Search

Background Chronic pain and mental disorders are leading causes of disability worldwide. Individuals with chronic pain are more likely to experience mental disorders compared to individuals without chronic pain, but large-scale estimates are lacking. We aimed to calculate overall prevalence of mental health diagnoses from primary and secondary care among individuals treated for chronic pain in 2019 and to compare prevalence among chronic pain patients receiving opioid versus non-opioid analgesics, according to age and gender. Methods It is a population-based cohort study. Linked data from nationwide health registers on dispensed drugs and diagnoses from primary (ICPC-2) and secondary (ICD-10) health care. Chronic pain patients were identified as all patients over 18 years of age filling at least one prescription of an analgesic reimbursed for non-malignant chronic pain in both 2018 and 2019 (N = 139,434, 69.3% women). Results Prevalence of any mental health diagnosis was 35.6% (95% confidence interval: 35.4%–35.9%) when sleep diagnoses were included and 29.0% (28.8%–29.3%) when excluded. The most prevalent diagnostic categories were sleep disorders (14% [13.8%–14.2%]), depressive and related disorders (10.1% [9.9%–10.2%]) and phobia and other anxiety disorders (5.7% [5.5%–5.8%]). Prevalence of most diagnostic categories was higher in the group using opioids compared to non-opioids. The group with the highest overall prevalence was young women (18–44 years) using opioids (50.1% [47.2%–53.0%]). Conclusions Mental health diagnoses are common in chronic pain patients receiving analgesics, particularly among young individuals and opioid users. The combination of opioid use and high psychiatric comorbidity suggests that prescribers should attend to mental health in addition to somatic pain. Significance This large-scale study with nation-wide registry data supports previous findings of high psychiatric burden in chronic pain patients. Opioid users had significantly higher prevalence of mental health diagnoses, regardless of age and gender compared to users of non-opioid analgesics. Opioid users with chronic pain therefore stand out as a particularly vulnerable group and should be followed up closely by their physician to ensure they receive sufficient care for both their mental and somatic symptoms.

Background and aims Pain catastrophizing has consistently been related to a variety of negative outcomes within chronic pain conditions, but competing models exist explaining the role of catastrophizing. According to the fear-avoidance model (FAM), catastrophizing is primarily related to the appraisal of pain (i.e. “intrapersonal”), whereas the communal coping model (CCM) suggests that catastrophizing is a strategy to elicit support (i.e. “interpersonal”). In order to examine the interpersonal nature of catastrophizing, this cross-sectional study examined interpersonal problems as a predictor of pain catastrophizing in a sample of patients (n = 97) with chronic pain. Methods Self-report data was taken from patients entering a multidisciplinary, inpatient rehabilitation program. The four quadrants of the Inventory of Interpersonal Problems circumplex model (Hostile-Dominant, Hostile-Submissive, Friendly-Submissive, Friendly-Dominant) were used as predictors of pain catastrophizing in a series of separate, hierarchical regression analyses. Results After controlling for relevant confounding variables such as demographics (gender, age), pain severity, psychiatric symptoms (anxiety/depression, fatigue, insomnia), adverse life experiences and perceived social support, higher levels of Hostile-Dominant interpersonal problems predicted higher levels of pain catastrophizing (p ≤ 0.01, d = 0.56). Conclusions The results add support to the notion that pain catastrophizing may serve a communicative functioning, as predicted by the CCM, with cold, dominant and controlling behaviors as a maladaptive interpersonal strategy to elicit support. It may thus be useful to consider the broader interpersonal context of the individual, and not only the patient’s appraisal of pain, when conceptualizing the role of pain catastrophizing in patients with chronic pain. Implications Future psychosocial research and treatment of chronic pain could be informed by including interpersonal theory as a useful theoretical framework, which may help shed more light on how interpersonal problems relates to pain catastrophizing.

