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22 T. Speaks et al.
and systems created to collect data, audit, and analyze protocol elements and patient
outcomes. Data collection and cyclical review and revision are crucial to the success
of enhanced recovery programs.
17 Emerging Therapies
New and emerging therapies create opportunities to optimize perioperative analgesia.
There are two broad areas of novelty to enhance perioperative analgesia. The first
are therapies that target specific nerves to achieve a longer duration of analgesia
compared to single injection or continuous perineural blocks using local anesthetics,
such as peripheral nerve stimulation and cryoneurolysis. The second are various
emerging pharmacologic agents that improve on existing drugs, such as opioids
with potentially less adverse effects (Oliceridine), TRPV1 agonists with potentially
more favorable pharmacokinetics than capsaicin, extended-release local anesthetic
formulations (bupivacaine/meloxicam, SABER-Bupivacaine, INL-001), and adju-
vants that may increase the duration of action of local anesthetics (tetrodotoxin and
neosaxitoxin).
18 Peripheral Nerve Stimulation
Peripheral nerve stimulation (PNS) is an emerging field in adjunctive perioperative
analgesic therapies [103]. As a temporary but semi-long duration analgesic technique,
PNS may serve as a useful modality in both acute and chronic pain management. The
approach to the targeted nerves is like that of peripheral nerve blocks, which allows
for PNS placement in any location commonly used for peripheral nerve blocks [104].
Ideally, the PNS lead should be placed at a slight distance to a nerve (0.5–1.5 cm),
which allows for optimal selective fiber stimulation, and studies have shown that
many nerves are acceptable targets, including the femoral nerve, sciatic nerve, sural
nerve, peroneal nerve, tibial nerve, brachial plexus, suprascapular nerve, radial nerve,
median nerve, ulnar nerve, greater occipital nerve and medial branch nerves of the
dorsal rami of the lumbar spine [104–106].
The most widely accepted theory to explain the analgesic effects of PNS is
Melzack and Wall’s “gate control theory” [107]. These two authors described in
1965 how exposing large, myelinated, afferent peripheral nerve fibers to an elec-
trical current results in pain signal conduction impedance within the spinal cord of
small-diameter pain fibers. Shortly after, they hypothesized that stimulating primary
afferent neurons could produce analgesia, eventually leading to the off-label use of
commercially available stimulators for peripheral nerves [103]. The clinical applica-
tion of PNS remained limited until the last ten years when PNS specific devices were
designed to improve their utility and function. PNS also activates and modulates the
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General Principles of Perioperative Pain Management 23
central nervous system at subcortical and cortical areas in ways that may impact the
processing of pain [108].
There is a wide range of indications for PNS, namely conditions resulting in
pain in the distribution of a single nerve or single group of nerves [109]. There are
very few contraindications for PNS. Absolute contraindications include allergy to
any component of the stimulator and patient refusal, while relative contraindications
include coagulopathy and local infection near the access site. Placing a PNS involves
using sterile technique and an ultrasound machine. Like a peripheral nerve block,
the targeted nerve is identified using ultrasound-guidance, and a monopolar needle
is inserted roughly 0.5–1.5 cm from the nerve. An electrical stimulator is attached
to the needle to deliver a test stimulation with the goal of localized stimulation
without muscle contractions or discomfort. Uncomfortable local sensations may be
due to superficial needle placement, while muscle contractions or distal extremity
discomfort may be due to deep needle placement. Once localized stimulation without
muscle contractions or discomfort is achieved, the monopolar needle is withdrawn,
and the stimulator lead is placed through the introducer needle in the same location.
The introducer needle is then withdrawn, the lead is attached to a stimulator, and the
surface electrode is placed on the ipsilateral limb. Appropriate lead placement results
in comfortable sensations in the desired dermatomal distribution without muscle
contractions. Once proper lead placement is confirmed, it is secured in place with a
sterile dressing. Although complication rates and risks are very low, some include
pain during the procedure, infection, allergic dermatitis, stimulation intolerance, and
hematoma formation. The most common complication is l ead migration, which is
more common with chronic stimulators. The helical shape of the lead may help
decrease the incidence of fracture, migration, and risk of infection to much less than
0.1% when left in for up to 60 days [104].
