Opioids

Introduction

To avoid the major adverse hemodynamic effects caused by potent inhalation anesthetic agents, the use of narcotic anesthesia has reemerged. Relative potencies of the various narcotics are listed in Table 12.1 . Initially, meperidine (0.5 to 1 mg/kg) and morphine (0.05 to 0.1 mg/kg) were used to reinforce nitrous oxide anesthesia in the neonate. However, concerns regarding the toxicity and increased sensitivity of neonates to opioids were raised. demonstrated that morphine depresses newborn respiration more than meperidine and that these decreases in ventilatory response to increased CO ₂ concentrations occur at a dose one-third (on a milligram per kilogram basis) of that administered to adults ( Fig. 12.1 ). In laboratory animals, narcotics are more toxic to newborn animals than to older animals ( ). For morphine and dihydromorphine, the blood-brain barrier is more permeable in newborn animals than in older animals. The brain concentration of morphine several hours after injection was two to four times greater in brains of younger rats despite equal blood concentration ( Fig. 12.2 ). This finding may be related to greater perfusion, to greater permeability, or to both in the newborn. Whereas increased permeability of the blood-brain barrier to morphine occurs in neonatal nonhuman primates (1 to 3 days after birth), the adult blood-brain barrier permeability is achieved by 2 months of age ( ).

Studies involving opiate receptor-binding sites in rats have suggested that changes in receptor ontogeny also may be responsible for the respiratory depressant and analgesic effects observed in newborns. showed that both low-affinity and high-affinity opiate receptors are present in rats. Low-affinity receptors are associated with respiratory depression, whereas high-affinity receptors are associated with analgesia. In the rat model, low-affinity receptors are present in large numbers at birth, and the number remains constant through 18 days of life. By contrast, high-affinity receptors are scarce at birth and do not reach significant proportions (50% of the adult value) until 15 days of life. Respiratory depression in infants may be a function not only of the lipophilicity of opioids but also of the maturational changes in the opiate receptor pool.

In addition to changes in opioid receptor ontogeny, developmental changes in drug-metabolizing enzymes may largely impact opioid pharmacokinetics in children ( ). Most notable are two members of the cytochrome P450 superfamily, CYP2D6 and CYP3A4, as well as one member of the glucuronosyltransferase family, UGT2B7 ( Fig. 12.3 a–c). CYP2D6 metabolizes several opioids by O-dealkylation, including codeine to morphine, tramadol to O-desmethyl tramadol, oxycodone to oxymorphone, and hydrocodone to hydromorphone. All four metabolites are active, each showing greater potency at the µ-opioid receptor than their parent compound ( ; ). After birth, CYP2D6 protein content and activity increases until 2 weeks of age, with no change thereafter ( ; ). On the other hand, CYP3A4 diminishes the action of several opioids, converting them into inactive metabolites. Examples include tramadol into nortramadol, oxycodone to noroxycodone, and fentanyl to norfentanyl ( ; ; ). CYP3A4 activity is very low in preterm and term neonates in the first days of life, but it surges in the first year of life. When corrected for body weight, young children (1 to 3 years old) have higher CYP3A4 activity levels than older children and adults ( ; ). UGT2B7 is responsible for the glucuronidation of morphine into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), which are then renally excreted. The former is not active at opioid receptors but has some convulsant activity. The latter is an active metabolite. Low UGT2B7 activity is present after birth, with low morphine clearance in term neonates less than 10 days of age, when a 50% dose reduction is needed to attain equivalent morphine exposure ( ). Subsequently, UGT2B7 activity increases rapidly in the first months of life.

Clinical studies on opioid sensitivity have been conflicting. Early reports by suggested that neonates had more respiratory depression after opioid administration than did adults. However, evaluated the respiratory depressant effects of intravenous morphine infusions in 30 postoperative patients aged 2 to 570 days and noted no evidence of a relationship of any given morphine concentration with respiratory depression and age. In this study, infants who had a morphine C _ss over 20 ng/mL, 67% of subjects, had elevated levels of arterial P co ₂ during spontaneous ventilation (six of nine infants), perhaps showing evidence of a threshold concentration.

studied the extent and duration of respiratory depression after intrathecal administration of 0.02 mg/kg of morphine to 10 patients aged 4 months to 15 years. Although intrathecal morphine depresses ventilation for at least 18 hours, there was no relationship between age and ventilatory depression. Age-related sensitivities have also been studied after intravenous fentanyl administration. determined that fentanyl-induced ventilatory depression, as assessed by skin surface P co ₂ and ventilatory patterns, was not greater in infants (older than 3 months) than in children or adults.

