Opioid trends in Finland: a register-based nationwide follow-up study.

The opioid epidemic in the U.S has gotten payers, prescribers, and policymakers alike interested in trends in opioid use. Despite no recognized opioid crisis in Europe, several countries have reported an increase in opioid-related deaths, which has further prompted discussion on the need of monitoring of opioid prescriptions. This study was conducted to offer information on opioid use during the escalation of the U.S. opioid epidemic in Finland, a Nordic country with universal tax-based health care. This is a nationwide retrospective register-based cohort study on all individuals in Finland who were dispensed opioids in 2009-2017 (n of unique patients = 1,761,584). By using the unique personal identification code assigned to every Finnish resident, we linked data from nationwide registers on dispensed drugs, medical history, and socio-demographic parameters. We report a wide set of patient demographics, dispensing trends for all opioid Anatomical Therapeutic Chemical (ATC) classes, and reasons for opioid initiation based on diagnostic coding for the most recent health care visit. For a cohort of incident opioid users with a four-year wash-out period (n = 1 370 057), we also present opioid use patterns in a three-year follow-up: the likelihood of becoming a persistent user or escalating from weak to strong opioids. A steady 7% of the Finnish population were dispensed opioids annually in 2009-2017. The mean annual quantity of dispensed opioids per opioid patient increased between 2009 and 2017 by 33%, reaching 2 583 oral morphine equivalent mg (OMEQ)/patient/year in 2017. The median quantity of dispensed opioids was lower: 315 OMEQ/year/patient. Depending on the opioid ATC class, there were either increasing or decreasing numbers of patients who had been dispensed said opioid class, and also in the mean quantity. The most common reason for opioid initiation was post-surgical pain (20%), followed by musculoskeletal pain (15%), injury (8.3%), and non-postsurgical dental pain (6.2%). 94% of new opioid initiators started with a weak opioid, i.e. codeine or tramadol. 85% of the patients who had been dispensed a weak opioid were not dispensed an opioid subsequently 3-6 months after the first one, and 95% of them had not escalated to a strong opioid in a 3-year follow-up. The number of patients dispensed opioids in Finland did not change during the escalation of the opioid epidemic in the U.S., but there were changes in the quantity of opioids dispensed per patient. Opioid therapy was typically initiated with weak opioid, the initial dispensed prescription was relatively small, and escalation to strong opioids was rare. A considerable share of patients had been prescribed opioids for chronic non-cancer pain - a type of pain where the risk-benefit ratio of opioids is controversial.

Worse health-related quality of life, impaired functioning and psychiatric comorbidities are associated with excess mortality in patients with severe chronic pain.

BACKGROUND: Severe chronic pain that interferes with daily activities is associated with an increased risk of mortality. We assessed the overall mortality of tertiary chronic pain patients in comparison with the general population, with a special aim to analyse the association of health-related quality of life (HRQoL) and its dimensions with the risk of death. METHODS: In this prospective observational follow-up study, patients with non-cancer chronic pain attended an outpatient multidisciplinary pain management (MPM) episode in a tertiary pain clinic in 2004-2012 and were followed until May 2019. Mortality between the patients and the general population was compared with standardized mortality ratios (SMR) in different age groups. Causes of death and comorbidities were compared among the deceased. Association of mortality and HRQoL and its dimensions, measured with the 15D instrument, was studied with Cox proportional hazards model. RESULTS: During a mean of 10.4-year follow-up of 1498 patients, 296 died. The SMR in the youngest age group (18-49 years) was significantly higher than that of the general population: 2.6 for males and 2.9 for females. Even elderly females (60-69 years) had elevated mortality (SMR 2.3). Low baseline HRQoL at the time of MPM, as well as poor ratings in the psychosocial dimensions of HRQoL, was associated with an increased risk of death. CONCLUSIONS: Our results support the role of HRQoL measurement by a validated instrument such as the 15D in capturing both the physical and the psychological symptom burden, and consequently, an elevated risk of death, in patients with chronic pain. SIGNIFICANCE: Severe chronic pain is associated with elevated mortality. In patients in chronic pain under 50 years old, the mortality was 2.5-3 times higher than in the general population. Psychological distress appears to contribute to the increased mortality. Regular follow-up by health-related quality of life (HRQoL) measurement could be useful in identifying patients in chronic pain who are in need of intensive symptom management and to prevent early death.