Background Postoperative pain, side‐effects and time to mobilisation are indicators for the quality of postoperative recovery. The aim of this randomised controlled study was to investigate if efficacy safety score (ESS) combined with a wireless patient monitoring system would improve these clinical outcomes for patients at a general surgical ward. Methods The trial included 195 patients randomised to a standard care group (SC‐Group) or intervention group (INT‐Group) receiving continuous wireless monitoring of vital signs combined with ESS during the first 24 postoperative hours. The primary outcome was time to mobilisation. Secondary outcomes were average pain, doses of postoperative opioids, unscheduled interventions, side‐effects, patient satisfaction and length of hospital stay (LOS). Results Mean time to postoperative mobilisation was 10.1 hours for patients in the INT‐Group compared to 14.2 hours in the SC‐Group; this corresponds to an adjusted hazard ratio of 1.54 (95% confidence interval 1.04‐2.28). INT‐Group patients received a higher dose of oral morphine equivalents; 26 mg vs 15 mg, P < .001; reported lower intensity of pain on a 0‐10 scale; 2.1 vs 3.3, P < .001; and had higher patient satisfaction on a 5‐point scale; 4.9 vs 4.3, P < .001. The LOS was similar between the groups; 71 hours in INT‐Group vs 77 hours in SC‐Group, P = .58. No serious side‐effects were registered in INT‐Group, whereas two were registered in SC‐Group. Conclusions Introducing ESS as a decision tool combined with a wireless monitoring system resulted in less pain, increased satisfaction and more rapid mobilisation for patients in this study. © 2019 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Background Although persons with chronic pain are frequent users of the health care system, they report poor satisfaction with health care services. Participants with persistent opioid use in Nord-Trondelag Health Study (HUNT)3 report severe pain in spite of treatment. The aim of the study was to test the hypothesis that subjects with persistent opioid use have both a higher consumption of health care services and a poorer satisfaction than the remaining subjects reporting chronic pain. Methods This cross-sectional study was based on linkage of self-reported data from the substudy (10,238 were invited, 6927 met the inclusion criteria) of health care use in HUNT3; a population-based health survey during the years 2006-2008 and the complete national registers of the Norwegian Prescription Database and the Cancer Registry of Norway. Patients with chronic pain are stratified according to the level of opioid use as persistent users of opioids, intermittent users, and persons not using opioids. Results Persons with chronic non-malignant pain reported a higher consumption of all health care services compared to the control group. Consumption of health care services increased with increasing level of opioid use. Persons with persistent opioid use were highly satisfied with all health care services, although less satisfied than persons without chronic pain. Conclusions Combined with previous findings of high levels of pain in spite of opioid treatment, the present findings indicate that symptomatic relief is not a prerequisite for patient satisfaction. The study shows higher patient satisfaction compared to previous studies.

Background There are few studies on the use of opioids among children and adolescents. The aim of this study was to determine the 1-year prevalence of prescribed opioid dispensing in Denmark, Norway and Sweden, and to compare gender and age differences in the use of weak and strong opioids between the three countries. Methods Data on the dispensing of opioids were collected from the websites of the complete national prescription databases in the three countries. All individuals aged 0–19 with at least one prescription of opioids during the study period were included. Results The 1-year prevalence of opioid use among young individuals aged 0–19 years increased during the study period (2006–2012) in Denmark from 2.5 to 3.4 per thousand, in Norway from 10.7 to 13.4 per thousand and in Sweden from 5.9 to 7.1 per thousand. In all three countries, more boys than girls used opioids between the ages of 0 and 10, whereas girls were the major users in the age range 11–19. Use of opioids in all three countries was dominated by weak opioids, codeine being the most dominant in Norway and Sweden and tramadol in Denmark. Conclusions The 1-year prevalence of prescribed opioid use among children and adolescents in Norway was far higher than in Denmark and Sweden. During the study period, an increasing use of opioids among children and adolescents was observed in all three countries.

Guidelines for opioid treatment of chronic non-malignant pain recommend long-acting over short-acting opioid formulations. The evidence for this recommendation is weak. This study is a randomized, double-blind, double-dummy, 8-week comparison of long-acting dihydrocodeine tablets (DHC-Continus) with short-acting dihydrocodeine tablets in 60 patients with chronic non-malignant pain who were referred to a multidisciplinary pain clinic. All patients used codeine-paracetamol tablets before the trial, and paracetamol was added in both groups during the trial. The primary outcome was stability in pain intensity, measured as the difference between the highest and least pain intensity reported on an 11-point numerical rating scale in a 7-day diary. The secondary outcomes were differences in quality of life, quality of sleep, depression, and episodes of breakthrough pain between the 2 formulations. Spontaneously reported adverse events were recorded. In all, 38 patients completed the trial, and 22 withdrew before the end. The reasons for withdrawal were adverse events, lack of efficacy, or both, and were similar between the groups. There were no significant differences in stability of pain intensity between groups. There were no significant differences between groups in quality of sleep, depression, health-related quality of life, or adverse events. Breakthrough pain was experienced in both groups during the trial. Long-acting dihydrocodeine was not observed to be superior for any of the outcomes in this trial. The results of this study do not support current guidelines recommending long-acting opioids.

In selected patients with chronic non-malignant pain, chronic opioid therapy is indicated. Published guidelines recommend long-acting over short-acting opioids in these patients. The aim of this systematic review was to investigate whether long-acting opioids in chronic non-malignant pain are superior to short-acting opioids in pain relief, physical function, sleep quality, quality of life or adverse events. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for relevant trials up to July 2012. Reference lists of included trials and relevant reviews were in addition searched by hand. Of the 1168 identified publications, 6 randomised trials evaluating efficacy and safety filled the criteria for inclusion. None of them found a significantly better pain relief, significantly less consumption of rescue analgesia, improved quality of sleep or improved physical function from long-acting opioids. None of the trials investigated quality of life. None of the trials investigated adverse events properly nor addiction, tolerance or hyperalgesia. Three trials in healthy volunteers with a recreational drug use, found no difference in abuse potential between long- and short-acting opioids. While long term, comparative data are lacking, there is fair evidence from short-term trials that long-acting opioids provide equal pain relief compared with short-acting opioids. Contrary to several guidelines, there is no evidence supporting long-acting opioids superiority to short-acting ones in improving functional outcomes, reducing side effects or addiction.

