Continuing Education Activity

Cryoanalgesia is a specialized technique for providing long-term pain relief in interventional pain management settings. Also known as cryoneuroablation and cryoneurolysis, this technique has historical roots dating back thousands of years. Modern cryoanalgesia, dating to the 1960s, applies freezing temperatures to specific nerves to alleviate persistent and intractable pain. There are multiple clinical applications for this technique.

This activity describes the history, techniques, indications, contraindications, and clinical significance of cryoanalgesia, highlighting the potential benefits for both acute and chronic pain conditions. The activity also emphasizes the importance of an interprofessional healthcare team in understanding and implementing cryoanalgesia to improve patient care and outcomes in pain management.

Objectives:

• Identify appropriate candidates for cryoanalgesia based on their clinical presentation, history, and pain characteristics, distinguishing those who may benefit from this intervention.

• Differentiate between the various clinical conditions and pain etiologies for which cryoanalgesia may be a suitable treatment option while considering alternative pain management approaches.

• Communicate effectively with patients, providing clear and comprehensive information about the cryoanalgesia procedure, expected outcomes, potential risks, and alternatives.

• Collaborate with interdisciplinary teams, including anesthesiologists, surgeons, nurses, and physical therapists, to ensure coordinated care for patients undergoing cryoanalgesia.

Introduction

Using cold temperatures to alleviate pain has a long-standing history in medicine. Hippocrates, the father of medicine, wrote about it thousands of years ago, explaining how snow could ease pain from injuries.[1] In the 1800s, a surgeon general under Napoleon noticed that soldiers who had endured cold weather in Russia felt less pain during amputations.[2] Around this time, topical anesthesia was also discovered in ether and ethyl chloride spray.

Cryoanalgesia, or cryoneuroablation or cryoneurolysis, is a specialized technique utilized in interventional pain management to achieve long-term pain relief. The origination of modern cryoanalgesia dates back to 1961 when Cooper et al introduced a device using liquid nitrogen within an insulated tube, capable of reaching a temperature as low as -196 °C.[3] Cryoanalgesia gained prominence in 1976 when Lloyd et al published the first significant paper suggesting its superiority over alternative peripheral nerve destruction methods like alcohol neurolysis, phenol neurolysis, or surgical lesions. In this paper, Lloyd et al demonstrated a significant reduction in intractable pain for 52 of 64 patients treated with cryoanalgesia, including sciatic, intercostal, and facial nerve treatments. The median duration of pain relief was 11 days, with some patients having significant pain relief for up to 224 days.[4]

Cryoanalgesia involves the application of cold to tissues (approximately -70 °C) to ablate the targeted nerve, resulting in reversible neuronal injury to the peripheral sensory nerve. This induces a conduction block similar to local anesthetics. The intense cold temperature produces Wallerian degeneration, a reversible breakdown of the nerve axon, inhibiting the transmission of afferent and efferent signals. Because the nerve endoneurium, perineurium, and epineurium remain intact, the axon regenerates along the exoskeleton at approximately 1 to 2 mm/day. Once the axon has regenerated, it reconnects with the sensory receptor, and conduction starts again. Regrowth of axons into the perineurium eventually restores sensation, and the block functionally resolves. Thus, pain sensation may return over time (after weeks to months) and requires repeat administration. Repeating cryoanalgesia in the same anatomic location for subsequent surgical procedures does not result in adverse sequelae.[5]

Cryoanalgesia is an old technique with many possible future applications. Data for cryoanalgesia is encouraging for postoperative pain and in select groups for chronic pain.[6] Clinical applications of cryoanalgesia encompass a wide range of conditions, including craniofacial pain (eg, trigeminal neuralgia, posterior auricular neuralgia, glossopharyngeal neuralgia), chest wall pain (eg, post-thoracotomy neuromas, rib fracture-related pain, post-herpetic neuralgia), abdominal and pelvic pain (eg, ilioinguinal, iliohypogastric, genitofemoral, subgastric neuralgia, pudendal neuralgia), low back and lower extremity pain (eg, lumbar facet joint pathology, pseudosciatica, intraspinous ligament or supragluteal nerve pain, sacroiliac joint pain, cluneal neuralgia, obturator neuritis, peripheral neuropathy), and upper extremity pain (eg, suprascapular neuritis, peripheral neuritis).

Anatomy and Physiology

Nerve Anatomy

Nerves consist of individual axons bundled together. The endoneurium, a layer of connective tissue, envelops each axon. These axons are organized into fascicles, with each fascicle encased by the perineurium, another connective tissue layer. Multiple fascicles are further enclosed by the epineurium, which serves as the outermost protective layer of the nerve. In myelinated nerves, the axons are sheathed in a myelin sheath formed by Schwann cells, providing insulation and facilitating nerve signal transmission.