The use of PNS provides regional anesthesia without the systemic effects of most
pain medications. Also, PNS may be left in longer (up to 60 days) than perineural
catheters with local anesthetic while also potentially sparing motor blockade. PNS
for analgesia could significantly change the practice of regional anesthesia and peri-
operative pain medicine by impacting patient satisfaction, pain control, and quality
of life. The idea of minimizing, or even replacing opioids with PNS in the setting
of the current opioid crisis makes this emerging modality an excellent and desirable
option to achieve analgesia when used concurrently with other multimodal agents
and techniques.
19 Cryoneurolysis
Cryoanalgesia is the use of cold temperature to treat pain. Though known by
ancient civilizations, such as the Egyptians and Greeks, the clinical application
remained crude until the first closed cryoprobe apparatus was described in 1961
[104]. Following this, more modern probes called cannulas, were invented.A cannula
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24 T. Speaks et al.
for cyroanalgesia is a tube within a tube that conveys a gas at high pressures (600–
800 psi) down its shaft through a small annulus (0.002 mm), and into a low-pressure
closed end before the gas is vented back up the shaft of the probe in a retrograde
direction. The decrease in pressure at the tip results in a corresponding volume
expansion, leading to a decrease in temperature due to the Joule–Thomson effect.
This drop in temperature results in an ice-ball formation around the tip of the probe,
which induces neuronal injury around the affected region. The target temperature is
between −20 and −100 °C, which is why nitrous oxide or carbon dioxide are the two
most frequently used gases for cryoneurolysis. With boiling points of −88 and −
78 °C, nitrous oxide and carbon dioxide become solid once temperatures fall below
these levels, inherently limiting their cooling process to within a safe and therapeutic
range [110].
After cryoneurolysis, axons re-grow distally at a rate of 1–2 mm/day from the
initial point of treatment, which most likely explains its prolonged duration of action.
Analgesia may last for weeks or months with a single treatment, with high vari-
ability based on the distance from the point of cryoneurolysis to the terminal nerve
branches innervating the affected tissue [104]. Due to the unpredictable duration
of hypesthesia, motor weakness, and loss of proprioception, the use of cryoneurol-
ysis may be limited in the treatment of acute pain. However, in situations where
these limitations are acceptable, cryoneurolysis may be a promising technique that
offers analgesia orders of magnitude beyond the duration of action provided by local
anesthetics [111]. Benefits of cryoneurolysis have been shown in the application of
surgically exposed intercostal nerves during thoracotomy, intraoperative application
in the setting of inguinal herniorrhaphy, repeated debridement of burns, severe pain
from traumatic rib fractures, limb or digit amputations of either the upper or lower
extremity, and pain after total knee or shoulder arthroplasty [112, 113]. Initially,
anatomic landmarks and/or nerve stimulation were used to guide probe insertion,
but these techniques were soon supplemented and replaced with imaging modalities,
particularly, fluoroscopy and ultrasound. Ultrasound-guided percutaneous cryoneu-
rolysis is a procedure that can be performed in an outpatient setting without seda-
tion, giving rise to a more accessible treatment plan for chronic pain. This technique
is nearly identical to that of a single injection peripheral nerve block. Instead of
injecting local anesthetic, the probe is inserted adjacent to the target nerve and the
ice ball that forms at the tip envelopes it. Relative contraindications to percutaneous
cryoneurolysis include local/systemic infection, anticoagulation, bleeding diathesis,
and immunosuppression. Specific contraindications to cryoneurolysis include cold
urticaria, Raynaud’sdisease, cryofibrinogenemia, cryoglobulinemia, and paroxysmal
cold hemoglobinuria.
Risks of cryoneurolysis include pain during and after the procedure, superficial
bruising, and transient or permanent alopecia or changes in hair pigmentation if the
ice ball involves the skin. Of note, due to a continuous flow of warm blood, large
blood vessels have been shown to tolerate the cold temperatures and demonstrate a
low risk of complications such as vessel rupture, coagulation, or thrombosis [104].
A few RCTs demonstrated an increased incidence of neuropathic pain 3–6 months
after open thoracotomy with surgically applied cryoneurolysis, but the majority of
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General Principles of Perioperative Pain Management 25
RCTs have not reported similar data [114, 115]. The variability in data may be
due to the differing techniques of exposing the target nerves intraoperatively among
surgeons prior to applying cryoneurolysis under direct visualization. Like the double
crush phenomenon, it is hypothesized that the physical manipulation of the target
nerve results in an afferent barrage, leading to central sensitization such that when
axonal regeneration occurs after injury, the fiber activity is perceived as dysesthetic
[116]. By eliminating the need of intraoperative nerve manipulation, ultrasound-
guided cryoneurolysis has demonstrated no incidence of neuropathic pain thus far, but
caution is still warranted because the number of patients who underwent ultrasound-
guided percutaneous cryoneurolysis is currently far fewer than those who received
intraoperative application under direct visualization [104, 117].
