Quality of Life Research

, Volume 19, Issue 10, pp 1407–1417 | Cite as

Biological pathways and genetic variables involved in pain

  • Qiuling Shi
  • Charles S. Cleeland
  • Pål Klepstad
  • Christine Miaskowski
  • Nancy L. Pedersen



This paper summarizes current knowledge of pain-related and analgesic-related pathways as well as genetic variations involved in pain perception and management.


The pain group of the GENEQOL Consortium was given the task of summarizing the current status of research on genetic variations in pain and analgesic efficacy. This review is neither exhaustive nor comprehensive; we focus primarily on single-nucleotide polymorphisms.


Two categories of potential genetic pain-perception pathways were identified: neurotransmission modulators and mechanisms that affect inflammation. Four categories were identified for analgesic efficacy: genes related to receptor interaction, modulation of opioid effects, metabolism, and transport. Various genetic variations involved in these pathways are proposed as candidate genetic markers for pain perception and for individual sensitivity to analgesics.


Candidate gene association studies have been used to provide evidence for the genetic modulation of pain perception and response to analgesics. However, the nature and range of genetic modulation of pain is not well addressed due to the limited number of patients and the limited number of genes and genetic variants investigated in studies to date. Moreover, personalized analgesic treatments will require a more complete understanding of the effects of genetic variants and gene–gene interactions in response to analgesics.


Pain Analgesic efficacy Genetic polymorphism Biological pathways 



5-Hydroxytryptamine (serotonin)


Serotonin transporter


Serotonin transporter gene repeated polymorphism




Adenosine-5′-triphosphate-binding cassette sub-family B member 1




Central nervous system




Cytochrome P450 2C9


Cytochrome P450 2D6


Deoxyribonucleic acid


Fatty acid amide hydrolase




Gamma amino butyric acid


Guanosine triphosphate cyclohydrolase 1


Interleukin 1


Interleukin 1 receptor antagonist


Interleukin 1α


Interleukin 1β


Interleukin 6


Interleukin 8


Melanocortin 1 receptor


Messenger ribonucleic acid


Nonsteroidal anti-inflammatory drug


μ-Opioid receptor gene




Single-nucleotide polymorphism




Tumor necrosis factor α


Transient receptor potential


Transient receptor potential cation channel, subfamily A, member 1


Transient receptor potential cation channel, subfamily V, member 1


Uridine 5′-diphospho-glucuronosyltransferase





The authors thank Drs. Jeff Sloan and Mirjam A. G. Sprangers for arranging the February 2009 GENEQOL Consortium, a two-day workshop that brought together experts in quality-of-life research, genetics, and pain medicine. The authors acknowledge the editorial assistance of Jeanie F. Woodruff, ELS.



One of various forms of a gene, usually referring to a specific genetic locus


Pain produced by a stimulus that does not normally provoke pain, i.e., pressure from clothing or simple touch


The essential basic component of DNA or RNA. There are four DNA bases: adenine (A), guanine (G), thymine (T), and cytosine (C)

Candidate gene association study

A method that determines whether a particular form of a DNA polymorphism occurs more frequently in subjects with a phenotype of interest, usually focusing on genes involved in the biological pathways of disease development and treatment


Thread-like structures of DNA found in the nucleus of a cell that carry hereditary information


The entire hereditary information of an organism

Genome-wide association study

A method to examine genetic variation across a given genome, designed to identify genetic associations with phenotypes of interest, usually 1,000,000 or more markers involved


Instructions of the internal inheritable information of any living organism


A set of genetic markers in the same chromosome that highly correlate to each other and tend to be inherited together


An organism with two different alleles at one gene location


An organism with two identical alleles at one gene location


Increased pain sensitivity, usually abnormal


Perception of pain

Nonsynonymous SNP

A DNA base change that results in an altered polypeptide sequence


Anything that is part of the observable structure, function, or behavior of a living organism


Variety in forms of a particular DNA sequence in a population


Short form for single-nucleotide polymorphism, a variation between individuals in a single nucleotide (A, T, C, or G) of the DNA sequence


