Classification of Opioid Compounds

Opioids can be classified as naturally occurring, semisynthetic, and synthetic ( Box 24.1 ). The naturally occurring opioids can be divided into two chemical classes, phenanthrenes (morphine and codeine) and benzylisoquinolines (papaverine). The semisynthetic opioids are morphine derivatives in which one of several changes has been made. Synthetic opioids are classified into four groups, the morphinan derivatives (levorphanol), the diphenyl or methadone derivatives (methadone, d -propoxyphene), the benzomorphans (phenazocine, pentazocine), and the phenylpiperidine derivatives (meperidine, fentanyl, sufentanil, alfentanil, and remifentanil). Structures of opioid compounds are shown in Fig. 24.1 and Table 24.1 .

Chemical structures of piperidine and phenylpiperidine analgesics.

From Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics . 10th ed. New York: McGraw-Hill; 2001:569–619.

Opioids can be classified as agonists, partial agonists, mixed agonist-antagonist, and antagonists on the basis of their interaction with the opioid receptors.

Basic Studies on Opioid Receptors

In 1973, three independent teams of investigators described the presence of opioid binding sites in the nervous system from the radioligand binding assays. From pharmacologic experiments, three types of opioid receptors were postulated. They were named μ for morphine type, κ for the ketocyclazocine type, and σ for the SKF10047 ( N -allylnormetazocine) type. In addition, a high-affinity receptor for enkephalins was found in the mouse vas deferens, and was named the δ-receptor. Furthermore, an ε-receptor was proposed as the binding site for β-endorphin in the rat vas deferens. Pharmacologic actions of opioids and the involved receptors have been analyzed ( Table 24.2 ).

Since the early 1990s, molecular biologic studies have elucidated the molecular structures and signal transduction mechanisms of the opioid receptors. Four different complementary DNAs (cDNAs) have been isolated as members of the opioid receptor family. Investigators demonstrated that three of them correspond to the pharmacologically defined μ-, δ-, and κ-opioid receptors. The fourth receptor did not bind with opioid ligands with high affinities. Later, a novel peptide, nociceptin/orphanin FQ, was identified as an endogenous agonist of the fourth member of the opioid receptor family. The μ-, δ-, and κ-opioid receptors and the nociceptin receptor share approximately 50% amino acid sequence homology with each other. Characteristics of three opioid receptors and the nociceptin/orphanin FQ receptor are listed in Table 24.3 . Hydropathy analysis of the primary structures of the opioid receptors predicted that the opioid receptors possess seven transmembrane domains ( Fig. 24.2 ). This is a characteristic structural feature of G-protein-coupled receptors. Crystallographic analysis revealed that the μ-, δ-, and κ-opioid receptors and the nociceptin receptor actually possess seven transmembrane domains and the agonist binds deeply within a large pocket ( Fig. 24.3 ). Furthermore, analysis of the crystal structure of the murine opioid receptor revealed agonist-induced conformational changes in detail, providing the basis for the development of new ligands.

Proposed structure of the μ-opioid receptor . Black circles indicate amino acid residues identical in the μ- and δ-opioid receptors. TM-I to VII show putative transmembrane segments composed of hydrophobic amino acid residues.

Overall view of the μ-opioid receptor structure . Views from within the membrane plane (left) , extracellular side (top) , and intracellular side (bottom) show the typical 7-transmembrane G-protein-coupled receptor architecture of the μ-opioid receptor. β-FNA, a semisynthetic opioid antagonist derived from morphine, is shown in black spheres.

From Manglik A, Kruse AC, Kobilka TS, et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature. 2012;485:321–326.

The σ (sigma) receptor, which was previously classified as a member of the opioid receptor, was shown to be an endoplasmic reticulum-resident protein, and has been implicated in many diseases, ranging from cocaine or alcohol addiction to the most recently reported familial adult or juvenile amyotrophic lateral sclerosis. The amino acid sequence of the σ-1 receptor does not resemble that of any other mammalian proteins.

Further pharmacologic classification of the μ-receptor as the μ ₁ , μ ₂ , and μ ₃ subtypes has been proposed, but the molecular identity of these receptor subtypes still remains to be clarified. Several possible molecular models of opioid receptor subtypes exist, including alternate splicing of a common gene product, receptor dimerization, and interaction of a common gene product with other receptor or signaling molecules. Multiple μ-opioid receptor species can be produced from a gene product of the μ-opioid receptor gene by alternate splicing ( Fig. 24.4 ). Analysis of the alternate splicing products reveals differences in ligand binding and G-protein activation. However, their physiologic, pharmacologic, or clinical implications remain to be elucidated. Interestingly, it was recently reported that the analgesic action of 3-iodobenzoyl-6β-naltrexamide, a potent analgesic against thermal, inflammatory, and neuropathic pain, is mediated by its interaction with mMOR-1G, a truncated splice variant possessing only six transmembrane segments, in mice.

μ-opioid receptor splicing in humans . Variants are grouped as full length, 7-transmembrane (7TM) , 6-transmembrane (6TM), and 1-transmebrane (1TM) with the predicted structure shown to the right and the exons color-coded to match the splicing schematic.

From Pasternak GW, Pan YX. Mu opioids and their receptors: evolution of a concept. Pharmacol Rev . 2013;65:1257–1317.

G-protein-coupled receptors can form dimers, homodimers (same receptor), and heterodimers (different receptor types). The existence of these homodimers and heterodimers has been shown in cultured cells and in vivo. Among opioid receptors (μ, δ, κ, and nociception receptors), various combinations of the molecules have been shown to form dimers, and the dimer formation has been shown to affect the ligand binding properties and signal transduction mechanisms. Physiologic and clinical implications of dimer formation of opioid receptors will be further clarified. For example, it is interesting that a bivalent ligand containing μ-agonist and δ-antagonist pharmacophores effectively bridges μ-δ opioid receptor heterodimers and exhibits enhanced efficacy and a reduced tendency for tolerance in mice. However, in the peripheral nervous system, μ and δ receptors are apparently expressed in different sensory neuronal subpopulations.

Taken together, the overwhelming evidence of opioid receptor diversity in structure, ligand binding, and distribution supports the concept they serve both essential and complex signaling roles throughout the nervous system.

Genetic Variations Which Influence Opioid Effects

Several single nucleotide polymorphisms (SNPs) have been identified in the human μ-opioid receptor gene ( Fig. 24.5 ). The A118G mutation, the most common of these SNPs, leads to a change in the gene product in the human μ-opioid receptors, which is an A-to-G substitution in exon 1 that results in an amino acid exchange at position 40 from asparagine to aspartate (N40D). Patients with cancer who are homozygous for the A118G variant required higher doses of oral morphine for long-term treatment of their pain. A118G mutation of the human μ-opioid receptor gene reduces analgesic responses to morphine-6-glucuronide (M6G), but it does not significantly affect the respiratory depression induced by M6G. Furthermore, morphine consumption with intravenous PCA after total abdominal hysterectomy is significantly greater in women homozygous for the A118G variant than in other patients. In a meta-analysis involving 18 studies and more than 4600 patients, carriers of A118G were observed to exhibit higher opioid analgesic requirements. Another meta-analysis showed significant association between A118G polymorphism and susceptibility to opioid dependence or addiction in Asian populations.

Reported mutations in the μ-opioid receptor related to the exonic organization of the gene . Twenty-four mutations that produce an amino acid exchange and are frequently reportedly (>1%) or are proposed to have functional consequences are indicated in the gene. Amino acids are symbolized as circles, colored according to the exons by which they are coded. Black circles represent a naturally occurring mutation at the respective position, and red circles when functional consequences are shown at molecular level. Mutations are indicated by the nucleotide exchange and the resulting amino acid exchange.

From Lötsch J, Geisslinger G. Are μ-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med . 2005;11:82–89.

In vitro experiments show that the variant receptors with A118G mutation are associated with higher binding affinity to and potency of β-endorphin, but lower potency of morphine. Studies in mouse models with analogous substitution of human A118G showed reduced analgesic response to morphine in some regions of the mouse brain with the GG genotype when compared with the AA genotype. A study also showed that 118A messenger RNA was 1.5- to 2.5-fold more abundant than the 118G messenger RNA in heterozygous brain autopsy tissues.

Overall, these findings suggest that the 118G allele may result in changes in abundance and/or function of the μ-opioid receptor leading to differences in antinociceptive potency of opioid analgesics. This in turn could misdirect healthcare providers in providing the most effective and safe opioid-based analgesic plan.

The C17T mutation of the human μ-opioid receptor, located in exon 1, causes an amino acid exchange from alanine to valine at receptor protein position 6 of the extracellular receptor terminal. This mutation has been reported to occur in a higher overall proportion of opioid-dependent persons, but the effects of the C17T polymorphism on analgesic responses are unknown. A recent study using cultured cells reported that adenylate inhibition via the C17T polymorphism was decreased for many opioids, including the clinically significant drugs morphine, buprenorphine, and fentanyl, as well as endogenous opioids, suggesting that this polymorphism may affect individual responses to opioid therapy, while the possible disruption of the endogenous opioid system may contribute to susceptibility to substance abuse.

It is known that genetic variation of genes other than opioid receptor genes can affect sensitivity to opioids. It has been demonstrated that the Val158Met polymorphism of the human catechol- O -methyltransferase (COMT) gene has contributed to differences in opioid consumption in patients treated for chronic cancer pain, and is associated with variability in opioid consumption in postoperative nephrectomy patients. COMT metabolizes biogenic amines including catecholamines such as dopamine, epinephrine, and norepinephrine, thereby acting as a key modulator of dopaminergic and adrenergic neurotransmission, and can affect the pharmacologic effects of opioids. Some studies have explored the relationship between gene-gene interactions and opioid responses. Kolesnikov and associates have demonstrated that the heterozygous patients with μ-opioid receptor A118G and COMT G1974A mutation consumed significantly less morphine compared with homozygous patients of A118. As investigation into the clinical impact of genetic variability continues, it is revealing that even greater complexity exists between gene-gene interactions and postoperative morphine consumption.

Endogenous Opioid Peptides

Enkephalin, β-endorphin, and dynorphin were identified as endogenous agonists for the δ-, μ-, and κ-opioid receptors, respectively. Following purification of these peptides from mammalian tissues, cDNAs for the precursors of these peptides were cloned. cDNA cloning and amino acid determination of preproopiomelanocortin demonstrated that the cleavage of this precursor protein produces not only β-endorphin but also several other neuropeptides including methionine-enkephalin, adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone. Amino acid sequence of preproenkephalin indicates that four methionine enkephalins and one leucine-enkephalin are cleaved from this precursor. Furthermore, the primary structure of preprodynorphin, the precursor of dynorphin, gives rise to dynorphin, leumorphin, and neoendorphin—ligands for the κ-opioid receptor.

Orphanin FQ or nociceptin, a novel endogenous opioid peptide with a significant sequence homology to dynorphin, was isolated in 1995 and so named because it lowered pain threshold under certain conditions in contrast to other endogenous opioid peptides. Pharmacologic and physiologic studies have demonstrated that orphanin FQ/nociceptin has behavioral and pain modulatory properties distinct from those of the three classic opioid peptides. However, studies of the effect of orphanin FQ/nociceptin on pain sensitivity have produced conflicting results, which may suggest that the effects of orphanin FQ/nociceptin on pain sensitivity depend on the underlying behavioral state of the animal. Prepronociceptin, the precursor of orphanin FQ/nociceptin, was cloned, and its amino acid sequence suggested the existence of prepronociceptin-derived neuropeptides other than orphanin FQ/nociception.

The search for endogenous ligand binding with the μ receptor with high affinity and high selectivity led to the discovery of a class of novel endogenous opioids termed endomorphin-1 and endomorphin-2. These peptides are tetrapeptides with the sequence Tyr-Pro-Trp-Phe and Tyr-Pro-Phe-Phe, respectively. An endomorphin gene has yet to be cloned, and much remains to be learned about the anatomic distribution, mode of interaction with the opioid receptors, function in vivo, and potential existence of other related peptides that are highly selective for each of the opioid receptors. It was recently demonstrated that both endomorphin-1 and endomorphin-2 given centrally and peripherally produced potent antiallodynic activities in a mouse model of neuropathic pain, and downregulation of endomorphin-2 correlates with mechanical allodynia in a rat bone cancer pain model.

Intracellular Signal Transduction Mechanism of Opioid Receptors

The opioid receptors belong to the G-protein-coupled receptor family. It has been demonstrated that activation of the opioid receptors leads to activation of the pertussis toxin-sensitive G proteins (G _i or G _o or both). Expression of the cloned opioid receptors in cultured cells by transfection of the cloned cDNAs has facilitated analysis of the intracellular signal transduction mechanisms activated by the opioid receptors ( Fig. 24.6 ). Adenylate cyclase is inhibited by opioid receptor activation, with a resulting reduction of the cellular cyclic adenosine monophosphate (AMP) content. Electrophysiologically, the voltage-gated Ca ²⁺ channel is inhibited and the inwardly rectifying potassium (K ⁺ ) channels are activated by the opioid receptors. As a result, neuronal excitability is reduced by activation of the opioid receptors. However, the role of adenylate cyclase in opioid receptor activation is complex. For example, long-term tolerance to opioids has been thought to be associated with superactivation of adenylyl cyclase activity, which is a counterregulatory response to the decrease in cyclic AMP levels seen after acute opioid administration. That this effect is prevented by pretreatment of cells with pertussis toxin demonstrates involvement of G proteins (G _i or G _o or both).

Intracellular signal transduction mechanisms linked with the opioid receptors . Opioid agonists bind with the opioid receptors, leading to activation of the G protein. Activity of adenylate cyclase and the voltage-dependent calcium (Ca ²⁺ ) channels is suppressed. On the other hand, inward rectifier potassium (K ⁺ ) channels and mitogen-activated protein kinase (MAPK) cascade are activated. AMP , Adenosine monophosphate; ATP , adenosine triphosphate.

Beyond adenylate cyclase, other regulatory components participate in the coupling of opioid receptor binding and a cellular response. It was shown that extracellular signal-related kinase, a class of mitogen-activated protein kinases, is activated by the opioid receptors. Opioid-induced activation of extracellular signal-related kinase can lead to increase in arachidonate release and expression of immediate early genes, c-fos and junB.

Chronic exposure of the opioid receptors to agonists induces cellular adaptation mechanisms, which may be involved in opioid tolerance, dependence, and withdrawal symptoms. Several investigators have shown that short-term desensitization probably involves phosphorylation of the opioid receptors through protein kinase C. A number of other kinases also have been implicated, including protein kinase A and β-adrenergic receptor kinase (BARK), a member of the G-protein-coupled receptor kinase (GRK). BARKs selectively phosphorylate agonist-bound receptors and thereby promote interactions with β-arrestins, which interfere with G-protein coupling and promote receptor internalization. β-Arrestin 2 functions as a scaffolding protein that interacts with signal transducers, and the recruitment of β-arrestin 2 induced by opioid receptor activation is involved in the regulation of activity of c-Src, Akt, and mitogen-activated protein kinases ( Fig. 24.7 ). The c-Src inhibitor, dasatinib, attenuated and reversed morphine-induced tolerance in mice, suggesting that c-Src recruited by β-arrestin 2 is involved in the morphine-induced tolerance. Acute morphine-induced analgesia was enhanced in mice lacking β-arrestin 2, suggesting that this protein contributes to regulation of responsivity to opioids in vivo. Therefore, β-arrestin modification by associated kinases serves a critical role in the coupling between agonist binding to opioid receptors and their ability to develop and sustain an analgesic response.

β-Arrestin 2 and G protein in μ-opioid receptor recycling, signaling, and degradation . The blue star represents an opioid agonist and the trimeric membrane-associated complex in brown , green , and blue represents G protein α, β, and γ subunits, respectively. The α subunit is shown associated with guanosine diphosphate ( GDP ; resting state) or guanosine triphosphate ( GTP ; activated state). The βγ dimer interacts directly with the voltage-activated Ca ²⁺ channel to inhibit calcium (Ca ²⁺ ) influx (indicated in yellow ). β-arr2, β-arrestin 2; GRK , G-protein-coupled receptor kinase; MAPK , mitogen-activated protein kinase; PO ₄ -ase , phosphatase.

From Hales TG. Arresting the development of morphine tolerance and dependence. Br J Anaesth . 2011;107:653–655.

