Summary

for people ages 18 years and up (full criteria)
at San Diego, California
study started
estimated completion:
Brian Ilfeld

Description

Summary

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 mastectomy or limb amputation; 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 a subsequent, definitive clinical trial. Specific Aim 1: To determine if, compared with current and customary analgesia, the addition of cryoanalgesia decreases the incidence and severity of post-mastectomy pain. Hypothesis 1a (primary): The severity of breast pain will be significantly decreased following mastectomy on postoperative day 2 with the addition of cryoanalgesia as compared with patients receiving standard-of-care treatment. Hypothesis 1b: The incidence of chronic pain will be significantly decreased one year following mastectomy with the addition of cryoanalgesia as compared with patients receiving standard-of-care treatment. Hypothesis 1c: The severity of chronic pain will be significantly decreased one year following mastectomy with the addition of cryoanalgesia as compared with patients receiving standard-of-care treatment. Specific Aim 2: To determine if, compared with current and customary analgesia, the addition of cryoanalgesia decreases the incidence and severity of post-amputation pain. Hypothesis 2a: The severity of operative limb pain will be significantly decreased in the week following a surgical limb amputation with the addition of cryoanalgesia as compared with patients receiving standard-of-care treatment. Hypothesis 2b: The incidence of chronic pain will be significantly decreased in the year following a surgical limb amputation with the addition of cryoanalgesia as compared with patients receiving standard-of-care treatment. Hypothesis 2c: The severity of chronic pain will be significantly decreased in the year following a surgical limb amputation with the addition of cryoanalgesia as compared with patients receiving standard-of-care treatment.

Details

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: 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).

Limb amputation 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 treating physicians, subjects, and all clinical staff will be masked to treatment group assignment [only the treating physician/investigator with be unmasked]. An angiocatheter/introducer will 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.

Keywords

Mastectomy Upper Limb Amputation Below Elbow Upper Limb Amputation Above Elbow Lower Limb Amputation Below Knee Lower Limb Amputation Above Knee Chronic Pain Cryoneurolysis (active) Sham cryoneurolysis procedure

Eligibility

You can join if…

Open to people ages 18 years and up

  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

You CAN'T join if...

  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

Location

  • UCSD Medical Center
    San Diego California 92103 United States

Details

Status
accepting new patients by invitation only
Start Date
Completion Date
(estimated)
Sponsor
University of California, San Diego
ID
NCT03578237
Lead Scientist
Brian Ilfeld
Study Type
Interventional
Last Updated
August 27, 2018