Alcohol Use, Unspecified, Chronic Pain, HIV Infections
Conditions
Keywords
Pain, Alcohol, HIV, Inflammation, Low-dose naltrexone, Gabapentin
Brief summary
This study is a 3-arm pilot, randomized, double-blinded, placebo-controlled study of low-dose naltrexone and gabapentin versus placebo among HIV-positive persons with heavy alcohol use and chronic pain to provide estimates of their effects on 1) pain; 2) inflammation; and 3) measures of HIV control. Participants will be followed for 12 weeks. Assessments of study outcomes will be compared at week 8 (end of treatment phase).
Detailed description
Pain is a common co-morbidity for HIV-positive patients.Prevalence studies suggest that, on average, half of all HIV-positive persons suffer pain. Chronic pain can lead to heavy alcohol use among HIV-positive persons, which may in turn be a barrier to treatment/control of HIV and contribute to spread of HIV. Thus there is an urgent need to address pain among persons with HIV. It is timely and relevant to conduct research on gabapentin, as it has emerged as one of the most commonly prescribed non-opioid medications for pain despite the fact that gabapentin is only FDA approved for post-herpetic neuralgia and the literature to support its use for generalized chronic pain is limited. And yet, gabapentin has demonstrated benefits for treatment of alcohol use disorder, and therefore, like naltrexone, it could have a specific role for treating patients with chronic pain and unhealthy alcohol use. This study is a 3-arm pilot, randomized, double-blinded, placebo-controlled study of low-dose naltrexone and gabapentin vs. placebo among HIV-positive persons with heavy alcohol use and chronic pain to provide estimates of their effects on 1) pain (both self-reported and experimental/cold pressor test; 2) inflammation (i.e., levels of inflammatory cytokines IL-6, IL-1β, IL-10, and TNF-α); and 3) measures of HIV control (CD4 count and viral load).
Interventions
4.5 mg of low dose naltrexone taken once daily for 8 weeks. In week 1, participants will take 4.5mg of naltrexone once daily. In week 2, participants will take 4.5mg of naltrexone once daily, and a placebo capsule twice daily. In weeks 3 through 7, participants will take 1 placebo capsule with 4.5 mg mg of naltrexone once daily, and 2 placebo capsules twice daily. In week 8, in days 1-4 participants will take 4.5 mg of naltrexone with a placebo capsule once daily and 2 placebo capsules twice daily; in days 5-7, participants will take 4.5 mg of naltrexone once daily, and a placebo capsule twice daily.
DRUGGabapentin
Dose will begin at 300 mg daily (300 mg qd), in week 2 the dose will be titrated up to 900 mg daily (300 mg tid). In week 3, the dose will be titrated to 1800 mg daily ( 2 capsules of 300 mg tid) and participants will remain on that dose until week 8. In week 8, in days 1-4 participants will take 1800 mg daily (300 mg+300 mg tid); in days 5-7, participants will take 900 mg daily (300 mg of gabapentin three times daily).
DRUGPlacebo
In week 1, participants will take 1 placebo capsule once daily. In week 2, participants will take 1 placebo capsule three times per day. In weeks 3 through 7, 2 placebo capsules three times per day. In week 8, in days 1-4 participants will take 2 placebo capsules three times per day; in days 5-7, participants will take 1 placebo capsule three times per day. The placebo medications will be composed of lactose and will not contain active ingredients.
