Cryoanalgesia to Prevent Acute and Chronic Pain Following Surgery: A Randomized, Double-Masked, Sham-Controlled Study

Study Overview
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Brief Summary
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The ultimate objective of the proposed line of research is to determine if cryoanalgesia is an effective adjunctive treatment for pain in the period immediately following various painful surgical procedures; and, if this analgesic modality decreases the risk of persistent postoperative pain, or chronic pain. The objective of the proposed pilot study is to optimize the protocol and collect data to power subsequent, definitive clinical trials. Specific Aim 1: To determine if, compared with current and customary analgesia, the addition of cryoanalgesia decreases the incidence and severity of post-surgical pain. Hypothesis 1a (primary): The severity of surgically-related pain will be significantly decreased on postoperative day 2 with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment. Hypothesis 1b: The incidence of chronic pain will be significantly decreased one year following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment. Hypothesis 1c: The severity of chronic pain will be significantly decreased one year following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment. Specific Aim 2: To determine if, compared with current and customary analgesia, the addition of cryoanalgesia improves postoperative functioning. Hypothesis 2a: Following primary unilateral knee and shoulder arthroplasty as well as rotator cuff repair, joint range of motion will be significantly increased within the year following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment. Hypothesis 2b: Following video-assisted thoracoscopic surgery, inspiratory spirometry will be improved within the month following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment.

Detailed Description
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Subjects will be individuals undergoing unilateral or bilateral mastectomy; upper or lower limb amputation; primary, unilateral total knee or shoulder arthroplasty; primary, unilateral rotator cuff repair; video-assisted thoracoscopic surgery; and burn-related skin grafting of the lateral thigh. Those who consent to participate in this study will have standard preoperative peripheral nerve blocks administered and catheters inserted: paravertebral blocks or a fascial plane block (e.g., erector spinae plane block) for mastectomy, femoral/sciatic for lower limb amputation, and brachial plexus (or terminal nerves) for upper limb amputation; femoral or adductor canal for total knee arthroplasty; interscalene for shoulder arthroplasty or rotator cuff repair; thoracic epidural for video-assisted thoracoscopic surgery (VATS); and lateral femoral cutaneous nerve for skin grafting of the lateral thigh. Treatment group assignment (randomization). Subjects with successfully-administered peripheral nerve blocks (defined by sensory changes in the appropriate nerve distribution) will be allocated to one of two possible treatments: cryoneurolysis sham cryoneurolysis (placebo control) Randomization will be stratified by surgery type (e.g., mastectomy, upper limb amputation, and lower limb amputation). Computer-generated randomization lists will be used to create sealed, opaque randomization envelopes with the treatment group assignment enclosed in each envelope labeled with the randomization number. The specific nerves targeted will depend on the surgical site: intercostal nervesblocks (4 levels depending on the specific surgical approach) for mastectomy; femoral/sciatic for lower limb amputation, and brachial plexus (or terminal nerves) for upper limb amputation; infrapatellar branch of the saphenous nerve for knee arthroplasty; suprascapular nerve for shoulder surgery; intercostal nerves for VATS procedures, and the lateral femoral cutaneous nerve for skin grafting of the lateral thigh. The cryoneurolysis sites will be cleansed with chlorhexidine gluconate and isopropyl alcohol. Using the optimal ultrasound transducer for the specific anatomic location and subject anatomy (linear vs curvilinear array), the target nerves will be identified in a transverse cross-sectional (short axis) view. We initially used a hand-held cryoneurolysis machine (Iovera, Myoscience, Redwood City, CA; prior to merger with Pacira Pharmaceuticals). For subjects randomized to sham, we inserted the angiocatheters just through the skin and subsequently place the probe through the angiocatheter, but not deeper than immediately subcutaneous (lidocaine 2% will be administered, as needed, to anesthetize the angiocatheter track). We simulated a cryo treatment but did not actually deliver gas to the probe. Therefore, there was no temperature change. However, since all subjects had a paravertebral block in place, and intercostal cryoneurolysis approach was via the subjects' back outside of their line of vision, subjects were unable to sense much besides the pressure of the angiocatheter insertion and remained masked to treatment group. For subjects randomized to receive cryoneurolysis, the same procedure was used, only the angiocatheters inserted deeper towards the intercostal nerves, the probes situated adjacent to the intercostal nerves, and active gas passed through the probe resulting in cryoneurolysis of the target nerves. When it became available, the hand-held device was replaced by a console cryoneurolysis device. Cryoneurolysis probes are available for a console neurolysis device (PainBlocker, Epimed, Farmers Branch, Texas) that either (1) pass nitrous oxide to the tip inducing freezing temperatures; or, (2) vent the nitrous oxide at the base of the probe so that no gas reaches the probe tip, resulting in no temperature change. Importantly, these probes are indistinguishable in appearance, and therefore treating physicians, subjects, and all clinical staff will be masked to treatment group assignment [only the treating physician/investigator performing the cryoneurolysis with be unmasked]. An angiocatheter/introducer may be inserted beneath the ultrasound transducer and directed until the probe tip is immediately adjacent to the target nerve (lidocaine 2% will be administered, as needed, to anesthetize the angiocatheter track). The angiocatheter needle will be removed, leaving the angiocatheter through which the appropriate Epimed probe will be inserted until it is adjacent to the target nerve. The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation (active or sham) separated by 1-minute defrost periods. For active probes, the nitrous oxide will be deployed to the tip where a drop in temperature to -70°C will result in cryoneurolysis. For the sham probes, the nitrous oxide will be vented prior to reaching the probe shaft, resulting in a lack of perineural temperature change. The process will be repeated with the same treatment probe for any additional nerves (e.g., all nerves will receive either active cryoneurolysis or sham/placebo, and not a mix of the two possible treatments). Statistical Analysis. The limb amputation, total knee and shoulder arthroplasty, rotator cuff repair, VATS, and skin grafting subjects will be included in pilot studies to help power a future clinical trials, so the investigators will enroll a convenience sample and not have a pre-determined primary endpoint or statistical plan. However, the end points of most interest will be average pain score on postoperative day 2 for shoulder arthroplasty and skin grafting subjects, range-of-motion at 6 weeks for the rotator cuff repairs, range-of-motion for knee arthroplasty, and FEV1 for the VATS procedures. For the subjects having mastectomy, the investigators will power this study for an acute pain end point which will provide conclusive results for that end point; but, the data will also be used to help power a subsequent large, multicenter clinical trial for a chronic pain-related end point (which will require far more subjects than the investigators will enroll for the current study). For the mastectomy subjects, sample size calculations are centered around the hypothesis that cryoneurolysis decreases the incidence and severity of post-mastectomy pain in the week following surgery. To this end, the primary outcome is the average NRS (as administered as part of the Brief Pain Inventory) queried on the afternoon of postoperative day 2. The difference in the distribution of NRS between groups will be assessed using the Mann-Whitney U test. The investigators approximate power using the two-sample t-test. Assuming a standard deviation of 2.25 NRS points, and minimum clinically meaningful difference of 2 NRS points, n=30 patients per group provide 86% power with two-sided alpha=5%. The t-test approximation was confirmed by simulating integer valued NRS scores in the range 0 to 10. One group was simulated by rounding normally distributed data with mean 1.5 and standard deviation 2.5 (resulting in median of 2 and interquartile range 0 to 3); and the other with mean 3.5 and standard deviation 2.5 (resulting in median of 4 and interquartile range 1 to 5). Note these resulting summary statistics are consistent with Ilfeld et al (2014). When 10,000 trials were simulated under these assumptions, the Mann-Whitney U test provided 89.5% power, and Type I error was maintained at 4.85%. Differences between groups in demographic variables and secondary endpoints will be assessed with the Mann-Whitney U test for continuous or ordinal data, and Fisher's Exact test for categorical data. Box-and-whisker plots will be used to visualize distributions by group. R version 3.4.4 (R-project.org) was used for sample size calculations and simulations; and the most recent version of R will be used at the time of analysis.

