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

All subjects would continue to receive standard and customary postoperative analgesics, so
there is no risk of subjects 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 our current
UCSD standard practice.

Subjects will be individuals undergoing unilateral or bilateral mastectomy or limb
amputation. 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.

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 (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 blocks (4 levels
per side depending on the specific surgical approach) for mastectomy; femoral/sciatic for
lower limb amputation, and brachial plexus (or terminal nerves) for upper limb amputation.
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.

Mastectomy subjects [up to the first 20 subjects]: We will use a hand-held cryoneurolysis
machine (Iovera, Myoscience, Redwood City, CA). For subjects randomized to sham, we will
insert 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 will simulate a cryo
treatment but not actually deliver gas to the probe. Therefore, there will be no temperature
change. However, since all subjects will have a paravertebral block in place—and intercostal
cryoneurolysis approach is via the subjects' back outside of their line of vision, subjects
will be unable to sense much besides the pressure of the angiocatheter insertion and will
remain masked to treatment group. For subjects randomized to receive cryoneurolysis, the same
procedure will be 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. For subjects having a bilateral
mastectomy, the same treatment as performed on the firs side will be performed on the
contralateral side (right side always performed first).

All limb amputation subjects and final (approx.) 40 mastectomy subjects: 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 investigators, subjects, and all clinical staff will be masked to
treatment group assignment [only the treating physician/investigator with be unmasked due to
the ice ball--or lack thereof--formation viewed by ultrasound]. 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 subjects will be included in a pilot study to help
power a future clinical trial, so we will enroll a convenience sample and not have a
pre-determined primary endpoint or statistical plan.

For the subjects having mastectomy, we 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 we 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. We approximate power using the two-sample t-test. Assuming a standard deviation of
2.25 NRS points,2 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.

Inclusion Criteria:

1. adult patients of at least 18 years of age

2. scheduled for a unilateral or bilateral mastectomy or unilateral limb amputation
distal to the femoral/humeral head and including at least one metatarsal/metacarpal
bone

3. continuous peripheral nerve blocks planned for perioperative analgesia

4. accepting of a cryoneurolysis procedure

Exclusion Criteria:

1. chronic opioid use (daily use within the 2 weeks prior to surgery and duration of use
> 4 weeks)

2. pregnancy

3. incarceration

4. inability to communicate with the investigators

5. morbid obesity (body mass index > 40 kg/m2)

6. possessing any contraindication specific to cryoneurolysis such as a localized
infection at the treatment site, cryoglobulinemia, cold urticaria and Reynaud's
Syndrome