Medical Policy

This document addresses cryoneurolysis, a surgical procedure that creates a temporary nerve block through application of extreme cold to the selected site for treatment of various peripheral nerve pain conditions.

Note: Please see the following related documents for additional information:

• CG-SURG-25 Injection Treatment for Morton’s Neuroma
• CG-SURG-89 Radiofrequency Neurolysis and Pulsed Radiofrequency Therapy for Trigeminal Neuralgia
• SURG.00096 Surgical and Ablative Treatments for Chronic Headaches
• SURG.00100 Cryoablation for Plantar Fasciitis and Plantar Fibroma
• SURG.00140 Peripheral Nerve Blocks for Treatment of Neuropathic Pain
• SURG.00142 Genicular Procedures for Treatment of Knee Pain
• SURG.00144 Occipital and Sphenopalatine Ganglion Nerve Block Therapy for the Treatment of Headache and Neuralgia

Investigational and Not Medically Necessary:

Cryoneurolysis is considered investigational and not medically necessary for all indications, including treatment of peripheral nerve pain associated with osteoarthritis of the knee.

Cryoneurolysis has been proposed as a treatment for peripheral nerve pain; however, there have been a limited number of studies published in the peer-reviewed literature addressing the use of this surgical procedure.

In 2016, Dasa and colleagues published a retrospective review of 100 individuals who underwent total knee arthroplasty (TKA) to compare perioperative pain management with and without cryoneurolysis. Cryoneurolysis was performed on the treatment group (n=50) 5 days prior to each TKA as part of a perioperative multimodal pain management program. The control group (n=50) did not receive cryoneurolysis. The results showed a significantly lower number of individuals in the treatment group with a length of stay (LOS) of greater than or equal to 2 days when compared to the control group (6% versus 67%, p<0.0001); however, no significant difference between groups was noted for 0 days and 1 day LOS. “The mean ± SE cumulative morphine use during the 12 weeks following surgery was significantly lower for the treatment versus control group (2069.12 ± 132.09 mg vs. 3764.42 ± 287.95 mg, p<0.0001)” (Dasa, 2016). Other outcomes evaluated included mean scores on the Knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), Oxford Knee Score, 12-item Short Form Health Survey (SF-12), and Patient-reported Outcomes Measurement Information System (PROMIS). Significant reductions in the KOOS from baseline to the 6- and 12-week post-operative visits were noted in the treatment group when compared to the control group (p=0.0037 at 6 weeks; p=0.0011 at 12 weeks), in the PROMIS pain intensity scores from baseline to 2 weeks post-surgery (p<0.0001), and also in the PROMIS pain interference scores from baseline to 6 weeks post-surgery (p<0.0001); however, the absolute values of the differences were not reported and there was overlap in the supplemental data. No significant results were noted in other outcomes. No complications were reported due to cryoneurolysis and the most common side effect was local bruising. There were several limitations to this study, including the retrospective, nonrandomized design, and lack of blinding. With the study being single-center and single-surgeon, there is limited generalizability of the results. Furthermore, no disclosure or denial of conflict of interest was reported.

Yoon and colleagues reported on a prospective study with the aim to evaluate the safety and efficacy of cryoneurolysis as a treatment for refractory peripheral neuropathic pain. The study was approved for 144 individuals; however, only 28 subjects were screened and 22 of those subjects were included in the study. All included individuals were treated with cryoneurolysis for peripheral neuropathy after failure of first- and second-line therapy. Results showed a significant decrease in self-reported pain using a visual analog scale (VAS) at 1 month (p=0.0001), 3 months (p=0.0002), 6 months (p=0.002), and 12 months (p=0.03) posttreatment. Cryoneurolysis had to be repeated for 11 (50%) individuals within 12 months of the original treatment. No complications were reported. While this study resulted in positive outcomes, the small sample size and lack of comparator group limits the applicability of the data. In addition, the authors did not disclose the reason for the large gap between the number of individuals approved for the study and the number of individuals screened for the study, which raises concerns of selection bias.

