Many patients with advanced cancer depend upon health care providers for symptom assessment. The extent of agreement between patient and provider symptom assessments and the association of agreement with demographic- and disease-related factors was examined.

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.

Background: Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy. Results: We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype. Conclusion: This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.

The Research Network of the European Association for Palliative Care (EAPC) performed a survey of 3030 cancer patients from 143 palliative care centres in 21 European countries. The survey addressed pain intensity and the use of non-opioid analgesics, adjuvant analgesics and opioids. Patients were treated with analgesics corresponding to the WHO pain ladder step I (n / 855), step II (n / 509) and step III (n / 1589). The investigators assessed 32% of the patients as having moderate or severe pain. In general there were small differences between pain intensities across different countries. Cancer primary sites and the presence of metastasis had only minor influences on pain intensity. The most frequently used nonopioid analgesics were NSAIDs (26%) and paracetamol (23%). Adjuvant analgesics or coanalgesics used by / 1% of the patients were corticosteroids (39%), tricylic antidepressants (11%), gabapentin (5%), bisphosphonates (4%), clonazepam (2%), carbamazepine (4%) and phenytoin (2%). The use of non-opioid analgesics and co-analgesics varied widely between countries. Opioids administered for mild to moderate pain were codeine (8%), tramadol (8%), dextropropoxyphene (5%) and dihydrocodeine (2%). Morphine was the most frequently used opioid for moderate to severe pain (oral normal release morphine: 21%; oral sustained-release morphine: 19%; iv or sc morphine: 10%). Other opioids for moderate to severe pain were transdermal fentanyl (14%), oxycodone (4%), methadone (2%), diamorphine (2%) and hydromorphone (1%). We observed large variations in the use of opioids across countries. Finally, we observed that only a minority of the patients who used morphine needed very high doses.

A titration procedure using immediate-release morphine given 4-hourly is recommended during start of oral morphine for cancer pain. This recommendation is not based on evidence from controlled studies, and many physicians start morphine treatment with controlled-release morphine. We included 40 patients with malignant disease and pain despite treatment with opioids for mild to moderate pain in a randomized, double-blind, double-dummy, parallel-group study comparing titration with immediate-release morphine given 4-hourly with titration with sustained-release morphine given once daily. The primary end point was the time needed to achieve adequate pain relief Secondary end points were other symptoms (nausea, tiredness, lack of sleep, vertigo, appetite and constipation), health related quality of life and patient satisfaction. The mean times needed for titration were 2.1 (95% CI; 1.4-2.7) days using immediate-release morphine and 1.7 (95% CI; 1.1-2.3) days using sustained-release morphine. Patients titrated with immediate-release reported statistically significant more tiredness at the end of titration. We observed no other differences in adverse effects or health related quality of life functions between the two treatments. Similar global satisfactions with the morphine treatments were reported. In conclusion, a simplified titration using sustained-release morphine once daily is equally effective as immediate-release morphine given 4-hourly.