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Pharmacogenetic profiling and individualised therapy in the treatment of degenerative spinal conditions

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Abstract

Patients presenting with degenerative spinal changes are often poor surgical candidates due to associated co-morbidities, frailty, or sarcopenia. Additionally, surgeries of a degenerative spine can prove difficult due to the distortion of normal surgical anatomy. Therefore, many patients are managed conservatively with a variety of modalities, including over-the-counter and prescription medications. Nevertheless, several patients do not experience adequate relief from pain with analgesic medications, precipitating multiple hospital visits, and usage of resources. As a result, back pain is regarded as a major economic burden, with total costs of associated treatment exceeding $100 billion annually. Pharmacogenetics is a relatively novel method of evaluating an individual’s response to analgesic medications, through analysis of germline polymorphisms. It entails obtaining a genetic sample, often via buccal swab or peripheral blood sample, and genetic analysis achieved through either polymerase chain reaction +/− Sanger sequencing, microassays, restriction length fragment polymorphism analysis, or genetic library preparation and next generation sequencing. The potential efficacy of pharmacogenetic analysis has been highlighted across several specialities to date. However, a paucity of evidence exists regarding spine surgery populations. Nevertheless, regular prospective pharmacogenetic analysis may ultimately prove beneficial when concerning degenerative spinal cohorts due to aforementioned surgical and economic considerations. The purpose of this narrative review is to outline how metaboliser profile variants affect the pharmacokinetics of specific analgesia used to treat back pain, and to discuss the current potential and limitations of employing regular pharmacogenetic analysis for spine surgery populations with degenerative conditions.

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References

  1. Roses A (2000) Pharmacogenetics and the practice of medicine. Nature 405:857–865

    Article  CAS  PubMed  Google Scholar 

  2. Spear BB, Heath-Chiozzi M, Huff J (2001) Clinical application of pharmacogenetics. Trends Mol Med 7(5):201–204

    Article  CAS  PubMed  Google Scholar 

  3. Vogel F (1959) Moderne probleme der humangenetik. Ergeb Inn Med Kinderheilkd 12:52–62

    Google Scholar 

  4. Evans DA, Manley KA, McKusick VA (1960) Genetic control of isoniazid metabolism in man. Br Med J 2(5197):485–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chial H (2008) DNA sequencing technologies key to the Human Genome Project. Nature Education 1(1):219

    Google Scholar 

  6. Bank PCD, Caudle KE, Swen JJ et al (2018) Comparison of the Guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group. Clin Pharmacol Ther 103(4):599–618

    Article  CAS  PubMed  Google Scholar 

  7. Hippman C, Nislow C (2019) Pharmacogenomic testing: clinical evidence and implementation challenges. J Pers Med 9(3):40

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mackay IM, Arden KE, Nitsche A (2002) Real-time PCR in virology. Nucleic Acids Res 30(6):1292–1305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sanger F, Coulson AR (1975) A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J Mol Biol 94(3):441–448

  10. Taub F (1983) Laboratory methods: Sequential comparative hybridizations analyzed by computerized image processing can identify and quantitate regulated RNAs. DNA 2(4):309–327

  11. Pollack JR, Perou CM, Alizadeh AA et al (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23(1):41–46

    Article  CAS  PubMed  Google Scholar 

  12. Young ND, Tanksley SD (1989) Restriction fragment length polymorphism maps and the concept of graphical genotypes. Theoret Appl Genetics 77:95–101

    Article  CAS  Google Scholar 

  13. Bean LJH, Funke B, Carlston CM et al (2020) Diagnostic gene sequencing panels: from design to report—a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med 22:453–461

    Article  PubMed  Google Scholar 

  14. Lelieveld SH, Spielmann M, Mundlos S et al (2015) Comparison of exome and genome sequencing technologies for the complete capture of protein-coding regions. Hum Mutat 36(8):815–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lundberg DS, Yourstone S, Mieczkowski P et al (2013) Practical innovations for high-throughput amplicon sequencing. Nat Methods 10(10):999–1002

