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Chronic neuropathic pain (CNP) is disabling. Research on frontline treatments for CNP, shows inconsistent outcomes and dissatisfaction among Veterans. Veterans and clinicians have shown significant interest in cannabis derivatives (THC, CBD) for neuropathic pain control, but there are no well-controlled trials guiding expectations for benefit and adverse outcomes associated with cannabis for CNP. Because Veterans are likely to present with pain and pain-related polymorbidity significantly differing from that of civilians, a well-structured clinical trial of cannabinoids for Veterans with CNP is vital.
Chronic pain is a significant burden to United States Veterans and is a particular concern for Veterans. One of the causes of pain is chronic neuropathic pain (CNP). Frontline treatment for CNP, show inconsistent outcomes and have significant side effects. The ongoing opioid crisis has led to significant interest in safe and effective alternatives for pain control, and there is a significant need for research on desirable options for pain control that are likely to improve treatment adherence and outcomes. Veterans groups and Veterans Affairs clinicians have expressed significant interest in cannabis and its principal constituents (delta-9-tetrahydrocannabinol, THC; cannabidiol, CBD) for pain management, but the extant research describing the potential risks and benefits of cannabis for pain is weak. This randomized trial was developed as a proof of concept study to determine if cannabis constituents (THC, CBD, and THC+CBD) are superior to placebo in reducing pain in Veterans with CNP. The study is to recruit a sample of 320 adult Veterans who meet diagnostic criteria for high-impact CNP, are on stable treatment(s) for CNP, are not current cannabis users and who do not meet diagnostic criteria for Cannabis Use Disorder. This randomized phase II, 4-arm clinical trial aims to determine if cannabis constituents (THC, CBD) or their combination (THC+CBD) are superior to placebo in reducing pain in Veterans with CNP. This trial will offer the first evidence describing the potential benefits and adverse effects of cannabinoids for CNP in Veterans.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| THC (Syndros) | Active Comparator | Target dose of 10mg per day. |
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| CBD (Epidolex) | Active Comparator | Target dose of 800 mg per day. |
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| THC + CBD (Nabiximols) | Active Comparator | Target dose of 10.8 mg / 10 mg per day. |
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| Placebo | Placebo Comparator | Identical in appearance to the three active comparators. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| THC (Syndros) | Drug | Participants will receive a target dose of 10mg per day of THC (Syndros). |
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| Measure | Description | Time Frame |
|---|---|---|
| To compare the short-term efficacy of THC, CBD, or THC+CBD vs Placebo on Neuropathic Pain as measured by the Numeric Rating Scale of Pain | The mean change in the weekly average of daily Numeric Rating Scale (NRS) pain score (0-10 scale; 0=no pain, 10=worst possible pain) from baseline to week 6. | Baseline, Week 6 |
| Measure | Description | Time Frame |
|---|---|---|
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in pain quality (allodynia) as measured by the Quantitative Sensory Testing. | Allodynia measured by Quantitative Sensory Testing (QST) (0-10 scale; 0=no pain, 10=worst possible pain) | Baseline, Week 2, Week 4, Week 6, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in disability and function as measured by the Neuropathic Pain Scale. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Courtney C DiCocco | Contact | (203) 932-5711 | Courtney.DiCocco@va.gov | |
| Mohini Ranganathan, MD | Contact | (203) 932-5711 | Mohini.Ranganathan@va.gov |
| Name | Affiliation | Role |
|---|---|---|
| Deepak D'Souza, MD MBBS | VA Connecticut Healthcare System West Haven Campus, West Haven, CT | Principal Investigator |
| Donald McGeary, PhD | South Texas Health Care System, San Antonio, TX | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA San Diego Healthcare System, San Diego, CA | Recruiting | San Diego | California | 92161-0002 | United States |
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Double-blind, randomized, placebo-controlled, parallel group Phase II study with randomization to one of the four treatment arms: 1) 10 mg mg THC , 2) 800 mg CBD , 3) 10.8 mg THC + 10 mg CBD , and 4) placebo. The 8-week treatment phase comprises a 2-week up-titration, 4 weeks maintenance on the target dose followed by 2 weeks down-titration, to minimize cannabis withdrawal syndrome. The two-weeks up titration phase is to minimize side effects and improve tolerability. Efficacy will be assessed by responses during the 4-week target dose phase.
