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We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Chronic pain and sleep problems frequently co-occur. Pain itself disturbs sleep, but other factors may also contribute to sleep problems in pain patients. This cross-sectional study of 473 patients (69.9% female, mean age 47 years) entering tertiary pain management compared normally sleeping pain patients with those having recurring sleep problems to determine the relationship between pain and sleep. Groups were compared for pain and pain aetiology, pain-related anxiety, childhood adversities, use of sleep and pain medications, self-reported diseases, and sleep disorders. Furthermore, the association of pain-related anxiety (cognitive anxiety, escape/avoidance, fear, and physiological anxiety) with more disturbing sleep problems was investigated in the whole cohort. The main results were that those with sleep problems more often reported multiple health conditions than those sleeping normally (depression 31.6% vs 5.0%; angina pectoris 6.5% vs 0.0%; asthma 19.6% vs 1.7%; low back problems 55.1% vs 23.3%; joint disease other than rheumatoid arthritis 32.3% vs 18.3%). Accumulations of 5 or more childhood adversities were more often present in those with sleep problems. Restless legs symptoms were more common in those with sleep problems than those sleeping normally (33.2% vs 11.7%). Patients having sleep problems reported more use of sleep and pain medications than those sleeping normally. Findings about pain-related anxiety suggest physiological reactions as significant factors for increased sleep disturbances. These factors need to be addressed in the management of the comorbidity of pain and sleep problems, and research to understand mechanisms in these is sorely needed.

Neuropathic pain is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. We used the spared nerve injury (SNI) model in rats to characterize sex differences in pain behaviour, unbiased RNA-Seq and proteomics to study the mechanisms. Male and female rats were subjected to SNI- and sham-surgery. Mechanical and cold allodynia were assessed. Ipsilateral lumbar dorsal root ganglia (DRG) and spinal cord (SC) segments were collected for RNA-seq analysis with DESeq2 on Day 7. Cerebrospinal fluid (CSF) samples for proteomic analysis and DRGs and SCs for analysis of IB-4 and CGRP, and IBA1 and GFAP, respectively, were collected on Day 21. Females developed stronger mechanical allodynia. There were no differences between the sexes in CGRP and IB-4 in the DRG or glial cell markers in the SC. No CSF protein showed change following SNI. DRG and SC showed abundant changes in gene expression. Sexually dimorphic responses were found in genes related to T-cells (cd28, ctla4, cd274, cd4, prf1), other immunological responses (dpp4, c5a, cxcr2 and il1b), neuronal transmission (hrh3, thbs4, chrna4 and pdyn), plasticity (atf3, c1qc and reg3b), and others (bhlhe22, mcpt1l, trpv6). We observed significantly stronger mechanical allodynia in females and numerous sexually dimorphic changes in gene expression following SNI in rats. Several genes have previously been linked to NP, while some are novel. Our results suggest gene targets for further studies in the development of new, possibly sex-specific, therapies for NP.

Neuropathic pain is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. We used the spared nerve injury (SNI) model in rats to characterize sex differences in pain behaviour, unbiased RNA-Seq and proteomics to study the mechanisms. Male and female rats were subjected to SNI- and sham-surgery. Mechanical and cold allodynia were assessed. Ipsilateral lumbar dorsal root ganglia (DRG) and spinal cord (SC) segments were collected for RNA-seq analysis with DESeq2 on Day 7. Cerebrospinal fluid (CSF) samples for proteomic analysis and DRGs and SCs for analysis of IB-4 and CGRP, and IBA1 and GFAP, respectively, were collected on Day 21. Females developed stronger mechanical allodynia. There were no differences between the sexes in CGRP and IB-4 in the DRG or glial cell markers in the SC. No CSF protein showed change following SNI. DRG and SC showed abundant changes in gene expression. Sexually dimorphic responses were found in genes related to T-cells (cd28, ctla4, cd274, cd4, prf1), other immunological responses (dpp4, c5a, cxcr2 and il1b), neuronal transmission (hrh3, thbs4, chrna4 and pdyn), plasticity (atf3, c1qc and reg3b), and others (bhlhe22, mcpt1l, trpv6). We observed significantly stronger mechanical allodynia in females and numerous sexually dimorphic changes in gene expression following SNI in rats. Several genes have previously been linked to NP, while some are novel. Our results suggest gene targets for further studies in the development of new, possibly sex-specific, therapies for NP.