  1. 1.
    Aubrun, F., Langeron, O., Quesnel, C., Coriat, P., & Riou, B. (2003). Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology, 98(6), 1415–1421.PubMedCrossRefGoogle Scholar
  2. 2.
    Klepstad, P., Dale, O., Kaasa, S., Zahlsen, K., Aamo, T., Fayers, P., et al. (2003). Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients. Acta Anaesthesiologica Scandinavica, 47(6), 725–731.PubMedCrossRefGoogle Scholar
  3. 3.
    Sprangers, M. A., Sloan, J. A., Veenhoven, R., Cleeland, C. S., Halyard, M. Y., Abertnethy, A. P., et al. (2009). The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes. Twin Research and Human Genetics, 12(3), 301–311.PubMedCrossRefGoogle Scholar
  4. 4.
    Lotta, T., Vidgren, J., Tilgmann, C., Ulmanen, I., Melén, K., Julkunen, I., et al. (1995). Kinetics of human soluble and membrane-bound catechol O-methyltransferase: A revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry, 34(13), 4202–4210.PubMedCrossRefGoogle Scholar
  5. 5.
    Zubieta, J. K., Heitzeg, M. M., Smith, Y. R., Bueller, J. A., Xu, K., Xu, Y., et al. (2003). COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science, 299(5610), 1240–1243.PubMedCrossRefGoogle Scholar
  6. 6.
    Nackley, A. G., Shabalina, S. A., Tchivileva, I. E., Satterfield, K., Korchynskyi, O., Makarov, S. S., et al. (2006). Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science, 314(5807), 1930–1933.PubMedCrossRefGoogle Scholar
  7. 7.
    Diatchenko, L., Slade, G. D., Nackley, A. G., Bhalang, K., Sigurdsson, A., Belfer, I., et al. (2005). Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human Molecular Genetics, 14(1), 135–143.PubMedCrossRefGoogle Scholar
  8. 8.
    Rakvåg, T. T., Ross, J. R., Sato, H., Skorpen, F., Kaasa, S., & Klepstad, P. (2008). Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Molecular Pain, 4, 64.PubMedGoogle Scholar
  9. 9.
    Ross, J. R., Riley, J., Taegetmeyer, A. B., Sato, H., Gretton, S., du Bois, R. M., 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.PubMedCrossRefGoogle Scholar
  10. 10.
    Pert, C. B., & Snyder, S. H. (1973). Opiate receptor: Demonstration in nervous tissue. Science, 179(77), 1011–1014.PubMedCrossRefGoogle Scholar
  11. 11.
    Stein, C. (1993). Peripheral mechanisms of opioid analgesia. Anesthesia and Analgesia, 76(1), 182–191.PubMedCrossRefGoogle Scholar
  12. 12.
    Bidlack, J. M., Khimich, M., Parkhill, A. L., Sumagin, S., Sun, B., & Tipton, C. M. (2006). Opioid receptors and signaling on cells from the immune system. Journal of Neuroimmune Pharmacology, 1(3), 260–269.PubMedCrossRefGoogle Scholar
  13. 13.
    McQuay, H. (1999). Opioids in pain management. Lancet, 353(9171), 2229–2232.PubMedCrossRefGoogle Scholar
  14. 14.
    Satoh, M., & Minami, M. (1995). Molecular pharmacology of the opioid receptors. Pharmacology and Therapeutics, 68(3), 343–364.PubMedCrossRefGoogle Scholar
  15. 15.
    Bond, C., LaForge, K. S., Tian, M., Melia, D., Zhang, S., Borg, L., et al. (1998). Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: Possible implications for opiate addiction. Proceedings of the National Academy of Sciences of the United States of America, 95(16), 9608–9613.PubMedCrossRefGoogle Scholar
  16. 16.
    Oertel, B. G., Kettner, M., Scholich, K., Renné, C., Roskam, B., Geisslinger, G., et al. (2009). A common human {micro}-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. The Journal of Biological Chemistry, 284(10), 6530–6535.PubMedCrossRefGoogle Scholar
  17. 17.
    Sia, A. T., Lim, Y., Lim, E. C., Goh, R. W., Law, H. Y., Landau, R., et al. (2008). A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology, 109(3), 520–526.PubMedCrossRefGoogle Scholar