Background In patients with chronic non-malignant pain (CNMP), co-morbid physical or mental health disorders are common and may have a negative impact on health-related quality of life and treatment outcomes. The purpose of this study was to examine the occurrence of chronic psychiatric and somatic diseases in persistent opioid users with CNMP compared with the general population in Norway. Methods In this cross-sectional study, prescription patterns of dispensed opioids were used to identify a study population of persistent opioid users with CNMP from the general population. Reimbursed prescriptions marked with diagnostic codes were used to identify the occurrence of 21 somatic and 3 psychiatric diseases for a 1-year period in the Norwegian Prescription Database. Occurrence of disease in persistent opioid users was compared to an age- and gender-specific population of all Norwegian residents aged 18–79 years in 2009. Standardized morbidity ratios (SMRs) for each disease were calculated. Results Eighty-five percent of the persistent opioid user population had at least one co-morbid disease compared with 45% of the general population. Forty-two percent had three or more co-morbidities. SMRs in both men and women were generally increased except for dementia, glaucoma and renal disease, indicating a higher occurrence of disease in persistent opioid users. Conclusions A higher occurrence of both somatic and psychiatric co-morbidities in disease stages warranting pharmacological treatment was found in persistent opioid users with CNMP compared with the general population of Norway.

Most occupational rehabilitation programmes target specific disorders. Crossover between programmes for mental and somatic disorders has been discussed and it has been pointed out that interventions may be applicable across different diagnostic categories. This study aimed to investigate the feasibility of introducing a novel transdiagnostic occupational rehabilitation programme that was delivered in groups mixing participants with chronic pain, chronic fatigue and common mental disorders.

Background Recent guidelines for opioid treatment of chronic non-malignant pain discourage co-medication with benzodiazepines and benzodiazepine-related hypnotics, whereas co-medication with non-opioid analgesics and co-analgesics may offer a beneficial opioid sparing effect, and is recommended. The aim of this study was to describe 1-year periodic prevalence of co-medication with benzodiazepines, benzodiazepine-related hypnotics, non-opioid analgesics, co-analgesics and antidepressants in persistent opioid users with chronic non-malignant pain. Methods The study is based on data from the Norwegian Prescription Database, covering all drugs dispensed to outpatients in 2008. Concomitant medication levels were compared between users in two definitions of persistent opioid use, all Norwegian adults dispensed opioids in 2008 and the Norwegian background population. Results Of the Norwegian adult population studied, 1.2% met the criteria of persistent opioid use based on prescription pattern and prescription level. Sixty per cent of persistent opioid users were dispensed a benzodiazepine or benzodiazepine-related hypnotic in amounts indicating regular use, with 15% dispensed a high amount of both classes. Sixty-two percent of persistent opioid users were dispensed one or more non-opioid analgesics, 47% an antidepressant and 33% were dispensed an antiepileptic drug. Conclusion Approximately 60% of persistent opioid users also receive benzodiazepines or benzodiazepine-related hypnotics in amounts indicating regular use. This is in conflict with recent guidelines for the treatment of chronic non-malignant pain and may indicate that these users are at an increased risk of developing problematic opioid use.

Introduction Recently, low-dose transdermal buprenorphine (LD-TD-BUP) was introduced for treatment of patients with chronic non-malignant pain. The primary aim of this study was to determine the proportion of patients who were prescribed LD-TD-BUP for non-malignant pain who became long-term users. The secondary aim was to determine the proportion of patients who co-medicated with other opioids or benzodiazepines during treatment with LD-TD-BUP. Methods Data were drawn from the Norwegian Prescription Database that covers all prescriptions dispensed at pharmacies to the entire Norwegian population (4.7 million inhabitants). The study population consisted of all patients who were dispensed at least one prescription of LD-TD-BUP from its introduction in November 2005 to 31 December 2008. Patients who were dispensed more than 24 patches (≥ 6 months) were defined as long-term users. Reimbursement codes were used to stratify patients as having cancer pain or non-malignant pain. Results Among new users of LD-TD-BUP for non-malignant pain (n = 13,451), only 22% became long-term users, while 44% were only dispensed one prescription. Among long-term users who were opioid naive when LD-TD-BUP was initiated, 43% co-medicated with other opioids or benzodiazepines, compared with 82% of those who previously had used opioids. Conclusion Three years after introduction, 0.4% of the Norwegian population had been dispensed LD-TD-BUP. Only one-fifth had become long-term users. Those who used opioids before the first dispension of LD-TD-BUP co-medicated with other potentially addictive drugs to a much higher degree compared with those who were opioid naive.

Transfer from on-site rehabilitation to the participant’s daily environment is considered a weak link in the rehabilitation chain. Various follow-up regimes have been implemented after multidisciplinary rehabilitation, however, consensus is lacking on recommended content, duration and intensity.