Like other G-protein-coupled receptors, the opioid receptors can undergo rapid agonist-mediated internalization by a classic endocytic pathway. These processes may be induced differentially as a function of the class of the ligand. For example, certain agonists, such as etorphine and enkephalins, cause rapid internalization of the μ receptor, whereas morphine, which decreases adenylyl cyclase activity equally well, does not cause μ receptor internalization in all cell types such as HEK293 cells. Although these findings may suggest that different ligands induce different conformational changes in the receptor that lead to divergent intracellular events, they also have revealed that rapid morphine–dependent μ receptor endocytosis is still possible in subpopulations of central nervous system (CNS) neurons such as striatal neurons. Taken together, they may help provide an explanation for differences in the efficacy and abuse potential of various opioids.

Biased Agonism

Chemically distinct ligands binding to the same G-protein–coupled receptor can stabilize the receptor in multiple active conformations. In this way, differential activation of G-protein–coupled cell signaling pathways may produce divergent physiologic outcomes, a phenomenon known as biased agonism. Biased agonism can be exploited to design drugs that selectively activate desired signaling pathways, while minimizing other signaling pathways via the same receptor subtype and associated side effects.

Morphine binds to the μ-opioid receptor protein to form an active complex with signaling proteins, including G _i/o and β-arrestin. The G _i/o signaling pathway is thought to mediate analgesic action of morphine, whereas β-arrestin signaling results in unwanted side effects including euphoria, which can lead to addiction, respiratory depression, and gastrointestinal effects. Consistently, it was shown that the analgesic properties of morphine were enhanced but morphine-induced respiratory depression and constipation were attenuated in β-arrestin 2 knockout mice. Emerging research in this evolving field includes a report by Manglik and associates, who computationally screened 3 million molecules, resulting in the compound PZM21, which showed high G _i/o -biased signaling and suppressed pain in mice without constipation, respiratory depression, hyperlocomotion, and addiction–related behaviors. The clinical importance of these findings awaits further confirmation given other reports showing little difference in adverse effect profiles between morphine and PZM21 in mice. However, TRV130, a “G protein-biased” μ-opioid ligand with G-protein–coupling efficacy similar to that of morphine, but markedly reduced receptor phosphorylation, recruitment of β-arrestin 2, and internalization, was tested in a randomized, double-blind, placebo-controlled crossover study in healthy volunteers. TRV130 produced greater analgesia than morphine, but less respiratory depression and less severe nausea ( Fig. 24.8 ). As additional biased-agonist candidates of the μ-opioid receptor emerge, so does the hope for a new generation of clinically effective analgesics with a reduced profile of harm.

Biased agonism . (A) Morphine binding to the μ-opioid receptor not only activates the G protein (G _i/o ) analgesic effect, but also recruits β-arrestins, which inhibits G protein coupling and promotes hypoventilation and gastrointestinal dysfunction. (B) TRV130 , a G protein–biased agonist, engages G-protein coupling similarly to morphine but with less β-arrestin recruitment, resulting in analgesic effect similar to morphine and less effects on respiratory and gastrointestinal function.

Mechanism of Opioid Analgesia

Mechanism of Mood Alterations and Rewarding Properties

The mechanisms by which opioids produce euphoria, tranquility, and other alterations of mood (including rewarding properties) remain an area of active investigation, especially given the expanding scope of opioid diversion and misuse. Behavioral and pharmacologic evidence points to the role of dopaminergic pathways, particularly involving the nucleus accumbens (NAcc), in drug-induced reward. Functional magnetic resonance imaging studies demonstrated that a small intravenous dose (4 mg) of morphine induces positive signal changes in reward structures, including the NAcc, sublenticular extended amygdala, orbitofrontal cortex, and hippocampus, and decreases signal in cortical areas similar to the action of sedative-hypnotics such as propofol and midazolam. These observations are consistent with results of pharmacologic studies.

The shell of the NAcc is the site that may be involved directly in the emotional and motivational aspects of drug-induced reward. All three opioid receptor types are present on the NAcc and are thought to mediate, at least in part, the motivational effects of opioid drugs. Selective μ- and δ-receptor agonists are rewarding when defined by place preference and intracranial self-administration paradigms. Conversely, selective κ-receptor agonists produce aversive effects. Positive motivational effects of opioids are partially mediated by dopamine release at the level of the NAcc.

The locus ceruleus contains both noradrenergic neurons and high concentrations of opioid receptors and is postulated to play a critical role in feelings of alarm, panic, fear, and anxiety. Neural activity in the locus ceruleus is inhibited by both exogenous opioids and endogenous opioid peptides.

Analysis of Knockout Mice

The physiologic roles of the opioid receptors and endogenous opioid peptides have been investigated mainly by pharmacologic and physiologic methods. However, it has been difficult to analyze functional roles of these proteins. With analysis of knockout mice, in which a specific gene is inactivated by molecular biologic methods, additional insight into the physiologic role of the respective opioid receptors and/or endogenous opioid peptide precursors can be determined.

In the μ-receptor knockout mice, analgesia, the reward effect, and the withdrawal effect of morphine were lost. Morphine-induced respiratory depression was not observed in the μ-receptor knockout mice. Therefore, the μ-receptor is a mandatory component of the opioid system for morphine action. In the μ-receptor knockout mice, ketamine-induced respiratory depression and antinociception are diminished, a finding suggesting that ketamine interacts with the μ receptor to lead to these phenomena. Furthermore, minimum alveolar concentration (MAC) of sevoflurane was significantly higher in the μ-receptor knockout mice than wild-type mice, an observation suggesting the involvement of the μ receptor in the anesthetic potency of sevoflurane. The δ-receptor knockout mice displayed a markedly reduced analgesic effect of opioids selective for δ-receptors at the spinal cord level. However, at the supraspinal level, analgesia could be induced by δ-receptor agonists in δ-receptor knockout mice, a finding suggesting the existence of a second δ-like analgesic system. Disruption of the κ receptor abolished the analgesic, hypolocomotor, and aversive actions of the κ-receptor agonists and induced hyperreactivity in the abdominal constriction test; this finding indicates that the κ receptor is involved in the perception of visceral chemical pain. Using gene knockout mice, a pharmacologic study demonstrated that the antinociceptive effect of N ₂ O may not be mediated by μ-receptor ; rather N ₂ O exerts its antinociceptive action and reduces MAC of volatile anesthetics in mice through complex mechanisms including activation of the κ receptor and the descending inhibitory pathway in the spinal cord, whereas its hypnotic potency is not dependent on κ-receptor activation.

In the mice lacking β-endorphin, morphine induced normal analgesia, but naloxone-reversible stress-induced analgesia could not be observed. The preproenkephalin knockout mice were more anxious than wild-type mice, and males displayed increased offensive aggressiveness. The mutant mice showed marked difference from controls in supraspinal, but not in spinal, responses to painful stimuli.

Thus, the functional roles of individual components of the opioid system continue to be elucidated by analysis of knockout mice. The μ-opioid receptor continues to be recognized as a predominant signaling receptor for both the affective and antinociceptive action of opioid agonism.

Actions of Opioids on Targets Other than Opioid Receptors

Molecular pharmacologic analyses have shown that opioids can interact with molecules other than the opioid receptors. In cardiac myocytes, morphine can inhibit voltage-dependent sodium (Na ⁺ ) current in a naloxone-insensitive manner, a finding suggesting the existence of a signal transduction mechanism that is not dependent on the opioid receptors. Buprenorphine, a partial μ-opioid receptor agonist, also has a local anesthetic property and blocks voltage-gated Na ⁺ channels through the local anesthetic binding site. Meperidine is an agonist of both μ and κ receptors. In addition, meperidine can block voltage-dependent Na ⁺ channels in amphibian peripheral nerves, as well as in the Xenopus oocyte expression system. Furthermore, meperidine exerts agonist activity at the α _2B -adrenoreceptor subtype. Yamakura and associates have shown that high concentrations of opioids, including meperidine, morphine, fentanyl, codeine, and naloxone, directly inhibit the N -methyl- d -aspartate (NMDA) receptor expressed in Xenopus oocytes. Methadone is clinically used as a racemic mixture of the l and d isomers. The opioid-like activity of the racemate seems to be almost entirely the result of l -methadone, whereas d -methadone acts as an NMDA antagonist. The commercially available remifentanil solution (Ultiva), which contains glycine, directly activates the NMDA receptor expressed in Xenopus oocytes. Furthermore, an electrophysiologic study in rat spinal cord showed that remifentanil hydrochloride does not directly activate NMDA receptors, the NMDA current recorded after application of Ultiva is related to the presence of glycine, and the glycine-induced NMDA current is potentiated by application of remifentanil hydrochloride through a pathway involving the μ-opioid receptor. The serotonin type 3A (5-HT _3A ) receptor, which is directly and indirectly linked to gastrointestinal motility, visceral pain, nausea, and vomiting, is competitively inhibited by morphine and hydromorphone, as well as naloxone; however, fentanyl-like opioids did not significantly affect activity of the 5-HT _3A receptor. The mechanism for tramadol analgesia is complex and appears to be composed of two actions that include reuptake inhibition of the noradrenergic serotonergic system and activation of the μ-opioid receptor. Tramadol’s analgesic effect is only partially reversed by the μ-opioid receptor antagonist, naloxone. Furthermore, tramadol also acts as an agonist of transient receptor potential vanilloid-1 (TRPV1) heterologously expressed in cultured cells. Tramadol may activate TRPV1 in sensory neurons, followed by local release of vasoactive neuropeptides and marked desensitization of the afferent fibers. Inhibition of the nicotinic acetylcholine receptor by tramadol has also been reported. It remains to be clarified which of these “off-target” actions of opioids have physiologic or clinical implications.

Physiologic Role of Nociceptin/Orphanin FQ

Nociceptin or orphanin FQ is a 17-amino-acid peptide, the sequence of which resembles those of opioid peptides. Nociceptin or orphanin FQ precursor mRNA and peptide are present throughout the descending pain control circuits. In the spinal cord, nociceptin or orphanin FQ-receptor mRNA expression is stronger in the ventral horn than in the dorsal horn, but higher levels of ligand binding occur in the dorsal horn. Targeted disruption of the nociceptin or orphanin FQ receptor in mice had little effect on basal pain sensitivity in several measures, whereas targeted disruption of the N nociceptin or orphanin FQ precursor consistently elevated basal responses in the tail-flick test, findings suggesting an important role for nociceptin or orphanin FQ in regulating basal pain sensitivity. Intrathecal injections of nociceptin or orphanin FQ have been shown to be analgesic ; however, supraspinal administration has produced hyperalgesia, antiopioid effects, or a biphasic hyperalgesic-analgesic response. Nociceptin or orphanin FQ inhibits both pain-facilitating and analgesia-facilitating neurons in the RVM. The effects of nociceptin or orphanin FQ on pain responses appear to depend on the preexisting state of pain in the animal. Involvement of nociceptin or orphanin FQ in physiologic functions such as regulation of feeding, body weight homeostasis, and stress response, and in psychiatric disorders such as depression, anxiety, and drug or alcohol dependence has also been reported.

Systemic administration of nonpeptide nociceptin or orphanin FQ receptor agonists revealed that such compounds were effective analgesics in animal pain models. It was reported that a nociceptin or orphanin FQ receptor agonist, Ro64-6198, has antinociceptive and antiallodynic potency and efficacy without side effects of opioids such as itching, respiratory depression, and addiction in monkeys. As nociceptin or orphanin FQ and opioid receptor agonists modulate pain by different targets, combining both mechanisms may constitute a novel approach for the development of innovative analgesics. Cebranopadol, a newly synthesized compound possessing nociceptin or orphanin FQ and opioid receptor agonist activity, exhibits highly potent and efficacious antinociceptive and antihyperalgesic effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy). In a phase 1 clinical trial, it was shown that cebranopadol produced respiratory depression with a ceiling effect, in contrast to apnea produced by full μ-opioid receptor agonists.

Expression of opioid receptors on peripheral blood mononuclear cells is controversial. Williams and associates reported that human peripheral blood mononuclear cells express the nociceptin receptor, but not μ-, δ-, or κ-opioid receptors. Nociceptin, produced by the peripheral blood mononuclear cells, is involved in the control of immune functions.

Characteristics of The Analgesic Action of Opioids

In human beings, morphine-like drugs produce analgesia, drowsiness, changes in mood, and mental clouding. A significant feature of opioid analgesia is that it is not typically associated with loss of consciousness. When morphine in the same dose is given to a normal, pain-free individual, the experience may be unpleasant. The relief of pain by morphine-like opioids is relatively selective, in that other sensory modalities are not affected. Patients frequently report that the pain is still present, but that they feel more comfortable. It is also important to distinguish between pain caused by stimulation of nociceptive receptors and transmitted over intact neural pathways (nociceptive pain) and pain that is caused by damage to neural structures, often involving neural supersensitivity (neuropathic pain). Although nociceptive pain usually is responsive to opioid analgesics, neuropathic pain may respond poorly to opioid analgesics and require higher doses of drug.

The analgesic effects, as well as side effects, of opioids vary greatly among individuals. A pharmacogenomic twin study has shown that the interindividual variations in opioid effects are likely the result of genetic and environmental factors. Animal and human studies indicate the existence of sex-related differences in opioid-mediated behavior. Sarton and associates examined the influence of morphine on experimentally induced pain in healthy volunteers, and demonstrated the gender differences in morphine analgesia, with greater morphine potency but slower speed of onset and offset in women. In contrast, in a study examining interindividual variability in alfentanil analgesic sensitivity in experimental pain models in humans, no gender differences were detected. In a study examining the effects of genetic factors on pain sensitivity, it was shown that males had higher pain thresholds in both thermal skin pain and muscle pressure pain than females. The mechanism of the gender difference in pain sensitivity and opioid effects remains to be clarified.

The pharmacokinetic and pharmacodynamic characteristics of opioids often vary throughout the day, as demonstrated for oral morphine in chronic pain. The duration of intrathecal sufentanil analgesia exhibited a temporal pattern, with 30% variation throughout the day in women in the first stage of labor. Scavone and colleagues reported that the time of day of administration does not seem to influence duration of labor analgesia with spinal-epidural administration of fentanyl or with systemic hydromorphone administration. The potential impact of chronobiology on clinical practice is not clear, and research on the influence of circadian rhythms on the actions of opioids is warranted.

Some controversy remains regarding analgesia produced by peripheral actions of opioids. One review concluded from meta-analysis that intraarticularly administered morphine has a definite but mild analgesic effect. It may be dose dependent, and a systemic effect cannot be completely excluded. The addition of opioids in brachial plexus block improves the success rate and postoperative analgesia. In contrast, the addition of sufentanil may not prolong the duration of brachial plexus block.

Despite variations in effect ascribed to the type of pain stimuli, genetics, gender, time of administration, or site of action (central versus peripheral), opioids remain one of the most potent classes of analgesic drugs.

Effects of Opioids on Consciousness

Cortical acetylcholine originates in the basal forebrain and is essential for maintaining normal cognition and arousal. Injection of morphine to the substantia innominata or intravenous morphine administration significantly decreased acetylcholine release within the prefrontal cortex in the rat, and this effect may be the neurochemical basis of opioid-induced change in consciousness. Although unconsciousness in humans can be produced with high doses of opioids alone, opioid-based anesthesia can be unpredictable and inconsistent. Therefore, opioids are not suitable as sole intravenous induction agents. The anesthetic potential of opioids was tested by measurement of MAC. Fentanyl can reduce the MAC of isoflurane at skin incision in patients by at least 80%. The relationship between the plasma fentanyl concentration and reduction in MAC is not linear, and fentanyl has a sub-MAC ceiling effect on reduction of the MAC of isoflurane. The MAC of sevoflurane was also dose dependently reduced by fentanyl, with 3 ng/mL resulting in a 61% reduction in MAC. A ceiling effect was observed for MAC; 6 ng/mL fentanyl provided only an additional 13% reduction in the MAC of sevoflurane. Even potency ratios have been established for the “reduction of volatile anesthetic MAC” for most opioids such as sufentanil, fentanyl, remifentanil, and alfentanil. However, the MAC-reducing capabilities of the opioids are not complete; that is, these are not complete anesthetics. The opioids must be combined with other anesthetics to produce a “complete anesthetic.” Esmolol, a short-acting β ₁ -receptor antagonist, significantly decreased the MAC of isoflurane in the presence of alfentanil, although it did not significantly affect this parameter in the absence of alfentanil. The mechanism of the interaction is unknown. Epidural fentanyl infusion reduces the awakening concentration of isoflurane more than does intravenous fentanyl infusion despite the lower plasma concentration, possibly by modulating the afferent nociceptive inputs in the spinal cord.