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Boston Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years or older * HIV-positive * Chronic pain (present ≥3 mo) of moderate to severe intensity * Heavy drinking past year (Based on NIAAA criteria: \> 14 standard drinks per week/ \> 4 drinks in a day for men; \> 7 drinks in the past week/ \> 3 drinks in a day for women) * If female, negative pregnancy test and willing to use adequate birth control * Provision of contact information for 2 contacts to assist with follow-up * Stable address within 100 kilometers of St. Petersburg * Possession of a telephone (home or cell) * Able and willing to comply with all study protocols and procedures
Exclusion criteria
* Not fluent in Russian * Cognitive impairment resulting in inability to provide informed consent based on research assessor (RA) assessment * Known active TB or current febrile illness * Breastfeeding * Known uncontrolled psychiatric illness (such as active psychosis) * Current suicidal ideation * History of hypersensitivity to naltrexone, gabapentin, or naloxone * Current use (past week) of illicit or prescribed opiates as documented by either self-report or positive urine drug test * Unwilling to abstain from opiates during the treatment period * Current use of neuroleptics * History of seizure disorder * Known liver failure * AST/ALT levels \>5x normal * CrCl\< 60mL/min * History of Reynaud's disease * Planned surgeries in the next 3 months * Enrolled in another HIV and/or substance use medication intervention study * Taking naltrexone in the past 30 days * Taking gabapentin in the past 30 days * Taking pregabalin in the past 30 days * Diagnosis of chronic obstructive pulmonary disease (COPD)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Past Week Pain Severity | Baseline, 8-weeks | Change in past week pain severity (score 0 \[no pain\] -10 \[high pain\]) from baseline to week 8. Pain severity will be measured using the Brief Pain Inventory, which allows patients to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function |
| Change in Past Week Pain Interference | Baseline, 8-weeks | Change in past week pain interference (score 0 \[no pain\]-10 \[high pain\]) from baseline to week 8. Pain interference will be measured using the Brief Pain Inventory, which allows patients to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cold Pain Tolerance | Baseline, 8-weeks | Mean change in the number of seconds a participant can keep their hand submerged in a container of iced water. Participants were instructed to keep their hand in as long as they could, up to 3 minutes. |
| Change in Percentage of Past Month Heavy Drinking Days | Baseline, 8-weeks | Mean percentage of change in self-reported heavy drinking in the past 30 days of alcohol consumption obtained via the Timeline Followback (TLFB) method. The NIAAA definition of heavy drinking is used (\> 4 drinks in a day for men; \> 3 drinks in a day for women). Participants were asked about their alcohol consumption on each day in the previous 30 days. |
| Change in Biomarker IL-6 | Baseline, 8-weeks | Mean change in IL-6 values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems). |
| Change in CD4 Count | Baseline, 8-weeks | Defined as mean change in CD4 values from lab assay |
| Change in TNF-alpha | Baseline, 8-weeks | Mean change in TNF-alpha values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems). |
| Change in IL-1beta | Baseline, 8-weeks | Mean change in IL-1beta values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems). |
| Change in Biomarker IL-10 | Baseline, 8 weeks | Mean change in IL-10 values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems). |
| Number of Participants With a Change in HIV Viral Load Suppression Status | Baseline, 8-weeks | Defined as number of participants who change from suppressed to unsuppressed or unsuppressed to suppressed from lab tests |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low-dose Naltrexone Participants randomized to this group will receive low dose naltrexone (4.5 mg) for 8 weeks.
Low-dose naltrexone: 4.5 mg of low dose naltrexone taken once daily for 8 weeks. In week 1, participants will take 4.5mg of naltrexone once daily. In week 2, participants will take 4.5mg of naltrexone once daily, and a placebo capsule twice daily. In weeks 3 through 7, participants will take 1 placebo capsule with 4.5 mg mg of naltrexone once daily, and 2 placebo capsules twice daily. In week 8, in days 1-4 participants will take 4.5 mg of naltrexone with a placebo capsule once daily and 2 placebo capsules twice daily; in days 5-7, participants will take 4.5 mg of naltrexone once daily, and a placebo capsule twice daily. | 15 |
| Gabapentin Participants randomized to the gabapentin arm begin on a dose of 300 mg daily (300 mg qd). In week 2, participants will take 300 mg of gabapentin three times daily. In week 3 the dose will be titrated up to 1800 mg daily (300 mg+300 mg tid) will remain on the dose until week 8, when they will be tapered back down to 900 mg daily (300 mg tid). In week 8, in days 1-4 participants will take 1800 mg daily (300 mg+300 mg tid); in days 5-7, participants will take 900 mg daily (300 mg of gabapentin three times daily).
