{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:16:10Z","timestamp":1760238970824,"version":"build-2065373602"},"reference-count":129,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T00:00:00Z","timestamp":1600646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Etiology of back pain is multifactorial and not completely understood, and for the majority of people who suffer from chronic low back pain (cLBP), the precise cause cannot be determined. We know that back pain is somewhat heritable, chronic pain more so than acute. The aim of this review is to compile the genes identified by numerous genetic association studies of chronic pain conditions, focusing on cLBP specifically. Higher-order neurologic processes involved in pain maintenance and generation may explain genetic contributions and functional predisposition to formation of cLBP that does not involve spine pathology. Several genes have been identified in genetic association studies of cLBP and roughly, these genes could be grouped into several categories, coding for: receptors, enzymes, cytokines and related molecules, and transcription factors. Treatment of cLBP should be multimodal. In this review, we discuss how an individual\u2019s genotype could affect their response to therapy, as well as how genetic polymorphisms in CYP450 and other enzymes are crucial for affecting the metabolic profile of drugs used for the treatment of cLBP. Implementation of gene-focused pharmacotherapy has the potential to deliver select, more efficacious drugs and avoid unnecessary, polypharmacy-related adverse events in many painful conditions, including cLBP.<\/jats:p>","DOI":"10.3390\/pharmaceutics12090894","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T08:18:01Z","timestamp":1600676281000},"page":"894","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Can Implementation of Genetics and Pharmacogenomics Improve Treatment of Chronic Low Back Pain?"],"prefix":"10.3390","volume":"12","author":[{"given":"Vladislav","family":"Suntsov","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 W. Wellington Ave. Suite 4815, Chicago, IL 60657, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9604-9006","authenticated-orcid":false,"given":"Filip","family":"Jovanovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 W. Wellington Ave. Suite 4815, Chicago, IL 60657, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilija","family":"Knezevic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 W. Wellington Ave. Suite 4815, Chicago, IL 60657, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth D.","family":"Candido","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 W. Wellington Ave. Suite 4815, Chicago, IL 60657, USA"},{"name":"Department of Anesthesiology, University of Illinois, Chicago, IL 60612, USA"},{"name":"Department of Surgery, University of Illinois, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nebojsa Nick","family":"Knezevic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 W. Wellington Ave. Suite 4815, Chicago, IL 60657, USA"},{"name":"Department of Anesthesiology, University of Illinois, Chicago, IL 60612, USA"},{"name":"Department of Surgery, University of Illinois, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/ner.12018","article-title":"Epidemiology of low back pain in adults","volume":"17","author":"Manchikanti","year":"2014","journal-title":"Neuromodulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1002\/acr.22890","article-title":"Epidemiology of Chronic Low Back Pain in US Adults: Data from the 2009-2010 National Health and Nutrition Examination Survey","volume":"68","author":"Shmagel","year":"2016","journal-title":"Arthritis Care Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/ng.3285","article-title":"Meta-analysis of the heritability of human traits based on fifty years of twin studies","volume":"47","author":"Polderman","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1002\/j.1532-2149.2012.00277.x","article-title":"Nature or nurture in low back pain? Results of a systematic review of studies based on twin samples","volume":"17","author":"Ferreira","year":"2013","journal-title":"Eur. J. Pain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.pain.2007.01.010","article-title":"Heritability of low back pain and the role of disc degeneration","volume":"131","author":"Battie","year":"2007","journal-title":"Pain"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rodriguez-Raecke, R., Niemeier, A., Ihle, K., Ruether, W., and May, A. (2013). Structural brain changes in chronic pain reflect probably neither damage nor atrophy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054475"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/nn.3153","article-title":"Corticostriatal functional connectivity predicts transition to chronic back pain","volume":"15","author":"Baliki","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7540","DOI":"10.1523\/JNEUROSCI.5280-10.2011","article-title":"Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function","volume":"31","author":"Seminowicz","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.neuroscience.2016.04.041","article-title":"Genetic