The MAC that prevents movement in response to laryngoscopy and tracheal intubation in 50% of patients (MAC-TI) is higher than the MAC that prevents movement in response to surgical incision (MAC). The MAC-TI of sevoflurane was 3.55% and was reduced markedly to 2.07%, 1.45%, and 1.37% by the addition of fentanyl 1, 2, and 4 μg/kg, respectively, with no significant difference in the reduction between 2 and 4 μg/kg, thus showing a ceiling effect. The MAC that prevents sympathetic responses to surgical incision in 50% of patients (MAC-BAR) decreased with increasing concentrations of fentanyl in plasma, and the initial steep reduction followed by a ceiling effect.

The bispectral index (BIS) is often used to determine the level of consciousness under anesthesia. In the presence of fentanyl, alfentanil, remifentanil, or sufentanil, loss of consciousness occurred at a lower effect-site concentration of propofol and at a higher BIS value as compared with propofol alone. Furthermore, Wang and associates reported that infusion of remifentanil (0.1-0.4 μg/kg/min) did not significantly change the median effective concentration (EC ₅₀ ) of propofol necessary to lower the BIS value to 50 or less. These results suggest that the hypnotic effect of propofol is enhanced by analgesic concentrations of opioids without changes in the BIS value. Conversely, infusion of remifentanil (effect-site target concentrations of 0.25, 2.5, and 10 ng/mL), combined with propofol infusion adjusted to a BIS of approximately 60, dose dependently decreased the BIS, thus suggesting a sedative or hypnotic effect of remifentanil. Response surface analysis showed considerable synergy between opioids and hypnotics for sedation and suppression of responses to various noxious stimuli. In contrast to the effect of opioids administered during anesthesia on the BIS, the impact of chronic opioid use on BIS is unknown. It was recently reported that the end-tidal concentration of sevoflurane necessary to maintain the BIS under 50 was 0.84% for chronic opioid users who received a stable dose of oral morphine of at least 60 mg/day according to the morphine equivalent daily dose for at least 4 weeks, which was lower than for opioid-naïve patients (1.18%).

Opioids administered as a mainstay of postsurgical pain management can inhibit sleep on the first night after surgery. However, the effects of opioids on sleep and circadian rhythm are not clearly understood. A human study demonstrated that an overnight constant infusion of remifentanil inhibited rapid eye movement sleep without suppressing the nocturnal melatonin surge, findings that may suggest a minimal effect of opioids on the circadian pacemaker.

Taken together, perioperative opioids have consistently been shown to dose dependently reduce the MAC and are well known to synergize with hypnotics to produce sedation; however, their ability to effect the BIS may vary depending on the context of opioid administration.

Hallucination

Opioid-induced hallucination is an uncommon yet significant adverse effect of opioid treatment, frequently attributed to underlying psychiatric disease or personality disorder rather than a direct neurobiologic effect of opioids. Hallucinations attributed to opioids have been typically described as auditory, visual, or rarely, tactile hallucinations. Although many reports have cited morphine as the causative agent, there is no evidence that across a population, one particular class of opioid is associated with a lower incidence of hallucinations. Moreover, there are reports of fentanyl, methadone, tramadol, hydromorphone, buprenorphine, pentazocine, and/or oxycodone–associated hallucinations and/or changes in mental status. Nevertheless, accumulation of morphine metabolites, particularly morphine-3-glucoronide, has been linked to the development of neurologic phenomena. Many hypotheses have been advanced to explain the etiology of opioid-induced hallucinations. One common feature of these hypotheses involves opioid-induced dopamine dysregulation. Overactivation of the dopaminergic pathways is thought to result in auditory and visual hallucinations. The simplest treatment for opioid-induced hallucination is discontinuing opioid therapy if practical. There are reports describing the successful use of naloxone and κ-selective opioid antagonists in the treatment of hallucinations associated with schizophrenia, although such κ-selective agents are known to be associated with hallucinations in subjects or patients without a diagnosis of mental illness.

Electroencephalography

Increasing concentrations of inhaled anesthetics produce a continuum of electroencephalogram (EEG) changes and eventually result in burst suppression and a flat EEG. In contrast, a ceiling effect is reached with opioids. Once this ceiling has been obtained, increasing opioid dosage does not further affect the EEG.

Although the potency and rate of equilibrium between plasma and brain are different among opioids, the effects of fentanyl, alfentanil, sufentanil, and remifentanil are consistent ( Fig. 24.9 ). Small doses of fentanyl (2-5 μg/kg) produce minimal EEG changes, whereas higher doses (30-70 μg/kg) result in high-voltage slow (δ) waves suggesting a state consistent with anesthesia. Although transient isolated (usually frontotemporal) sharp wave activity can be observed after large doses of fentanyl and other opioids, it is not generalized. In a study examining the effect of morphine (3-10 mg) on EEG in patients (14.8 ± 2.8 years) who stayed overnight for pain relief after otologic surgery, it was demonstrated that morphine reduced high-frequency β ₁ (13.5-20 Hz) and β ₂ (20-30 Hz) EEG powers and decreased coherence between frontal and occipital β ₂ EEG activities compared to wakefulness and non–rapid eye movement sleep, indicating that morphine induced a deep sedative state ( Fig. 24.10 ). Khodayari-Rostamabad and associates studied the effect of remifentanil administration on resting EEG functional connectivity and its relationship to cognitive function and analgesia in healthy volunteers. Remifentanil administration was associated with significant changes in functional cortical connectivity, which seem to disrupt the complex cortical network subserving normal brain function and can have the potential to be a biomarker for the sedative effects of opioids.

Representative 4-s electroencephalogram (EEG) tracings during infusion of sufentanil (total dose shown in the right column ) . The awake baseline EEG consists of mixed β and α activity. At 1 minute, the EEG showed loss of β activity and the presence of primarily α waves (8-13 Hz). At 3.5 minutes, the EEG consisted of mixed θ (4-7 Hz) and δ (<4 Hz) waves, and at 4.0 min, it consisted of δ waves of high amplitude.

From Scott JC, Cooke JE, Stanski DR. Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology. 1991;74:34–42.

Impacts of morphine on electroencephalography (EEG) spectral content . EEG activity of a representative 30-s epoch and power spectrograms of C4-M1 (C4 = central electrode; M1 = mastoid electrode) derivation at baseline and after morphine administration. In a representative patient (A) and in the analyzed group data (B and C), high-frequency power (α, β ₁ , and β ₂ ) was decreased by morphine. Mean data for 10 patients showed that morphine decreased α ( P = .039, n = 10), β ₁ ( P = .003, n = 10), and β ₂ ( P = .020, n = 10) powers but did not change δ ₂ ( P = .375, n = 10), δ ₁ ( P = .922, n = 10), and θ ( P = .331, n = 10) powers. Data are shown as mean ± 95% CI. ∗mean values significantly different from baseline with a P < .05.

From Montandon G, Cushing SL, Campbell F, et al. Distinct cortical signatures associated with sedation and respiratory rate depression by morphine in a pediatric population. Anesthesiology. 2016;125:889–903.

As an effect-site measure, EEG can be employed to assess onset of drug action and drug potency ratios. The spectral edge and serum concentration are closely parallel for remifentanil, whereas a significant time lag is found for recovery of the spectral edge for fentanyl and sufentanil ( Fig. 24.11 ). In healthy volunteers, approximate entropy derived from a parietal montage showed significant correlation with remifentanil concentration, and it was shown to be appropriate for the assessment of the remifentanil effect on the EEG. Potency ratios based on EEG studies are similar to those obtained from studies determining the plasma drug levels of each opioid necessary to reduce the MAC of isoflurane by 50%. Overall, opioids produce dose-dependent changes in the EEG that can mimic those of volatile anesthetics, however opioids show a ceiling effect at higher doses.

Time course of spectral edge and serum opioid concentration . Fentanyl (A) and sufentanil (B) were infused at 150 μg/min and 18.75 μg/min, respectively. Remifentanil (C) was administered at 3 μg/kg/min for 10 minutes. The spectral edge changes lag behind the serum concentration changes in the case of fentanyl and sufentanil, whereas the spectral edge and serum concentration closely parallel in the cases of remifentanil.

From Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology . 1985;62:234–241; and Egan TD, Minto CF, Hermann DJ, et al. Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology . 1996;84:821–833.

Evoked Responses

Because opioids do not appreciably alter sensory-evoked potentials elicited at the posterior tibial or median nerve, sensory-evoked potentials can be used for spinal cord function monitoring during anesthesia using opioids. Although remifentanil produced dose-dependent reduction in auditory-evoked potentials, it was also reported that remifentanil infusion (target plasma concentrations of 1, 2, and 3 ng/mL) did not affect evoked potential amplitudes and latencies. In healthy human volunteers receiving 3 μg/kg fentanyl, amplitude and latency of motor-evoked responses to transcranial stimulation were not significantly affected. This is consistent with the report by Kawaguchi and colleagues that intraoperative myogenic motor-evoked potential monitoring is feasible during isoflurane or sevoflurane anesthesia with fentanyl.

Middle latency auditory-evoked potentials (MLAEPs) and their derivatives are increasingly used as a surrogate measure of the level of anesthesia. Changes in MLAEPs following the administration of opioids occur and may result from either a direct depressant effect of opioids on MLAEPs itself or an indirect effect reflecting the action of opioids in attenuating CNS arousal associated with noxious stimuli. Wright and associates examined the effect of remifentanil (1 or 3 μg/kg/min) on MLAEPs in tracheally intubated and nonintubated patients and showed that remifentanil has an effect on MLAEPs in attenuating the arousal associated with tracheal intubation but had no effect in the absence of a stimulus. Similarly, Schraag and associates found no significant contribution of remifentanil alone on MLAEPs, whereas increasing the concentration of remifentanil led to a significant decrease of the calculated propofol effect-site concentrations necessary for unconsciousness.

Cerebral Blood Flow and Cerebral Metabolic Rate

Opioids generally produce modest decreases in cerebral metabolic rate and intracranial pressure (ICP), although the changes are influenced by the concomitant administration of other agents and anesthetic drugs, as well as by the patients’ conditions. When vasodilation is produced by coadministered anesthetics, opioids are more likely to cause cerebral vasoconstriction. Opioids also decrease cerebral blood flow (CBF) when they are combined with nitrous oxide (N ₂ O). When opioids are administered alone or when the coadministered anesthetics cause cerebral vasoconstriction, opioids usually have no influence or result in a small increase in CBF.

Endogenous opioid activity is present in the cerebral arteries, although exogenously administered opioids were found to exert little effect on pial artery diameter in several animal models. In the piglet, fentanyl, alfentanil, and sufentanil decreased arteriolar diameter in a dose-dependent naloxone-reversible manner. In human volunteers, PET demonstrated that CBF changes induced by fentanyl are regionally heterogenous.

In healthy volunteers, sufentanil (0.5 μg/kg intravenously [IV]) produces no significant effect on CBF. Alfentanil (25-50 μg/kg IV), administered to patients receiving isoflurane (0.4%-0.6%)-N ₂ O anesthesia, produces minimal reductions in middle cerebral artery flow velocity. A PET study in human volunteers showed that remifentanil induced dose-dependent changes in relative regional CBF in areas involved in pain processing, such as the lateral prefrontal cortex, inferior parietal cortex, and supplementary motor area. In patients scheduled to undergo a supratentorial tumor surgical procedure and receiving N ₂ O, remifentanil (1 μg/kg/min), similar to fentanyl (2 μg/kg/min), reduced CBF and did not significantly affect cerebrovascular carbon dioxide (CO ₂ ) reactivity.

Opioid-induced neuroexcitation and focal seizure activity can cause regional increases in brain metabolism. Regional increases in glucose use induced by high doses of alfentanil in the rat were associated not only with epileptiform activity but also with neuropathic lesions. In humans, PET evaluation demonstrated that a 1 to 3 μg/kg/min infusion of remifentanil induces significant increase in the cerebral metabolic rate for glucose. In summary, opioids, in general, do not significantly effect measures of CBF.

Intracranial Pressure

Opioids are generally thought to affect ICP minimally under conditions of controlled ventilation. When given with background anesthesia (isoflurane-N ₂ O), opioids do not cause significant increases in ICP undergoing craniotomy for supratentorial space-occupying lesions. Opioid sedation does not alter ICP in patients with head injuries. Light sedation with remifentanil (4.2 ± 1.8 μg/kg/h) does not result in higher ICP than that observed with propofol (4.3 ± 2.5 mg/kg/h) in patients undergoing stereotactic brain tumor biopsy, and cerebral perfusion pressure might be better preserved with remifentanil.

Opioids may produce increases in ICP in patients undergoing craniotomy for excision of supratentorial space-occupying lesions, especially if intracranial compliance is compromised. In a study of patients with severe head injury who have preserved and impaired autoregulation, morphine (0.2 mg/kg) and fentanyl (2 μg/kg) moderately increased ICP, a finding suggesting that mechanisms other than vasodilation could be implicated in the opioid-induced ICP elevation. Investigators also demonstrated no change in ICP in hydrocephalic children after administration of alfentanil (70 μg/kg). Whether these discrepancies of the opioid effects on ICP reflect pressure assessment methods or the effects of other drugs is not clear. If opioids do increase ICP, whether cerebrovascular dilatation is directly induced by opioids or indirectly resulted from opioid-induced decrease in blood pressure is not known.

Neuroprotection

Although certain early studies suggested potentially adverse effects of μ-opioid agonists on ischemic brain, other studies documented that certain opioid agents, such as the κ-agonists, can be neuroprotective in animal models of focal ischemia. Investigators also showed that activation of δ-opioid receptors increases survival time of mice during lethal hypoxia. An in vitro study using rat cerebellar brain slices demonstrated that pretreatment with morphine at clinically relevant concentrations induced acute neuroprotection mediated by activation of the δ ₁ -opioid receptors, activation of adenosine triphosphate (ATP)-sensitive K ⁺ channels, and free radical production in mitochondria. In the rat focal ischemia model, fentanyl neither increased nor decreased brain injury compared with awake unanesthetized rats. It was demonstrated that at a supraclinical concentration remifentanil had no pronecrotic effect but exerted ex vivo antiapoptotic action on the immature mouse brain, involving the opioid and NMDA receptors, and the mitochondrial-dependent apoptotic pathway. A recent study reported that κ-opioid receptors were upregulated and played a critical role in brain ischemia and reperfusion in mice, and that κ-opioid receptor activation could potentially protect the brain and improve neurologic outcome via blood-brain barrier protection, apoptosis reduction, and inflammation inhibition. Although there is contradicting evidence for a potential neuroprotection in animal models, there is no clear evidence for neuroprotective effects in humans.

Muscle Rigidity

Opioids can increase muscle tone and may cause muscle rigidity. The incidence of rigidity noted with opioid anesthetic techniques varies greatly because of differences in dose and speed of opioid administration, the concomitant use of N ₂ O, the presence or absence of muscle relaxants, and the patient’s age. Opioid-induced rigidity is characterized by increased muscle tone that sometimes progresses to severe stiffness and associated clinical challenges ( Table 24.4 ). Clinically significant opioid-induced rigidity usually begins just as, or after, a patient loses consciousness. Mild manifestations of rigidity, such as hoarseness, can occur in conscious patients. Vocal cord closure is primarily responsible for the difficult ventilation with bag and mask that follows the administration of opioids. Although opioids are generally thought to affect ICP minimally, it was demonstrated that alfentanil-induced rigidity can cause increase in ICP in rats. Delayed or postoperative rigidity may be related to second peaks that can occur in plasma opioid concentrations, similar to the recurrence of respiratory depression.

The precise mechanism by which opioids cause muscle rigidity is not clearly understood. Muscle rigidity is not the result of a direct action on muscle fibers because it can be decreased or prevented by pretreatment with muscle relaxants. Mechanisms of opioid-induced muscle rigidity involving the CNS have been postulated. The nucleus raphe pontis within the reticular formation and the caudate nucleus within the basal ganglia have been implicated mechanistically. Pharmacologic investigation using selective agonists and antagonists suggests that systemic opioid-induced muscle rigidity is primarily caused by the activation of central μ-receptors, whereas supraspinal δ ₁ and κ ₁ receptors may attenuate this effect. Some aspects of opioid-induced catatonia and rigidity (increased incidence with age, muscle movements resembling extrapyramidal side effects) are similar to Parkinson disease and suggest similarities in neurochemical mechanisms. Patients with Parkinson disease, particularly if they are inadequately treated, may experience reactions such as dystonia following opioid administration.

Pretreatment with or concomitant use of nondepolarizing muscle relaxants can decrease the incidence and severity of rigidity. Opioid-induced muscle rigidity can also be reversed with the μ-receptor antagonist naloxone. Induction doses of sodium thiopental and subanesthetic doses of diazepam and midazolam can prevent, attenuate, or successfully treat rigidity.

