Diabetes, Pain, Peripheral Neuropathy
Conditions
Brief summary
Diabetic nerve pain \[painful diabetic peripheral neuropathy\] is a common medical problem with few reliably effective treatments. There is some evidence that sensory testing may help determine how individuals will respond to analgesic therapy. In this study, the investigators are evaluating the relationship between sensory testing and subject response to lidocaine infusion therapy.
Detailed description
Diabetic peripheral neuropathy \[DPN\] is caused by diabetes-related metabolic damage to the sensory nervous system. It affects more than 3 million Americans and is leading cause of nerve damage-associated pain worldwide. Currently approved drugs such as gabapentin, pregabalin, and duloxetine provide pain relief only in 1 out of 4 or 5 people with DPN, pointing to a great need to identify effective therapy for these patients. Recent literature suggests that certain methods of assessing sensory nerve function in neuropathic pain patients may provide prediction to individual analgesic response; however, no placebo-controlled studies have been performed with the primary goal of identifying treatment response predictors in DPN. We propose in this study to examine whether sensory testing to determine mechanical pain threshold \[MPT\] or heat pain threshold \[HPT\] will predict the subject's response to IV lidocaine analgesic therapy. We hypothesize that people with painful DPN who have high MPT or HPT are more likely to respond to lidocaine treatment. This is a prospective, double blind, placebo-controlled study with the primary objective of determining whether the results from the sensory testing predict the response to systemic lidocaine in patients with painful DPN. Consented subjects will attend a screening visit and two intervention visits, during which they will undergo sensory testing and receive intravenous lidocaine or placebo infusion in a cross-over design. At enrollment, each patient will be assigned a study number, which will match a previously prepared computer-generated list of randomization numbers to determine the sequence of interventions: lidocaine and then placebo, or vice versa. An unblinded research nurse coordinator will be assigned to match the study number with randomized treatment sequence, and this person will prepare the study medications, which will look identical. This research nurse coordinator will not be involved at any stage at patient assessment or data analysis. The participants and all other study personnel will be blinded to the treatment allocation.
Interventions
DRUGlidocaine
lidocaine is a sodium channel blocker/analgesic. It is approved for intravenous administration for cardiac arrhythmias.
DRUGPlacebo
Normal saline, approved for hypovolemia, and homeostasis.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18; 2. Diagnosis of Diabetes Mellitus (Fasting Plasma Glucose \> 126 mg/dL and/or HbA1C \>6.5%); 3. Distal symmetric pain in lower extremities with duration of more than 3 months; 4. Presence of either numbness or at least 1 sensory disturbance (increased or decreased sensitivity) in the feet. 5. Spontaneous pain with intensity of ≥ 4 on 0-10 Numerical Rating Scale (NRS).
Exclusion criteria
1. Not giving consent to participate in the study; 2. Unable to complete self-report pain questionnaire; 3. History of moderate to severe renal or liver failure; 4. History of other central or peripheral neurologic disorders; 5. History of cardiac arrhythmias; 6. Contraindication to intravenous lidocaine; 7. Pregnancy or lactation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Spontaneous Pain at 60-120 Minutes After Lidocaine Infusion Initiated (Assessed on 0-10 NRS) | Baseline compared to 60-120 minutes after starting the infusion | Spontaneous pain will be assessed on numerical rating scale NRS (0= no pain, 10=worst pain imaginable) prior to infusion and then repeatedly for 120 minutes. The outcome measure will use the average of pain intensity measured at timepoints in the 60-120 min range after beginning of infusion. The mean %change in pain (from baseline) will be compared between lidocaine and placebo arms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | - 60 minutes (baseline) and + 60 minutes of initiating infusion | Thermal and mechanical responses will be assessed at baseline and 60 minutes after infusions. Evoked intensities measured on a 0-10 sensory scale, where 5 is normal sensation, a number lower than 5 is reduced sensation and a number higher than 5 is greater sensation. |
| NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Baseline to 60 minutes of initiating infusion | NPSI pain descriptors will be assessed prior to infusion of placebo and lidocaine (baseline) and again at 60 minutes post-infusion. Descriptors are expressed on a 0-10 scale; 0-minimum (least), and 10 maximum (worst) score. |
| Change in Spontaneous Pain Intensity as a Function of Baseline MPT | baseline to 60-120 minutes after starting the infusion | Correlation between Mechanical Pain Threshold (MPT in mN) at baseline and reduction in spontaneous pain intensity (% reduction on 0-10 NRS) at 60-120 minutes (averaged) from the study drug infusion. The slopes (Pearson coefficients) of the correlation obtained from lidocaine vs. placebo will be compared. |
| Change in Spontaneous Pain Intensity as a Function of Baseline HPT | Baseline to 60-120 minutes after starting the infusion | Correlation between Heat Pain Threshold (HPT in degrees Celsius) at baseline and reduction in spontaneous pain intensity (% reduction on 0-10 NRS) at 60-120 minutes (averaged) from the study drug infusion. The slopes (Pearson coefficients) of the correlation obtained from lidocaine vs. placebo will be compared. |
Countries
United States
Participant flow
Pre-assignment details
One participant only received lidocaine infusion and did not return to receive saline infusion.
Participants by arm
| Arm | Count |
|---|---|
| Saline First, Then Lidocaine Intravenous infusion of normal saline (placebo) over a 40 minute period (Period 1). Intravenous infusion of lidocaine 5mg/kg IBW over a 40 min period (Period 2) | 17 |
| Lidocaine First, Then Saline Intravenous infusion of lidocaine 5mg/kg IBW over a 40 min period (Period 1). Intravenous infusion of normal saline (placebo) over a 40 minute period (Period 2). | 17 |
| Total | 34 |
Baseline characteristics
| Characteristic | Saline First, Then Lidocaine | Lidocaine First, Then Saline | Total |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 12 | 56 years STANDARD_DEVIATION 10 | 57 years STANDARD_DEVIATION 11 |
| Average pain intensity within the past week | 6 units on a scale | 6.5 units on a scale | 6.25 units on a scale |
| 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 | 3 Participants | 7 Participants | 10 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 | 14 Participants | 10 Participants | 24 Participants |
| Region of Enrollment United States | 17 participants | 17 participants | 34 participants |
| Sex: Female, Male Female | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 34 |
| other Total, other adverse events | 11 / 33 | 13 / 34 |
| serious Total, serious adverse events | 0 / 33 | 0 / 34 |
Outcome results
Primary
Change in Spontaneous Pain at 60-120 Minutes After Lidocaine Infusion Initiated (Assessed on 0-10 NRS)
Spontaneous pain will be assessed on numerical rating scale NRS (0= no pain, 10=worst pain imaginable) prior to infusion and then repeatedly for 120 minutes. The outcome measure will use the average of pain intensity measured at timepoints in the 60-120 min range after beginning of infusion. The mean %change in pain (from baseline) will be compared between lidocaine and placebo arms.
Time frame: Baseline compared to 60-120 minutes after starting the infusion
Population: Participants who completed both infusions and had non-zero pain scores at the start of each infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline Infusion | Change in Spontaneous Pain at 60-120 Minutes After Lidocaine Infusion Initiated (Assessed on 0-10 NRS) | 33 percentage of pain change from baseline | Standard Deviation 46 |
| Lidocaine Infusion | Change in Spontaneous Pain at 60-120 Minutes After Lidocaine Infusion Initiated (Assessed on 0-10 NRS) | 51 percentage of pain change from baseline | Standard Deviation 40 |
p-value: 0.03t-test, 2 sided
Secondary
Change in Spontaneous Pain Intensity as a Function of Baseline HPT
Correlation between Heat Pain Threshold (HPT in degrees Celsius) at baseline and reduction in spontaneous pain intensity (% reduction on 0-10 NRS) at 60-120 minutes (averaged) from the study drug infusion. The slopes (Pearson coefficients) of the correlation obtained from lidocaine vs. placebo will be compared.
Time frame: Baseline to 60-120 minutes after starting the infusion
Population: Participants who completed both infusions and had non-zero pain scores at the start of each infusion. Two additional participants excluded as they could not sense heat on test site.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Saline Infusion | Change in Spontaneous Pain Intensity as a Function of Baseline HPT | .023 Pearson coefficient |
| Lidocaine Infusion | Change in Spontaneous Pain Intensity as a Function of Baseline HPT | -.151 Pearson coefficient |
Secondary
Change in Spontaneous Pain Intensity as a Function of Baseline MPT
Correlation between Mechanical Pain Threshold (MPT in mN) at baseline and reduction in spontaneous pain intensity (% reduction on 0-10 NRS) at 60-120 minutes (averaged) from the study drug infusion. The slopes (Pearson coefficients) of the correlation obtained from lidocaine vs. placebo will be compared.