Background and aims: Health-related quality of life (HRQoL) assessments have been widely used in pain medicine as they are able to reflect the subjective and multidimensional nature of chronic pain. Studies have shown a consistent impairment in HRQoL in different chronic pain conditions. However, it is not known whether HRQoL is impaired in chronic orofacial pain (OFP). The generic 15D HRQoL instrument has been shown to fare as well as or better than other generic HRQoL instruments in the study of chronic pain. The aim was to investigate HRQoL in patients with chronic OFP using the generic 15D HRQoL instrument. The validity of the instrument was tested by studying the association of the 15D data with pain interference. Methods: One hundred fifty-one patients (mean age 50 years, SD 15 years, 119 females) were recruited from three tertiary facial pain clinics. HRQoL data of the participants were contrasted with that of an age- and gender- standardized sample of general population by comparing the mean 15D scores and profiles. The data for the general population came from the National Health 2011 Survey representing Finnish population aged 18 years and older. Pain interference was assessed using Brief Pain Inventory. Based on pain interference distribution the participants were divided into tertiles. Statistical comparison between patient and population HRQoL values were performed using Monte-Carlo-type simulations. Statistical significance for the hypothesis of linearity was evaluated by using generalized linear models. Results: The mean 15D score of OFP patients (0.824, SD 0.113) was statistically significantly lower than that of the age- and gender-standardized general population (0.929, SD 0.019) (p < 0.001). The difference between the patients and the general population was also clinically important, i.e. over the minimum clinically important difference in the 15D score. All mean 15D dimension values were significantly lower compared with the general p

Remifentanil (Ultiva(R)) is a potent ultra-short acting mu-opioid receptor agonist used for perioperative pain treatment and anaesthesia. So far, it is not known how sensitive the cognitive processing of auditory perception elicited by the mismatch negativity (MMN) paradigm is to opioids. The present exploratory study investigated how the opioid remifentanil modulates different stages of auditory processing as reflected in the MMN(m) and P3a(m). We recorded electroencephalography (EEG) and magnetoencephalography (MEG) during auditory stimulation under remifentanil or placebo infusion in 20 healthy participants. For the MMN, a gender effect was found for tones deviating in frequency (+/- 10%) from the standard tone. Remifentanil increased the amplitude of the frequency MMN at F3 in females but not in males. No effect of treatment was found for the MMN(m) or the novel P3a(m). These results suggest that while the bottom-up stimulus change detection system for auditory stimuli appears to be relatively insensitive to opioids, the automatic attention switch caused by the change detection seems to be modulated by the opioid system in females. The multiple deviant paradigm including novel sounds is a promising tool for investigating pharmacological manipulation of different stages of auditory processing. Furthermore, combining the two techniques will yield more specific information about the drug effects on MMN(m).

Remifentanil (Ultiva(R)) is a potent ultra-short acting mu-opioid receptor agonist used for perioperative pain treatment and anaesthesia. So far, it is not known how sensitive the cognitive processing of auditory perception elicited by the mismatch negativity (MMN) paradigm is to opioids. The present exploratory study investigated how the opioid remifentanil modulates different stages of auditory processing as reflected in the MMN(m) and P3a(m). We recorded electroencephalography (EEG) and magnetoencephalography (MEG) during auditory stimulation under remifentanil or placebo infusion in 20 healthy participants. For the MMN, a gender effect was found for tones deviating in frequency (+/- 10%) from the standard tone. Remifentanil increased the amplitude of the frequency MMN at F3 in females but not in males. No effect of treatment was found for the MMN(m) or the novel P3a(m). These results suggest that while the bottom-up stimulus change detection system for auditory stimuli appears to be relatively insensitive to opioids, the automatic attention switch caused by the change detection seems to be modulated by the opioid system in females. The multiple deviant paradigm including novel sounds is a promising tool for investigating pharmacological manipulation of different stages of auditory processing. Furthermore, combining the two techniques will yield more specific information about the drug effects on MMN(m).

A double-blind, randomized, placebo-controlled cross-over multi-center study was conducted to evaluate the efficacy and safety of gabapentin in the treatment of neuropathic pain caused by traumatic or postsurgical peripheral nerve injury, using doses up to 2400 mg/day. The study comprised a run-in period of two weeks, two treatment periods of five weeks separated by a three weeks' washout period. The primary efficacy variable was the change in the mean pain intensity score from baseline to the last week of treatment. Other variables included pain relief, health related quality of life (SF-36), interference of sleep by pain, Clinician and Patient Global Impression of Change, and adverse effects. Nine centers randomized a total of 120 patients, 22 of whom withdrew. There was no statistically significant difference between the treatments for the primary outcome efficacy variable. However, gabapentin provided significantly better pain relief (p = 0.015) compared with placebo. More patients had at least a 30% pain reduction with gabapentin compared with placebo (p = 0.040) and pain interfered significantly less with sleep during gabapentin treatment compared with placebo (p = 0.0016). Both the Patient (p = 0.023) and Clinician (p = 0.037) Global Impression of Change indicated a better response with gabapentin compared with placebo. Gabapentin was well tolerated. The most common adverse effects were dizziness and tiredness. © 2007 International Association for the Study of Pain.