Neuroexcitatory Phenomena

Fentanyl causes seizure activity seen on the EEG in animals, but EEG evidence of seizure activity after fentanyl, alfentanil, or sufentanil is generally lacking in humans. Remifentanil induced generalized tonic-clonic seizure-like activity in an otherwise healthy adult. Morphine produces tonic-clonic activity after epidural and intrathecal administration. Focal neuroexcitation on the EEG (e.g., sharp and spike wave activity) occasionally occurs in humans after large doses of fentanyl, sufentanil, and alfentanil.

The mechanisms underlying opioid-induced neuroexcitatory phenomena are not completely clear. Excitatory opioid actions may be related to coupling to mitogen-activated protein kinase cascades. Local increases in CBF and metabolism are also of theoretic concern because prolonged seizure activity, even if focal, could lead to neuronal injury and/or cellular death. Fentanyl, alfentanil, and sufentanil in large doses also induced hypermetabolism and histopathologic alterations of the limbic system in rats. Experimental study using excised mouse hippocampus showed that the proseizure effect of morphine is mediated by selective stimulation of the μ- and κ-opioid receptors but not the activation of the δ-opioid receptor. In rats, midazolam, naloxone, and phenytoin prevented EEG seizure activity and histologically evident brain damage induced by large doses of fentanyl.

Measurement of CBF by magnetic resonance imaging in human volunteers indicated that the cingulate cortex is the most susceptible to activation by remifentanil (0.05-0.2 μg/kg/min), and susceptibility is affected by the apolipoprotein E genotype. These findings support the notion that neuroactivation of limbic areas by the perioperative use of opioids may have a role in the genesis of postoperative cognitive dysfunction.

Pupil Size

Morphine and most μ− and κ−agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. Light induces excitation of the Edinger-Westphal nucleus leading to pupillary constriction, which is inhibited by hypercarbia, hypoxia, and nociception. Opioids release the effect of inhibitory neurons on the Edinger-Westphal nucleus, resulting in papillary constriction ( Fig. 24.12 ). After intravenous administration of morphine (0.125 mg/kg) in one report, a 26% decrease in pupil diameter occurred at 1 hour, and a period of more than 6 hours was necessary for complete recovery of pupil diameter. The pupillary dilatation reflex has been successfully used to assess the analgesic component of a balanced anesthetic regimen. The pupillometer may be a valuable tool to guide morphine administration in the immediate postoperative period. A prospective randomized study evaluated the impact of intraoperative pupillometry monitoring on perioperative opioid consumption in major gynecologic surgery. It was demonstrated that the use of pupillometry to guide intraoperative analgesia reduced intraoperative remifentanil consumption and postoperative morphine requirements. Pupillary unrest is the fluctuation in pupil diameter, and pupillary unrest under ambient light (PUAL) is present even in well-rested individuals. Although the underlying mechanisms are unknown, PUAL is depressed by opioids. Administration of fentanyl to healthy volunteers diminishes PUAL, and the decrease is proportionally larger than the change in pupil diameter. The pretreatment magnitude of PUAL is correlated with the analgesic response to opioid therapy, and patients who exhibit higher levels of PUAL change after opioid administration have a more beneficial analgesic effect from opioids.

Pathways and nerve centers that control pupil size and the pupillary light reflex in humans . Colored structures are the central nerve centers and pathways that modify the pupillary light reflex. Edinger-Westphal (E.W.) nucleus neurons are pacemaker cells that are modified by excitatory and inhibitory inputs. Opioids block the inhibition of the EW nucleus. Green asterisks (∗) show locations where hypercarbia, hypoxia, and opioids might potentially interfere with the light reflex. ∗ = locations where hypercarbia, hypoxia, and opioids might potentially interfere with the light reflex. IN , Inhibitory neuron.

From Rollins MD, Feiner JR, Lee JM, et al. Pupillary effects of high-dose opioid quantified with infrared pupillometry. Anesthesiology . 2014;84:1037–1044.

Pupillary constriction represents a well-known phenomenon following opioid administration and the use of pupillometry may help guide intraoperative opioid dosing to optimize analgesia.

Thermoregulation and Shivering

Opioid-based anesthesia probably reduces thermoregulatory thresholds to a degree similar to that of the potent inhaled anesthetics. However, meperidine is unique among opioids in its ability to effectively terminate or attenuate shivering. The antishivering effect of meperidine is primarily related to a reduction in the shivering threshold, and seems to be mediated by meperidine’s activity on the κ receptor. However, the relatively specific κ-receptor agonist, nalbuphine, did not show significant antishivering activity. Meperidine exerts agonist activity at the α _2B -adrenoreceptor subtype, a finding suggesting the involvement of this action in the antishivering action of meperidine. Alfentanil, morphine, and fentanyl are not as effective as meperidine in the treatment of postoperative shivering. However, alfentanil and nefopam, a centrally acting analgesic, additively reduce the shivering threshold in humans. Tramadol (0.5 mg/kg) suppressed postepidural anesthetic shivering in parturients as effectively as meperidine (0.5 mg/kg). A quantitative systematic review of randomized controlled trials found that meperidine 12.5 to 35 mg and tramadol 35 to 220 mg were more effective than control for parenteral pharmacologic interventions for the prevention of postoperative shivering.

Remifentanil is associated with an increased incidence of postanesthetic shivering, which is not related with intraoperative hypothermia. The higher incidence of postanesthetic shivering with higher doses of remifentanil probably reflects acute opioid tolerance and stimulation of the NMDA receptors. A small dose of ketamine, 0.5 mg/kg at induction of anesthesia followed by infusion at 0.3 mg/kg/hour, can prevent remifentanil-induced postanesthetic shivering.

Pruritus

Opioid-induced pruritis is one of several perpetual challenges associated with opioid-based analgesia. With the possible exception of morphine, histamine release, once thought to underlie this phenomenon, is not causative because non-histamine-releasing opioids also produce pruritus. Both central and peripheral nervous system mechanisms have been explored. Facial itching may not necessarily be a manifestation of direct opioid action at the level of the trigeminal nucleus, but rather, it may be a reflection of opioid-triggered neural transmission at a distant site. It is not known why the face is prone to pruritus even after spinal opioids. Interestingly, pruritus due to cholestasis is ameliorated by opioid antagonists. Intrathecal morphine-induced itching in monkeys was suggested to be mediated by the μ receptor. Activation of a μ-opioid receptor isoform MOR1D by morphine induced activation of the gastrin-releasing peptide receptor that heterodimerized with MOR1D, thus resulting in activation of phospholipase β3 and intracellular Ca ²⁺ increase in neurons leading to itch sensation in mice.

Naloxone reverses opioid-induced itching, but opioid antagonists are not ideal therapeutic agents against pruritus because opioid analgesia is often reversed by these agents. A subcutaneous administration (12 mg) of methylnaltrexone bromide, a peripherally acting μ-opioid antagonist, did not reduce the overall severity or incidence of pruritus in women having elective cesarean section under spinal anesthesia with intrathecal morphine 100 μg, suggesting that peripheral mechanisms do not significantly contribute to spinal opioid-induced pruritus. Ondansetron, a serotonin 5-HT ₃ receptor antagonist has been proposed to treat spinal or epidural morphine-induced pruritus, and a metaanalysis has demonstrated that prophylactic use of 5-HT ₃ antagonists significantly reduced the severity and the need for treatment of pruritus. Another meta-analysis showed that prophylactic intravenous administration of 8 mg ondansetron does not decrease the incidence of fentanyl- or sufentanil-induced pruritus but may decrease the need for pruritus rescue medication. The application of mixed or partial opioid agonists, such as nalbuphine and butorphanol, are growing in popularity as antipruritics because they may partially antagonize μ receptor function with intact κ actions to maintain analgesia. In fact, activation of the κ-opioid receptor inhibits pruritus evoked by subcutaneous and intrathecal morphine in animal models.

Other agents that have been investigated include pentazocine (15 mg), an agonist of the κ-opioid receptor and partial agonist of the μ-opioid receptor. Pentazocine has been found to be superior to 4 mg of ondansetron for the treatment of pruritus induced by intrathecal morphine in parturients undergoing cesarean delivery. It was recently reported that the antipruritic effect of κ-receptor agonists may not require interaction between the κ receptor and β-arrestins. Tenoxicam, a nonsteroidal antiinflammatory drug (NSAID), was reported to be effective for pruritus induced by epidural fentanyl. Other approaches include intravenous administration of droperidol (1.25 mg), propofol (20 mg), or alizapride (100 mg), which reduced the incidence of pruritus induced by the use of morphine 0.2 mg intrathecally in patients undergoing cesarean section under spinal anesthesia. Preoperative gabapentin prevents pruritus induced by intrathecal morphine in patients undergoing lower limb surgery with spinal anesthesia.

As opioid-induced pruritis continues to be a clinical challenge, current strategies have shifted away from the consequences of histamine release (morphine) and are focused on exploiting partial blockade/activation of the μ-opioid receptor, activation of the κ-receptor, and non-opioid receptor pathways.

Opioid-Induced Hyperalgesia

There is growing evidence that opioid-induced hyperalgesia (OIH) can represent a major adverse effect of opioid administration, especially when driven by potent formulations and escalating dosages. Experimentally, opioids have elicited hyperalgesia in animal models after repeated opioid administration or continuous delivery. A systematic review to evaluate the clinical implication of OIH demonstrated that high intraoperative doses of remifentanil are associated with small but significant increases in acute pain after surgery as assessed by: pain intensity at rest 24 hours after surgery, 24-hour morphine use, pain intensity on movement, and hyperalgesia measured after an operation. In a randomized, double-blind, crossover study with 24 healthy male volunteers, it was demonstrated that when compared with low-dose (1 μg/kg) fentanyl, high-dose fentanyl (10 μg/kg) increased the area of hyperalgesia from 4.5 to 6.5 hours after fentanyl administration. This result suggests that fentanyl can also produce OIH in humans.

OIH was shown to be due to spinal sensitization to glutamate and substance P. Activation of glycogen synthase kinase-3β (GSK-3β) contributes to remifentanil-induced hyperalgesia by regulating NMDA receptor plasticity in the spinal dorsal horn, and further demonstrated that GSK-3β inhibition prevented remifentanil-induced postoperative hyperalgesia via regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression and function in the spinal dorsal horn. Importantly, abrupt withdrawal of opioid administration may also contribute to induction of OIH, although its mechanism is not clear. In contrast to the high incidence of hyperalgesia induced after abrupt withdrawal of remifentanil (administered at 2.5 ng/mL for 30 minutes), no hyperalgesia was observed after gradual withdrawal by 0.6 ng/mL every 5 minutes.

There have been reports that OIH and subsequent acute opioid tolerance can be prevented by ketamine, suggesting the involvement of the NMDA receptor. Methadone is unique in possessing both μ-opioid receptor activating and NMDA antagonist properties. Opioid-induced hyperalgesia resulted from the presence in the racemate of the l -methadone (μ-opioid agonist) and was antagonized by the presence of the d -methadone (NMDA antagonist). Low-dose buprenorphine (25 μg/h for 24 h), an opioid with NMDA antagonist activity, in patients receiving remifentanil infusion during major lung surgery prevented postoperative secondary hyperalgesia. Butorphanol (0.2 μg/kg) was also effective for prevention of postoperative hyperalgesia after laparoscopic cholecystectomy performed with remifentanil (0.3 μg/kg/min). N ₂ O, an inhalation anesthetic, is an effective NMDA antagonist. Intraoperative 70% N ₂ O administration significantly reduced postoperative opioid-induced hyperalgesia in patients receiving propofol (approximately 120 μg/kg/min) and remifentanil (0.3 μg/kg/min). A randomized, double-blind, prospective study showed that a relatively high dose of remifentanil (0.2 μg/kg/min) enhances periincisional hyperalgesia in patients undergoing thyroidectomy, and intraoperative magnesium sulfate (30 mg/kg at induction followed by 10 mg/kg/h) can prevent remifentanil-induced hyperalgesia.

Other strategies have focused on the upregulation of spinal cyclooxygenase-2 (COX-2) and increased prostaglandin E2 release in the spinal cord after morphine withdrawal in rats. In humans, hyperalgesia after a 30-minute intravenous infusion of remifentanil (0.1 μg/kg/min) can be prevented by administration of parecoxib, a COX-2 inhibitor, before remifentanil infusion, suggesting the involvement of COX-2 in OIH. Alternatively, it was reported that an ultra-low dose of naloxone blocked remifentanil-induced hyperalgesia but did not change opioid tolerance in rats under inhaled anesthesia, and that the MAC increase associated with hyperalgesia was also blocked by naloxone. In patients undergoing elective thyroid surgery, intraoperative use of naloxone (0.05 μg/kg/h) reduced postoperative hyperalgesia after remifentanil infusion of 4 ng/mL.

Genetic variants of the β ₂ -adrenergic receptor gene may explain some part of the differences between various strains of mice to develop OIH, and the selective β ₂ -adrenergic receptor antagonist butoxamine was shown to dose dependently reverse OIH. In mice, systemic or intrathecal injection of the 5-HT ₃ receptor antagonist, ondansetron, was shown to prevent or reverse opioid-induced tolerance or hyperalgesia.

Interestingly, the occurrence of OIH might be affected by general anesthetics coadministered with opioids. When women undergoing breast cancer surgery were anesthetized with sevoflurane or propofol to keep BIS value at 40 to 50, postoperative hyperalgesia induced by intraoperative remifentanil infusion (effect-site target 4 ng/mL) was significant with sevoflurane anesthesia, but not apparent with propofol anesthesia.

A follow-up study on the postoperative course of cardiac surgery demonstrated that intraoperative remifentanil was predictive for chronic thoracic pain 1 year after surgery in a dose-dependent manner. It can be anticipated that hyperalgesia during the perioperative period is linked to peripheral and central pain sensitization and thereby correlates with the development of postoperative chronic pain. This suggests that hyperalgesia due to remifentanil in the early postoperative period may explain the higher incidence of chronic pain.

Overall, human data generally support the existence of OIH in a few specific settings. Clinically relevant mechanisms of OIH include involvement of the NMDA receptor with ketamine as an appealing remedy. Although all potent opioids such as fentanyl are apparently capable of inducing OIH, ultrapotent opioid agonists such as remifentanil may pose even greater risks. The conditions under which OIH is expressed should be clarified and the extent of its clinical significance remains to be elucidated.

Effects on Airways

The antitussive actions of opioids are well known and central in origin. Opioids blunt or eliminate somatic and autonomic responses to tracheal intubation. They allow patients to tolerate endotracheal tube placement without coughing or “bucking.” Conversely, two successive doses of 1.5 μg/kg fentanyl did not effectively prevent laryngospasm in children aged 2 to 6 years old who were anesthetized with sevoflurane. Opioids can also help avoid increases in bronchomotor tone in asthma. In addition, fentanyl also has antimuscarinic, antihistaminergic, and antiserotoninergic actions and may be more effective than morphine in patients with asthma or other bronchospastic diseases.

Nevertheless, several studies have reported a depressant effect of morphine on respiratory mucus transport, which is one of the most important defenses against respiratory tract infections. However, morphine had no effect on the beating frequency of nasal cilia in vitro. Opioids can affect pharyngeal function, airway protection, and coordination of breathing and swallowing. A sedative dose of morphine (0.1 mg/kg) was associated with increased incidence of pharyngeal dysfunction and discoordinated breathing and swallowing, a combination impairing airway protection and potentially increasing the risk for pulmonary aspirations.

More potent opioids such as remifentanil (effect-site concentration of 2 ng/mL) can suppress coughing induced by extubation after propofol or sevoflurane anesthesia. In contrast, fentanyl, sufentanil, and alfentanil curiously elicit a brief cough in up to 50% of patients when the drug is injected by intravenous bolus. Fentanyl, administered through a peripheral intravenous cannula, provoked cough when it was injected rapidly, but the incidence of cough decreased significantly as the injection time was increased, as well as by the administration of 1.5 mg/kg lidocaine 1 minute before fentanyl administration. A meta-analysis showed that the lowest effective dose of lidocaine on the risk of opioid-induced cough was 0.5 mg/kg. It was also reported that preemptive use of fentanyl 25 μg, administered 1 minute before bolus injection of fentanyl (125 or 150 μg), can effectively suppress fentanyl-induced cough. Propofol, α ₂ agonists (clonidine, dexmedetomidine), inhalation of β ₂ agonists (terbutaline, salbutamol), and NMDA-receptor antagonists (ketamine, dextromethorphan) were also effective for suppression of fentanyl-induced cough. A prospective randomized controlled study demonstrated that a huffing maneuver, consisting of a forced expiration against open glottis, just before intravenous fentanyl administration significantly reduced the incidence and severity of fentanyl-induced coughing in the majority of the patients. Li and associates reported that nonsmoking women undergoing gynecological surgery who develop fentanyl-induced cough during induction of anesthesia have a higher incidence of postoperative nausea and vomiting (PONV).

