Abstract
The abuse of opioids has become one of the most serious concerns in the world. Opioid use can cause serious adverse reactions, including respiratory depression, postoperative nausea and vomiting, itching, and even death. These adverse reactions are also important complications of clinical application of opioid drugs that may affect patient safety and recovery. Due to the fear of adverse reactions of opioids, clinicians often do not dare to use opioids in an adequate or appropriate amount, thus affecting the clinical medication strategy and the quality of treatment for patients. The prediction of adverse reactions to opioids is one of the most concerned problems in clinical practice. At present, the correlation between gene polymorphism and the efficacy of opiates has been widely studied and preliminarily confirmed, but the research on the effect of gene polymorphism on the adverse reactions of opiates is relatively limited. Existing studies have made encouraging progress in predicting the incidence and severity of adverse opioid reactions and clinical management by using genetic testing, but most of these studies are single-center, small-sample clinical studies or animal experiments, which have strong limitations. When the same receptor or enzyme is studied by different experimental methods, different or even opposite conclusions can be drawn. These phenomena indicate that the correlation between gene polymorphism and adverse opioid reaction still needs further research and demonstration. At present, it is still too early to use genetic testing to predict opioid adverse reactions in clinic. In this paper, the correlation between gene polymorphism and adverse opioid reactions and a small number of clinical applications were reviewed in terms of pharmacokinetics and pharmacodynamics, in order to provide some suggestions for future research and clinical drug decision making.
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Avoid common mistakes on your manuscript.
A possible uncertain correlation between single-nucleotide polymorphisms (SNPs) and opioid adverse reactions is being investigated. |
A variety of genes, including those affecting the pharmacokinetics and pharmacodynamics of opioids, may promote or inhibit the occurrence of adverse reactions to opioids, but this possible role has not been effectively demonstrated. |
At present, evidence-based approaches are lacking from most studies focused on the effects of SNPs on adverse reactions to opioids, and most are single-center studies. The results of studies on the same genotype can be contradictory. |
Pharmacogenomics (PGx) can tailor the use of specific analgesics based on different genotypes, improving the efficacy of the analgesics and minimizing adverse reactions to opioids. |
Introduction
Opioids are used for acute pain (e.g., perioperative analgesia), moderate and severe cancer pain, and malignant chronic pain [1], and are the cornerstone of analgesic therapy. However, the abuse of opioids has become one of the most serious public health concerns in the world, especially in North America [2]. Due to the significant difference in the number and sensitivity of opioid receptors in the central distribution, individuals have great differences in drug dose and efficacy [3]. How to apply the minimum dose of opiates to obtain the maximum effect has been a research hotspot in recent years. However, in clinical formulation of medication strategies, in addition to considering the efficacy of opioids, adverse reactions of opioids are an important factor limiting their use [4]. These include severe postoperative nausea and vomiting (PONV), respiratory depression (RD), lethargy, and constipation [5]. Some patients have experienced obvious adverse reactions without the expected analgesic effect of opioids, which seriously affect the quality of life of patients [6]. These adverse reactions can even lead to death due to severe respiratory depression [7], or it may force clinicians to lower or even stop opioid medication, resulting in further pain [14], there are some studies that disagree [15]. Therefore, we only review current studies that are based on the correlation between gene polymorphisms of the above two transporters and adverse opioid reactions, and do not suggest genetic testing of opioids for these two gene polymorphisms.