Objective: The objective of this paper was to analyse opioid consumption in a number European countries using different sources of data. Methods: Data were extracted from the United Nations' International Narcotics Control Board Report (INCB) 2003 and from the registers of the national health authorities in seven countries where data were available for 2002. The amount of opioid used was calculated as daily defined doses per 1000 inhabitants per day (DDD/1000/day). Danish Register of Medicinal Products Statistics was further explored for characteristics of opioid consumption (age, gender, type of opioids consumed) by patients in primary care. Total opioid consumption and consumption of 11 selected opioids (7 strong and 4 weak) were analysed. The amount of opioids consumed by outpatients was also examined. Results: There were considerable differences in the number of opioids reported and significant discrepancies in the amounts Of opioids consumed between the national data and the INCB report. The source of data for the national registers on drug consumption varied (pharmacies or wholesale). The INCB data provide information oil opioid import and estimated need rather than on medical consumption. Conclusions: Caution is required when interpreting the data on opioid consumption between countries because of differences in the collection and reporting of data. Better recording of opioid consumption is needed for meaningful analysis of opioid consumption and its possible effect on pain management in different countries. Data on opioids consumed for cancer-related pain in comparison with chronic non-malignant pain are needed. A uniform method of collection of data on analgesic consumption should be established for all European countries. (C) 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved Udgivelsesdato: 2008/8

Objective: The objective of this paper was to analyse opioid consumption in a number European countries using different sources of data. Methods: Data were extracted from the United Nations' International Narcotics Control Board Report (INCB) 2003 and from the registers of the national health authorities in seven countries where data were available for 2002. The amount of opioid used was calculated as daily defined doses per 1000 inhabitants per day (DDD/1000/day). Danish Register of Medicinal Products Statistics was further explored for characteristics of opioid consumption (age, gender, type of opioids consumed) by patients in primary care. Total opioid consumption and consumption of 11 selected opioids (7 strong and 4 weak) were analysed. The amount of opioids consumed by outpatients was also examined. Results: There were considerable differences in the number of opioids reported and significant discrepancies in the amounts Of opioids consumed between the national data and the INCB report. The source of data for the national registers on drug consumption varied (pharmacies or wholesale). The INCB data provide information oil opioid import and estimated need rather than on medical consumption. Conclusions: Caution is required when interpreting the data on opioid consumption between countries because of differences in the collection and reporting of data. Better recording of opioid consumption is needed for meaningful analysis of opioid consumption and its possible effect on pain management in different countries. Data on opioids consumed for cancer-related pain in comparison with chronic non-malignant pain are needed. A uniform method of collection of data on analgesic consumption should be established for all European countries. (C) 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved Udgivelsesdato: 2008/8

Contains fulltext : 57294.pdf (publisher's version ) (Closed access), Breakthrough pain (BKP) is a transitory flare of pain that occurs on a background of relatively well controlled baseline pain. Previous surveys have found that BKP is highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress and functional impairment, and relatively poor quality of life. An international group of investigators assembled by a task force of the International Association for the Study of Pain (IASP) evaluated the prevalence and characteristics of BKP as part of a prospective, cross-sectional survey of cancer pain. Fifty-eight clinicians in 24 countries evaluated a total of 1095 patients with cancer pain using patient-rated items from the Brief Pain Inventory (BPI) and observer-rated measures. The observer-rated information included demographic and tumor-related data, the occurrence of BKP, and responses on checklists of pain syndromes and pathophysiologies. The clinicians reported BKP in 64.8% of patients. Physicians from English-speaking countries were significantly more likely to report BKP than other physicians. BKP was associated with higher pain scores and functional interference on the BPI. Multivariate analysis showed an independent association of BKP with the presence of more than one pain, a vertebral pain syndrome, pain due to plexopathy, and English-speaking country. These data confirm the high prevalence of BKP, its association with more severe pain and functional impairment, and its relationship to specific cancer pain syndromes. Further studies are needed to characterize subtypes of BKP. The uneven distribution of BKP reporting across pain specialists from different countries suggests that more standardized methods for diagnosing BKP are needed.

