Pulsed Electromagnetic Fields for Post-Amputation Pain

Study Overview
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Brief Summary
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Pulsed electromagnetic field therapy is a possible method of pain control involving the application of electromagnetic energy (also termed nonthermal, pulsed, shortwave radiofrequency therapy). Food and Drug Administration-cleared devices have been in clinical use for over 70 years. For decades, available devices consisted of a large signal generator and bulky coil applicator that were not portable and produced significant electromagnetic interference, making them impractical for common use. However, small, lightweight, relatively inexpensive, noninvasive, Food and Drug Administration-cleared devices that function for 30 days are now available to treat acute and chronic pain, decrease inflammation and edema, and hasten wound healing and bone regeneration. Therefore, it has the potential to concurrently improve analgesia and decrease or even negate opioid requirements, only without the limitations of opioids and peripheral nerve blocks. The purpose of this pilot study is to explore the possibility of treating chronic post-amputation pain with nonthermal, pulsed shortwave (radiofrequency) therapy, optimize the study protocol, and estimate the treatment effect in preparation for developing subsequent definitive clinical trials.

Detailed Description
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The proposed study will be a randomized, participant- and observer-masked, sham-controlled, crossover, human participants pilot study with two primary aims: Specific Aim 1: To determine the feasibility and optimize the protocol for subsequent clinical trials that will compare the addition of nonthermal, pulsed shortwave therapy to usual and customary analgesia for post-amputation phantom and residual limb pain. Specific Aim 2: To estimate the treatment effect of adding nonthermal, pulsed shortwave therapy to usual and customary analgesia for post-amputation phantom and residual limb pain. This will provide an idea of the optimal amputee characteristics amenable to this analgesic technique and allow determination of the required sample sizes of subsequent definitive clinical trials. Hypothesis: Nonthermal, pulsed shortwave therapy will decrease pain in the 28 days following application for post-amputation pain. This will be a single-center (University of California San Diego), randomized, participant- and observer-masked, sham-controlled, crossover human subjects pilot study. Enrollment. Participants will be consenting adults experiencing post-amputation phantom and/or residual limb pain. Study inclusion will be proposed after an amputee contacts the investigators. If an individual desires study participation, written, informed consent will be obtained using a current University of California San Diego Institutional Review Board-approved informed consent form. The study population of interest includes adult women and men of all races, ethnicity, sexual identity, and socioeconomic status. Procedures. Following written, informed consent, we will record baseline anthropometric information (age, sex, height, weight, amputation details and current pain levels). Treatment Group Assignment. Each participant will be randomized to one of two treatment groups: Active or Sham treatment. There are sham devices produced that are identical to active devices, only they do not deliver pulsed electromagnetic energy. Randomization will be in block sizes of 2. The computer-generated randomization lists will be created by the University of California San Diego Investigational Drug Service in a 1:1 treatment group ratio using opaque envelopes. The active and sham devices are indistinguishable in appearance, and therefore investigators, participants, and all clinical staff other than the individual who opens the randomization envelope and chooses a sham or active device will be masked to treatment group assignment for the duration of the data collection period. An Investigational Drug Service pharmacist will open the envelope and provide the investigators with the appropriate device, keeping all investigators masked to treatment group assignment. Upon completion of data collection, the pharmacist will provide the investigators with a masked list of the treatment groups (e.g., Treatment A and Treatment B), and the active/sham lists only following analysis for that subgroup, resulting in a triple-masked study (investigators, participants, statistician). Study intervention. The pulsed shortwave devices used are over-the-counter (Model 088, BioElectronics, Frederick, Maryland) and 2 devices (both the same treatment group) will be shipped to the patient either in or out of California who will then contact an investigator for assistance in self-placement of the device on the residual limb. The optimal location to treat phantom pain is currently unknown and will partially informed by the results of this pilot study, and patients will be encouraged to move the devices to a new anatomic location every two days until relief is experienced. Supplemental analgesics. In addition to the pulsed shortwave device(s), participants will receive standard-of-care supplemental analgesics which can include acetaminophen, ibuprofen, ketorolac, opioids, gabapentin (this is provider- and patient-dependent). Therefore, all patients of this study-regardless of the treatment arm they are randomized to-will continue to receive current usual and customary analgesia: all will receive the same combination of supplemental analgesics they would regardless of study participation. Participants will be provided with verbal and written instructions, and the telephone and pager numbers of an investigator available during business hours throughout the treatment period. Participants can shower with the device in place, but not submerge it during swimming or a bath, as advised by the manufacturer. Amputees will return their initial devices in pre-addressed and -stamped envelopes that we provide. They will be sent a second device which is the opposite treatment of the initial device: participants who initially received sham will subsequently receive active, and vice versa. These will be applied on (approximately) Day 35 and the same protocol will be repeated as for the initial device, with additional data collected for 35 days after placement of the second device. The second device will be discarded in the trash. Of note, if a device is reported lost or nonfunctional during the study, it will be replaced by the investigators by mail if more than 7 days of treatment remain. Primary end points: This is an exploratory pilot study to assist in planning subsequent definitive trials and we therefore have no data analysis plan. We will enroll a convenience sample of up to 40 participants. The outcome measures of primary interest will be (1) the change in average residual and phantom limb pain scores between baseline and Day 28 of the initial treatment, as well as (2) the Patient Global Impression of Change on Day 28 of the initial treatment.

