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

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:

1. cryoneurolysis
2. 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.