Gabapentin: Dose will begin at 300 mg daily (300 mg qd), in week 2 the dose will be titrated up to 900 mg daily (300 mg tid). In week 3, the dose will be titrated to 1800 mg daily ( 2 capsules of 300 mg tid) and participants will remain on that dose until week 8. In week 8, in days 1-4 participants will take 1800 mg daily (300 mg+300 mg tid); in days 5-7, participants will take 900 mg daily (300 mg of gabapentin three times daily). | 15 |
| Placebo Participants will receive a placebo to be taken three times daily for 8 weeks.
Placebo: In week 1, participants will take 1 placebo capsule once daily. In week 2, participants will take 1 placebo capsule three times per day. In weeks 3 through 7, 2 placebo capsules three times per day. In week 8, in days 1-4 participants will take 2 placebo capsules three times per day; in days 5-7, participants will take 1 placebo capsule three times per day. The placebo medications will be composed of lactose and will not contain active ingredients. | 15 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Low-dose Naltrexone | Total | Placebo | Gabapentin |
|---|---|---|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 6 | 41 years STANDARD_DEVIATION 7 | 41 years STANDARD_DEVIATION 7 | 41 years STANDARD_DEVIATION 7 |
| Anxiety Mild anxiety | 2 Participants | 7 Participants | 3 Participants | 2 Participants |
| Anxiety Minimal anxiety | 11 Participants | 33 Participants | 11 Participants | 11 Participants |
| Anxiety Moderate anxiety | 2 Participants | 5 Participants | 1 Participants | 2 Participants |
| CD4 count | 648 cell/mm^3 STANDARD_DEVIATION 273 | 791 cell/mm^3 STANDARD_DEVIATION 331 | 917 cell/mm^3 STANDARD_DEVIATION 381 | 808 cell/mm^3 STANDARD_DEVIATION 290 |
| Cold pain threshold | 21 seconds STANDARD_DEVIATION 17 | 17 seconds STANDARD_DEVIATION 13 | 14 seconds STANDARD_DEVIATION 6 | 15 seconds STANDARD_DEVIATION 13 |
| Cold pain tolerance | 42 seconds STANDARD_DEVIATION 33 | 37 seconds STANDARD_DEVIATION 33 | 36 seconds STANDARD_DEVIATION 41 | 33 seconds STANDARD_DEVIATION 25 |
| Depressive symptoms Depressive symptoms | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Depressive symptoms No depressive symptoms | 12 Participants | 36 Participants | 12 Participants | 12 Participants |
| Education - 9 grades or more | 15 Participants | 45 Participants | 15 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 45 Participants | 15 Participants | 15 Participants |
| Harmful or hazardous drinking (AUDIT) AUDIT score <8 | 5 Participants | 18 Participants | 7 Participants | 6 Participants |
| Harmful or hazardous drinking (AUDIT) AUDIT score 8+ | 10 Participants | 27 Participants | 8 Participants | 9 Participants |
| HIV viral load suppression Suppressed viral load | 12 Participants | 41 Participants | 15 Participants | 14 Participants |
| HIV viral load suppression Unsuppressed viral load | 3 Participants | 4 Participants | 0 Participants | 1 Participants |
| IL-10 biomarker | 3.81 pg/ml STANDARD_DEVIATION 0.7 | 3.86 pg/ml STANDARD_DEVIATION 0.7 | 3.92 pg/ml STANDARD_DEVIATION 0.8 | 3.85 pg/ml STANDARD_DEVIATION 0.7 |
| IL-1-beta biomarker | 5.73 pg/ml STANDARD_DEVIATION 0.5 | 5.61 pg/ml STANDARD_DEVIATION 0.6 | 5.53 pg/ml STANDARD_DEVIATION 0.6 | 5.57 pg/ml STANDARD_DEVIATION 0.7 |
