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494 M. Gyorfi et al.
1 Introduction
Despite numerous advancements, acute pain management continues to be a chal-
lenging aspect of patient management. Pharmacologic management remains the
preferred modality of analgesia in post-surgical and trauma patient populations.
With the ongoing opioid epidemic, alternative analgesic modalities are still needed to
manage post-intervention pain and prevent pain-related complications. Multimodal
analgesic approaches are gaining favor and have demonstrated a reasonable ability
to reduce pain even in the setting of heightened pain management complexity. Non-
pharmacologic interventions have recently been recognized for their ability to provide
adjunctive benefits and facilitate further management and pain reduction in the acute
setting. Regional analgesic interventions should be considered broadly, and may offer
particular benefits in patient populations with intense and multifaceted acute pain.
An important consideration is that adequate analgesia has shown improved rates
of recovery and an enhanced ability to modulate the transition of acute to chronic
pain symptomology [1]. In this chapter we highlight cryoneurolysis as a developing
modality for the treatment and prevention of acute and chronic pain in surgical and
trauma settings.
Targeted cryoneurolysis procedures are comparable in many ways to common
peripheral nerve blocks using local anesthetics. The major difference between the
two interventions is secondary to the mechanism of cryoanalgesia and the destruc-
tion of neural tissue that occurs with this technique. The primary mechanism of
the cryoneurolysis process is the utilization of isolated and controlled cold temper-
atures (−20 to −100 °C) that reversibly damage the myelin sheath of the target
peripheral nerve. The myelin sheath of the nerve is damaged to such a degree that
the resulting edema and neurolysis decrease the targeted nerve’s overall ability to
transmit sensory information [2]. Afferent and efferent sensory conduction is inhib-
ited in this process, which may markedly reduce pain perception. Furthermore, a
degree of neural Wallerian degeneration is observed distal to the site of intervention,
further extending analgesic duration until regrowth is achieved over the course of
weeks to months at a rate of 1–2 mm per day [3]. Regrowth is possible as neurol-
ysis achieves temperatures incapable of causing damage to the connective tissue of
the nerve. The endoneurium, perineurium and epineurium remain completely intact
after this procedure [3]. The extent of cryoneurolysis is modulated by the temperature
achieved (a process affected by the gaseous medium) and duration of intervention in
units of time. The range of targeted temperature application for cryoneurolysis is set
between −20 and less than −100 °C and is partially dependent on the gas utilized
(e.g., carbon dioxide, nitrous oxide, argon, helium). With this technique, the duration
of analgesia may be difficult to predict but may range from weeks to months [4].
Additionally, both motor and sensory nerves may be affected, which makes targeted
nerve selection and precise needle tip localization necessary as collateral motor nerve
involvement can hinder physical recovery.
The current procedure of cryoneurolysis attempts to optimize the efficiency of
targeted analgesia. The localization of the procedure is through focal use of a device
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Ultrasound-Guided Percutaneous Cryoneurolysis for Acute Pain … 495
called a cryoprobe. The cryoprobe is designed as a hollow tube consisting of both
inner and outer chambers that are designed to overlap. This design facilitates travel
of a gaseous medium, in many cases nitrous oxide or carbon dioxide. The medium
of choice is meant to flow from a high-pressure inner chamber, toward the tip of
the probe and double-back through the larger outer chamber [5]. Flow dynamics
and thermal equilibrium facilitate the delivery of desired temperatures to neural
tissue. The narrowed tip of the cryoprobe allows for targeted therapeutic delivery
and rapid heat extraction minimizes collateral tissue destruction. This design creates
an effective closed system that maintains a targetted temperature and minimizes
gas deposition in patient tissues. The gas is not able to escape the system but the
mechanics of this design result in the creation of an ice-ball at the tip of the cryoprobe,
through the Joule–Thomson effect. This ice-ball acts as a medium for further delivery
of temperature focused treatment [6].
