Anesthesia: Essays and Researches

REVIEW ARTICLE
Year
: 2021  |  Volume : 15  |  Issue : 1  |  Page : 4--7

Fentanyl-induced respiratory depression: A narrative review on the possible single-nucleotide polymorphism


Prabha Udayakumar1, Srisruthi Udayakumar2,  
1 Department of Anesthesiology, Sri Ramakrishna Hospital, Coimbatore, Tamil Nadu, India
2 Department of Biotechnology, PSG College of Technology, Coimbatore, Tamil Nadu, India

Correspondence Address:
Dr. Prabha Udayakumar
Department of Anesthesiology, Sri Ramakrishna Hospital, Coimbatore - 641 044, Tamil Nadu
India

Abstract

Opioid-related respiratory depression is a serious clinical problem as it can cause multiple deaths and anoxic brain injury. Genetic variations influence the safety and clinical efficacy of fentanyl. Pharmacogenetic studies help in identifying single-nucleotide polymorphisms (SNPs) associated with fentanyl causing respiratory depression and aid clinician in personalized pain medicine. This narrative review gives an insight of the common SNPs associated with fentanyl.



How to cite this article:
Udayakumar P, Udayakumar S. Fentanyl-induced respiratory depression: A narrative review on the possible single-nucleotide polymorphism.Anesth Essays Res 2021;15:4-7


How to cite this URL:
Udayakumar P, Udayakumar S. Fentanyl-induced respiratory depression: A narrative review on the possible single-nucleotide polymorphism. Anesth Essays Res [serial online] 2021 [cited 2021 Dec 6 ];15:4-7
Available from: https://www.aeronline.org/text.asp?2021/15/1/4/325039


Full Text

 Introduction



An individual's response to a drug may vary according to the age, gender, weight, pharmacokinetics, disease severity, concomitant diseases, and environmental factors.[1] The sensitivity of an individual toward a drug is innate, and it depends on their genetic makeup. Administration of any drug to an individual should be carried out with caution. Hence, knowing their sensitivity is crucial. The activity of a drug is by its interaction with proteins involved in absorption, distribution, metabolism, elimination, and molecular drug targets. The genes that code for these metabolizing enzymes or drug transporters play a pivotal role, because single-nucleotide polymorphism (SNP) in these genes can produce a significant influence on an individuals' response to the drug. The inter-individual variability in drug metabolism, caused by genetic variation, is hence the significant reason for the response to drugs.

Opioid drugs that include morphine, methadone, fentanyl, alfentanil, sufentanil, and remifentanil are used to provide sedation and analgesia. There is tremendous variability in pharmacological response of these drugs among patients due to the lack of knowledge about an individual's genotype. Although there is a known genetic influence on the potency of the opioid-induced analgesia, the genetic component of opioid-induced respiratory depression is still unclear. Determining genetic profiles of the patients susceptible to respiratory depression could prove useful in further tailoring the treatment of pain both in perioperative setting and in chronic pain management.

Incidence of postoperative opioid-induced respiratory depression in the UK has been estimated to be approximately 1%.[2] Respiratory depression can occur in clinical care setting in patients undergoing procedures requiring sedation with monitored anesthesia care to treating acute and chronic pain.

An SNP represents a variation in a DNA sequence among individuals at one location. SNP is considered to exist when more than 1% of population does not bear the same nucleotide at a certain position in the DNA sequence. When a single nucleotide polymorphism exists in a gene, the gene is said to have more than one allele. These associations enable scientists to look for SNPs to analyze the genetic predisposition of an individual for the development of a disease. Furthermore, if such SNPs are found to be associated with a trait, then researchers may analyze DNA stretches near these SNPs in an effort to identify the genes that are responsible for a given behavioral pattern.[3]

Many research projects have focused on unraveling the inter-individual variability in opioid response. Pharmacogenetics is one of the most promising disciplines in this respect. It is assumed that specific inherited genetic variations can predict a patient's response to drugs. The findings from transgenic knockout mice studies, candidate gene analysis, and genomic-wide association studies in humans point toward a genetic component in relation toward the efficacy of the drug, thus confirming that pharmacogenetics may help improve patient care.[4] Although several reviews and scientific findings have identified and studied over 400 genes using in vitro and in vivo models, they typically have not focused on translation into clinical practice.

