The Effects of Minocycline in Opioid-maintained Patients

Pain Clinical Trial

Official title:

The Effects of Minocycline on Opioid-induced Hyperalgesia in Opioid-Maintained Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02359006
• Other study ID #: 1412015119
• Secondary ID: 2T32DA007238-26
• Status: Completed
• Phase: N/A
• Start date: March 12, 2015
• Est. completion date: April 19, 2017

Study information

• Verified date: March 2020
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 27
• Est. completion date: April 19, 2017
• Est. primary completion date: April 19, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Opioid Dependence
• Opioid-Related Disorders
• Pain

Intervention

Drug:
• Minocycline
Minocycline will be compared with placebo
• Placebo
Placebo will be compared with minocycline

Locations

Country	Name	City	State
United States	VA Hospital	West Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	National Institute on Drug Abuse (NIDA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pain Threshold	The Cold Pressor Test (CPT) measures pain threshold (in seconds). For this test, two water coolers filled with either warm (100.04ºF/37.8ºC) or cold water (32.9-34.7ºF/0.5-1.5ºC) are used. To begin the CPT, participants first immerse their hand into the warm-water bath for 2 min. Participants are then instructed to immerse their hand into the cold water bath and report the first time they experience pain (pain threshold). Lower scores indicate lower pain threshold. Minimum score is 0 seconds, and a maximum cut-off score of 300 seconds is used to prevent tissue damage.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Primary	Pain Tolerance	The Cold Pressor Test (CPT) measures pain threshold and pain tolerance (in seconds). For this test, two water coolers filled with either warm (100.04ºF/37.8ºC) or cold water (32.9-34.7ºF/0.5-1.5ºC) are used. To begin the CPT, participants first immerse their hand into the warm-water bath for 2 min. Participants are then instructed to immerse their hand into the cold water bath and report when the pain becomes unbearable (pain tolerance). Lower scores indicate lower pain tolerance. Minimum score is 0 seconds, and a maximum cut-off score of 300 seconds is used to prevent tissue damage.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Brief Pain Inventory - Short Form: Pain Severity	Brief Pain Inventory - Short Form: BPI-SF is a self-report questionnaire that assesses the impact of pain on daily function, location of pain, pain medications, and amount of pain relief in the past 24 hours or the past week. Each question is scored 0-10, and the scores are summed and then averaged to create a pain severity score. Minimum score is 0; maximum score is 10. Higher scores indicate more severely perceived pain.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Brief Pain Inventory - Short Form: Interference	Brief Pain Inventory - Short Form: BPI-SF is a self-report questionnaire that assesses 7 questions each rated on a scale of 0-10, which are added and divided by 7. This average score of 7 questions gives a "pain interference with living" score, with a minimum score of 0 and a maximum score of 10.; Higher scores indicate that pain interferes more with aspects of daily life.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Opioid Withdrawal Symptom Checklist (OWSC): Back Pain Item	For safety reasons, withdrawal signs and symptoms were assessed using a 22-item withdrawal instrument that has been reliably used to assess opiate withdrawal. As an additional assessment of daily pain, the presence of "back pain" item was analyzed. This item has a minimum score of 0 and maximum score of 4, with higher scores indicates more agreement with statement/more back pain.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Profile of Mood States (POMS) Depression Subscale	The POMS is a 65-item scale that divides items amongst eight mood states (tension, depression, anger, fatigue, confusion, vigor) on a 5-point rating scale (0=not at all to 5=extremely). We analyzed the 15-item "Depression" subscale, which has a minimum score of 0 and a maximum score of 75. Higher score indicate more agreement with the statement/more feelings of depression.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Profile of Mood States (POMS) - Total Mood Disturbance	The POMS is a 65-item scale that divides items amongst eight mood states (tension, depression, anger, fatigue, confusion, vigor) on a 5-point rating scale (0=not at all to 5=extremely). Total Mood Disturbance is calculated by adding the "tension, depression, anger, fatigue, and confusion" subscale scores and subtracting the "vigor" subscale score. This has a minimum of 0 and a maximum score of 210. Higher score indicate more mood disturbance.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Subscale	This measure is a subscale of the SF-MPQ, comprised of 11 of the 15 total items. The measure is completed immediately after the CPT, where participants describe their experience of CPT pain by choosing among a series of possible answers [none (score=0), mild (score=1), moderate (score=2), or severe (score=3)]. The items to describe the pain are 'Throbbing','Shooting', 'Stabbing', 'Sharp', 'Cramping', 'Gnawing', 'Hot/burning', 'Aching', 'Heavy', 'Tender', and 'Splitting'. The scores for these 11 items are summed as a measure of Sensory pain, with a minimum score of 0 and a maximum score of 33.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Subscale	This measure is a subscale of the SF-MPQ, comprised of 4 of the 15 total items. The measure is completed immediately after the CPT, where participants describe their experience of CPT pain by choosing among a series of possible answers [none (score=0), mild (score=1), moderate (score=2), or severe (score=3)]. The items to describe the pain are 'Tiring-Exhausting', 'Sickening', 'Fearful', 'Punishing-Cruel'. The scores for these 4 items are summed as a measure of Affective pain, with a minimum score of 0 and a maximum score of 12.	One measurement at each of 5 weekly sessions: Baseline, Day 8, Day 15, Day 22 and at Follow-up (~Day 28)