Nerve Injury

• Reversible
• Neuropraxia (1st degree): This is an interruption of conduction with a short recovery time observed at +10 to -20 °C.
• Axonotmesis (2nd degree): This is a loss of axon continuity with noticeable Wallerian degeneration. There is preservation of endo-, peri-, and epineurium; this is observed at -20 to -100 °C.
• Non-reversible
• Neurotmesis (3rd/4th degree): There is some loss of continuity of epineurium and perineurium. The endoneurium may or may not be disrupted. This is observed at -140 °C and colder.
• Transection (5th degree): There is a gross loss of continuity; this is impossible with cryoanalgesia. 

Cryoanalgesia entails applying extreme cold (approximately -70 °C) to tissues to ablate the targeted nerve, inducing reversible injury to the peripheral sensory nerve. This creates a conduction block akin to local anesthetics. The intense cold triggers Wallerian degeneration, causing a breakdown of the nerve axon and disrupting afferent and efferent signal transmission. As the nerve's endoneurium, perineurium, and epineurium remain intact, the axon regenerates along the exoskeleton at 1 to 2 mm/day. Upon regeneration, the axon reconnects with the sensory receptor, restoring conduction. Axon regrowth into the perineurium eventually reinstates sensation, resolving the block's function. Over time, pain sensation may return, necessitating repeat administration, with no adverse effects noted when repeating cryoanalgesia in the same anatomical location for subsequent surgical procedures.[5]

The extent of tissue freezing and subsequent nerve damage depends on several factors, including the proximity of the probe to the nerve, the size of the cryoprobe, the cryoprobe temperature, the completeness of freezing in terms of rate and duration, and the temperature of the surrounding tissues influenced by local heat sinks, such as cerebral spinal fluid and blood flow. The intensity and duration of analgesia are directly related to the degree of nerve damage caused by the probe.

Autoimmune processes are also implicated in the long-term effects of cryoneuroablation, involving the release of sequestered proteins that may trigger an autoimmune response targeted at the lesioned tissues. This phenomenon could account for the prolonged therapeutic effect. 

The anatomy pertinent to performing cryoanalgesia depends on where the planned procedure will occur in the body. Care should be taken to localize the target nerve with high fidelity, using ultrasound, fluoroscopy, imaging-guided, or a nerve stimulator.[7][8][9][10] One reason for this is that motor nerves should not be lesioned. Therefore, to most practitioners, nerve stimulation is essential before lesioning. Additionally, care should be taken to avoid creating a lesion near the skin or large blood vessels. 

Indications

Cryoanalgesia is useful in addressing many persistent and intractable painful conditions, especially when a specific peripheral nerve can be accurately pinpointed as the pain source. Prominent targets include the iliohypogastric and ilioinguinal nerves (associated with laparotomy, nerve entrapment, and post-therapeutic herniorrhaphy pain), intercostal nerves (linked to neuralgia after mastectomy and thoracotomy, as well as rib fractures), pudendal nerves (related to perianal and rectal pain), lateral femoral cutaneous nerves (associated with meralgia paresthetica), and sacral nerve roots S4 to S5 (implicated in coccydynia).[6][11][12] Notably, the application of cryoanalgesia for thoracotomy pain has waned in popularity due to increased neuropathic pain at 8 weeks postoperatively, albeit with no discernible difference noted at 6 months.[13] In addition, cryoanalgesia effectively manages temporomandibular joint pain, paroxysmal trigeminal neuralgia, posterior auricular neuralgia, glossopharyngeal neuralgia, phantom limb pain, neuroma, and idiopathic neuralgia pain.[13][14][15][16][17] 

Cryoanalgesia is also used to treat pain associated with low back and lower extremity pain (eg, lumbar facet joint pathology, pseudosciatica, intraspinous ligament or supragluteal nerve pain, sacroiliac joint pain, cluneal neuralgia, obturator neuritis, peripheral neuropathy), and upper extremity pain (eg, suprascapular neuritis, peripheral neuritis). Cryoanalgesia continues to be useful in acute pain from surgical procedures other than thoracotomies, such as total knee arthroplasties, shoulder arthroplasties, and mastectomies.[18] Furthermore, topical cryoanalgesia has shown promise in managing cutaneous pain stemming from intravenous access, joint aspiration, and neuropathic pain induced by herpes zoster.[19][20] Consulting a knowledgeable healthcare professional to determine if cryoanalgesia is an appropriate treatment option for a specific pain condition is crucial.[21]

Contraindications

Absolute contraindications to cryoanalgesia include a bleeding diathesis where hemorrhaging could result in catastrophic consequences, active infections at the procedure site, and patient refusal.[6] Relative contraindications entail situations where careful consideration is warranted, including treating areas with high visibility, which carries the risk of hyperpigmentation or hypopigmentation at the ablation site, and when potential alopecia concerns in supraorbital lesions near the eyebrow are present. Cryoalagesia can also lead to postprocedural pain and damage to adjacent structures. Skin frostbite may occur if the lesion is excessively superficial.[22] Notably, intercostal cryoanalgesia for thoracotomy has been linked to moderate to severe neuralgia, making it a relative contraindication. 