  18. 18.
    Chou, W. Y., Wang, C. H., Liu, P. H., Liu, C. C., Tseng, C. C., & Jawan, B. (2006). Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology, 105(2), 334–337.PubMedCrossRefGoogle Scholar
  19. 19.
    Klepstad, P., Rakvåg, T. T., Kaasa, S., Holthe, M., Dale, O., Borchgrevink, P. C., et al. (2004). The 118 A>G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiologica Scandinavica, 48(10), 1232–1239.PubMedCrossRefGoogle Scholar
  20. 20.
    Landau, R., Kern, C., Columb, M. O., Smiley, R. M., & Blouin, J. L. (2008). Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women. Pain, 139(1), 5–14.PubMedCrossRefGoogle Scholar
  21. 21.
    Blakely, R. D., De Felice, L. J., & Hartzell, H. C. (1994). Molecular physiology of norepinephrine and serotonin transporters. Journal of Experimental Biology, 196, 263–281.PubMedGoogle Scholar
  22. 22.
    Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274(5292), 1527–1531.PubMedCrossRefGoogle Scholar
  23. 23.
    Heils, A., Teufel, A., Petri, S., Stöber, G., Riederer, P., Bengel, D., et al. (1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry, 66(6), 2621–2624.PubMedCrossRefGoogle Scholar
  24. 24.
    Kosek, E., Jensen, K. B., Lonsdorf, T. B., Schalling, M., & Ingvar, M. (2009). Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans. Molecular pain, 5, 37.PubMedCrossRefGoogle Scholar
  25. 25.
    Herken, H., Erdal, E., Mutlu, N., Barlas, O., Cataloluk, O., Oz, F., et al. (2001). Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene. American Journal of Orthodontics and Dentofacial Orthopedics, 120(3), 308–313.PubMedCrossRefGoogle Scholar
  26. 26.
    Tegeder, I., Costigan, M., Griffin, R. S., Abele, A., Belfer, I., Schmidt, H., et al. (2006). GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nature Medicine, 12(11), 1269–1277.PubMedCrossRefGoogle Scholar
  27. 27.
    Lötsch, J., Belfer, I., Kirchhof, A., Mishra, B. K., Max, M. B., Doehring, A., et al. (2007). Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms. Clinical Chemistry, 53(6), 1010–1015.PubMedCrossRefGoogle Scholar
  28. 28.
    Story, G. M., Peier, A. M., Reeve, A. J., Eid, S. R., Mosbacher, J., Hricik, T. R., et al. (2003). ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell, 112(6), 819–829.PubMedCrossRefGoogle Scholar
  29. 29.
    Kim, H., Mittal, D. P., Iadarola, M. J., & Dionne, R. A. (2006). Genetic predictors for acute experimental cold and heat pain sensitivity in humans. Journal of Medical Genetics, 43(8), e40.PubMedCrossRefGoogle Scholar
  30. 30.
    Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., & Julius, D. (1997). The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature, 389(6653), 816–824.PubMedCrossRefGoogle Scholar
  31. 31.
    Kim, H., Neubert, J. K., San Miguel, A., Xu, K., Krishnaraju, R. K., Iadarola, M. J., et al. (2004). Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain, 109(3), 488–496.PubMedCrossRefGoogle Scholar
  32. 32.
    Lichtman, A. H., Shelton, C. C., Advani, T., & Cravatt, B. F. (2004). Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain, 109(3), 319–327.PubMedCrossRefGoogle Scholar
  33. 33.
    Chiang, K. P., Gerber, A. L., Sipe, J. C., & Cravatt, B. F. (2004). Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: Evidence for a link between defects in the endocannabinoid system and problem drug use. Human Molecular Genetics, 13(18), 2113–2119.PubMedCrossRefGoogle Scholar
  34. 34.
