359006: The Effects of Minocycline in Opioid-maintained Patients
Official title: The Effects of Minocycline on Opioid-induced Hyperalgesia in Opioid-Maintained Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Opioid Dependence
Pain
Keywords: Analgesia
pain analgesia
methadone
opiates
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2015-02-09
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Opioids are the most commonly utilized pharmacological treatment for moderate to severe pain. However, their clinical value is hindered by the development of opioid-induced hyperalgesia (OIH). OIH manifests as heightened pain sensitivity, and is an increasingly challenging drawback to the efficacy of opioid treatment. Although the mechanism of action modulating OIH is not completely understood, previous animal studies suggest that this phenomenon is a result of proinflammatory responses. Thus, administering an adjunct anti-inflammatory agent may attenuate OIH. Minocycline is one such agent; it is a tetracycline derivative antibiotic that inhibits microglia activation, nitric oxide (NO) production, and the release of pro-inflammatory cytokines and chemokines. In fact, recent evidence suggests that minocycline may attenuate the neuroinflammatory effects of opioids while enhancing their antinociceptive effects. Therefore, the investigators will determine if minocycline will mitigate OIH in methadone-maintained patients.

Detailed description: Sixty completers will be recruited through the VA methadone clinic, as well as through the APT Foundation Methadone Maintenance Program. After the initial phone screening, potential subjects will undergo a comprehensive evaluation which will include medical, psychiatric, and drug use histories as well as physical, psychiatric, and laboratory examinations. Laboratory examination will include CBC, liver and thyroid function tests, serum electrolytes, BUN, creatinine, PT, PTT, urine analysis (including urine pregnancy for women) and urine toxicology screening.

Participants will be terminated from the study following opioid relapse, or use of any other psychotropic medications. If participants are noncompliant (no-show, positive urine screening, noncompliance with medication protocol/missing more than one dose of minocycline/placebo), participation will be terminated.

This double-blind, randomized clinical trial will randomize male and female veterans and non-veterans currently undergoing methadone maintenance treatment for opioid dependence to either minocycline (200mg/day) or placebo for 15 days. Upon inclusion, participants will be subjected to a pain assessment to evaluate baseline pain thresholds and tolerance: the Cold Pressor Test. An experimental treatment of either minocycline or placebo will then be initiated and maintained for 15 days. Additionally, at the beginning of Week 2 of treatment, participants will be given a Personal Digital Assistant (PDA) an HP iPAQ Pocket PC 2003 Pro that will administer Ecological Momentary Assessments (EMA). Using EMA, we can assess change in pain sensitivity, withdrawal symptoms and cognitive performance in the participants' natural environment, which increases the ecological validity of the study. Participants will be asked to return to the laboratory several times a week for the 15 consecutive days that they are taking minocycline in order to receive the study medication and to assess changes in pain thresholds and tolerance (i.e. to assess the presence, or lack thereof of hyperalgesia). Upon completion of experimental treatment, participants will be asked to return a final time to undergo pain measurement once more, to assess any changes in pain sensitivity after completion of minocycline.

Eligibility criteria: Inclusion Criteria:

* Males and females, between the ages of 18 and 55
* Diagnosed with opioid dependence and currently enrolled in methadone maintenance treatment
* Compliant in methadone maintenance treatment and on a stable dose for two weeks or greater
* No current dependence or abuse of any other drugs (other than tobacco or marijuana)
* No current medical problems
* For women:

  * not pregnant as determined by pregnancy screening;
  * not breast feeding; u
  * using acceptable birth control methods;
  * not experiencing moderate to severe premenstrual symptoms (may interfere with pain assessment);
  * regular menstrual cycles

Exclusion Criteria:

* Current major psychiatric illnesses including mood, psychotic, or anxiety disorders
* History of major medical illnesses, including liver diseases, heart disease, or other medical conditions that the physician investigator deems contraindicated for inclusion in the study
* Current use of over-the-counter or prescription psychoactive drugs (including regular use of NSAIDS, antidepressant, anxiolytics, antipsychotics, mood stabilizers, psychostimulants) or drugs that would be expected to have major interactions with drugs to be tested, e.g., benzodiazepines, codeine, Percocet, and other opiate drugs
* Liver function tests (ALT or AST) greater than 3x normal
* Allergy to minocycline or other tetracyclines

Primary outcomes:
measure: Pain Threshold
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Pain Tolerance
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary outcomes:
measure: Brief Pain Inventory - Short Form: Pain Severity
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Brief Pain Inventory - Short Form: Interference
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Opioid Withdrawal Symptom Checklist (OWSC): Back Pain Item
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Profile of Mood States (POMS) Depression Subscale
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Profile of Mood States (POMS) - Total Mood Disturbance
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Subscale
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Subscale
timeFrame: One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
measure: Interleukin-1 Beta (IL-1β)
timeFrame: Pre/post : At Screening before medication, and on Day 22 of medication
measure: Interleukin-6 (IL-6)
timeFrame: Pre/post : At Screening before medication, and on Day 22 of medication
measure: Tumor Necrosis Factor Alpha (TNF-α)
timeFrame: Pre/post : At Screening before medication, and on Day 22 of medication
measure: Ecological Momentary Assessments (EMA) - Pain
timeFrame: 4x/day for one week
measure: Ecological Momentary Assessments (EMA) - Craving
timeFrame: 4x/day for one week
measure: Ecological Momentary Assessments (EMA): SOWS
timeFrame: 4x/day over one week
measure: Digit Symbol Substitution Test
timeFrame: Baseline (Day 0), Pre- and 1-hour post-medication treatment on Test Days 8, 15 and 22, and at Follow-up (~Day 28
measure: Sustained Attention to Response Test (SART): No-go Trials: Errors of Commission
timeFrame: Baseline (Day 0), Pre- and 1-hour post-medication treatment on Test Days 8, 15 and 22, and at Follow-up (~Day 28
measure: Sustained Attention to Response Test (SART): Go Trials: Errors of Omission
timeFrame: Baseline (Day 0), Pre- and 1-hour post-medication treatment on Test Days 8, 15 and 22, and at Follow-up (~Day 28
Other outcomes:
Locations:
city: West Haven
country: United States
facility: VA Hospital
state: Connecticut
Study officials:
affiliation: Yale University
name: Mehmet Sofuoglu, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: