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 three doses of chronic oral (PO) dextromethorphan compared to placebo in central neuropathic pain following spinal cord injury. Subjects' maximally tolerated doses (MTD) were first determined to establish individual dose-analgesic response relationships in a run-in period; following a washout period, subjects were then randomized to receive an order of four doses of dextromethorphan (including placebo) in a 4x4 Latin square cross-over design.
Interventions
DRUGDextromethorphan
0, 25, 50 and 100% of maximum tolerated dose, each administered over a 4 week period
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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: * Liver function tests (albumin within 20% of normal, SGOT/SGPT within 50% of normal). * For women of childbearing age: negative serum beta HCG. 4. Postmenopausal women, or be physically incapable of childbearing, or be practicing an acceptable method of birth control. 5. Normal cognitive function. 6. Normal communicative ability (English). 7. Ability to demonstrate competence in recording five times daily in pain diary for 1 week (with 100% compliance), and in completing required questionnaires. 8. 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. Concurrent use of monoamine oxidase inhibitors within 2 weeks prior to study entry. 7. Use of known CYP2D6 (but not CYP3A4) inhibitors or inducers. 8. History of hypersensitivity or intolerance to dextromethorphan or lidocaine. 9. Chronic substance abuse, including alcohol. 10. Participation in a study of an investigational drug or device within 30 days prior to screening for this study. 11. Poor metabolizer of P450 2D6 substrates.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Pain Intensity (Percent Change From Baseline) | 1st week of maintenance period (week prior to hospital admission for nested study; subjects traveled to Boston on days 6-7 of the maintenance period) | Primary outcome was percent change from baseline in mean pain intensity (transformed Gracely Scale; 0-35). Baseline was defined as the week prior to randomization. The greater the percent change, the bigger the reduction in pain intensity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Satisfaction | Last week prior to admission (end of 1-week maintenance period) | Satisfaction with study treatment assessed over the 7 days prior to admission (5-point categorical scale) |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited nationally from referring physicians, through advertisements, and through existing databases.
Pre-assignment details
During the screening visit, P450 2D6 phenotype status was determined for each subject to identify drug-metabolizing capacity; those who were P450 2D6 poor-metabolizers were excluded. Following screen, each subject entered a dose escalation period to determine his/her maximum tolerated dose (MTD), prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Dextromethorphan Dose Response Clinical Trial Each subject received four doses of dextromethorphan; 0% (placebo), 25%, 50%, and 100% of the maximum tolerated dose in a balanced randomized order. Each dose was administered for a period of 28 days; on day 21 of each phase, subjects traveled to the study site to undergo study procedures in a nested clinical trial (not described here). | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Dextromethorphan Dose Response 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 |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 25 | 3 / 26 | 2 / 25 | 16 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 26 | 0 / 25 | 0 / 25 |
Outcome results
Primary
Mean Pain Intensity (Percent Change From Baseline)
Primary outcome was percent change from baseline in mean pain intensity (transformed Gracely Scale; 0-35). Baseline was defined as the week prior to randomization. The greater the percent change, the bigger the reduction in pain intensity.
Time frame: 1st week of maintenance period (week prior to hospital admission for nested study; subjects traveled to Boston on days 6-7 of the maintenance period)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0% MTD Dex | Mean Pain Intensity (Percent Change From Baseline) | -0.006 Percent change from baseline | Standard Error 0.01 |
| 25% MTD Dex | Mean Pain Intensity (Percent Change From Baseline) | -0.018 Percent change from baseline | Standard Error 0.005 |
| 50% MTD Dex | Mean Pain Intensity (Percent Change From Baseline) | -0.073 Percent change from baseline | Standard Error 0.01 |
| 100% MTD Dex | Mean Pain Intensity (Percent Change From Baseline) | -0.24 Percent change from baseline | Standard Error 0.01 |
Secondary
Satisfaction
Satisfaction with study treatment assessed over the 7 days prior to admission (5-point categorical scale)
Time frame: Last week prior to admission (end of 1-week maintenance period)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 0% MTD Dex | Satisfaction | Very/Extremely Satisfied | 0 Participants |
| 0% MTD Dex | Satisfaction | Not Satisfied | 20 Participants |
| 0% MTD Dex | Satisfaction | Satisfied | 3 Participants |
| 0% MTD Dex | Satisfaction | Fairly Satisfied | 2 Participants |
| 25% MTD Dex | Satisfaction | Fairly Satisfied | 5 Participants |
| 25% MTD Dex | Satisfaction | Satisfied | 2 Participants |
| 25% MTD Dex | Satisfaction | Not Satisfied | 18 Participants |
| 25% MTD Dex | Satisfaction | Very/Extremely Satisfied | 1 Participants |
| 50% MTD Dex | Satisfaction | Not Satisfied | 16 Participants |
| 50% MTD Dex | Satisfaction | Very/Extremely Satisfied | 2 Participants |
| 50% MTD Dex | Satisfaction | Fairly Satisfied | 7 Participants |
| 50% MTD Dex | Satisfaction | Satisfied | 0 Participants |
| 100% MTD Dex | Satisfaction | Very/Extremely Satisfied | 3 Participants |
| 100% MTD Dex | Satisfaction | Satisfied | 5 Participants |
| 100% MTD Dex | Satisfaction | Fairly Satisfied | 8 Participants |
| 100% MTD Dex | Satisfaction | Not Satisfied | 9 Participants |