Petter C. Borchgrevink

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 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.

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.

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.

Increasing use of opioids from 2004 to 2007 – Pharmacoepidemiological data from a complete national prescription database in Norway

Background: A high opioid consumption for cancer related and acute pain may indicate adequate pain treatment. Analysis of a national, compulsory and complete database of all dispensed prescription drugs in Norway (NorPD) may reveal important epidemiological data on prescription pattern of opioids. This study investigated the prevalence of opioid dispensions in 2004–2007 and explored patterns of use.

Chronic non-malignant pain patients report as poor health-related quality of life as palliative cancer patients

Background: Patients with chronic non‐malignant pain (CNMP) conditions are known to report reduced health‐related quality of life (HRQoL). The objective of this exploratory study was to compare HRQoL between patients admitted to a multidisciplinary pain centre, palliative cancer (PC) patients and national norms.

Immediate- or sustained-release morphine for dose finding during start of morphine to cancer patients: a randomized, double-blind trial.

&NA; 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.

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.

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.

Personality profile among symptomatic and recovered patients with neck sprain injury, measured by MCMI-I acutely and 6 months after car accidents

The relationships between personality and psychiatric symptoms and long-lasting physical symptoms were assessed in 88 neck sprain patients injured in car accidents. The Millon Clinical Multiaxial Inventory (MCMI-I) was completed at time of occurrence (intake) and 6 months after the injury. The neck sprain patients were divided into three subgroups according to symptoms 6 months after the accident. In addition, the total neck sprain group was compared with three other subject groups. The results indicated that the three neck sprain subgroups did not differ on the MCMI-I neither at intake nor 6 months later. The total neck sprain patients group was significantly different from patients with major depression on all scales of the MCMI-I, but not significantly different compared to patients with localized musculoskeletal pain. Compared to a group of health personnel, there were only a few significant differences. The study does not support the view that premorbid personality traits can predict outcome for neck sprain patients.