Official Title
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Cryoanalgesia to Prevent Acute and Chronic Pain Following Surgery

Conditions
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Mastectomy, Upper Limb Amputation Below Elbow, Upper Limb Amputation Above Elbow, Lower Limb Amputation Below Knee, Lower Limb Amputation Above Knee, Knee Arthropathy, Shoulder Arthroplasty, Rotator Cuff Repair, Video-Assisted Thoracoscopic Surgery (VATS), Skin Grafting

Intervention / Treatment
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* Device: Cryoneurolysis (active)
* Device: Sham cryoneurolysis procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients of at least 18 years of age scheduled for a primary, unilateral total knee or shoulder arthroplasty, primary unilateral rotator cuff repair, VATS procedure, skin grafting of the lateral thigh, unilateral or bilateral mastectomy, or limb amputation distal to the femoral/humeral head and including at least one metatarsal/metacarpal bone single-injection or continuous peripheral nerve blocks block or epidural infusion planned for perioperative analgesia accepting of a cryoneurolysis procedure Exclusion Criteria: chronic opioid use (daily use within the 2 weeks prior to surgery and duration of use > 4 weeks) pregnancy incarceration inability to communicate with the investigators morbid obesity (body mass index > 40 kg/m2) possessing any contraindication specific to cryoneurolysis such as a localized infection at the treatment site, cryoglobulinemia, cold urticaria and Reynaud's Syndrome