Is Europe also facing an opioid crisis?-A survey of European Pain Federation chapters.

BACKGROUND: There is considerable public interest in whether Europe is facing an opioid crisis comparable to the one in the United States and the contribution of opioid prescriptions for pain to a potential opioid crisis. METHODS: A task force of the European Pain Federation (EFIC) conducted a survey with its national chapter representatives on trends of opioid prescriptions and of drug-related emergency departments and substance use disorder treatment admissions and of deaths as proxies of opioid-related harms over the last 20 years. RESULTS: Data from 25 European countries were received. In most European countries opioid prescriptions increased from 2004 to 2016. The levels of opioid consumption and their increase differed between countries. Some Eastern European countries still have a low opioid consumption. Opioids are mainly prescribed for acute pain and chronic noncancer pain in some Western and Northern European countries. There was a parallel increase in opioid prescriptions and some proxies of opioid-related harms in France, Finland and the Netherlands, but not in Germany, Spain and Norway. In United Kingdom, opioid overdose deaths, but not opioid prescriptions increased between 2016 and 2018. There are no robust data available on whether prescribed opioids for pain patients contributed to opioid-related harms. CONCLUSIONS: There are marked differences between European countries in trends of opioid prescribing and of proxies for opioid-related harms. Europe as a whole is not facing an opioid crisis. Discussions on the potential harms of opioids should not obstruct their prescription for cancer pain and palliative care. SIGNIFICANCE: Europe as a whole is not facing an opioid crisis. Some Eastern European countries have limited access to opioid medicines. Discussions on the potential harms of opioid medicines for noncancer pain should not obstruct opioid therapy for cancer therapy and palliative care.

Differential DNA methylation in recovery from shift work disorder.

The human DNA methylome is responsive to our environment, but its dynamics remain underexplored. We investigated the temporal changes to DNA methylation (DNAme) in relation to recovery from a shift work disorder (SWD) by performing a paired epigenome-wide analysis in an occupational cohort of 32 shift workers (25 men, age = 43.8 ± 8.8 years, 21 SWD cases). We found that the effect of vacation on DNAme was more prominent in the SWD-group as compared to controls, with respect to the amount of significantly differentially methylated positions (DMPs; Punadj < 0.05) 6.5 vs 3.7%, respectively. The vast majority (78%) of these DMPs were hypomethylated in SWD but not in controls (27%) during the work period. The Gene Ontology Cellular component "NMDA glutamate receptor" (PFDR < 0.05) was identified in a pathway analysis of the top 30 genes in SWD. In-depth pathway analyses revealed that the Reactome pathway "CREB phosphorylation through the activation of CaMKII" might underlie the recovery. Furthermore, three DMPs from this pathway, corresponding to GRIN2C, CREB1, and CAMK2B, correlated with the degree of recovery (Punadj < 0.05). Our findings provide evidence for the dynamic nature of DNAme in relation to the recovery process from a circadian disorder, with biological relevance of the emerging pathways.

Maternal stress or sleep during pregnancy are not reflected on telomere length of newborns.

