Pharmacogenetics of opioids: a narrative review (original) (raw)
Related papers
Pain polymorphisms and opioids: An evidence based review
Molecular Medicine Reports, 2018
Despite the various different candidate genetic polymorphisms of potential clinical relevance, there is not enough understanding of the inter-individual variability in analgesic administration. The cytochrome P450 2D6 (CYP2D6) genotype is thought to be one of the most studied. The aim of the present evidence-based review was to determine if there is now sufficient evidence to make clinical recommendations based on a specific genomic profile. The data sources utilized were as follows: PubMed (NLM) database, Evidence Based Medicine Guidelines and Google. Research on clinical guidance standards, systematic reviews, meta-analyses and clinical trials, published prior to January 2018, were evaluated in English, using the MeSH terms 'cancer pain', 'polymorphism', 'genetic' and 'gene polymorphism'. To assess the level of evidence, the Strength of Recommendation Taxonomy of the American Family Physician was applied. From the initial search, 12 systematic reviews and/or meta-analyses, 5 clinical trials and 10 guidelines were selected. The results indicated that genetic variation of µ-opioid receptor 1 (OPRM1) may contribute to inter-individual differences in morphine consumption with recommendation grade A for OPRM A118G single nucleotide polymorphism (rs1799971). Polymorphisms associated with the metabolization process of morphine and other opioid drugs are very relevant in opioid titration and ethnic subgroup differences which have to be taken into account (particularly, for the recommendation grade A for the CYP2D6 polymorphism). In human studies, the catechol-O-methyl transferase (COMT) genotype affects the efficacy of opioids in acute and chronic pain under different settings, with recommendation grade B to the COMT single nucleotide polymorphism rs4680 (Val/Met). Finally, polymorphisms of the ATP-binding cassette family of efflux transporters were highlighted. Consistent data on pain polymorphisms is now widely available; however, these results have had very little impact on clinical guidelines and daily oncologist practice. Persisting pain, side effects of grade 3 (NCI-CTCAE v4.0) and breakthrough pain with more than 4 episodes/day should be considered the criteria for pain multidisciplinary team discussions and for polymorphism screening.
Pharmacogenetics and Genomics, 2009
Aim A finite number of variants in the OPRM1, COMT, MC1R, ABCB1 and CYP2D6 genes has been identified to significantly modulate the effects of opioids in controlled homogenous settings. We analyzed the imprint of these variants in opioid therapy in a highly variable cohort of pain patients treated in outpatient units to test whether genotyping may play a role in this clinical setting. Methods In a multicenter study conducted in tertiary care outpatient pain centers, 352 patients (156 men and 196 women, aged 58.5 ± 14.6 years) treated for 1-600 months (63.4 ± 92.4 months) with various opioids for pain of various origins were included. Genotyping was performed for all the variants reportedly modulating pain in well-defined cohorts. Association analyses focused on opioid dosing, the actual 24-h pain score on a 0-10 rating scale and the occurrence of side effects. Results The frequency of the genetic variants in the patients did not significantly differ from that in the average Caucasian population. Daily opioid doses ranged from 4 to 1750 mg oral morphine equivalents (133.4 ± 203.2 mg) and significantly decreased in a gene dose-dependent manner with the P-glycoprotein variant ABCB1 3435C > T. Pain was rated on average at 3.7 ± 2.6. There was a tendency towards increased pain in a gene dose-dependent manner with the l-opioid receptor variant OPRM1 118A > G. Conclusion Genetics were reflected in the outpatient pain therapy only to a modest degree. The need of outpatient therapy of pain of various causes guided by the presently known functional genetic variants cannot be convincingly concluded from the present data. Using the ABCB1 3435 genotype to predefine lower individual opioid doses barely merits the laboratory effort. If any, the results suggest that a genetics guided outpatient pain therapy may be based on ABCB1 and OPRM1 variants. Pharmacogenetics and Genomics 19:429-436 c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.
