Neuropathic Pain
Conditions
Keywords
neuropathic pain, diabetic neuropathy, neuropathic pain after back surgery
Brief summary
Based on laboratory studies, donepezil will improve pain relief more than placebo in patients with chronic neuropathic pain who are currently taking gabapentin or pregabalin.
Detailed description
Investigators are currently examining in the laboratory the mechanisms which lead to sprouting of noradrenergic fibers in the spinal cord in models of chronic pain as well as the mechanisms that lead to a novel noradrenergic - cholinergic circuit in the spinal cord. In addition to examining the circumstances which generate this increased capacity for analgesia and the mechanisms by which they occur, investigators will test in this protocol whether approved and experimental treatments for neuropathic pain exploit this increased capacity. This study is in patients with neuropathic pain taking gabapentin or pregabalin, and will test the clinical relevance of these preclinical data by comparing placebo to the cholinesterase inhibitor. Investigators focus not only on mechanistic hypotheses in the laboratory studies, but also on practical applications, using clinically approved drugs, including gabapentin and pregabalin to activate noradrenergic activity and donepezil (Aricept®), approved for the treatment of Alzheimer's dementia, but not previously tested to treat neuropathic pain, to inhibit cholinesterase. Each of these drugs may act by mechanisms in addition to those involved in descending noradrenergic inhibition, but investigators hypothesize that the therapeutic strength of their combination relies heavily on this cascade engendered by noradrenergic sprouting and altered α2-adrenoceptor function. The proposed studies will provide critical tests of this hypothesis and critical information to guide more effective clinical therapy of neuropathic pain.
Interventions
DRUGDonepezil
donepezil 5 mg once daily for 6 weeks
DRUGPlacebo
placebo or sugar pill will be taken once daily for 6 weeks
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Wake Forest University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of diabetic neuropathy or failed back syndrome with neuropathic symptoms * Age 18-80 * Taking a stable dose of gabapentin or pregabalin
Exclusion criteria
* Pregnant women or women of child-bearing potential not willing to practice a reliable form of birth control * Allergy to donepezil or other piperidine derivatives (including fentanyl, alfentanil, sulfentanil, remifentanyl, demerol, tramadol, loperamide, diphenoxylate, betaprodine, alphaprodine, ethopropazine, anileridine, piminodine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP),loratadine, fexofenadine * Unstable medical conditions including cardiac, pulmonary, renal or hepatic diseases that, in the opinion of the investigator, would preclude patients from finishing the trial * Any person with pending litigation * A history of major psychosis requiring hospitalization within the last three years * Non-English speaking, illiterate, unable to comprehend consent * Lack of contact information * Uncontrolled narrow-angle glaucoma * Currently being treatment with thioridazine (Mellaril) * Patients taking opioids will be excluded if they are taking a dosage that exceeds an equivalent of 30 mg of morphine per day * Patients taking more than one regular (not rescue) medication for pain * Patients taking donepezil for dementia * Patients with a baseline pain score less than 2 (0-10 scale) or greater than 8 (0-10) will be excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity | baseline | A greater number is considered a worse outcome. VAS Range (0-10) 0=No Pain 10=The worst pain imaginable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks | baseline, week 8 after baseline, and week 10 after baseline | The questionnaire records total mood disturbance. The scale ranges from 0-100 with a greater number denoting a worse outcome. |
| Number of Days With Rescue Treatment | Days: baseline, week 8 after baseline, and week 10 after baseline | Questionnaires detailing the amount of rescue pain medications will be completed twice daily. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Donepezil donepezil 5 mg every day
Donepezil: donepezil 5 mg once daily for 6 weeks | 2 |
| Placebo Placebo (sugar pill) every day
Placebo: placebo or sugar pill will be taken once daily for 6 weeks | 3 |
| Total | 5 |
Baseline characteristics
| Characteristic | Donepezil | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 44 years | 50 years | 52 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 2 participants | 5 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 2 | 0 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 3 |
Outcome results
Primary
McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity
A greater number is considered a worse outcome. VAS Range (0-10) 0=No Pain 10=The worst pain imaginable.
Time frame: baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Donepezil | McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity | 3.0 units on the scale |
| Placebo | McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity | 5.0 units on the scale |
Primary
McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity
A greater number is considered a worse outcome. VAS Range (0-10) 0=No Pain 10=The worst pain imaginable.
Time frame: Week 8: last week of study drug treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Donepezil | McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity | 0.7 units on the scale |
| Placebo | McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity | 2.4 units on the scale |
Primary
McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity
A greater number is considered a worse outcome. VAS Range (0-10) 0=No Pain 10=The worst pain imaginable.
Time frame: Week 10: last week of washout
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Donepezil | McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity | 0.4 units on the scale |
| Placebo | McGill Short Form Pain Questionnaire (SF MPQ) Visual Analog Scale (VAS) Pain Intensity | 2.8 units on the scale |
Secondary
Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks
The questionnaire records total mood disturbance. The scale ranges from 0-100 with a greater number denoting a worse outcome.
Time frame: baseline, week 8 after baseline, and week 10 after baseline
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Donepezil | Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks | baseline | 27 Total score on POM-S scale |
| Donepezil | Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks | Week 8 after Baseline | 25 Total score on POM-S scale |
| Donepezil | Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks | Week 10 after Baseline | 33 Total score on POM-S scale |
| Placebo | Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks | baseline | 53 Total score on POM-S scale |
| Placebo | Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks | Week 8 after Baseline | 24 Total score on POM-S scale |
| Placebo | Average From Baseline Profile of Mood States-Short Form (POMS-SF) at 10 Weeks | Week 10 after Baseline | 24 Total score on POM-S scale |
Secondary
Number of Days With Rescue Treatment
Questionnaires detailing the amount of rescue pain medications will be completed twice daily.
Time frame: Days: baseline, week 8 after baseline, and week 10 after baseline
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Donepezil | Number of Days With Rescue Treatment | Baseline | .5 Days |
| Donepezil | Number of Days With Rescue Treatment | Week 8 after Baseline | 0 Days |
| Donepezil | Number of Days With Rescue Treatment | Week 10 after Baseline | 0 Days |
| Placebo | Number of Days With Rescue Treatment | Baseline | 0 Days |
| Placebo | Number of Days With Rescue Treatment | Week 8 after Baseline | 0 Days |
| Placebo | Number of Days With Rescue Treatment | Week 10 after Baseline | 0 Days |