The size and dimensions of the cryoprobe depend on the tissues targeted for
cryoneurolysis application. Currently, two divergent systems are available for the
application of crynoneurolysis therapy. Cryoprobes may be used by s urgeons for the
application of cryoneurolysis as a component of a surgical intervention. For example,
these probes may be used by surgeons to perform intercostal cryoneurolysis under
direct visualization intraoperatively in the setting of thoracic surgery. Cryoneurolysis
for pain management often involves the use of smaller gauge needles/probes that
may be inserted percutaneously, with the size of these applicators ranging from
18 to 24 gauge. These percutaneous systems often include the ability to perform
nerve stimulation [2]. Nerve stimulators facilitate the differentiation between motor
and sensory nerves and are therefore utilized for neural target confirmation and
improved localization prior to gas delivery. Accurate guidance of the cryoprobe
during instrument insertion may be facilitated by the use of an intravenous catheter;
termed an introducer. This practice also facilitates the application of local anesthetic
to the intended area prior to cryoneurolysis [2]. Careful selection of an introducer of
adequate size is necessary as the catheter must be larger than the intended cryoprobe.
Some image-guidance is often included in the procedure, in many cases this
includes the initial diagnostic evaluation as well as during the actual cryoneu-
rolytic procedure. Ultrasound, guided fluoroscopy, and computed tomography are all
respected and viable options and imaging type is often influenced by the area targeted
for intervention. With advances in ultrasound technology, this imaging type has been
increasingly utilized secondary to its ability to support accurate needle placement
and avoid injury to aberrant anatomic structures [7]. Furthermore, case studies have
highlighted the successful use of this imaging modality to support cryoneurolysis
application in surgical and trauma settings [8].
Prior to the application of cryoneurolyis, an injection of local anesthetic may be
performed to target the presumed loci of pain transmission. This local injection serves
to block the afflicted nerve, therefore confirming the target, while also establishing a
pain relief baseline for the patient that can be used as a metric during the procedure
[2]. The patient can reference this initial nerve block and future procedures can
be titrated to the overall level of intervention required to achieve desired relief.
Some degree of conscious sedation and local anesthetic is typically used during the
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496 M. Gyorfi et al.
cryoneurolysis procedure as well. However, complete sedation is often not needed
and negates a thorough intervention as the patient must be conscious enough to
express a satisfactory degree of sensation loss [5].
The use of a cryoprobe with nerve stimulator capacity further increases accuracy.
Many protocols use 100 Hz as a set frequency to help isolate sensory from motor
nerves [2]. While various techniques exist for the use of a cryoprobe, many involve
pinning of the targeted nerve to surrounding bone to minimize movement of the nerve
and maintain proper contact with the cryoprobe. Repeated cycles of stimulation
at sequential decreasing hertz are utilized, with reliable stimulation at a minimal
amplitude, often 0.5 V, being the last measure. This is often segued into repeat nerve
stimulation at 2 Hz to elicit any nearby motor nerve stimulation as cryoneurolysis of
motor nerves may need to be avoided in certain circumstances [6]. From this point,
cryoneurolysis is ready to commence. Flow of the selected gas medium should be
optimized relative to cryoprobe size. If not already conferred, the patient should be
informed that there will be multiple repetitions of cryoneurolysis, with the first being
known to elicit pain similar to their initial complaint. Pain should only be appreciated
during the first cycle of the process and is generally less than a minute in duration. Ice
ball formation is expected with each cycle of cryoneurolysis, often requiring at least
one to three minutes of duration for adequate formation and area of effect. Following
completion of freezing and thawing cycles, the probe can be withdrawn [5].
Peripheral nerve blocks represent an alternative option to cryoneurolysis for post-
surgical and traumatic pain in the acute setting. Peripheral nerve blocks are conducted
as a single injection or through continuous infusions, both with the use of local
anesthetic. Comparisons between the two options highlight limitations and specific
risks of neural blockage versus cryoanalgesia. Both interventions confer a degree
of risk for unintended neural damage, circulatory puncture, and local anesthetic
systemic toxicity (LAST).
