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Opioid Agonists and Perioperative
Management of Patients on Maintenance
Therapy
Sherief Boss, Thomas Bielawiec, Michael Gwede,
Bhuvaneswari Sandeep Ram, and Dalia H. Elmofty
Abstract Opioids are commonly used analgesic agents. They bind to specific recep-
tors found throughout the body exerting agonistic, antagonistic, or mixed (partial
agonistic) response. Opioids are associated with addiction potential due to activation
of reward centers and can cause opioid use disorder (OUD). Methadone, Buprenor-
phine, and Naltrexone are medications used to treat OUD commonly known as main-
tenance therapy. Due to the increasing number of patients presenting to the periop-
erative arena on maintenance therapy, it is imperative for physicians to be familiar
with the complexity involved in managing patients with OUD. This chapter reviews
the literature on opioid agonists and the perioperative management of patients with
OUD on maintenance therapies.
Keywords Opioids
· Opioid use disorder · Perioperative pain management ·
Methadone · Buprenorphine · Naltrexone
1 Opioids
Introduction
Opioids are a class of drugs which are primarily used for analgesia with additional
applications as anesthetics, antitussives, and antidiarrheal agents. “Opioid” is an
umbrella term referring to both natural, semi-synthetic, and synthetic drug variants
[1]. “Opiate” refers to the naturally-produced subset of opiates that include morphine,
heroin, and codeine [1]. These natural substances were first derived from opium
which is a dark resin present in poppy seeds. Opiates are all structurally like morphine.
The term “narcotic” is typically used to describe substances with morphine-like
activity [1].
S. Boss · T. Bielawiec · M. Gwede · B. S. Ram · D. H. Elmofty (
B
)
University of Chicago, Chicago, USA
e-mail: delmofty@bsd.uchicago.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. Abd-Elsayed and K. Schroeder (eds.), Perioperative Pain Management,
https://doi.org/10.1007/978-3-031-67648-2_21
319
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320 S. Boss et al.
Opioids can be divided into several groups based on the response elicited when the
substance is bound to an opioid receptor: opioid receptor agonists, opioid receptor
antagonists, or partial agonists. Opioid receptor agonists activate opioid recep-
tors leading to the primary analgesic effect. Examples of opioids agonists include
oxycodone, morphine, and fentanyl. In contrast, opioid receptor antagonists inhibit
opioid receptors and can further prevent opiate agonists from acting on these recep-
tors. Opioid receptor antagonists include pentazocine, butorphanol, and nalbuphine.
Opioid receptor partial agonists display agonist and antagonist effect. They have less
effect at the receptor than full agonists and can be used to mitigate or antagonize the
action of full agonists. Buprenorphine is an example of an opioid partial agonists
[1, 2].
There are also endogenous substances which carry morphine-like activity. These
have been classified as three families of neuropeptides: enkephalins, endorphins,
and dynorphins [1]. Each of these groups are distinguished from one another by their
precursor polypeptides: pro-enkephalin, pro-opiomelanocortin, and prodynorphin.
They each have a unique anatomical distribution. While several other morphine-like
molecules have been found in mammalian brains, it is not currently clear if these are
endogenous substances are derived from dietary intake [1].
2 Mechanisms of Action
Opioids act by binding to specific receptors found throughout the body, exerting
agonistic, antagonistic, or mixed (partial agonistic) response. There are three widely
accepted opioid receptor types, each designated by a Greek symbol: mu (μ), kappa
(κ), and delta (δ). In additional, the opioid receptor-like receptor-1 (ORL-1) also
known as the Nociception Opioid Receptor (NOP) receptor is often included in
the opioid receptor family due to its structural similarity [1]. These opioid recep-
tors work by coupling to inhibitory G proteins. When an endogenous opioid or
opioid agonist binds to these receptors, the inhibitory g-protein leads to an inhibi-
tion of enzyme adenylyl cyclase which leads to a downstream reduction of cyclic
adenosine monophosphate (cAMP) and activation of phospholipase C. The g-protein
leads to inhibition of voltage-gated calcium influx channels and activation of K+
efflux channels that results in membrane hyperpolarization. These changes cause a
decrease in neurotransmission of excitatory neurotransmitters such as acetylcholine
and substance P from the nociceptive neuron involved leading to the opiate effect of
analgesia [1].