    Raimondi, S., Sera, F., Gandini, S., Iodice, S., Caini, S., Maisonneuve, P., et al. (2008). MC1R variants, melanoma and red hair color phenotype: A meta-analysis. International Journal of Cancer, 122(12), 2753–2760.CrossRefGoogle Scholar
  35. 35.
    Liem, E. B., Joiner, T. V., Tsueda, K., & Sessler, D. I. (2005). Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology, 102(3), 509–514.PubMedCrossRefGoogle Scholar
  36. 36.
    Mogil, J. S., Wilson, S. G., Chesler, E. J., Rankin, A. L., Nemmani, K. V., Lariviere, W. R., et al. (2003). The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proceedings of the National Academy of Sciences of the United States of America, 100(8), 4867–4872.PubMedCrossRefGoogle Scholar
  37. 37.
    Mogil, J. S., Ritchie, J., Smith, S. B., Strasburg, K., Kaplan, L., Wallace, M. R., et al. (2005). Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. Journal of Medical Genetics, 42(7), 583–587.PubMedCrossRefGoogle Scholar
  38. 38.
    Lee, B. N., Dantzer, R., Langley, K. E., Bennett, G. J., Dougherty, P. M., Dunn, A. J., et al. (2004). A cytokine-based neuroimmunologic mechanism of cancer-related symptoms. Neuroimmunomodulation, 11(5), 279–292.PubMedCrossRefGoogle Scholar
  39. 39.
    Maier, S. F., & Watkins, L. R. (2003). Immune-to-central nervous system communication and its role in modulating pain and cognition: Implications for cancer and cancer treatment. Brain, Behavior, and Immunity, 17(Suppl 1), S125–S131.PubMedCrossRefGoogle Scholar
  40. 40.
    Oh, S. B., Tran, P. B., Gillard, S. E., Hurley, R. W., Hammond, D. L., & Miller, R. J. (2001). Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. Journal of Neuroscience, 21(14), 5027–5035.PubMedGoogle Scholar
  41. 41.
    Bennett, G. J., & Xie, Y. K. (1988). A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain, 33(1), 87–107.PubMedCrossRefGoogle Scholar
  42. 42.
    Bennett, G. J. (1999). Does a neuroimmune interaction contribute to the genesis of painful peripheral neuropathies? Proceedings of the National Academy of Sciences of the United States of America, 96(14), 7737–7738.PubMedCrossRefGoogle Scholar
  43. 43.
    Bennett, G. J. (2000). A neuroimmune interaction in painful peripheral neuropathy. Clinical Journal of Pain, 16(3 Suppl), S139–S143.PubMedGoogle Scholar
  44. 44.
    Reeve, A. J., Patel, S., Fox, A., Walker, K., & Urban, L. (2000). Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. European Journal of Pain: Ejp, 4(3), 247–257.PubMedCrossRefGoogle Scholar
  45. 45.
    Sommer, C., Petrausch, S., Lindenlaub, T., & Toyka, K. V. (1999). Neutralizing antibodies to interleukin 1-receptor reduce pain associated behavior in mice with experimental neuropathy. Neuroscience Letters, 270(1), 25–28.PubMedCrossRefGoogle Scholar
  46. 46.
    Dominici, R., Cattaneo, M., Malferrari, G., Archi, D., Mariani, C., Grimaldi, L. M., et al. (2002). Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1 alpha. Immunogenetics, 54(2), 82–86.PubMedCrossRefGoogle Scholar
  47. 47.
    Hulkkonen, J., Laippala, P., & Hurme, M. (2000). A rare allele combination of the interleukin-1 gene complex is associated with high interleukin-1 beta plasma levels in healthy individuals. European Cytokine Network, 11(2), 251–255.PubMedGoogle Scholar
  48. 48.
    McDowell, T. L., Symons, J. A., Ploski, R., Førre, O., & Duff, G. W. (1995). A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. Arthritis and Rheumatism, 38(2), 221–228.PubMedCrossRefGoogle Scholar
  49. 49.
    Pociot, F., Mølvig, J., Wogensen, L., Worsaae, H., & Nerup, J. (1992). A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. European Journal of Clinical Investigation, 22(6), 396–402.PubMedCrossRefGoogle Scholar
