Ultrasound-Guided Percutaneous Cryoneurolysis to Treat Postoperative Pain After Mastectomy

All participants will continue to receive standard and customary postoperative analgesics of their local treatment center, so there is no risk of participants receiving a lower degree of analgesia than if they otherwise did not enroll in the study. The cryoneurolysis procedure will be done in addition to standard local institutional standard analgesic treatments.

The investigators propose a pragmatic, multicenter, randomized, triple-masked (investigators, participants, statisticians), sham/placebo-controlled, parallel-arm, human-subjects clinical trial to determine if cryoneurolysis is an effective non-opioid treatment for pain following mastectomy. Participants will be individuals undergoing unilateral or bilateral mastectomy, recruited at 6 centers:

* Walter Reed National Military Medical Center, Bethesda, Maryland * U.C. San Diego, San Diego, California * University of Florida, Gainesville, Florida * Cedars-Sinai, Los Angeles, California * Cleveland Clinic, Cleveland, Ohio

For women of childbearing age with the possibility of pregnancy, a sample of urine will be collected before any study interventions to confirm a non-pregnant state. Participants will have a peripheral intravenous (IV) catheter inserted, standard noninvasive monitors applied (blood pressure cuff, pulse oximeter, 5-lead ECG), and oxygen administered via a facemask. Midazolam and fentanyl (IV) will be titrated for patient comfort as needed throughout the procedure, while ensuring that patients remain responsive to verbal cues.

Peripheral nerve block. Not all enrolling centers provide peripheral blocks as part of their standard-of-care. Due to the pragmatic design of this trial, study participation will not alter an institution's current practice. If the local practice includes a postoperative continuous peripheral nerve block, a perineural catheter will be inserted 2-5 cm beyond the needle tip, the needle withdrawn over the catheter, the catheter affixed with an occlusive sterile dressing.

Participants will be allocated to one of two treatments:

1. cryoneurolysis 2. sham cryoneurolysis (placebo control)

Randomization will be stratified by enrolling institution, surgical site (unilateral vs. bilateral), and axillary involvement (none/biopsy vs. dissection) in a 1:1 ratio, and in randomly chosen block sizes. Randomization lists will be created using Statistical Analysis Software computer-generated tables by the informatics division of the Department of Outcomes Research (Cleveland Clinic, Cleveland, OH). Treatment group assignment will be conveyed to the enrolling sites via the same secure web-based system (REDCap) used to collect and collate all post-intervention endpoints.

There are multiple types of cryoneurolysis machines cleared by the US FDA, all of which work on the same principle of a gas being passed through a small annulus, resulting in a dramatic pressure drop and accompanying temperature drop due to the Joule-Thomson effect. This study will utilize two different consoles \[second option added May 8, 2023\]: the Epimed International (Farmers Branch, TX) and Varian Medical Systems (Palo Alto, CA) machines. Which machine is used is determined simply by the machine that each enrolling center has at its disposal.

Varian: This machine uses argon for the freeze cycle and helium to help decrease the thaw period duration. Sham probes are not available for this type of machine, and therefore an active probe will be used for all participants. For participants randomized to active treatment, the probe will be connected to the machine as usual, the argon (and helium) passed through the probe and then back into the machine, and finally vented out from the console. For participants randomized to sham treatment, the probe will be connected to an inactive connector on the back of the machine. For these participants the gas will simply be ejected directly from the console without ever having passed through the probe. The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the probe (active) or leave the tubing end close to the machine (sham). Therefore, all investigators, participants, and clinical staff will be masked to treatment group assignment, with the only exception being the unmasked individual who performs the procedure (and will not have subsequent contact with the participant).

Epimed: This machine uses nitrous oxide for the freeze cycle with a passive thaw (no gas flow). Cryoneurolysis probes are available that either (1) pass nitrous oxide to the distal end inducing freezing temperatures; or (2) vent the nitrous oxide at the proximal end of the probe so that no gas reaches the distal end, resulting in no temperature change. The latter is a sham procedure since without the temperature change, no ice ball forms and therefore the target nerve is not affected. Importantly, these probes are indistinguishable in appearance and will be differentiated only by an identifying stamp on the underside of the connector which is not visible during use.

The investigator administering the study intervention will access the treatment group assignment using the secure web-based system and attach the appropriate probe to the cryoneurolysis device. Therefore, all investigators, participants, and clinical staff will be masked to treatment group assignment, with the only exception being the unmasked individual who performs the procedure (and will not have subsequent contact with the participant). For both types of machines, it is impossible to mask the individual performing the cryoneurolysis procedure because the ice ball forming at the distal end of the probe-with active treatment-is clearly visible by ultrasound; and the lack of an ice ball for placebo participants is equally clear. It is essential to continuously visualize the probe and target nerve throughout the freeze/thaw cycle(s) to ensure the entire nerve diameter is adequately treated and remains relatively motionless. This cannot be achieved if the ultrasound is turned off during gas administration in an attempt to mask the provider.

Study intervention. The 2nd-6th thoracic intercostal nerves will be treated on the ipsilateral surgical side (bilaterally for bilateral surgical procedures). Using a curved-array transducer, the intercostal nerve will be visualized using ultrasound just inferior to each treated rib immediately distal to the costotransverse joint. For participants without a paravertebral block, a skin wheal of lidocaine 1% will be raised immediately inferior to the transducer to anesthetize the skin. An IV-like hollow-bore introducer may be inserted through the skin and guided to the target nerve--this is based on operator personal preference. For participants without anesthetized intercostal nerves from a peripheral nerve block, lidocaine 1.5-2.0% 2 mL may be injected through the introducer prior to the cryoneurolysis probe introduction to provide anesthesia during the cryoneurolysis cycles, although this is not universally applied (they cryoneurolysis treatment itself induces anesthesia).