The duration of effect differs between modalities with peripheral nerve blockage
generally persisting for a limited number of hours. To warrant analgesia beyond
24 hours, a perineural catheter and continuous infusion is required. With catheter
placement, there is an increased risk of infection, hardware migrations, accidental
removal, and leakage of local anesthetic. Peripheral nerve blockage has been asso-
ciated with a degree of muscular weakness, an effect that potentially limits patient
ambulation and recovery [9].
2 Applications in Acute Pain Management
Cryoneurolysis is used in a variety of surgical procedures to manage acute pain at an
increasing rate. The development of ultrasound-guided cryoneurolysis, which allows
for precisely localizing targeted nerves, is largely responsible for the expanded scope
of the procedure.
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While the cryoneurolysis of the intercostal nerves during thoracotomy surgery
was one of the first reported use of cryoanalgesia, it has more recently been investi-
gated for the treatment of postoperative pain following mastectomy surgery, shoulder
arthroplasty, and total knee arthroplasty [10].
The remaining chapter summarizes the use of cryoanalgesia in the treatment of
acute pain with the expectation that more indications will arise in the near future.
The following surgical procedures result in moderate to severe postoperative pain,
which, if not properly managed, can become chronic. Thus, the long-term advantages
of cryoneurolysis are applicable to these procedures. Recent research has shown that
cryoneurolysis is safe, effective, and provides long-lasting pain relief when used in
these procedures [10].
Thoracotomy
Thoracotomies are painful operations with significant postoperative pain that is diffi-
cult to manage. It has been noted that 22–67% of thoracotomy patients experience
chronic postsurgical pain. The gold standard for managing post-thoracotomy pain is
typically thoracic epidural analgesia. Epidural anesthesia is not without risk and is not
suitable for all patients. Risks and limitations include dural perforation, hematoma,
infection, hypotension/bradycardia, and urinary retention. In addition, epidural place-
ment can be technically more challenging to perform, and even the most experienced
providers may fail to accurately access the epidural space, leading to unsatisfactory
analgesia [11].
When used to treat acute postoperative thoracotomy pain, cryoneurolysis has
shown comparable efficacy to epidural analgesia. Numerous studies have demon-
strated that intraoperative cryoneurolysis of the intercostal nerve causes significant
and enduring postoperative incisional pain relief [12].
In 1974, Nelson et al. [13] demonstrated a decrease in postoperative opioid use
without neuritis or neuromas within 24 months of follow-up after cryoneurolysis
was performed for thoracic surgery. A similar study performed by Yang et al. [14],
combined the use of cryoneurolysis with epidural analgesia and reported that the
combination group required less rescue morphine over the first week when compared
to epidural analgesia alone. A more recent study performed by Clemence et al. [12]
found similar results with an average reduction of 28 morphine milligram equivalents
(MME) over the first 10 postoperative days. However, this study did not show a
reduction in overall pain scores. Lastly, a study by Chen et al. [15] found a significant
reduction in opioid use after thoracotomies in a pediatric oncology population.
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498 M. Gyorfi et al.
Total Knee Arthroplasty
Cryoneurolysis of the infrapatellar branch of the saphenous nerve and anterior
femoral cutaneous nerve has been used for postoperative pain management in patients
undergoing total knee arthroplasty (TKA) [16].
According to a retrospective study of 100 patients undergoing TKA, preoperative
cryoneurolysis of the superficial genicular nerves (SGN) led to an overall improve-
ment in clinical performance when compared to standard multimodal pain regimens.
This finding is in line with previous research. The postoperative length of stay was
reduced for those who received cryoneurolysis (stayed 2 days, 6% vs. 67%, p 0.0001).
The MME opioid consumption in the cryoneurolysis group was 45% lower at the 12
week follow up. Six weeks after the operation, the patients receiving cryoneurolysis
also reported lower levels of pain intensity and interference with daily activities,
as determined by the Patient-reported Outcomes Measurement Information System
(PROMIS) [17].