In summary, opioids engender potent antitussive properties that can help blunt airway responsiveness to endotracheal intubation. However, depending on the class of opioid and rate of administration, they may evoke a brief cough that can be subverted through the use of preadministered agents such as lidocaine. Ultimately, caution should be exercised in the administration of opioids as they can also interfere with protective aspects of airway physiology.

Respiratory Depression

The lack of adequate pain relief can cause shallow respiration leading to postoperative respiratory dysfunction including atelectasis, and therefore opioids can serve as a foundational component of postoperative analgesia to prevent or correct respiratory impairment. However, opioids can also dose dependently depress respiration, representing the most feared adverse effect. The incidence of opioid-induced respiratory depression varies from 0.1% to 37%, depending on the route of opioid administration, the type of opioid, the definition and method of monitoring opioid-induced respiratory depression, and the prospective versus retrospective nature of the study, and is a significant cause of death and brain damage in the perioperative period.

Opioids activating the μ receptor cause dose-dependent depression of respiration, primarily through a direct action on brainstem respiratory centers. The stimulatory effect of CO ₂ on ventilation is significantly reduced by opioids. Hypercapnic responses can be separated into central and peripheral components. In one report, morphine-induced changes in the central component were equal in men and women, whereas changes in the peripheral component were larger in women. In addition, the apneic threshold and pressure of end-tidal carbon dioxide (PETCO ₂ ) are increased by opioids ( Fig. 24.13 ). Opioids also decrease hypoxic ventilatory drive.

Influence of morphine administration (bolus dose of 100 μg/kg given at the start of the infusion [0 minute], followed by a continuous infusion of 30 μg/kg/h) on resting inspired minute ventilation (V _i ) and resting pressure of end-tidal carbon dioxide (PETCO ₂ ) in a single subject. A one-component exponential was fitted to the data. The estimated time constant for the V _i data is 3.0 minutes and for PETCO ₂ data is 2.6 minutes. The time delays are between 1 and 2 minutes.

From Sarton E, Teppema L, Dahan A. Sex differences in morphine-induced ventilatory depression reside within the peripheral chemoreflex loop. Anesthesiology . 1999;90:1329–1338.

Respiratory rate is usually drastically decreased in opioid overdose, although hypoxic CNS insult can counter this effect. The prolonged expiratory time in the respiratory cycle induced by opioids frequently results in greater reductions in respiratory rate than in tidal volume. Monitoring of breath intervals can sensitively detect fentanyl-induced respiratory depression and can be used as a measure of dynamic opioid effect. High doses of opioids usually eliminate spontaneous respirations without necessarily producing unconsciousness. Patients receiving high doses of opioids may still be responsive to verbal command and often breathe when they are directed to do so.

Peak onset of respiratory depression after an analgesic dose of morphine is slower than after comparable doses of fentanyl, and respiratory depression induced by small doses of morphine usually lasts longer than after equipotent doses of fentanyl. Plasma fentanyl concentrations of 1.5 to 3.0 ng/mL are associated with significant decreases in CO ₂ responsiveness. With higher doses of fentanyl (50-100 μg/kg), respiratory depression can persist for many hours. When moderately large doses (20-50 μg/kg or greater) of fentanyl are used, the potential need for postoperative mechanical ventilation should be anticipated. The effects of remifentanil are attenuated rapidly and completely within 5 to 15 minutes following termination of its administration. In healthy humans, the EC ₅₀ for depression of minute ventilation with remifentanil and alfentanil was 1.17 ng/mL and 49.4 ng/mL, respectively. In healthy volunteers, fentanyl 1 μg/kg and remifentanil 0.5 μg/kg had similar maximum decreases in minute ventilation (∼50%), but the onset of and recovery from ventilatory depression were faster with remifentanil. Naloxone has been accepted as a standard therapy for opioid-induced respiratory depression. However, reports have noted naloxone-resistant respiratory depression after intrathecal morphine administration.

A major component of the excitatory synaptic drive necessary for respiratory rhythmogenesis and activation of respiratory motoneurons is via the amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type of glutamate receptors. This finding has led to investigations of ampakine (positive modulators of AMPA receptors) therapy to alleviate opioid-induced respiratory depression. 5-HT released from the raphe nuclei potently alters the excitability of respiratory motoneurons, the preBötzinger complex (preBötC), and other brainstem respiratory nuclei. The activation of 5-HT _1A receptors with befiradol alleviates fentanyl-induced respiratory depression in rats. PreBötC, the main region of respiratory rhythm–pattern generation, is the main target of opioid-induced respiratory depression. However, it has been demonstrated that preBötC partially mediates opioid effects on respiratory phase timing, but does not mediate the opioid-induced depression of respiratory rate. By the use of knockout mice and pharmacologic approaches, G-protein–gated inwardly rectifying κ channels were shown to contribute to respiratory depression by μ-opioid receptors and opioids. In healthy humans, GAL021, a calcium-activated potassium (BKCa) channel blocker possessing a stimulatory effect on ventilation at the carotid bodies, was preliminarily shown to reverse alfentanil-induced respiratory depression.

Factors Affecting Opioid-Induced Respiratory Depression

Many factors affect the magnitude and duration of opioid-induced respiratory depression ( Box 24.2 ).

Older patients are more sensitive to the anesthetic and respiratory depressant effects of opioids and experience higher plasma concentrations of opioids administered on a weight basis. In addition, morphine can produce greater respiratory depression on a weight basis in neonates than adults, because morphine easily penetrates the brain of neonates and infants with incomplete blood-brain barriers.

The respiratory depressant effects of opioids are increased or prolonged (or both) when these drugs are administered with other CNS depressants, including potent inhaled anesthetics, alcohol, barbiturates, benzodiazepines, most intravenous sedatives, and hypnotics. However, droperidol, scopolamine, and clonidine do not enhance the respiratory depressant effects of fentanyl or other opioids. Curiously, Setnik and associates observed a decrease in end-tidal CO ₂ when 0.7 g/kg ethanol was administered in addition to 80 mg oral morphine, suggesting a stimulatory effect of ethanol on opioid-induced respiratory depression. However, it was reported that ethanol (1 g/L of breath ethanol concentration) caused a significant increase in the apneic events and increased end-tidal CO ₂ induced by 20 mg oxycodone per os in opioid-naïve healthy volunteers.

Although opioid action is usually dissipated by redistribution and hepatic metabolism, rather than by urinary excretion, the adequacy of renal function may influence the duration of opioid activity. In renal insufficiency, the respiratory depressant properties of morphine and hydromorphone, as well as of the morphine metabolite M6G, become evident as these accumulate.

Hypocapnic hyperventilation enhances and prolongs postoperative respiratory depression after fentanyl (10 and 25 μg/kg). Intraoperative hypercarbia produces the opposite effects. Possible explanations for these findings include increased brain opioid penetration (increased un-ionized fentanyl with hypocarbia) and removal (decreased CBF with hypocarbia). In patients who hyperventilate because of anxiety or pain, even small doses of intravenous opioids can result in transient apnea because of acute shifts in apneic thresholds. Respiratory depression by remifentanil (50 μg infused over 60 seconds) was more pronounced in hyperoxia (inhaling 50% O ₂ ) than normoxia as determined by minute ventilation, end-tidal PCO ₂ , and respiratory rate. During hyperoxia, respiratory depression may be masked when measuring SpO ₂ as pulse oximetry remains in normal values during the first minutes of respiratory depression.

All opioid agonists with a longer plasma half-life than naloxone have a hypothetical potential to show renarcotization with time, especially when a bolus dose of naloxone is used to treat opioid-induced respiratory depression.

Overall, opioids exert their primary respiratory depressant effects through μ-receptor activation in the brainstem respiratory center, although other pathways have been defined. Dose-dependent opioid respiratory depression increases the apneic threshold, and reduces the respiratory stimulatory drive of CO ₂ and hypoxia. Research efforts to block or reverse opioid-induced respiratory depression are ongoing and include a focus on AMPA, 5-HT _1A , and calcium-activated potassium channels. The μ-receptor antagonist, naloxone, continues to be the most commonly used clinical intervention to reverse opioid-induced respiratory depression, however its effectiveness may be limited if the administered opioid has a greater binding affinity and/or half-life than naloxone.

Neurologic Mechanisms

Key areas of the brainstem that integrate cardiovascular responses and maintain cardiovascular homeostasis are the nucleus solitarius, the dorsal vagal nucleus, the nucleus ambiguous, and the parabrachial nucleus. The nucleus solitarius and parabrachial nucleus play an important role in the hemodynamic control of vasopressin secretion. Enkephalin-containing neurons and opioid receptors are distributed in these regions. The direct administration of μ-agonists into the CNS of rats most commonly, but not always, produces hypotension and bradycardia. The ventrolateral PAG region, a key central site mediating opioid analgesia, also affects hemodynamic control. In addition, opioids can modulate the stress response through receptor-mediated actions on the hypothalamic-pituitary-adrenal axis. Most opioids reduce sympathetic and enhance vagal and parasympathetic tone. Patients who are volume depleted, or individuals depending on high sympathetic tone or exogenous catecholamines to maintain cardiovascular function, are predisposed to hypotension after opioid administration.

The predominant and usual effect of opioids on heart rate is bradycardia resulting from stimulation of the central vagal nucleus. Blockade of sympathetic actions may also play a role in opioid-induced bradycardia. Meperidine, in contrast to other opioids, rarely results in bradycardia, but it can cause tachycardia. Tachycardia after meperidine may be related to its structural similarity to atropine, to normeperidine, its principal metabolite, or to early manifestations of its toxic CNS effects.

Cardiac Mechanisms

The direct cardiac actions of opioids, in particular the effects on myocardial contractile mechanisms, are significantly less pronounced than are those of many other intravenous and inhaled anesthetics. However, opioid receptors exist in cardiac myocytes of several species.

Histamine Release

It is well known that morphine causes histamine release and sympathoadrenal activation. Increases in plasma histamine after morphine cause dilation of terminal arterioles and direct positive cardiac chronotropic and inotropic actions. In patients pretreated with both H ₁ – and H ₂ -antagonists, the cardiovascular responses are significantly attenuated despite comparable increases in plasma histamine concentrations. Codeine and meperidine are examples of other opioids that can induce mast cell activation with the release of histamine, probably by a mechanism other than the μ-opioid receptors. Unlike morphine or meperidine, the opioids fentanyl, alfentanil, sufentanil, and remifentanil do not produce increases in plasma histamine, subsequently hypotension is less frequent with their administration.

Vascular Mechanisms

The pharmacologically defined opioid receptor subtype μ ₃ is expressed in human endothelial cells and coupled to vasodilation via nitric oxide (NO) production. Although μ ₃ is opiate alkaloid sensitive it is insensitive to opioid peptides including peptides previously shown to have affinities for the μ-opioid receptors. Morphine-induced vasodilation may be partially caused by activation of the μ ₃ receptor. Other pharmacologic studies evaluating alfentanil, fentanyl, and sufentanil in the dog also demonstrate direct peripheral vessel smooth muscle relaxation although exact mechanism(s) remains under study. For example, measurement of forearm blood flow after infusion of sufentanil into the brachial artery indicated that sufentanil has a direct vasodilatory effect on human vascular tissue that is likely independent of a neurogenic or systemic mechanism. A supraclinical dose of alfentanil attenuates the phenylephrine-induced contraction via an inhibitory effect on calcium influx by blocking the L-type calcium channels in the rat aortic vascular smooth muscle. Remifentanil can cause transient instability in hemodynamic variables. However, this change may not be solely the result of autonomic or central nervous system inhibition or of centrally mediated vagal stimulation. A pharmacologic study using rat thoracic aortic rings indicated that remifentanil vasodilates by an endothelium-dependent mechanism, involving prostacyclin and NO released from the endothelium, and an endothelium-independent vasodilation probably mediated by the suppression of voltage-sensitive Ca ²⁺ channels. In patients with a total artificial heart in which cardiac output is preload-independent, remifentanil induces a dose-dependent and significant systemic vasodilation without significant effects on capacitance vessels.

Opioids may affect the pulmonary vasculature as well as systemic circulation. It was shown that phenylephrine-induced contraction of canine pulmonary artery is primarily mediated by α _1B -adrenergic receptor activation, and is attenuated by fentanyl by binding to and directly inhibiting the α _1B -adrenergic receptor. Pharmacologic studies in cats demonstrated that sufentanil and remifentanil have potent vasodepressor activity in the pulmonary vascular bed and these responses may be mediated by histamine and opioid receptor-sensitive pathway.

Opioids in Shock

Opioids are often administered for patients requiring surgical intervention for the control of hemorrhage. An animal study demonstrated that pretreatment with morphine before inducing shock state decreases leukocyte adhesion and vascular permeability in the microcirculation of the mesenteric venule, suggesting the survival benefit for use of morphine during acute resuscitation.

It has been shown that endogenous opioids contribute to the pathophysiology of hypovolemic shock through central and peripheral sympathetic inhibition and contributes to hypotension during severe hemorrhage. Liu et al. reported that the selective δ-opioid receptor antagonist (ICI 174,864) may be beneficial for the early management of traumatic hemorrhagic shock in rats, suggesting a pathophysiological role of the δ-opioid receptor in hemorrhagic shock.

Stress Reduction and Outcome

Anesthetic techniques or agents that minimize the stress response may reduce morbidity and mortality in a variety of circumstances. Anand and Hickey evaluated the impact of sufentanil versus morphine-halothane anesthesia on hormonal and metabolic responses and morbidity and mortality in neonates undergoing cardiac surgery. Most strikingly, a difference in postoperative mortality was observed (0 of 30 given sufentanil versus 4 of 15 given halothane plus morphine). Mangano et al. also reported that, after myocardial revascularization, patients receiving intense postoperative analgesia with sufentanil (1 μg/kg/h) experience a decrease in the incidence and severity of electrocardiographically documented ischemia compared with patients receiving intermittent IV morphine (2.2 ± 2.1 mg/h) for postoperative analgesia. It was also shown that large-dose opioids (remifentanil 0.85 μg/kg/min or fentanyl 28 μg/kg) were associated with a decreased rate of myocardial infarction after cardiac surgery.

Many different hormonal changes induced by surgery have been described. However, the concomitant neural, cellular, immune, and biochemical changes have been less well defined, and little is understood or proven with regard to how modifying hormonal responses alters outcome. Additional studies are necessary for complete elucidation of the relationship between control of the surgery-induced hormonal responses and outcome.

In summary, the mechanisms underlying the ability of opioids to provide perioperative cardiovascular stability include: a reduced sympathetic tone and enhanced parasympathetic activity often producing bradycardia; minimal changes in cardiac contractility; function generally as an antiarrhythmic; potentially function as cardioprotective agents to reduce the effect of ischemia by mimicking an endogenous opioid-peptide/preconditioning pathway; have no significant effect on the coronary circulation; produce modest vascular smooth muscle relaxation with the exception of a morphine-induced histaminergic mechanism; reduce the surgical stress response through the nervous system and adrenal-pituitary axis—depending on the opioid class.

Opioid Tolerance

The precise mechanism(s) that drive opioid dependence and tolerance are not known, however they appear to encompass a range of factors including: genetic, molecular, cellular, physiologic, and functional. In the locus ceruleus, the major noradrenergic nucleus in the brain, long-term opioid exposure results in inhibition of adenylyl cyclase, reduced activity of protein kinase A, and upregulation of the cyclic AMP pathway. Changes in μ-receptor density that occur prior to or during the development of tolerance do not appear to be essential for development of opioid tolerance. Possible mechanisms involve protein kinase signal transduction cascades that link extracellular signals to cellular changes by regulating target gene expression. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. It was shown that the development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist was coadministered with morphine but the GR agonist dexamethasone facilitated the development of morphine tolerance, suggesting an important role of spinal GRs in the cellular mechanisms of morphine tolerance in rats. Cholecystokinin and NMDA-NO system were also shown to be involved in development of acute tolerance to opioids, which is also affected by spinal serotonin activity. Neuroinflammation driven by chemokines may represent one of the major mechanisms underlying pathologic pain. A chemokine, CXCL1, was upregulated in both opioid-tolerant patients and rodents, and the onset and extent of opioid tolerance was affected by antagonizing intrathecal CXCL1/CXCR2 signaling. A chemokine, CXCL12, was significantly upregulated in the cerebrospinal fluid of opioid-tolerant patients, and CXCL12 neutralizing antibody and antagonist for CXCR4, a receptor which interacts with CXCL12, attenuated morphine tolerance in rats.