A portable cryoneurolysis device (Varian CryoCare or Epimed PainBlocker) will be used. The probe will be inserted adjacent to the intercostal nerve.

Varian: The cryoneurolysis device will be triggered using 1 cycle of 5.5-minute \[all but 4 participants: 064-067\] or 3 minutes \[only 4 participants 064-067; change based on new laboratory data, then changed back based on inadequate freeze\] argon activation (2000 psi and 100% power) followed by a 30-second helium defrost.

Epimed: The cryoneurolysis device will be triggered using 2 cycles of 2-minute gas activation (active or sham) separated by a 1-minute defrost.

The introducer and probe will be withdrawn and this process repeated for each additional intercostal nerve to be treated. For bilateral mastectomies, the study intervention will be repeated on the contralateral side with the same probe.

Intraoperative course. Due to the pragmatic nature of this trial, the investigators aim to change each center's standard practice as little as possible and rather investigate the results of adding the intervention to current practice. The investigators will therefore record intraoperative factors such as type of general anesthetic, axillary dissection, opioid administration, and local anesthetic supplementation; however, the investigators will not require changes to current standard practice.

Postoperative course. Standard local supplemental analgesics will be used due to the pragmatic design of this trial. For analysis purposes, all opioids will be converted to oral oxycodone equivalents. Following a cryoneurolysis treatment, no action is required by patients regarding this intervention. For example, in contrast to epidural infusions, there is no infusion pump to manage or anesthetic fluid to replenish. At enrolling centers that provide a postoperative continuous peripheral nerve block, the ropivacaine or bupivacaine infusions will be administered per local protocol with the catheters removed on postoperative day 1 or 2 prior to hospital discharge.

Following study completion, the results will be mailed electronically or by the United States Postal Service to all enrolled participants in written form using non-technical (e.g., "layperson") language.

Outcome Measurements (End Points). The investigators 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 World Health Organization and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus statement (Table 1, below).5 End points will be evaluated at baseline (prior to surgery on postoperative day 0), as well as postoperative days 1, 2, 3, 4, 7, 21, 30, 45; and months 2, 3, 6, 9 and 12).

Statistical Plan and Data Analysis

Primary Specific Aim: To determine the effect of cryoneurolysis on postoperative opioid requirements and analgesia following mastectomy.

Hypothesis 1: Opioid consumption will be significantly decreased in the first two months following surgery with cryoneurolysis compared with usual and customary analgesia.

Hypothesis 2: Surgical pain will be significantly decreased within the first two months following surgery with cryoneurolysis compared with usual and customary analgesia (measured with a Numeric Rating Scale).

Primary end point: In order to claim that cryoneurolysis is superior to usual and customary analgesia, at least one of Hypotheses 1 and 2 above must be superior while the other at least noninferior.

Secondary Specific Aims: To determine the effect of cryoneurolysis on physical and emotional functioning and chronic pain following mastectomy.

Hypothesis 3: Physical and emotional functioning will be significantly improved within the first two months following surgery with cryoneurolysis as compared with usual and customary analgesia (measured with the Interference Domain of the Brief Pain Inventory).

Hypothesis 4: The incidence of chronic pain will be significantly decreased 6 and 12 months following surgery with cryoneurolysis as compared with usual and customary analgesia.

Hypothesis 5: The intensity of chronic pain will be significantly decreased 6 and 12 months following surgery with cryoneurolysis as compared with usual and customary analgesia (measured with a Numeric Rating Scale).

Balance on baseline covariates will be assessed using absolute standardized difference (ASD):50 i.e., difference in means or proportions divided by the standard deviation. ASD \> 0.1 will be considered to indicate imbalance, and these variables will be adjusted for in the statistical analyses. Analyses will be carried out using modified intention-to-treat (i.e., patients who received any study treatment will be analyzed according to the group to which they were randomized). The overall t

• Opioid consumption [Срок оценки: Collected on postoperative days 1, 2, 3, 4, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Average Pain [Срок оценки: Collected on postoperative days 1, 2, 3, 4, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Worst/maximum Pain [Срок оценки: Collected on postoperative days 1, 2, 3, 4, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Least/lowest/minimal Pain [Срок оценки: Collected on postoperative days 3, 7, 14, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Current Pain [Срок оценки: Collected on postoperative days 3, 7, 14, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Brief pain Inventory, short form (interference subscale) [Срок оценки: Collected on postoperative days 3, 7, 14, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• First 2 months Brief pain Inventory, short form (interference subscale) [Срок оценки: Collected on postoperative days 3, 7, 14, 30, 45 and 60]
• Pain with arm raise [Срок оценки: Collected on postoperative days 1, 2, 3, 4, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Awakenings due to pain [Срок оценки: Collected on postoperative days 1, 2, 3, 4, 7, 14, 21, 30, and 45; as well as months 2, 3, 6, 9, and 12]
• Post-Traumatic Stress Disorder checklist (PCL-5) [Срок оценки: Postoperative day 0 (baseline)]
• Masking assessment [Срок оценки: Postoperative day 7]
• Phantom Breast Pain (WORST/maximum) [Срок оценки: Collected on postoperative days 30 and 45; as well as months 2, 3, 6, 9, and 12]