Telomeres play an important role in maintaining chromosomal integrity. With each cell division, telomeres are shortened and leukocyte telomere length (LTL) has therefore been considered a marker for biological age. LTL is associated with various lifetime stressors and health-related outcomes. Transgenerational effects have been implicated in newborns, with maternal stress, depression, and anxiety predicting shorter telomere length at birth, possibly reflecting the intrauterine growth environment. Previous studies, with relatively small sample sizes, have reported an effect of maternal stress, BMI, and depression during pregnancy on the LTL of newborns. Here, we attempted to replicate previous findings on prenatal stress and newborn LTL in a sample of 1405 infants using a qPCR-based method. In addition, previous research has been expanded by studying the relationship between maternal sleep quality and LTL. Maternal prenatal stress, anxiety, depression, BMI, and self-reported sleep quality were evaluated with self-reported questionnaires. Despite sufficient power to detect similar or even considerably smaller effects than those previously reported in the literature, we were unable to replicate the previous correlation between maternal stress, anxiety, depression, or sleep with LTL. We discuss several possible reasons for the discrepancies between our findings and those previously described.

The Wequedong Lodge Cancer Screening Program: implementation of an opportunistic cancer screening pilot program for residents of rural and remote Indigenous communities in Northwestern Ontario, Canada.

INTRODUCTION: The rural and remote nature of many First Nations communities in Northwestern Ontario, Canada poses unique obstacles to physically accessing health care, in addition to other barriers. Indigenous peoples face similar challenges globally. First Nations communities experience significant health inequities, including cancer burden, which can be attributed to complex factors associated with colonization and Westernization. One potentially promising intervention to decrease the burden of advanced cancers is the provision of accessible, convenient and culturally sensitive cancer screening services, leading to early detection and treatment. The Wequedong Lodge Cancer Screening Program (WLCSP) was a pilot project aiming to provide cancer screening education and opportunistic cancer screening to residents from rural and remote First Nations communities while accessing health services in the urban center of Thunder Bay, Ontario, Canada. METHODS: Cancer screening education and opportunistic breast, cervical and colorectal cancer screening appointments were offered to individuals and their travel escorts already staying at Wequedong Lodge. Program uptake was determined primarily by education participation, and secondarily by client participation in screening. RESULTS: In total, the WLCSP booked 1033 appointments, with 841 being attended. Over the program's 3 years there was an increase in clients each year. Specifically, 22% (60/275) of age-eligible women completed a mammogram. Pap tests were provided to 8% (45/554) of age-eligible females. Finally, 32% (106/333) of all age-eligible service participants were given a fecal occult blood test kit. An evaluation survey (n=396) demonstrated overall client satisfaction with the program. CONCLUSION: The WLCSP aimed to provide education about, access to and uptake of cancer screening services for First Nations people from rural and remote communities in Northwestern Ontario by targeting inequalities in accessing cancer screening opportunities. Therefore, program uptake may provide helpful numerical comparisons for similar future programs globally. Other entities working to improve cancer screening rates in remote and/or rural populations and/or amongst Indigenous peoples may find consideration of the WLCSP processes, successes and challenges helpful to their efforts.

Development of sleep-wake rhythms during the first year of age.

Circadian rhythms refer to biological rhythms that have an endogenous period length of approximately 24 hr. However, not much is known about the variance in the development of the sleep-wake rhythm. The study objectives were (a) to describe the normative variation in the development of a sleep-wake rhythm in infancy, (b) to assess whether slower development is related to sleep quality and (c) to evaluate factors that are related to the slower development of a sleep-wake rhythm. The study is based on a representative birth cohort. Questionnaires at the ages of 3 (n = 1,427) and 8 months (n = 1,302) and actigraph measurement at 8 months (n = 372) were available. Infants with significant developmental delays (n = 11) were excluded. The results are based on statistical testing and multivariate modelling. We found that the average percentage of daytime sleep was 36.3% (standard deviation [SD], 8.5%) at 3 months and 25.6% (SD, 6.6%) at 8 months. At both time-points, infants with slower sleep-wake rhythm development slept more hours per day, had a later sleep-wake rhythm, more difficulties in settling to sleep and longer sleep-onset latency; they also spent a longer time awake during the night. According to actigraph registrations, we found that the infants with slow development of a sleep-wake rhythm slept less and had a later start and end to night-time sleep than the other infants. Infants' sleep-wake rhythm development is highly variable and is related to parent-reported and objectively measured sleep quality and quantity. Interventions to improve the sleep-wake rhythm might improve sleep quality in these infants.