ABCB1
The target of opioids is mainly in the central nervous system (CNS), so the transport of opiates across the blood–brain barrier (BBB) is one of the key factors affecting the efficacy and clearance of opiates. Opioids enter the CNS via the BBB mainly through passive transport, while removal is mainly through an efflux transporter at the BBB [16]. These efflux transporters are essential for the prevention and treatment of adverse reactions caused by opioid abuse and overdose. ABCB1-coded P-glycoprotein (P-gp) is an efflux transporter that limits intracellular drug accumulation by pum** compounds out of cells [17]. A study in mice showed that P-gp is one of the main components of the blood–cerebrospinal fluid (CSF) barrier. As an outward drug transporter for ATP energy supply, P-gp plays an important role in regulating the clearance of opioids from the CNS [18]. ABCB1 and C. 3435C>T polymorphisms are associated with adult morphine BBB transporter activity, and the homozygous TT genotype is associated with a higher maximum morphine concentration in the CSF than that observed in those with other genotypes [19]. This correlation can lead to an increase in the incidence of opioid-related respiratory depression after surgery [20]. Recent research has revealed that mutations in ABC family genes in the morphine response pathway affect the clinical outcome of morphine administration, including RD, in children [21]. Chidambaran et al. [22] first confirmed that ABCC3 variation has a significant effect on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G). A further study selected 42 ABCC3 gene polymorphisms for comparative analysis of the incidence of RD and the incidence of prolonged anesthesia recovery time caused by RD. The results revealed that although there was no significant statistical association between ABCC3 polymorphism and RD, seven ABCC3 polymorphisms located in the 48731392-48744612 bp chromosome 17 region, especially two adjacent polymorphisms, rs739923 and rs4148412, resulted in a significant association with prolonged recovery time in the postanesthesia care unit (PACU).
Compared with mean duration to achieve PACU discharge readiness (duration of PACU stay), children with these high-risk genotypes for prolonged RD stayed in the PACU about 50 min longer [21]. This finding suggests that polymorphisms found in specific regions of the ABCC3 gene (CHR17: 48731392-48744612) are associated with severe RD.
OCT1
Opioids are mainly metabolized in hepatocytes [23], so the rate of uptake of opioids by hepatocytes is one of the important factors determining the rate of opioid metabolism. OCT1 (alternative name SLC22A1) is a transporter in the liver that transports morphine from the bloodstream to hepatocytes. The downregulation of OCT1 protein expression due to the gene polymorphisms and decreased OCT1 transporter activity results in a decrease in intrahepatic morphine uptake, a decrease in the morphine clearance rate, and an increase in systemic morphine levels. The higher the plasma morphine level, the higher the incidence of morphine-induced PONV and RD will be. An in vitro study by Tzvetkov et al. [24] showed that overexpression of OCT1 by HEK293 cells is associated with a fourfold increase in morphine uptake. OCT1 genotypic variation can affect morphine clearance, characterized by decreased morphine clearance in children with OCT1 genotypic deficiency [25]. This genotype may affect the incidence of morphine-related adverse reactions. In a prospective study of 311 children who underwent tonsillectomy, Balyan et al. [26] found an association between non-synonymous polymorphisms in the OCT1 gene and morphine-induced adverse postoperative outcomes. There was a significant correlation between OCT1 SNP rs12208357 and refractory PONV, and another SNP, rs72552763, was associated with RD. Previous studies have suggested that both SNP rs12208357 and SNP rs72552763 are associated with reduced liver intake of morphine in European Americans [27]. However, their expression was not observed in the Asian population [28]. This finding suggests that race is an important factor in adverse reactions to opioids (Table 1).
Drug-Metabolizing Enzymes
The liver is the main site of opioid metabolism, in which opioids are dealkylated by cytochrome P450 enzymes [29]. Different enzymes metabolize different opioids. For example, CYP2D6 is the main enzyme involved in the metabolism of codeine, hydrocodone, and oxycodone. Another cytochrome P450 enzyme, CYP3A5, is involved in the metabolism of the opioids fentanyl and oxycodone. UGT2B7 is involved in drug glucuronidation, which is related to improved analgesic effects [30]. Genetic polymorphisms of these drug-metabolizing enzymes can yield 0- to 10,000-fold differences in drug efficacy [31], thus affecting the incidence of opioid-related adverse reactions.