Contains fulltext : 57294.pdf (publisher's version ) (Closed access), Breakthrough pain (BKP) is a transitory flare of pain that occurs on a background of relatively well controlled baseline pain. Previous surveys have found that BKP is highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress and functional impairment, and relatively poor quality of life. An international group of investigators assembled by a task force of the International Association for the Study of Pain (IASP) evaluated the prevalence and characteristics of BKP as part of a prospective, cross-sectional survey of cancer pain. Fifty-eight clinicians in 24 countries evaluated a total of 1095 patients with cancer pain using patient-rated items from the Brief Pain Inventory (BPI) and observer-rated measures. The observer-rated information included demographic and tumor-related data, the occurrence of BKP, and responses on checklists of pain syndromes and pathophysiologies. The clinicians reported BKP in 64.8% of patients. Physicians from English-speaking countries were significantly more likely to report BKP than other physicians. BKP was associated with higher pain scores and functional interference on the BPI. Multivariate analysis showed an independent association of BKP with the presence of more than one pain, a vertebral pain syndrome, pain due to plexopathy, and English-speaking country. These data confirm the high prevalence of BKP, its association with more severe pain and functional impairment, and its relationship to specific cancer pain syndromes. Further studies are needed to characterize subtypes of BKP. The uneven distribution of BKP reporting across pain specialists from different countries suggests that more standardized methods for diagnosing BKP are needed.

Contains fulltext : 57294.pdf (publisher's version ) (Closed access), Breakthrough pain (BKP) is a transitory flare of pain that occurs on a background of relatively well controlled baseline pain. Previous surveys have found that BKP is highly prevalent among patients with cancer pain and predicts more severe pain, pain-related distress and functional impairment, and relatively poor quality of life. An international group of investigators assembled by a task force of the International Association for the Study of Pain (IASP) evaluated the prevalence and characteristics of BKP as part of a prospective, cross-sectional survey of cancer pain. Fifty-eight clinicians in 24 countries evaluated a total of 1095 patients with cancer pain using patient-rated items from the Brief Pain Inventory (BPI) and observer-rated measures. The observer-rated information included demographic and tumor-related data, the occurrence of BKP, and responses on checklists of pain syndromes and pathophysiologies. The clinicians reported BKP in 64.8% of patients. Physicians from English-speaking countries were significantly more likely to report BKP than other physicians. BKP was associated with higher pain scores and functional interference on the BPI. Multivariate analysis showed an independent association of BKP with the presence of more than one pain, a vertebral pain syndrome, pain due to plexopathy, and English-speaking country. These data confirm the high prevalence of BKP, its association with more severe pain and functional impairment, and its relationship to specific cancer pain syndromes. Further studies are needed to characterize subtypes of BKP. The uneven distribution of BKP reporting across pain specialists from different countries suggests that more standardized methods for diagnosing BKP are needed.

Objectives To compare patients' preference for transdermal fentanyl or sustained release oral morphine, their level of pain control, and their quality of life after treatment. Design Randomised, multicentre, international, open label, crossover trial. Setting 35 centres in Belgium, Canada, Denmark, Finland, the United Kingdom, the Netherlands, and South Africa. Participants 256 patients (aged 26-82 years) with chronic non-cancer pain who had been treated with opioids. Main outcome measures Patients' preference for transdermal fentanyl or sustained release oral morphine, pain control, quality of life, and safety assessments. Results Of 212 patients, 138 (65%) preferred transdermal fentanyl, whereas 59 (28%) preferred sustained release oral morphine and 15 (7%) expressed no preference. Better pain relief was the main reason for preference for fentanyl given by 35% of patients. More patients considered pain control as being "good" or "very good'' with fentanyl than with morphine (35% v 23%, P = 0.002). These results were reflected in both patients' and investigators' opinions on the global efficacy of transdermal fentanyl. Patients receiving fentanyl had on average higher quality of life scores than those receiving morphine. The incidence of adverse events was similar in both treatment groups; however, more patients experienced constipation with morphine than with fentanyl (48% v 29%, P< 0.001). Overall, 41% of patients experienced mild or moderate cutaneous problems associated with wearing the transdermal fentanyl patch, and more patients withdrew because of adverse events during treatment with fentanyl than with morphine (10% v 5%). However, within the subgroup of patients naive to both fentanyl and morphine, similar numbers of patients withdrew owing to adverse effects (11% v 10%. respectively). Conclusion Transdermal fentanyl was preferred to sustained release oral morphine by patients with chronic non-cancer pain previously treated with opioids. The main reason fo