Pulsed Shortwave Therapy for Postoperative Analgesia

Study Overview
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Brief Summary
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Pulsed shortwave (radiofrequency) therapy is a possible method of pain control involving the application of electromagnetic energy (also termed pulsed electromagnetic fields). 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 8 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 study is to explore the possibility of treating acute postoperative pain with nonthermal, pulsed shortwave (radiofrequency) therapy, optimize the study protocol, and estimate the treatment effect.

Detailed Description
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The proposed study will be a randomized, participant- and observer-masked, sham-controlled, parallel-arm, human participants 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 following moderate-to-severely painful surgical procedures. Specific Aim 2: To estimate the treatment effect of adding nonthermal, pulsed shortwave therapy to usual and customary analgesia on pain and opioid consumption following moderate-to-severely painful surgical procedures. Hypothesis 1 (primary): Nonthermal, pulsed shortwave therapy decreases pain in the 7 days following moderate-to-severely painful surgical procedures. Hypothesis 2: Nonthermal, pulsed shortwave therapy decreases opioid use in the 7 days following moderate-to-severely painful surgical procedures. This will be a single-center (University of California San Diego), randomized, participant- and observer-masked, sham-controlled, parallel-arm human subjects study. Enrollment. Participants will be consenting adults undergoing various surgical procedures usually resulting in moderate-to-severe postoperative pain. Study inclusion will be proposed to eligible presurgical patients. 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). Participants will receive any standard peripheral nerve block(s) administered using bupivacaine or ropivacaine 0.5% with epinephrine (standard at University of California San Diego) prior to undergoing their surgical procedure per standard of care. Treatment Group Assignment. Each participant will be randomized to one of two treatment groups: Active or Sham treatment. Randomization will be stratified by surgical procedure 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. An Investigational Drug Service pharmacist will provide the investigators with the appropriate device. Upon completion of data collection for a specific subgroup (e.g., total knee and hip arthroplasty; cholecystectomy), 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 device will be affixed over the primary wound area(s) using tape and activated prior to recovery room discharge. The optimal location to treat phantom pain is currently unknown and will partially informed by the results of this study, and patients will be encouraged to move the devices to a new anatomic location until relief is optimized. Supplemental analgesics. In addition to the pulsed shortwave device, participants will receive standard-of-care supplemental analgesics. 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 (and their caretakers) 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 cannot shower or submerge the device, as advised by the manufacturer; but will be allowed to remove it to bathe, and subsequently replace the device following bathing. Participants will be discharged with their pulsed shortwave device in situ and a prescription for immediate-release oral opioid, preferably oxycodone 5 mg tablets, taken for breakthrough pain (surgeons occasionally prefer a different type of opioids such as hydrocodone, which is why we analyze the data using oral oxycodone equivalents). The pulsed shortwave devices will be removed by participants at home following Day 8 when the battery is exhausted. Removing the devices encompasses tape removal and discarding (these are disposable, single-use devices). Outcome measurements (end points). We have selected outcome measures that have established reliability and validity, with minimal inter-rater discordance, and are recommended for pain-related clinical trials by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus statement. All data collection will be through standard UCSD EPIC notes and patient interviews in-person during hospitalization or via a telephone call for outpatients. Postoperatively, surgical endpoints will be recorded such as surgical duration. All pain scores will be measured using the Numeric Rating Scale (0: no pain, 10: worst imaginable pain). Statistical plan and sample size estimation. there will be a total of 70 surgical participants, and these patients will be analyzed separately from Phase I surgical and amputation patients. Sample size calculations are based upon the hypothesis that pulsed electromagnetic field therapy decreases pain in the 7 days following moderate-to-severely painful surgical procedures. The primary outcome calculated as follows: for each participant all of the average and worst daily pain scores collected within the first 7 postoperative days will be summed. We will use these summed scores from participants having cholecystectomy (n=30), and hip and knee arthroplasty (n=40) to estimate a probable sample size. We will consider a 33% reduction in pain scores to be the minimal clinically important difference [Farrar et al. J Pain Symptom Management 2003; 25: 406-11]. Based on values from patients receiving sham in an (as-of-yet) unpublished pilot study, we anticipate the sham group to have an anticipated mean (SD) of 23.9 (12.3). Assuming a two-sided type I error protection of 0.05 and a power of 0.80, approximately 25 patients in each group are required (ClinCalc.com, accessed 2/23/23). To allow for a higher degree of variability than anticipated we will enroll a total of 70 participants: cholecystectomy (n=30), and hip and knee arthroplasty (n=40). Continuous, normally-distributed data will be reported as mean ± standard deviation. Nonparametric continuous or categorical data will be reported as median [10th-90th percentiles] or precents, as appropriate. Comparisons of independent samples will be performed using Student's t-test for parametric continuous variables or Mann-Whitney U test for nonparametric or categorical variables. The Chi Square test and Fisher's Exact test will be used for differences in proportions, as appropriate. P<0.05 will be considered statistically significant for the primary outcome. Results of comparisons in secondary outcomes will be interpreted as suggestive, requiring confirmation in a future trial before considering them as definitive.

