Differential Patterns of Synaptic Plasticity in the Nucleus Accumbens Caused by Continuous and Interrupted Morphine Exposure.

Opioid exposure and withdrawal both cause adaptations in brain circuits that may contribute to abuse liability. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological impact. In this study, we compared cellular and synaptic adaptations in the nucleus accumbens shell caused by morphine exposure that was either continuous or interrupted by daily bouts of naloxone-precipitated withdrawal. At the behavioral level, continuous morphine administration caused psychomotor tolerance, which was reversed when the continuity of morphine action was interrupted by naloxone-precipitated withdrawal. Using ex vivo slice electrophysiology in female and male mice, we investigated how these patterns of morphine administration altered intrinsic excitability and synaptic plasticity of medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. We found that morphine-evoked adaptations at excitatory synapses were predominately conserved between patterns of administration, but there were divergent effects on inhibitory synapses and the subsequent balance between excitatory and inhibitory synaptic input. Overall, our data suggest that continuous morphine administration produces adaptations that dampen the output of D1-MSNs, which are canonically thought to promote reward-related behaviors. Interruption of otherwise continuous morphine exposure does not dampen D1-MSN functional output to the same extent, which may enhance behavioral responses to subsequent opioid exposure. Our findings support the hypothesis that maintaining continuity of opioid administration could be an effective therapeutic strategy to minimize the vulnerability to opioid use disorders.SIGNIFICANCE STATEMENT Withdrawal plays a key role in the cycle of addiction to opioids like morphine. We studied how repeated cycles of naloxone-precipitated withdrawal from otherwise continuous opioid exposure can change brain function of the nucleus accumbens, which is an important brain region for reward and addiction. Different patterns of opioid exposure caused unique changes in communication between neurons in the nucleus accumbens, and the nature of these changes depended on the type of neuron being studied. The specific changes in communication between neurons caused by repeated cycles of withdrawal may increase vulnerability to opioid use disorders. This highlights the importance of reducing or preventing the experience of withdrawal during opioid treatment.

Differential patterns of basal and naloxone-evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged-intermittent exposure to morphine.

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.

The association of pain impact and sleep disruption with opioid withdrawal during opioid-use disorder treatment.

AIMS: Persons with opioid-use disorder (OUD) often experience opioid withdrawal and opioid craving, which can drive continued opioid use and treatment discontinuation. In addition, hyperalgesia is common among persons with OUD, yet few studies have examined the role of pain impact during OUD treatment. The purpose of the present study was to test whether opioid withdrawal and craving were elevated in the context of greater pain impact (i.e. greater pain intensity and interference), and whether these associations changed throughout treatment. METHODS: Participants in residential OUD treatment (n = 24) wore wrist actigraphy to measure sleep and completed daily measures of pain impact, opioid withdrawal and opioid craving for up to 28 days. Mixed effects models were used to examine whether daily elevations in pain impact and sleep continuity were associated with withdrawal severity and opioid craving. RESULTS: Elevations in withdrawal, but not craving, occurred on days when individuals reported higher scores on the pain impact scale. Associations between pain impact and withdrawal were present throughout treatment, but stronger during early treatment. In contrast, both withdrawal and opioid craving were elevated following nights of greater wake after sleep onset and awakenings, but these findings were often more pronounced in early treatment. CONCLUSIONS: Pain impact and sleep disturbance are 2 factors associated with opioid withdrawal and opioid craving. Novel pharmacotherapies and scalable adjunctive interventions targeting sleep and pain impact should be tested in future work to improve OUD treatment outcomes.

Maternal opioid use disorder and infant mortality in Wisconsin, United States, 2010-2018.

OBJECTIVE: The difference in infant health outcomes by maternal opioid use disorder (OUD) status is understudied. We measured the association between maternal OUD during pregnancy and infant mortality and investigated whether this association differs by infant neonatal opioid withdrawal syndrome (NOWS) or maternal receipt of medication for OUD (MOUD) during pregnancy. METHODS: We sampled 204,543 Medicaid-paid births from Wisconsin, United States (2010-2018). The primary exposure was any maternal OUD during pregnancy. We also stratified this exposure on NOWS diagnosis (no OUD; OUD without NOWS; OUD with NOWS) and on maternal MOUD receipt (no OUD; OUD without MOUD; OUD with <90 consecutive days of MOUD; OUD with 90+ consecutive days of MOUD). Our outcome was infant mortality (death at age <365 days). Demographic-adjusted logistic regressions measured associations with odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Maternal OUD was associated with increased odds of infant mortality (OR 1.43; 95% CI 1.02-2.02). After excluding infants who died <5 days post-birth (i.e., before the clinical presentation of NOWS), regression estimates of infant mortality did not significantly differ by NOWS diagnosis. Likewise, regression estimates did not significantly differ by maternal MOUD receipt in the full sample. CONCLUSIONS: Maternal OUD is associated with an elevated risk of infant mortality without evidence of modification by NOWS nor by maternal MOUD treatment. Future research should investigate potential mechanisms linking maternal OUD, NOWS, MOUD treatment, and infant mortality to better inform clinical intervention.