  50. 50.
    di Giovine, F. S., Takhsh, E., Blakemore, A. I., & Duff, G. W. (1992). Single base polymorphism at -511 in the human interleukin-1 beta gene (IL1 beta). Human Molecular Genetics, 1(6), 450.PubMedCrossRefGoogle Scholar
  51. 51.
    Tarlow, J. K., Blakemore, A. I., Lennard, A., Solari, R., Hughes, H. N., Steinkasserer, A., et al. (1993). Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Human Genetics, 91(4), 403–404.PubMedCrossRefGoogle Scholar
  52. 52.
    Tountas, N. A., Casini-Raggi, V., Yang, H., di Giovine, F. S., Vecchi, M., Kam, L., et al. (1999). Functional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis. Gastroenterology, 117(4), 806–813.PubMedCrossRefGoogle Scholar
  53. 53.
    Solovieva, S., Leino-Arjas, P., Saarela, J., Luoma, K., Raininko, R., & Riihimäki, H. (2004). Possible association of interleukin 1 gene locus polymorphisms with low back pain. Pain, 109(1–2), 8–19.PubMedCrossRefGoogle Scholar
  54. 54.
    Bessler, H., Shavit, Y., Mayburd, E., Smirnov, G., & Beilin, B. (2006). Postoperative pain, morphine consumption, and genetic polymorphism of IL-1 beta and IL-1 receptor antagonist. Neuroscience Letters, 404(1–2), 154–158.PubMedCrossRefGoogle Scholar
  55. 55.
    Winkelstein, B. A., Rutkowski, M. D., Weinstein, J. N., & DeLeo, J. A. (2001). Quantification of neural tissue injury in a rat radiculopathy model: Comparison of local deformation, behavioral outcomes, and spinal cytokine mRNA for two surgeons. Journal of Neuroscience Methods, 111(1), 49–57.PubMedCrossRefGoogle Scholar
  56. 56.
    Bianchi, M., Maggi, R., Pimpinelli, F., Rubino, T., Parolaro, D., Poli, V., et al. (1999). Presence of a reduced opioid response in interleukin-6 knock out mice. European Journal of Neuroscience, 11(5), 1501–1507.PubMedCrossRefGoogle Scholar
  57. 57.
    Wang, X. S., Shi, Q., Williams, L. A., Cleeland, C. S., Mobley, G. M., Reuben, J. M., et al. (2008). Serum interleukin-6 predicts the development of multiple symptoms at nadir of allogeneic hematopoietic stem cell transplantation. Cancer, 113(8), 2102–2109.PubMedCrossRefGoogle Scholar
  58. 58.
    Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V., Yudkin, J. S., Humphries, S., et al. (1998). The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. Journal of Clinical Investigation, 102(7), 1369–1376.PubMedCrossRefGoogle Scholar
  59. 59.
    Reyes-Gibby, C. C., El Osta, B., Spitz, M. R., Parsons, H., Kurzrock, R., Wu, X., et al. (2008). The influence of tumor necrosis factor-alpha -308 G/A and IL-6–174 G/C on pain and analgesia response in lung cancer patients receiving supportive care. Cancer Epidemiology, Biomarkers and Prevention, 17(11), 3262–3267.PubMedCrossRefGoogle Scholar
  60. 60.
    Oen, K., Malleson, P. N., Cabral, D. A., Rosenberg, A. M., Petty, R. E., Nickerson, P., et al. (2005). Cytokine genotypes correlate with pain and radiologically defined joint damage in patients with juvenile rheumatoid arthritis. Rheumatology (Oxford), 44(9), 1115–1121.CrossRefGoogle Scholar
  61. 61.
    Karppinen, J., Daavittila, I., Noponen, N., Haapea, M., Taimela, S., Vanharanta, H., et al. (2008). Is the interleukin-6 haplotype a prognostic factor for sciatica? European Journal of Pain: Ejp, 12(8), 1018–1025.PubMedCrossRefGoogle Scholar
  62. 62.
    Utreras, E., Futatsugi, A., Rudrabhatla, P., Keller, J., Iadarola, M. J., Pant, H. C., et al. (2009). Tumor necrosis factor-alpha regulates cyclin-dependent kinase 5 activity during pain signaling through transcriptional activation of p35. The Journal of Biological Chemistry, 284(4), 2275–2284.PubMedCrossRefGoogle Scholar