Variation near MTNR1A associates with early development and interacts with seasons.

Melatonin is a circadian regulatory hormone with neuroprotective properties. We have previously demonstrated the association of the genetic variant rs12506228 near the melatonin receptor 1A gene (MTNR1A) with intolerance to shift-work. Furthermore, this variant has been connected to Alzheimer's disease. Because of the previously suggested role of melatonin signalling in foetal neurocognitive and sleep development, we studied here the association of rs12506228 with early development. The study sample comprised 8-month-old infants from the Finnish CHILD-SLEEP birth cohort (n = 1,301). Parental questionnaires assessed socioemotional, communication and motor development, as well as sleep length and night awakenings. The A allele of rs12506228 showed an association with slower socioemotional (p = .025) and communication (p = .0098) development, but no direct association with sleep. However, the association of the Finnish seasons with infant sleep length interacted with rs12506228. Taken together, rs12506228 near MTNR1A, which has been previously linked to adult and elderly traits, is shown here to associate with slower early cognitive development. In addition, these results suggest that the darker seasons associate with longer infant sleep time, but only in the absence of the rs12506228 AA genotype. Because the risk allele has been connected to fewer brain MT1 melatonin receptors, these associations may reflect the influence of decreased melatonin signalling in early development.

Health-related quality of life change in patients treated at a multidisciplinary pain clinic.

BACKGROUND: Multidisciplinary pain management (MPM) is a generally accepted method for treating chronic pain, but heterogeneous outcome measures provide only limited conclusions concerning its effectiveness. Therefore, further studies on the effectiveness of MPM are needed to identify subgroups of patients who benefit, or do not benefit, from these interventions. Our aim was to analyse health-related quality of life (HRQoL) changes after MPM and to identify factors associated with treatment outcomes. METHODS: We carried out a real world observational follow-up study of chronic pain patients referred to a tertiary multidisciplinary outpatient pain clinic to describe, using the validated HRQoL instrument 15D, the HRQoL change after MPM and to identify factors associated with this change. 1,043 patients responded to the 15D HRQoL questionnaire at baseline and 12 months after the start of treatment. Background data were collected from the pre-admission questionnaire of the pain clinic. RESULTS: Fifty-three percent of the patients reported a clinically important improvement and, of these, 81% had a major improvement. Thirty-five percent reported a clinically important deterioration, and 12% had no change in HRQoL. Binary logistic regression analysis revealed that major improvement was positively associated with shorter duration of pain (<3 years), worse baseline HRQoL, higher education levels and being employed. CONCLUSIONS: The majority of the patients reported significant HRQoL improvement after multidisciplinary pain management. Better understanding of the factors associated with treatment outcomes is needed to meet the needs of those who had unfavourable outcomes. SIGNIFICANCE: Multidisciplinary pain management (MPM) increases the health-related quality of life (HRQoL) in most patients. More research into factors associated with HRQoL change is needed to understand why not all patients benefit from MPM and how MPM approaches could be improved to meet the needs of these patients.

The role of parental circadian preference in the onset of sleep difficulties in early childhood.