Secondary	Interleukin-1 Beta (IL-1ß)	Serum cytokine analysis assayed using electrochemiluminescence multi-array technology (Meso Scale Discovery, Gaithersburg, MD). IL-1ß is measured in pictograms per milliliter (pg/ml). Cytokines were assessed at screening (approximately 1 week prior to medication), and on the last day of medication treatment. Higher numbers indicate higher blood levels of this cytokine.	Pre/post : At Screening before medication, and on Day 22 of medication
Secondary	Interleukin-6 (IL-6)	Serum cytokine analysis assayed using electrochemiluminescence multi-array technology (Meso Scale Discovery, Gaithersburg, MD). IL-6 is measured in pictograms per milliliter (pg/ml).Cytokines were assessed at screening (approximately 1 week prior to medication), and on the last day of medication treatment. Higher numbers indicate higher blood levels of this cytokine.	Pre/post : At Screening before medication, and on Day 22 of medication
Secondary	Tumor Necrosis Factor Alpha (TNF-a)	Serum cytokine analysis assayed using electrochemiluminescence multi-array technology (Meso Scale Discovery, Gaithersburg, MD). TNF-a is measured in pictograms per milliliter (pg/ml).Cytokines were assessed at screening (approximately 1 week prior to medication), and on the last day of medication treatment. Higher numbers indicate higher blood levels of this cytokine.	Pre/post : At Screening before medication, and on Day 22 of medication
Secondary	Ecological Momentary Assessments (EMA) - Pain	Participants will be asked "Do you feel any pain at this moment" on seven-point Likert scales (1=strongly disagree to 7=strongly agree) 4 times per day outside of the laboratory (in their natural environment) using a personal digital assistant on days 8-14 of medication treatment. All scores were averaged to compute one score. Higher scores indicate more feelings of pain.	4x/day for one week
Secondary	Ecological Momentary Assessments (EMA) - Craving	Participants will be asked "Are you craving heroin at this moment" on seven-point Likert scales (1=strongly disagree to 7=strongly agree) 4 times per day outside of the laboratory (in their natural environment) using a personal digital assistant on days 8-14 of medication treatment. All scores were averaged to compute one score. Higher scores indicate more craving for heroin.	4x/day for one week
Secondary	Ecological Momentary Assessments (EMA): SOWS	Self-report opioid withdrawal scale. Withdrawal symptoms are measured on a 7-point Likert scale (1=strongly disagree, 7=strongly agree). Participants complete these ratings 4 times per day on days 8-14 of medication treatment. All scores were averaged to compute one score. Higher scores indicate more withdrawal symptoms.	4x/day over one week
Secondary	Digit Symbol Substitution Test	The DSST is a test of psychomotor performance, which measures motor persistence, sustained attention, response speed and visuomotor coordination. The task is to fill in blank spaces with the symbols that are paired with the number above the blank space as fast as possible for 90 sec. The minimum score is 0 and the maximum score is 120. Higher numbers indicate better cognitive performance.	Baseline (Day 0), Pre- and 1-hour post-medication treatment on Test Days 8, 15 and 22, and at Follow-up (~Day 28
Secondary	Sustained Attention to Response Test (SART): No-go Trials: Errors of Commission	The SART is a Go No-Go task. It assesses the ability to withhold responses to an infrequently occurring target (No-Go trials). A total of 225 single digits (25 x 9 digits) are presented on a computer monitor for 250 ms each, immediately followed by a mask for 900 ms. Subjects must press a spacebar in response to every digit except the "3". Higher numbers indicate more errors of commission.	Baseline (Day 0), Pre- and 1-hour post-medication treatment on Test Days 8, 15 and 22, and at Follow-up (~Day 28
Secondary	Sustained Attention to Response Test (SART): Go Trials: Errors of Omission	The SART is a Go No-Go task. It assesses the ability to withhold responses to an infrequently occurring target (No-Go trials).The SART is a Go No-Go task. It assesses the ability to withhold responses to an infrequently occurring target (No-Go trials). A total of 225 single digits (25 x 9 digits) are presented on a computer monitor for 250 ms each, immediately followed by a mask for 900 ms. Subjects must press a spacebar in response to every digit except the "3". Higher numbers indicate more errors of omission.	Baseline (Day 0), Pre- and 1-hour post-medication treatment on Test Days 8, 15 and 22, and at Follow-up (~Day 28