An epidemiological examination of neonatal opioid withdrawal syndrome and maternal and infant characteristics.

PURPOSE: Analyze maternal and infant characteristics by Neonatal Opioid Withdrawal Syndrome (NOWS) status and examine the association between mothers with Hepatitis C Virus (HCV) and infants diagnosed with NOWS. METHODS: Hospital discharge diagnoses of low-income women in Tennessee were used to identify NOWS cases (n = 1,369) in 2013 and 2014 and randomly selected controls (n = 1,369) were matched on county of residence and birth year. Maternal and infant characteristics were obtained by linking these data to birth certificate data. RESULTS: Of Tennessee's 683 cases of NOWS in 2013 and 686 in 2014, most (69%) occurred in Eastern Tennessee. Mothers of infants with NOWS were more likely to be older, unmarried, and white than mothers of infants without NOWS. Mothers of infants with NOWS also faced greater health risk: more smoking, HCV, herpes simplex diagnosis, and no or less frequent prenatal care (p < .0001). Infants with NOWS were more likely to present with infection, be admitted into the NICU, have lower birth weight, be enrolled in TennCare, but less likely to be breastfed than infants without NOWS (p < .0001). After adjusting for demographic factors and smoking, compared to mothers of infants without NOWS, mothers of infants with NOWS had an alarmingly increased odds of HCV [OR = 12.97 (95% CI 7.42, 22.66)]. CONCLUSIONS: This study emphasizes the complexity of challenges facing families impacted by NOWS, the importance of multifaceted prevention, and the need to conduct HCV testing in NOWS infants.

Precipitated opioid withdrawal in a patient started on olanzapine/samidorphan.

BACKGROUND: Olanzapine/Samidorphan (Lybalvi®) is a novel oral agent for the treatment of schizophrenia and bipolar I disorder. It was designed to reduce weight gain associated with olanzapine. Samidorphan is an analog of naltrexone, initially intended to treat substance use disorders by antagonizing mu, delta, and kappa opioid receptors. CASE REPORT: We present the case of a 36-year-old who took their first dose of olanzapine/samidorphan shortly before calling for emergency services. The patient took diphenhydramine and an epinephrine autoinjector for what they thought was an allergic reaction but continued to have symptoms. EMS reported involuntary muscle movements thought to be due to dystonia from olanzapine. In the ED, they experienced generalized muscle spasms lasting for several seconds and diaphoresis. Initially, the staff treated for a presumed dystonic reaction to olanzapine and administered diphenhydramine 25 mg IV, diazepam 2 mg IV, midazolam 5 mg IV, and benztropine 1 mg IV without improvement. It was later determined that the patient took 16 mg of buprenorphine SL daily. With this information, precipitated opioid withdrawal was felt to be the likely cause of symptoms. The patient received 16 mg of buprenorphine for an initial Clinical Opiate Withdrawal Scale (COWS) score of 11 with repeat COWS of 6. Why should an emergency physician be aware of this? Initiating olanzapine/samidorphan in the setting of chronic opioid therapy may result in precipitated opioid withdrawal. Additional SL buprenorphine may be a reasonable treatment modality.

Successful administration of extended-release buprenorphine in the emergency department.