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| CBD (Epidolex) | Drug | Participants will receive a target dose of 800 mg per day of CBD (Epidolex). |
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| THC + CBD (Nabiximols) | Drug | Participants will receive a target dose of 10.8 mg / 10 mg per day of THC + CBD (Nabiximols). |
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| Placebo | Drug | Placebo |
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Neuropathic Pain Scale (NPS) total score; 7 different questions/sensations (for each individual item 0-10 scale; 0= not present/no pain, 10= most sensation). Individual scores analyzed separately for pain quality and mean score analyzed for overall neuropathic pain). |
| Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in disability and function as measured by the Gait Speed Test | Distance walked (meters)/time (seconds) measured by Gait Speed Test (lower score = worse, higher score =better) | Baseline, Week 4, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in perceived improvement as measured by the Patient Global Impression of Change | Patient Global Impression of Change (PGIC) 1-7 point ordinal scale assessed (1 = worse, 7 = better) | Baseline, Week 2, Week 4, Week 6, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in perceived improvement as measured by the patient satisfaction visual analog scale. | Patient satisfaction with intervention on visual analog scale (VAS, 0-100, 0=no satisfaction, 100 = complete satisfaction). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in quality of life measured by the Veterans RAND 12 Item Health Survey | Mental Component Score (MCS) and Physical Component Score (PCS) measured by Veterans RAND 12 Item Health Survey (VR-12). VR-12 is an algorithmic score with ranges from 0-100 (0 indicates worse health-related quality of life and 100 represents better health-related quality of life). | Baseline, Week 4, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in anxiety measured by the Generalized Anxiety Disorder-7. | Generalized anxiety symptomology is measured by Generalized Anxiety Disorder-7 (GAD-7) total score. (total score ranges from 0-21; Score 0-4 = minimal anxiety, Score 5-9 = mild anxiety, Score 10-14 = moderate anxiety, Score 15-21 = severe anxiety) | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in pain quality as measured by the Short Form McGill Pain Questionnaire (SF-MPQ-2). | Short Form McGill Pain Questionnaire (SF-MPQ-2) total score and four subscales (continuous pain, intermittent pain, predominantly neuropathic pain, affective). (0= no pain to 5= excruciating pain) | Baseline, Week 2, Week 4, Week 6, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in mean changes in disability and function as measured by the Brief Pain Inventory-Diabetic Peripheral Neuropathy. | Brief Pain Inventory-Diabetic Peripheral Neuropathy (BPI-DPN) pain intensity score (first four items 0-10; 10= pain as bad as can imagine) (remaining items 0% (no relief)-100% (complete relief)) and pain interference score (0-10, 10= completely intense). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in emotional functioning (severity of depression) as measured by the Patient Health Questionnaire-9. | Severity of depression is measured by Patient Health Questionnaire-9 (PHQ-9) total score (0-27; 0=none, 27=worst). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 |
| To assess the efficacy of THC, CBD, or THC+CBD vs Placebo in emotional functioning (PTSD symptoms) as measured by the PTSD Checklist-DSM-5 (PCL-5). | PTSD symptoms are assessed by PTSD Checklist-DSM-5 (PCL-5) total score symptom severity score (0-80; 0= not at all to 80= worst). | Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 |
| VA Greater Los Angeles Healthcare System, West Los Angeles, CA | Active, not recruiting | West Los Angeles | California | 90073-1003 | United States |
| VA Connecticut Healthcare System West Haven Campus, West Haven, CT | Recruiting | West Haven | Connecticut | 06516-2770 | United States |
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| Providence VA Medical Center, Providence, RI | Recruiting | Providence | Rhode Island | 02908-4734 | United States |
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| South Texas Health Care System, San Antonio, TX | Recruiting | San Antonio | Texas | 78229-4404 | United States |
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| VA Puget Sound Health Care System Seattle Division, Seattle, WA | Terminated | Seattle | Washington | 98108-1532 | United States |
| ID | Term |
|---|---|
| D009437 | Neuralgia |
| ID | Term |
|---|---|
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D013759 | Dronabinol |
| C587251 | nabiximols |
| ID | Term |
|---|---|
| D002186 | Cannabinoids |
| D013729 | Terpenes |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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