| IL-6 biomarker | 3.77 pg/ml STANDARD_DEVIATION 0.66 | 3.67 pg/ml STANDARD_DEVIATION 0.5 | 3.5 pg/ml STANDARD_DEVIATION 0.38 | 3.73 pg/ml STANDARD_DEVIATION 0.4 |
| Lifetime opioid use No use of opioids in lifetime | 6 Participants | 20 Participants | 8 Participants | 6 Participants |
| Lifetime opioid use Use of opioids in lifetime | 9 Participants | 25 Participants | 7 Participants | 9 Participants |
| Marital status Married/living with partner/long-term relationship | 5 Participants | 22 Participants | 6 Participants | 11 Participants |
| Marital status Never married/divorced/widowed/separated | 10 Participants | 23 Participants | 9 Participants | 4 Participants |
| Number of heavy drinking days in past 30 days | 2 days STANDARD_DEVIATION 4 | 2 days STANDARD_DEVIATION 4 | 2 days STANDARD_DEVIATION 4 | 2 days STANDARD_DEVIATION 3 |
| Past month heavy drinking days (%) | 8 % days STANDARD_DEVIATION 14.6 | 7.6 % days STANDARD_DEVIATION 12.8 | 8 % days STANDARD_DEVIATION 14.5 | 6.7 % days STANDARD_DEVIATION 9.4 |
| Past week pain interference | 3 units on a scale STANDARD_DEVIATION 2 | 3 units on a scale STANDARD_DEVIATION 2 | 3 units on a scale STANDARD_DEVIATION 2 | 3 units on a scale STANDARD_DEVIATION 2 |
| Past week pain severity | 3.2 units on a scale STANDARD_DEVIATION 1.4 | 3.2 units on a scale STANDARD_DEVIATION 1.3 | 3.3 units on a scale STANDARD_DEVIATION 1.5 | 3.1 units on a scale STANDARD_DEVIATION 1.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 45 Participants | 15 Participants | 15 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Russia | 15 participants | 45 participants | 15 participants | 15 participants |
| Sex: Female, Male Female | 6 Participants | 16 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 9 Participants | 29 Participants | 10 Participants | 10 Participants |
| TNF-alpha biomarker | 5.70 pg/ml STANDARD_DEVIATION 0.7 | 5.97 pg/ml STANDARD_DEVIATION 1 | 6.35 pg/ml STANDARD_DEVIATION 1.2 | 5.86 pg/ml STANDARD_DEVIATION 0.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 4 / 15 | 5 / 15 | 2 / 15 |
| serious Total, serious adverse events | 1 / 15 | 0 / 15 | 1 / 15 |
Outcome results
Primary
Change in Past Week Pain Interference
Change in past week pain interference (score 0 \[no pain\]-10 \[high pain\]) from baseline to week 8. Pain interference will be measured using the Brief Pain Inventory, which allows patients to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in Past Week Pain Interference | -1.73 units on a scale | Standard Error 0.47 |
| Gabapentin | Change in Past Week Pain Interference | -1.97 units on a scale | Standard Error 0.64 |
| Placebo | Change in Past Week Pain Interference | -2.14 units on a scale | Standard Error 0.58 |
Primary
Change in Past Week Pain Severity
Change in past week pain severity (score 0 \[no pain\] -10 \[high pain\]) from baseline to week 8. Pain severity will be measured using the Brief Pain Inventory, which allows patients to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in Past Week Pain Severity | -0.97 units on a scale | Standard Error 0.63 |
| Gabapentin | Change in Past Week Pain Severity | -2.12 units on a scale | Standard Error 0.38 |
| Placebo | Change in Past Week Pain Severity | -1.85 units on a scale | Standard Error 0.61 |
Secondary
Change in Biomarker IL-10
Mean change in IL-10 values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems).
