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Opioid Agonists and Perioperative Management of Patients … 327
peripheral action of opiates at the enteric nerves of the colon [32]. Opioid antago-
nists that act on peripheral opioid receptors such as methylnaltrexone and naltrexone
are used to mitigate these side effects [32].
Immunological
Immune cells secrete endogenous opioids that act peripherally at opioid receptors.
The association between opioids and immunosuppression is an activearea of research
with mixed findings. Some research has shown chronic opioid use has been asso-
ciated with decreased expression of genes that mediate antiviral and other immune
responses in the body while other studies have found an upregulation of immune
system responses with opioid therapy [33]. Exogenous opioids impair the function
of several i mmune cells such as macrophages, natural killer cells, and t-cells that
disrupt the gut microbiome [33]. Studies have shown a link between opioids admin-
istered with general anesthesia for cancer surgery and recurrence of cancer possibly
through a similar immune modulation mechanism [33]. Some clinicians advocate
for the use of regional anesthesia and other opiate sparing techniques for patients
with cancer.
6 Maintenance Therapy and Perioperative Pain
Management
Introduction
3.4% (9.5 million) individuals aged 26 older were reported to misuse opioids. [34]
2.7 million were diagnosed with OUD [34]. According to the American Psychiatric
Association, OUD is a chronic problematic pattern of opioid use leading to behavioral
changes and problems or distress [34]. Initiatives by the Secretary of Health and
Human Services have been set forth to improve treatment and recovery services for
patients who suffer from OUD. Although still underutilized, effective medications
exist to aid in the treatment of OUD. As services expand, patients on maintenance
therapies will be encountered in the perioperative setting and require unique pain
management considerations. Patients on maintenance therapy perioperatively are
at an above average risk of having poorly controlled postoperative pain leading to
longer hospital course [35, 36]. Physicians may also carry a stigma towards patient
that suffer from OUD [37]. Many providers share misconceptions and fears regarding
managing these patients. There are reported concerns for over-prescribing and further
contributing to their OUD along with apprehensions for physical dependence, opioid
induced tolerance, hyperalgesia, withdrawal, and pseudo-addiction behaviors [38].
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328 S. Boss et al.
There are many clinical challenges that can present in a patient on maintenance
therapy. Opioid tolerance can develop in patients with chronic exposure to opioids
and is defined as a physiological state where an increased dose of opioid is required
to provide an analgesic effect. Tolerance can lead to a decreased effect on analgesia,
sedation, respiratory depression, anti-diuresis, emetic and hypotensive effects but
typically spares constipation, miosis, and convulsions [39]. Tolerance can be vari-
able by patient and depend on the drug used, dosage administered, length of time
on a drug, and individual genetic factors [39]. The pathophysiology behind toler-
ance it thought to be due to upregulation of metabolism, desensitization of receptor
signaling, downregulation of receptors, and via the adjustments in compensatory
circuits that regulate nociception and mood [39]. Tolerance can abate with reduction
in dosing or cessation of the opioid.
Patients exhibiting opioid tolerance require higher doses of opioids or alterna-
tive means of pain control in the perioperative setting. Tolerance should be distin-
guished from addiction and pseudo-addiction. Addiction is a chronic medical disease
that incorporates neurobiological, physiological, psychosocial, genetic, and environ-
mental components that creates a dysfunction in brain circuitry and exhibits impaired
control of drug use and cravings with use of substances despite damaging conse-
quences [40]. Pseudo-addiction is term which describes behavioral symptoms of
addiction but in patients receiving inadequate doses of opioids for pain [40].
Tolerance should be distinguished from opioid induced hyperalgesia (OIH). OIH
results in a generalized hypersensitive state to painful stimuli where opioid therapy
causes an exacerbation in pain sensation rather than relief [41]. While increasing
the dosage of opioids in a tolerant individual will improve pain, it will aggravate the
pain in OIH. Opioid cessation or de-escalation is necessary to relieve hyperalgesia, in
conjunction with other treatment strategies to address the pain. Symptoms of hyper-
algesia might continue for months. The distinction between tolerance and OIH can be
quite complex. Clinicians often increase doses to address suspected tolerance which
in turn aid in the evolution of OIH. The diagnosis can be confounded by the progres-
sion of the disease process or misdiagnosed as a stress response or anxious state. There
are many complex mechanisms in play that lead to tolerance and OIH. These includes
changes occurring in the central nociceptive descending pathways by the rostral
ventral medulla, microglial activation, N-methyl-D-aspartate (NMDA) receptor up-
regulation, non-central signal pathway changes, inflammation, purinergic signaling,
epigenetics, and neuropeptides [41, 42]. While variable in clinical presentation, the
pain associated with OIH is typically more diffuse and less defined, involving areas
other than those initially involved in patients’ pain complaints [42]. Increasing the
opioid dose worsens the pain. Non-opioid analgesia should be utilized to treat OIH.