Palliative Medicine Unit,Department of Oncology, St Olav University Hospital, Trondheim, NorwayBackground: Brief treatments for chronic non-malignantpain patients with problematicopioidusearewarranted.The aims of the present study were to investigate (1)whether it is possible to withdraw codeine use in suchpatients with a brief cognitive-behavioural therapy (CBT),(2) whether this could be done without pain escalation andreduction in quality of life and (3) to explore the effects ofcodeine reduction on neurocognitive functioning.Methods: Eleven patients using codeine daily correspond-ing to 40–100mg morphine were included. Two specificallytrained physicians treated the patients with six CBT ses-sions, tapering codeine gradually within 8 weeks. Codeineuse, pain intensity, quality of life and neuropsychologicalfunctioning were assessed at pre-treatment to the 3-monthfollow-up.Results: Codeine use was significantly reduced from mean237mg [standard deviation (SD) 65] pre-treatment to 45mg(SD 66) post-treatment and to 48mg (SD 65) at follow-upwithout significant pain escalation or reductions in qualityof life. Moreover, neuropsychological functioning im-proved significantly on some tests, while others remainedunchanged.Conclusion: The promising findings of codeine reductionin this weaning therapy programme for pain patients withproblematic opioid use should be further evaluated in alarger randomized control trial comparing this brief CBTwith both another brief treatment and attention placebocondition.

Background: This topical review addresses methadone's 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. Methods: Relevant papers were identified in PubMed and EMBASE. Results: Methadone is advocated by experts as a second line opioid when first line opioids fail to provide a satisfactory balance between pain control and side effects (opioid switching). Although randomized-controlled studies are lacking, current evidence suggests that switching to methadone in this situation reduces pain intensity. However, interindividual variability in its pharmacokinetics make its application challenging and metabolism by CYP 3A4 and 2B6 implies a substantial risk of drug–drug interactions. Several ways of switching to methadone have been presented, with a gradual switch during 3 days or ‘stop and go’ as the dominating strategies. Episodes of torsade de pointes arrhythmia during methadone treatment have been reported in patients with other risk factors for arrhythmia, while small prospective studies have reported a small, lasting and stable increase in QTc time. The extensive use of methadone for opioid replacement in addicts has added additional patient barriers to its use for pain control. Conclusion: In spite of challenges related to the variable pharmacokinetics and concerns regarding increase in QTc time, current evidence indicates that opioid switching to methadone improves pain control in a substantial proportion of patients who are candidates for opioid switching. Measures must be instituted to secure that patients receiving methadone for pain are not considered opioid addicts.

IntroductionThe patients with the most severe and complex chronic non-malignant pain (CNMP) conditions are admitted to multidisciplinary pain centres. A poor health related quality of life (HRQoL) has been documented in these patients but their HRQoL scores have to a very limited degree been compared to other patient groups. Such comparisons require the application of the same HRQoL instruments in different populations. While nonpharmacological treatment is preferred in this patient group, treatment with strong opioids is an option for some patients. After start of opioid therapy about half the patients experience an unacceptable balance between side effects and pain relief. According to research in cancer pain, a switch to methadone may improve pain control in these patients. However, there are several areas of uncertainty related to this switch in CNMP patients. It has not been evaluated in prospective studies with long-term follow up and both increased QTc time (QT time adjusted for heart rate) and autoinduction of methadone metabolism during long term treatment have been indicated in other patient populations.Research questionsHRQoL assessment methodology in CNMP patients:I. Is the EORTC QLQ-C30 a valid alternative to the SF-36 for assessment of HRQoL in CNMP patients?Comparison of HRQoL scores between patient groups:II. How is the HRQoL of CNMP patients admitted to multidisciplinary pain centre treatment compared to the HRQoL of palliative cancer patients?Opioid switching from morphine to methadone in CNMP patients with an unacceptable balance between pain control and side effects during morphine therapy:III. What are the effects on pain control, HRQoL, cognitive functioning and patient preference?IV. What is the effect on QTc time?V. Are methadone serum concentrations stable during long term treatment and are there interindividual differences in opioid metabolism?MethodsHRQoL data were collected from 288 CNMP patients admitted to multidisciplinary pain treatment. These data were used for psychometric validation of the EORTC QLQ-C30 HRQoL questionnaire and for comparison of HRQoL with palliative cancer patients. Twelve patients with unacceptable balance between pain control and side effects during morphine treatment for CNMP switched to methadone. Pain, HRQoL, cognitive functioning, opioid serum concentrations and QTc were evaluated at baseline and one, two, six and 13 weeks and nine months later.ResultsInternal consistency was below 0.70 for five of nine EORTC QLQ-C30 multi-item scales. Large floor or ceiling effects were seen for several scales. These weaknesses do not disrupt the picture of overall acceptable psychometric properties in this population.Compared to palliative cancer patients, patients with CNMP reported poorer global quality of life and cognitive functioning and more pain, sleep disturbances and financial difficulties as well as equally poor physical, social and emotional functioning and equally high levels of diarrhoea, dyspnoea and fatigue.Seven patients preferred long-term (> nine months) treatment with methadone and reported reduced pain and improved functioning while cognition was not improved. On the other hand one patient experienced sedation requiring naloxone and four patients were switched back to morphine due to poor pain control, drowsiness or sweating. Mean increase in QTc was 0.020 seconds. Serum concentrations of methadone and its metabolite EDDP were stable from the end of dose titration and during the nine months.Conclusions-The EORTC QLQ-C30 is a valid alternative to the SF-36 for HRQoL assessment in CNMP patients.-CNMP patients admitted to multidisciplinary pain centres report as poor HRQoL as palliative cancer patients.-Opioid switching to methadone causes improved pain control and HRQoL in some patients but is not beneficial to all patients and poses a risk of serious sedation.