In 2017, Radnovich and colleagues released the results of a multicenter, randomized, double-blind, sham-controlled trial that evaluated cryoneurolysis for the treatment of pain and symptoms of knee osteoarthritis. From April 2013 to June 2016, 180 individuals were recruited and enrolled into either the active treatment group (n=121) or the sham treatment group (n=59). No significant difference in demographic or clinical characteristics between the two groups was found. Prior to the baseline visit, all individuals discontinued all prescription and over-the-counter (OTC) pain medications, herbal supplements, and all other treatments for knee osteoarthritis for a duration of five times the half-life of the medication, and discontinued adjunctive therapies for knee pain for 72 hours. The sham treatment used a sham cryoneurolysis device that did not produce any freezing and had no therapeutic effect. After cryoneurolysis or sham treatment was administered, individuals were assessed at eight follow-up visits (Day 1, Day 7, Day 30, Day 60, Day 90, and Day 120; Days 150 and 180 were included if there was a continued effect reported at the previous visit as determined by WOMAC pain subscale score). “Compared to the sham group, patients who received active treatment had a statistically significant greater change from baseline in the WOMAC pain subscale score at Day 30 (p=0.0004), Day 60 (p=0.0176), and Day 90 (p=0.0061)” (Radnovich, 2017). While the evaluators focus their discussion of the results on the statistical significance in these self-reported outcomes, it should be noted that the least squares (LS) mean absolute differences are small. For example, the LS mean absolute difference from sham (95% confidence interval [CI]) for the WOMAC pain subscale score at Day 30 (primary endpoint) was −7.12 (−11.01 to −3.22). No significant difference in WOMAC pain response rate was noted at Day 120 and beyond. There was a significant difference found between the two groups in the WOMAC physical function and stiffness subscales at Day 30 (p=0.0012; p=0.0060), but not at later follow-up points. Also, a significant difference was noted in VAS responders when comparing the two groups at Day 30 (p=0.0124). “There were no statistically significant differences in [VAS] response rates between the groups at Day 60 (p=0.180), Day 90 (p=0.400), and Day 120 (p=0.5060)” (Radnovich, 2017). Use of medications taken for knee pain during the treatment phase of the study was recorded 33 times in 15 (8.3%) individuals (10 [8.3%] active, 5 [8.4%] sham), and use of medications taken for pain other than knee pain was recorded 52 times in 48 (26.6%) individuals (32 [26.4%] active, 16 [27.1%] sham). Out of 243 recorded adverse events, 84 were deemed possibly or probably related to the cryoneurolysis device. All adverse events were mild to moderate except for 1 severe adverse event, which was altered sensation. There were 4 serious adverse events reported, which were all determined to be unrelated to the cryoneurolysis device. While individuals in this study were blinded, the evaluators noted that individuals began to accurately guess their assigned group over time, which could have affected self-reported outcomes and resulted in biased results. Cryoneurolysis for the treatment of knee osteoarthritis resulted in significant outcomes in this study; however, more randomized controlled trials are needed with comparisons to standard pain treatments to validate these findings.

The American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine published Practice Guidelines for Chronic Pain Management in 2010. These guidelines include cryoneurolysis and cryoablation in the discussion section; however, the recommendations only include cryoablation for the treatment of peripheral nerve pain and do not address cryoneurolysis (American Society of Anesthesiologists, 2010). Currently, other major authoritative organizations have not published recommendations on the use of cryoneurolysis for the treatment of peripheral nerve pain. The American Academy of Orthopedic Surgeons (AAOS)’s evidence-based clinical practice guideline on the surgical management of osteoarthritis of the knee noted that cryotherapy is one of the interventions that were considered but not recommended (AAOS, 2013).

Cryoneurolysis has been proposed for a variety of indications including shoulder, hip, and knee pain. The majority of peer-reviewed evidence on cryoneurolysis focuses on peripheral nerve pain associated with osteoarthritis of the knee. Additional proposed indications include pediatric use following thoracotomy surgery. Evidence published for these other indications consists primarily of small, single-center, retrospective case series and chart reviews with few trial participants.

Cha and colleagues conducted a systematic review that evaluated the efficacy of intercostal cryoneurolysis as an analgesic adjunct for chest wall pain, specifically addressing the applicability of intercostal cryoneurolysis for pain control after chest wall trauma. Twenty-three studies including 570 subjects undergoing cryoneurolysis met eligibility criteria for quantitative analysis. Five subgroups of participants treated with intercostal cryoneurolysis were identified: pectus excavatum (nine studies); thoracotomy (eight studies); post-thoracotomy pain syndrome (three studies); malignant chest wall pain (two studies); and traumatic rib fractures (one study). The authors concluded that overall low-quality evidence supported intercostal cryoneurolysis as an analgesic adjunct for chest wall pain, and further prospective studies are needed to improve the quality of evidence supporting cryoneurolysis for postop pain management compared to other pain treatments.

At the present time, cryoneurolysis is not a generally accepted practice for any indication including peripheral nerve pain associated with osteoarthritis of the knee.

There are many disorders that can cause peripheral nerve pain. Some of these disorders include diabetes, peripheral vascular disease, and autoimmune diseases. Treatment for peripheral nerve pain can be accomplished through medical or surgical management. Cryoneurolysis and cryoablation are two surgical procedures that are used to block peripheral nerve pain through different processes.

Cryoneurolysis, also referred to as cryoanalgesia, creates a temporary nerve block through application of extreme cold to the selected site for treatment of various peripheral nerve pain conditions. There are several cryogenic devices, which is the U.S. Food and Drug Administration (FDA) identification for devices using cryoneurolysis technology, such as the iovera° System (Myoscience, Inc., Fremont, CA), that have received FDA 510k clearance to administer cryoneurolysis for this indication (FDA, 2018; FDA, 2019b). The device uses cryogenic fluid to cool the cryoneurolysis probe, which is introduced percutaneously at the treatment site. Once the probe is under the skin, a localized cold zone is generated and it creates lesions in nervous tissue producing a temporary nerve block for up to 90 days.

While cryoablation is similar to cryoneurolysis in that it uses extreme cold, cryoablation destroys nerve endings and creates a permanent nerve block. Cryoablation devices have been identified as cryosurgical by the FDA, which is a different device identification than cryoneurolysis devices (FDA, 2019a).

Cryoablation: A minimally invasive procedure using a closed-probe, gas-based system. This procedure uses extremely cold temperatures to selectively destroy nerve endings to create a block that stops the conduction of pain.

Cryoneurolysis: A surgical procedure that produces lesions in peripheral nervous tissue through application of extreme cold. This process creates a temporary blocking of nerve pain.

Osteoarthritis: A degenerative condition of the joints that causes destruction of the material in the joints that absorbs shock and allows proper movement.

Peripheral nervous system: The collection of nerves and ganglia outside the brain and spinal cord that connects the central nervous system to the rest of the body.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure codes; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Cazzato RL, Garnon J, Ramamurthy N, et al. Percutaneous MR-guided cryoablation of Morton's neuroma: Rationale and technical details after the first 20 patients. Cardiovasc Intervent Radiol. 2016; 39(10):1491-1498.
2. Cha PI, Min JG, Patil A, et al. Efficacy of intercostal cryoneurolysis as an analgesic adjunct for chest wall pain after surgery or trauma: systematic review. Trauma Surg Acute Care Open. 2021 May 18; 6(1):e000690.
3. Dasa V, Lensing G, Parsons M, et al. Percutaneous freezing of sensory nerves prior to total knee arthroplasty. Knee. 2016; 23(3):523-528.
4. Friedman T, Richman D, Adler R. Sonographically guided cryoneurolysis: preliminary experience and clinical outcomes. J Ultrasound Med. 2012; 31(12):2025-2034.
5. Graves CE, Idowu O, Lee S, et al. Intraoperative cryoanalgesia for managing pain after the Nuss procedure. J Pediatric Surg. 2017; 52 (6):920-924.
6. Ilfeld BM, Finneran JJ. Cryoneurolysis and percutaneous peripheral nerve stimulation to treat acute pain. Anesthesiology. 2020; 133(5):1127-1149.
7. Ilfeld BM, Finneran JJ, Swisher MW, et al. Preoperative ultrasound-guided percutaneous cryoneurolysis for the treatment of pain after mastectomy: A randomized, participant- and observer-masked, sham-controlled study. Anesthesiology. 2022; 137(5):529-542.
8. Ilfeld BM, Smith CR, Turan A, et al. Ultrasound-guided percutaneous cryoneurolysis to treat chronic postamputation phantom limb pain: A multicenter randomized controlled trial. Anesthesiology. 2023; 138(1):82-97.
9. Mihalko WM, Kerkhof AL, Ford MC, et al. Cryoneurolysis before total knee arthroplasty in patients with severe osteoarthritis for reduction of postoperative pain and opioid use in a single-center randomized controlled trial. J Arthroplasty. 2021; 36(5):1590-1598.
10. Radnovich R, Scott D, Patel AT, et al. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. Osteoarthritis Cartilage. 2017; 25(8):1247-1256.
11. Swisher MW, Ball ST, Gonzales FB, et al. A randomized controlled pilot study using ultrasound-guided percutaneous cryoneurolysis of the infrapatellar branch of the saphenous nerve for analgesia following total knee arthroplasty. Pain Ther. 2022; 11(4):1299-1307.
12. Tanaka A. Al-Rstum Z, Leonard SD, et al. Intraoperative intercostals nerve cryoanalgesia improves pain control after descending and thoracoabdominal aortic aneurysm repairs. Ann Thorac Surg. 2020; 109(1):249-254.
13. Yoon JH, Grechushkin V, Chaudhry A, et al. Cryoneurolysis in patients with refractory chronic peripheral neuropathic pain. J Vasc Interv Radiol. 2016; 27(2):239-243.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Academy of Orthopaedic Surgeons (AAOS). Treatment of osteoarthritis of the knee. Evidence-Based Guidelines, 2nd ed. Adopted by the American Academy of Orthopaedic Surgeons Board of Directors, May 18, 2013. Rosemont, IL: AAOS; 2013.
2. American Society of Anesthesiologists. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010; 112(4):810-833.
3. Barrett SL, Nickerson DS, Elison P, et al. The Association of Extremity Nerve Surgeons. Clinical Practice Guidelines 2014. Available at: http://www.aens.us/images/aens/AENSGuidelinesFinal-12082014.pdf. Accessed on May 15, 2023.
4. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Rheumatol. 2020; 72(2):220-233.
5. Thomas JL, Blitch EL 4th, Chaney DM, et al. Clinical Practice Guideline Forefoot Disorders Panel. Diagnosis and treatment of forefoot disorders. Section 3. Morton's intermetatarsal neuroma. J Foot Ankle Surg. 2009; 48(2):251-256.
6. Thomson CE, Gibson JNA, Martin D. Interventions for the treatment of Morton's neuroma. Cochrane Database of Syst Rev. 2004; 3(CD003118).
7. U.S. Food and Drug Administration 510(k) Premarket Notification Database. iovera° system 510(k) Summary. No. K173763. Rockville, MD: FDA. February 28, 2018. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf17/K173763.pdf. Accessed on May 15, 2023.
8. U.S. Food and Drug Administration Code of Federal Regulations. Title 21 Food and Drugs. Sec. 878.4350. Rockville, MD: FDA. April 1, 2019a. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=878.4350. Accessed on May 15, 2023.
9. U.S. Food and Drug Administration Code of Federal Regulations. Title 21 Food and Drugs. Sec. 882.4250. Rockville, MD: FDA. April 1, 2019b. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=882.4250. Accessed on May 15, 2023.

Cryoanalgesia
iovera° system

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