CYP2D6
Because of its extensive enzyme activity, CYP2D6 is generally classified according to its unique genotype [32]. According to the activity of CYP2D6 allele-related enzymes, CYP2D6 genotypes are divided into ultrafast metabolite (UM), extensive or normal metabolite (EM/NM), intermediate metabolite (IM), or poor metabolite (PM) phenotypes [33]. Many studies have shown that CYP2D6 polymorphisms are associated with adverse events after opioid intake. Candiotti et al. [34] found that the copy number of the CYP2D6 allele influenced the success or failure of ondansetron for PONV prevention. Another comparative study showed that UM patients with three active alleles of CYP2D6 vomited more than EM or PM patients [35]. This effect is because codeine, tramadol, and hydrocodone are degraded into morphine, nortramadol, and hydroxymorphinone, respectively, by CYP2D6. The degradation products of codeine, tramadol, and hydrocodone have stronger analgesic efficacy and lead to an increase in the incidence of adverse reactions, while CYP2D6 PM will lead to a decrease in degradation and reduced effects [36]. In contrast, a case report suggests that CYP2D6 UM status predisposes patients to severe respiratory depression [37]. These findings suggest that choosing which metabolic type of opioid to administer based on the individual’s CYP2D6 genotype may lead to improved, individualized dosing and reduced adverse reactions to opioids after surgery.
FAAH
The fatty acid amide hydrolase (FAAH) gene encodes the FAAH enzyme that hydrolyzes endocannabinoids such as anandamide and other classes of lipids [38, 39]. Anandamide acts on cannabinoid (CB) receptors and potentiates opioid action, as evidenced by its ability to attenuate naloxone-induced morphine withdrawal in mice [40, 41]. Hence, in patients receiving opioids such as morphine, factors that increase anandamide levels or decrease anandamide hydrolysis would be expected to potentiate opioid effects, such as in individuals with FAAH variants that reduce function, thus affecting anandamide hydrolysis. Sadhasivam et al. [42] showed a significant correlation between FAAH SNP rs324420 and refractory PONV after tonsillectomy and a prolonged stay in the recovery room due to opioid-induced RD. Chidambaran et al. [43] also proved a significant correlation between the FAAH SNP rs324420 and morphine-induced RD by analyzing the hypercapnic ventilatory response (HCVR). In addition, they found that the incidence of PONV in individuals with the AA genotype of rs11576941 was 2.14 times higher than that in those with other genotypes. In the future, prospective genoty** could be used to predict the potentially high incidence of opioid-induced RD and PONV in children with certain FAAH gene mutations, which is conducive to promoting personalized pain management.
PDE3A
SNP rs12305038 is a missense variant in exon 1 of the PDE3A gene, which encodes phosphodiesterase 3A. This protein belongs to a class of enzymes that degrades cGMP and cAMP and is an important regulator of cyclic nucleotide signaling in numerous pathways [44]. Phosphodiesterase (PDES) is involved in the morphine addiction pathway (HSA05032 KEGG pathway), as well as the bitter and sweet signaling pathways of the morphine addiction pathway [45]. In the European Opioid Genetics Study (EPS), Colombo et al. [46] calculated and analyzed the nausea and vomiting score (NVS) after opioid analgesia in 1494 cancer patients and found a strong correlation between PDE3A rs12305038 and NVS. Thus, mutations in these taste-altering enzymes may also modulate the response to nausea and vomiting.
UGT2B7
The biological significance of UGT2B7 C802T mutations in the opioid response remains controversial. Some studies have shown that the T allele is associated with a higher morphine-6-glucoside (M6G)/morphine plasma ratio [47], resulting in improved analgesic effects due to the increased potency of M6G [48]. Other published studies have shown no relationship between the genotype and the M6G-to-morphine ratio and a lack of improved analgesic effects associated with M6G [49, 50]. Among the studies on the relationship between this gene and opioid adverse reactions, a Japanese study found that 802T carriers had a lower frequency of nausea than noncarriers among cancer patients administered morphine for analgesia [51]. Contradictory results suggest that C802T decreases opioid requirement among postpartum patients and increases risk for CNS depression among mothers and their breastfeeding infants [46].
OPRM1
OPRM1 encodes the μ-opioid receptor, which is the main target receptor of opiates. An SNP of OPRM1, A118G, has been a major focus of opioid response pharmacogenetics research. Hwang et al. [57] recently showed in a meta-analysis that the OPRM1-A118G polymorphism is associated with interindividual differences in postoperative opioid responses. In reviews and subsequent studies, some authors investigated the effect of the OPRM1-A118G polymorphism on postoperative adverse reactions after anesthesia, primarily PONV. Although A118G has been reported to be associated with postoperative side effects, the results of different studies have varied widely. Zhang et al. [58] found that AA, AG, and GG genotypes showed no significant differences in effects on nausea and vomiting. Liu also studied the association between the A118G polymorphism and the incidence of postoperative nausea, vomiting, and itching. After Bonferroni correction, no significant difference in PONV incidence was found between the A genotype group and the G + G genotype group [70] designed and developed a Japanese-specific DNA chip for high-throughput SNP genoty** based on whole-genome sequencing. Then, they identified a novel SNP (rs11232965) associated with PONV in the lncRNA miR4300Hg.1070 in Japanese patients. This suggests a potential molecular mechanism of PONV and may enable the prediction of PONV occurrence (Table 3).