Official Title
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Pulsed Electromagnetic Fields for Post-Amputation Pain: A Randomized, Triple-Masked, Sham-Controlled, Crossover Pilot Study

Conditions
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Phantom Limb Pain, Residual Limb Pain

Intervention / Treatment
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* Device: Active then Sham Treatment
* Device: Sham then Active Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients of at least 18 years of age [19 years in Alabama and Nebraska] with an upper or lower limb amputation at least 12 weeks prior to enrollment distal to the shoulder or hip (femoral head remaining), respectively, and including at least one metacarpal or metatarsal bone, respectively experience at least moderate residual and/or phantom limb pain-defined as a 3 or higher on the Numeric Rating Scale (NRS; 0-10, 0= no pain; 10=worst imaginable pain)-at least daily for the previous 2 months willing to avoid both changes to their analgesic regimen as well as elective surgical procedures for 70 days after initiation of treatment with PEMF therapy Exclusion Criteria: concurrent use of an implanted pulse generator (e.g., cardiac pacemaker) pregnancy incarceration

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants will be randomized to either active or sham treatment for 30 days; and will then crossover and receive the alternative treatment for 30 additional days. The primary analysis will compare the initially-randomized active and sham treatment groups--thus, a parallel group (inter-participant) comparison; but secondary analyses will compare intra-participant changes as well.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active then Sham Treatment<br>Application of 30 days of nonthermal, pulsed shortwave (radiofrequency) therapy, 7 day washout, 30 days of sham. | Device: Active then Sham Treatment<br>* Application of 30 days of nonthermal, pulsed shortwave (radiofrequency) therapy; then sham treatment after a 7-day washout period<br>* Other names: pulsed electromagnetic fields therapy then sham;|
| Experimental: Sham then Active Treatment<br>Application of 30 days of a nonfunctional sham device, 7 day washout, then 30 days of nonthermal, pulsed shortwave (radiofrequency) therapy | Device: Sham then Active Treatment<br>* Application of 30 days of sham treatment; then 30 days of nonthermal, pulsed shortwave (radiofrequency) therapy after a 7-day washout period<br>* Other names: Sham then pulsed electromagnetic fields therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in average RESIDUAL limb pain scores between baseline and Day 28 of the initial treatment as measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will be the difference between the baseline and Day 28 timepoints. | Baseline and Day 28 | 
| Change in average PHANTOM limb pain scores between baseline and Day 28 of the initial treatment as measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will be the difference between the baseline and Day 28 timepoints. | Baseline and Day 28 | 
| Patient Global Impression of Change for RESIDUAL limb pain between baseline and Day 28 of the initial treatment | A 7-point Likert scale with 1 equivalent to much worse, 4 equivalent to no change, and 7 equivalent to much improved. Patients compare their current pain level with baseline using this scale. | Day 28 | 
| Patient Global Impression of Change for PHANTOM limb pain between baseline and Day 28 of the initial treatment | A 7-point Likert scale with 1 equivalent to much worse, 4 equivalent to no change, and 7 equivalent to much improved. Patients compare their current pain level with baseline using this scale. | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Global Impression of Change for RESIDUAL limb pain | A 7-point Likert scale with 1 equivalent to much worse, 4 equivalent to no change, and 7 equivalent to much improved. Patients compare their current pain level with baseline using this scale. | Days 2, 4, 7, 21, 28, and 35 for both initial and crossover treatments | 