In 2022, a large retrospective review evaluated total opioid consumption and length
of stay following total knee arthroplasties with cryoneurolysis and non cryoneurol-
ysis cases in a similar time frame. They found a small reduction in MME and a
reduced length of stay by 1 day [18]. In addition to retrospective data, a recently
published randomized control trial of 124 patients compared cryoneurolysis of the
superficial genicular nerve to a standard of care control group. This study found a
statistically significant reduction in opioid use and overall function improvement in
the cryoneurolysis group [19].
Shoulder Arthroplasty
Despite the increased use of brachial plexus blockade, inadequate pain management
following shoulder arthroplasty remains a significant concern. Continuous inter-
scalene blocks, which can be used for orthopedic shoulder surgery on moderately
painful shoulders, may sometimes have a high failure rate of up to 25% and significant
inherent risks (eg, pneumothorax, phrenic nerve injury, and diaphragm paralysis). As
a result, patients who have compromised respiratory function might need an alter-
native method of managing their postoperative pain. For prolonged postoperative
analgesia following shoulder procedures, cryoneurolysis of the suprascapular nerve
has emerged as a safe and efficious analgesic modality. The suprascapular nerve
arises from the upper trunk of the brachial plexus and innervates the supraspinatus,
infraspinatus, and the shoulder join [20].
The first report of cryoneurolysis for shoulder arthroplasty analgesia was docu-
mented in 2017 after a small case report by Ilfeld et al., which included both shoulder
arthroplasty and knee arthroplasty. All 5 patients reported a postoperative pain score
of < 2 on a 0–10 numeric rating scale and required less opioids compared to histor
controls [8].
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Acute Burns
In burn patients, pain management is frequently necessary for both the burn site
and the donor sites for autologous split thickness skin grafting (STSG). Since the
lower extremity is typically the site of harvesting, the patient’s ability to engage
in physical therapy is frequently hindered by pain at the graft donor site, which in
many patients is worse than the pain from the burn. The lateral femoral cutaneous
nerve (LFCN), which innervates the lateral aspect of the thigh, can be seen with
ultrasound in the intermuscular space between the tensor fascia latae and sartorius
muscles. A case report demonstrated cryoneurolysis as an effective alternative to
LFCN blocks performed with bupivacaine. In this report, analgesic duration with
cryoneurolysis persisted for weeks and far exceeded what might be expected with
local anesthetic-based approaches [21].
Rib Fractures
In trauma patients, rib fractures are a frequent injury that significantly increases
morbidity and mortality. There is evidence that local anesthetic-based nerve blocks
can significantly reduce pain and prevent complications. However, the duration of
this pain frequently lasts for weeks, while the analgesia offered by these blocks
is limited to hours for single injection blocks or days for continuous infusions. A
study performed evaluated 5 patients with rib fractures and treated their rib fracture
pain with ultrasound-guided percutaneous cryoneurolysis and had promising results,
which suggests the need for larger studies [22].
Breast Surgery
Post-mastectomy pain is often hard to manage with traditional pain regimens
and the incidence of chronic postsurgical pain remains alarmingly high. A case
series that consisted of three patients who received preoperative ultrasound-guided
percutaneous intercostal nerve cryoneurolysis to treat pain following mastectomy
surgery was reported. All three patients reported an average pain score of 0 and
received no supplemental opioid analgesics during the measured postoperative
period. These findings were a significant improvement over historic cohorts, however
appropriately powered randomized controlled clinical trials are necessary to quantify
potential risks and benefits [23].
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500 M. Gyorfi et al.