PGx Advocates for Preoperative Genetic Screening to Guide Analgesic Protocols and Personalize Precision Medicine
I. PGx Can Be Used for the Preoperative Screening of Severe Adverse Reactions to Perioperative Anesthesia and Analgesia
The most clinically useful genes to identify in the preoperative decision-making phase are those known to present potentially life-threatening anesthesia reactions or adverse effects. Pharmacogenetic testing may take several different forms. Clinicians possibly order single-gene tests through large laboratory companies. Patients can be referred to physician medical geneticists or genetic counselors, although many of these clinics in the United States focus on prenatal genetic testing or cancer genetics. At some institutions, preoperative evaluation clinics partner with a third-party vendor to offer pharmacogenetic testing via saliva samples at the time of the preoperative clinic visit. This panel possibly includes the hyperthermia (RYR1) and pseudocholinesterase deficiency (BCHE) genes, as well as those involved in opioid metabolism. This will offer the opportunity to identify patients at risk before administering anesthesia and reduce adverse effects [71]. Of course, given the high cost of this technique and the uncertainty of its effectiveness, we do not recommend genetic testing as a routine preoperative examination at present.
PGx can also guide the selection of analgesics following major abdominal surgery. Senagore et al. [72] evaluated a consecutive series of patients undergoing open or laparoscopic colorectal and major ventral hernia surgery who received pharmacogenetic testing prior to surgery (PGx group) and compared them to a historical group (H group) of patients who underwent the same operations but were managed with their standard enhanced recovery protocol. The overall benefit of analgesia score (OBAS) was used to assess the combined impact on analgesia, patient satisfaction, and the impact of drug-associated side effects [73]. The results demonstrated a significantly lower OBAS rating (p < 0.01) for the PGx group than for the H group, representing a reduction in the score. Similarly, the pain subscore of the OBAS demonstrated a statistically significant improvement in analgesia reported by patients in the PGx group. This indicates that PGx-guided postoperative analgesia not only achieves good analgesic effects but also reduces related adverse reactions.
II. Clinical Implementation of Genotype Guidance Can Be Used to Monitor Analgesic Security Profiles and Limit Adverse Drug Effects in Patients with Chronic Pain (CP)
The CYP2D6 gene is highly polymorphic, with over 100 alleles defined. UMs with multiple gene copies are at increased risk for adverse drug effects, including life-threatening toxicities, compared to NMs. For patients with PM, IM, or UM phenotypes (based on genotype results), pharmacists recommend avoiding codeine, hydrocodone, oxycodone, and tramadol. The Clinical Pharmacogenetics Implementation Consortium (CPIC) developed guidelines that recommend monitoring the responses of patients administered codeine [74]. In a precision medicine-guided treatment for cancer pain pragmatic clinical trial [75], 142 patients were evaluable, of whom 43 consented for the pharmacogenomics team. Anxiety, appetite, depression, drowsiness, fatigue, nausea, pain, shortness of breath, and well-being were evaluated on a scale from 0 (no symptoms) to 10 (worst severity), using the Edmonton Symptom Assessment Scale. In the pharmacogenomics team, subjects were tested for multiple SNP genotypes, including catechol-o-methyl transferase (COMT), OPRM1 (A118G), and the CYP family. Physicians reviewed the results of genetic tests and adjusted the treatment regimen based on the literature and CPIC guidelines. At the end of the trial, while there was no significant difference in pain improvement between the two groups based on whether or not there was a pharmacogenomics test, 15 of the 43 patients in the genetic testing group had an actionable genotype for therapy modification and showed significantly more improvement in their pain than the other patients in the group (73% vs. 46%). This trial is unique because it will provide prospective data on pain-related outcomes with clinical implementation of genotype-guided pain management in a real-world setting.