Changes in cuff pressure and volume of tracheal tubes were studied in 60 patients undergoing lower abdominal surgery under general anaesthesia with nitrous oxide and oxygen as the anaesthetic gas mixture. The cuffs were inflated with either anaesthetic gas mixture or air. Three different brands of tubes were used. The pressure in the air filled cuffs increased steadily throughout the procedure and reached level high enough to impede microcirculation in the tracheal mucosa within one hour. We conclude that filling the cuff with anaesthetic gas mixture is a simple and reliable way to achieve stable cuff pressure during anaesthesia.

The number of cancer patients in the world is increasing mainly because of ageing populations. In developed countries it is estimated that about one in three will get cancer during their lifetime. In addition to anticancer treatment, pain treatment at all stages of the cancer disease is of high priority and an ongoing challenge in clinical practice. Whilst oral morphine has been the first line drug of choice for moderate to severe cancer pain, 10-30 % of patients treated with morphine do not have successful outcomes, either because of intolerable adverse effects or inadequate analgesia - or a combination of both. Another issue of morphine treatment is that in cases where it does prove efficient, the dose needed to relieve pain varies widely between patients. One explanation of the interindividual variation in response to morphine may lie within the genes. How many genes are involved, and which variation within well studied genes and yet unknown genes, however, is still an unraveled puzzle. Pharmacogenetics is the studies of how genetic variability influences the responses to drugs. In this thesis, using a pharmacogenetic approach, we have investigated the geneopioid interaction in patients receiving oral morphine for cancer pain. The genetic focus in this thesis has been on two systems, the μ-opioid receptor system and the catechol-O-methyltransferase system. The μ-opioid receptor is the major site for activation of most clinically important opioids, including morphine. Therefore, the gene encoding the μ-opioid receptor (the-OPRM1 gene) was selected for investigation. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Variation within the COMT gene is believed to influence pain sensitivity and therefore we hypothesized that the COMT gene is a contributor that influences the response of morphine in cancer pain treatment. Our findings indicate that genetic variation in the OPRM1 and the COMT genes are influencing the analgesic effect of morphine for patients experiencing cancer pain. Our data also indicate that two genetic variants of the OPRM1 and COMT genes display joint effects, but larger cohorts are needed to investigate whether these effects are enhancing the efficacy of morphine. The phenotype “morphine response in cancer pain treatment” is a multiplex phenotype that has a complex genetic basis. Most likely more than two genes influence the phenotype. We are only at the beginning of the journey towards a better understanding of the complex biology of opioid response.

Background: In order to make treatment decisions physicians should have knowledge about the relations between patient characteristics and drug disposition. Dose, route of administration, gender, age and renal function are reported to influence the serum concentrations of morphine, morphine-6-glucurnide (M6G) and morphine-3-glucuronide (M3G) during chronic treatment of cancer pain. These factors, however, are not evaluated in studies with a sample size sufficient to explore predictive factors. Methods: Three hundred consecutive morphine users admitted because of a malignant disease were recruited. The relations of serum concentrations of morphine, M6G and M3G to patient characteristics (gender, age, weight, renal function, liver function, dose, route of administration) were explored, and regression analysis performed to investigate whether these characteristics predicted serum concentrations obtained during routine clinical drug monitoring. Results: Morphine dose was associated with serum concentrations of morphine (r = 0.69), M6G (r = 0.76) and M3G (r = 0.76). Oral morphine resulted in higher dose-adjusted M6G and M3G serum concentrations compared with s.c. morphine. Creatinine serum concentrations correlated with serum concentrations of M6G and M3G. Dose and route of administration predicted morphine serum concentrations, while dose and renal function predicted M6G and M3G serum concentrations. Age was an additional factor predicting M3G concentrations. Dose was the only factor that explained a clinically significant part of the observed variability. Conclusion: Patient characteristics predict only minor parts of the variability of morphine, M3G and M6G serum concentrations observed during routine clinical drug-monitoring in cancer patients.