Phantom Limb Pain
It is estimated that 50–85% of people with a lower limb amputation develop chronic
pain in the missing limb, termed phantom limb pain. The etiology of phantom limb
pain is not fully understood and has few adequately powered and randomized trials to
help guide pain management. A randomized trial evaluated 144 patients and random-
ized them to a singled injection femoral and sciatic nerve block with lidocaine paired
with an ultrasound guided percutaneous cryoneurolysis vs sham treatment at the
same location. The pain scores were re-evaluated after 4 months without a statisti-
cally significant reduction in pain s cores, however some benefits are shown in those
with below-the-knee amputation (versus above-the-knee amputation). The lack of
response to cryoneurolysis in this population was theorized to be a result of the
underlying mechanism of phantom limb pain vs non-optimal treatment parameters
such as freeze duration and anatomic treatment locations [24].
3 Benefits and Risks of Cryoneurolysis
Cryoneurolysis is a minimally invasive technique that offers several advantages
over other treatments for certain medical conditions. One of the main advantages
of cryoneurolysis is that it can be performed on an outpatient basis, thus patients can
usually go home the same day as the procedure. This can help reduce the cost and
inconvenience of hospital stays and allows patients to return to their normal activities
more quickly [2].
Another advantage of cryoneurolysis is that it is generally considered to be a
safe procedure. The technique uses extreme cold to destroy abnormal tissue or cells
with less risk of damage to healthy tissue when compared with other treatments
such as radiation therapy or chemotherapy. Additionally, because the procedure is
minimally invasive, there is typically less pain and scarring than with traditional
surgical procedures [4].
While cryoneurolysis is generally considered a safe and effective procedure, there
are still potential risks and complications that patients and clinicians need to consider.
One of the most common risks associated with cryoneurolysis is bleeding. Generally,
any risk of bruising or bleeding is usually minor and resolves on its own. In rare cases,
bleeding can be more significant and require additional treatment or even surgery
and the coagulation status of the patient should be considered prior to considering a
cryoneurolysis procedure [5].
Another potential complication of cryoneurolysis is damage to nearby organs or
tissues. Because the procedure involves freezing tissue, there is a risk that the cold
temperature could damage healthy tissue surrounding the area being treated. This
can lead to pain, swelling, or even organ dysfunction [5].
In some cases, cryoneurolysis can cause permanent nerve injury. This can lead
to numbness, tingling, or weakness in the affected area, and may require additional
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Ultrasound-Guided Percutaneous Cryoneurolysis for Acute Pain … 501
treatment to manage. The avoidance of nerves with motor innervation should help
minimize the risk of any significant and permanent weakness [5]. Finally, like any
interventional procedure, there i s a risk of infection with cryoneurolysis. The admin-
istration of pre-procedure antibiotics may decrease this risk but patients should still
be aware of the signs of infection, such as fever, swelling, and redness at the site of
probe insertion [5].
4 Contraindications
Cryoneurolysis is relatively safe; however, there are still contraindications. These
include Raynaud’s syndrome, cryoglobulinemia, cold urticaria, bleeding disor-
ders, localized infection, and anticoagulation. Risks include depigmentation, hyper-
pigmentation, alopecia in the hairline, and “frostbite” of the skin if the ice ball encom-
passes the dermis, as well as bruising and bleeding. Three clinical trials involving
cryoneurolysis of intercostal nerves through thoracotomy i ncisions reported an
increased risk of postoperative neuropathic pain, while many others found no such
association [25].
5 Follow-Up and Recovery After Cryoneurolysis
Following cryoneurolysis, patients are typically monitored for a short duration to
ensure that there are no immediate complications associated with the procedure and
that any effects associated with conscious sedation have abated.
6 Conclusion
While pain is a constant throughout life, it’s management represents an ever-changing
sector of medical practice. Today, while a multitude of options exist for the manage-
ment of acute pain, percutaneous cryoneurolysis represents a potentially effective
alternative that extends analgesic efficacy far beyond what is normally experienced
with local anesthetic-based regional anesthesia procedures. The high success rate,
minimal recovery time, and low complication rate highlight a potential therapeutic
niche for cryoneurolysis in the future of acute pain management and prevention
of chronic pain. Further research efforts should focus on further optimizing this
procedure for various specific pain etiologies.
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502 M. Gyorfi et al.
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