predictors of human chronic pain conditions","volume":"338","author":"Meloto","year":"2016","journal-title":"Neuroscience"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hasvik, E., Iordanova Schistad, E., Grovle, L., Julsrud Haugen, A., Roe, C., and Gjerstad, J. (2014). Subjective health complaints in patients with lumbar radicular pain and disc herniation are associated with a sex\u2014OPRM1 A118G polymorphism interaction: A prospective 1-year observational study. BMC Musculoskelet. Disord., 15.","DOI":"10.1186\/1471-2474-15-161"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.jpsychores.2010.11.008","article-title":"Comorbid subjective health complaints in patients with sciatica: A prospective study including comparison with the general population","volume":"70","author":"Grovle","year":"2011","journal-title":"J. Psychosom. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1176\/ajp.156.6.842","article-title":"Gender and age influences on human brain mu-opioid receptor binding measured by PET","volume":"156","author":"Zubieta","year":"1999","journal-title":"Am. J. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9268","DOI":"10.1073\/pnas.1018699108","article-title":"Human Mu Opioid Receptor (OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers","volume":"108","author":"Ray","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.bbi.2009.03.007","article-title":"Association of polymorphism in the human mu-opioid receptor OPRM1 gene with proinflammatory cytokine levels and health perception","volume":"23","author":"Matsunaga","year":"2009","journal-title":"Brain Behav. Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15079","DOI":"10.1073\/pnas.0812612106","article-title":"Variation in the mu-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection","volume":"106","author":"Way","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/syn.21683","article-title":"Stress differentially alters mu opioid receptor density and trafficking in parvalbumin-containing interneurons in the female and male rat hippocampus","volume":"67","author":"Milner","year":"2013","journal-title":"Synapse"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/art.30185","article-title":"Association of HTR2A polymorphisms with chronic widespread pain and the extent of musculoskeletal pain: Results from two population-based cohorts","volume":"63","author":"Nicholl","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.5606\/ArchRheumatol.2017.5846","article-title":"Assessment of Pain Sensitivity in Patients with Chronic Low Back Pain and Association with HTR2A Gene Polymorphism","volume":"32","author":"Yildiz","year":"2017","journal-title":"Arch. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1097\/BRS.0b013e318173298b","article-title":"Participation of 5-hydroxytryptamine in pain-related behavior induced by nucleus pulposus applied on the nerve root in rats","volume":"33","author":"Kato","year":"2008","journal-title":"Spine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1097\/01.blo.0000065840.77325.8f","article-title":"Efficacy of serotonin receptor blocker for symptomatic lumbar disc herniation","volume":"411","author":"Kanayama","year":"2003","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Suri, P., Palmer, M.R., Tsepilov, Y.A., Freidin, M.B., Boer, C.G., Yau, M.S., Evans, D.S., Gelemanovi\u0107, A., Bartz, T.M., and Nethander, M. (2018). Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007601"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.pbiomolbio.2015.04.001","article-title":"Signaling mechanism of the netrin-1 receptor DCC in axon guidance","volume":"118","author":"Finci","year":"2015","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5640","DOI":"10.1007\/s12035-015-9482-x","article-title":"Netrin-1 Contributes to Myelinated Afferent Fiber Sprouting and Neuropathic Pain","volume":"53","author":"Wu","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Dun, X.P., and Parkinson, D.B. (2017). Role of Netrin-1 Signaling in Nerve Regeneration. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030491"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1097\/BRS.0b013e31825d4ebc","article-title":"Increased expression of netrin-1 and its deleted in colorectal cancer receptor in human diseased lumbar intervertebral disc compared with autopsy control","volume":"37","author":"Bu","year":"2012","journal-title":"Spine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/S0140-6736(97)02135-1","article-title":"Nerve ingrowth into diseased intervertebral disc in chronic back pain","volume":"350","author":"Freemont","year":"1997","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1097\/01.j.pain.0000460330.56256.25","article-title":"Genetics and the environment affect the relationship between depression and low back pain: A co-twin control study of Spanish twins","volume":"156","author":"Pinheiro","year":"2015","journal-title":"Pain"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/ng.3552","article-title":"Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses","volume":"48","author":"Okbay","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"E53","DOI":"10.1097\/BSD.0b013e318260a09c","article-title":"Association between estrogen receptor gene polymorphism and back pain intensity in female patients with degenerative lumbar spondylolisthesis","volume":"26","author":"Roh","year":"2013","journal-title":"J. Spinal Disord. Tech."