BACKGROUND: Chronotype is a construct contributing to individual differences in sleep-wake timing. Previous studies with children have found that evening-types exhibit greater sleep difficulties. Infant sleep quality can be modulated by several factors, such as parental characteristics. We examined the association between parental circadian preference and sleep in early childhood. METHODS: This study was based on a longitudinal birth cohort, with several measurement points. We used information regarding parental questionnaires during pregnancy and children's sleep measures at three, eight, 18 and 24 months. In total, 1220 mothers, 1116 fathers, 993 infants at three months, 990 infants at eight months, 958 children at 18 months, and 777 children at 24 months were analyzed. Parental circadian preference was measured using the Horne-Östberg Morningness-Eveningness Questionnaire. Concerning children's sleep, we used the Brief Infant Sleep Questionnaire (BISQ) and the Infant Sleep Questionnaire (ISQ) at each time point. RESULTS: Maternal circadian preference was associated with infants' circadian rhythm development at three, eight, 18 and 24 months. Furthermore, increased maternal eveningness was also related to short sleep during daytime at three months, and nighttime at three and eight months, to long sleep-onset latency at three, 18 and 24 months, to late bedtime at three, eight and 18 months, and to sleep difficulties at eight and 24 months. Paternal circadian preference was not associated with any sleep variable at any time point. CONCLUSION: Maternal circadian preference is related to several sleep difficulties in early childhood, and it may be considered a potential risk factor for the onset of early sleeping problems.

Intracerebral Adenosine During Sleep Deprivation: A Meta-Analysis and New Experimental Data.

The neuroregulator adenosine is involved in sleep-wake control. Basal forebrain (BF) adenosine levels increase during sleep deprivation. Only a few studies have addressed the effect of sleep deprivation on extracellular adenosine concentrations in other brain regions. In this paper, we describe a microdialysis experiment as well as a meta-analysis of published data. The 64 h microdialysis experiment determined the extracellular adenosine and adenosine monophosphate (AMP) concentrations in the medial prefrontal cortex of rats before, during and after 12 h of sleep deprivation by forced locomotion. The meta-analysis comprised published sleep deprivation animal experiments measuring adenosine by means of microdialysis. In the animal experiment, the overall median adenosine concentration was 0.36 nM and ranged from 0.004 nM to 27 nM. No significant differences were observed between the five conditions: 12 h of wash-out, baseline light phase, baseline dark phase, 12 h of sleep deprivation and 12 h of subsequent recovery. The overall median AMP concentration was 0.10 nM and ranged from 0.001 nM to 7.56 nM. Median AMP concentration increased during sleep deprivation (T = 47; p = 0.047) but normalised during subsequent recovery. The meta-analysis indicates that BF dialysate adenosine concentrations increase with 74.7% (95% CI: 54.1-95.3%) over baseline during sleep deprivation. Cortex dialysate adenosine concentrations during sleep deprivation were so far only reported by 2 publications. The increase in adenosine during sleep deprivation might be specific to the BF. At this stage, the evidence for adenosine levels in other brain regions is based on single experiments and insufficient for generalised conclusions. Further experiments are currently still warranted.

The effects of maternal risk factors during pregnancy on the onset of sleep difficulties in infants at 3 months old.

Sleep problems in young children are among the most common concerns reported to paediatricians. Sleep is thought to have important regulatory functions, and sleep difficulties in early childhood are linked to several psychosocial and physiological problems. Moreover, several prenatal factors have been found to influence infants' sleep. Among them, most of the studies have been focused on maternal prenatal depression and/or anxiety as potential risk factors for sleep problems in childhood, whereas other relevant psychological factors during pregnancy have not received as much attention. Therefore, we aimed to examine the effect of several psychiatric maternal risk factors during pregnancy (i.e. symptoms of anxiety, depression, insomnia, alcohol use, seasonality, attention deficit and hyperactivity disorder and/or stressful life events) on the onset of some sleep problems related to sleep quality and sleep practices in 3-month-old infants. We examined 1,221 cases from a population-based birth cohort, with subjective measures during pregnancy in mothers, and at 3 months after birth in the infants. The findings showed that all the maternal risk factors during pregnancy, except for symptoms of alcoholism and sleepiness, were related to sleep difficulties in infants. Interestingly, attention deficit and hyperactivity disorder symptomatology in mothers during pregnancy was the only variable that predicted more than two sleeping difficulties (i.e. long sleep-onset latency, co-sleeping with parents and irregular sleeping routines) at 3 months old. Our results highlight the relevance of maternal risk factors during pregnancy, and not only prenatal depression and/or anxiety, as variables to be considered when examining sleep difficulties in infants.

