Mental disorder prevalence in chronic pain patients using opioid versus non-opioid analgesics: A registry-linkage study.

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.

Ischemic Lesions in the Brain of a Neonate With SARS-CoV-2 Infection.

AIM: To describe a term newborn with acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and multisystem involvement including seizures associated to ischemic lesions in the brain. BACKGROUND: Coronavirus disease 2019 (COVID-19) is predominantly a respiratory infection, but it may affect many other systems. Most pediatric COVID-19 cases range from asymptomatic to mild-moderate disease. There are no specific clinical signs described for neonatal COVID-19 infections. In children, severe central nervous system compromise has been rarely reported. CASE DESCRIPTION: We describe a 17-day-old newborn who acquired a SARS-CoV-2 infection in a family meeting that was admitted for fever, seizures and lethargy and in whom consumption coagulopathy, ischemic lesions in the brain and cardiac involvement were documented. CONCLUSIONS: SARS-CoV-2 neonatal infection can be associated with multi-organic involvement. In our patient, significant central nervous system compromise associated to ischemic lesions and laboratory findings of consumption coagulopathy were found. CLINICAL SIGNIFICANCE: Although neonatal SARS-CoV-2 infections are infrequent, they can be associated with multi-organic involvement. Neonatologists and pediatricians should be aware of this unusual way of presentation of COVID-19 in newborn infants.

Attention-deficit/hyperactivity disorder in children following prenatal exposure to antidepressants: results from the Norwegian mother, father and child cohort study.

OBJECTIVE: To determine the association between child attention-deficit/hyperactivity disorder (ADHD) and prenatal exposure to selective serotonin (SSRI) and serotonin-norepinephrine (SNRI) reuptake inhibitor antidepressants, by timing and duration, with quantification of bias due to exposure misclassification. DESIGN: Norwegian Mother, Father and Child Cohort Study and national health registries. SETTING: Nationwide, Norway. POPULATION: A total of 6395 children born to women who reported depression/anxiety in pregnancy and were either medicated with SSRI/SNRI in pregnancy (n = 818) or non-medicated (n = 5228), or did not report depression/anxiety but used antidepressants 6 months before pregnancy (discontinuers, n = 349). MAIN OUTCOME MEASURE: Diagnosis of ADHD or filled prescription for ADHD medication in children, and mother-reported symptoms of ADHD by child age 5 years. RESULTS: When the hazard was averaged over the duration of the study follow up, there was no difference in ADHD risk between ever in utero SSRI/SNRI-exposed children and comparators (weighted hazard ratio [wHR] 1.07, 95% CI 0.76-1.51 versus non-medicated; wHR 1.53, 95% CI 0.77-3.07 versus discontinuers). Underestimation of effects due to exposure misclassification was modest. In early childhood, the risk for ADHD was lower with prenatal SSRI/SNRI exposure compared with no exposure, and so were ADHD symptoms (weighted ß -0.23, 95% CI -0.39 to -0.08); this risk became elevated at child age 7-9 years (wHR 1.93, 95% CI 1.22-3.05). Maternal depression/anxiety before pregnancy was independently associated with child ADHD. CONCLUSION: Prenatal SSRI/SNRI exposure is unlikely to considerably increase the risk of child ADHD beyond that posed by maternal depression/anxiety. The elevated risk at child age 7-9 years needs to be elucidated. TWEETABLE ABSTRACT: Women with depression who use antidepressants in pregnancy do not have greater risk of having children with ADHD. Findings in school-age children needs follow up.

Osseointegration for Amputees: Current Implants, Techniques, and Future Directions.

Osseointegrated prostheses provide a rehabilitation option for amputees offering greater mobility, better satisfaction, and higher use than traditional socket prostheses. There are several different osseointegrated implant designs, surgical techniques, and rehabilitation protocols with their own strengths and limitations. The 2 most prominent risks, infection and periprosthetic fracture, do not seem unacceptably frequent or insurmountable. Proximal amputations or situations leading to reduced mobility are exceptionally infrequent. Osseointegrated implants can be attached to advanced sensory and motor prostheses.

Increase in diagnosis of depressive disorders contributes to the increase in antidepressant use in adolescents.

