[Mental disorders and symptoms with persistent opioid use for chronic non-cancer pain ­ a registry study]. / Psykiske lidelser og plager ved vedvarende opioidbruk for langvarige ikke-kreftrelaterte smerter ­ en registerstudie.

Background: Knowledge of mental disorders among patients with persistent opioid use for the treatment of chronic non-cancer pain is essential, as mental disorders and symptoms can exacerbate or perpetuate pain and impact on the ability of patients to manage their illness. We have studied the prevalence of mental disorders and symptoms, including substance use disorders, in patients with persistent opioid use in 2019. Material and method: Persons ≥ 18 years with persistent opioid use and persons ≥ 18 years with at least one registered mental disorder in the specialist healthcare service in 2019 were included. Data were retrieved from national health registries in Norway. Patients who received opioids reimbursed for the treatment of chronic pain were compared with those who received opioids without reimbursement. Results: The prevalence of mental disorders and symptoms was 34 % among 14 403 persons who received reimbursed opioids, and 42 % among 38 001 persons who received opioids without reimbursement. This is equivalent to a two to threefold increase in prevalence compared to the general population. There was a particularly higher prevalence of anxiety disorders and substance use disorders. The prevalence of mental disorders and symptoms was highest in the age group 18-44 years (49-55 %). Interpretation: Among patients with persistent opioid use, a large proportion had mental disorders and symptoms, which are known risk factors for developing problematic opioid use and opioid use disorder.

Long-term use of opioids and concomitant use of other habit-forming drugs. / Vedvarende bruk av opioider og samtidig bruk av andre vanedannende legemidler.

BACKGROUND: Long-term use of opioids may have undesirable consequences. We have investigated long-term opioid use in patient groups that were prescribed opioids for various indications (chronic pain, palliative care, other (white prescriptions, not generally covered by the Norwegian National Insurance Scheme)) as well as the groups' concomitant use of some other addictive medications. MATERIAL AND METHOD: Persons registered in the Norwegian Prescription Database with at least one filled prescription of an opioid in the period 2011-19 were included. Long-term use in a calendar year was defined as the dispensing of > 180 defined daily doses or > 4 500 mg oral morphine equivalents distributed over at least 3 periods of 3 months. RESULTS: The number of long-term opioid users was 50 422 in 2011 and 59 996 in 2019 (10.1 and 10.7 % of all opioid users). The number who received opioids on blue prescription (partly covered by the Norwegian National Insurance Scheme) for chronic pain increased in the period by 9 952 persons, but the majority (n=38 006, 63.3 %) continued to receive opioids exclusively on white prescription in 2019. A total of 15 623 (41.1 %) and 14 881 (39.2 %), respectively, of the long-term opioid users who received opioids solely on white prescription in 2019 also received benzodiazepines and Z-hypnotics in the same year. Of the 23 967 long-term users who also received benzodiazepines, 88 % were dispensed opioids and benzodiazepines on the same day at least once in 2019. INTERPRETATION: Prolonged prescribing of opioids on white prescription and concurrent prescribing of other addictive drugs may indicate undesirable use with no clear indication.

B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Objective: To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS. Design: Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942). Setting: 4 university hospitals and 1 general hospital in Norway. Patients: 151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years. Intervention: Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74). Measurements: Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures. Results: Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, -5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, -0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events. Limitation: Self-reported primary outcome measures and possible recall bias. Conclusion: B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS. Primary Funding Source: The Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association.

Prescribing of opioids for chronic pain on reimbursable prescription. / Forskrivning av opioider på blå resept mot langvarige smerter.

BACKGROUND: In 2008 the reimbursable prescription scheme was amended so that patients with severe, chronic pain could be prescribed opioids on reimbursable prescription. The purpose of this study was to investigate the prescribing of opioids on reimbursable prescription, the proportion of patients who started opioid treatment on reimbursable prescription who became long-term users, and the number of patients in 2018 who received higher dosages than the reimbursable prescription scheme permits. MATERIAL AND METHOD: Data were retrieved from the Norwegian Prescription Registry. Persons aged 18 or over who were dispensed at least one opioid on reimbursable prescription for severe, chronic pain in the period 2008-2018, were included. RESULTS: The number of patients who were prescribed opioids on reimbursable prescription increased during the study period, and in 2018 the number was 17 383. Of these, 331 (1.9 %) were prescribed more than 300 mg oral morphine equivalents per day. After nine years, 48 % of the patients who started with opioids in 2009 were still being prescribed opioids on reimbursable prescription. INTERPRETATION: A high proportion of patients with severe, chronic pain who started with opioids on reimbursable prescription became long-term users. A number of patients received higher dosages than are recommended.