Cryoneurolysis is a promising, emerging therapy that could potentially provide a
safe, effective, and non-pharmacological therapeutic option for perioperative pain.
The shift from current pain treatments that may have limited efficacy or potential risks
to multimodal treatment plans that incorporate non-pharmacologic modalities makes
cryoneurolysis a promising, emerging therapy that provides immediate, localized,
and long-lasting analgesia.
20 Oliceridine—Biased Ligand
Conventional opioids exert their analgesic effects by activating the μ-opioid receptor
and its downstream G-protein signaling pathway [118]. Unfortunately, the activated
μ-opioid receptor also stimulates an alternative pathway mediated by β-arrestin,
which has been associated with opioid-induced respiratory depression, gastroin-
testinal effects, and attenuation of analgesia. This information directed the novel idea
of creating an agent that preferentially activates the G-protein pathway while mini-
mizing the adverse effects mediated by β-arrestin seen with conventional opioids.
Oliceridine (brand name Olinvyk), is the first drug in this new class of opioids called
biased ligands. Unlike conventional opioids, oliceridine has been shown in vitro to
induce only 14% of β-arrestin signaling activity compared to morphine [119]. An
Oliceridine dose of 1 mg is equipotent to 5 mg of intravenous morphine. The time
of onset of analgesia occurs rapidly within 1–2 minutes, peaks at 6–12 minutes, and
lasts for 1–3 hours [118].
Several randomized controlled Phase III studies comparing oliceridine with
morphine showed significantly higher treatment response rates, shorter time to mean-
ingful pain relief (12 versus 30 minutes), and non-inferior analgesia in the oliceridine
groups. One study showed a dose-dependent decrease in the incidence of respiratory
events across all oliceridine regimens, though the highest dose of oliceridine was not
much different from morphine [120]. In another study, the oliceridine groups were
not associated with a significantly different respiratory safety burden than the placebo
group [121]. In the same studies, gastrointestinal adverse effects increased in a dose-
dependent manner, but the odds of requiring rescue antiemetics were significantly
lower with all oliceridine regimens than morphine.
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26 T. Speaks et al.
Although Phase I and II studies suggested that oliceridine may be associated with
a lower risk of opioid-induced respiratory depression and adverse gastrointestinal
side effects compared to morphine, the modest differences or lack of differences
in subsequent Phase III clinical trials suggest that further prospective studies eval-
uating these safety parameters as their primary outcomes are needed [118]. With
future studies, biased ligands like oliceridine may play an important and favorable
pharmacological role in the multimodal analgesic pathway while minimizing adverse
effects seen with conventional opioids.
21 Transient Receptor Potential Vanilloid 1 Channel
Agonists
The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is a polymodal
protein with functions linked to the generation of pain. These ion channels are mainly
expressed in all sensory ganglia and smaller-diameter neurons, such as sensory-
C and Aδ [122]. TRPV1 receptors are activated by mediators of noxious stimuli
and up-regulated in chronic pain states, increasing the perception of pain. TRPV1
agonists, like capsaicin, activate and depolarize TRPV1 receptors, leading to an
initial burning sensation from the nerve stimulation, but eventual desensitization and
analgesia once the receptors are completely depolarized [123]. Multiple molecules
have been identified that have similar agonist effects as capsaicin but with more
favorable pharmacokinetics [124]. One such molecule, vocacapsaicin, is a water-
soluble prodrug that rapidly converts to capsaicin and has shown promise in a pilot
study [125]. Various TRPV1 agonists with more favorable pharmacodynamics than
capsaicin may play an important role in the setting of perioperative pain management.
When we think of multimodal analgesia and all the implicated receptors and pathways
associated with pain, TRPV1 is yet another target that should be considered, making
these various emerging TRPV1 agonists important medications to study.
22 Extended-Release Local Anesthetic Formulations
Extended-release bupivacaine is a newer technique for administering local anesthetic
over a longer period, allowing for an increased duration of action. Liposomal bupiva-
caine (Exparel), the most widely used and clinically relevant long-acting local anes-
thetic, uses a multivesicular liposomal delivery system that releases bupivacaine in a
steady, controlled fashion. In recent years, other extended-release formulations have
been developed, including bupivacaine/meloxicam (Zynrelef), SABER-Bupivacaine
(Posimir), and INL-001 (Xaracoll).
