Cryoanalgesia to Prevent Acute and Chronic Pain Following Surgery: A Randomized, Double-Masked, Sham-Controlled Study
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|ClinicalTrials.gov Identifier: NCT03578237|
Recruitment Status : Completed
First Posted : July 6, 2018
Results First Posted : February 10, 2023
Last Update Posted : February 10, 2023
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|First Submitted Date ICMJE||June 25, 2018|
|First Posted Date ICMJE||July 6, 2018|
|Results First Submitted Date ICMJE||December 5, 2022|
|Results First Posted Date ICMJE||February 10, 2023|
|Last Update Posted Date||February 10, 2023|
|Actual Study Start Date ICMJE||August 25, 2018|
|Actual Primary Completion Date||January 7, 2022 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Average Pain (Mastectomy Subjects Only) [ Time Frame: afternoon of postoperative day 2 ]
Measured with the 0-10 numeric rating scale as part of the Brief Pain Inventory, with 0 equivalent to no pain and 10 equivalent to the worst imaginable pain
|Original Primary Outcome Measures ICMJE
||Average pain (mastectomy subjects only) [ Time Frame: afternoon of postoperative day 2 ]
Measured with the NRS as part of the Brief Pain Ineventory
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Cryoanalgesia to Prevent Acute and Chronic Pain Following Surgery: A Randomized, Double-Masked, Sham-Controlled Study|
|Official Title ICMJE||Cryoanalgesia to Prevent Acute and Chronic Pain Following Surgery|
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 various painful surgical procedures; 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 subsequent, definitive clinical trials.
Specific Aim 1: To determine if, compared with current and customary analgesia, the addition of cryoanalgesia decreases the incidence and severity of post-surgical pain.
Hypothesis 1a (primary): The severity of surgically-related pain will be significantly decreased on postoperative day 2 with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment.
Hypothesis 1b: The incidence of chronic pain will be significantly decreased one year following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment.
Hypothesis 1c: The severity of chronic pain will be significantly decreased one year following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment.
Specific Aim 2: To determine if, compared with current and customary analgesia, the addition of cryoanalgesia improves postoperative functioning.
Hypothesis 2a: Following primary unilateral knee and shoulder arthroplasty as well as rotator cuff repair, joint range of motion will be significantly increased within the year following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment.
Hypothesis 2b: Following video-assisted thoracoscopic surgery, inspiratory spirometry will be improved within the month following surgery with the addition of cryoanalgesia as compared with patients receiving solely standard-of-care treatment.
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:
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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Only the investigator/physician applying the cryoneurolysis will be aware of the treatment group assignment.Primary Purpose: Prevention
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date ICMJE||November 25, 2022|
|Actual Primary Completion Date||January 7, 2022 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT03578237|
|Other Study ID Numbers ICMJE||Cryo Prevention PILOTs|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Current Responsible Party||Brian M. Ilfeld, MD, MS, University of California, San Diego|
|Original Responsible Party||Same as current|
|Current Study Sponsor ICMJE||University of California, San Diego|
|Original Study Sponsor ICMJE||Same as current|
|PRS Account||University of California, San Diego|
|Verification Date||January 2023|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP