Technique and context matter in cryoneurolysis for knee osteoarthritis

Knee osteoarthritis (OA) is one of the largest contributors to chronic musculoskeletal pain and disability in adults worldwide (1). Despite first-line therapies including physical therapy, nonsteroidal anti-inflammatory drugs, and intra-articular injections, many patients experience persistent pain and functional limitation (2). As demand for minimally invasive treatments that reduce opioid consumption grows, interest in treatments that reduce pain with limited systemic risk has flourished (3,4). Cryoneurolysis, which produces reversible axonal disruption through targeted cold application, has emerged as a promising option (5). Several high-quality studies have demonstrated the efficacy of this procedure after total knee arthroplasty, with clear reductions in pain, opioid consumption, and improvements in functional scores at 12 months (6,7).

The randomized, double-blind, sham-controlled trial by Nygaard et al. represents a methodologically rigorous evaluation of cryoneurolysis for chronic knee OA pain (8). The authors conducted a well-designed trial by implementing ultrasound-guided nerve targeting, a sham comparator, standardizing rehabilitation across treatment arms, and blinding outcome assessment. These features substantially strengthen internal validity and have been identified as standards for quality research in pain management (9,10).

This study does contain several key limitations. The authors’ choice of the anterior femoral cutaneous nerve and the infrapatellar branch of the saphenous nerve may represent a limitation. While these superficial sensory nerves are anatomically accessible, their contribution to the complex pain experience of knee OA, particularly pain arising from intra-articular structures, may be limited (11).

Knee OA pain is known to arise from multiple sources, including synovium, subchondral bone, periosteum, and capsular structures, with innervation patterns extending well beyond superficial cutaneous distribution; deep articular innervation is mediated in part by the superomedial, superolateral, and inferomedial genicular nerve branches, posterior articular branches of the tibial nerve, and nociceptive afferents within subchondral bone and periosteum (12-14). Consequently, targeting superficial cutaneous branches alone may fail to meaningfully modulate the deeper articular and periosteal nociceptive generators that characterize chronic OA pain. This anatomical mismatch between intervention target and primary nociceptive source may partially explain the absence of a clinically meaningful difference at the 14-day primary endpoint. Increasing evidence suggests that central sensitization, altered descending modulation, and psychosocial factors substantially shape pain perception in knee OA (15,16).

The substantial improvement observed in both treatment arms also highlights the contextual and placebo effects inherent to procedural interventions. Sham-controlled trials of intra-articular injections and other minimally invasive treatments for knee OA have consistently demonstrated meaningful improvements attributable to expectancy, provider interaction, and procedural ritual (17,18). These effects tend to be most pronounced in early follow-up, which may have further obscured any treatment-specific signal at the 14-day endpoint (19).

Importantly, acknowledgment of contextual effects should not be conflated with dismissal of cryoneurolysis’ biological mechanism. Cryoneurolysis induces controlled axonotmesis with Wallerian degeneration while preserving endoneurial architecture, allowing predictable regeneration (5). This represents a mechanism-specific neuromodulatory intervention distinct from contextual analgesia alone. The presence of a strong placebo response does not negate the potential efficacy of an intervention; rather, it emphasizes the need for precise targeting and appropriate outcome selection to detect incremental benefit beyond context alone.

Nygaard et al. also reported a modest secondary signal favoring cryoneurolysis at 6 months. While the study was under-powered for long-term secondary outcomes and multiple comparisons increase the risk of type I error, this finding is biologically plausible and should be considered. Peripheral nerve modulation has been hypothesized to influence central pain processing over time, potentially through reductions in peripheral nociceptive drive and downstream central sensitization (20). The absence of consistent improvements across all pain and functional domains appropriately tempers overinterpretation, but the signal at 6 months raises the possibility that cryoneurolysis may exert delayed or cumulative effects not captured by short-term primary endpoints. Although axonal regeneration typically suggests a 3–4-month window of effect, transient interruption of peripheral input may induce longer-lasting changes in central sensitization. In addition, temporary pain relief may enable improved rehabilitation engagement and biomechanical optimization, potentially extending clinical benefit beyond the expected timeline of nerve recovery (21).

From a clinical perspective, the results of this trial should not be interpreted as evidence against cryoneurolysis as a therapeutic concept. Cryoneurolysis offers several theoretical and practical advantages over alternative interventional techniques, including a favorable safety profile, reversibility, avoidance of permanent neural destruction, and the option for repeat treatment (22). These features are particularly attractive in chronic, progressive conditions like knee OA, where long-term risk-benefit considerations are paramount. Rather than positioning cryoneurolysis as a stand-alone intervention, its most rational future application may lie within a multimodal, phenotype-driven framework of knee OA care. In this context, cryoneurolysis could function as one component of comprehensive care alongside rehabilitation, pharmacologic optimization, and behavioral strategies, particularly for patients with predominantly peripheral nociceptive phenotypes and limited central sensitization.

The study by Nygaard et al. helps to refine future research efforts. Alternative nerve targets, especially genicular branches with more direct innervation of intra-articular structures, may be more appropriate for addressing OA pain (2,23). Procedural optimization, including freeze duration, cycle number, probe placement, and treatment extent, justifies additional investigation (24). Additionally, stratifying patients by pain phenotype, including markers of neuropathic or centrally mediated pain, may help identify subgroups most likely to benefit (25). Finally, future trials should incorporate outcomes beyond pain intensity alone, such as functional recovery, activity tolerance, and patient-reported quality of life, which may better reflect meaningful clinical benefit.

Finally, future trials should expand outcome assessment beyond pain intensity alone. Validated multidimensional instruments such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), and activity-based or performance metrics may better capture meaningful functional change. Incorporation of quality-of-life measures and objective activity monitoring could further enhance translational relevance.

In summary, the trial by Nygaard et al. represents a high-quality and necessary contribution to the literature on interventional pain management for knee OA. The results of the primary outcome should not be viewed as a failure of cryoneurolysis, but rather as evidence that technique, target selection, and patient phenotype matter. By clarifying these limitations, the study provides a valuable foundation for more precise, mechanism-informed trials that can better define the role of cryoneurolysis within multimodal, evidence-based care for knee OA.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Joint. The article has undergone external peer review.

Peer Review File: Available at https://aoj.amegroups.com/article/view/10.21037/aoj-2026-1-0007/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoj.amegroups.com/article/view/10.21037/aoj-2026-1-0007/coif). M.N. has the following disclosures: Stryker. Inc. (paid consultant), Johnson & Johnson Ethicon Inc. (paid consultant), CurvaFix Inc. (paid consultant), Pacira BioSciences Inc. (paid consultant), Sage Products Inc. (paid consultant), Alafair Biosciences Inc. (paid consultant), Next Science LLC (paid consultant), Bonutti Technologies Inc. (paid consultant), Hippocrates Opportunities Fund LLC (paid consultant), and Ferghana Partners Inc. (paid consultant), VB Spine (paid consultant), and Elevation Spine (paid consultant). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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