Genetic and Non-genetic Factors Associated With Constipation in Cancer Patients Receiving Opioids

Abstract

Objectives:To examine whether the inter-individual variation in constipation among patients receiving opioids for cancer pain is associated with genetic or non-genetic factors.Methods:Cancer patients receiving opioids were included from 17 centers in 11 European countries. Intensity of constipation was reported by 1,568 patients on a four-point categorical scale. Non-genetic factors were included as covariates in stratified regression analyses on the association between constipation and 75 single-nucleotide polymorphisms (SNPs) within 15 candidate genes related to opioid- or constipation-signaling pathways (HTR3E, HTR4, HTR2A, TPH1, ADRA2A, CHRM3, TACR1, CCKAR, KIT, ARRB2, GHRL, ABCB1, COMT, OPRM1, and OPRD1).Results:The non-genetic factors significantly associated with constipation were type of laxative, mobility and place of care among patients receiving laxatives (N=806), in addition to Karnofsky performance status and presence of metastases among patients not receiving laxatives (N=762) (P<0.01). Age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to the inter-individual differences in constipation. Five SNPs, rs1800532 in TPH1, rs1799971 in OPRM1, rs4437575 in ABCB1, rs10802789 in CHRM3, and rs2020917 in COMT were associated with constipation (P<0.01). Only rs2020917 in COMT passed the Benjamini–Hochberg criterion for a 10% false discovery rate.Conclusions:Type of laxative, mobility, hospitalization, Karnofsky performance status, presence of metastases, and five SNPs within TPH1, OPRM1, ABCB1, CHRM3, and COMT may contribute to the variability in constipation among cancer patients treated with opioids. Knowledge of these factors may help to develop new therapies and to identify patients needing a more individualized approach to treatment.

A Longitudinal Study of Predictors of Constipation Severity in Oncology Outpatients With Unrelieved Pain

“…Despite this level of intervention, w70.0% of our patients had constipation as indicated by CAS scores of $2. Taken together and consistent with previous research, 22,23,25 our findings confirm that constipation is an extremely difficult symptom to manage in oncology patients taking analgesic medications.…”

“…Consistent with a previous report, 25 a higher percentage of days with the use of constipation treatments, in the week before the initiation of the intervention, was associated with higher constipation severity scores (Fig. 4c).…”

“…In the third cross-sectional study that evaluated for genetic and nongenetic factors associated with the severity of constipation in cancer patients receiving opioids (n ¼ 1568), 25 age, gender, body mass index, cancer diagnosis, time on opioids, opioid dose, and type of opioid did not contribute to interindividual differences in constipation severity. However, the nongenetic factors associated with constipation in patients receiving laxatives were type of laxative, decreased mobility, and place of care.…”

Genetic findings related to pain and analgesics–why are they so inconsistent?

“…Genetic variation is related to adverse effects of opioids, such as nausea, constipation and cognitive failure. [18][19][20] Variations in opioid doses may therefore be caused not only by genetic variability resulting in poorer analgesic efficacy, but also by genetic variation putting the patients at higher risk for opioid-induced adverse effects.…”

The rare Arg181Cys mutation in the μ opioid receptor can abolish opioid responses

“…It is demonstrated in various categories of pain that patients respond differently to opioid treatment, both with regard to dose requirements, degree of pain relief and to the type and severity of adverse effects. [1][2][3][4] Individuals may also respond differently to different opioids, which is the rationale for an opioid switch if the first choice opioid does not give adequate pain relief, gives rise to intolerable adverse effects, or both. 5,6 These interindividual differences, differences between ethnic groups, and data from well-designed twin studies strongly suggest that opioid efficacy is influenced by genetic variability.…”