Biopsychosocial predictors and trajectories of work participation after transdiagnostic occupational rehabilitation of participants with mental and somatic disorders: a cohort study.

BACKGROUND: Group-based transdiagnostic occupational rehabilitation programs including participants with mental and somatic disorders have emerged in clinical practice. Knowledge is sparse on subsequent participation in competitive work. This study aimed to investigate trajectories for (re)entry to work for predefined subgroups in a diagnostically heterogeneous sample of sick-listed participants after completing occupational rehabilitation. METHODS: A cohort of 212 participants aged 18-69 on long-term sick leave (> 8 weeks) with chronic pain, chronic fatigue and/or common mental disorders was followed for one year after completing a 3½-week rehabilitation intervention based on Acceptance and Commitment Therapy. Self-reported, clinical and registry data were used to study the associations between predefined biopsychosocial predictors and trajectories for (re)entry to competitive work (≥ 1 day per week on average over 8 weeks). Generalized estimating equations analysis was used to investigate trajectories. RESULTS: For all biopsychosocial subgroups (re)entry to work increased over time. Baseline employment, partial sick leave and higher expectation of return to work (RTW) predicted higher probability of having (re)entered work at any given time after discharge. The odds of increasing reentry over time (statistical interaction with time) was weaker for the group receiving the benefit work assessment allowance compared with those receiving sickness benefit (OR = 0.92, p = 0.048) or for those on partial sick leave compared with full sick leave (OR 0.77, p < 0.001), but higher for those who at baseline had reported having a poor economy versus not (OR 1.16, p = 0.010) or reduced emotional functioning compared with not (OR 1.11, p = 0.012). Health factors did not differentiate substantially between trajectories. CONCLUSIONS: Work participation after completing a transdiagnostic occupational rehabilitation intervention was investigated. Individual and system factors related to work differentiated trajectories for (re)entry to work, while individual health factors did not. Having a mental disorder did not indicate a worse prognosis for (re)entry to work following the intervention. Future trials within occupational rehabilitation are recommended to pivot their focus to work-related factors, and to lesser extent target diagnostic group.

Processes in acceptance and commitment therapy and the rehabilitation of chronic fatigue.

Acceptance and commitment therapy (ACT) has never been tested for patients with chronic fatigue. We aimed to test if a 3.5-week ACT rehabilitation program for patients with chronic fatigue improved quality of life (QoL), fatigue, and psychological flexibility. Further, to test if improvements in QoL and fatigue were associated with improvement in psychological flexibility, and if psychological flexibility explained variance above and beyond maladaptive cognitions typically targeted in CBT for fatigue. Patients (n = 140) who had been on sick leave > 8 weeks due to chronic fatigue received a 3.5-week non-controlled inpatient rehabilitation program based on ACT. A physician and a psychologist examined the patients, assessing medication use and SCID-I diagnoses. Patients completed questionnaires about somatic complaints, psychological complaints, and maladaptive cognitions before and after treatment. At post-treatment, patients reported improved QoL (p < 0.001; g = 1.07) and less fatigue (p < 0.001; g = 1.08), but not increased psychological flexibility (p = 0.6). Changes in psychological flexibility was associated with improved QoL, but not fatigue, in hierarchical regression analyses. When adjusting for other cognitions, changes in fear-avoidance cognitions and all-or-nothing thoughts, but not psychological flexibility, were associated with improved QoL and fatigue. The ACT-based treatment improved QoL and reduced fatigue for patients with chronic fatigue with large effect sizes. Improvement was associated with a reduction in fear-avoidance cognitions and all-or-nothing thoughts, but not psychological flexibility.

Use of nasal fentanyl for cancer pain: A pharmacoepidemiological study.