Moreover, cryoanalgesia should be cautiously approached in cases of Raynaud syndrome, cryoglobulinemia, cold urticaria, bleeding disorders, localized infection, and anticoagulation. Cryoanalgesia is contraindicated when extremity muscle weakness is unacceptable, such as ablating the femoral nerve for analgesia following knee surgery, as a weak quadriceps muscle prevents postoperative ambulation.[5] Potential risks include depigmentation, hyperpigmentation, alopecia near the treatment site, skin "frostbite" if the ice ball affects the dermis, bruising, and bleeding. Clinicians should educate patients about expected numbness, potential discomfort, and realistic outcomes of the procedure. Informed consent remains essential. While there is no evidence of neuroma formation or permanent nerve injury, results from some clinical trials reported an increased risk of postoperative neuropathic pain following intercostal cryoanalgesia for thoracotomy. However, other trials did not find such an association. Cryoanalgesia holds promise, but its use requires careful consideration of contraindications and potential risks to ensure patient safety and realistic expectations.

Equipment

Advancements in cryotechnology have ushered in handheld devices featuring cryoprobes, revolutionizing the visualization of nerve anatomy through ultrasound guidance. These cryoprobes come with various needle tips, generating ice balls of varying dimensions on targeted superficial peripheral nerves.[5] Available probes range in size from 1.4 to 2 millimeters, boasting integrated nerve stimulators for precise nerve localization and thermistors to monitor temperature at the probe's tip. The nerve stimulator allows selecting between sensory (100 Hz) or motor (2 Hz) responses. Using an introducer is recommended for optimal procedure performance. This multifunctional tool isolates electrical current to the probe tip, shields the skin from the ice ball when treating superficial structures, and facilitates local anesthetic infiltration. This anesthetic infiltration is to localize the nerve to be blocked, including but not limited to fluoroscopy, ultrasound, and nerve stimulators.[22] 

Typically, a large gauge intravenous catheter is the introducer, characterized by a sharp tip that easily penetrates tissues. The stylet can be removed for straightforward probe insertion. For the 2.0 mm probe, a 12-gauge catheter is used, while the 1.4 mm probe pairs with a 14- or 16-gauge catheter. These portable devices come with a compact charging dock, making them compatible with ultrasound and facilitating their use across diverse clinical settings, from office-based practices to hospitals and ambulatory surgery centers where various departments may share the same handpiece. The confluence of accessible ultrasound devices, the increasing expertise of anesthesia providers in ultrasound imaging, and the availability of the Food and Drug Administration-approved handheld cryoanalgesia devices have transformed cryoanalgesia into a pragmatic intervention for acute and chronic pain management.[5]

Personnel

Potential personnel needed for a cryoanalgesia procedure include those listed below.

• Clinician with the knowledge and skill to perform the procedure
• An assistant may be utilized at the clinician's discretion
• A nurse may be needed to help monitor the patient
• A radiology technologist may be required if fluoroscopy is needed

Preparation

Preparation and patient positioning depend largely on the target location and the implicated nerve. Access to all necessary personnel and equipment should be verified. Room temperature gas should be purged from the system. Sedation is rarely required, and heavy sedation should be avoided to facilitate patient localization of stimuli. Appropriate informed consent should be obtained. The patient should be positioned comfortably. A pre-procedural pause and time-out are then performed, identifying the correct patient, side, site, and allergies. An aseptic technique should be observed.[23]

Technique or Treatment

To begin the cryoanalgesic procedure, accurately identifying the target nerve is essential, employing techniques like fluoroscopy, ultrasound, nerve stimulation, or other reliable methods.[8] Subsequently, the cryoprobe is carefully maneuvered into the precise location. Many cryoprobe models employ a sheath equipped with a sharp stylet that is initially inserted and later removed, allowing the cryoprobe to advance to the tip of the sheath. The sheath is then retracted to expose the cryoprobe. Diagnostic nerve stimulation or a diagnostic block with local anesthetic is employed to confirm the probe's correct placement. In cases of nerve stimulation, the nerve of interest should reliably respond at 0.5 volts or less, followed by maximum stimulation to rule out the presence of nearby nerves.