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (active cryoneurolysis)<br>Receiving active cryoneurolysis | Device: Cryoneurolysis (active)<br>* Mastectomy (subjects 1-18): Myoscience Iovera device: full cryo cycle. Mastectomy (subjects 19-end) and all other procedures: Epimed PainBlocker device: 3 cycles of 2-minute gas activation separated by 1-minute defrost periods with an active probe which results in a decrease in temperature<br>|
| Sham Comparator: Sham<br>Receiving sham cryoneurolysis procedure | Device: Sham cryoneurolysis procedure<br>* Mastectomy (subjects 1-18): Myoscience Iovera device: simulated full cryo cycle without administering gas to the probe. Mastectomy (subjects 19-end) and all other procedures: 3 cycles of 2-minute gas activation separated by 1-minute defrost periods with a SHAM probe that does not deliver gas to the tip or result in a drop in temperature<br>* Other names: Placebo treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Pain (Mastectomy Subjects Only) | Measured with the 0-10 numeric rating scale as part of the Brief Pain Inventory, with 0 equivalent to no pain and 10 equivalent to the worst imaginable pain | afternoon of postoperative day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analgesic Consumption | Analgesic consumption for previous 24 hours | Postoperative days 1, 2, 3, 4, 7, 14, 21, as well as months 1, 3, 6, and 12 | 
| Brief Pain Inventory (Interference Subscale) | The Brief Pain Inventory short form (interference scale) is designed to assess pain's impact on physical and emotional functioning. It has established reliability and validity, with minimal inter-rater discordance, and is recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus statement. The interference domaine is comprised of 7 questions involving the degree of pain's interference on physical and emotional functioning using a 0-10 Likert scale (0 = none; 10 = complete). The scale is thus 0-70 with higher scores equivalent to more interference due to pain> | Months 1, 3, 6, and 12 | 
| Worst Pain Measured on the 11 Point Numeric Rating Scale | The subjects' perception of their worst level pain in the previous 24 hours measured with the 0-10 numeric rating scale as part of the Brief Pain Inventory, with 0 equivalent to no pain and 10 equivalent to the worst imaginable pain | Postoperative days 1, 2, 3, 4, 7, 14, and 21 | 
| Average Pain Measured on the 11 Point Numeric Rating Scale | The subjects' perception of their average level pain in the previous 24 hours measured with the 0-10 numeric rating scale as part of the Brief Pain Inventory, with 0 equivalent to no pain and 10 equivalent to the worst imaginable pain | Postoperative days 1, 2, 3, 4, 7, 14, and 21 | 
| Difficultly Sleeping Due to Pain | Difficulty sleeping due to pain (binary answer: yes or no; not based on a scale or instrument). The numbers presented in the results are the number of participants in each treatment group answering YES, they DID have difficulty sleeping due to pain | Postoperative days 1, 2, 3, 4, 7, 14, and 21 | 
| Number of Awakenings | Number of awakenings from sleep due to pain (simply the number of times of awakenings--not based on a scale or instrument) | Postoperative days 1, 2, 3, 4, 7, 14, and 21 | 
| Nausea | Nausea measured on a 0-10 scale with 0=no nausea and 10=vomiting; thus higher on the scale is worse | Postoperative days 1, 2, 3, 4, 7, 14, and 21 | 
| Phantom Pain Occurences [Mastectomy & Amputation] | How many times in the previous 3 days subject experienced phantom pain (the number of times experienced--not based on a scale or instrument) | Postoperative months 1, 3, 6, and 12 | 
| Phantom Pain Duration [Mastectomy & Amputation] | The average duration of phantom pain occurrences in the previous 3 days | Postoperative months 1, 3, 6, and 12 | 
| Phantom Sensation Occurrences [Mastectomy & Amputation] | How many times in the previous 3 days subject experienced phantom sensations (the number of times experienced--not based on a scale or instrument). This outcome differs from phantom pain occurrences in that for this outcome no pain is necessary; rather, participants feel the missing body part is actually there, when it is not--yet it is not a painful sensation. | Postoperative months 1, 3, 6, and 12 | 
| Phantom Sensation Duration [Mastectomy & Amputation] | The average duration of phantom sensation occurrences in the previous 3 days. This outcome differs from phantom pain duration in that for this outcome no pain is necessary; rather, participants feel the missing body part is actually there, when it is not--yet it is not a painful sensation. | Postoperative months 1, 3, 6, and 12 | 
| Residual Limb or Wound Pain Occurences | How many times in the previous 3 days subject experienced residual limb or wound pain (the number of times experienced--not based on a scale or instrument) | Postoperative months 1, 3, 6, and 12 | 
| Residual Limb or Wound Pain Duration | The average duration of residual limb or wound pain occurrences in the previous 3 days | Postoperative months 1, 3, 6, and 12 |