Background and objective Epidural analgesia with bupivacaine plus either sufentanil or fentanyl is widely used during labour, but it is not clear which opioid is to be preferred. The study compared these opioids at equianalgesic doses in terms of analgesia, onset time and side-effects. Methods Ninety females in active labour were entered into the randomized, double-blind trial. A test dose of bupivacaine was given into the epidural space. Parturients in Group S received sufentanil 8 mL as a bolus dose, followed by an infusion at a rate of 5 mL h(-1) of a mixture containing sufentanil 1 microg mL(-1) and bupivacaine 1 mg mL(-1). Patients in Group F received fentanyl 8 mL as a bolus, followed by an infusion at 5 mL h(-1) of a solution containing fentanyl 3.5 microg mL(-1) and bupivacaine 1 mg mL(-1). Additional boluses of 5 mL were of the relevant solution were given if necessary. Results In a ratio of 1.0:3.5 (sufentanil 1 microg versus fentanyl 3.5 microg), both groups reported the same analgesia with the same onset time. The onset time to obtain 50% of the initial visual analogue score was 10 and 11 min for Groups S and F, respectively. Mean visual analogue scores in Groups S and F respectively declined from 77 and 82 before epidural blockade, to 29 and 27 during the first stage of labour, and to 69 and 59 respectively during the second stage. Overall satisfaction among parturients was high (98 and 96%), particularly during the first stage (98 and 98%), and also to a large degree during the second stage of labour (74 and 79%). Furthermore, only a few extra bolus doses were required (mean 0.9 and 1.2, Groups S and F, respectively). All the females could stand on their own, and almost all (81% Group S; 79% Group F) could walk 20 m without help. There were no serious adverse effects. Moderate side-effects occurred equally often with the possible exception of less nausea and vomiting in the fentanyl group. Conclusions Epidural analgesia for ambulatory parturients with bupivacaine plus either sufentanil or fentanyl (ratio 1.0:3.5) provides good analgesia with a low frequency of modest side-effects. No clinical differences were found between the opioids.

In selected patients with chronic non-malignant pain, chronic opioid therapy is indicated. Published guidelines recommend long-acting over short-acting opioids in these patients. The aim of this systematic review was to investigate whether long-acting opioids in chronic non-malignant pain are superior to short-acting opioids in pain relief, physical function, sleep quality, quality of life or adverse events. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for relevant trials up to July 2012. Reference lists of included trials and relevant reviews were in addition searched by hand. Of the 1168 identified publications, 6 randomised trials evaluating efficacy and safety filled the criteria for inclusion. None of them found a significantly better pain relief, significantly less consumption of rescue analgesia, improved quality of sleep or improved physical function from long-acting opioids. None of the trials investigated quality of life. None of the trials investigated adverse events properly nor addiction, tolerance or hyperalgesia. Three trials in healthy volunteers with a recreational drug use, found no difference in abuse potential between long- and short-acting opioids. While long term, comparative data are lacking, there is fair evidence from short-term trials that long-acting opioids provide equal pain relief compared with short-acting opioids. Contrary to several guidelines, there is no evidence supporting long-acting opioids superiority to short-acting ones in improving functional outcomes, reducing side effects or addiction.

Background: Considerable dose variations and frequent initial side effects have been postulated during start of morphine treatment to patients with pain caused by malignant disease. However, to our knowledge, only one previous study has reported effective doses in morphine naive cancer patients and no prospective evaluation has compared symptoms before with symptoms during morphine titration. Methods: We recruited 40 cancer patients with uncontrolled pain despite receiving codeine or dextropropoxyphen. Baseline data were obtained for two days before start of morphine titration using a fixed scheduled escalation of immediate-release (IR) morphine. When a stable morphine dose was achieved, IR morphine was replaced with slow-release (SR) morphine in equivalent doses. Intensity of pain and side effects were assessed daily. The daily consumption of morphine, rescue analgesics and rescue antiemetics were registered. Results: The mean titration time to achieve adequate analgesia was 2.3 days (range: 1–6) using a mean daily morphine dose of 97 mg (range: 60–180). Nausea was unaltered after start with morphine but an increased incidence of vomiting occurred (premorphine period 5%, IR morphine period 29%). Transient sedation delayed dose increment in 9 of the 40 patients but mean sedation scores were unaltered. Constipation scores increased while other side effect scores were unaltered. Eighty-two percent of the patients were satisfied or very satisfied with the pain treatment during introduction of morphine. Conclusion: In cancer patients with uncontrolled pain on weak opioids, successful titration of morphine is achieved fast, with a three-fold morphine dose variation and with little increase in side effects.

Objective: 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.

Background: There was an obvious need to improve the quality and safety of our postoperative pain treatment and to introduce an improved routine service on surgical wards. Methods: It was decided to use postoperative epidural infusion of morphine 0.04 mg/ml and bupivacaine 2.5 mg/ml (0.25%): 4–8 ml/h as pain relief after major surgery. An education programme was run emphasising the benefits, side-effects and the importance of regular monitoring of pain intensity, vital functions (respiratory rate, blood pressure, heart rate), motor function of the legs and the need for additional drugs in order to detect side-effects as well as lack of adequate analgesic effect. A detailed observation sheet was used collecting information every 2 h throughout the epidural treatment period in order to secure monitoring and adjustment of the treatment. Close contact was maintained with the wards. Results: We present a detailed analysis of our first 2000 postoperative patients, mainly after orthopaedic (46.1%), gastrointestinal (32.0%), urologic (8.7%) and vascular (8.5%) surgery. Duration of the treatment was less than 24 h in 41.4% and more than 48 h in 29.7%. Pain relief was adequate in most patients, best after vascular surgery in the lower extremities (mean VAS 0.15/10.0 (95% confidence interval 0.09–0.23)) and less after gastrointestinal (mean VAS 0.49/10 (0.43–0.54)) and thoracic surgery (mean VAS 0.59/10 (0.38–0.81)). The infusion was stopped due to respiratory depression in 3 patients (0.15%). Four (0.2%) had systolic blood pressure