  63. 63.
    Segond von Banchet, G., Boettger, M. K., Fischer, N., Gajda, M., Bräuer, R., & Schaible, H. G. (2009). Experimental arthritis causes tumor necrosis factor-alpha-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior. Pain, 145(1–2), 151–159.PubMedCrossRefGoogle Scholar
  64. 64.
    Wilson, A. G., Symons, J. A., McDowell, T. L., McDevitt, H. O., & Duff, G. W. (1997). Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proceedings of the National Academy of Sciences of the United States of America, 94(7), 3195–3199.PubMedCrossRefGoogle Scholar
  65. 65.
    Ahn, S. H., Cho, Y. W., Ahn, M. W., Jang, S. H., Sohn, Y. K., & Kim, H. S. (2002). mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Phila Pa 1976), 27(9), 911–917.Google Scholar
  66. 66.
    Wang, X. M., Hamza, M., Wu, T. X., & Dionne, R. A. (2009). Upregulation of IL-6, IL-8 and CCL2 gene expression after acute inflammation: Correlation to clinical pain. Pain, 142(3), 275–283.PubMedCrossRefGoogle Scholar
  67. 67.
    Hull, J., Thomson, A., & Kwiatkowski, D. (2000). Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax, 55(12), 1023–1027.PubMedCrossRefGoogle Scholar
  68. 68.
    Reyes-Gibby, C. C., Spitz, M., Wu, X., Merriman, K., Etzel, C., Bruera, E., et al. (2007). Cytokine genes and pain severity in lung cancer: Exploring the influence of TNF-alpha-308 G/A IL6–174G/C and IL8–251T/A. Cancer Epidemiology, Biomarkers and Prevention, 16(12), 2745–2751.PubMedCrossRefGoogle Scholar
  69. 69.
    Schinkel, A. H., Wagenaar, E., van Deemter, L., Mol, C. A., & Borst, P. (1995). Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. Journal of Clinical Investigation, 96(4), 1698–1705.PubMedCrossRefGoogle Scholar
  70. 70.
    Thompson, S. J., Koszdin, K., & Bernards, C. M. (2000). Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology, 92(5), 1392–1399.PubMedCrossRefGoogle Scholar
  71. 71.
    King, M., Su, W., Chang, A., Zuckerman, A., & Pasternak, G. W. (2001). Transport of opioids from the brain to the periphery by P-glycoprotein: Peripheral actions of central drugs. Nature Neuroscience, 4(3), 268–274.PubMedCrossRefGoogle Scholar
  72. 72.
    Higgins, C. F. (2001). ABC transporters: Physiology, structure and mechanism–an overview. Research in Microbiology, 152(3–4), 205–210.PubMedCrossRefGoogle Scholar
  73. 73.
    Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H. P., Brockmöller, J., Johne, A., et al. (2000). Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proceedings of the National Academy of Sciences of the United States of America, 97(7), 3473–3478.PubMedCrossRefGoogle Scholar
  74. 74.
    Lötsch, J., von Hentig, N., Freynhagen, R., Griessinger, N., Zimmermann, M., Doehring, A., et al. (2009). Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers. Pharmacogenetics and genomics, 19(6), 429–436.PubMedCrossRefGoogle Scholar
  75. 75.
    Campa, D., Gioia, A., Tomei, A., Poli, P., & Barale, R. (2008). Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clinical Pharmacology and Therapeutics, 83(4), 559–566.PubMedCrossRefGoogle Scholar
  76. 76.
    Coller, J. K., Barratt, D. T., Dahlen, K., Loennechen, M. H., & Somogyi, A. A. (2006). ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clinical Pharmacology and Therapeutics, 80(6), 682–690.PubMedCrossRefGoogle Scholar
  77. 77.
    Park, H. J., Shinn, H. K., Ryu, S. H., Lee, H. S., Park, C. S., & Kang, J. H. (2007). Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clinical Pharmacology and Therapeutics, 81(4), 539–546.PubMedCrossRefGoogle Scholar