    Article  CAS  PubMed  Google Scholar 

  16. Flusberg BA, Webster DR, Lee JH et al (2010) Direct detection of DNA methylation during single-molecule, real-time sequencing. Nat Methods 7(6):461–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Deamer D, Akeson M, Branton D (2016) Three decades of nanopore sequencing. Nat Biotechnol 34:518–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Milosavljevic F, Bukvic N, Pavlovic Z et al (2021) Association of CYP2C19 and CYP2D6 poor and intermediate metabolizer status with antidepressant and antipsychotic exposure: a systematic review and meta-analysis. JAMA Psychiat 78(3):270–280

    Article  Google Scholar 

  19. Furuya H, Fernandez-Salguero P, Gregory W et al (1995) Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 5:389–392

    Article  CAS  PubMed  Google Scholar 

  20. Lennard L, Van Loon JA, Weinshilboum RM (1989) Pharmacogenetics of acute azathioprine toxicity: Relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46:149–154

    Article  CAS  PubMed  Google Scholar 

  21. Israel E, Drazen JM, Liggett SB et al (2000) The effect of polymorphisms of the β2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 162:75–80

    Article  CAS  PubMed  Google Scholar 

  22. Ruzzo A, Graziano F, Kawakami K et al (2006) Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol 24(12):1883–1891

    Article  CAS  PubMed  Google Scholar 

  23. Roberto M, Romiti A, Botticelli A et al (2017) Evaluation of 5-fluorouracil degradation rate and pharmacogenetic profiling to predict toxicity following adjuvant capecitabine. Eur J Clin Pharmacol 73(2):157–164

    Article  CAS  PubMed  Google Scholar 

  24. Wu X, Lu C, Chiang SS, Ajani JA (2005) Pharmacogenetics in esophageal cancer. Semin Oncol 32(6 Suppl 9):S87–S89

    Article  CAS  PubMed  Google Scholar 

  25. Dahan L, Norguet E, Etienne-Grimaldi MC et al (2011) Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer. BMC Cancer 25(11):496

    Article  Google Scholar 

  26. Pohl A, El-Khoueiry A, Yang D et al (2013) Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab-based chemotherapy. Pharmacogenomics J 13(2):173–180

    Article  CAS  PubMed  Google Scholar 

  27. Brugts JJ, Boersma E, Simoons ML (2010) Tailored therapy of ACE inhibitors in stable coronary artery disease: Pharmacogenetic profiling of treatment benefit. Pharmacogenomics 11(8):1115–1126

    Article  CAS  PubMed  Google Scholar 

  28. Hamilton WG, Gargiulo JM, Parks NL (2020) Using pharmacogenetics to structure individual pain management protocols in total knee arthroplasty. Bone Joint J 102-B(6_Supple_A):73–78

  29. Herkowitz HN, Sidhu KS (1995) Lumbar spine fusion in the treatment of degenerative conditions: Current indications and recommendations. J Am Acad Orthop Surg 3(3):123–135

    Article  CAS  PubMed  Google Scholar 

  30. Schofferman J, Mazanec D (2008) Evidence-informed management of chronic low back pain with opioid analgesics. Spine J 8(1):185–194

    Article  PubMed  Google Scholar 

  31. DeLeo JA (2006) Basic science of pain. JBJS 88(2):58–62

    Google Scholar 

  32. Stucky CL, Gold MS, Zhang X (2001) Mechanisms of pain. Proc Natl Acad Sci 98(21):11845–11846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kaye AD, Garcia AJ, Hall OM et al (2019) Update on the pharmacogenomics of pain management. Pharmgenomics Pers Med 12:125–143

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kushchayev SV, Glushko T, Jarraya M et al (2018) ABCs of the degenerative spine. Insights Imaging 9(2):253–274

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gouveia N, Rodrigues A, Ramiro S et al (2017) The use of analgesic and other pain-relief drugs to manage chronic low back pain: Results from a national survey. Pain Pract 17(3):353–365