OBJECTIVE: To study if the observed increase in use of antidepressants (AD) among adolescents may be explained by higher incidence of depressive disorder diagnosis, increasing treatment of other mental disorders or more liberal prescribing practice. METHODS: We used three different study populations of girls and boys aged 13-17 years in Norway: 1) individuals who were diagnosed with depressive disorders in primary health care, 2) individuals who were diagnosed with depressive disorders in secondary health care; 3) individuals who were dispensed ADs as recorded in the prescription database. Dataset 2) and 3) were linked. RESULTS: Incidence of depressive disorders increased from 2010 to 2015 both in primary and secondary health care, especially in girls. One in four girls with incident depressive disorders was prescribed ADs and this proportion was stable over time. Among girls treated with ADs the proportion with a diagnosis where AD treatment is indicated increased from 61.1% to 66.0%. Furthermore, the proportion with moderate or severe episodes of major depressive disorders was stable and high, 72.9% in 2014. CONCLUSION: The only issue studied that could explain increasing AD use in girls was increasing incidence of depressive disorders. Most adolescents with incident diagnosis of depressive disorders were not treated with ADs.

Antidepressant drug use among adolescents during 2004-2013: a population-based register linkage study.

OBJECTIVE: To study trends in use of antidepressants (ADs) by adolescents, and psychiatric morbidity and use of other psychotropic drugs as a measure of psychiatric comorbidity. METHODS: One-year prevalence of AD drug use was analyzed for 13- to 17-year-old Norwegians during 2004-2013. Use of other psychotropic drugs and specialist healthcare services was analyzed for incident AD users in 2012, using linked data from the Norwegian Prescription Database and the Norwegian Patient Register. RESULTS: The 1-year prevalence of AD drug use increased from 6.4/1000 to 9.1/1000 during 2004-2013, with the steepest increase from 2010, particularly among girls. The highest prevalence was found in 17-year-old girls (17.8/1000 in 2010, 27.5/1000 in 2013). Of incident AD drug users in 2012, 84.4% had been in contact with specialist health care. As the first drug, 78.4% were prescribed a selective serotonin reuptake inhibitor. The most common types of other psychotropic drugs were melatonin (24.6%), antipsychotic drugs (13.2%), stimulants (8.8%), and anxiolytics (6.0%). CONCLUSIONS: Use of ADs among adolescents has increased over the last 3-4 years, particularly among 16- to 17-year-old girls. A total of 85% of incident users had been in contact with specialist health care, which may indicate that drug-therapy is used by adolescents with more severe symptoms.

Motor development in children prenatally exposed to selective serotonin reuptake inhibitors: a large population-based pregnancy cohort study.

OBJECTIVES: To estimate the association between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and motor development in children considering the effect of maternal symptoms of anxiety and depression before, during and after pregnancy. DESIGN: Population-based prospective pregnancy cohort study. SETTING: The Norwegian Mother and Child Cohort study (MoBa) (1999-2008). POPULATION: A total of 51 404 singleton pregnancies. METHODS: Self-reported use of SSRIs was collected for the 6 months before pregnancy and prospectively during pregnancy. We used ordinal logistic regression as the statistical analysis. MAIN OUTCOME MEASURES: Motor development was assessed by maternal reports of fine and gross motor development at child age 3 years by items from the Ages and Stages Questionnaire (ASQ). The maternal ASQ scores were compared with data from a MoBa sub-study where clinicians assessed motor development with the Gross and Fine Motor Mullen scales of early learning. RESULTS: In all 381 women (0.7%) reported use of SSRIs during pregnancy, of these 159 reported on at least two questionnaires (prolonged use). Prolonged SSRI exposure was associated with a delay in fine motor development, odds ratio 1.42 (95% CI 1.07-1.87) compared with no SSRI exposure, after adjusting for symptoms of anxiety and depression before and during pregnancy. Severity of maternal depression seemed to explain the association only partially. Stratifying on depression after pregnancy had no impact on the estimated effect of SSRIs. CONCLUSIONS: Prolonged prenatal exposure to SSRIs was weakly associated with a delayed motor development at age 3 years, but not to the extent that the delay was of clinical importance. TWEETABLE ABSTRACT: Long-term prenatal SSRI exposure is weakly associated with delayed motor development independent of depression.

Pharmacokinetic interactions between ethanol and heroin: a study on post-mortem cases.