Pharmacogenetics

Many opioids are available for the treatment of pain in children. On the population level, there is no difference in analgesic efficacy (see Table 12.1 ) or adverse reactions between the drugs ( ). However, on the individual level, there is wide variation in clinical response to different opioids ( ). For example, almost a third of cancer patients do not respond well to morphine, but the majority of them achieve improved clinical outcomes upon switching to an alternate opioid ( ; ). Furthermore, most studies of morphine pharmacokinetics in infants and children have reported large interindividual variability, as shown in Fig. 12.4 . The same variability has been seen with meperidine and even with fentanyl ( ). These large interindividual differences make predicting effect and duration of action in an individual problematic and contribute to the difficulty of achieving successful pain control.

Ethnic differences account for some of the observed variability. demonstrated ethnic differences in the disposition and effects of morphine. In a study in Chinese and Caucasian adult volunteers, they found that Chinese subjects had an increased morphine clearance with decreased respiratory and hemodynamic depressant effects. Interestingly, the decreased respiratory and hemodynamic susceptibility did not correlate with the gastrointestinal effects, with Chinese subjects experiencing more nausea and vomiting than Caucasians.

More recently, several studies have discovered ethnic differences in the analgesic response and side-effect profile of opioids in children undergoing ENT surgery. studied African American and Caucasian children aged 5 to 15 years undergoing adenotonsillectomy. They identified a higher morphine clearance in African American children relative to Caucasian children. Furthermore, morphine in the pediatric African American population was preferentially metabolized to the inactive M3G rather than the active M6G. Congruent with elevated morphine clearance, found that African American children experienced significantly more posttonsillectomy pain than their Caucasian counterparts, despite similar use of intraoperative morphine.

Sadhasivam’s study also demonstrated an ethnic difference in opioid side effects. Although Caucasian children received less morphine perioperatively than the African American children in the study, they experienced a 2.8-fold higher incidence of opioid-related adverse effects. (Respiratory depression, nausea/vomiting, excessive sedation, and pruritus were assessed.) While African American children as a whole are less sensitive to the adverse effects of opiates, Latino children appear to be at the other end of the spectrum. found that posttonsillectomy, Latino children have a sevenfold higher incidence of nausea and vomiting and a fourfold higher incidence of pruritus than Caucasian children. The higher incidence of gastrointestinal effects and pruritus were found despite no difference in pain scores, need for rescue analgesia, or measurable pharmacokinetic parameters (plasma morphine, M3G, and M6G concentrations), suggesting pharmacodynamic differences between the populations.

Differing alleles and allele frequencies between ethnic groups likely underlie much of the observed differences in opioid response. Pharmacogenetics is the study of how genetic variation impacts the pharmacokinetic and pharmacodynamic properties of an administered drug. In this chapter, some of the most studied and best-delineated examples from the field of opioid pharmacogenetics are highlighted. They are summarized in Table 12.2 .

Opioid pharmacokinetics are influenced by drug transporters and drug metabolism. When an opioid is ingested, efflux transporters that restrict absorption and influx transporters that facilitate absorption may alter bioavailability. Transporters in the brain regulate drug passage across the blood-brain barrier into the central nervous system (CNS), and transporters in the liver influence hepatic extraction of drugs. Within the hepatocyte, drugs undergo phase one and phase two metabolism. The former involves modification by oxidation, reduction, or hydrolysis, such as by the cytochrome P450 (CYP) enzymes. The latter involves conjugation, such as glucuronidation by the uridine diphosphate glucuronosyltransferase (UGT) enzymes ( ). Ultimately, transporters in the liver and kidneys facilitate hepatobiliary and renal excretion of opioids and their metabolites ( ; ; ; ).

The best clinical example of how genetic variation in drug transporters can affect opioid response is the ATP-binding cassette subfamily B member 1 ( ABCB1 ), also known as Multidrug Resistance Gene 1 ( MDR1 ); this gene encodes the efflux transporter P-glycoprotein 1 (P-gp). P-gp is present in the kidneys, liver, intestines, brain, and placenta, where it acts on many drugs, including morphine, methadone, and fentanyl. Inhibition of P-gp results in elevated plasma concentrations of fentanyl and methadone ( ).

examined the effects of five single-nucleotide P-gp polymorphisms on methadone dosage requirements in the treatment of opioid dependence. By definition, the wild-type haplotype contains none of the mutations, each of which is common in the Caucasian population and together are found in linkage disequilibrium (the nonrandom association of genes in different areas of the chromosome in a specific population). Individuals with two wild-type haplotypes required almost twice as much methadone for maintenance than individuals with one or no wild-type haplotypes. With P-gp acting on many drugs, the effects of ABCB1 mutations are not limited to methadone. Some of the same mutations have been linked to increased analgesia and decreased CNS side effects (drowsiness and confusion) from morphine ( ; ), as well as decreased morphine equivalent daily dose in chronic opioid users ( ).