    Article  PubMed  Google Scholar 

  36. Deyo RA, Von Korff M, Duhrkoop D (2015) Opioids for low back pain. BMJ 350:g6380

    Article  PubMed  PubMed Central  Google Scholar 

  37. Flexman AM, Charest-Morin R, Stobart L et al (2016) Frailty and postoperative outcomes in patients undergoing surgery for degenerative spine disease. Spine J 16(11):1315–1323

    Article  PubMed  Google Scholar 

  38. Gibbons D, Ahern DP, Curley AE et al (2021) Impact of sarcopenia on degenerative lumbar spondylosis. Clin Spine Surg 34(2):43–50

    Article  PubMed  Google Scholar 

  39. Park S, Kim HJ, Ko BG et al (2016) The prevalence and impact of sarcopenia on degenerative lumbar spinal stenosis. Bone Joint J 98-B(8):1093–1098

  40. Hersey AE, Durand WM, Eltorai AEM et al (2019) Longer operative time in elderly patients undergoing posterior lumbar fusion is independently associated with increased complication rate. Global Spine J 9(2):179–184

    Article  PubMed  Google Scholar 

  41. Samuel AM, Fu MC, Anandasivam NS et al (2017) After posterior fusions for adult spinal deformity, operative time is more predictive of perioperative morbidity, rather than surgical invasiveness: a need for speed? Spine (Phila Pa 1976) 42(24):1880–1887

  42. Suh SP, Jo YH, Jeong HW et al (2017) Outcomes of revision surgery following instrumented posterolateral fusion in degenerative lumbar spinal stenosis: a comparative analysis between pseudarthrosis and adjacent segment disease. Asian Spine J 11(3):463–471

    Article  PubMed  PubMed Central  Google Scholar 

  43. Paulozzi LJ, Jones CM, Mack KA, Rudd RA (2011) Vital signs: Overdoses of prescription opioid pain relievers, United States, 1999–2008. MMWR Morb Mortal Wkly Rep 60:1487–1492

    Google Scholar 

  44. Rudd RA, Seth P, David F, Scholl L (2016) Increases in drug and opioid-involved overdose deaths—United States, 2010–2015. MMWR Morb Mortal Wkly Rep 65:1445–1452

    Article  PubMed  Google Scholar 

  45. Meske DS, Lawal OD, Elder H et al (2018) Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials. J Pain Res 11:923–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lötsch J, Geisslinger G (2011) Pharmacogenetics of new analgesics. Br J Pharmacol 163(3):447–460

    Article  PubMed  PubMed Central  Google Scholar 

  47. Rosemary J, Adithan C (2007) The Pharmacogenetics of CYP2C9 and CYP2C19: Ethnic variation and clinical significance. Curr Clin Pharmacol 2(1):93–109

    Article  CAS  PubMed  Google Scholar 

  48. Smith HS (2009) Opioid metabolism. Mayo Clin Proc 84(7):613–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shmagel A, Ngo L, Ensrud K, Foley R (2018) Prescription medication use among community-based US adults with chronic low back pain: a cross-sectional population based study. J Pain 19(10):1104–1112

    Article  PubMed  PubMed Central  Google Scholar 

  50. Altamura AC, Moliterno D, Paletta S et al (2013) Understanding the pharmacokinetics of anxiolytic drugs. Expert Opin Drug Metab Toxicol 9(4):423–440

    Article  CAS  PubMed  Google Scholar 

  51. Figueiras A, Estany-Gestal A, Aguirre C et al (2016) CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case-control study. Pharmacogenet Genom 26(2):66–73

    Article  CAS  Google Scholar 

  52. Tremont-Lukats IW, Megeff C, Backonja MM (2000) Anticonvulsants for neuropathic pain syndromes: Mechanisms of action and place in therapy. Drugs 60(5):1029–1052