INTRODUCTION: Ethanol and heroin are both depressant drugs on the central nervous system, and combined use is known to be dangerous due to pharmacodynamic interactions, leading to an even higher risk of respiratory depression and death. In addition, previous studies have suggested a pharmacokinetic interaction between ethanol and the metabolism of heroin. The aim of the present study was to investigate if there was a pharmacokinetic interaction between heroin and ethanol, by comparing concentrations of heroin metabolites in cases with and without ethanol, as detected in blood samples collected from a large material of forensic autopsy cases. METHODS: The material consisted of 1583 forensic autopsy cases, all containing 6-monoacetylmorphine (6-MAM), as evidence of heroin intake, in either blood or urine samples, from the time period between the 1st of January 2000 and the 31st of December 2012. Due to the high risk of post-mortem ethanol formation in cases revealing blood ethanol concentrations between 0.1 and 0.3‰, these cases were excluded from the study, along with cases where the analysis for ethanol was missing. After this exclusion of cases, the material (n=1474) was divided into two groups; one group where ethanol was not detected in blood (n=1160), and another group where ethanol was detected in blood at or above the concentration of 0.4‰ (n=314). Furthermore, the material was also divided into two other subgroups; one group where 6-MAM was detected in blood samples, indicating a very recent intake of heroin, and another group where 6-MAM was detected in the urine, but not in blood, indicating a less recent heroin intake. RESULTS: The concentration ratios of morphine/6-MAM, morphine-3-glucuronide (M3G)/morphine, and morphine-6-glucuronide (M6G)/morphine in blood samples, were all significantly lower in the ethanol positive cases compared with that of the ethanol negative cases. For the subgroup of cases revealing a very recent intake of heroin (n=645), only the morphine/6-MAM ratio was significantly lower in the ethanol positive cases than in the ethanol negative cases. For the subgroup of cases with a less recent heroin intake (n=817), lower M3G/morphine and M6G/morphine ratios were found among the ethanol positive cases. CONCLUSIONS: The results indicate that ethanol inhibits two steps in the heroin metabolism; the hydrolysis of 6-MAM to morphine, and the glucuronidation of morphine to M3G and M6G. This pharmacokinetic interaction could further complicate the outcome after combined use of heroin and ethanol, in addition to the already well-known pharmacodynamic interactions.

Prenatal exposure to antidepressants and language competence at age three: results from a large population-based pregnancy cohort in Norway.

OBJECTIVE: To examine the association between maternal use of selective serotonin reuptake inhibitors (SSRI) in pregnancy and language competence in their children at age three taking into account maternal symptoms of anxiety and depression. DESIGN: Population-based prospective pregnancy cohort study. SETTING: The Norwegian Mother and Child Cohort Study; recruited pregnant women from 1999 through 2008. POPULATION: 45,266 women with 51,748 singleton pregnancies. METHODS: The association between short- or long-term use of SSRI during pregnancy and language competence in the child was investigated using multinomial logistic regression with three outcome categories: long, complicated sentences, fairly complete sentences and language delay. MAIN OUTCOME MEASURES: Children's language competence at age three measured by maternal report on a validated language grammar scale. RESULTS: Women reported use of SSRI in 386 (0.7%) pregnancies. Of these, 161 (42%) reported long-term use. Compared with children whose mothers took no SSRI, using the best language category as the reference, adjusted relative risk ratios (RRR) of having fairly complete sentences were 1.21 (95% CI 0.85-1.72) and 2.28 (1.54-3.38) for short- and long-term SSRI use, respectively. The adjusted RRRs of language delay were 0.86 (0.42-1.76) and 2.30 (1.21-4.37). Symptoms of anxiety and depression in pregnancy were independently related to language delay, adjusted RRR 1.25 (1.03-1.50) and 1.83 (1.40-2.40) for short- and long-term symptoms, respectively. CONCLUSIONS: Prolonged use of SSRI during pregnancy was associated with lower language competence in children by age three independently of depression. Having symptoms of depression throughout pregnancy had an independent effect.

Morphine-6-glucuronide-induced locomotor stimulation in mice: role of opioid receptors.