In patients with chronic non-malignant pain (CNMP), co-morbid physical or mental health disorders are common and may have a negative impact on health-related quality of life and treatment outcomes. The purpose of this study was to examine the occurrence of chronic psychiatric and somatic diseases in persistent opioid users with CNMP compared with the general population in Norway.In this cross-sectional study, prescription patterns of dispensed opioids were used to identify a study population of persistent opioid users with CNMP from the general population. Reimbursed prescriptions marked with diagnostic codes were used to identify the occurrence of 21 somatic and 3 psychiatric diseases for a 1-year period in the Norwegian Prescription Database. Occurrence of disease in persistent opioid users was compared to an age- and gender-specific population of all Norwegian residents aged 18-79 years in 2009. Standardized morbidity ratios (SMRs) for each disease were calculated.Eighty-five percent of the persistent opioid user population had at least one co-morbid disease compared with 45% of the general population. Forty-two percent had three or more co-morbidities. SMRs in both men and women were generally increased except for dementia, glaucoma and renal disease, indicating a higher occurrence of disease in persistent opioid users.A higher occurrence of both somatic and psychiatric co-morbidities in disease stages warranting pharmacological treatment was found in persistent opioid users with CNMP compared with the general population of Norway.

Recent guidelines for opioid treatment of chronic non-malignant pain discourage co-medication with benzodiazepines and benzodiazepine-related hypnotics, whereas co-medication with non-opioid analgesics and co-analgesics may offer a beneficial opioid sparing effect, and is recommended. The aim of this study was to describe 1-year periodic prevalence of co-medication with benzodiazepines, benzodiazepine-related hypnotics, non-opioid analgesics, co-analgesics and antidepressants in persistent opioid users with chronic non-malignant pain.The study is based on data from the Norwegian Prescription Database, covering all drugs dispensed to outpatients in 2008. Concomitant medication levels were compared between users in two definitions of persistent opioid use, all Norwegian adults dispensed opioids in 2008 and the Norwegian background population.Of the Norwegian adult population studied, 1.2% met the criteria of persistent opioid use based on prescription pattern and prescription level. Sixty percent of persistent opioid users were dispensed a benzodiazepine or benzodiazepine-related hypnotic in amounts indicating regular use, with 15% dispensed a high amount of both classes. Sixty-two percent of persistent opioid users were dispensed one or more non-opioid analgesics, 47% an antidepressant and 33% were dispensed an antiepileptic drug.Approximately 60% of persistent opioid users also receive benzodiazepines or benzodiazepine-related hypnotics in amounts indicating regular use. This is in conflict with recent guidelines for the treatment of chronic non-malignant pain and may indicate that these users are at an increased risk of developing problematic opioid use.

The aim of this study was to develop definitions to identify persons with clinically different patterns of persistent opioid use based on data from prescription databases.The study is based on data from the Norwegian Prescription Database using all dispensed opioid prescriptions during 2005-2008. Three definitions of persistent opioid use were developed using the following patient criteria: different levels of dispensed opioid amounts, number of prescriptions and the number of quarters out of the year in which prescriptions were dispensed. The three definitions each have some typical patient characteristics attached to them. The strict definition describes a typical patient using opioids to achieve a continuous serum concentration in the therapeutic range, the intermediate definition represents a typical patient using opioids daily but not around the clock and the wide definition describes a typical patient who uses opioids most of the days. To study whether the definitions accurately represent long-term use, the patient population was followed for 3 years, and the retention rate within each definition was measured.The point prevalence of persistent opioid use in Norway (4,681,134 inhabitants) as defined by the strict, intermediate and wide definitions was 0.16% (n = 7663), 0.50% (n = 23,498) and 1.08% (n = 50,791), respectively, as of 31 December 2007. At the end of the 3-year study period, the retention within any of the definitions was 83%, 84% and 68% for patients who met the criteria of the strict, intermediate and wide definitions, respectively.In the patient populations identified by the three definitions, a high rate of retention was observed, indicating that the proposed definitions can identify patients with long-term persistent use of opioids.

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.

Background: Opioid prescription for pain relief is increasing. Codeine is the dominating opioid in several European countries, with Norway being among the highest codeine users. Aim: To determine whether codeine is primarily used for acute pain or whether there is a prescription pattern indicating problematic opioid use. Methods: All pharmacies in Norway are obliged to submit data electronically to the Norwegian Prescription Database at the Norwegian Institute of Public Health on all dispensed prescriptions. Because all prescriptions are identified with a unique person identifier, it is possible to identify all prescriptions to one subject. All subjects who had prescription(s) of codeine dispensed to them in 2004, 2005 or 2006 are included in the study. Results: 385 190 Norwegian persons had at least one prescription of codeine dispensed to them due to non-cancer pain in 2005, corresponding to a 1-year periodic prevalence of 8.3%. 223 778 (58%) received only one prescription in 2005, 121 025 (31%) received more than one prescription but