Potential options include ketamine, alpha-2 adrenoreceptor agonists, regional anal-
gesia, antidepressant therapy, anticonvulsant agents, or anti-inflammatories. Opioid
rotation should be considered [42].
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Opioid Agonists and Perioperative Management of Patients … 329
7 Maintenance Therapies
Maintenance therapy involves using a long-acting opioid agonist (i.e. methadone),
partial agonist (i.e. buprenorphine), or antagonist (i.e. naltrexone) to assist individ-
uals in abstaining from illicit substances or improper use of prescription opioids [40].
Patients on maintenance therapy, in contrast to total abstinence, are more likely to
stay in treatment. They are less likely to relapse or overdose, be exposed to infec-
tious disease, or participate in criminal activity [40, 43]. Although methadone and
buprenorphine work on similar receptors as other opioids, they help eliminate with-
drawal symptoms and relieve drug cravings [43]. Naltrexone limits the reward effect
from opioids by blocking activation of certain receptors [43].
Methadone
Methadone is a μ- receptor agonist. Its racemic mixture of D- and L- methadone
isomers block monoaminergic reuptake and NMDA receptors. It has been used since
the 1940s in maintenance therapies. Methadone can be administered via the subcuta-
neous, oral, intravenous, and rectal routes with good bioavailability without forma-
tion of active metabolites [44]. The medication is relatively low cost and works to
suppress withdrawal symptoms and relieve drug cravings. For most opioid-dependent
patients, it does not create a sensation of euphoria and allows normal daily func-
tioning. Methadone has a long half-life of 24–60 h [7, 44]. The combination of
opioid and non-opioid receptor properties of methadone is useful in the treatment of
complex pain and is often used in cancer pain, opioid tolerance, or OIH. A Cochrane
database review compared methadone maintenance to placebo maintenance or other
non-pharmacological therapy for opioid dependance and found that methadone was
more effective in retaining patients in treatment and suppressed heroin use [44].
Maintenance therapy with methadone is initiated with 50–100 mg/day daily dosing.
Given methadone’s highly variable pharmacokinetics, individuals beginning therapy
should be closely observed for adverse events. Methadone is metabolized by CYP2B6
and CYP3A4 isoforms in the liver [3]. Caution should be used in patients with
hepatic dysfunction or with medications altering hepatic metabolism. Methadone can
prolong the QTC interval. EKG monitoring is recommended. A thorough review of
the patient’s medication history should be conducted to avoid drug-drug interactions
with other medications that can prolong the QTC interval [44].
Buprenorphine
Buprenorphine is a long acting phenanthrene derivative, full μ- receptor agonist for
analgesia, partial μ- receptor agonist for respiratory depression, and κ- and δ-opioid
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330 S. Boss et al.
receptor antagonist [45]. It is a mixed agonist-antagonist [45]. It has effects on the
ORL-1 receptor and may contribute to an anti-hyperalgesia effect but its full contribu-
tion is still being investigated [45]. Buprenorphine has a ceiling effect for respiratory
depression and analgesia but can be altered when other sedating medications are
given. Buprenorphine reduces withdrawal symptoms and cravings, and its partial
agonist effect minimizes euphoria [45]. The drug has a slow onset of action and a
long half-life because of its delayed dissociation from receptors. This property may
contribute to its mild withdrawal-like effects with cessation. A Cochrane database
review found similar effectiveness between buprenorphine and methadone. It was
suggested that doses of at least 16 mg/day be administered [45]. The drug has a high
affinity for opioid receptors making it more challenging for other opioid agonists
to bind. Higher doses of opioids are required when co-administered with buprenor-
phine. Administrating buprenorphine to a patient taking opioids may precipitate with-
drawal as it antagonizes the action of μ- receptor agonists. Buprenorphine can be
administered orally but has 10–15% bioavailability due to first-pass liver metabolism.
Sublingual administration improves the bioavailability and buccal films provide over
50% availability [45]. It can also be administered via transdermal, intravenous (IV),
or intramuscular (IM) route. The drug is metabolized by the CYP450 3A4 system
into nonactive and active (norbuprenorphine) metabolites. Caution should be used in
patients with liver disease or with medications affecting CYP3A4, as norbuprenor-
phine is more potent in its effects on respiratory depression. Other adverse effects
include anxiety, nightmares, and hallucinations [45]. Buprenorphine is available in
combination with naloxone to decrease illicit use. Naloxone is a potent μ- receptor
antagonist with weak affinity at the κ- and δ-sites. While this medication is primarily
administered IV, IM or intra-nasally in cases of suspected opioid overdose, it is also
used in low dose to treat itching, vomiting, or nausea in patients receiving epidural
or IV opioids.
