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Innate Immune Signalling Genetics of Pain, Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl.

Barratt DT, Klepstad P, Dale O, Kaasa S, Somogyi AA - PLoS ONE (2015)

Bottom Line: Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment.Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1.Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, Australia; Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.

ABSTRACT
Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients.

No MeSH data available.


Related in: MedlinePlus

Predictors of cognitive dysfunction in cancer patients receiving transdermal fentanyl.Solid lines and filled circles are predicted frequency, and dotted lines and error bars are 95% confidence intervals, holding other variables to typical values. Hollow circles are unadjusted (raw) frequencies for each Karnofsky score, within 10-year bins from 30 years of age, or for each MYD88 rs6853 genotype group. Vertical bars above the x-axes of Karnofsky score and Age represent the distributions of patients’ Karnofsky scores and ages, respectively.
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pone.0137179.g001: Predictors of cognitive dysfunction in cancer patients receiving transdermal fentanyl.Solid lines and filled circles are predicted frequency, and dotted lines and error bars are 95% confidence intervals, holding other variables to typical values. Hollow circles are unadjusted (raw) frequencies for each Karnofsky score, within 10-year bins from 30 years of age, or for each MYD88 rs6853 genotype group. Vertical bars above the x-axes of Karnofsky score and Age represent the distributions of patients’ Karnofsky scores and ages, respectively.

Mentions: Serum fentanyl concentrations were not associated with cognitive dysfunction (median ± SD in cognitive dysfunction = 7.1 ± 7.9 μM versus not cognitive dysfunction = 5.5 ± 11.3 μM). Older age and lower Karnofsky functional status were associated with increased cognitive dysfunction, with a modest predictive value (area under the ROC curve = 0.71). MYD88 rs6853 heterozygous and variant genotypes (combined) were associated with reduced cognitive dysfunction (Table 3 and Fig 1) (optimal k = 7.4). Addition of MYD88 rs6853 genotype (variant carrier versus non-carrier) slightly increased the predictive ability over the non-genetic model (area under the ROC curve = 0.73), and cross-validation performance of this model (CVE = 0.136) was better than randomised controls [median (25–75th percentile) CVE = 0.138 (0.138–0.138)]. The incidence of cognitive dysfunction in MYD88 rs6853 variant carriers was less than half that of wild-type patients [11/111 (10%) versus 69/325 (21%), respectively), with a relative risk of 0.45 when accounting for age and Karnofsky functional score (Table 3 and Fig 1).


Innate Immune Signalling Genetics of Pain, Cognitive Dysfunction and Sickness Symptoms in Cancer Pain Patients Treated with Transdermal Fentanyl.

Barratt DT, Klepstad P, Dale O, Kaasa S, Somogyi AA - PLoS ONE (2015)

Predictors of cognitive dysfunction in cancer patients receiving transdermal fentanyl.Solid lines and filled circles are predicted frequency, and dotted lines and error bars are 95% confidence intervals, holding other variables to typical values. Hollow circles are unadjusted (raw) frequencies for each Karnofsky score, within 10-year bins from 30 years of age, or for each MYD88 rs6853 genotype group. Vertical bars above the x-axes of Karnofsky score and Age represent the distributions of patients’ Karnofsky scores and ages, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557995&req=5

pone.0137179.g001: Predictors of cognitive dysfunction in cancer patients receiving transdermal fentanyl.Solid lines and filled circles are predicted frequency, and dotted lines and error bars are 95% confidence intervals, holding other variables to typical values. Hollow circles are unadjusted (raw) frequencies for each Karnofsky score, within 10-year bins from 30 years of age, or for each MYD88 rs6853 genotype group. Vertical bars above the x-axes of Karnofsky score and Age represent the distributions of patients’ Karnofsky scores and ages, respectively.
Mentions: Serum fentanyl concentrations were not associated with cognitive dysfunction (median ± SD in cognitive dysfunction = 7.1 ± 7.9 μM versus not cognitive dysfunction = 5.5 ± 11.3 μM). Older age and lower Karnofsky functional status were associated with increased cognitive dysfunction, with a modest predictive value (area under the ROC curve = 0.71). MYD88 rs6853 heterozygous and variant genotypes (combined) were associated with reduced cognitive dysfunction (Table 3 and Fig 1) (optimal k = 7.4). Addition of MYD88 rs6853 genotype (variant carrier versus non-carrier) slightly increased the predictive ability over the non-genetic model (area under the ROC curve = 0.73), and cross-validation performance of this model (CVE = 0.136) was better than randomised controls [median (25–75th percentile) CVE = 0.138 (0.138–0.138)]. The incidence of cognitive dysfunction in MYD88 rs6853 variant carriers was less than half that of wild-type patients [11/111 (10%) versus 69/325 (21%), respectively), with a relative risk of 0.45 when accounting for age and Karnofsky functional score (Table 3 and Fig 1).

Bottom Line: Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment.Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1.Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, Australia; Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.

ABSTRACT
Common adverse symptoms of cancer and chemotherapy are a major health burden; chief among these is pain, with opioids including transdermal fentanyl the mainstay of treatment. Innate immune activation has been implicated generally in pain, opioid analgesia, cognitive dysfunction, and sickness type symptoms reported by cancer patients. We aimed to determine if genetic polymorphisms in neuroimmune activation pathways alter the serum fentanyl concentration-response relationships for pain control, cognitive dysfunction, and other adverse symptoms, in cancer pain patients. Cancer pain patients (468) receiving transdermal fentanyl were genotyped for 31 single nucleotide polymorphisms in 19 genes: CASP1, BDNF, CRP, LY96, IL6, IL1B, TGFB1, TNF, IL10, IL2, TLR2, TLR4, MYD88, IL6R, OPRM1, ARRB2, COMT, STAT6 and ABCB1. Lasso and backward stepwise generalised linear regression were used to identify non-genetic and genetic predictors, respectively, of pain control (average Brief Pain Inventory < 4), cognitive dysfunction (Mini-Mental State Examination ≤ 23), sickness response and opioid adverse event complaint. Serum fentanyl concentrations did not predict between-patient variability in these outcomes, nor did genetic factors predict pain control, sickness response or opioid adverse event complaint. Carriers of the MYD88 rs6853 variant were half as likely to have cognitive dysfunction (11/111) than wild-type patients (69/325), with a relative risk of 0.45 (95% CI: 0.27 to 0.76) when accounting for major non-genetic predictors (age, Karnofsky functional score). This supports the involvement of innate immune signalling in cognitive dysfunction, and identifies MyD88 signalling pathways as a potential focus for predicting and reducing the burden of cognitive dysfunction in cancer pain patients.

No MeSH data available.


Related in: MedlinePlus