    Article  CAS  PubMed  Google Scholar 

  53. Faught E (2001) Pharmacokinetic considerations in prescribing antiepileptic drugs. Epilepsia 42(4):19–23

    Article  PubMed  Google Scholar 

  54. Bockbrader HN, Wesche D, Miller R et al (2010) A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 49(10):661–669

    Article  CAS  PubMed  Google Scholar 

  55. Forrest JA, Clements JA, Prescott LF (1982) Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 7(2):93–107

    Article  CAS  PubMed  Google Scholar 

  56. Witenko C, Moorman-Li R, Motycka C et al (2014) Considerations for the appropriate use of skeletal muscle relaxants for the management of acute low back pain. P T 39(6):427–435

    PubMed  PubMed Central  Google Scholar 

  57. See S, Ginzburg R (2008) Skeletal muscle relaxants. Pharmacotherapy 28(2):207–213

    Article  CAS  PubMed  Google Scholar 

  58. Shu-Feng Z (2009) Polymorphism of human cytochrome P450 2D6 and its clinical significance. Clin Pharmacokinet 48(11):689–723

    Article  Google Scholar 

  59. Ross JR, Riley J, Taegetmeyer AB et al (2008) Genetic variation and response to morphine in cancer patients: Catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer 112(6):1390–1403

    Article  CAS  PubMed  Google Scholar 

  60. Sadhasivam S, Chidambaran V, Zhang X et al (2015) Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics. Pharmacogenomics J 15(2):119–126

    Article  CAS  PubMed  Google Scholar 

  61. Lassen D, Damkier P, Brøsen K (2015) The pharmacogenetics of tramadol. Clin Pharmacokinet 54(8):825–836

    Article  CAS  PubMed  Google Scholar 

  62. Stamer UM, Stüber F, Muders T, Musshoff F (2008) Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107(3):926–929

    Article  PubMed  Google Scholar 

  63. Crews KR, Gaedigk A, Dunnenberger HM et al (2014) Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 95(4):376–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Naito T, Takashina Y, Yamamoto K et al (2011) CYP3A5*3 affects plasma disposition of noroxycodone and dose escalation in cancer patients receiving oxycodone. J Clin Pharmacol 51(11):1529–1538

    Article  CAS  PubMed  Google Scholar 

  65. Andersson T, Flockhart DA, Goldstein DB et al (2005) Drug-metabolizing enzymes: Evidence for clinical utility of pharmacogenomic tests. Clin Pharmacol Ther 78(6):559–581

    Article  CAS  PubMed  Google Scholar 

  66. Karolinska Institutet. The human cytochrome P450 (CYP) allele nomenclature Database Stockholm. http://www.cypalleles.ki.se/. Accessed 25 May 2021

  67. Li-Wan-Po A, Girard T, Farndon P et al (2010) Pharmacogenetics of CYP2C19: Functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol 69(3):222–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nakajima M, Yokoi T, Mizutani M et al (1999) Genetic polymorphism in the 5’-flanking region of human CYP1A2 gene: Effect on the CYP1A2 inducibility in humans. J Biochem 125:803–808

    Article  CAS  PubMed  Google Scholar 

  69. Fric M, Pfuhlmann B, Laux G et al (2008) The influence of smoking on the serum level of duloxetine. Pharmacopsychiatry 41:151–155

    Article  CAS  PubMed  Google Scholar 

  70. Rodriguez-Antona C, Sayi JG, Gustafsson LL et al (2005) Phenotypegenotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles. Biochem Biophys Res Commun 338:299–305

    Article  CAS  PubMed  Google Scholar 

  71. Bijl MJ, Visser LE, Hofman A et al (2008) Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants. Br J Clin Pharmacol 65(4):558–564

    Article  CAS  PubMed  Google Scholar 

  72. Hicks JK, Bishop JR, Sangkuhl K et al (2015) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 98(2):127–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Carbonell N, Verstuyft C, Massard J et al (2010) CYP2C9*3 loss-of-function allele is associated with acute upper gastrointestinal bleeding related to the use of NSAIDs other than aspirin. Clin Pharmacol Ther 87(6):693–698

    Article  CAS  PubMed  Google Scholar 

  74. Tanno LK, Kerr DS, dos Santos B et al (2015) The absence of CYP3A5*3 is a protective factor to anticonvulsants hypersensitivity reactions: a case-control study in Brazilian subjects. PLoS One 10(9):e0139861