Bupivacaine/meloxicam (HTX-011) is an extended-release local anesthetic that
consists of a combination of bupivacaine and meloxicam [126]. Meloxicam is added
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General Principles of Perioperative Pain Management 27
in the attempt to decrease local inflammation and decrease local environment acid-
ification, thereby improving the pH balance for bupivacaine, resulting in enhanced
effectiveness. Bupivacaine/meloxicam is encapsulated in a polymer that hydrolyzes
slowly, releasing bupivacaine and meloxicam at a gradual and sustained rate, with
analgesic effects lasting for up to 72 hour. Due to its high viscosity, HTX-011 is a
formulation that cannot be injected perineurally, but instead, it is designed for the
surgical team to apply it on the surgical site prior to final closure. While it has been
shown to be more effective than placebo and plain bupivacaine, it is not yet known
if it is more effective than liposomal bupivacaine [127].
Like other extended-release local anesthetics, SABER-bupivacaine is a depot
formulation of slowly released bupivacaine. In contrast to other formulations,
SABER-bupivacaine is a polymer that uses a sucrose acetate isobutyrate 66%
in benzyl alcohol 22% to deliver the active component, bupivacaine 12%. This
compound was also designed for surgical infiltration and allows for slow release
of bupivacaine over several days following injection; however, the benzyl alcohol
component prevents the perineural use of SABER-bupivacaine [128]. While it has
had a positive phase 3 clinical trial, other trials of effectiveness have been negative
[129]. It received a narrow FDA approval in 2021 for shoulder analgesia for subacro-
mial decompression surgery with administration into the subacromial space under
direct arthroscopic visualization [130].
The final extended-release local anesthetic formulation is INL-001 (Xaracoll),
which is a biodegradable resorbable collagen matrix impregnated with bupivacaine.
It is designed for direct deposit in the surgical site, providing extended delivery of
local anesthetic directly at the site. With few studies yet to support its efficacy, it has
only been FDA-approved for placement into the surgical site following open inguinal
hernia repair [131].
23 Local Anesthetic Adjuvants
The ability to prolong the duration of action of local anesthetics has long been a topic
of great interest in the field of regional anesthesia. Various efforts to accomplish this
goal include the use of additives to local anesthetic. The most commonly used addi-
tives currently include epinephrine, dexamethasone, buprenorphine, clonidine, and
dexmedetomidine. Other additives currently being studied include sodium channel
toxins, like tetrodotoxin and neosaxitoxin.
Tetrodotoxin is a naturally occurring reversible sodium channel toxin derived from
pufferfish and shellfish that has been shown to block conduction of isolated nerves.
In preliminary animal studies, tetrodotoxin significantly prolonged block duration
when used with bupivacaine [132, 133]. Neosaxitoxin, found in pufferfish and other
shellfish, is a more potent reversible sodium channel toxin that preferentially targets
sodium channels in the periphery compared to the myocardium. Combined with
bupivacaine, neosaxitoxin demonstrates a prolonged duration of effect compared to
bupivacaine, neosaxitoxin, and placebo independently [134, 135]. Sodium channel
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28 T. Speaks et al.
toxins are still investigational but hold promise to extend the duration of action of
local anesthetics to better match the needs of patients undergoing surgery associated
with moderate to severe pain of longer duration.
24 Summary
Perioperative pain management is a dynamic field with many emerging therapies
aimed to improve analgesia and overall patient care. The quest for safe, effective, and
longer-acting therapies to improve pain control while minimizing the adverse effects
of traditional therapies continues. Withmore research in these emerging therapies, the
road to improvement looks very promising. While that search continues, we utilize a
solid framework of pain management strategy in patient and pain mechanism-specific
multimodal analgesia that employs pharmacologic and interventional therapies that
mitigate pain and the physiologic stresses of surgery.
25 Key Takeaways of Chapter
Perioperative pain management attempts to mitigate post-surgical pain and help
patients supersede the challenges and stressors of surgery.
Non-opioid pain medications of different classes with relevant regional anesthesia
or local anesthetic infiltration provide a foundation of analgesia upon which judicial
use of opioids can be added as needed to provide post-surgical pain control while
decreasing opioid-related adverse events.
Interventional acute pain management techniques are effective modalities for
patients undergoing surgeries associated with severe and moderately-severe pain.
Enhanced recovery protocols aim to decrease physiologic stress, restore home-
ostasis, and lead patients to faster recovery and optimal quality outcomes.
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