Physiological and autonomic stress responses after prolonged sleep restriction and subsequent recovery sleep in healthy young men.

PURPOSE: Sleep restriction is increasingly common and associated with the development of health problems. We investigated how the neuroendocrine stress systems respond to prolonged sleep restriction and subsequent recovery sleep in healthy young men. METHODS: After two baseline (BL) nights of 8 h time in bed (TIB), TIB was restricted to 4 h per night for five nights (sleep restriction, SR, n = 15), followed by three recovery nights (REC) of 8 h TIB, representing a busy workweek and a recovery weekend. The control group (n = 8) had 8 h TIB throughout the experiment. A variety of autonomic cardiovascular parameters, together with salivary neuropeptide Y (NPY) and cortisol levels, were assessed. RESULTS: In the control group, none of the parameters changed. In the experimental group, heart rate increased from 60 ± 1.8 beats per minute (bpm) at BL, to 63 ± 1.1 bpm after SR and further to 65 ± 1.8 bpm after REC. In addition, whole day low-frequency to-high frequency (LF/HF) power ratio of heart rate variability increased from 4.6 ± 0.4 at BL to 6.0 ± 0.6 after SR. Other parameters, including salivary NPY and cortisol levels, remained unaffected. CONCLUSIONS: Increased heart rate and LF/HF power ratio are early signs of an increased sympathetic activity after prolonged sleep restriction. To reliably interpret the clinical significance of these early signs of physiological stress, a follow-up study would be needed to evaluate if the stress responses escalate and lead to more unfavourable reactions, such as elevated blood pressure and a subsequent elevated risk for cardiovascular health problems.

Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate.

The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl-D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23 µg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3 h with 0.3 mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24 h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate.

Sleep and slow-wave activity in depressed adolescent boys: a preliminary study.

OBJECTIVE: Adolescence is a vulnerable period of life that is characterized by increasing incidence of depression. Sleep disturbance is one of the diagnostic symptoms of depressive disorder. Adolescence is also characterized by dramatic maturational changes in sleep and its regulation. The goal of this study was to assess sleep macroarchitecture and slow-wave activity (SWA) in depressed adolescent boys. METHODS: Eight non-medicated adolescent boys meeting the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for depressive disorder and 10 age-matched healthy controls (average age 16.0 years) underwent polysomnography in their home environment for two consecutive nights. Sleep macroarchitecture, SWA, and SWA dissipation were assessed in all subjects. RESULTS: Depressed boys showed a flattened pattern of SWA dissipation through the night. SWA power was lower during the first non-rapid eye movement (NREM) episode in the frontal derivation and higher during the third NREM episode in the central derivation in the group of depressed boys as compared to healthy boys. The SWA dissipation pattern correlated with the severity of depressive symptoms, and the correlation was strongest in the frontal derivation. In addition, total sleep time was shorter in patients as compared to the control group, but no other differences were found in the macroarchitecture of sleep. CONCLUSION: Depression in adolescent boys is characterized by more evenly distributed SWA through the night as compared to healthy subjects, and we showed for the first time that this pattern of SWA distribution is associated with severity of depressive symptoms. These findings suggest that homeostatic regulation of sleep may be impaired in adolescent depression.

Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia.

Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC) and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline, and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.

Spinal analgesia for severe cancer pain: A retrospective analysis of 60 patients.