| Patient Global Impression of Change for PHANTOM limb pain | A 7-point Likert scale with 1 equivalent to much worse, 4 equivalent to no change, and 7 equivalent to much improved. Patients compare their current pain level with baseline using this scale. | Days 2, 4, 7, 21, 28, and 35 for both initial and crossover treatments | 
| Change in AVERAGE RESIDUAL pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 2, 4, 7, 21, 28, and 35 for both initial and crossover treatments | 
| Change in WORST RESIDUAL pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 2, 4, 7, 21, 28, and 35 for both initial and crossover treatments | 
| Change in LEAST RESIDUAL pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 28 and 35 for both initial and crossover treatments | 
| Change in CURRENT RESIDUAL pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 28 and 35 for both initial and crossover treatments | 
| Change in AVERAGE PHANTOM pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 2, 4, 7, 21, 28, and 35 for both initial and crossover treatments | 
| Change in WORST PHANTOM pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 2, 4, 7, 21, 28, and 35 for both initial and crossover treatments | 
| Change in LEAST PHANTOM pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 28 and 35 for both initial and crossover treatments | 
| Change in CURRENT PHANTOM pain from baseline measured with the Numeric Rating Scale | The numeric rating scale is a 0-10 Likert scale measuring pain level with 0 = no pain and 10 = worst imaginable pain scale. The outcome will the difference between the baseline and current pain level measured with the Numeric Rating Scale | Days 28 and 35 for both initial and crossover treatments | 
| As-needed (non-scheduled) analgesic use | Patient's perception of requirements over the previous 24 hours of as-needed (non-scheduled) analgesic use | Inquired on Day 2, 4, 7, 21, 28 and 35 for both initial and crossover treatments | 
| Brief pain inventory, short form (interference sub scale) | The Brief pain Inventory (short form) is an instrument specifically designed to assess pain and its impact on physical and emotional functioning. The brief Inventory is comprised of three domains: (1) pain, with four questions involving worst, average and current pain levels using a 0-10 numeric rating scale;(2) percentage of relief provided by pain treatments with one question [reported score is the percentage divided by 10 and then subtracted from 10: 0=complete relief,10=no relief] and, (3) interference with 7 questions involving physical and emotional functioning using a 0-10 Likert scale [0=no interference;10=complete interference]: general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life. This outcome will include the interference subscale. | Inquired on Days 28 and 35 for both initial and crossover treatments | 
| Awakenings due to pain the previous evening | The number of awakenings due to pain that occurred the previous evening | Inquired on Days 2, 4, 7, 21, 28, and 35 for both initial and crossover treatments | 
| Does patient want to continue using device? | Does the patient want to continue using device answered as yes, no or unsure | Inquired on Day 35 for both initial and crossover treatments | 
| Device location changes | If a patient moves the anatomic location of one or both of the intervention devices (and where the device is moved to) since the last contact | Inquired on Days 2, 4, 7, 21, 28 and 35 for both initial and crossover treatments |