The use of cold temperatures for analgesia has been in medical practice for thousands of years, with the first written account by Hippocrates where he described snow being carried down from high places and applied to wounds for pain control. In the 1800’s Napoleon’s surgeon general remarked on the ease and relative painless amputation of the limbs of soldiers who were exposed to the elements in Russia. Also in the 1800s, the discovery of ether and ethyl chloride spray for topical anesthesia was introduced. The modern iteration of cryoanalgesia was developed by Cooper et al. in 1962 when liquid nitrogen was introduced via a long probe targeted to specific nerves with an average temperature of -196 C. In 1976, the first large paper showing benefit was published. Lloyd et al. demonstrated a significant reduction in pain for 52 of 64 patients with intractable pain treated with cryoanalgesia (including sciatic, intercostal, and facial nerves). The median duration of pain relief was 11 days, with some patients having significant pain relief for up to 224 days. Since this time, many delivery devices, and targets have been investigated.
The anatomy to avoid is based on the planned procedure. Care should be taken to localize the target nerve with high fidelity, using ultrasound, fluoroscopy, or a nerve stimulator. Additionally, care should be taken to avoid creating a lesion in proximity to the skin or large blood vessels. Motor nerves should not be lesioned; therefore, nerve stimulation is essential prior to lesioning.
Cryoanalgesia can be utilized for numerous persistent and intractable painful conditions, particularly when mediated by a peripheral nerve which can be confidently identified. Common targets include the iliohypogastric nerves, ilioinguinal nerves (laparotomy, nerve entrapment, post-therapeutic herniorrhaphy pain), intercostal nerves (neuralgia, mastectomy and thoracotomy pain, rib fractures), pudendal nerves (perianal, rectal pain), lateral femoral cutaneous nerves (meralgia paresthetica), and the sacral nerve roots S4-5 (coccydynia).  Cryoanalgesia has also shown benefit for temporomandibular joint pain, paroxysmal trigeminal neuralgia, phantom limb pain, neuroma, and idiopathic neuralgia pain. 
There are multiple acute pain indications for cryoanalgesia, including intra-operative cryoneurolysis of ilioinguinal and iliohypogastric nerves for postherniorrhaphy pain and intercostal cryoneurolysis for thoracotomy pain. However, the use of cryoneurolysis for thoracotomy pain has fallen out of favor based on increased neuropathic pain at eight weeks postoperatively, though no difference was noted at six months.
Additionally, topical cryoanalgesia has been used in the treatment of painful cutaneous processes from intravenous access, joint aspiration, and neuropathic pain due to herpes zoster.
Absolute contraindications include bleeding diathesis where bleeding would be catastrophic, infection at the site, and patient refusal. Relative contraindications include locations on the face or highly visible locations as there is a risk of hyperpigmentation or hypopigmentation at the ablation site. Alopecia may also occur at the cryoablation site, which can be a concern for the eyebrow during supraorbital lesions. Postprocedural pain and damage to adjacent structures can occur. In the case of pneumothorax, patients should be placed on 100% oxygen to de-nitrogenate the pneumothorax (if nitrogen was used as the expansion gas). Skin frostbite can occur if the lesion is too superficial. There are reports of moderate to severe neuralgia for intercostal cryoanalgesia for thoracotomy, making this a relative contraindication.
A small-gauge needle is needed for local infiltration of skin. The method is to localize the nerve to be blocked, including but not limited to fluoroscopy, ultrasound, and nerve stimulators. A cryo machine with cooling agents such as nitrous oxide or carbon dioxide is needed. A 12 to 14 gauge angiocatheter is used depending on the manufacturer and size of a cryoprobe to be used, which are often 1.4 to 2 millimeters in size. Many probes incorporate a nerve stimulator in addition to the thermistor for temperature recording. A cryoprobe is compatible with cryo machine.
Preparation and patient positioning depend largely on which nerve is the target. 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 is then performed, identifying correct patient, side, site, and allergies. Aseptic technique should be observed.
The nerve that is to be blocked is identified with fluoroscopy, ultrasound, nerve stimulation, or other reliable methods. Next, the cryoprobe is advanced into the correct position. Many models use a sheath with a sharp stylet, which is then removed, and the cryoprobe advanced to the tip of the sheath. The sheath is then pulled back to expose the cryoprobe. Next, diagnostic nerve stimulation or diagnostic block with local anesthetic is used to confirm the correct position of the probe. If using nerve stimulation, the nerve of interest should be stimulated reliably at 0.5 volts or less, and maximum stimulation then performed to ensure lack of other nearby nerves. The probe is then activated, often with two- or three-minute freeze cycles interspersed with half-minute defrosting periods between doses, however, this can vary based on manufacturer. In general, the tissues should be allowed to recover to above 0 C before the next freeze cycle. After the final freeze cycle, care must be taken to ensure proper thawing (greater than 120 seconds) before removal of the cryoprobe to avoid tissue damage when removing the adhered frozen tissue. A small volume of local anesthetic can then be infiltrated into the tissues as the sheath is withdrawn.
Post-procedural complications include the usual complications of interventional procedures: bleeding, infection, and damage to adjacent tissue structures. With superficial procedures, damage to skin with resulting alopecia, hyper- and hypopigmentation can occur. This can be avoided by injecting saline solution to elevate the skin surface. For intercostal nerves, there are reports of neuroma formation. If pneumothorax is caused by needle placement, the expanding gas cooling agent may worsen the pneumothorax.
Cryoanalgesia has shown good postoperative pain reduction, with a possible increase in long-term pain when used intraoperatively. In a double-blind, randomized study of 55 patients cryoneurolysis provides superior postsurgical pain for intercostal cryoanalgesia compared to standard care for posterolateral thoracotomy.  A second randomized controlled trial with 100 patients found similar results as well as improved pulmonary function after video-assisted thoracic surgery. Further, a 50-patient post-thoracotomy observational study found similar improvements in pain, FEV1, FVC, improved ventilation by blood gas, reduced opioid consumption, and reduced nausea and vomiting.
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 eight weeks and statistically more neuropathic-type pain, this resolved at six months with no difference between groups.
For chronic pain, cryoanalgesia can be effective for lumbar facet pain, intercostal neuralgia, and phantom limb pain. In a retrospective study of 91 patients who underwent cryoneurolysis for lumbar facet pain, the mean pain scores (VAS) were decreased from 7.70 to 3.72 following treatment. Pain scores continued to remain low at three months (VAS 4.99) and over the mean follow-up length of 1.7 years. In a study with 145 patients with refractory trigeminal neuralgia, cryoablation of the trigeminal nerve provided a significant improvement in pain for an average of 13 to 20 months, depending on the branch blocked. In a proof of concept study for phantom limb pain, three out of five patients had greater than 90% pain reduction at 2.5 years, and the other two had 20% to 40% pain reduction. For intercostal neuralgia, a retrospective study showed 60% of patients reported significant pain relief at the completion of the procedure, with 50% of patients continuing to have significant relief at three months.
Cryoneurolysis is an old technique with many possible future applications. Data for its use is encouraging for postoperative pain, and in select groups, for chronic pain. There is a possible increased risk of neuroma formation, and more research is required to understand this incidence. Cryoneurolysis can be another useful tool in the interventional pain specialists armamentarium.
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