BACKGROUND: Breakthrough pain affects 40%-90% of patients with cancer pain. Nasal fentanyl is one of the recommended treatments, particularly if the breakthrough pain is of rapid onset. AIM: To investigate the prevalence of use of nasal fentanyl, to study which strong opioids have been used prior to nasal fentanyl and to examine which opioids are used concomitantly with nasal fentanyl. DESIGN: Longitudinal cohort study based on death cohorts defined according to year of death. SETTING/PARTICIPANTS: The study is based on data from the complete national Norwegian Prescription Database. The study population included all persons in Norway who died in the years 2010, 2011 and 2012 and who had received nasal fentanyl with reimbursement for palliative treatment. RESULTS: Of those who died from cancer in 2010, 2011 and 2012, 611 persons (2%) received dispensed prescriptions of nasal fentanyl. Two-thirds had received other short-acting strong opioids before nasal fentanyl. One quarter did not receive a long-acting opioid concomitantly with nasal fentanyl, but 68% of these received only one dispensed prescription of nasal fentanyl. Of those who received a long-acting opioid together with nasal fentanyl, transdermal fentanyl was the most common drug (65%). One-third received another short-acting opioid concomitantly with nasal fentanyl. CONCLUSION: The use of nasal fentanyl was surprisingly low. There is a need for clinical research addressing the use of nasal fentanyl without a long-acting opioid for background pain and the use of nasal fentanyl together with another short-acting opioid.

Prevalence of use of non-prescription analgesics in the Norwegian HUNT3 population: Impact of gender, age, exercise and prescription of opioids.

BACKGROUND: There are concerns about potential increasing use of over-the-counter (OTC) analgesics. The aims of this study were to examine 1) the prevalence of self-reported use of OTC analgesics; 2) the prevalence of combining prescription analgesics drugs with OTC analgesics and 3) whether lifestyle factors such as physical activity were associated with prevalence of daily OTC analgesic use. METHODS: Questionnaire data from the Nord-Trøndelag health study (HUNT3, 2006-08), which includes data from 40,000 adult respondents. The questionnaire included questions on use of OTC analgesics, socioeconomic conditions, health related behaviour, symptoms and diseases. Data were linked to individual data from the Norwegian Prescription Database. A logistic regression was used to investigate the association between different factors and daily use of paracetamol and/or non-steroid anti-inflammatory drugs (NSAIDs) in patients with and without chronic pain. RESULTS: The prevalence of using OTC analgesics at least once per week in the last month was 47%. Prevalence of paracetamol use was almost 40%, compared to 19% and 8% for NSAIDs and acetylsalicylic acid (ASA), respectively. While the use of NSAIDs decreased and the use of ASA increased with age, paracetamol consumption was unaffected by age. Overall more women used OTC analgesics. About 3-5% of subjects using OTC analgesics appeared to combine these with the same analgesic on prescription. Among subjects reporting chronic pain the prevalence of OTC analgesic use was almost twice as high as among subjects without chronic pain. Subjects with little physical activity had 1.5-4 times greater risk of daily use of OTC compared to physically active subjects. CONCLUSIONS: Use of OTC analgesics is prevalent, related to chronic pain, female gender and physical inactivity.

Persistent opioid use and socio-economic factors: a population-based study in Norway.

BACKGROUND: A growing proportion of the population is using opioids for longer time periods, but little is known about the characteristics of patients who are persistent opioid users. We therefore studied the association between socio-economic factors and persistent vs. short-term opioid use 4 years later. METHODS: The background population is the complete Norwegian population in 2001. The study population is derived from two groups aged 35 years or older in 2001 who met one of the following criteria in 2005: (1) persistent opioid users (n = 15,113) or (2) short-term opioid users (n = 214,061). The applied definition of persistent opioid use corresponds to an average daily dose indicating likely daily use of opioids during 365 consecutive days. The socio-economic factors work status, income, marital status, immigrant status and education were obtained from the Population and Housing Census of 2001, and data on opioid use in 2005 were obtained from the complete national Norwegian Prescription Database. For logistic regression analyses, the study population was stratified by gender and by age over/under 67 years. RESULTS: In the 35- to 67-year-old age group, receiving a disability pension was more common in persistent opioid users compared with short-term opioid users (48% vs. 16% for women, 36% vs. 9% for men). Adjusted odds ratios for receiving a disability pension were 6.51 and 5.77 for women and men, respectively. Being divorced/separated was associated with being a persistent opioid user (odds ratio of 1.4 for both genders). There were also negative associations between persistent opioid use and attained education level, an unemployed working status and income status. CONCLUSION: Disability pension, not working, divorce, low income and low education in 2001 were associated with persistent opioid use in 2005.

Occupational rehabilitation programs for musculoskeletal pain and common mental health disorders: study protocol of a randomized controlled trial.