Pharmacogenomic-guided prescription applied to chronic pain and in other therapeutic areas has been shown to be a rational tool for precision medicine [76]. If this intervention proves beneficial, it could significantly improve pain management and limit adverse drug effects, which are common issues with opioids (Fig. 1).
Clinical application of genetic screening. RYR1, hyperthermia; BCHE, pseudocholinesterase deficiency; OPRM1, μ-opioid receptor gene; COMT, catechol-o-methyl transferase; *codeine, hydrocodone, oxycodone, and tramadol
III. Future Perspective of PGx in Clinical Practice
The implementation of PGx in clinical practice is still challenging. Medical personnel do not have the ability to effectively genotype the efficacy or adverse reactions of specific drugs, so it is difficult to use PGx as a tool to improve treatment [77]. This may be the greatest obstacle limiting the clinical use of PGx. The CPIC and the Dutch Pharmacogenetics Working Group have worked tirelessly to identify the best matches between several genes and drugs and have published relevant guidelines. These guidelines help clinicians select the most appropriate drug based on the genotype of the patient to achieve the best efficacy while minimizing adverse reactions. Unfortunately, patients encountered in clinical work are highly variable, and there is not a one-to-one correspondence between genotype and specific drug. Specific drugs often act on different genetic targets, resulting in adverse reactions that are difficult to be explained simply by a single genotype. However, for patients with severe adverse drug reactions, drug monitoring in combination with PGx may still be beneficial.
In addition, the cost of PGx gene testing also restricts its clinical application. Codeine is commonly used to treat postpartum pain in the United States, but this drug can cause drowsiness and respiratory depression in infants, which can lead to death in severe cases. Prenatal testing for specific genotypes of codeine is available, but Moretti et al.'s study showed that an additional $7700 was needed to avoid one adverse event in the infant [78]. Such low efficiency is harder to afford by ordinary people. Of course, if the number of patients who agree to genetic testing increases, the cost can be spread evenly and reduced.
Conclusion
Precision medicine requires that postoperative analgesia treatment achieve the best analgesic effect with minimum adverse reactions. PGx could help physicians avoid risks and adverse experiences resulting from RD and PONV, but there is insufficient evidence to confirm which gene polymorphism predicts postoperative adverse reactions to opioids. To date, the application of PGx in the analgesia field has been limited to isolated, single-center studies with a small sample size; there is a lack of evidence-based medicine approaches, and the conclusions are often contradictory. There is also a lack of evidence-based study of the positive effects of PGx on analgesia approaches. It is also important to note that individual responses to opioids are determined by polygenetic inheritance, and the role of any single gene is limited. This results in a low cost-effectiveness ratio for genetic testing, which is the greatest obstacle to the application of PGx in precision medicine.
In future research, we should pay attention to the interactions among SNPs in multiple genes and the interaction between genes and the environment; additionally, it is necessary to conduct a large number of multicenter and multiethnic studies.
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Acknowledgements
The authors thank the patient for participating in this project.
Funding
This work was supported by Key R&D Program of Zhejiang (No. 2022C03081) and Ningbo Yinzhou district agricultural and social development science and technology project fund (No. 20180229). The Rapid Service Fee was funded by Key R&D Program of Zhejiang.
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All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
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**song Zhao and Zhiying Feng contributed to the concept of the manuscript and outline. **song Zhao, Shihong Cai and Long Zhang were responsible for writing the manuscript. Yuefeng Rao, **anhui Kang and Zhiying Feng were responsible for editing.
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**song Zhao, Shihong Cai, Long Zhang, Yuefeng Rao, **anhui Kang and Zhiying Feng have nothing to disclose.
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This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
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Zhao, J., Cai, S., Zhang, L. et al. Progress, Challenges, and Prospects of Research on the Effect of Gene Polymorphisms on Adverse Reactions to Opioids. Pain Ther 11, 395–409 (2022). https://doi.org/10.1007/s40122-022-00374-0
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DOI: https://doi.org/10.1007/s40122-022-00374-0