Morphine-6beta-glucuronide is a major metabolite of morphine with potent analgesic actions. To explore the importance of this opiate when administered as a drug by its own or in morphine action, we studied the locomotor activity response to morphine and morphine-6-glucuronide in drug-naive C57 BL/6JBom mice. The effects of administration of the two opiates on a battery of 7 different locomotor activities were studied and compared to saline controls. A dose of 20 micromol/kg morphine-6-glucuronide resulted in more locomotion than the same dose of morphine, while at higher doses (up to 120 micromol/kg), similar increases for most locomotor behaviours were recorded for both drugs. Pretreatment with naltrindole indicated that the delta-receptors play an equivalent but minor role in mediating both morphine-6-glucuronide and morphine hyperlocomotion. Administration of high naltrexone doses (10 mg/kg) completely abolished the locomotor stimulation induced by both opiates. However, at intermediate naltrexone doses of 0.25 and 0.5 mg/kg, morphine-induced behaviours was completely inhibited while morphine-6-glucuronide induced behaviours demonstrated partial resistance to naltrexone inhibition. The mu1-specific receptor antagonist naloxonazine caused 75% reduction of morphine induced behaviours and only 50% inhibition of morphine-6-glucuronide induced behaviors. Taken together our observations indicated general similarity but also marked differences between morphine and morphine-6-glucuronide with respect to opiate receptors mediating the locomotor stimulatory effect.

[Is drug use in maternity wards baby-friendly enough?]. / Er medikamentbruken ved føde- og barselavdelingene mor-barn-vennlig nok?

Quality assurance in the care of breast-feeding women and their nursing infants also applies to drugs administered during delivery and puerperium. Large variations among hospitals may indicate that drug use is irrational. A survey comparing the extent of drug sales from the hospital pharmacy to maternity wards in eight Norwegian hospitals was performed in 1992 and the results were compared with data from 1988. The purpose was to examine whether the drug use was "baby-friendly" with regard to the following criteria; proven efficacy for the indication; no effect on milk ejection, milk production and interaction with infant; minimal transfer of drug to milk. Large variations were found among hospitals in the case of some oxytocic drugs. High use of oxytocin as nasal spray and metylergometrine as tablets may indicate unnecessary use of drugs. A large decrease (89%) in the use of hypnotics was found from 1988 to 1992, which may indicate previous irrational use of these drugs. Pethidine as pain relief during delivery remained stable during this period, and was received by 40-60% of women giving birth. None of the drugs given to the mothers was assessed to represent a risk to the breast-fed infant. In general, drug use in maternity wards had decreased during the last four years and, with some exceptions, appeared to be more baby-friendly.

[Antipsychotic agents and pregnant women. A case report]. / Antipsykotika og gravide. En kasuistikk.

Teratogenic effects of drugs are not limited to visual malformations but also include developmental disturbances. Probably drugs that inhibit nerve signals such as dopamine in the central nervous system can affect the maturing of the foetal brain in the last trimester and in the postpartum period, as shown in animal studies. We have observed an infant girl with psychomotoric disturbances which occurred at the age of two weeks. The mother had received 108 mg perfenazin decanoate intramuscular injections four times during the second and third trimester, the last two times were three weeks and two days before delivery, which was at term. The symptoms resembled tardive dyskinesia. Periodically the baby showed restlessness and uttered high-pitched cries. The literature on neuroleptics indicates no major teratogenic risk, but possible risk of behavioural teratogenicity. We recommend greater caution in connection with prescribing neuroleptics in pregnancy.

[Deaths caused by antidepressive agents and neuroleptics. Risk groups illustrated by a forensic material]. / Dødsfall forårsaket av antidepressiva og neuroleptika. Risikogrupper belyst ved et rettsmedisinsk materiale.

At the Institute of Forensic Medicine, University of Oslo, legal autopsy was performed on 153 persons who died from poisoning by neuroleptics and/or antidepressants from 1986 to 1989. In one third of the cases, only neuroleptics were found at autopsy, and in little less than half of these cases the post mortem blood concentrations were considered rather low in relation to the fatal outcome. A larger proportion of alcohol abusers were found in the group with low post mortem concentrations of neuroleptics than in the rest of the material. This group contained mainly men and was further characterized by a high proportion of unintentional deaths. In the light of these facts the authors speculate whether neuroleptics represent increased risk of sudden death among alcohol abusers. The deaths due to an overdose of antidepressants were mostly suicides, and involved high post mortem blood concentrations of the drugs.