We performed literature search for this review in PubMed and Google Scholar using the following MeSH terms: “Pharmacogenetics;” “Fentanyl;” “Single Nucleotide Polymorphism;” “Respiratory depression.” With this survey, we have shortlisted five genes – OPRM1, CYP3A4, CYP3A5, ABCB1, and ABCC1 and their SNPs that can lead to fentanyl-induced respiratory depression.

 Fentanyl



Fentanyl is a 2-phenylethyl-substituted 4-anilinopiperidine derivative containing a propionylamide moiety linked to the nitrogen in the aniline. It is an aliphatic heterocyclic tertiary amine which has two phenyl groups and an aromatic amide function [Figure 1].{Figure 1}

Various routes of fentanyl administration are accepted for use, including sublingual tablets, oral transmucosal lozenges, effervescent buccal tablets, sublingual sprays, nasal sprays, injectable formulations, and transdermal patches. Such formulations are used as analgesics in surgical settings and chronic pain therapies and as rescue medicines for breakthrough pain in cancer patients.

Fentanyl is partially absorbed in the gastrointestinal tract and has only half the bioavailability when compared to that of the intravenous route. It is primarily metabolized in the liver, and renal excretion accounts for less than 10%. Fentanyl is 100 times more potent than morphine.

Fentanyl attaches to opioid receptors that are coupled with G-proteins, particularly the mu opioid receptor (MOR). Opioid receptor activation by fentanyl allows GTP on the G-proteins to be substituted for GDP, which in effect downregulates adenylate cyclase, decreasing cAMP concentrations. Reduced cAMP lowers the influx of calcium into the cell, thus inhibiting pain transmission. Fentanyl is metabolized in the liver via N-dealkylation to its inactive form norfentanyl, by cytochrome P450 enzymes. The cytochrome P450 enzyme is encoded by the genes CYP3A4 and CYP3A5.

 Opioid Receptors



Four opioid receptor subtypes namely mu opioid receptor (MOR), Kappa opioid receptor (KOR), delta opioid receptor (DOR), and opioid receptor-like 1 (ORL-1) are described. These receptors are all G-protein-coupled receptors (GPCRs). They possess a conserved transmembrane composition, but vary substantially in both intracellular and extracellular structure, and are believed to have fundamentally different but closely interrelated functions.[5]

MORs are present in high concentration in the limbic system and in the brain areas associated with neurohormonal secretion, for example, in the hypothalamus. Mu receptors have essential roles in the regulation of pain and stress responses. For most of the current opioid agonists, the mu receptor is the primary target to treat pain. MORs are also involved in euphoria, sedation, meiosis, addiction, truncal rigidity, nausea, and respiratory control in the central nervous system.[6]

When compared with the mu receptor, KORs are thought to mediate distinct physiological processes. They are found in the higher concentration in the spinal cord and are thought to play a significant role in the hyperalgesic production. Kappa receptors were deemed essential for the modulation of visceral pain.

The delta receptor is the third type of opioid receptor. Similar to the mu receptors, DORs are present in the midbrain at relatively small concentrations but at high density in the peripheral nerve dorsal root ganglia. These have a relatively small effect on the experience of acute pain, but may have a more important role in modulating chronic pain and peripheral nociception, and are a focus for current pharmacological study. The primary endogenous agonist for delta receptors is the enkephalins developed in the intestine, the sympathetic nervous system, and the adrenal glands.[7]

The ORL-1 presents a high percentage of sequence homology to the other opioid receptor subtype.[8] However, studies have shown that they have very low affinity for binding with the opioid ligands.[8],[9]

The ligand-induced activation mechanism of G-proteins of the opioid receptors is depicted [Figure 2]. Binding of an opioid receptor ligand such as fentanyl contributes to an increased receptor affinity with intracellular G-proteins through a conformation transition, which on stimulation results in activation of downstream effectors such as adenylate cyclase and Ca2+ channels or stimulation of K+ channels. As a result, concentrations of intracellular cAMP, K+, and Ca2+ decrease, preventing neurotransmitter release and neuron excitation.{Figure 2}