Morphine tolerance occurs more rapidly in younger rats than older rats and is unlikely to be the result of differences in drug metabolism or clearance, suggesting that aging may impact molecular processes involved in development of tolerance. It has been suggested that activation of glial cells, including astrocytes and microglia, at the level of the spinal cord plays an important role in the development of opioid tolerance. However, the mechanism for opioid-induced activation of glial cells is not completely understood.

Although the notion that opioid tolerance and dependence occur only after chronic administration has been widespread, it has now become recognized that tolerance can also develop rapidly after acute opioid exposure in animals and humans. Intraoperative remifentanil infusion (0.3 μg/kg/min) in patients undergoing major abdominal surgery under desflurane anesthesia increased postoperative pain and morphine requirement compared with low-dose remifentanil (0.1 μg/kg/min), suggesting the development of acute remifentanil tolerance. In contrast, there is a report that target-controlled infusion of alfentanil and remifentanil for postoperative analgesia does not lead to opioid tolerance. In human volunteers, continuous infusion of remifentanil (0.08 μg/kg/min) for 3 hours did not decrease the pain threshold. On the other hand, intraoperative use of 0.3 μg / kg/min remifentanil for approximately 3 hours did not induce acute tolerance, but the administration of 0.6 and 0.9 μg / kg/min remifentanil to young children resulted in acute tolerance for 24 hours after surgery revealed by increased use of postoperative fentanyl in an apparently dose-related manner. Differences in these outcomes may reflect divergent methodologies and limited sample size and are an area of ongoing investigation.

Differential opioid tolerance, an important phenomenon in clinical opioid pharmacology, proposes that different targets of opioid drugs do not develop tolerance at the same rate and to the same degree. In a study using rhesus monkeys, acute morphine administration predictably induced dose-dependent analgesia, and chronic morphine administration induced dose-dependent tolerance to the analgesic effect, while no tolerance development to the respiratory depressive effect could be demonstrated in the chronically opioid-treated animals ( Fig. 24.14 ). In humans, patients receiving chronic opioids for pain control, especially at high doses, most likely have developed opioid tolerance. However, there is little data to help predict the magnitude or clinical impact of an individual’s loss of opioid-induced analgesia or potentially their resistance/vulnerability to the respiratory depressive effects of opioids. As discussed later, individuals chronically consuming opioids are dose dependently at increased risk for overdose and death.

The effects of chronic opioid administration on analgesia and respiratory response in rhesus monkeys . The animals were studied under baseline conditions, after receiving 3.2 or 6.4 mg/kg/day for 4 weeks, and after abstinence. After each treatment course, they were challenged with various doses of morphine, and analgesic and respiratory responses were assessed. Analgesic effects were assessed by tail withdrawal latency and shown as percentage of maximum possible effect (MPE) ; respiratory depression was shown as decrease in minute ventilation (V _E ) . The results show development of reversible tolerance to the analgesic effects of opioids (A), but no tolerance development to the respiratory depression (B).

From Paronis CA, Woods JH. Ventilation in morphine-maintained rhesus monkeys. ii: tolerance to the antinociceptive but not the ventilatory effects of morphine. J Pharmacol Exp Ther . 1997;282:355–362.

Management of Opioid-Dependent Patients

A variety of problems should be taken into consideration for anesthetic management of opioid-dependent patients or patients suffering from opioid use disorder (OUD). Complications in opioid-addicted patients include cardiopulmonary problems, renal problems, and anemia. Long-term morphine administration causes adrenal hypertrophy and impairs corticosteroid secretion. Viral and nonviral hepatitis, acquired immunodeficiency syndrome, osteomyelitis, muscle weakness, and neurologic complications may be found in patients suffering from OUD or poly substance use disorder. As it is common to underestimate and undertreat pain in opioid-dependent patients, it is important to identify the goals in their acute pain management ( Box 24.3 ). Anesthetic management for the opioid-dependent or patient with OUD should include adequate premedication with opioids, administration of supplemental intraoperative and postoperative opioids, and providing nonopioid analgesics and neural blockade. There is no ideal anesthetic agent or technique to employ in the patient with OUD or in the patient with an acute opioid overdose—with the possible exception of judicious use of an opioid antagonist as indicated. As mentioned previously, combined techniques utilizing regional anesthetic approaches, as well as concurrent use of low-dose ketamine and α2-agonists have been successful. Support of the circulatory system with fluids and monitoring of arterial blood gases and pulmonary function are essential.

Owing to the high risk of relapse, overdose, and death in individuals with OUD, medication-assisted treatment (MAT) in which opioids with different pharmacokinetic and pharmacodynamic properties such as methadone or buprenorphine are commonly prescribed. Because of the injection-deterring potential of naloxone hydrochloride and a better safety profile compared with methadone, daily administration of combined buprenorphine and naloxone is becoming a first-line choice for MAT in a number of countries. Other treatment approaches have emerged including rapid opioid detoxification with high-dose naloxone or naltrexone. For this treatment, general anesthesia is induced before the start of opioid antagonization and maintained for several hours to prevent perception of withdrawal symptoms by the patient. Blockade of μ-opioid receptors by naloxone (total dose of 12.4 mg) in opioid-addicted patients induces sympathetic neural activation, including increase in plasma catecholamine concentration and cardiovascular stimulation, which can be managed in part by α ₂ -agonists. Long-term opioid abstinence is not guaranteed, even with an ongoing program that includes MAT, given the neurobiology, societal factors involved in addiction, and potential for repeat exposure—often medically in the perioperative period.

Effects on Gastrointestinal Tract

The adverse gastrointestinal effects of exogenous opioid treatment include nausea, vomiting, altered fluid dynamics, inhibited gastric emptying, inhibited intestinal coordinated propulsive activity, and increased transit time, all of which may contribute to postoperative ileus ( Table 24.6 ). Opioid-dependent mechanisms driving these effects are complex and those involving GI motility are believed to involve opioid receptors expressed throughout the myenteric plexus. Several opioid receptor types can be demonstrated on myenteric neurons, and both κ- and μ-receptor agonists regulate cholinergic transmission in the myenteric plexus. κ-Agonists appear to modulate acetylcholine release more potently than μ-agonists by inhibition of N-type voltage-sensitive Ca ²⁺ channels via a pertussis toxin-sensitive G protein in guinea pig ileum.

The effect of morphine on esophageal motility has been little explored. Morphine (80 μg/kg) increased the velocity but did not alter the amplitude or duration of primary peristalsis of the esophagus, and it decreased the duration and magnitude of swallow-induced lower esophageal sphincter relaxation. Gastric emptying is delayed by opioids, via supraspinal (vagus nerve-mediated) and spinal, as well as peripheral, mechanisms. Intrathecal morphine (0.4 mg) significantly decreased the gastroduodenal propagation velocity and acetaminophen absorption, and intramuscular morphine (4 mg) gave additional effects. Tramadol (1.25 mg/kg IV) has a measurable but smaller inhibitory effect on gastric emptying compared with codeine (1 mg/kg IV) or morphine (0.125 mg/kg IV). Opioids administered epidurally as well as intrathecally reduce gastrointestinal motility. It was reported that translocation of enteric microorganisms from the intestinal tract to extraintestinal sites is promoted by reduction of gut propulsion after morphine treatment in rats. Propofol (0.3 mg/kg bolus and 1.0 mg/kg/h) abolished the decrease of gastric tone induced by morphine (0.1 mg/kg intravenously), but did not abolish morphine-induced delay of gastric emptying.

Naloxone reverses opioid-induced delays in gastric emptying. Methylnaltrexone, a quaternary naloxone derivative that does not cross the blood-brain barrier, can attenuate morphine-induced delays in gastric emptying, suggesting that a peripheral mechanism is involved in the opioid effect on gastrointestinal tract. Naloxone (0.7 mg/kg) significantly inhibited gastric emptying of saline and milk in rats. This observation might suggest that opioids can affect the gastrointestinal tract by a mechanism independent from the opioid receptors. Intravenous, but not intramuscular, metoclopramide (10 mg) also can reverse morphine-induced delays in gastric emptying.

Opioid effects on the intestine are complex. Transit time from mouth to ileum may not be significantly altered by morphine, because morphine enhances ileal propulsion before decreasing motility. Opioids increase tone and decrease propulsive activity in most of the intestine. Constipation is the frequent side effect in patients who are administered opioids. Naloxonazine attenuated the fentanyl-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine or oxycodone. Naloxone methiodide suppressed the oxycodone-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine. Thus, μ-opioid receptor agonists induce the inhibition of gastrointestinal transit and drive constipation through different mechanisms.

Biliary and Hepatic Effects

Opioid agonists increase biliary duct pressure and sphincter of Oddi (choledochoduodenal sphincter) tone in a dose- and drug-dependent manner through opioid receptor-mediated mechanisms. However, the clinical consequences of opioid-induced biliary tract actions are usually minimal. Although traditional teaching dictates that morphine induces “spasm” in the sphincter of Oddi and should not be used in acute pancreatitis, no studies or evidence exist to indicate morphine is contraindicated for use in acute pancreatitis. Increases in biliary pressure caused by opioids are, with the exception of meperidine, reversible with naloxone. Oddi’s sphincter manometry via choledochoscope demonstrated that the regular dose of morphine could increase common bile duct pressure, whereas pethidine had no effect on Oddi’s sphincter motility and tramadol shows inhibited motility of the sphincter of Oddi. Fragen et al. studied the effect of remifentanil (0.1 mg/kg/min) on the flow of dye from the gall bladder into the duodenum, and showed that remifentanil delays the drainage of dye from the gall bladder into the duodenum, but the delay is shorter than that reported after morphine or meperidine.

Opioids produce minimal effects on liver function during anesthesia and surgery but can affect ischemia-reperfusion injury. Remifentanil pretreatment can attenuate liver injury induced by ischemia-reperfusion, which was shown to be mediated by inducible NO synthase expression and exhausting reactive oxygen species but does not involve opioid receptors. Morphine administered either intravenously or intrathecally 10 minutes before 1 hour of ischemia protects against ischemia-reperfusion injury after 6 hours of reperfusion in both normal and cirrhotic rat liver by a mechanism involving the opioid receptor. Remifentanil significantly attenuated increases in serum aminotransferase levels and the liver histological changes induced by ischemia-reperfusion injury of the liver in rats, by a mechanism possibly involving hepatic interleukin-18. These reports might suggest the beneficial effects of opioids in anesthetic management of liver surgery.

Nausea and Vomiting

Postoperative nausea and vomiting are serious problems which often embarrass anesthesiologists. Etiology, treatment, and prevention of PONV have been extensively investigated ( Fig. 24.15 ). Intraoperative use of opioids is a well-known risk factor for PONV . Opioids stimulate the chemoreceptor trigger zone in the area postrema of the medulla possibly through δ-receptors, leading to nausea and vomiting. Alfentanil, compared with approximately equipotent doses of fentanyl and sufentanil, was found in one study to be associated with a lower incidence of PONV .

The chemoreceptor trigger zone and the emetic center with the agonist and antagonist sites of action of various anesthetic-related agents and stimuli. GI , Gastrointestinal.

From Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology . 1992;77:162–184.

The use of propofol in balanced or total IV anesthesia (TIVA) significantly reduces the incidence of opioid-induced nausea and vomiting. When opioids are employed, antiemetic prophylaxis should be considered, which includes drugs with anticholinergic activity, butyrophenones, dopamine antagonists, serotonin antagonists and acupressure. Ondansetron, a serotonin type 3 (5-HT ₃ ) receptor antagonist, was proved to be effective for postoperative opioid-induced nausea and vomiting. A meta-analysis concluded that prophylactic use of 5-HT ₃ receptor antagonists significantly reduced the incidence of PONV and the need of rescue antiemetic therapy in parturients who received intrathecal morphine for cesarean delivery. Nausea and vomiting after epidural morphine (3 mg) for postcesarean section analgesia could be prevented by dexamethasone (8 mg IV) as efficiently as droperidol (1.25 mg IV). Cannabinoid receptor agonists have been demonstrated to be effective antiemetics in some clinical settings. Animal experiments have shown that the cannabinoid agonist suppresses opioid-induced retching and vomiting by activation of the cannabinoid CB1 receptor. A continuous low-dose naloxone infusion (0.25 μg/kg/h) ameliorates some of the opioid-induced side effects, including nausea, vomiting, and pruritus, in many but not all patients without adversely affecting analgesia. Transdermal scopolamine was shown to be effective for prophylactic use in parturients receiving intrathecal morphine while undergoing cesarean delivery but was associated with higher incidence of side effects such as dry mouth and blurry vision.

Taken together, the prevention and/or treatment of opioid-induced nausea and vomiting continues to be a clinical challenge. Strategies that include the administration of 5-HT ₃ receptor antagonists and/or the steroid dexamethasone show efficacy in well controlled trials. However, such approaches require exposure to additional medications that, in themselves, may carry additional risks of side effects.

Obstetrics

The parenteral administration of opioids for oocyte retrieval and prior to delivery remains a commonly used method of analgesia.

Alfentanil and pethidine have been safely used as analgesics during the harvesting of human oocytes for subsequent in vitro fertilization. Teratogenic actions of opioids, including fentanyl, sufentanil, and alfentanil, at least in animal models, appear to be minimal. Nociception due to uterine cervical distension could be suppressed by μ- and κ-agonists in rats, but the analgesic effect of μ-agonist but not κ-agonist was reduced by estrogen. Aortocaval compression and associated hypotension may be exacerbated by parenteral opioids, especially following morphine or meperidine. Fetal manifestations of maternal opioid administration include decreases in heart rate variability. Adverse neonatal effects can occur after either morphine or meperidine administration to mothers. Fetal acidosis increases opioid transfer from the mother. Attempts to minimize neonatal effects of opioids include restricting opioid administration to the first stage of labor. The short-acting opioid alfentanil administered before cesarean delivery attenuated the maternal stress response, but led to slightly reduced Apgar score. In a randomized, double-blind, controlled study, it was shown that a single bolus of 1 μg/kg remifentanil administered to patients undergoing elective cesarean delivery effectively attenuated hemodynamic changes after induction and tracheal intubation, but remifentanil crosses the placenta and may cause mild neonatal depression.

Because the fetus is capable of pain perception after the 26th week of gestation, adequate postoperative fetal pain management is essential after fetal surgery. It was shown that the sheep fetus absorbs sufentanil after intraamniotic instillation, and that significantly greater plasma concentrations were obtained in the fetal lamb as compared with the mother sheep.

Morphine and meperidine have been found in the breast milk of mothers receiving intravenous opioid analgesia. Although both fentanyl and morphine are concentrated in breast milk in milk-to-plasma ratios of 2 to 3:1, newborn exposure is reported to be insignificant. Newborns of mothers with OUD or taking prescription opioids can exhibit opioid withdrawal often referred to as neonatal abstinence syndrome (NAS) and require appropriate treatment and observation.

Anaphylactoid Reactions

True allergic reactions and systemic anaphylactoid reactions to opioids are rare. More commonly, local reactions caused by preservatives or histamine may occur. In 32% of heroin addicts dying suddenly after injection, the concentration of tryptase was elevated (>10 μg/L), but no correlation was found between the IgE levels and tryptase, supporting the hypothesis that mast cell degranulation was not mediated by allergic reaction. This report suggests that heroin fatalities may be in part driven by anaphylactoid reaction.

Ocular Effects

The use of fentanyl, sufentanil, and alfentanil during induction of anesthesia can help to prevent increases in intraocular pressure. Fentanyl, alfentanil, and sufentanil doses as small as 2.5, 10, and 0.1 μg/kg, respectively, may be sufficient as long as appropriate anesthetic depth is achieved prior to tracheal intubation. Remifentanil (1 μg/kg) combined with propofol (2 mg/kg) or thiopental (5 mg/kg) was reported to be effective for prevention of intraocular pressure change after succinylcholine and tracheal intubation.

Immune Effects

Opioids can affect immune function through adaptive immunity, innate immunity, and neuroendocrine system ( Box 24.4 ). The literature investigating the function of classical opioid receptors (μ, δ, and κ) present on immune cells suggest a complex relationship between clinically used opioids and immune function, including through indirect mechanisms. However, because the μ-opioid receptor knockout mice showed no immune modulatory effects after central administration of opioids, the central immune modulatory effect of opioids is mediated by μ-opioid receptors.