  78. 78.
    Guengerich, F. P. (2008). Cytochrome p450 and chemical toxicology. Chemical Research in Toxicology, 21(1), 70–83.PubMedCrossRefGoogle Scholar
  79. 79.
    Stamer, U. M., Musshoff, F., Kobilay, M., Madea, B., Hoeft, A., & Stuber, F. (2007). Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clinical Pharmacology and Therapeutics, 82(1), 41–47.PubMedCrossRefGoogle Scholar
  80. 80.
    Zanger, U. M., Klein, K., Saussele, T., Blievernicht, J., Hofmann, M. H., & Schwab, M. (2007). Polymorphic CYP2B6: Molecular mechanisms and emerging clinical significance. Pharmacogenomics, 8(7), 743–759.PubMedCrossRefGoogle Scholar
  81. 81.
    Paar, W. D., Poche, S., Gerloff, J., & Dengler, H. J. (1997). Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. European Journal of Clinical Pharmacology, 53(3–4), 235–239.PubMedCrossRefGoogle Scholar
  82. 82.
    de Leon, J., Susce, M. T., & Murray-Carmichael, E. (2006). The AmpliChip CYP450 genotyping test: Integrating a new clinical tool. Molecular diagnosis & therapy, 10(3), 135–151.Google Scholar
  83. 83.
    Desmeules, J., Gascon, M. P., Dayer, P., & Magistris, M. (1991). Impact of environmental and genetic factors on codeine analgesia. European Journal of Clinical Pharmacology, 41(1), 23–26.PubMedCrossRefGoogle Scholar
  84. 84.
    Yue, Q. Y., Hasselström, J., Svensson, J. O., & Säwe, J. (1991). Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: Comparisons between extensive and poor hydroxylators of debrisoquine. British Journal of Clinical Pharmacology, 31(6), 635–642.PubMedGoogle Scholar
  85. 85.
    Wang, G., Zhang, H., He, F., & Fang, X. (2006). Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. European Journal of Clinical Pharmacology, 62(11), 927–931.PubMedCrossRefGoogle Scholar
  86. 86.
    Crettol, S., Déglon, J. J., Besson, J., Croquette-Krokar, M., Hämmig, R., Gothuey, I., et al. (2006). ABCB1 and cytochrome P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment. Clinical Pharmacology and Therapeutics, 80(6), 668–681.PubMedCrossRefGoogle Scholar
  87. 87.
    Pilotto, A., Seripa, D., Franceschi, M., Scarcelli, C., Colaizzo, D., Grandone, E., et al. (2007). Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: Role of cytochrome P450 2C9 polymorphisms. Gastroenterology, 133(2), 465–471.PubMedCrossRefGoogle Scholar
  88. 88.
    Armstrong, S. C., & Cozza, K. L. (2003). Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: Theory and clinical reality, part I. Psychosomatics, 44(2), 167–171.PubMedCrossRefGoogle Scholar
  89. 89.
    Holthe, M., Rakvåg, T. N., Klepstad, P., Idle, J. R., Kaasa, S., Krokan, H. E., et al. (2003). Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: Identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. The Pharmacogenomics Journal, 3(1), 17–26.PubMedCrossRefGoogle Scholar
  90. 90.
    Duguay, Y., Báár, C., Skorpen, F., & Guillemette, C. (2004). A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clinical Pharmacology and Therapeutics, 75(3), 223–233.PubMedCrossRefGoogle Scholar
  91. 91.
    Darbari, D. S., van Schaik, R. H., Capparelli, E. V., Rana, S., McCarter, R., & van den Anker, J. (2008). UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. American Journal of Hematology, 83(3), 200–202.PubMedCrossRefGoogle Scholar
  92. 92.
    Mogil, J. S. (2009). Are we getting anywhere in human pain genetics? Pain, 146(3), 231–232.PubMedCrossRefGoogle Scholar
  93. 93.
    Rakvåg, T. T., Klepstad, P., Báár, C., Kvam, T. M., Dale, O., Kaasa, S., et al. (2005). The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain, 116(1–2), 73–78.PubMedCrossRefGoogle Scholar
