CRPS
Conditions
Brief summary
The Department of Anesthesiology is conducting a clinical trial to evaluate if pregabalin given prior to and for several days after Total Knee Arthroplasty (TKA) will reduce the prevalence of Complex Regional Pain Syndrome (CRPS) at late postoperative times. The prevalence of complex regional pain syndrome (CRPS) following total knee arthroplasty (TKA) is 13% at 6 months post-surgery. CRPS is a painful debilitating condition, with 4 main classes of symptoms : sensory, including burning, allodynia, and hyperalgesia in the affected limb; vasomotor, including temperature asymmetry and skin color changes; edema and sudomotor, including sweating; and movement disorders and dystrophy, including decreased range of motion, motor dysfunction (weakness, tremor, dystonia) and changes in hair, nails or skin.
Detailed description
The Department of Anesthesiology is conducting a clinical trial to evaluate if pregabalin given prior to and for several days after Total Knee Arthroplasty (TKA) will reduce the prevalence of Complex Regional Pain Syndrome (CRPS) at late postoperative times. The prevalence of complex regional pain syndrome (CRPS) following total knee arthroplasty (TKA) is 13% at 6 months post-surgery. CRPS is a painful debilitating condition, with 4 main classes of symptoms : sensory, including burning, allodynia, and hyperalgesia in the affected limb; vasomotor, including temperature asymmetry and skin color changes; edema and sudomotor, including sweating; and movement disorders and dystrophy, including decreased range of motion, motor dysfunction (weakness, tremor, dystonia) and changes in hair, nails or skin. Gabapentin and the related more potent compound pregabalin have been shown to reduce postoperative pain in animal models. Pregabalin also reduces neuropathic pain in rats. In patients, gabapentin has been administered before surgery to treat postoperative pain. In addition, pregabalin has been given postoperatively to reduce dental pain after molar extraction. Gabapentin has been used for many years in patients with neuropathic pain, including reflex sympathetic dystrophy. More recently, pregabalin has also been shown to be efficacious in the treatment of neuropathic pain. However, no clinical study has investigated whether perioperative administration of gabapentin or pregabalin can reduce persistent long-term pain syndromes e.g. CRPS.Subjects between the ages of 21 and 80 will be recruited after obtaining an Informed Consent.
Interventions
DRUGpregabalin
PO pregabalin 300 mg 2 hours prior to surgery, and 150 mg twice a day for 10 postoperative days. Pregabalin will be tapered to 75 mg twice daily between days 11 to 12 and then to 50 mg twice daily between days 13 to 14 post operatively and then stopped.
DRUGPlacebo
Placebo for Given 2 hours prior to surgery, and twice a day for 14 postoperative days.
Sponsors
Pfizer
Rush University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. History of osteoarthritis 2. Subjects who can understand and communicate in English.
Exclusion criteria
1. Younger than 21 years or older than 80 years. 2. American Society of Anesthesiologists physical status IV. 3. Prior usage of gabapentin (or pregabalin) will not be an exclusionary criterion; however, patients will have been withdrawn from these medications for at least 7 days before surgery. 4. Patients with a history of neuropathic pain conditions. 5. Patients who are currently enrolled in another investigational study. 6. Pre-existing heart conditions 7. Patients on thiazolidinedione class of anti-diabetic medications (eg. rosiglitazone, pioglitazone). \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Epidural Medication Consumption Rate | 36 h | Epidural medication consumption was recorded for each 4-h interval from the completion of surgery to the time that the epidural was discontinued (same as the time to achieve hospital discharge criteria). Because the discontinuation time varied from patient to patient (as they achieved physical therapy criteria), the average hourly consumption (total analgesic used divided by the total infusion time) was used as the measure of epidural drug use. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Knee Range of Motion (Active Flexion) | 1-30 days | — |
| Neuropathic Pain (S-LANSS > 12) | 3 and 6 months post-surgery | Patients will be evaluated in blinded fashion for lower extremity Complex Regional Pain Syndrome(CRPS) at pre-op, 1, 3, and 6 months postsurgery based initially on telephone interviews. An S-LANSS score of 12 or more was an indication of chronic neuropathic pain. Patients with an Self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs(S-LANSS) score of 12 or more at 6 mo came to the physician's office for a standardized physical examination, which included the S-LANSS examination items (allodynia and hyperalgesia) directly assessed by the physician, plus a pinprick evaluation. |
Participant flow
Recruitment details
From August 2006 to August 2007, 350 consecutive patients scheduled to undergo elective primary Total knee arthroplasty (TKA) were contacted and assessed for study eligibility. There were 110 Screen Failures (31 Not meeting inclusion criteria, 79 eligible but did not give consent), resulting in 240 enrolled subjects.
Pre-assignment details
There were 110 Screen Failures (31 Not meeting inclusion criteria, 79 eligible but did not give consent), resulting in 240 enrolled subjects.