Genetic variants in another drug transporter, the organic cation transporter OCT1, have been linked to postoperative morphine-related adverse effects in children ( ). Mutations in OCT1 , which is highly expressed in the liver, affect hepatic uptake and therefore metabolism of opioids, like morphine, codeine, and tramadol ( ). found that OCT1 mutation rs12208357 (missense) is associated with an increased incidence of postoperative nausea and vomiting and prolonged PACU stay secondary to postoperative nausea and vomiting, whereas OCT1 mutation rs72552763 (in frame deletion) is associated with increased incidence of respiratory depression.

Polymorphisms affecting drug-metabolizing enzymes have been studied as well. In fact, they account for an estimated 10- to 10,000-fold variation in drug activity ( ). Known examples that affect clinical opioid pharmacology are found in the genes that encode CYP2D6, CYP3A4, and UGT (see Tables 12.2 , 12.3 , and 12.4 ).

TABLE 12.4

Major Enzymes for Opioid Metabolism

(Adapted with permission from Bosilkovska M, Walder B, Besson M, et al. (2012). Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs, 72, 1645–1669.)

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CYP2D6 metabolizes codeine, tramadol, oxycodone, and hydrocodone (see Fig. 12.3 a–c). For each of these opioids, CYP2D6 variants have been shown to alter clinical response (Tramadol: ; Oxycodone: ; ). The most noteworthy example involves codeine, because codeine has minimal intrinsic analgesic activity; instead, analgesic effect is attributed to O-demethylation to morphine by CYP2D6 ( ; ).

There are over 70 CYP2D6 alleles, including single-nucleotide polymorphisms (SNPs), deletions, insertions, and copy number variations ( ). Phenotypically, the alleles are divided into four classes, defined relative to the activity of a single normal allele, which is equal to 1. Poor metabolizers have no (0) CYP2D6 enzyme activity; intermediate metabolizers have low activity (<1); extensive metabolizers have normal activity (≥1, <3); and ultrarapid metabolizers have excess functional copies of CYP2D6 and therefore excess activity (≥3).

Because CYP2D6-poor metabolizers are unable to convert codeine into morphine, they receive little or no analgesia from codeine ( ; ). Extensive metabolizers convert about 10% of codeine into morphine, but ultrarapid metabolizers produce larger amounts of morphine, resulting in exaggerated analgesic and adverse effects ( ). Neonates and young children are at particular risk. Case reports of severe morbidity and mortality from toxic levels of morphine have been reported following administration of typical dosages of codeine to both children and nursing mothers ( ; ; ). Ethnic differences in CYP2D6 activity have been reported. Although up to 10% of Caucasians are poor metabolizers ( ), less than 1% of Asians are poor metabolizers ( ). Prevalence of the ultrarapid phenotype varies as well, from 3% of northern Europeans and 5% to 10% of southern Europeans to up to 30% of Arabian and northeast African populations ( ; ; ).

CYP3A4 metabolizes fentanyl and oxycodone, and CYP3A allele frequencies are highly variable among different ethnic groups ( ). One allele, CYP3A4*1G , which is shared by more than a quarter of Chinese, results in decreased fentanyl metabolism, higher plasma concentrations, and lower postoperative requirements ( ; ; ). Although numerous other alleles have been identified, they appear to have little clinical effect, possibly due to the redundancy of CYP3A4 and CYP3A5 ( ).

UGT expression is no different and varies widely within the population ( ). Genetic variants have been linked to altered levels of mRNA expression, enzyme activity, and differential metabolite production (plasma M3G:M6G ratios) ( ; ; ).