Naltrexone
Naltrexone is used in opioid and alcohol addiction maintenance programs. The drug
is a μ- receptor antagonist with weaker antagonism also at the κ- and δ-sites [46].
The medication is administered orally but can be given IM. Given its long duration
of action, it serves to block the effects of the abused substance and limits reinforcing
pathways [46]. Its clinical effectiveness has been debated. The medication is pharma-
cologically effective but often suffers from poor adherence and retention in real world
settings [47]. Extended-release formulations that are injected monthly may improve
adherence. Studies have shown promising effectiveness with abstinence, treatment
retention, and reduction in cravings [48–50]. Buprenorphine-naloxone and extended-
release naltrexone combinations were both similarly effective in treating OUD once
detoxification was achieved [51]. Side effects associated with naltrexone include
gastrointestinal irritation, headaches, and anxiety. It is important that patients are
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Opioid Agonists and Perioperative Management of Patients … 331
fully detoxified prior to initiating opioid antagonist therapy because they precipitate
withdrawal-like symptoms.
8 Perioperative Management of Pateint’s with Opioid Use
Disorder
The perioperative phase is often a challenging time for patients with OUD because
it is associated with fear of judgement and stigma that may result in a failure to seek
medical care [52]. These patients report difficulties in controlling perioperative pain
due to decreased tolerance to pain, increased perception of pain, and baseline chronic
pain conditions [53, 54].
The preoperative evaluation is critical in guiding pain management. Patients
should have consultation with a pain specialist or the preoperative anesthesia clinic
prior to elective surgery to formulate an individualized pain management plan.
Communication with the provider managing the patient’s maintenance therapy is
imperative. Obtaining a thorough pain history, medication history, and assessment
of their current state regarding their psychiatric and substance use disorders is r ecom-
mended. Urine toxicology screen may be indicated. Current medication use should
be verified using prescription monitoring programs [55–59]. Screening question-
naires can be used to determine the degree of catastrophizing or anxiousness related
to surgery. The opioid risk tool can assist in identifying patient at high risk of opioid
misuse [60–62].
Patients with a history of OUD in remission are also at a high risk for relapse
during the perioperative setting. The anxiety associated with surgery and concerns
regarding the management of postoperative pain are significant stressor.
Clinicians treating these patients have concerns regarding unsupervised access to
opioids that can trigger relapse but are also worried about undertreating postoperative
pain that can trigger relapse as well [63–66]. Consulting the acute pain service can
introduce alternative options include regional analgesia and non-opioid therapies to
manage postoperative pain [67].
It is important to educating the patient and the family about the risks of opioid use
and relapse. Clinicians should prescribe the minimally required dose and provide
a weaning plan for opioid therapy. The patient and family should be educated
regarding safe disposal of the unused pills, identify a responsible person to super-
vise intake, and assess for side effects from opioid therapy [60]. Patients should be
discharged with naloxone to decrease the risk of opioid overdose. Patients should have
a follow-up visit scheduled with the provider managing their maintenance therapy
upon discharge. The in-patient team should directly communicate with the provider
regarding the discharge pain management plan.
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332 S. Boss et al.
9 Management of Patients on Methadone Tre atent
Patients should continue their outpatient regimen of methadone during hospitaliza-
tion [68, 69]. The dose should be confirmed from the opioid treatment program
managing the therapy. Patient’s daily dose of methadone will not be sufficient
to control their postoperative pain. [68, 69] Guidelines published on managing
postoperative pain for patients on methadone therapy recommend the use of non-
pharmacological interventions (peripheral, neuraxial or regional analgesia) and
non-opioid pharmacological medications depending on the severity of the surgery
[69]. Partial-agonist opioid analgesics (buprenorphine and butorphanol) are absolute
contraindication because they will trigger withdrawal symptoms [69].
10 Mangement of Patients on Buprenorphine-Naloxone
Treatment
Multiple papers have been published on the acute pain management for
patients receiving buprenorphine [69–71]. Earlier guidelines recommended stop-
ping buprenorphine 2–5 days before an elective surgery and replace it with opioid
agonist in higher doses and supplementing with non-opioid analgesics and regional
anesthesia procedures [72, 73]. Several healthcare systems have published protocols
for the management of acute pain in patients receiving buprenorphine illustrated in
Table 3 [60, 73–75].
A multi-society expert panel published recommendations in 2021 recommending
buprenorphine therapy not be routinely discontinued in the perioperative setting in
efforts to reduce the risk of OUD recurrence. They also recommended that buprenor-
phine therapy can be initiated in patient with untreated OUD and acute pain in the
perioperative setting to reduce the risk of death from overdose [75]. They reported
that effective analgesia can be obtained with concomitant use of full mu agonists in
patient receiving buprenorphine therapy but also recommended the use of additional
non-opioid and non-pharmacological therapy [75].