PAIN, 2011
Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n = 830), oxycodone (n = 446), fentanyl (n = 699), or other opioids (n = 234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample.None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed. Ó
Current Oncology Reports, 2020
Purpose of Review Pain is multifactorial and complex, often with a genetic component. Pharmacogenomics is a relative new field, which allows for the development of a truly unique and personalized therapeutic approach in the treatment of pain. Recent Findings Until recently, drug mechanisms in humans were determined by testing that drug in a population and calculating response averages. However, some patients will inevitably fall outside of those averages, and it is nearly impossible to predict who those outliers might be. Pharmacogenetics considers a patient's unique genetic information and allows for anticipation of that individual's response to medication. Summary Pharmacogenomic testing is steadily making progress in the management of pain by being able to identify individual differences in the perception of pain and susceptibility and sensitivity to drugs based on genetic markers. This has a huge potential to increase efficacy and reduce the incidence of iatrogenic drug dependence and addiction. The streamlining of relevant polymorphisms of genes encoding receptors, transporters, and drug-metabolizing enzymes influencing the pain phenotype can be an important guide to develop safe new strategies and approaches to personalized pain management. Additionally, some challenges still prevail and preclude adoption of pharmacogenomic testing universally. These include lack of knowledge about pharmacogenomic testing, inadequate standardization of the process of data handling, questionable benefits about the clinical and financial aspects of pharmacogenomic testing-guided therapy, discrepancies in clinical evidence supporting these tests, and doubtful reimbursement of the tests by health insurance agencies.
Anesthesia & Analgesia, 2006
In this prospective, observational study we explored whether A118G single nucleotide polymorphism in the human -opioid receptor (MOR) gene could explain the inter-individual differences in opioid analgesic requirements in patients with acute postoperative pain and chronic pain. The frequency of the wild-type A118 MOR (major) and variant G118 MOR (minor) alleles in the subjects with chronic, noncancer pain (n ϭ 121) and opioid-naïve subjects with acute postoperative pain (n ϭ 101), serving as the control group, were examined. The relationships among the A118G MOR genotype, opioid requirements, and the numerical pain score were analyzed in both groups. The frequency of the minor allele was significantly lower in the subjects with chronic pain when compared with the group with acute postoperative pain (0.079 versus 0.158; P ϭ 0.009 by 2 test). No statistically significant association was observed between the presence of A118G MOR polymorphism and the average postoperative pain score or the doses of morphine used in the immediate postoperative period. In the high-quartile, opioid utilization, chronic pain patients, the homozygotic carriers of the major allele required significantly higher opioid dose than did the carriers of the minor allele.
The Role of Pharmacogenomics in Opioid Prescribing
Current Treatment Options in Oncology
Opinion statementPharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person’s genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. ...
Oral opioid metabolism and pharmacogenetics
SA Pharmaceutical Journal, 2019
Opioid analgesics are widely used as the standard of care for the management of moderate to severe nociceptive pain. The opioids' analgesic properties mainly emanate from stimulation of the µ-receptors, which are encoded by the OPRM1 gene. Most opioids are fat-soluble, requiring conversion to water-soluble compounds for excretion, but for some opioids, namely tramadol and codeine, hepatic metabolism is necessary for their bioactivation into more potent analgesics. Hepatic biotransformation generally occurs as Phase I and Phase II metabolism. The highly polymorphic nature of the genes, coding for Phase I and II enzymes involved in the metabolism and bioactivation of opioids, suggests potential interindividual variation in patient response in terms of efficacy and safety. Patients can be classified by their genetic ability to metabolise medication. The inherent differences in the genes that encode the CYP450 enzymes, particularly CYP3A4 and CYP2D6, can affect the metabolic capacity of an individual, leading to over-or underexposure to an opioid, making opioid pharmacokinetics and pharmacodynamics variable between individuals. Other medications that also utilise the CYP450 pathway can lead to interactions. In addition to pharmacogenomics, other factors like age, ethnicity and renal impairment also contribute to differences in opioid metabolism and variation in patient response. This article provides a review of the metabolism of commonly prescribed oral opioids, and pharmacogenetic considerations.
Pharmacogenetics of lethal opioid overdose: Study protocol and preliminary findings
There has been a worldwide substantial increase in accidental lethal opioid-overdose (ALOO). In this project, we will examine the role of genetic variation in opioid metabolism, transport, or opioid receptors, in contributing to opioid-related overdose deaths by 1) comparing the frequency of those variants to a corresponding reference population and exploring sex differences; 2) investigating the association between the metabolizer type (i.e., CYP2D6 poor metabolizers) and plasma concentrations; and 3) generating a series of polygenic risk scores (PRS) for predicting ALOO by using summary statistics from several large-scale genome-wide association studies (GWAS) of phenotypes relevant to opioid use disorder. This sample is currently being collected; however, we have analyzed the frequency of CYP2B6*4, CYP2B6*9 and OPRM1 A118G variants in methadone-only fatalities (n = 41). Findings showed a higher frequency of impaired CYP2B6 metabolism in males compared to females (p = 0.009, chi s...