 Opioid Receptor Mu 1



Opioids such as fentanyl and morphine exert their action primarily through the opioid receptor mu 1 (OPRM1) gene encoded MOR. The MOR is a member of the GPCR family of rhodopsin. The human OPRM1 gene is located at 6q25.2 on the chromosome and spans more than 200 Kb, with at least 9 exons and 19 different splice variants under multiple promoter sequences regulation, and includes several different splice sites.[10] Large amounts of genetic variation were identified in OPRM1, with relatively high frequency of the minor alleles (MAF). The most studied opioid pharmacogenetic variant is 118A > G (SNP database[dbSNP] Accession No. rs1799971), which is located in exon 1 of the gene OPRM1. In this SNP, adenine (A) is substituted with guanine (G), which in turn causes a change in the translated amino acid at position 40 from asparagine to aspartic acid (N40D) in the MOR protein, leading to the loss of an N-glycosylation site in the receptor extracellular region.[11]

Fentanyl shows a high affinity with OPRM1 gene.[12] Fentanyl binding activates the MOR and results in a change in its conformation, which triggers the activation/inactivation process of the G protein (particularly, the Gi/Go toxin-sensitive pertussis proteins). In vivo studies on 118A > G demonstrated a reduction in fentanyl-binding affinity and signal transduction for the receptor having this variant. It is also reported that carriers of the variant 118A > G need to be given high amounts of opioids.[13]

 Cytochrome P450 Family 3 Subfamily A Members 4 and 5



The cytochrome P450 family 3 subfamily A members 4 and 5 (CYP3A4/3A5) is a group of heme-thiolate mono-oxygenases, and their genes on chromosome 7q22.1 are part of a cluster of cytochrome P450 genes. The gene CYP3A4 spans with 13 exons over 27 Kb and the gene CYP3A5 spans with 14 exons over 30 Kb. Over 20 variant alleles were discovered in the gene CYP3A4. For most Caucasians, the CYP3A5 enzyme is not expressed because the SNP 6986A > G induces a splicing defect.[14] Most Caucasians are nonexpressors of CYP3A5, and this variant of CYP3A5 * 3 has an allele frequency of 90%.[15] The intron 6 SNP rs35599367 is associated with a reduction in the expression of CYP3A4 mRNA and its enzymatic activity in the human liver.[16]

As for opioids, the genetic variation in both CYP3A4/CYP3A5 affected opioid metabolism in European research (n = 620). A similar Chinese study on human liver microsomes (n = 88) showed that SNP in CYP3A4 gene resulted in a decrease in CYP3A4 mRNA levels and metabolism of fentanyl.[17] Both studies showed an effect on Pharmacokinetics and Pharmacodynamics (PK/PD) fentanyl. Such enzymes are highly important for the removal of fentanyl through norfentanyl bioinactivation.[18]

 Adenosine triphosphate-Binding Cassette Subfamily B Member 1/Subfamily C Member 3



Adenosine triphosphate-binding cassette (ABC) subfamily B member 1 (ABCB1), also referred to as P-glycoprotein or multidrug resistance protein 1, is known from its role as an efflux pump at the blood–brain barrier. It is located at 7q21.12 on the chromosome and covers more than 200 Kb. The ABCC3, also referred to as multidrug resistance protein 3, is known from its role as an efflux pump from liver to the bloodstream. It is located on the chromosome at 17q21.33 and spans over 57 Kb.[19]

The ABCB1 is one of the many ubiquitous ABC genes that play a significant role in cellular homeostasis.[20] More than 8000 SNPs for the ABCB1 gene have been reported, but only 4% have a MAF above 5%. The SNP that is most studied is 3435C > rs1045642. A study found that SNP 211C > T (rs4793665) was associated with decreased expression of ABCC3 mRNA and changes in transcription binding factors.[21]

 Future Perspectives



Fentanyl is a commonly prescribed pain medicationRoutinely, genetic testing is not performed in patients to screen for fentanyl-induced respiratory depressionEvaluating patients developing fentanyl-induced respiratory depression may open avenues to establish correlation between fentanyl-induced respiratory depression and existing SNPs and also pave way to integrate evidence for new SNPs causing fentanyl-induced respiratory depressionThus bridging the gap between genetic studies and there important clinical implications.

