Influence from genetic variability on opioid use for cancer pain

A European genetic association study of 2294 cancer pain patients

P. Klepstad*, T. Fladvad, F. Skorpen, K. Bjordal, A. Caraceni, O. Dale, A. Davies, M. Kloke, S. Lundström, M. Maltoni, L. Radbruch, R. Sabatowski, V. Sigurdardottir, F. Strasser, P. M. Fayers, S. Kaasa

*Corresponding author for this work

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n = 830), oxycodone (n = 446), fentanyl (n = 699), or other opioids (n = 234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed. Variability in 112 single nucleotide polymorphisms in 25 candidate genes did not influence opioid doses in 2294 European cancer pain patients.

Original languageEnglish
Pages (from-to)1139-1145
Number of pages7
JournalPain
Volume152
Issue number5
DOIs
Publication statusPublished - May 2011

Fingerprint

Genetic Association Studies
Opioid Analgesics
Single Nucleotide Polymorphism
Genes
Pain
Cancer Pain
Oxycodone
Fentanyl
Morphine
Population

Keywords

  • Cancer
  • Genetic
  • Opioid
  • Pain
  • Polymorphism

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Klepstad, P., Fladvad, T., Skorpen, F., Bjordal, K., Caraceni, A., Dale, O., ... Kaasa, S. (2011). Influence from genetic variability on opioid use for cancer pain: A European genetic association study of 2294 cancer pain patients. Pain, 152(5), 1139-1145. https://doi.org/10.1016/j.pain.2011.01.040

Influence from genetic variability on opioid use for cancer pain : A European genetic association study of 2294 cancer pain patients. / Klepstad, P.; Fladvad, T.; Skorpen, F.; Bjordal, K.; Caraceni, A.; Dale, O.; Davies, A.; Kloke, M.; Lundström, S.; Maltoni, M.; Radbruch, L.; Sabatowski, R.; Sigurdardottir, V.; Strasser, F.; Fayers, P. M.; Kaasa, S.

In: Pain, Vol. 152, No. 5, 05.2011, p. 1139-1145.

Research output: Contribution to journalArticle

Klepstad, P, Fladvad, T, Skorpen, F, Bjordal, K, Caraceni, A, Dale, O, Davies, A, Kloke, M, Lundström, S, Maltoni, M, Radbruch, L, Sabatowski, R, Sigurdardottir, V, Strasser, F, Fayers, PM & Kaasa, S 2011, 'Influence from genetic variability on opioid use for cancer pain: A European genetic association study of 2294 cancer pain patients', Pain, vol. 152, no. 5, pp. 1139-1145. https://doi.org/10.1016/j.pain.2011.01.040
Klepstad, P. ; Fladvad, T. ; Skorpen, F. ; Bjordal, K. ; Caraceni, A. ; Dale, O. ; Davies, A. ; Kloke, M. ; Lundström, S. ; Maltoni, M. ; Radbruch, L. ; Sabatowski, R. ; Sigurdardottir, V. ; Strasser, F. ; Fayers, P. M. ; Kaasa, S. / Influence from genetic variability on opioid use for cancer pain : A European genetic association study of 2294 cancer pain patients. In: Pain. 2011 ; Vol. 152, No. 5. pp. 1139-1145.
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abstract = "Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n = 830), oxycodone (n = 446), fentanyl (n = 699), or other opioids (n = 234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed. Variability in 112 single nucleotide polymorphisms in 25 candidate genes did not influence opioid doses in 2294 European cancer pain patients.",
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note = "Acknowledgements The Norwegian Research Council and the European Union’s 6th framework (Contract No. 037777) financially supported the study. In addition to the authors, the following investigators participated in the study: Gunnhild Jakobsen, Jon H{\aa}vard Loge (Norway), Sigridur Gunnarsdottir (Iceland), Per Sj{\o}gren (Denmark), Danilo Miotti, Alessandra Pigni, Emanuala Scarpi, Barbara Marelli (Italy), Irena Poviloniene (Lithuania), Eeva Salminen (Finland), and Eriphili Argyra (Greece).",
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T2 - A European genetic association study of 2294 cancer pain patients

AU - Klepstad, P.

AU - Fladvad, T.

AU - Skorpen, F.

AU - Bjordal, K.

AU - Caraceni, A.

AU - Dale, O.

AU - Davies, A.

AU - Kloke, M.

AU - Lundström, S.

AU - Maltoni, M.

AU - Radbruch, L.

AU - Sabatowski, R.

AU - Sigurdardottir, V.

AU - Strasser, F.

AU - Fayers, P. M.

AU - Kaasa, S.

N1 - Acknowledgements The Norwegian Research Council and the European Union’s 6th framework (Contract No. 037777) financially supported the study. In addition to the authors, the following investigators participated in the study: Gunnhild Jakobsen, Jon Håvard Loge (Norway), Sigridur Gunnarsdottir (Iceland), Per Sjøgren (Denmark), Danilo Miotti, Alessandra Pigni, Emanuala Scarpi, Barbara Marelli (Italy), Irena Poviloniene (Lithuania), Eeva Salminen (Finland), and Eriphili Argyra (Greece).

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AB - Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n = 830), oxycodone (n = 446), fentanyl (n = 699), or other opioids (n = 234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed. Variability in 112 single nucleotide polymorphisms in 25 candidate genes did not influence opioid doses in 2294 European cancer pain patients.

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