BACKGROUND: Long-term sick leave has considerably negative impact on the individual and society. Hence, the need to identify effective occupational rehabilitation programs is pressing. In Norway, group based occupational rehabilitation programs merging patients with different diagnoses have existed for many years, but no rigorous evaluation has been performed. The described randomized controlled trial aims primarily to compare two structured multicomponent inpatient rehabilitation programs, differing in length and content, with a comparative cognitive intervention. Secondarily the two inpatient programs will be compared with each other, and with a usual care reference group. METHODS/DESIGN: The study is designed as a randomized controlled trial with parallel groups. The Social Security Office performs monthly extractions of sick listed individuals aged 18-60 years, on sick leave 2-12 months, with sick leave status 50% - 100% due to musculoskeletal, mental or unspecific disorders. Sick-listed persons are randomized twice: 1) to receive one of two invitations to participate in the study or not receive an invitation, where the latter "untouched" control group will be monitored for future sick leave in the National Social Security Register, and 2) after inclusion, to a Long or Short inpatient multicomponent rehabilitation program (depending on which invitation was sent) or an outpatient cognitive behavioral therapy group comparative program. The Long program consists of 3 ½ weeks with full rehabilitation days. The Short program consists of 4 + 4 full days, separated by two weeks, in which a workplace visit will be performed if desirable. Three areas of rehabilitation are targeted: mental training, physical training and work-related problem solving. The primary outcome is number of sick leave days. Secondary outcomes include time until full sustainable return to work, health related quality of life, health related behavior, functional status, somatic and mental health, and perceptions of work. In addition, health economic evaluation will be performed, and the implementation of the interventions, expectations and experiences of users and service providers will be investigated with different qualitative methods. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01926574.

The effect of a music-based caregiving intervention on pain intensity in nursing home patients with dementia: a cluster-randomized controlled study.

ABSTRACT: Treatment of chronic pain in patients with dementia is challenging because they have reduced ability to report pain and are particularly vulnerable to side effects of analgesics. Different types of music-based therapy have been recommended and are used as an alternative to analgesics, but the evidence is lacking. Therefore, we performed a cluster-randomized controlled study (RCT) to reduce pain intensity using music-based caregiving (MBC) over 8 weeks in nursing home patients with dementia and chronic pain. We also investigated if the amount of MBC and different chronic pain syndromes would impact on the effect. Of the 645 patients, 498 patients from 36 wards in 12 nursing homes were screened for dementia and pain. Using the Clinical Dementia Rating Scale and the Mobilization-Observation-Behavior-Intensity-Dementia Pain Scale (range 0-10), 279 (71% females, 42% severe dementia) nursing home patients were randomized to intervention group (n = 134, 18 wards) or control group (n = 145, 18 wards). The main outcome was change in pain intensity before and after the intervention. The study did not reveal any effect of MBC on pain intensity when compared with the control group (B = -0.15, 95% CI [-0.72 to 0.43]). No significant difference was found within the intervention group analyzing the impact of intervention time (B = 0.73, 95% CI [-0.55 to 2.02]) or chronic primary vs secondary pain syndromes (B = 0.45, 95% CI [-0.05 to 0.96]). Our data from this first RCT on music and pain intensity in patients with dementia and chronic pain did not find an effect of MBC on pain.

Laxative prescriptions to cancer outpatients receiving opioids: a study from the Norwegian prescription database.

BACKGROUND: During opioid treatment of cancer pain, constipation is one of the most prevalent and bothersome side effects. Guidelines suggest that treatment with laxatives should be initiated when opioid therapy is started. AIM: This study aims: (1) to determine to what extent patients, starting on opioids due to cancer pain, receive laxatives; (2) to examine the temporal relationship between initiation of opioid therapy and initiation of treatment with laxatives; and (3) to study to which extent the treatment follows current guidelines. METHODS: Data from the Norwegian prescription database (NorPD) were used to investigate dispensed prescriptions of laxatives to outpatients in Norway, who are receiving opioids for cancer pain. Data from NorPD cover all dispensed prescriptions of drugs to outpatients, making it possible to follow patients over time. The study cohort was followed from 2005 to the end of 2008. RESULTS: Of 2,982 patients who started opioid therapy directly with WHO step III opioids, 1,325 patients (44.4 %) did not receive laxatives during the study period. Only 738 patients (24.7 %) received laxatives at the same time as opioid therapy was initiated. Another 657 patients (22.0 %) received laxatives after their initiation of opioids at some time during the study period. CONCLUSION: Of those who started directly on a strong opioid, only one fourth received laxatives concomitantly with the first opioid, and nearly half did not receive laxatives at all. These findings indicate that the current guidelines are not followed.

Chronic pain conditions and use of analgesics among nursing home patients with dementia.