The probe is then activated, typically using 2- or 3-minute freeze cycles interspersed with half-minute defrosting periods between applications; however, these timings may vary based on the manufacturer's guidelines.[24] Generally, it is essential to allow the tissues to warm up to above 0 °C before initiating the subsequent freeze cycle. Following the final freeze cycle, meticulous care is taken to ensure proper thawing, typically exceeding 120 seconds, before removing the cryoprobe to prevent tissue damage when detaching it from adhered frozen tissue. During the sheath's withdrawal, a small volume of local anesthetic can infiltrate the tissues.

Complications

Post-procedural complications include the usual complications of interventional procedures: bleeding, infection, and damage to adjacent tissue structures like a muscle (ie, myonecrosis).[21][25] Other potential procedural complications include but are not limited to hypoalgesia, hyperalgesia, allodynia, and prolonged numbness greater than 3 months. With superficial procedures, damage to the skin with resulting alopecia, hyperpigmentation, and hypopigmentation can occur. This damage can be avoided by injecting a saline solution to elevate the skin surface. For intercostal nerves, there are reports of neuroma formation and pneumothorax. If a pneumothorax is caused by needle placement, the expanding gas cooling agent may worsen the pneumothorax. Patients experiencing pneumothorax should be administered 100% oxygen to de-nitrogenate the pneumothorax, mainly if nitrogen was used as the expansion gas.[26]

Clinical Significance

While traditional site-specific regional anesthesia using local anesthetic offers effective pain relief, its duration can be limited. Emerging evidence highlights cryoanalgesia as potentially superior, demonstrating prolonged analgesia with fewer side effects. Results from multiple studies have shown cryoanalgesia to be a good postoperative pain reduction method, among other benefits.[22] In a double-blind, randomized study of 55 patients, cryoanalgesia provided superior postsurgical pain for intercostal neuralgia compared to standard care for posterolateral thoracotomy.[13] A second randomized controlled trial with 100 patients found similar results and improved pulmonary function after video-assisted thoracic surgery.[13] Further, results from a 50-patient post-thoracotomy observational study found similar improvements in pain, forced expiratory volume in one second, forced vital capacity, improved ventilation by blood gas, reduced opioid consumption, and reduced nausea and vomiting.[27]

Conversely, research has shown that long-term postoperative pain scores may be worsened with intraoperative cryoanalgesia. A double-blind, randomized study of 42 patients after posterolateral thoracotomy found increased pain scores in the cryoanalgesia arm at 8 weeks and statistically more neuropathic-type pain; this resolved at 6 months with no difference between groups.[28]   

Cryoanalgesia is also effective for chronic pain in patients with lumbar facet pain, intercostal neuralgia, and phantom limb pain. In a retrospective study of 91 patients who underwent cryoanalgesia for lumbar facet pain, the mean pain scores (visual analog scale, VAS) decreased from 7.70 to 3.72 following treatment.[29] Pain scores remained low at 3 months (VAS 4.99) and over the mean follow-up length of 1.7 years. In another study with 145 patients with refractory trigeminal neuralgia, cryoablation of the trigeminal nerve significantly improved pain for an average of 13 to 20 months, depending on the branch blocked.[30] In a proof of concept study for phantom limb pain, 3 out of 5 patients had greater than 90% pain reduction at 2.5 years, and the other 2 patients had 20% to 40%.[31] For intercostal neuralgia, a retrospective study showed that 60% of patients reported significant pain relief after the procedure, with 50% continuing to have effective relief at 3 months.[26]

Cryoanalgesia presents a non-opioid alternative, minimizing infection risk and avoiding complications seen in other pain management techniques. With its safety margin and efficacy, cryoanalgesia is a promising option in the current opioid epidemic, offering improved pain management in perioperative and office-based settings. However, it is essential to consider the potential risks and complications associated with cryoanalgesia, such as nerve injury, persistent neuropathic pain, and unpredictable duration of action.[5]

Enhancing Healthcare Team Outcomes

Cryoanalgesia demands a collaborative and multidisciplinary approach involving physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals, each contributing unique skills and roles to enhance patient-centered care. Physicians and advanced practitioners are responsible for meticulous patient assessment, selection, and procedural expertise. Nurses ensure patient comfort, monitor vital signs and provide essential pre- and post-operative care. Pharmacists play a role in medication management and addressing potential drug interactions. Ethical considerations are integral, with all team members upholding principles of informed consent and respecting patient autonomy. Responsibility for patient safety extends to all, necessitating vigilant monitoring and prompt intervention in case of complications. Effective interprofessional communication ensures seamless coordination, from patient evaluation to post-procedure follow-up. By collectively embracing these responsibilities and roles, healthcare teams can optimize cryoanalgesia outcomes, minimize risks, and prioritize patient well-being while delivering comprehensive pain management solutions.