It was shown that the maximal suppression of natural killer (NK) cell activity, proliferation of splenic T and B cells, and interferon-γ production are observed 0.5 to 1 hour after 15 mg/kg morphine injection in rats. The time course was nearly concordant with the antinociceptive effect of morphine. Postoperative administration of morphine (10 mg IM) did not significantly affect the NK cell activity, while tramadol (100 mg IM) enhanced NK cell activity. It was reported that intravenously administered fentanyl causes a rapid increase in NK cell cytotoxicity, which was coincident with an increase in the percentage of CD16 ⁺ and CD8 ⁺ cells in peripheral blood. Compared with fentanyl (1000 μg), administration of morphine (40 mg) as part of balanced anesthetic technique suppressed several components of the inflammatory response (IL-6, CD11b, CD18, postoperative hyperthermia) to cardiac surgery and cardiopulmonary bypass.

As a potential mechanism for the immunosuppressive effects of morphine, it was demonstrated that NF-κβ activation induced by an inflammatory stimulus was inhibited by morphine-induced activation of μ ₃ -opioid receptors in a NO-dependent manner. Several investigators have independently reported direct effects of morphine on apoptosis in cultured human peripheral blood lymphocytes, which may result in compromising immune functions. However, there is also a report that morphine has no effect on apoptosis-related molecules and does not promote apoptosis of human peripheral blood lymphocytes.

With respect to the effects of opioids on neutrophils, it was reported that remifentanil, but not sufentanil, alfentanil, or fentanyl, could attenuate activation of human neutrophils exposed to lipopolysaccharides, and decreased activation of intracellular signaling pathways, including p38 and ERK1/2, and expression of proinflammatory cytokines, including TNF-α, IL-6, and IL-8, through a mechanism involving the κ-opioid receptor. It was also reported that remifentanil attenuates lipopolysaccharide-induced acute lung injury by inhibition of proinflammatory cytokine production by downregulating the NF-κβ pathway, suggesting a beneficial effect of remifentanil in acute lung injury or acute respiratory distress syndrome in sepsis.

A prospective study for adult patients who underwent elective colorectal surgery demonstrated that the number of patients who developed surgical site infection was higher after remifentanil-based anesthesia (11.6%) compared with fentanyl-based anesthesia (3.4%). A possible reason for this finding may be opioid-induced immunosuppression or opioid withdrawal-induced immunosuppression.

Cancer Progression

Epidemiological studies have suggested that patients who receive general anesthesia with opioids have a greater rate of cancer recurrence than patients who receive local or regional anesthetics, although there is no direct evidence to support altering anesthetic technique in cancer patients. Opioids may directly stimulate proliferation and invasion of tumor cells and inhibit apoptosis of tumor cells, or indirectly affect cancer recurrence by immunosuppression. Overexpression of the μ-opioid receptor in human non-small cell lung cancer was suggested to promote tumor growth and progression. Furthermore, it was reported that women with A118G genotype of the μ-opioid receptor have decreased breast cancer-specific mortality, suggesting that opioid pathways may be involved in tumor growth. Drawing from preclinical studies using animals or cultured cells opioids may promote tumor growth and metastasis through multiple mechanisms, whereas it is also reported that opioids can direct various anticarcinogenic pathways ( Fig. 24.16 ). Preclinical data have also suggested that μ-opioid receptor inhibition can reverse the adverse effect of μ-opioid receptor signaling on cancer progression, when a combination of methylnaltrexone, which blocks peripheral but not central μ-opioid receptor, and chemotherapy is tested.

Effects of morphine on cancer cells . It is important to note that the same pathway can have opposing end results, depending on the morphine doses, mode of administration, and animal models used. cAMP , Cyclic adenosine monophosphate; COX-2 , cyclooxygenase-2; ECM , extracellular matrix; EGFR , epidermal growth factor receptor; Erk , extracellular-regulated kinase; HIF-1α , hypoxia inducible factor 1 alpha; IL , interleukin; M2 , “alternative” activation of macrophages; MAPK , mitogen-activated protein kinase; MMPs , matrix metalloproteinases; NO , nitric oxide; PGE ₂ , Prostaglandin E ₂ ; Src , non-receptor tyrosine kinase; TLR-4 , toll-like receptor 4; Th2 , T helper 2 cells; uPA , urokinase plasminogen activator; VEGF , vascular endothelial growth factor.

From Sekandarzad MW, van Zundert AAJ, Lirk PB, et al. Perioperative anesthesia care and tumor progression. Anesth Analg . 2017;124;1697–1708.

One of the mechanisms involved in the effects of opioids on cancer prognosis is their effects on angiogenesis. Morphine can stimulate angiogenesis by a variety of mechanisms involving NO, MAPK, VEGF, and Rho/Rho kinase. Blebea et al. reported that activation of opioid receptors inhibited angiogenesis, via endogenous opioid ligands. Although both pro- and anti-angiogenic actions of opioids have been reported, it is generally believed that the pro-angiogenic (or neo-vasculogenic) effects predominate.

The opioid growth factor receptor (OGFR) is localized in both the nucleus and the cytoplasm and functions as a receptor for OGF, also known as methionine-enkephalin. OGFR is distinguished from classic opioid receptors (μ, δ, and κ) as not having any role in analgesia but functions as a negative regulator of cell proliferation. Morphine can also interact with OGFR expressed in lung cancer tissues and cell lines and may suppress lung cancer progression.

Wound Healing

Topical application of opioids has been explored as a strategy for reducing pain associated with cutaneous wounds. In addition to its analgesic functions, the peripheral opioid receptor system affects skin homeostasis by influencing cell differentiation, migration, and adhesion. Activation of peripheral opioid receptors on primary afferent neurons reduces the excitability of these neurons and suppresses the antidromic release of substance P and calcitonin gene-related peptide, which play an essential role in wound repair. It was shown that topical morphine application significantly reduced the number of myofibroblasts and macrophages in the closing wound. These findings might limit the topical application of opioids as an analgesic therapeutic strategy in the treatment of painful cutaneous wounds. In contrast, it was shown that activation of the δ-opioid receptors destabilizes intercellular adhesion and promotes the migratory keratinocyte phenotype, which is required for fast wound closure. If these divergent findings can be resolved in favor of wound healing and enhanced localized analgesia, there is great potential for opioid applications in wound healing. Most clinical studies have not focused on opioid effects on the wound healing process but substantial analgesic effects without delaying wound closure were found. Larger clinical trials are required to examine whether opioids interfere with wound healing by inhibition of proinflammatory cytokine release or by development of hypertrophic scars, as shown in animal studies.

Physicochemical Properties

Opioids are weak bases. When dissolved in solution, they are dissociated into protonated and free-base fractions, with the relative proportions depending on the pH and pKa. The free-base fraction is more lipid-soluble than the protonated fraction. High lipid solubility facilitates opioid transport into the biophase or site of action. Therefore, highly lipid-soluble opioids have a more rapid onset of action. However, because the opioid receptor recognizes an opioid molecule in the protonated form, the intensity of opioid effects is closely related to the ionized concentration of drug in the biophase.

All opioids are to some extent bound to plasma proteins, including albumin and α ₁ -acid glycoprotein. It is only the un-ionized, unbound fraction that constitutes the diffusible fraction and provides the concentration gradient that promotes diffusion of opioid from the blood to the tissue of interest. Thus, the speed of onset of opioid effect is affected by both the lipid solubility and the protein binding.

Pharmacokinetic Features of Individual Drugs

Representative pharmacokinetic parameters for the opioids commonly used in anesthesia are displayed in Table 24.7 .

Morphine

Morphine pharmacokinetics is notably different from that of the fentanyl congeners. This difference is in large part due to morphine’s comparatively low lipid solubility. There is relatively little transient first-pass uptake of morphine by the lung. The pKa of morphine (8.0) is greater than physiologic pH, and thus after intravenous injection only a small fraction (10%-20%) of morphine is un-ionized. Penetration of morphine into and out of the brain is presumably slower compared with that of other opioids. Approximately 20% to 40% of morphine is bound to plasma proteins, mostly albumin.

Morphine is principally metabolized by conjugation in the liver, but the kidney plays a key role in the extrahepatic metabolism of morphine. M3G is the major metabolite of morphine, but does not bind to opioid receptors and possesses little or no analgesic activity. M3G may actually antagonize morphine, and this effect may contribute to both variability in response and resistance to morphine analgesic therapy. M3G was reported to produce seizures in animals and cause allodynia in children. M6G accounts for nearly 10% of morphine metabolite and is a more potent μ-receptor agonist than morphine with a similar duration of action. It was reported that M6G contributes substantially to morphine’s analgesic effects even in patients with normal renal function. A recent study reported that based on area under the concentration–time curve there was a major contribution of M6G to the overall analgesic effect; the mean contributions being estimated as 96.6%, 85.6%, 85.4%, and 91.3% after oral, subcutaneous, intravenous, and rectal administration of morphine, respectively. In patients with renal insufficiency, 97.6% of the analgesic effect is caused by M6G when morphine is given orally. Especially in patients with renal dysfunction, the accumulation of M6G can lead to an increased incidence of adverse effects, including respiratory depression. Except for renal function, M6G accumulation was shown to be affected by transmembrane transporters inhibited by probenecid. M6G can induce respiratory depression similarly as morphine, but the site of action in the ventilatory control system might be different between M6G and morphine. It was suggested that SNP at the μ-opioid receptor affects the susceptibility to M6G-related opioid toxicity. Because the hepatic extraction ratio of morphine is high, the bioavailability of orally administered morphine is significantly lower (20%-30%) than after intramuscular or subcutaneous injection. It appears that M6G is in fact the primary active compound when morphine is administered orally ( Fig. 24.17 ). In contrast to the reports suggesting the high potency of M6G, there have been reports showing that short-term intravenous administration of M6G does not provide effective analgesia.

Mean plasma concentrations (± standard error of means) of morphine, morphine-6-glucuronide (M6G) , and morphine-3-glucuronide (M3G) after intravenous and oral administration of morphine.

From Osborne R, Joel S, Trew D, et al. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther . 1990;47:12–19.

Remifentanil

Although chemically related to the fentanyl congeners, remifentanil is structurally unique because of its ester linkages. Remifentanil’s ester structure renders it susceptible to hydrolysis by blood- and tissue-nonspecific esterases, resulting in rapid metabolism and rapid reduction of blood concentration after an infusion has stopped ( Fig. 24.18 ). Remifentanil thus constitutes the first ultrashort-acting opioid for use as a supplement to general anesthesia.

Mean (± standard deviation) blood concentration-time curves of remifentanil and its metabolite GI90291 after a 1-minute transfusion of remifentanil of 2, 5, 15, and 30 μg/kg ( n = 6 for each dose).

From Westmoreland CL, Hoke JF, Sebel PS, et al. Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology. 1993;79:893–903.

Pharmacokinetic properties of remifentanil are best described by a three-compartment model. Its clearance is several times greater than normal hepatic blood flow, consistent with widespread extrahepatic metabolism. But, remifentanil is not significantly metabolized or sequestered in the lungs. It is a weak base with a pKa of 7.07. It is highly lipid-soluble with an octanol/water partition coefficient of 19.9 at pH 7.4. Remifentanil is highly bound (= 70%) to plasma proteins (mostly α ₁ -acid glycoprotein). The remifentanil free base is formulated with glycine. Because glycine has been shown to act as an inhibitory neurotransmitter that causes a reversible motor weakness when injected intrathecally in rodents, remifentanil is not approved for spinal or epidural use.

The primary metabolic pathway of remifentanil is de-esterification to form a carboxylic acid metabolite, GR-90291 ( Fig. 24.19 ), which is 0.003 to 0.001 times as potent as remifentanil. The low in vivo potency of GR90291 can be explained by its low affinity to the μ-receptor in combination with a poor brain penetration. Excretion of GR-90291 is dependent on renal clearance mechanisms. Evidence from dogs suggests that the remifentanil metabolites are, for practical purposes, completely inactive, even in the face of renal failure. Its pharmacokinetics is not appreciably influenced by renal or hepatic failure. In blood, remifentanil is metabolized primarily by enzymes within erythrocytes. Remifentanil is not a good substrate for pseudocholinesterase and, therefore, is not influenced by pseudocholinesterase deficiency.

Metabolic pathway of remifentanil . Deesterification by nonspecific plasma and tissue esterases to form a carboxylic acid metabolite (GR90291) that has only 1/300 to 1/1000 the potency of the parent compound is the primary metabolic pathway. N -dealkylation of remifentanil to GR94219 is a minor metabolic pathway.

From Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology . 1993;79:881–892.

Surrogate Measures of Opioid Potency

Because a high-resolution measure of analgesia is not available, opioid potencies are usually estimated by some surrogate measures. Reduction of the MAC required to produce lack of movement to skin incision has been a frequently utilized surrogate measure in the estimation of opioid potency ( Fig. 24.20 ). However, MAC is not useful as a surrogate measure of opioid potencies outside the operation rooms.

The reduction in isoflurane concentration to prevent movement at skin incision in 50% of patients by increasing measured remifentanil whole blood concentrations. F represents a patient who moved and S represents a patient who did not move. The solid line is the logistic regression solution for a 40-year-old patient.

From Lang E, Kapila A, Shlugman D, et al. Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology . 1995;85:721–728.

To guide the administration of opioids in anesthetized patients, indirect parameters that reflect the patient’s physiologic reaction to nociception like sweating, movement, heart rate, and blood pressure should be monitored. However, the low specificity of these signs can cause underdosage or overdosage of intraoperative analgesia. The Analgesia Nociception Index (ANI), derived from an electrocardiogram trace, has been proposed as a noninvasive guide to analgesia. The ANI monitor calculates heart rate variation with respiration, a response mediated primarily by changes in the parasympathetic nervous system stimulation to the sinoatrial node of the heart. Patients receiving intraoperative ANI-guided fentanyl administration during sevoflurane anesthesia for lumbar discectomy and laminectomy demonstrated decreased pain in the recovery room, likely as a result of more objective intraoperative fentanyl administration.

The EEG has been another widely utilized surrogate measure in estimating opioid potency. The EEG is advantageous, because it is noninvasive and can be used as an effect measure when an experimental subject is unconscious or apneic. When processed by Fourier spectral analysis, the raw EEG changes translate into a significant decrease in the value of the spectral edge, a parameter that quantitates the frequency below which a given percentage (usually 95%) of the power in the EEG signal is found. Although the clinical meaning of the EEG changes produced by opioids is unclear, the opioid potencies estimated using the EEG as a surrogate measure appear to be clinically reliable because they relate to clinically determined potencies in a proportional, reproducible fashion. However, because the surrogate measures do not always assess the drug effect of clinical interest (analgesia), estimations of potency based on surrogate measures must be interpreted with caution.

Factors Affecting Pharmacokinetics and Pharmacodynamics of Opioids

Age

Pharmacokinetics and pharmacodynamics of opioids can be influenced by age. It is clear that neonates exhibit a reduced rate of elimination of essentially all opioids. This is presumably due to immature metabolic mechanisms, including the cytochrome P-450 system. The prolonged elimination of opioids observed in the neonatal period quickly normalizes toward adult values within the first year of life.

Intraoperative requirements of opioids are different between adults and children. The infusion rate of remifentanil to block somatic and autonomic response to skin incision was almost 2-fold higher in children (2-11 years) than adults (20-60 years). With advanced age, although pharmacokinetic changes may play a minor role, pharmacodynamic differences are primarily responsible for the decreased dose requirement in the elderly. Age was inversely correlated with central volume of distribution, clearance, and potency of remifentanil ( Fig. 24.21 ). These combined pharmacokinetic and pharmacodynamic changes mandate a reduction in remifentanil dosage by at least 50% or more in the elderly.

Relationship between pharmacokinetic and pharmacodynamic parameters and age for remifentanil . Volume of distribution (V ₁ ) and clearance (Cl ₁ ) are estimated using a three-compartment model. t _1/2 k _e0 is a half-life corresponding to k _e0 , a first-order rate constant for elimination of drug from the effect compartment.

From Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology . 1997;86:24–33.

Body Weight

Many opioid pharmacokinetic parameters, especially clearance, appear to be more closely related to lean body mass. Total body weight-based dosing in an obese patient results in much higher remifentanil effect-site concentrations than does lean body mass-based dosing. In contrast, for lean patients, the concentrations that result from total body weight-based dosing are not much greater than those based on body mass ( Fig. 24.22 ). Clinically, context-sensitive half-times are not significantly different between obese and lean subjects ( Fig. 24.23 ). There is mounting evidence to suggest that lean body mass is a better predictor of metabolic capacity than total body weight. Ideal body weight, a parameter closely related to lean body mass and one that is perhaps more easily estimated by the clinician, is probably an acceptable alternative of lean body mass. Because obesity and obesity-associated disease have increased and continue to do so, obese patients will frequently present for anesthesia and operations. Understanding the influence of obesity on the disposition of opioids is an important question in contemporary anesthesia practice. In response, new pharmacokinetic models incorporating the influence of body mass have been recently reported.