Official Title
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Pulsed Electromagnetic Fields for Postoperative and Post-Amputation Analgesia: A Randomized, Participant- and Observer-Masked, Sham-Controlled Pilot Study

Conditions
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Postoperative Pain, Acute

Intervention / Treatment
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* Device: Active Pulsed Shortwave Treatment
* Device: Sham Treatment


Participation Criteria
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Eligibility Criteria
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Adult patients of at least 18 years of age undergoing one of these primary surgical procedures: primary knee arthroplasty primary hip arthroplasty cholecystectomy Exclusion Criteria: concurrent use of an implanted pulse generator (e.g., cardiac pacemaker) pregnancy incarceration chronic opioid/tramadol use (daily use within the 2 weeks prior to surgery and duration of use > 4 weeks) neuro-muscular deficit of the surgical area/limb a planned postoperative perineural local anesthetic infusion

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: Parallel Assignment
Interventional Model Description: Parallel Assignment: Randomized, Triple-Masked, Placebo-Controlled, Parallel-Arm Human Subjects Clinical Trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Pulsed Shortwave Treatment with SofPulse<br>Application of 8 days of nonthermal, pulsed shortwave (radiofrequency) therapy with Endonovo Therapeutics SofPulse | Device: Active Pulsed Shortwave Treatment<br>* Application of 8 days of nonthermal, pulsed shortwave (radiofrequency) therapy with Endonovo Therapeutics SofPulse<br>* Other names: pulsed electromagnetic fields therapy;|
| Sham Comparator: Sham Treatment<br>Application of 8 days of sham device | Device: Sham Treatment<br>* Application of 8 days of a nonfunctional sham device<br>* Other names: Placebo treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain 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 primary outcome calculated as follows: for each participant all of the average and worst daily pain scores collected within the first 7 postoperative days will be summed. | First postoperative week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AVERAGE pain 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 | postoperative day 1 | 
| AVERAGE pain 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 | postoperative day 2 | 
| AVERAGE pain 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 | postoperative day 3 | 
| AVERAGE pain 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 | postoperative day 7 | 
| AVERAGE pain 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 | postoperative day 14 | 
| AVERAGE pain 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 | postoperative day 180 | 
| Median AVERAGE pain 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 mean value of daily average pain scores measured with the Numeric Rating Scale. | Median value of the average daily pain measured on postoperative days 1, 2, 3, and 7 | 
| Median WORST pain 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 mean value of daily worst pain scores measured with the Numeric Rating Scale. | Median value of the worst daily pain measured on postoperative days 1, 2, 3, and 7 | 
| WORST pain 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 | postoperative day 1 | 
| WORST pain 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 | postoperative day 2 | 
| WORST pain 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 | postoperative day 3 | 
| WORST pain 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 | postoperative day 7 | 
| WORST pain 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 | postoperative day 14 | 
| WORST pain 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 | postoperative day 180 | 
| LEAST pain 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 | postoperative day 7 | 
| LEAST pain 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 | postoperative day 14 | 
| CURRENT pain 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 | postoperative day 7 | 
| CURRENT pain 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 | postoperative day 14 | 
| Total OPIOID consumption from recovery room discharge until the data collection phone call on postoperative day 7 (measured in oral oxycodone equivalents) | Total opioid consumption from recovery room discharge until the data collection phone call on postoperative day 7 (measured in oral oxycodone equivalents). | Cumulative opioid consumption queried on postoperative days 1, 2, 3, and 7 | 
| Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | postoperative day 1 | 
| Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | postoperative day 2 | 
| Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | postoperative day 3 | 
| Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | postoperative day 7 | 
| Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | postoperative day 14 | 
| Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | Opioid consumption of the previous 24 hours (measured in oral oxycodone equivalents) | postoperative day 180 | 
| Brief pain Inventory, short form (interference subscale) | 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. | postoperative day 7 | 
| Brief pain Inventory, short form (interference subscale) | 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. | postoperative day 14 | 
| Awakenings due to pain | The number of times the participant awoke the previous night due to pain | postoperative day 1 | 
| Awakenings due to pain | The number of times the participant awoke the previous night due to pain | postoperative day 2 | 
| Awakenings due to pain | The number of times the participant awoke the previous night due to pain | postoperative day 3 | 
| Awakenings due to pain | The number of times the participant awoke the previous night due to pain | postoperative day 7 | 
| Awakenings due to pain | The number of times the participant awoke the previous night due to pain | postoperative day 14 | 
| Hospitalization duration measured in days | Day relative to the day of surgery that patient was discharged from the hospital (e.g., same day is postoperative day 0, while the day following surgery is postoperative day 1) | First postoperative week | 
| Surgical start as recorded using military time format | The time of the surgical incision as recorded using military time format | intraoperative (within the operating room) | 
| Surgical stop as recorded using military time format | The time of the final suture insertion as recorded using military time format | intraoperative (within the operating room) | 
| Surgical duration | The time from surgical start to surgical stop measured in minutes and hours | intraoperative (within the operating room) | 
| 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 phone contact | postoperative day 1 | 
| 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 phone contact | postoperative day 2 | 
| 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 phone contact | postoperative day 3 | 
| 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 phone contact | postoperative day 7 | 
| 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 phone contact | postoperative day 14 | 
| Passive joint flexion | The number of degrees the patient can flex their knee or hip (for these procedures only; cholecystectomy excluded) | postoperative day 14 |