    Article  PubMed  PubMed Central  Google Scholar 

  75. Manuyakorn W, Siripool K, Kamchaisatian W et al (2013) Phenobarbital-induced severe cutaneous adverse drug reactions are associated with CYP2C19*2 in Thai children. Pediatr Allergy Immunol 24(3):299–303

    Article  PubMed  Google Scholar 

  76. López-García MA, Feria-Romero IA, Serrano H et al (2017) Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy. Pharmacol Rep 69(3):504–511

    Article  PubMed  Google Scholar 

  77. Du Z, Jiao Y, Shi L (2016) Association of UGT2B7 and UGT1A4 polymorphisms with serum concentration of antiepileptic drugs in children. Med Sci Monit 22:4107–4113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gulcebi MI, Ozkaynakcı A, Goren MZ et al (2011) The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy. Epilepsy Res 95(1–2):1–8

    Article  CAS  PubMed  Google Scholar 

  79. Raftogianis RB, Wood TC, Weinshilboum RM (1999) Human phenol sulfotransferases SULT1A2 and SULT1A1: Genetic polymorphisms, allozyme properties, and human liver genotypephenotype correlations. Biochem 58(4):605–616

    CAS  Google Scholar 

  80. Cottrill E, Pennington Z, Ahmed AK et al (2021) First report of pharmacogenomic profiling in an outpatient spine setting: preliminary results from a pilot study. World Neurosurg 145:e21–e31

    Article  PubMed  Google Scholar 

  81. Perera RS, Dissanayake PH, Senarath U et al (2017) Variants of ACAN are associated with severity of lumbar disc herniation in patients with chronic low back pain. PLoS One 12(7):e0181580

    Article  PubMed  PubMed Central  Google Scholar 

  82. Liu S, Wu N, Liu J et al (2016) Association between ADAMTS-4 gene polymorphism and lumbar disc degeneration in Chinese Han population. J Orthop Res 34(5):860–864

    Article  CAS  PubMed  Google Scholar 

  83. Gruber HE, Sha W, Brouwer CR et al (2014) A novel catechol-O-methyltransferase variant associated with human disc degeneration. Int J Med Sci 11(7):748–753

    Article  PubMed  PubMed Central  Google Scholar 

  84. Crow WT, Willis DR (2009) Estimating cost of care for patients with acute low back pain: a retrospective review of patient records. J Am Osteopath Assoc 109(4):229–233

    PubMed  Google Scholar 

  85. Raman T, Nayar SK, Liu S et al (2018) Cost-effectiveness of primary and revision surgery for adult spinal deformity. Spine (Phila Pa 1976) 43(11):791–797

  86. Brixner D, Biltaji E, Bress A et al (2016) The effect of pharmacogenetic profiling with a clinical decision support tool on healthcare resource utilization and estimated costs in the elderly exposed to polypharmacy. J Med Econ 19(3):213–228

    Article  CAS  PubMed  Google Scholar 

  87. McDonnell JM, Ahern DP, Ross TD et al (2020) Regenerative medicine modalities for the treatment of degenerative disk disease. Clin Spine Surg. (Epub ahead of print)

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  1. National Spinal Injuries Unit, Mater Misericordiae University Hospital, Eccles St., Dublin, D07 R2WY, Ireland

    Jake M. McDonnell, Brian Rigney, James Storme, Daniel P. Ahern, Gráinne Cunniffe & Joseph S. Butler

  2. School of Medicine, Trinity College, Dublin, Ireland

    Daniel P. Ahern

  3. School of Medicine, University College Dublin, Dublin, Ireland

    Joseph S. Butler

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McDonnell, J.M., Rigney, B., Storme, J. et al. Pharmacogenetic profiling and individualised therapy in the treatment of degenerative spinal conditions. Ir J Med Sci 192, 1215–1224 (2023). https://doi.org/10.1007/s11845-022-03112-9

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