Pål Klepstad

The 118 A > G polymorphism in the human µ‐opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease

Background:  Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine‐6‐glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the µ‐opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients.

The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients.

&NA; Catechol‐O‐methyltransferase (COMT) inactivates dopamine, epinephrine and norepinephrine in the nervous system. A common functional polymorphism (Val158Met) leads to a three‐ to‐four‐fold variation in the COMT enzyme activity, the Met form displaying lower enzymatic activity. The Val158Met polymorphism affects pain perception, and subjects with the Met/Met genotype have the most pronounced response to experimental pain. Based on this information we analyzed the influence from the COMT Val158Met polymorphism on the efficacy of morphine in a cohort of patients suffering from cancer pain. We genotyped 207 Caucasian cancer patients on morphine treatment with respect to the Val158Met polymorphism and compared the morphine doses, serum concentrations of morphine and morphine metabolites between the genotype groups. Patients with the Val/Val genotype (n=44) needed more morphine (155±160 mg/24 h) when compared to the Val/Met (117±100 mg/24 h; n=96) and the Met/Met genotype (95±99 mg/24 h; n=67) groups (P=0.025). This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, perceived pain intensity, adverse symptoms, or time until death. These results suggest that genetic variation in the COMT gene may contribute to variability in the efficacy of morphine in cancer pain treatment.

The Norwegian brief pain inventory questionnaire: translation and validation in cancer pain patients.

The European Association of Palliative Care recommends the Brief Pain Inventory questionnaire (BPI) as a pain assessment tool in clinical studies. After translation into Norwegian, we administered the BPI to 300 hospitalized cancer patients. Cronbachs alphas were computed to assess reliability, and factor analysis was utilized to ascertain construct validity. The BPI interference and pain severity scales were validated against items on pain intensity and pain influence on daily function in the European Organization for Research and Therapy of Cancer (EORTC) QLQ-C30 questionnaire. In total, 235 patients (78%) were able to complete the BPI questionnaire, but 82 (35%) of these questionnaires had one or more missing items. Cronbachs alphas were 0.87 for the pain severity and 0.92 for the interference scales. A factor analysis identified three factors; pain intensity, interference with physical function, and interference with psychological functions/sleep. These three factors explained 82% of the variance. The correlation between BPI pain severity index and the EORTC QLQ-C30 item on pain intensity was 0.70 (P < 0.001). The correlation between BPI interference index and the EORTC QLQ-C30 item on pain influence on daily living was 0.62 (P < 0.001). We conclude that BPI has satisfactory psychometric properties, but is not completed by a significant proportion of patients. Further research is needed to establish pain assessment tools for patients unable to answer a comprehensive pain questionnaire, to establish routines for analysis of missing values, and to investigate if pain interference items also reflect disease-related impairment.

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

ABSTRACTWe have screened a cohort of 239 Norwegian cancer patients for sequence variation in the coding and regulatory regions of the UDP-glucuronosyltransferase 2B7 gene (UGT2B7) and analyzed the impact of gene variants on morphine glucuronidation in vivo. In all, 12 single nucleotide polymorphisms (SNPs) were identified, 10 of which have not been previously described. Only one SNP causes a change in amino acid sequence (H268Y). Seven UGT2B7 genotypes were observed and three main haplotypes predicted. There was no correlation between UGT2B7 genotype or haplotype and morphine glucuronide to morphine serum ratios among 175 patients who received chronic oral morphine therapy, and who had normal renal and hepatic function. The apparent lack of functional polymorphisms fits well with the near unimodal, but broad, distributions of the ratios (morphine 3-glucuronide/morphine: 6.4–309.2; morphine 6-glucuronide/morphine: 0.5–72.8). Our results suggest that factors other than UGT2B7 polymorphism may be more deciding for the variability in morphine glucuronide to morphine serum ratios.

Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy

HeadingAbstractObjective. UDP-glucuronosyltransferase (UGT) 2B7 is the major UGT isoform responsible for the 3- and 6-glucuronidation of morphine in humans. Studies in rats have indicated that UGT1A1 may also contribute to the formation of morphine 3-glucuronide (M3G). Our objective was to investigate whether the UGT2B7 H268Y and UGT1A1*28 polymorphisms contribute to the variability in morphine glucuronide-to-morphine plasma ratios among cancer patients undergoing analgesic therapy with morphine.Methods. Seventy patients with normal hepatic and renal function using slow-release morphine to relieve cancer pain were included. UGT2B7 genotyping was performed using restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Wild-type and variant alleles of the UGT1A1 gene were identified using sizing of PCR-amplified fragments. Morphine 6-glucuronide (M6G)/morphine, M3G/morphine, and M3G/M6G plasma ratios were compared between genotypes.Results. The M3G/morphine, M6G/morphine, and M3G/M6G plasma ratios varied 16-, 42-, and sevenfold, respectively, among individuals. No statistically significant differences in plasma ratios were found between individuals possessing UGT2B7 H/H (n=20), H/Y (n=30), or Y/Y (n=20) genotypes. Five patients were homozygous for the UGT1A1 TA7 allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/morphine plasma ratios in TA7 homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA6) individuals.Conclusion. The UGT2B7 H268Y polymorphism cannot account for the considerable variation in glucuronide-to-morphine ratios in cancer patients. Moreover, the contribution of UGT1A1 to the formation of M3G appears to be of minor biological significance, at least in a UGT2B7 background.