A computer simulation of the time course of remifentanil concentration change, when the dosage regimen is calculated based on lean body mass (LBM) or total body weight (TBW) for both obese and lean patients. Note that TBW-based dosing in an obese patient results in dramatically higher concentrations.

From Egan TD, Huizinga B, Gupta SK, et al. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology . 1998;89:562–573.

A computer simulation of the context-sensitive half-times (50% decrement times) and 80% decrement times of remifentanil in obese vs. lean subjects. In clinical terms, the curves are not grossly different in obese and lean subjects.

From Egan TD, Huizinga B, Gupta SK, et al. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology . 1998;89:562–573.

Renal Failure

Renal failure has implications of major clinical importance with respect to morphine, hydromorphone, and meperidine. For the fentanyl congeners, the clinical importance of renal failure is less marked.

Morphine is an opioid with active metabolites that are dependent on renal clearance mechanisms for elimination. Morphine is principally metabolized by conjugation in the liver, and the water-soluble glucuronides (M3G and M6G) are excreted via kidney. The kidney also plays a role in the conjugation of morphine, accounting for nearly 40% of its metabolism. Patients with renal failure can develop very high levels of M6G and life-threatening respiratory depression ( Fig. 24.24 ). In view of these changes induced by renal failure, morphine is not considered a good choice in patients with severely altered renal clearance mechanisms. There are similar concerns for the use of hydromorphone in the setting of renal dysfunction.

Effect of renal failure on pharmacokinetics of morphine . The graphs show the time-dependent change of the serum concentration of morphine and its metabolite in patients of renal failure (A) and in patients with normal renal function (B) who received 0.1 mg/kg morphine intravenously.

From Osborne R, Joel S, Grebenik K, et al. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther . 1993;54:158–167.

The clinical pharmacology of meperidine is also significantly altered by renal failure. Because normeperidine, the main metabolite of meperidine with analgesic and CNS excitatory effect, is subject to renal excretion, the potential CNS toxicity secondary to normeperidine accumulation is especially a concern in patients in renal failure.

In contrast, the clinical pharmacology of the fentanyl congeners is not grossly altered by renal failure, although a decrease in plasma protein binding may potentially alter the free fraction of the fentanyl class of opioids. In the presence of renal impairment, none of fentanyl, alfentanil, sufentanil, and remifentanil deliver a high active metabolite load, or suffer from significantly prolonged clearance. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is altered by impaired renal function. Levels of GI-90291 that develop during a remifentanil infusion in patients in renal failure are not likely to produce any clinically significant effects.

Hepatic Failure

Even though the liver is the metabolic organ primarily responsible for opioid biotransformation, the degree of liver failure typically observed in perioperative patients, with the exception of patients undergoing liver transplantation, does not have a major impact on the pharmacokinetics of most opioids. In addition to reduced metabolic capacity (i.e., cytochrome P-450 system and conjugation), liver disease may also lead to reductions in hepatic blood flow, hepatocellular mass, and plasma protein binding. The increase in total body water and the edema of advanced liver disease may alter the distribution characteristics of a drug. Enzyme induction such as observed in early alcoholism can actually increase metabolic capacity of the liver.

Morphine pharmacokinetics is relatively unchanged by developing liver disease, such as liver cirrhosis and hepatic carcinoma, because of the substantial compensatory extrahepatic metabolism of morphine. A reduction in hepatic blood flow would be expected to slow the decline of morphine plasma concentrations. After liver resection, M6G/morphine and M3G/morphine ratios were significantly reduced and circulating morphine concentration was increased mainly due to a lower morphine clearance. In patients with cirrhosis, the metabolism of meperidine is decreased, leading to accumulation of the parent drug and possible CNS depressive effects similar to hepatic encephalopathy. Although the elimination of normeperidine is decreased as well in these patients, the ratio of normeperidine to meperidine is generally low, and the opioid effects of meperidine usually predominate. The disposition of fentanyl and sufentanil appears to be unaffected in liver diseases. Reductions in liver blood flow that result from either liver disease or some other disorder (e.g., shock) can affect the pharmacokinetic parameters of alfentanil, fentanyl, and sufentanil. It was demonstrated that there was a significant decrease in clearance of alfentanil in patients with mild to moderate cirrhosis compared with volunteers from the historical control group. Remifentanil is an opioid whose pharmacokinetics is completely unchanged by liver disease ( Fig. 24.25 ). Its kinetics does not change during the anhepatic phase of orthotopic liver transplantation. It was reported that 0.25 to 0.5 μg/kg/min remifentanil could provide perioperative analgesia without neurological deterioration in a patient suffering from chronic hepatic failure with mild encephalopathy.

Time-dependent changes of blood concentration of remifentanil in patients with liver disease (A) and in control subjects (B) . In the low-dose group, remifentanil was infused at 0.0125 μg/kg/min for 1 hour and then 0.025 μg/kg/min for 3 hours. In the high-dose group, the infusion rate of remifentanil was 0.025 μg/kg/min for 1 hour and then 0.05 μg/kg/min for 3 hours.

From Dershwitz M, Hoke JF, Rosow CE, et al. Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesthesiology . 1996;84:812–820.

In summary, a reduction in renal function may have the greatest effects on morphine due to a decrease in capacity for extrahepatic glucuronidation and clearance. Therefore, fentanyl may be a safer choice in renal failure patients due to their lack of active metabolites. In contrast, only under conditions of severe hepatic failure does one observe clinically significant changes in morphine or fentanyl clearance.

Hemorrhagic Shock

It is a common practice to administer reduced doses of opioids to patients suffering from hemorrhagic shock to minimize adverse hemodynamic consequences and to prevent prolonged opioid effect. This is at least partially attributable to a pharmacokinetic mechanism. Analysis with pigs receiving fentanyl suggested that central clearance and central- and second-compartment distribution volumes were significantly reduced in hemorrhagic shock, resulting in higher fentanyl concentrations for any given dosages and prolonged context-sensitive half-time ( Fig. 24.26 ). Hemorrhagic shock also altered pharmacokinetics of remifentanil, suggesting that less remifentanil would be required to maintain a target plasma concentration ( Fig. 24.27 ). However, because of its rapid metabolism, changes in context-sensitive half-time are small. In a stepwise hemorrhage model of pigs receiving total intravenous anesthesia with remifentanil (0.5 μg/kg/min) and propofol (6 mg/kg/h after 2 mg/kg bolus), the plasma remifentanil concentration showed a threefold greater increase than that of propofol. Thus, the remifentanil dose should be reduced substantially compared with propofol during total intravenous anesthesia for patients with significant blood loss.

A computer simulation of the context-sensitive half-times (50% decrement times) and 80% decrement times of fentanyl in shock versus control animals.

From Egan TD, Kuramkote S, Gong G, et al. Fentanyl pharmacokinetics in hemorrhagic shock: a porcine model. Anesthesiology . 1999;91:156–166.

Mean spectral edge changes versus time during remifentanil infusion . The graph indicates spectral edge measurements for control animals and for animals with hemorrhagic shock, respectively.

From Johnson KB, Kern SE, Hamber EA, et al. Influence of hemorrhagic shock on remifentanil: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology . 2001;94:322–332.

Analgesia

Opioids are frequently used to relieve pain during monitored anesthesia care and regional anesthesia. A single bolus administration of opioids can provide significant pain relief. Morphine is slow in onset and does not allow rapid titration to effect. Meperidine (50-100 mg IV) produces variable degrees of pain relief and is not always effective in patients with severe pain. IV boluses of fentanyl (1-3 μg/kg), alfentanil (10-20 μg/kg), or sufentanil (0.1-0.3 μg/kg) can produce potent and short-lasting analgesia. Infusion rates range from 0.01 to 0.05 μg/kg/min for fentanyl, 0.0015 to 0.01 μg/kg/min for sufentanil, 0.25 to 0.75 μg/kg/min for alfentanil, and 0.05 to 0.25 μg/kg/min for remifentanil. Plasma concentrations of opioids necessary for various purposes are listed in Table 24.8 .

Changes in the excitability of central neurons play an important role in establishment of pain. In rats, low doses of fentanyl block the synaptic form of central sensitization in the rat spinal cord in vivo, suggesting the possibility of preemptive analgesia by fentanyl, but higher doses do not have this effect. In fact, dose escalation of fentanyl or other potent opioids may produce a hyperalgesic state—mentioned previously. Reductions in postoperative pain and improved recovery have been attributed to preemptive analgesia with either epidural fentanyl or bupivacaine after radical prostatectomy. In contrast, in patients undergoing transperitoneal tumor nephrectomy, preoperative intravenous administration of a combination of morphine, ketamine, and clonidine failed to exert a clinically relevant effect on postoperative pain. Aida et al. reported that the effectiveness of preemptive analgesia varies according to the type of surgery, and preemptive analgesia with epidural morphine was reliably effective in limb and breast surgeries but ineffective in abdominal surgery. A meta-analysis demonstrated that the results of preemptive analgesia with systemic administration of opioids are equivocal. Thus, whether or not preemptive analgesia can be effectively achieved clinically by the early administration of opioids remains uncertain and may be highly context specific.

Patient-controlled analgesia (PCA) with opioids has become a widely accepted technique in which to provide postoperative analgesia, but pharmacokinetic optimization of opioid treatment in acute pain is a complex matter. Without considering effect-site drug concentrations over time, the choice of opioid and the amount, method, and frequency of its administration cannot be optimal. Morphine and fentanyl are often used for PCA therapy, and piritramide is also frequently used for PCA in European countries. A double-blind randomized study demonstrated that effect-site target-controlled remifentanil PCA with a slow and progressive adapted algorithm is feasible in young women undergoing uterine artery embolization. Combination of opioid with other drugs might be a method for improvement of PCA. For thoracic surgery, addition of ketamine to opioid for intravenous PCA was superior to intravenous PCA opioid alone, whereas the effect of added ketamine was not significant for orthopedic or abdominal surgery. Despite the utility of an opioid-based PCA, critical considerations must also be made as to an individual patient’s relative risk of opioid-induced respiratory depression with appropriate oversight and monitoring.

Sedation

Critically ill subjects in the intensive care unit (ICU) often experience anxiety and agitation while being exposed to numerous stressful or noxious stimuli. ICU patients generally require a combination of analgesia and sedation to relieve their state of anxiety, improve adaptation to the endotracheal tube, and aid compliance with mechanical ventilation. Morphine, fentanyl, and sufentanil are frequently used intravenous analgesic agents in the ICU. A randomized double-blind study indicated that remifentanil (0.15 μg/kg/min) and morphine (0.75 μg/kg/min) could provide comparable levels of sedation, and the remifentanil-based regimen allowed a more rapid emergence from sedation and facilitated earlier extubation. However, use of ultrapotent opioid agents such as remifentanil may also drive tolerance development and OIH—as discussed previously.

Balanced Anesthesia

Anesthesia with a single agent can often require doses that produce excessive hemodynamic depression. Alternately, “balanced anesthesia” with a balance of agents and techniques can be used to more selectively direct different components of anesthesia (i.e., analgesia, amnesia, muscle relaxation, and abolition of autonomic reflexes with maintenance of homeostasis). For example, inclusion of an opioid as a component of balanced anesthesia can reduce preoperative pain and anxiety, decrease somatic and autonomic responses to airway manipulations, improve hemodynamic stability, lower requirements for inhaled anesthetics, and provide immediate postoperative analgesia. Opioids interact synergistically and markedly reduce the dose of propofol and other sedative-hypnotics required for loss of consciousness and during noxious stimulation such as skin incision ( Fig. 24.28 ). Although the intent of combining opioids with sedative-hypnotics and/or volatile anesthetics is to produce anesthetic conditions with stable hemodynamics prior to as well as after noxious stimulation, this ideal is not always achieved.

(A) Measured arterial propofol and fentanyl concentrations at which patients did and did not respond to a verbal command at 10 minutes after the initiation of the infusion of these drugs. The solid lines represent the modeled concentration of propofol, according to decade of age when combined with the measured fentanyl concentrations, at which 50% of patients did not respond to verbal command (Cp50s). (B) Reduction by increasing concentration of fentanyl of propofol concentration at which 50% or 95% of patients did not move at skin incision (Cp50i and CP95i, respectively). The solid lines represent logistic regression solution.

From Smith C, McEwan AI, Jhaveri R, et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology . 1994;81:820–828.

The timing, rate of administration, and dose of supplemental opioids should also be tailored to the specific condition of the patient and the expected duration of the operation in order to avoid problems. Giving a large dose of any opioid shortly before the end of surgery is very likely to result in postoperative respiratory depression. However, analgesic concentrations of opioids have little effect on the MAC awake of inhaled anesthetics.

The ideal opioid would permit rapid titration, prevent unwanted responses to noxious stimuli, require little supplementation, not depress cardiovascular function, permit the return of adequate spontaneous ventilation in a timely manner, and produce effective postoperative analgesia with minimal side effects. Alfentanil and remifentanil provide the greatest ability to titrate opioids rapidly because of their extremely rapid time to onset (1-2 minutes) of peak effect. Sufentanil, alfentanil, and remifentanil are arguably superior to fentanyl in most respects. Antagonism of opioid action with naloxone for troublesome respiratory depression is required less frequently after alfentanil and sufentanil compared with fentanyl. Pharmacologic antagonism is not required after remifentanil administration because of its short half-life.

Total Intravenous Anesthesia

Many different IV anesthetic and analgesic compounds can be employed in a number of combinations to provide TIVA. Most commonly, an opioid is combined with another drug more likely to provide hypnosis and amnesia. For example, combination of alfentanil and propofol can produce desirable TIVA. Alfentanil provides analgesia and hemodynamic stability while blunting responses to noxious stimuli. On the other hand, propofol provides hypnosis and amnesia and is antiemetic. Anesthetic induction with alfentanil (25-50 μg/kg) and propofol (0.5-1.5 mg/kg) followed by infusions of 0.5 to 1.5 μg/kg/min of alfentanil and 80 to 120 μg/kg/min of propofol will produce complete anesthesia for a variety of procedures. It is proposed that alfentanil concentrations as low as 85 ng/mL, when combined with a blood propofol concentration of 3.5 μg/mL, can produce both optimal anesthetic conditions and speed of recovery. Stanski and Shafer suggested that bolus doses and initial infusion rates would be 30 μg/kg and 0.35 μg/kg/min for alfentanil and 0.7 mg/kg and 180 μg/kg/min for propofol. Recognizing that these calculations were based on EC ₅₀ data in patients undergoing only moderately painful procedures, anesthesiologists should adjust these doses accordingly. In patients undergoing ear-nose-throat surgery, TIVA with remifentanil and propofol provided a more rapid respiratory recovery after brief surgical procedures, compared with TIVA with alfentanil and propofol.

Maintenance infusions vary according to patient condition and surgical stimuli. Propofol (75-125 μg/kg/min) and alfentanil (1.0-2.0 μg/kg/min) were initially recommended. Propofol infusions should be terminated 5 to 10 minutes before anticipated patient awakening. Alfentanil infusion rates do not need to be less than 0.25 to 0.5 μg/kg/min until surgery is terminated. A multicenter evaluation demonstrated that in patients of elective inpatient surgery remifentanil 1 μg/kg IV followed by 1.0 μg/kg/min, when combined with propofol 75 μg/kg/min, effectively controlled responses to tracheal intubation. Reduction of remifentanil infusion rate to 0.25-0.40 μg/kg/min after tracheal intubation was also recommended. Although midazolam-opioid combinations can also provide complete anesthesia, midazolam-alfentanil TIVA has not been found to compare favorably to propofol-alfentanil TIVA even with flumazenil reversal of benzodiazepine actions.

TIVA techniques are especially useful when delivery of inhaled agents is compromised. By keeping the goals of balanced anesthesia in mind, combining modern opioids and other drugs, utilizing infusion pumps, and employing an increased understanding of pharmacokinetics, clinicians can successfully perform a variety of TIVA techniques. Approximate opioid doses and infusion rates for TIVA are listed in Table 24.9 .

Related posts:

Perioperative Medicine Patient Simulation Local Anesthetics Management of the Patient with Chronic Pain Anesthesia for Obstetrics Anesthesia for Fetal Surgery and Other Fetal Therapies