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1677\/joe.0.1710229","article-title":"Estrogen receptor specificity in the regulation of the skeleton in female mice","volume":"171","author":"Lindberg","year":"2001","journal-title":"J. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5474","DOI":"10.1073\/pnas.97.10.5474","article-title":"Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice","volume":"97","author":"Vidal","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","first-page":"134","article-title":"Estrogen receptor gene polymorphism and generalized osteoarthritis","volume":"25","author":"Ushiyama","year":"1998","journal-title":"J. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12125","DOI":"10.1523\/JNEUROSCI.3400-08.2008","article-title":"Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain","volume":"28","author":"Racz","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/AJP.0000000000000508","article-title":"Contribution of Endocannabinoid Gene Expression and Genotype on Low Back Pain Susceptibility and Chronicity","volume":"34","author":"Ramesh","year":"2018","journal-title":"Clin. J. Pain"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/j.1532-2149.2012.00131.x","article-title":"Genetic variation in the beta-2 adrenergic receptor is associated with chronic musculoskeletal complaints in adolescents","volume":"16","author":"Skouen","year":"2012","journal-title":"Eur. J. Pain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/ajmg.b.30324","article-title":"Three major haplotypes of the beta2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder","volume":"141B","author":"Diatchenko","year":"2006","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1002\/art.24655","article-title":"Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains","volume":"60","author":"Fragoso","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1097\/AJP.0000000000000347","article-title":"Acute Low Back Pain: Differential Somatosensory Function and Gene Expression Compared with Healthy No-Pain Controls","volume":"32","author":"Starkweather","year":"2016","journal-title":"Clin. J. Pain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1111\/ejn.13414","article-title":"Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats","volume":"44","author":"Xu","year":"2016","journal-title":"Eur. J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1007\/s00586-015-3866-5","article-title":"Catechol-O-methyltransferase (COMT) gene polymorphisms are associated with baseline disability but not long-term treatment outcome in patients with chronic low back pain","volume":"24","author":"Omair","year":"2015","journal-title":"Eur. Spine J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.pain.2006.09.022","article-title":"Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors","volume":"128","author":"Nackley","year":"2007","journal-title":"Pain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.neulet.2010.02.049","article-title":"Catechol-O-methyltransferase (COMT) inhibition reduces spinal nociceptive activity","volume":"473","author":"Jacobsen","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1126\/science.1078546","article-title":"COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor","volume":"299","author":"Zubieta","year":"2003","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/j.1532-2149.2011.00102.x","article-title":"The COMT rs4680 Met allele contributes to long-lasting low back pain, sciatica and disability after lumbar disc herniation","volume":"16","author":"Jacobsen","year":"2012","journal-title":"Eur. J. Pain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00701-013-1895-6","article-title":"Influence of variation in the catechol-O-methyltransferase gene on the clinical outcome after lumbar spine surgery for one-level symptomatic disc disease: A report on 176 cases","volume":"156","author":"Rut","year":"2014","journal-title":"Acta Neurochir."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"133","DOI":"10.3109\/03008207.2010.487621","article-title":"Association between Caspase-9 promoter region polymorphisms and discogenic low back pain","volume":"52","author":"Guo","year":"2011","journal-title":"Connect. Tissue Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0092-8674(00)81476-2","article-title":"Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9","volume":"94","author":"Kuida","year":"1998","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S1097-2765(00)80095-7","article-title":"Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization","volume":"1","author":"Srinivasula","year":"1998","journal-title":"Mol. Cell."