Pharmacokinetic variation results in differential exposure of target organs to opioids and goes far to explain the wide range in clinical response to opioids. Yet genetic variation in pharmacodynamics causes further diversity by altering the response to narcotics that make it to the target site. Indeed, mutations have been identified in the opioid receptors and the enzymes involved in intracellular signaling. There have been more than 100 polymorphisms identified in the human µ-opioid receptor ( OPRM1 ), a G protein–coupled receptor. The most widely studied SNP, found in 10% to 15% of the Caucasian population, is A118G ( ). This mutation results in both reduced expression of the µ-opioid receptor and reduced signaling efficacy ( ; ; ). Individuals with two copies of the mutation (GG) have been found in numerous studies to have higher pain scores and larger requirements for morphine, fentanyl, and alfentanil in the setting of acute postoperative pain ( ; ; ; ; ; ; ; ). Even heterozygote individuals were shown to have a reduced analgesic response to M6G in experimentally induced pain ( ).

Two proteins, STAT6 and β-arrestin 2, alter µ-opioid receptor activity and are linked to overall response to morphine and opioid switching ( ). STAT6 is a transcription factor activated with TH2 cytokine stimulation (e.g., IL-4). Activated STAT6 binds the promoter region of OPRM1 and upregulates receptor expression ( ; ). On the other hand, β-arrestin 2 augments µ-opioid receptor inactivation and internalization ( ). Opioids appear to differentially induce receptor phosphorylation, β-arrestin 2 recruitment, and opioid receptor internalization ( ; ). Due to the critical roles of STAT6 and β-arrestin 2 in opioid signaling, genotyped cancer patients on chronic opioids for pain control. Patients who responded poorly to morphine and were switched to a different opioid were more likely to have four specific SNPs in these two genes.

Modifying systems have a more indirect effect on the opioid response. Catechol-O-methyl transferase (COMT) is one of several enzymes that metabolizes catecholamines. A single nucleotide substitution (rs4680) results in a change from valine to methionine at position 158. The resultant protein has a three- to fourfold reduction in enzyme activity, and homozygote individuals have increased pain sensitivity and diminished µ-opioid system activation ( ). The mutation has been linked to variability in pain and narcotic consumption in a wide range of clinical settings, such as cancer, sickle cell, and postoperative ( ; ; ).

It is clear that many polymorphisms affect an individual’s response to narcotics, from drug uptake and metabolism to intracellular signaling. Pharmacogenetic analysis as a diagnostic tool has the potential to predict the individual response of a particular narcotic and will hopefully individualize pain management to a greater extent in the future ( ).

Although there is great promise for the field of pharmacogenetics, genotype is not the sole determinant of phenotype. The environment influences gene expression, ultimately resulting in cellular phenotype. The field of epigenetics studies this influence. In an intriguing example of how epigenetics may affect opioid pharmacology, quantified DNA methylation in two patient populations exposed to chronic opioids. DNA methylation is a major mechanism to alter gene transcription and is altered by age, smoking, and drug exposure. Doehring and colleagues found that methylation was increased at both the OPRM1 gene and at a global methylation site ( LINE-1 ). The changes were found in patients who were exposed to chronic opioids for separate indications: opioid addiction and chronic pain. For the patients with chronic pain, the amount of methylation at LINE-1 correlated with severity of pain.

Another example of DNA methylation altering opioid response and addiction is found in neonatal abstinence syndrome (NAS) from in utero opioid exposure. investigated cytosine:guanine (CpG) dinucleotide methylation in the promoter region of OPRM1 . They discovered that infants requiring treatment for NAS had hypermethylation at −10 CpG. Furthermore, in neonates requiring stronger therapy (two or more medications), hypermethylation was additionally seen at −14 and +84 CpG. Increased methylation in the OPRM1 promoter region was associated with worse NAS outcomes and consistent with gene silencing and decreased opioid receptor expression. looked at DNA methylation of additional genes involved in opioid pharmacokinetics and pharmacodynamics. In addition to the OPRM1 locus in neonates with NAS, hypermethylation was found at the ABCB1 and CYP2D6 loci in both methadone-maintained, opioid-dependent mothers and their newborns. Collectively, these studies demonstrate that chronic opioid exposure alters DNA methylation and presumably gene expression, in turn affecting pain and analgesia phenotype.

Opioid analgesics

Opioids are frequently administered during anesthesia to attenuate the hemodynamic effects and reduce the anesthetic requirements of the inhaled anesthetic agents. The pharmacokinetic and pharmacodynamic effects of opioids are dependent on the dose administered, the duration of their administration, and the route of administration. Although opioids can markedly reduce patients’ inhaled anesthetic requirements, they cannot act as a sole anesthetic agent for general anesthesia, even at high doses. Potencies of the various opioids are listed in Table 12.1 , and their schedule classifications are listed in Box 12.1 , where they are classified according to their potential for abuse.