Time frame: Baseline, 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in Biomarker IL-10 | -0.13 pg/ml | Standard Error 0.25 |
| Gabapentin | Change in Biomarker IL-10 | 0.07 pg/ml | Standard Error 0.16 |
| Placebo | Change in Biomarker IL-10 | -0.26 pg/ml | Standard Error 0.23 |
Secondary
Change in Biomarker IL-6
Mean change in IL-6 values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems).
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in Biomarker IL-6 | -0.12 pg/ml | Standard Error 0.19 |
| Gabapentin | Change in Biomarker IL-6 | 0.04 pg/ml | Standard Error 0.12 |
| Placebo | Change in Biomarker IL-6 | 0.29 pg/ml | Standard Error 0.14 |
Secondary
Change in CD4 Count
Defined as mean change in CD4 values from lab assay
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in CD4 Count | 15.85 cell/mm^3 | Standard Error 74.96 |
| Gabapentin | Change in CD4 Count | -106.47 cell/mm^3 | Standard Error 64.94 |
| Placebo | Change in CD4 Count | -52.13 cell/mm^3 | Standard Error 82.43 |
Secondary
Change in Cold Pain Tolerance
Mean change in the number of seconds a participant can keep their hand submerged in a container of iced water. Participants were instructed to keep their hand in as long as they could, up to 3 minutes.
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in Cold Pain Tolerance | -14.78 seconds | Standard Error 7.61 |
| Gabapentin | Change in Cold Pain Tolerance | -3.33 seconds | Standard Error 4.56 |
| Placebo | Change in Cold Pain Tolerance | -3.15 seconds | Standard Error 6.89 |
Secondary
Change in IL-1beta
Mean change in IL-1beta values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems).
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in IL-1beta | 0.30 pg/ml | Standard Error 0.22 |
| Gabapentin | Change in IL-1beta | 0.95 pg/ml | Standard Error 0.29 |
| Placebo | Change in IL-1beta | 0.41 pg/ml | Standard Error 0.2 |
Secondary
Change in Percentage of Past Month Heavy Drinking Days
Mean percentage of change in self-reported heavy drinking in the past 30 days of alcohol consumption obtained via the Timeline Followback (TLFB) method. The NIAAA definition of heavy drinking is used (\> 4 drinks in a day for men; \> 3 drinks in a day for women). Participants were asked about their alcohol consumption on each day in the previous 30 days.
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in Percentage of Past Month Heavy Drinking Days | 3.07 % of change in heavy drinking days | Standard Error 5.17 |
| Gabapentin | Change in Percentage of Past Month Heavy Drinking Days | -4.22 % of change in heavy drinking days | Standard Error 2.07 |
| Placebo | Change in Percentage of Past Month Heavy Drinking Days | -4.63 % of change in heavy drinking days | Standard Error 4.64 |
Secondary
Change in TNF-alpha
Mean change in TNF-alpha values measured on blood samples collected using commercially available enzyme-linked immunosorbent assay kits (R&D Systems).
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-dose Naltrexone | Change in TNF-alpha | 0.27 pg/ml | Standard Error 0.31 |
| Gabapentin | Change in TNF-alpha | 0.47 pg/ml | Standard Error 0.15 |
| Placebo | Change in TNF-alpha | 0.21 pg/ml | Standard Error 0.42 |
Secondary
Number of Participants With a Change in HIV Viral Load Suppression Status
Defined as number of participants who change from suppressed to unsuppressed or unsuppressed to suppressed from lab tests
Time frame: Baseline, 8-weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low-dose Naltrexone | Number of Participants With a Change in HIV Viral Load Suppression Status | 1 Participants |
| Gabapentin | Number of Participants With a Change in HIV Viral Load Suppression Status | 0 Participants |
| Placebo | Number of Participants With a Change in HIV Viral Load Suppression Status | 0 Participants |