BACKGROUND AND AIM OF INVESTIGATION: Intramuscular (IM) administration has been considered to be safer than intravenous (IV) for opioids on wards, but a comparative knowledge of patient safety and analgesic potency following a single dose of IV and IM administration is lacking. This study was carried out to compare patient safety and analgesic efficacy of a single and high dose of morphine given IM or IV for post-operative pain management.Thirty-eight patients with post-operative pain following hip replacement surgery were given IM or IV morphine 10 mg at a specified pain level. The study was randomized and double blinded. Time to onset of analgesic effect (11-point numeric rating scale), respiratory function (p(a)CO2, p(a)O2, and respiratory rate), level of sedation (5-point verbal rating scale), and hemodynamic function were recorded.In the IV group there was a slight but significant increase in p(a)CO2 after 5, 10, and 15 min compared with the IM group (5.2 vs. 4.8, 5.4, vs. 5.0 and 5.5 vs. 5.1 kPa, respectively). The IV group had a significantly faster onset of analgesic effect than the IM group (5 vs. 20 min). Between 5 and 25 min after morphine administration, pain status in the IV group was significantly improved compared with the IM group. Patients in the IV group were slightly more sedated than the IM group 5 and 10 min after morphine.A 10 mg bolus dose of IV morphine given to patients with moderate pain after surgery does not cause severe respiratory depression, but provides more rapid and better initial analgesia than 10 mg given IM. IV morphine even at a dose as high as 10 mg IV is well tolerated if there is a certain level of pain at its administration. The safety of IV morphine on the general ward needs to be further explored in adequately controlled studies.

Valid and reliable assessment of pain is essential for both clinical trials and effective pain management. The nature of pain makes objective measurement impossible. Acute pain can be reliably assessed, both at rest (important for comfort) and during movement (important for function and risk of postoperative complications), with one-dimensional tools such as numeric rating scales or visual analogue scales. Both these are more powerful in detecting changes in pain intensity than a verbal categorical rating scale. In acute pain trials, assessment of baseline pain must ensure sufficient pain intensity for the trial to detect meaningful treatment effects. Chronic pain assessment and its impact on physical, emotional, and social functions require multidimensional qualitative tools and health-related quality of life instruments. Several disease- and patient-specific functional scales are useful, such as the Western Ontario and MacMaster Universities for osteoarthritis, and several neuropathic pain screening tools. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations for outcome measurements of chronic pain trials are also useful for routine assessment. Cancer pain assessment is complicated by a number of other bodily and mental symptoms such as fatigue and depression, all affecting quality of life. It is noteworthy that quality of life reported by chronic pain patients can be as much affected as that of terminal cancer patients. Any assessment of pain must take into account other factors, such as cognitive impairment or dementia, and assessment tools validated in the specific patient groups being studied.

This topical review addresses methadone's 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.Relevant papers were identified in PubMed and EMBASE.Methadone is advocated by experts as a second line opioid when first line opioids fail to provide a satisfactory balance between pain control and side effects (opioid switching). Although randomized-controlled studies are lacking, current evidence suggests that switching to methadone in this situation reduces pain intensity. However, interindividual variability in its pharmacokinetics make its application challenging and metabolism by CYP 3A4 and 2B6 implies a substantial risk of drug-drug interactions. Several ways of switching to methadone have been presented, with a gradual switch during 3 days or 'stop and go' as the dominating strategies. Episodes of torsade de pointes arrhythmia during methadone treatment have been reported in patients with other risk factors for arrhythmia, while small prospective studies have reported a small, lasting and stable increase in QTc time. The extensive use of methadone for opioid replacement in addicts has added additional patient barriers to its use for pain control.In spite of challenges related to the variable pharmacokinetics and concerns regarding increase in QTc time, current evidence indicates that opioid switching to methadone improves pain control in a substantial proportion of patients who are candidates for opioid switching. Measures must be instituted to secure that patients receiving methadone for pain are not considered opioid addicts.

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.HRQoL data from 288 patients with CNMP admitted to the multidisciplinary pain centre at Trondheim University Hospital were compared with 434 patients with advanced cancer included in a trial of comprehensive palliative care in the hospital palliative medicine unit and national norms. HRQoL was assessed using the EORTC QLQ-C30. Age- and gender-adjusted norm data were calculated and compared between the two groups.Scores from both groups deviated from adjusted norm data on all scales, with poorer functioning and more symptoms. Compared with PC patients, CNMP patients reported a larger deviation (worse scores) on global quality of life, cognitive functioning, pain, sleep disturbances and financial difficulties. Deviations from norm data were similar for physical, social and emotional functioning, diarrhoea, dyspnoea and fatigue. PC patients reported worse scores on role functioning, nausea/vomiting, loss of appetite and constipation.CNMP patients admitted to multidisciplinary pain centres report significantly reduced HRQoL, in addition to severe pain. They consider their HRQoL to be as poor as HRQoL reported from dying cancer patients and substantially poorer than national norms. Factors other than the biological severity of the disease seem to be of major importance for self-reported HRQoL.