Allodynia, Central Neuropathic Pain, Spinal Cord Injury
Conditions
Keywords
chronic pain, central neuropathic pain, spinal cord injury, dextromethorphan, lidocaine, combination therapy, analgesia
Brief summary
This randomized, placebo-controlled, double-blind 4x4 crossover clinical trial was part of a larger NIH-funded study to evaluate the analgesic efficacy of multiple dose-combinations of chronic oral (PO) dextromethorphan and intravenous (IV) lidocaine in central neuropathic pain following spinal cord injury.
Detailed description
This trial has several objectives: Primary Objective To determine which combination (dose-ratio) of dextromethorphan and lidocaine provides the best balance of pain reduction and toxicity. Secondary Objectives include To evaluate the analgesic efficacy of both dextromethorphan and lidocaine in attenuating pain related to central nervous system sensitization, specifically spontaneous pain, mechanical allodynia, and hyperalgesia.
Interventions
DRUGDextromethorphan
Administered in 4 periods (placebo, low dose, medium dose, and high dose) for each subject, relative to each subject's MTD)
DRUGLidocaine
0mg, 1mg, 2mg, and 4mg Lidocaine per kg of lean body mass (LBM), during each of the 4 dextromethorphan periods (placebo, low dose, medium dose, and high dose)
DRUGPlacebo (Dextromethorphan)
0mg Dextromethorphan
DRUGPlacebo (Lidocaine)
0mg/kg LBM Lidocaine
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Healthy male or female adults, age 18 to 70 with central neuropathic pain for a minimum of 3 months following SCI as confirmed by neurologic evaluation, with an average pain intensity score of at least moderate over at least 50% of the day for the 7 days prior to the screening visit and over the 7 days prior to starting study medication. 2. Subjects used no medication or a stabilized medication regimen for chronic and well-controlled medical conditions 3. Serum laboratory examination obtained at study entry: 4. Normal cognitive function. 5. Signed informed consent.
Exclusion criteria
1. Pregnancy or breast-feeding. 2. Renal or hepatic dysfunction. 3. Significant cardiac disease (e.g. MI within 1 year). 4. Signs or symptoms of central neurological disorder, excluding SCI. 5. Severe psychological disorder requiring treatment. 6. History of hypersensitivity or intolerance to dextromethorphan or lidocaine. 7. Participation in a study of an investigational drug or device within 30 days prior to screening for this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Peak Pain Intensity | 30 minutes post-infusion (Cmax) | Primary outcome was percent change from baseline in mean pain intensity at Cmax (transformed Gracely Scale; 0-35). Higher values on the Gracely scale represent greater pain intensity; the greater the percent change from baseline in mean pain intensity, the bigger the reduction in pain intensity. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in March 2003. Subjects were recruited nationally from referring physicians, through advertisements, and through an existing database held by the PI.
Pre-assignment details
During the screening visit, P450 2D6 phenotype status was determined for each subject to identify dextromethorphan-metabolizing capacity; those who were P450 2D6 poor-metabolizers were excluded. Following screen, subjects entered a dose escalation study to determine their maximum tolerated dose of dextromethorphan, prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Dextromethorphan/Lidocaine Combination Clinical Trial This randomized, placebo-controlled, double-blind 4x4 factorial crossover clinical trial was part of a larger NIH-funded study to evaluate the analgesic efficacy of multiple dose-combinations of chronic oral (PO)dextromethorphan (placebo, low dose, medium dose, and high dose) and intravenous (IV) lidocaine (0mg/kg LBM, 1mg/kg LBM, 2mg/kg LBM, and 4mg/kg LBM) in central neuropathic pain following spinal cord injury. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Dextromethorphan/Lidocaine Combination Clinical Trial |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Age, Continuous | 46.84 years STANDARD_DEVIATION 11.32 |
| Region of Enrollment North America | 26 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 26 | 0 / 26 | 0 / 26 | 0 / 26 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 4 / 24 | 3 / 24 | 5 / 24 | 10 / 24 | 5 / 26 | 7 / 26 | 8 / 26 | 15 / 26 | 3 / 24 | 6 / 24 | 6 / 24 | 15 / 24 | 3 / 24 | 3 / 24 | 6 / 24 | 17 / 24 |
| serious Total, serious adverse events | 0 / 0 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 26 | 0 / 26 | 0 / 26 | 0 / 26 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 |
Outcome results
Primary
Percent Change in Peak Pain Intensity
Primary outcome was percent change from baseline in mean pain intensity at Cmax (transformed Gracely Scale; 0-35). Higher values on the Gracely scale represent greater pain intensity; the greater the percent change from baseline in mean pain intensity, the bigger the reduction in pain intensity.
Time frame: 30 minutes post-infusion (Cmax)
Population: Central neuropathic pain following SCI; we present the primary efficacy endpoint (percent change in peak pain intensity) of this nested IV lidocaine dose-response clinical trial independent of the dextromethorphan doses, because the distribution of the dextromethorphan doses is balanced across the lidocaine treatment arms.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dextromethorphan/ 0mg/kg Lidocaine Combination | Percent Change in Peak Pain Intensity | -2.5 percentage change from baseline | Standard Error 0.0049 |
| Dextromethorphan/1mg/kg Lidocaine Combination | Percent Change in Peak Pain Intensity | -7.9 percentage change from baseline | Standard Error 0.0176 |
| Dextromethorphan/2mg/kg Lidocaine Combination | Percent Change in Peak Pain Intensity | -11.2 percentage change from baseline | Standard Error 0.0015 |
| Dextromethorphan/4mg/kg Lidocaine Combination | Percent Change in Peak Pain Intensity | -19.2 percentage change from baseline | Standard Error 0.0226 |
Comparison: We performed a lidocaine dose response clinical trial nested within a dextromethorphan clinical trial to evaluate a potential interaction between lidocaine dose and dextromethorphan dose (pain intensity; Gracely scale).p-value: 0.032295% CI: [0.0004, 0.0081]Pearson's Chi-squared test