Cryoanalgesia to Treat Post-Amputation Phantom Limb Pain: A Department of Defense Funded Multicenter Study

Subjects will be asked to make no changes to their analgesic regimen for at least 1 month
prior to the cryoneurolysis procedure and continuing for 4 months until the measurement of
the primary end point-for the duration of the study, all patients will be allowed to continue
their pre-intervention analgesics. All subjects will have a peripheral intravenous catheter
inserted, standard noninvasive monitors applied, and oxygen administered via a facemask or
nasal cannula. Midazolam and fentanyl (IV) will be titrated for patient comfort. The specific
nerves targeted will be the sciatic and femoral (or their distal branches). The potential
cryoneurolysis sites will be cleansed with chlorhexidine gluconate and isopropyl alcohol. The
target nerves will be identified in a transverse cross-sectional (short axis) view using
ultrasound. A Tuohy-tip needle will be inserted beneath the ultrasound transducer and
directed until the needle tip is immediately adjacent to the target nerve. Local anesthetic
(1-3 mL, lidocaine 2%) will be injected. This will be repeated for the femoral nerve. Within
20 minutes of the second injection, the subject's limb pain level will be evaluated on the
0-10 NRS and if higher than at baseline prior to injection, the subject will NOT continue
with treatment and their participation in the study will terminate upon discharge.

Treatment group assignment (randomization). Remaining subjects will be allocated to one of
two possible treatments:

1. cryoneurolysis

2. sham cryoneurolysis (placebo control)

Randomization will be computer-generated and stratified by enrolling institution in randomly
chosen block sizes. Cryoneurolysis probes are available 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 (PainBlocker,
Epimed, Farmers Branch, Texas). Importantly, these probes are indistinguishable in
appearance. Unmasking will not occur until statistical analysis is complete.

Intervention. The potential cryoneurolysis sites will be again cleansed with chlorhexidine
gluconate and isopropyl alcohol. With the same ultrasound transducer used to previously
administer local anesthetic, the target nerve will again be identified in a transverse
cross-sectional (short axis) view at or distal to the deposition of local anesthetic. A
cryoneurolysis device (PainBlocker, Epimed, Farmers Branch, Texas) will be inserted with the
appropriate randomization-designated probe (either active or sham/placebo) and nitrous oxide.
The cryoneurolysis device will be triggered using 3 cycles of 2-minute gas activation (active
or sham) separated by 1-minute defrost periods. The process will be repeated with the same
treatment probe for the femoral nerve (e.g., both nerves will receive either active
cryoneurolysis or sham/placebo, and not a mix of the two possible treatments).

Optional crossover treatment. Four to 6 months following the initial treatment, subjects may
return for an optional repeated intervention procedure ("crossover") with the alternative
treatment (either active cryoneurolysis or sham/placebo), again in a double-masked fashion
using the same protocol as described for the initial intervention. The crossover treatment is
not required for study participation, as the primary analyses will include a parallel study
design for the initial intervention evaluated prior to any crossover treatment. This
crossover will not affect the primary analyses, which will involve a parallel group study
design and investigate the effects of cryoneurolysis within 4 months of the initial
intervention.

Outcome measurements (endpoints). The primary end point will be the difference in average
daily phantom pain intensity at baseline and 4 months following the initial intervention
(measured with the NRS as part of the Brief Pain Inventory). The primary analyses will
compare the two treatments (inter-subject comparisons) during the initial treatment period in
which half of the subjects will receive active cryoneurolysis and the other half a
sham/placebo treatment. Endpoints will be evaluated at baseline and post-treatment (Day 0),
Days 1 and 7; and Months 1, 2, 3, 4, and 12. These same time points through Month 4 will be
evaluated following the optional second (crossover) treatment.

Data collection. The questionnaires for all subjects-regardless of enrolling center-will be
administered by telephone from the University of California San Diego by research
coordinators specifically trained in these instruments' application, minimizing inter-rater
discordance. Staff masked to treatment group assignment will perform all assessments.

Inclusion Criteria:

- Adult patients of at least 18 years of age

- with a lower limb traumatic or surgical amputation at least 12 weeks prior to
enrollment distal to the hip (femoral head remaining)

- who experience at least moderate phantom limb pain-defined as a 3 or higher on the
Numeric Rating Scale (NRS; 0-10, 0= no pain; 10=worst imaginable pain)-at least daily
for the previous 2 months.

- accepting of a cryoneurolysis procedure

- willing to avoid both changes to their analgesic regimen as well as elective surgical
procedures from 1 month prior to and at least 4 months following the initial
cryoneurolysis procedure.

Exclusion Criteria:

- allergy to amide local anesthetics

- 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.