Opioid receptors are primarily found in the central nervous system at the dorsal
horn of the spinal cord and can be augmented through both neuraxial and systemic
administration. They have also been found in the peripheral nervous system and
binding can augment the somatic and autonomic nervous system [1].
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Opioid Agonists and Perioperative Management of Patients … 321
3 Pharmacookinetics and Pharmacoodynamics
Most opioids go through first pass metabolism in the liver before entering the systemic
circulation. This can lead to a decrease in the amount of bioavailable metabolites. The
liver produces specific enzymes that aid in the metabolism of the opioids. Phase 1
metabolism, otherwise known as the modification reaction, involves the cytochrome
P450 enzymes and results in oxidation or hydrolysis [3]. Phase 2 metabolism, or
the conjugate reaction, conjugates the drugs with hydrophilic substances as sulfate,
glucuronic acid, glycine, or glutathione. This creates highly hydrophilic products
that can be easily excreted [3]. Some opioids are processed into inactive and active
metabolites as summarized in Table 1 [3–6].
Opioids metabolisms differ from one individual to another based on the age,
ethnicity and sex as described in Table 2 [3]. Half-life of a drug is the time it takes
for the amount of the drug’s active substance in the body to reduce by half. This
can vary from a few hours to a few days. The half-life of Morphine is 2–3.5 h,
Hydromorphone 2–3 h, Oxycodone 2–3 h, Fentanyl 3.7 h, Buprenorphine 3–5 h, and
Methadone 24 h [7].
Table 1 Opioids and Metabolites
Opioid Inactive metabolites Active metabolites
with
pharmacological
opioids
Active metabolites with
non-pharmacological
opioids
Morphine Normorphine Hydromorphone Morphine 3- glucuronide
Morphine 6-glucuronide
Hydromorphone Minor metabolites None Morphine 3- glucuronide
Hydrocodone Norhydrocodone Hydromorphone None
Codeine Norcodeine Hydrocodone
Morphine
None
Oxycodone None Oxymorphone Noroxycodone
Oxymorphone Oxymorphone
3-glucuronide
None 6-Hydroxy-oxymorphone
Fentanyl Norfentanyl None None
Tramadol Nortramadol None O-desmethyltramadol
Methadone 2-Ethylidene-1,
5dimethyl-3,
3-diphenylpyrolidine
2-Ethyl-5-Methyl-3,
3-Diphenylpyroline
None None
Heroin Normorphine Morphine 6-Monoacetylmorphine
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322 S. Boss et al.
Table 2 Opioid metabolism based on age, sex, ethnicity, and hepatic or renal impairment
Opioid Age Sex Ethnicity Hepatic impairment Renal impairment
Morphine Clearance may be
reduced in older
patients
No effect Chinese patients have
higher clearance of
morphine
Dose adjustment recommended Dose adjustment recommended
Codeine Caution
recommended in
older patients
No effect CYP2D6 allelic
variants may alter
metabolism more
common in population
of Asian or African
Descent
Dose adjustment recommended Dose adjustment recommended
Hydrocodone Caution
recommended in
older patients
No effect CYP2D6 allelic
variants may alter
metabolism more
common in population
of Asian or African
Descent
Most frequently administered in
combination with
acetaminophen, liver function
monitoring is advised during
treatment in patient with
hepatic impairment
Most frequently administered in
combination with
acetaminophen, renal function
monitoring is advised during
treatment in patient with severe
renal impairment
Oxycodone Concentration
normally higher in
older patients
Concentration 25%
higher in women than
men
No effect Dose adjustment recommended Dose adjustment recommended
Methadone Dose adjustment may
be necessary in older
patients
No effect No Effect Dose adjustment recommended
in patients with severe
impairment
Dose adjustment recommended
in patients with severe
impairment
Tramadol Effects of age on
pharmacokinetics
have not been studied
No effect No Effect Pharmacokinetics is severely
altered in patients with severe
hepatic impairments
Pharmacokinetics is severely
altered in patients with severe
renal impairments
Fentanyl Clearance may be
reduced in older
patients
No effect No Effect Dose adjustment may not be
necessary in patient with
hepatic impairment
Dose adjustment may not be
necessary in patient with renal
impairment
(continued)
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Opioid Agonists and Perioperative Management of Patients … 323
Table 2 (continued)
Opioid Age Sex Ethnicity Hepatic impairment Renal impairment
Hydromorphone No effect Concentration
maximum (C-max)
25% higher in women
than in men with
similar area under
plasma concentration
No Effect Dose adjustment recommended Dose adjustment recommended
Oxymorphone Steady state
concentration, 40%
higher in patients >
65
Concentration same
in men and women
after controlling body
weight
No Effect Contraindicated in patient with
moderate or severe hepatic
impairment
Dose adjustment recommended
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324 S. Boss et al.