Genetic variation in the Catechol-O-Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain

BackgroundGenetic 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.ResultsWe 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.ConclusionThis 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.

Health care providers underestimate symptom intensities of cancer patients: A multicenter European study

BackgroundMany 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.MethodsThis cross-sectional study included 1933 patient-health care provider dyads, from 11 European countries. Patients reported symptoms by using the four-point scales of the European Organization of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) version 3, and providers used corresponding four-point categorical scales. Level of agreement was addressed at the group level (Wilcoxon Signed-Rank test), by difference scores (provider score minus patient score), at the individual level (Intraclass Correlation Coefficients, ICCs) and visually by Bland-Altman plots. Absolute numbers and chi-square tests were used to investigate the relationship between agreement and demographic-, as well as disease-related factors.ResultsThe prevalence of symptoms assessed as moderate or severe by patients and providers, respectively, were for pain (67 vs.47%), fatigue (71 vs. 54%), generalized weakness (65 vs. 47%), anorexia (47 vs. 25%), depression (31 vs. 17%), constipation (45 vs. 30%), poor sleep (32 vs. 21%), dyspnea (30 vs. 16%), nausea (27 vs. 14%), vomiting (14 vs. 6%) and diarrhea (14 vs. 6%). Symptom scores were identical or differed by only one response category in the majority of patient-provider assessment pairs (79-93%). Providers underestimated the symptom in approximately one of ten patients and overestimated in 1% of patients. Agreement at the individual level was moderate (ICC 0.38 to 0.59). Patients with low Karnofsky Performance Status, high Mini Mental State-score, hospitalized, recently diagnosed or undergoing opioid titration were at increased risk of symptom underestimation by providers (all p < 0.001). Also, the agreement was significantly associated with drug abuse (p = 0.024), provider profession (p < 0.001), cancer diagnosis (p < 0.001) and country (p < 0.001).ConclusionsConsiderable numbers of health care providers underestimated symptom intensities. Clinicians in cancer care should be aware of the factors characterizing patients at risk of symptom underestimation.

Pain and pain treatments in European palliative care units. A cross sectional survey from the European Association for Palliative Care Research Network

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.

Severe head injury: control of physiological variables, organ failure and complications in the intensive care unit.

Background:  In patients with severe head injury, control of physiological variables is important to avoid intracranial hypertension and secondary injury to the brain. The aims of this retrospective study were to evaluate deviations of physiological variables and the incidence of extracranial complications in patients with severe head injury. We also studied if these deviations could be related to outcome.

Start of oral morphine to cancer patients: effective serum morphine concentrations and contribution from morphine-6-glucuronide to the analgesia produced by morphine.

AbstractObjective: To investigate the serum concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) and the relationships between serum concentrations and clinical effects associated with start of morphine treatment in cancer patients. Methods: Forty patients with malignant disease and intolerable pain on weak opioids (codeine/dextropropoxyphen) were included. After a wash-out period, titration with immediate-release (IR) morphine was started. When a stable dose was achieved, the morphine treatment was changed to slow-release (SR) morphine in equivalent daily dosages. Clinical data and serum concentrations of morphine, M3G and M6G were obtained at the end of the IR and SR morphine treatment periods. Results: The mean trough serum morphine concentration associated with pain relief was 66 nmol/l. The corresponding mean concentrations of M6G and M3G were 257 nmol/l and 1943 nmol/l, respectively. Morphine serum trough concentrations showed a 33-fold variation. Seventy percent of the variation was predicted in a model including age, daily morphine dose and M6G/morphine ratio as independent variables. No associations were observed between side effects and serum concentrations of morphine and its metabolites. Conclusion: In this study, a mean serum trough morphine concentration of 66 nmol/l was associated with satisfactory pain relief when disease progression required an increase in intensity of pain therapy from step II to step III in the World Health Organization pain ladder. An increased ratio of M6G to morphine serum concentrations predicted lower effective serum morphine concentrations at the time of satisfactory pain relief. This observation supports that M6G contributes to the pain control produced by oral morphine in patients with pain caused by malignant disease.