BACKGROUND AND AIMS: Pain is highly prevalent in advanced cancer, and in some patients refractory to conventional opioid treatment. For these patients, invasive methods of pain relief should be considered. Spinal administration of opioids has been shown to be an effective alternative in refractory cancer pain. The aim of this retrospective study was to collect information on the use of spinal analgesia for cancer pain in Helsinki University Hospital. METHODS: A retrospective patient chart study of all cancer patients with spinal analgesia, either intrathecal or epidural, in a single academic center during a five year period (n=60). RESULTS: Forty-four patients were treated with intrathecal (IT) and sixteen with epidural (EP) technique. The most common indication for spinal analgesia was pain refractory to systemic analgesics. Good analgesia was achieved in 50% and 70% of the patients in the EP and IT groups, respectively. The median daily systemic opioid doses prior to spinal analgesia were 874.5mg and 730.5mg as oral morphine equivalents in the IT and EP groups, respectively. The systemic opioid could be discontinued or significantly reduced in 83% of the patients. Morphine was used in all IT infusions and most EP infusions, mostly combined with bupivacaine 10mg (IT) or 66mg (EP). The median starting doses of morphine were 3mg/day (IT) and 19mg/day (EP) and were increased during titration 27% to 3.8mg/day (IT) and 91% to 36.2mg/day (EP). Clonidine (median 0.015mg/day IT and 0.15mg/day EP) and/or ketamine were used as adjuvants. The average titration time to stable analgesia was 7-9 days. Numbness in lower limbs was reported by 24% of the IT group. On average, catheters were placed 98 and 61 days before death in IT and EP groups, respectively. No serious complications occurred. Catheter dislocation occurred in 27% of all sixty patients during follow-up. Treatment was discontinued in 10 patients because of catheter dislocation (n=7) or local infection (n=3). CONCLUSIONS AND IMPLICATIONS: Spinal administration of opioids is a safe and effective method of pain management in patients with severe cancer pain and can greatly reduce the need of systemic opioids. We are implementing closer collaboration with oncologists to provide spinal analgesia to more patients and earlier to reduce suffering. Catheter dislocation led to discontinuation of spinal analgesia in 17% of the patients and we are evaluating new ways to prevent catheter dislocation. The initial median spinal opioid dose was too low in both groups, and we are now using higher initial doses. A common adverse effect was numbness of the lower limbs, regardless of the relatively low doses of spinal bupivacaine. We now use lower doses and introduce the intrathecal catheter higher at L1-2 to reduce motor blockade at the level of conus. As an initial intrathecal infusions we suggest: morphine dose calculated using an oral to intrathecal ratio of 1:100 (unless the patient is elderly or already drowsy), clonidine dose 30µg/day and bupivacaine dose 7.5mg/day.

Variants in calcium voltage-gated channel subunit Alpha1 C-gene (CACNA1C) are associated with sleep latency in infants.

Genetic variants in CACNA1C (calcium voltage-gated channel subunit alpha1 C) are associated with bipolar disorder and schizophrenia where sleep disturbances are common. In an experimental model, Cacna1c has been found to modulate the electrophysiological architecture of sleep. There are strong genetic influences for consolidation of sleep in infancy, but only a few studies have thus far researched the genetic factors underlying the process. We hypothesized that genetic variants in CACNA1C affect the regulation of sleep in early development. Seven variants that were earlier associated (genome-wide significantly) with psychiatric disorders at CACNA1C were selected for analyses. The study sample consists of 1086 infants (520 girls and 566 boys) from the Finnish CHILD-SLEEP birth cohort (genotyped by Illumina Infinium PsychArray BeadChip). Sleep length, latency, and nightly awakenings were reported by the parents of the infants with a home-delivered questionnaire at 8 months of age. The genetic influence of CACNA1C variants on sleep in infants was examined by using PLINK software. Three of the examined CACNA1C variants, rs4765913, rs4765914, and rs2239063, were associated with sleep latency (permuted P<0.05). There was no significant association between studied variants and night awakenings or sleep duration. CACNA1C variants for psychiatric disorders were found to be associated with long sleep latency among 8-month-old infants. It remains to be clarified whether the findings refer to defective regulation of sleep, or to distractibility of sleep under external influences.