Ola Dale

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.

Nasal administration of opioids for pain management in adults

Background: Nasal administration of opioids may be an alternative route to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in some patients. Key features may be self‐administration, combined with rapid onset of action. The aim of this paper is to evaluate the present base of knowledge on this topic.

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.

Influence from genetic variability on opioid use for cancer pain: A European genetic association study of 2294 cancer pain patients

&NA; 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.

Clinical pharmacology of methadone for pain.

Background: This topical review addresses methadones pharmacology, its application in malignant and non‐malignant pain conditions, practical issues related to methadone for the treatment of pain and its influence on QTc time.

Choosing the unit of measurement counts: the use of oral morphine equivalents in studies of opioid consumption is a useful addition to defined daily doses.

Aim: Defined daily dose (DDD) is the most common measurement unit used in drug consumption studies. The DDD for opioids may not reflect their relative clinical potencies. The aim of this study was to explore whether opioid consumption data may be interpreted differently when adding oral morphine equivalent (OMEQ) dose as a measurement unit compared with using DDD. Methods: The equianalgesic ratio of each opioid relative to morphine was tabulated. Data on opioid consumption expressed in DDD were converted to OMEQs using the equianalgesic ratios. The opioid consumption was compared in three different study settings: clinical data from an opioid switching study, trends within one country and a comparison between countries. Results: Using DDD, the opioid consumption in Norway between 2004–2008 increased of 6.7%, while the increase was 23.6% using OMEQ. While DDD/1000 inhabitants/day showed that Sweden had the highest consumption of opioids among the Nordic countries, OMEQ/1000 inhabitants/day showed that Denmark had the highest consumption. In the switching study DDD indicated a reduction in analgesic dosing and OMEQ an increase when switching from WHO step II to III. Conclusion: OMEQ reflects clinical dosing better than DDD, and can give additional insight into opioid consumption when combined with DDD. Using OMEQ can also lead to different conclusions in opioid consumption studies compared with using DDD alone.

Associations between recreational exercise and chronic pain in the general population: evidence from the HUNT 3 study.

Summary Recreational exercise is associated with a lower prevalence of chronic pain in the general population. Abstract The evidence for an association between leisure‐time physical activity and prevalence of pain is insufficient. This study investigated associations between frequency, duration, and intensity of recreational exercise and chronic pain in a cross‐sectional survey of the adult population of a Norwegian county (the Nord‐Trøndelag Health Study; HUNT 3). Of the 94,194 invited to participate, complete data were obtained from 46,533 participants. Separate analyses were performed for the working‐age population (20–64 years) and the older population (65 years or more). When defined as pain lasting longer than 6 months, and of at least moderate intensity during the past month, the overall prevalence of chronic pain was 29%. We found that increased frequency, duration, and intensity of exercise were associated with less chronic pain in analyses adjusted for age, education, and smoking. For those aged 20–64 years, the prevalence of chronic pain was 10–12% lower for those exercising 1–3 times a week for at least 30 minutes duration or of moderate intensity, relative to those not exercising. Dependent on the load of exercise, the prevalence of chronic pain was 21–38% lower among older women who exercised, relative to those not exercising. Similar, but somewhat weaker, associations were seen for older men. This study shows consistent and linear associations between frequency, duration, and intensity of recreational exercise and chronic pain for the older population, and associations without an apparent linear shape for the working‐age population.

Nitrous oxide: an ageing gentleman

IN 1994 Acta Anaesthesiologica Scandinavica celebrated the 150th anniversary for the clinical use of nitrous oxide with a series of articles covering all important aspects related to this anaesthetic agent (1, 2). These were the benefits and adverse effects of clinical use of nitrous oxide, as well as the possible harm of nitrous oxide for operating room staff, and last, but not least, the environmental aspects of medical use of nitrous oxide. Since then the use of the old-timer has come under attack again (3, 4). In this editorial we will discuss briefly the status of nitrous oxide, and then focus on any new information that requires that the clinical use of nitrous oxide should be altered.

Estimating the prevalence of chronic pain: validation of recall against longitudinal reporting (the HUNT pain study).

TOC Summary Pain reporting in the general population is stable, and recall measures of chronic pain may give valid estimates compared with longitudinal recordings. ABSTRACT Methods for classifying chronic pain in population studies are highly variable, and prevalence estimates ranges from 11% to 64%. Limited knowledge about the persistence of pain and the validity of recall questions defining chronic pain make findings difficult to interpret and compare. The primary aim of the current study was to characterize the persistence of pain in the general population and to validate recall measures against longitudinal reporting of pain. A random sample of 6419 participants from a population study (the HUNT 3 study in Norway) was invited to report pain on the SF‐8 verbal pain rating scale every 3 months over a 12‐month period and to report pain lasting more than 6 months at 12‐month follow‐up. Complete data were obtained from 3364 participants. Pain reporting was highly stable (intraclass correlation 0.66, 95% confidence interval 0.65 to 0.67), and the prevalence of chronic pain varied considerably according to level of severity and persistence: 31% reported mild pain or more, whereas 2% reported severe pain on 4 of 4 consecutive measurements. When defined as moderate pain or more on at least 3 of 4 consecutive measurements, the prevalence was 26%. Compared with the longitudinal classification, a cross‐sectional measure of moderate pain or more during the last week on the SF‐8 scale presented a sensitivity of 82% and a specificity of 84%, and a sensitivity of 80% and a specificity of 90% when combined with a 6‐month recall question. Thus pain reporting in the general population is stable and cross‐sectional measures may give valid prevalence estimates of chronic pain.