4 Indications for Use
Opioids are mainly used as analgesics but some opioids, such as codeine, are indi-
cated for use as an antitussive [8, 9]. Diphenoxylate and Loperamide are used in the
treatment of diarrhea. There is strong evidence for the benefit of opioids in treatment
of acute and subacute pain but there is a lack of evidence of the benefit of opioids in
the chronic pain management specially in non-cancer related pain [10–13].
5 Effects on Organ Systems
Cardiovascular
The cardiovascular system is least effected by opioids with minimal effects on
chronotropy, inotropy, dromotropy, and lusitropy. The effect is variable depending on
the opioid administered. Most opiates have a neutral to negative chronotropic effect
caused by vagal nerve stimulation leading to a bradycardic response [14]. This can
explain the hemodynamic depressive effect noted with administration of opioids.
While opioids do not have a profound effect on most functional dynamics of the
heart, the bradycardic effect can lead to a decrease in blood pressure by reducing
cardiac output (C0) as CO = stroke volume (SV) x heart rate (HR). Opioids cause
vasodilation of peripheral arteries and veins. The primary analgesic effect of opioids
causes a decrease in sympathetic tone which further contributes to the decrease in
blood pressure. Meperidine is an exception as its administration leads to increased
chronotropy due to its structural similarity to atropine. Meperidine decreases inotropy
when given in large doses. With meperidine, while heart rate may increase, the
decrease in inotropy, loss of tone, and increased vasodilation, leads to a net decrease
in blood pressure [15]. Histamine release is noted with the administration of certain
opioids when given intravenous such morphine and meperidine and leads to vasodi-
lation. This effect can be countered by decreasing the dose or rate of administration
along with pre-treating via antihistamine agents [16]. These effects do not cause
significant shifts in cardiovascular function. But in patients with significant comor-
bidities, these factors should be considered, particularly in the perioperative setting as
these patients are are exposed to additional medications that can cause cardiovascular
instability. Care must be taken when crafting an anesthetic plan [17].
Respiratory
Opioids primarily affect the respiratory system by decreasing respiratory drive and
ventilation. Opioids bind to mu receptors at respiratory neurons in the brainstem via
the pre-botzinger complex which is responsible for generating respiratory rhythm
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Opioid Agonists and Perioperative Management of Patients … 325
in the pons [18, 19]. This binding results in the blockade of carbon dioxide (CO
2)
chemoreceptors in the medulla and an increase of the arterial carbon dioxide partial
pressure (PaCO
2
). This leads to a right and downward shift of the CO
2
response curve
[20]. These changes blunt the ventilatory response to increased levels of PaCO
2
as
well as increases the apneic threshold and put patients at risk of opioid-induced
respiratory failure. The apneic threshold is described as the level of PaCO
2
at which
apnea is tolerated. Given these respiratory changes, patients with comorbidities that
lead to baseline chronic CO
2
retention, such as obesity and obstructive sleep apnea,
are at a higher risk of clinically significant respiratory depression when treated with
opioids. These effects can be mitigated by judicious titration of opiates and close
monitoring. Respiratory rate is particularly affected and makes this an ideal marker
for respiratory compromise and overdose in patients receiving opioids [19].