 Conclusion



While the literature survey has provided important information that sheds light on the SNPs in the genes that can lead to fentanyl-induced respiratory depression, further research is needed to understand this relationship in a clinical setting. As genetic testing becomes more affordable and feasible in clinical practice, personalized tailoring of opioid analgesics by utilizing SNP analysis is possible in deserving patients ensuring their safety.

Acknowledgment

We thank Dr. Vinodhadevi Vijayakumar, DA, M.D., DNB., for reviewing the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Siva C, Yokoyama WM, McLeod HL. Pharmacogenetics in rheumatology: The prospects and limitations of an emerging field. Rheumatology (Oxford) 2002;41:1273-9.
2Cashman JN, Dolin SJ. Respiratory and haemodynamic effects of acute postoperative pain management: Evidence from published data. Br J Anaesth 2004;93:212-23.
3Muraoka W, Nishizawa D, Fukuda K, Kasai S, Hasegawa J, Wajima K, et al. Association between UGT2B7 gene polymorphisms and fentanyl sensitivity in patients undergoing painful orthognathic surgery. Mol Pain 2016;12:1744806916683182.
4Mercadante S. Opioid metabolism and clinical aspects. Eur J Pharmacol 2015;769:71-8.
5Friedman A, Nabong L. Opioids: Pharmacology, physiology, and clinical implications in pain medicine. Phys Med Rehabil Clin N Am 2020;31:289-303.
6Cuitavi J, Hipólito L, Canals M. The life cycle of the mu-opioid receptor. Trends Biochem Sci 2021;46:315-28.
7Pradhan AA, Befort K, Nozaki C, Gavériaux-Ruff C, Kieffer BL. The delta opioid receptor: An evolving target for the treatment of brain disorders. Trends Pharmacol Sci 2011;32:581-90.
8Chen Y, Fan Y, Liu J, Mestek A, Tian M, Kozak CA, et al. Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family. FEBS Lett 1994;347:279-83.
9Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, et al. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 1994;341:33-8.
10Shabalina SA, Zaykin DV, Gris P, Ogurtsov AY, Gauthier J, Shibata K, et al. Expansion of the human μ-opioid receptor gene architecture: Novel functional variants. Hum Mol Genet 2009;18:1037-51.
11Huang P, Chen C, Mague SD, Blendy JA, Liu-Chen LY. A common single nucleotide polymorphism A118G of the μ opioid receptor alters its N-glycosylation and protein stability. Biochem J 2012;441:379-86.
12Mura E, Govoni S, Racchi M, Carossa V, Ranzani GN, Allegri M, et al. Consequences of the 118A>G polymorphism in the OPRMI gene: Translation from bench to bedside? J Pain Res 2013;6:331-53.
13Hwang IC, Park JY, Myung SK, Ahn HY, Fukuda K, Liao Q. OPRM1 A118G gene variant and postoperative opioid requirement: A systematic review and meta-analysis. Anesthesiology 2014;121:825-34.
14Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383-91.
15van Schaik RH, van der Heiden IP, van den Anker JN, Lindemans J. CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 2002;48:1668-71.
16Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011;11:274-86.
17Yuan JJ, Hou JK, Zhang W, Chang YZ, Li ZS, Wang ZY, et al. CYP3A4 * 1G genetic polymorphism influences metabolism of fentanyl in human liver microsomes in chinese patients. Pharmacology 2015;96:55-60.
18Guitton J, Buronfosse T, Désage M, Lepape A, Brazier JL, Beaune P. Possible involvement of multiple cytochrome P450S in fentanyl and sufentanil metabolism as opposed to alfentanil. Biochem Pharmacol 1997;53:1613-9.
19Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR, et al. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci U S A 2005;102:7274-9.
20Jones PM, George AM. The ABC transporter structure and mechanism: Perspectives on recent research. Cell Mol Life Sci 2004;61:682-99.
21Lang T, Hitzl M, Burk O, Mornhinweg E, Keil A, Kerb R, et al. Genetic polymorphisms in the multidrug resistance-associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics 2004;14:155-64.