Time frame: baseline to 60-120 minutes after starting the infusion
Population: Participants who completed both infusions and had non-zero pain scores at the start of each infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Saline Infusion | Change in Spontaneous Pain Intensity as a Function of Baseline MPT | .249 Pearson coefficient |
| Lidocaine Infusion | Change in Spontaneous Pain Intensity as a Function of Baseline MPT | .063 Pearson coefficient |
Secondary
Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation.
Thermal and mechanical responses will be assessed at baseline and 60 minutes after infusions. Evoked intensities measured on a 0-10 sensory scale, where 5 is normal sensation, a number lower than 5 is reduced sensation and a number higher than 5 is greater sensation.
Time frame: - 60 minutes (baseline) and + 60 minutes of initiating infusion
Population: Participants who received both lidocaine and normal saline infusions were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Saline Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Brush intensity | 4 score on a scale |
| Normal Saline Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Heat intensity | 2 score on a scale |
| Normal Saline Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Pinprick intensity | 4 score on a scale |
| Normal Saline Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Cold intensity | 2 score on a scale |
| Lidocaine Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Cold intensity | 4 score on a scale |
| Lidocaine Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Pinprick intensity | 3 score on a scale |
| Lidocaine Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Brush intensity | 4 score on a scale |
| Lidocaine Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Heat intensity | 2 score on a scale |
| Lidocaine: Prior to Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Cold intensity | 3 score on a scale |
| Lidocaine: Prior to Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Brush intensity | 5 score on a scale |
| Lidocaine: Prior to Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Heat intensity | 2 score on a scale |
| Lidocaine: Prior to Infusion | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Pinprick intensity | 4 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Pinprick intensity | 3 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Heat intensity | 1 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Cold intensity | 3 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | Evoked Mechanical and Thermal Sensation at Baseline and 60 Minutes After Infusion Initiation. | Brush intensity | 4 score on a scale |
Secondary
NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion
NPSI pain descriptors will be assessed prior to infusion of placebo and lidocaine (baseline) and again at 60 minutes post-infusion. Descriptors are expressed on a 0-10 scale; 0-minimum (least), and 10 maximum (worst) score.
Time frame: Baseline to 60 minutes of initiating infusion
Population: Participants who received both lidocaine and normal saline infusions analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Saline Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like squeezing? | 2 score on a scale |
| Normal Saline Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like burning? | 3 score on a scale |
| Normal Saline Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel tingling? | 3 score on a scale |
| Normal Saline Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel pins and needles? | 2 score on a scale |
| Normal Saline Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like electric shocks? | 0 score on a scale |
| Normal Saline Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like stabbing? | 0 score on a scale |
| Lidocaine Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like electric shocks? | 0 score on a scale |
| Lidocaine Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like stabbing? | 0 score on a scale |
| Lidocaine Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel pins and needles? | 0 score on a scale |
| Lidocaine Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like squeezing? | 0 score on a scale |
| Lidocaine Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like burning? | 0 score on a scale |
| Lidocaine Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel tingling? | 1 score on a scale |
| Lidocaine: Prior to Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like electric shocks? | 0 score on a scale |
| Lidocaine: Prior to Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like burning? | 3 score on a scale |
| Lidocaine: Prior to Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like squeezing? | 2 score on a scale |
| Lidocaine: Prior to Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like stabbing? | 0 score on a scale |
| Lidocaine: Prior to Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel pins and needles? | 4 score on a scale |
| Lidocaine: Prior to Infusion | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel tingling? | 4 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like squeezing? | 0 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel pins and needles? | 0 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Do you feel tingling? | 1 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like electric shocks? | 0 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like burning? | 0 score on a scale |
| Lidocaine: 60 Minutes After Infusion Initiation | NPSI (Neuropathic Pain Symptom Inventory) Descriptors of Pain at Baseline and 60 Min After Infusion | Does your pain feel like stabbing? | 0 score on a scale |