Opioids have additional effects on respiratory physiology. Large doses of fentanyl
can lead to profound chest wall, diaphragmatic, and airway rigidity due to the binding
of central and peripheral muscle receptors [21]. This phenomenon is known as
fentanyl-induced chest wall rigidity or wooden chest syndrome and can be life-
threatening. Administration of neuromuscular blockade agents is the most appro-
priate treatment. Certain opioids also have additional indirect respiratory effects
beyond the direct depression caused by mu receptor binding. Morphine and meperi-
dine both lead to significant histamine release, which can lead to bronchospasm
[16].
Given that mu receptor binding is the primary mediator of respiratory depression,
drugs with more pronounced action on alternative receptors have been hypothesized
to be safer for patients who are at risk of respiratory depression [19]. Active research
is being performed into the selective blocking or downregulating receptors at these
sites to reduce the respiratory side effects of opiate administration [19].
Cerebral
When adjusted for changes in PaCO
2
, opioids cause a reduction in cerebral blood
flow and cerebral O
2
consumption [22]. Intracranial pressure (ICP) is not signifi-
cantly affected by opioid administration in healthy patients. There can be a small
physiological increase that is typically blunted by autoregulation mechanisms [23].
Opioids have little to no effect on EEG. It was previously thought that large
doses of opiates could produce or mimic seizures, but this was attributed to the
motor manifestations of muscle rigidity, with no associated EEG changes during
episodes [24]. This explains the lack of reliable amnesia with opioid administration.
Administration of large opioid doses have been associated with a degree of slow
brain wave activity, however the significance of this is unclear [24]. The exception to
this is seen with meperidine as it has been associated with EEG effects and potential
for seizure [16].
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326 S. Boss et al.
Endocrine and Reproductive
Opioids act on the hypothalamus by inhibiting pulsatile gonadotropin releasing
hormone (GnRH) release that leads to a reduction in adrenocorticotropic hormone
(ACTH) and growth hormone (GH) release, and in turn cortisol secretion [25].
Opioids administered prior to incision can reduce the surgical stress response.
Reducing the surgical stress response has been correlated with improved post-
surgical outcomes and decreased morbidity [26]. The dose needed to suppress these
neuroendocrine markers has been reported as doses as high as > 50 mg/kg [21].
Chronic opioid use is linked to hypogonadism via inhibition of the gonadal axis of
the hypothalamus. Hyperprolactinemia is associated with chronic opioid use causing
GnRH suppression and further hypogonadism. Testosterone levels can decrease
causing sexual dysfunction and gynecomastia in men and menstrual irregularity in
women [27].
Opioid receptors have been found in reproductive tissue including the granulosa
cells in the ovarian follicle, the oocyte, endometrial tissue, and somatic and germ cells
of the testis. Research suggests that these receptors and endogenous opioids affect
the maturation of oocytes and sperm production in women and men respectively [27].
These endogenous pathways have been the target of reproductive related treatment,
for example the opiate antagonist naltrexone has been prescribed to target conditions
like amenorrhea, polycystic ovarian disease, and male sexual dysfunction/infertility
[27].
Opioid receptors have been found in pancreatic tissue. Increased levels of endoge-
nous opioid β-endorphin have been noted in response to low blood glucose levels.
Studies have shown that intravenous administration of opioids lead to insulin suppres-
sion at pancreatic beta cells and potentially induce hyperglycemia [28]. Paradoxi-
cally,patients with baseline hyperglycemia, opioid stimulation has been seen to lower
blood glucose levels [29]. The clinical significance and mechanisms of these glucose
modulating effects is an active area of research.
Gastrointestinal
Opioids have an inhibitory effect on gastrointestinal function that is mediated by
direct binding of opioid receptors at peripheral receptors in the gut. This leads to
decreased peristalsis and motility causing severe constipation [30]. Opioids delay
gastric emptying and predispose patients to vomiting and aspiration [31]. Opioids
cause contractions at the sphincter of Oddi triggering biliary colic and spasms
mimicking choledocholithiasis [32]. There is an association between opioids and
the incidence of acute pancreatitis secondary to long-term opioid-induced contrac-
tions and associated ductal dilation. Patients taking chronic opioids experience these
side effects despite displaying tolerance to other opiate effects. This is due to the
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