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1002\/jcb.10440","article-title":"Apoptosis and lung cancer: A review","volume":"88","author":"Shivapurkar","year":"2003","journal-title":"J. Cell Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1093\/hmg\/ddi032","article-title":"Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis","volume":"14","author":"Sang","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1007\/s10495-006-0290-7","article-title":"Programmed cell death in intervertebral disc degeneration","volume":"11","author":"Zhao","year":"2006","journal-title":"Apoptosis"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/nm1490","article-title":"GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence","volume":"12","author":"Tegeder","year":"2006","journal-title":"Nat. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pain.2009.10.021","article-title":"A GTP cyclohydrolase 1 genetic variant delays cancer pain","volume":"148","author":"Lotsch","year":"2010","journal-title":"Pain"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/ng1194-236","article-title":"Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene","volume":"8","author":"Ichinose","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1086\/321970","article-title":"Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia","volume":"69","author":"Bonafe","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0304-3959(00)00406-1","article-title":"Characteristics and prediction of early pain after laparoscopic cholecystectomy","volume":"90","author":"Bisgaard","year":"2001","journal-title":"Pain"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1080\/00365520510023675","article-title":"From acute to chronic pain after laparoscopic cholecystectomy: A prospective follow-up analysis","volume":"40","author":"Bisgaard","year":"2005","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Song, Y.Q., Ho, D.W., Karppinen, J., Kao, P.Y.P., Fan, B.J., Luk, K.D.K., Yip, S.P., Leong, J.C.Y., Cheah, K.S.E., and Sham, P.C. (2008). Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese. BMC Med. Genet., 9.","DOI":"10.1186\/1471-2350-9-38"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1097\/AJP.0b013e31827df7fd","article-title":"The MMP1 rs1799750 2G allele is associated with increased low back pain, sciatica, and disability after lumbar disk herniation","volume":"29","author":"Jacobsen","year":"2013","journal-title":"Clin. J. Pain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1517\/13543781003643486","article-title":"Therapeutic potential of matrix metalloprotease inhibitors in neuropathic pain","volume":"19","author":"Dev","year":"2010","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1007\/s00586-007-0454-3","article-title":"Association between the -1306C\/T polymorphism of matrix metalloproteinase-2 gene and lumbar disc disease in Chinese young adults","volume":"16","author":"Dong","year":"2007","journal-title":"Eur. Spine J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1302\/0301-620X.83B4.0830491","article-title":"The association of degeneration of the intervertebral disc with 5a\/6a polymorphism in the promoter of the human matrix metalloproteinase-3 gene","volume":"83","author":"Takahashi","year":"2001","journal-title":"J. Bone Jt. Surg. Br."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Omair, A., Holden, M., Lie, B.A., Reikeras, O., and Brox, J.I. (2013). Treatment outcome of chronic low back pain and radiographic lumbar disc degeneration are associated with inflammatory and matrix degrading gene variants: A prospective genetic association study. BMC Musculoskelet. Disord., 14.","DOI":"10.1186\/1471-2474-14-105"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1208\/s12248-008-9075-y","article-title":"Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation","volume":"11","author":"Schlosburg","year":"2009","journal-title":"AAPS J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/nn.3612","article-title":"Peripheral gating of pain signals by endogenous lipid mediators","volume":"17","author":"Piomelli","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1016\/j.pain.2012.04.020","article-title":"An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee","volume":"153","author":"Huggins","year":"2012","journal-title":"Pain"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1007\/s00586-013-3059-z","article-title":"A SNP in the 5\u2032UTR of GDF5 is associated with susceptibility to symptomatic lumbar disc herniation in the Chinese Han population","volume":"23","author":"Mu","year":"2014","journal-title":"Eur. Spine J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1097\/AJP.0000000000000048","article-title":"The interleukin-1alpha gene C > T polymorphism rs1800587 is associated with increased pain intensity and decreased pressure pain thresholds in patients with lumbar radicular