Participants by arm
| Arm | Count |
|---|---|
| 1 Placebo Half of the patients will receive PO placebo for 14 days | 120 |
| 2 Pregabalin PO pregabalin 300 mg 2 hours prior to surgery, and 150 mg twice a day for 10 postoperative days. Pregabalin will be tapered to 75 mg twice daily between days 11 to 12 and then to 50 mg twice daily between days 13 to 14 post operatively and then stopped. | 120 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 7 |
Baseline characteristics
| Characteristic | 1 Placebo | 2 Pregabalin | Total |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 8.9 | 64.0 years STANDARD_DEVIATION 8.3 | 63.7 years STANDARD_DEVIATION 8.6 |
| BMI | 34.6 kg/m^2 STANDARD_DEVIATION 7.7 | 34.2 kg/m^2 STANDARD_DEVIATION 8.4 | 34.4 kg/m^2 STANDARD_DEVIATION 8 |
| Sex: Female, Male Female | 84 Participants | 91 Participants | 175 Participants |
| Sex: Female, Male Male | 36 Participants | 29 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 120 | 69 / 120 |
| serious Total, serious adverse events | 0 / 120 | 0 / 120 |
Outcome results
Primary
Epidural Medication Consumption Rate
Epidural medication consumption was recorded for each 4-h interval from the completion of surgery to the time that the epidural was discontinued (same as the time to achieve hospital discharge criteria). Because the discontinuation time varied from patient to patient (as they achieved physical therapy criteria), the average hourly consumption (total analgesic used divided by the total infusion time) was used as the measure of epidural drug use.
Time frame: 36 h
Population: Because of structural missing data, sample sizes are smaller than the samples size for the secondary measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 Placebo | Epidural Medication Consumption Rate | 6.40 mL/h | Standard Deviation 1.26 |
| 2 Pregabalin | Epidural Medication Consumption Rate | 5.77 mL/h | Standard Deviation 1.31 |
p-value: 0.003t-test, 2 sided
Secondary
Knee Range of Motion (Active Flexion)
Time frame: 1-30 days
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 1 Placebo | Knee Range of Motion (Active Flexion) | Day 1 | 75.6 Degrees | Standard Error 1.5 |
| 1 Placebo | Knee Range of Motion (Active Flexion) | Day 2 | 76.7 Degrees | Standard Error 1.3 |
| 1 Placebo | Knee Range of Motion (Active Flexion) | Day 3 | 80.4 Degrees | Standard Error 1.5 |
| 1 Placebo | Knee Range of Motion (Active Flexion) | Day 30 | 103.0 Degrees | Standard Error 1.3 |
| 2 Pregabalin | Knee Range of Motion (Active Flexion) | Day 30 | 107.2 Degrees | Standard Error 1.4 |
| 2 Pregabalin | Knee Range of Motion (Active Flexion) | Day 1 | 77.8 Degrees | Standard Error 1.6 |
| 2 Pregabalin | Knee Range of Motion (Active Flexion) | Day 3 | 84.2 Degrees | Standard Error 1.6 |
| 2 Pregabalin | Knee Range of Motion (Active Flexion) | Day 2 | 81.0 Degrees | Standard Error 1.4 |
Comparison: Mixed model test of condition (Placebo v Pregabalin) main effect.p-value: 0.0133Mixed Models Analysis
Comparison: Test of Condition Effect (Placebo v Pregabalin) at the 1-day post surgery time point (Slice)p-value: 0.3097Mixed Models Analysis
Comparison: Test of Condition Effect (Placebo v Pregabalin) at the 2-day post surgery time point (Slice)p-value: 0.0247Mixed Models Analysis
Comparison: Test of Condition Effect (Placebo v Pregabalin) at the 3-day post surgery time point (Slice)p-value: 0.0786Mixed Models Analysis
Comparison: Test of Condition Effect (Placebo v Pregabalin) at the 30-day post surgery time point (Slice)p-value: 0.0254Mixed Models Analysis
Secondary
Neuropathic Pain (S-LANSS > 12)
Patients will be evaluated in blinded fashion for lower extremity Complex Regional Pain Syndrome(CRPS) at pre-op, 1, 3, and 6 months postsurgery based initially on telephone interviews. An S-LANSS score of 12 or more was an indication of chronic neuropathic pain. Patients with an Self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs(S-LANSS) score of 12 or more at 6 mo came to the physician's office for a standardized physical examination, which included the S-LANSS examination items (allodynia and hyperalgesia) directly assessed by the physician, plus a pinprick evaluation.
Time frame: 3 and 6 months post-surgery
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1 Placebo | Neuropathic Pain (S-LANSS > 12) | Neuropathic pain at 6 Month Follow up | 6 participants |
| 1 Placebo | Neuropathic Pain (S-LANSS > 12) | Neuropathic pain at 3 Month Follow up | 10 participants |
| 2 Pregabalin | Neuropathic Pain (S-LANSS > 12) | Neuropathic pain at 6 Month Follow up | 0 participants |
| 2 Pregabalin | Neuropathic Pain (S-LANSS > 12) | Neuropathic pain at 3 Month Follow up | 0 participants |
Comparison: For 3 month followup on incidence of neuropathic pain.p-value: 0.0013Chi-squared
Comparison: For 6 month followup on incidence of neuropathic pain.p-value: 0.0139Chi-squared