Buprenorphine is a reasonable and recommended alternative to methadone for
managing pregnant women with UOD [40]. There is insufficient evidence on the
safety of combination buprenorphine/naloxone during pregnancy [40]. The American
Society of Addiction Medicine practice guidelines recommend continuing buprenor-
phine for pregnant women before elective cesarean section to decrease t he chances
of fetal opioid withdrawal [40, 76].
One study found that pregnant women on buprenorphine therapy had similar
intrapartum pain and analgesic needs during labor, but experience more postpartum
pain and require 47% more opioid analgesic following cesarean delivery [77].
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Opioid Agonists and Perioperative Management of Patients … 333
Table 3 Protocols for Pain Management in Patients taking Buprenorphine-Naloxone
Patients taking buprenorphine-naloxone with
mild pain
Patient taking buprenorphine-naloxone with
moderate to severe pain
(a) Boston Medical Center
1. Continue bup-nx and contact prescribing
provider
a. Consider dividing bup-nx dose to a
q6–8 h scheduling regimen
b. Consider increasing bup-nx dose
2. Consider adding NSAIDs and
acetaminophen
3. Consider adding short-acting opioid
analgesics
1. Hold bup-nx on the day of the surgery
2. Give single-dose ER/LA opioid before the
surgery and continue ER/LA to manage
baseline pain control
3. Use PCA with no basal dose or IR/SA
opioid therapy for breakthrough pain
4. Return to bup-nx provider within a week for
consideration to reinduce bup-nx
(b) University of Michigan Health System
1. Continue Bup-nx and contact prescribing
provider
a. If off Bup-nx > 5 days, treat with opioid
if indicated
2. Consider adding NSAIDs or
Acetaminophen
1. Cancel elective surgery
2. Coordinate with bup-nx provider to stop
bup-nx ≥ 5 d, transition to short-acting
opioids before surgery
3. If off bup-nx ≥ 5 d, use opioid therapy for
pain
4. Consider adjunct pain therapy
(acetaminophen, NSAIDs, gabapentin/
pregabalin, alpha-2 agonist, or ketamine
infusion)
5. Consider regional anesthesia
6. Return to bup-nx provider for reinduction
(c) University of Kentucky Healthcare System
1. Continue bup-nx and contact prescribing
provider
a. Consider dividing bup-nx dose every
6–8 h scheduling regimen
b. If off bup-nx, consider short course of
opioid therapy if indicated
2. Consider adjunct therapy (acetaminophen/
NSAIDs)
1. Continue bup-nx and contact prescribing
provider
2. Consider acute pain consult for PCA or
regional analgesia
3. Close observation to assess analgesia
4. Continue opioid therapy for postoperative
pain after discharge
Bup-nx Buprenorphine-naloxone, NSAIDs non-steroidal anti-inflammatories, ER/LA extended
release/long-acting, PCA patient controlled analgesia, IR/SA immediate release/short acting)
11 OUD for Patients on Injectable Naltrexone
There is no standardized approach on managing perioperative pain in patients on
injectable naltrexone. The plan should be discussed with the patient and prescriber
prior to elective surgery or procedure. The possibility of managing the pain with
opioids needs to be balanced against the risk of the patient relapsing. If the decision
is made to stop naltrexone, it is recommended to arrange the surgery at least 4 weeks
from the last injectable dose of extended-release form and 72 h from the last oral
dose [78]. A degree of resistance to opioid analgesics is expected, although increased
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334 S. Boss et al.
sensitivity is also possible. These patients should be closely monitored while on
opioid therapy. In the event of emergency surgery or if the decision is made to operate
while the patient is taking his naltrexone, it is recommended to use a higher dose
of non-opioid analgesics. Non-steroidal anti-inflammatory drugs, acetaminophen,
ketamine, or regional anesthesia should be considered [78–81]. Some animal studies
have suggested that opioid receptor blockade with naltrexone can be overcome with
higher doses of opioids [81]. It is recommended to consult the Acute Pain Service to
help manage the perioperative pain in this patient population.
Key Points
•
Patients with OUD on maintenance therapy are at high risk for uncontrolled
postoperative pain.
•
Patients with OUD on maintenance therapy who are at risk for increased post-
operative pain may benefit from consultation by a pain medicine or acute pain
specialists.
•
Multimodal analgesia with regional techniques when feasible should be the
cornerstone of management while applying individualized tailoring of analgesic
regimen based on the type of maintenance therapy.
•
Upon discharge, patients with OUD on maintenance therapy should have appro-
priate follow-up with treating physician and given a taper plan for postoperative
opioid therapy.
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