pain","volume":"30","author":"Schistad","year":"2014","journal-title":"Clin. J. Pain"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/art.24268","article-title":"Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing","volume":"60","author":"Videman","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1073\/pnas.96.5.2256","article-title":"Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells","volume":"96","author":"Puren","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1097\/00007632-199508150-00011","article-title":"Neural mechanisms of lumbar pain","volume":"20","author":"Cavanaugh","year":"1995","journal-title":"Spine"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/00007632-200001010-00005","article-title":"Sensitivity of anulus fibrosus cells to interleukin 1 beta. Comparison with articular chondrocytes","volume":"25","author":"Rannou","year":"2000","journal-title":"Spine"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1097\/00007632-200107150-00004","article-title":"Influence of macrophage infiltration of herniated disc tissue on the production of matrix metalloproteinases leading to disc resorption","volume":"26","author":"Doita","year":"2001","journal-title":"Spine"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1136\/ard.2008.102236","article-title":"Association of the DVWA and GDF5 polymorphisms with osteoarthritis in UK populations","volume":"68","author":"Valdes","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/hmg\/ddn038","article-title":"A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5\u2032 UTR of GDF5 with osteoarthritis susceptibility","volume":"17","author":"Chapman","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1002\/art.30169","article-title":"GDF5 single-nucleotide polymorphism rs143383 is associated with lumbar disc degeneration in Northern European women","volume":"63","author":"Williams","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Zhang, L., Stuber, F., and Stamer, U.M. (2013). Inflammatory mediators influence the expression of nociceptin and its receptor in human whole blood cultures. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074138"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3171\/2013.4.SPINE12782","article-title":"Analysis of association between IL-1beta, CASP-9, and GDF5 variants and low-back pain in Chinese male soldier: Clinical article","volume":"19","author":"Mu","year":"2013","journal-title":"J. Neurosurg. Spine"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1136\/annrheumdis-2012-201551","article-title":"Novel genetic variants associated with lumbar disc degeneration in northern Europeans: A meta-analysis of 4600 subjects","volume":"72","author":"Williams","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"8183","DOI":"10.1093\/nar\/gkv688","article-title":"The transcription factors SOX9 and SOX5\/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis","volume":"43","author":"Liu","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S1534-5807(01)00003-X","article-title":"The transcription factors L-Sox5 and Sox6 are essential for cartilage formation","volume":"1","author":"Smits","year":"2001","journal-title":"Dev. Cell"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.semcdb.2016.10.004","article-title":"Transcriptional control of chondrocyte specification and differentiation","volume":"62","author":"Liu","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1242\/dev.00331","article-title":"Sox5 and Sox6 are required for notochord extracellular matrix sheath formation, notochord cell survival and development of the nucleus pulposus of intervertebral discs","volume":"130","author":"Smits","year":"2003","journal-title":"Development"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1002\/art.38300","article-title":"Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies","volume":"66","author":"Calaza","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"14265","DOI":"10.1038\/ncomms14265","article-title":"Sequence variant at 8q24.21 associates with sciatica caused by lumbar disc herniation","volume":"8","author":"Bjornsdottir","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1007\/s11999-014-3633-7","article-title":"A history of lumbar disc herniation from Hippocrates to the 1990s","volume":"473","author":"Truumees","year":"2015","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1097\/BRS.0b013e31822ef700","article-title":"Degenerative magnetic resonance imaging changes in patients with chronic low back pain: A systematic review","volume":"36","author":"Chou","year":"2011","journal-title":"Spine"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1097\/BRS.0b013e3181cd9adb","article-title":"Potential of magnetic resonance imaging findings to refine case definition for mechanical low back pain in epidemiological studies: A systematic review","volume":"36","author":"Endean","year":"2011","journal-title":"Spine"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.joca.2015.12.013","article-title":"Genome-wide DNA methylation profile implicates potential cartilage regeneration at the late stage of knee osteoarthritis","volume":"24","author":"Zhang","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"34460","DOI":"10.1038\/srep34460","article-title":"Identification of DNA methylation changes associated with disease progression in subchondral bone with site-matched cartilage in knee osteoarthritis","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Burston, J.J., Sagar, D.R., Shao, P., Bai, M., King, E., Brailsford, L., Turner, J.M., Hathway, G., Bennett, A.J., and Walsh, D.A. (2013). Cannabinoid CB2 receptors regulate central sensitization and pain responses associated with osteoarthritis of the knee joint. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080440"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.15585\/mmwr.mm655051e1","article-title":"Increases in Drug and Opioid-Involved Overdose Deaths\u2014United States, 2010\u20132015","volume":"65","author":"Rudd","year":"2016","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1146\/annurev-publhealth-031914-122957","article-title":"The prescription opioid and heroin crisis: A public health approach to an epidemic of addiction","volume":"36","author":"Kolodny","year":"2015","journal-title":"Annu. Rev. Public Health"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Knezevic, N.N., Tverdohleb, T., Knezevic, I., and Candido, K.D. (2018). The Role of Genetic Polymorphisms in Chronic Pain Patients. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061707"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1097\/j.pain.0000000000001135","article-title":"Human pain genetics database: A resource dedicated to human pain genetics research","volume":"159","author":"Meloto","year":"2018","journal-title":"Pain"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00008571-200401000-00001","article-title":"Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants","volume":"14","author":"Nelson","year":"2004","journal-title":"Pharmacogenetics"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Preissner, S.C., Hoffmann, M.F., Preissner, R., Dunkel, M., Gewiess, A., and Preissner, S. (2013). Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082562"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1007\/s00228-013-1477-9","article-title":"Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: Clinical implications","volume":"69","author":"Yiannakopoulou","year":"2013","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/cpt.1830","article-title":"Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs","volume":"108","author":"Theken","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1053\/j.gastro.2007.05.025","article-title":"Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: Role of cytochrome P450 2C9 polymorphisms","volume":"133","author":"Pilotto","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/clpt.2011.287","article-title":"Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype","volume":"91","author":"Crews","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_103","first-page":"179","article-title":"CYP2D6 genotype can help to predict effectiveness and safety during opioid treatment for chronic low back pain: Results from a retrospective study in an Italian cohort","volume":"11","author":"Dagostino","year":"2018","journal-title":"Pharmgenomics Pers. Med."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Batistaki, C., Chrona, E., Kostroglou, A., Kostopanagiotou, G., and Gazouli, M. (2020). CYP2D6 Basic Genotyping of Patients with Chronic Pain Receiving Tramadol or Codeine. A Study in a Greek Cohort. Pain Med.","DOI":"10.1093\/pm\/pnaa122"},{"key":"ref_105","first-page":"E227","article-title":"The role of hydromorphone and OPRM1 in postoperative pain relief with hydrocodone","volume":"16","author":"Boswell","year":"2013","journal-title":"Pain Physician"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1111\/papr.12816","article-title":"Genetic Contribution in Low Back Pain: A Prospective Genetic Association Study","volume":"19","author":"Margarit","year":"2019","journal-title":"Pain Pract."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"163","DOI":"10.2217\/pme.14.61","article-title":"Pharmacogenetics and analgesic effects of antidepressants in chronic pain management","volume":"12","author":"Rodieux","year":"2015","journal-title":"Pers. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s40291-013-0028-5","article-title":"Applications of CYP450 testing in the clinical setting","volume":"17","author":"Samer","year":"2013","journal-title":"Mol. Diagn. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s00213-002-1084-4","article-title":"Clinical applications of pharmacogenetics in psychiatry","volume":"162","author":"Staddon","year":"2002","journal-title":"Psychopharmacology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1046\/j.0306-5251.2001.01548.x","article-title":"Molecular genetics of CYP2D6: Clinical relevance with focus on psychotropic drugs","volume":"53","author":"Bertilsson","year":"2002","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/clpt.2011.34","article-title":"Pharmacogenetics: From bench to byte\u2014An update of guidelines","volume":"89","author":"Swen","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"250","DOI":"10.9758\/cpn.2015.13.3.250","article-title":"Association between ABCB1 Polymorphisms and Antidepressant Treatment Response in Taiwanese Major Depressive Patients","volume":"13","author":"Chang","year":"2015","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e198","DOI":"10.1038\/tp.2012.115","article-title":"ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression","volume":"27","author":"Singh","year":"2012","journal-title":"Transl. Psychiatry"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"829","DOI":"10.2217\/pgs-2019-0031","article-title":"Venlafaxine pharmacogenetics: A comprehensive review","volume":"20","author":"Suwala","year":"2019","journal-title":"Pharmacogenomics"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.neuroimage.2016.04.064","article-title":"Serotonin transporter polymorphism alters citalopram effects on human pain responses to physical pain","volume":"135","author":"Ma","year":"2016","journal-title":"Neuroimage"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1177\/0091270002042001007","article-title":"Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency","volume":"42","author":"Winchell","year":"2002","journal-title":"J. Clin. Pharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/clpt.2011.177","article-title":"Linking pharmacology to clinical reports: Cyclobenzaprine and its possible association with serotonin syndrome","volume":"90","author":"Mestres","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/j.1365-2125.2005.02529.x","article-title":"Clinically relevant drug interactions with antiepileptic drugs","volume":"61","author":"Perucca","year":"2006","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.0013-9580.2004.455003.x","article-title":"Pregabalin pharmacology and its relevance to clinical practice","volume":"45","year":"2004","journal-title":"Epilepsia"},{"key":"ref_120","first-page":"1062","article-title":"Gabapentin: An update of its pharmacological properties and therapeutic use in epilepsy","volume":"16","author":"Honarmand","year":"2011","journal-title":"J. Res. Med. Sci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.mam.2012.10.010","article-title":"The SLC22 family with transporters of organic cations, anions and zwitterions","volume":"34","author":"Koepsell","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s11095-007-9254-z","article-title":"Polyspecific organic cation transporters: Structure, function, physiological roles, and biopharmaceutical implications","volume":"24","author":"Koepsell","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/bcpt.13126","article-title":"Pharmacogenetics-based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms","volume":"124","author":"Yamamoto","year":"2019","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/j.1533-2500.2010.00413.x","article-title":"Prevalence of exposure to potential CYP450 pharmacokinetic drug-drug interactions among patients with chronic low back pain taking opioids","volume":"11","author":"Pergolizzi","year":"2011","journal-title":"Pain Pract."},{"key":"ref_125","first-page":"467","article-title":"The prevalence of opioid-related major potential drug-drug interactions and their impact on health care costs in chronic pain patients","volume":"20","author":"Pergolizzi","year":"2014","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"655","DOI":"10.2217\/pgs.14.6","article-title":"How common are drug and gene interactions? Prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and CYP2D6 genotyping","volume":"15","author":"Verbeurgt","year":"2014","journal-title":"Pharmacogenomics"},{"key":"ref_127","first-page":"355","article-title":"Drug-drug-gene interactions and adverse drug reactions","volume":"20","author":"Malki","year":"2020","journal-title":"Pharm. J."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/psp4.12411","article-title":"Physiologically-Based Pharmacokinetic Modeling for the Prediction of CYP2D6-Mediated Gene-Drug-Drug Interactions","volume":"8","author":"Storelli","year":"2019","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"425","DOI":"10.36076\/ppj.2014\/17\/425","article-title":"A review of the role of genetic testing in pain medicine","volume":"17","author":"Trescot","year":"2014","journal-title":"Pain Physician"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/9\/894\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:11:56Z","timestamp":1760177516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/9\/894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,21]]},"references-count":129,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["pharmaceutics12090894"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12090894","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2020,9,21]]}}}