ABSTRACT: Pain management for patients with dementia is challenging because many experience pain while being unable to communicate their pain. The aim of this study was to describe pain, pain management, and to perform a thorough clinical examination of chronic pain conditions among patients with dementia. Residents (n = 498) from 12 nursing homes were assessed for dementia (Clinical Dementia Rating scale [CDR]) and for pain with the Mobilization-Observation-Behavior-Intensity-Dementia-2 (MOBID-2) assessment form. Of all examined nursing home patients with dementia, 68% had moderate or severe chronic pain. The final study population (n = 262) with a CDR score of ≥1 and a MOBID-2 score of ≥3 were examined by pain expert physicians for chronic pain and categorized according to the International Classification of Disease (ICD-10/-11) classification systems. More than half (54.6%) had chronic pain conditions without underlying disease classified as chronic primary pain by ICD-11. Chronic widespread pain was the most prevalent (14.5%) followed by nonspecific pain from the back (13.4%), whereas the most prevalent chronic secondary pain conditions were chronic pain caused by osteoarthritis (15.4%) and stroke (8.0%). One-fourth received opioids, which was significantly associated with severe pain ( P < 0.001) compared with moderate pain, although no significant association was found between opioid use and the type of pain condition. Although knowledge of the severity and specific types of pain conditions is recommended to direct the choice of treatment, these areas are not sufficiently explored in the nursing home populations with dementia and may hinder a better treatment of pain in this population.

Opioid switching to methadone: a pharmacoepidemiological study from a national prescription database.

BACKGROUND: Opioid switching to methadone is reported frequently to improve pain control in patients with an unacceptable balance between pain control and side effects during treatment with first line opioids, but carries a risk of drug accumulation and respiratory depression. To justify this risk it is required that less risky treatments are tried beforehand and that a sufficiently large proportion of patients experience a long-lasting improvement in pain control. RESEARCH QUESTIONS: How large was the proportion of patients remaining on long term methadone treatment after a switch from a strong opioid to methadone? How long had the patients been treated with opioids before the switch to methadone? METHODS: Longitudinal pharmacoepidemiological study from the complete national Norwegian Prescription Database. RESULTS: One hundred and thirty (77%) cancer patients received more than one dispensed prescription of methadone. Forty-nine (40%) chronic non-malignant pain (CNMP) patients continued to have methadone prescriptions dispensed more than 6 months after the switch. Of 168 cancer patients, 48 (29%) had tried two strong opioids prior to the switch to methadone whereas 21 (12.5%) had tried three or more strong opioids. Similar numbers for 124 CNMP patients were 26 (21%) and 34 (27%), respectively. INTERPRETATION: Opioid switching to methadone appears to provide a long lasting improvement in pain control in a significant proportion of patients. However, the study raises concerns that treatment options with less risk are not being exhausted prior to switching to methadone.

Reimbursement of analgesics for chronic pain.

BACKGROUND: The prevalence of chronic non-malignant pain in Norway is between 24% and 30%. The proportion of the population using opioids for non-malignant pain on a long-term basis is around 1%. The purpose of our study was to investigate how many were prescribed analgesics on reimbursable prescription under reimbursement code -71 (chronic non-malignant pain) in 2009 and 2010, which analgesics were prescribed and whether prescribing practices were in accordance with national guidelines. MATERIAL AND METHOD: We retrieved pseudonymised data from the National Prescription Database on all those who received drugs with reimbursement code -71 in 2009 and 2010. The data contain information on drug, dosage, formulation, reimbursement code and date of issue. RESULTS: 90,731 patients received reimbursement for drugs indicated for chronic non-malignant pain in 2010. Of these, 6,875 were given opioids, 33,242 received paracetamol, 25,865 non-steroid inflammatory drugs (NSAIDs), 20,654 amitryptiline and 16,507 gabapentin. Oxycodone was the most frequently prescribed opioid, followed by buprenorphine, tramadol and codeine/paracetamol. Of those who were prescribed opioids, 4,047 (59%) received mainly slow-release opioids, 2,631 (38%) also received benzodiazepines and 2,418 (35%) received benzodiazepine-like sleep medications. CONCLUSION: The number of patients who received analgesics and opioids on reimbursable prescriptions was low compared to the proportion of the population with chronic pain and the proportion using opioids long-term. 38% of those reimbursed for opioids also used benzodiazepines, which is contrary to official Norwegian guidelines.

Corrigendum: Cognitive behavioral therapy improves physical function and fatigue in mild and moderate chronic fatigue syndrome: A consecutive randomized controlled trial of standard and short interventions.

[This corrects the article DOI: 10.3389/fpsyt.2021.580924.].