  94. 94.
    Hagen, K., Pettersen, E., Stovner, L. J., Skorpen, F., & Zwart, J. A. (2006). The association between headache and Val158Met polymorphism in the catechol-O-methyltransferase gene: The HUNT Study. The Journal of Headache and Pain, 7(2), 70–74.PubMedCrossRefGoogle Scholar
  95. 95.
    Vargas-Alarcón, G., Fragoso, J. M., Cruz-Robles, D., Vargas, A., Vargas, A., Lao-Villadóniga, J. I., et al. (2007). Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Research & Therapy, 9(5), R110.CrossRefGoogle Scholar
  96. 96.
    Kim, H., Lee, H., Rowan, J., Brahim, J., & Dionne, R. A. (2006). Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans. Molecular Pain, 2, 24.PubMedCrossRefGoogle Scholar
  97. 97.
    Ruaño, G., Thompson, P. D., Windemuth, A., Seip, R. L., Dande, A., Sorokin, A., et al. (2007). Physiogenomic association of statin-related myalgia to serotonin receptors. Muscle and Nerve, 36(3), 329–335.PubMedCrossRefGoogle Scholar
  98. 98.
    Guimarães, A. L., Correia-Silva Jde, F., Sá, A. R., Victória, J. M., Diniz, M. G., Costa Fde, O., et al. (2007). Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-alpha in individuals with recurrent aphthous stomatitis. Archives of Oral Biology, 52(3), 268–272.PubMedCrossRefGoogle Scholar
  99. 99.
    Klepstad, P., Dale, O., Skorpen, F., Borchgrevink, P. C., & Kaasa, S. (2005). Genetic variability and clinical efficacy of morphine. Acta Anaesthesiologica Scandinavica, 49(7), 902–908.PubMedCrossRefGoogle Scholar
  100. 100.
    Pedersen, R. S., Damkier, P., & Brosen, K. (2005). Tramadol as a new probe for cytochrome P450 2D6 phenotyping: A population study. Clinical Pharmacology and Therapeutics, 77(6), 458–467.PubMedCrossRefGoogle Scholar
  101. 101.
    Coller, J. K., Joergensen, C., Foster, D. J., James, H., Gillis, D., Christrup, L., et al. (2007). Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone. International Journal of Clinical Pharmacology and Therapeutics, 45(7), 410–417.PubMedGoogle Scholar
  102. 102.
    Ferrari, A., Coccia, C. P., Bertolini, A., & Sternieri, E. (2004). Methadone–metabolism, pharmacokinetics and interactions. Pharmacological Research, 50(6), 551–559.PubMedCrossRefGoogle Scholar
  103. 103.
    Shiran, M. R., Lennard, M. S., Iqbal, M. Z., Lagundoye, O., Seivewright, N., Tucker, G. T., et al. (2009). Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment. British Journal of Clinical Pharmacology, 67(1), 29–37.PubMedCrossRefGoogle Scholar
  104. 104.
    Cai, W., Chen, B., Tao, X., Ling, S., & Zhang, Y. (2000). Correlation of genetic polymorphism of cytochrome P4502D6 with dextromethorphan oxidative metabolism in Chinese. Zhonghua Yixue Yichuanxue Zazhi, 17(3), 181–184.PubMedGoogle Scholar
  105. 105.
    Takashima, T., Murase, S., Iwasaki, K., & Shimada, K. (2005). Evaluation of dextromethorphan metabolism using hepatocytes from CYP2D6 poor and extensive metabolizers. Drug Metabolism and Pharmacokinetics, 20(3), 177–182.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Qiuling Shi
    • 1
  • Charles S. Cleeland
    • 1
  • Pål Klepstad
    • 2
  • Christine Miaskowski
    • 3
  • Nancy L. Pedersen
    • 4
  1. 1.Department of Symptom ResearchThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of AnesthesiologyUniversity Hospital of TrondheimTrondheimNorway
  3. 3.Department of Physiological NursingUCSF School of NursingSan FranciscoUSA
  4. 4.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden

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