INTRODUCTION: The ongoing opioid epidemic in the United States has resulted in a substantial increase in overdose deaths and related morbidity and mortality. Given that emergency departments (ED) frequently serve as the initial point of contact for individuals experiencing opioid overdose or seeking treatment for opioid use disorder (OUD), ED clinicians have a pivotal role to play in providing prompt and effective treatment for OUD. While ED clinicians routinely administer sublingual and other transmucosal formulations of buprenorphine, extended-release buprenorphine (BUP-XR) remains underutilized in the ED. CASE REPORT: We present a case involving the successful administration of BUP-XR in the ED to a patient experiencing spontaneous opioid withdrawal. The patient tolerated test dosing of sublingual buprenorphine (BUP-SL) and subsequently received BUP-XR in the ED. Following this intervention, the patient was referred to the hospital-affiliated substance use disorder outpatient clinic, where he has since demonstrated successful follow-up and retention in treatment. CONCLUSION: Our report adds to the existing limited literature on the administration of BUP-XR in the ED and highlights the need for more comprehensive clinician teaching and guidance, as well as the establishment of in-hospital protocols for BUP-XR. Despite these challenges, our case indicates that initiating BUP-XR could be a viable and effective option for ED patients with OUD.

Tranq Dope: Characterization of an ED cohort treated with a novel opioid withdrawal protocol in the era of fentanyl/xylazine.

BACKGROUND: Treating opioid use disorder has reached a new level of challenge. Synthetic opioids and xylazine have joined the non-medical opioid supply, multiplying the complexities of caring for individuals in emergency departments (ED). This combination, known as 'tranq dope,' is poorly described in literature. Inadequate withdrawal treatment results in a disproportionately high rate of patient-directed discharges (also known as against medical advice dispositions, or AMA). This study aimed to describe a cohort of individuals who received a novel order set for suspected fentanyl and xylazine withdrawal in the ED. METHODS: This is a descriptive study evaluating a cohort of ED patients who received withdrawal medications from a novel protocol and electronic health record order set. Individuals being assessed in the ED while suffering from withdrawal were eligible. Individuals under age 18, on stable outpatient MOUD or who were pregnant were excluded. Treatment strategies included micro-induction buprenorphine, short acting opioids, non-opioid analgesics, and other adjunctive medications. Data collected included: demographics including zip code, urine toxicology screening, order set utilization and disposition data. Clinical Opiate Withdrawal Scale (COWS) scores were recorded, where available, before and following exposure to the medications. RESULTS: There were 270 patient encounters that occurred between September 14, 2022, and March 9, 2023 included in the total study cohort. Of those, 66 % were male, mean age 37 with 71 % residing within Philadelphia zip codes. 100 % of urine toxicology screenings were positive for fentanyl. Of the 177 patients with both pre- and post-exposure COWS scores documented, constituting the final cohort, patients receiving medications had their COWS score decrease from a median of 12 to a median of 4 (p < 0.001). The AMA rate for this cohort was 3.9 %, whereas the baseline for the population with OUD was 10.7 %. Recorded adverse effects were few and resolved without complication. CONCLUSIONS: Fentanyl and xylazine withdrawal are challenging for patients and providers. A novel tranq dope withdrawal order set may reduce both COWS scores and rate of patient-directed discharge in this cohort of patients, though further investigation is needed to confirm findings.

Evaluating a web-based training curriculum for disseminating best practices for the care of newborns with neonatal opioid withdrawal syndrome in a rural hospital, the NOWS-NM Program.

BACKGROUND: The incidence of neonatal opiate withdrawal syndrome (NOWS) in the US has grown dramatically over the past two decades. Many rural hospitals not equipped to manage these patients transfer them to hospitals in bigger cities. METHODS: We created a curriculum, the NOWS-NM Program, a web-based curriculum training in best practices. To evaluate the curriculum, we conducted pre- and post-surveys of NOWS knowledge, attitudes, and care practices, plus post-curriculum interviews and focus groups. RESULTS: Fourteen participants completed both pre- and post-curriculum surveys. They indicated an increase in knowledge and care practices. A small number of respondents expressed negative attitudes about parents of infants with NOWS at pre-test, the training curriculum appeared to have no impact on such attitudes at post-test. Sixteen participants participated in focus groups or interviews. Qualitative data reinforced the positive quantitative results and contradicted the negative survey results, respondents reported that the program did reduce stigma and improve provider/staff interactions with patients. CONCLUSIONS: This curriculum demonstrated positive impacts on NOWS knowledge and care practices. Incorporating focus on core concepts of trauma-informed care and self-regulation in future iterations of the curriculum may strengthen the opportunity to change attitudes and address the needs expressed by participants and improve care of families and babies with NOWS.

Auricular Acupressure Adjunct Treatment for Opioid Tapering: A Randomized Pilot Feasibility Study.

PURPOSE: Opioid medications are necessary in the treatment of critically ill infants; however. prolonged use may lead to withdrawal syndrome. The purpose of this study was to assess feasibility of delivering an acupressure protocol for the treatment of iatrogenic withdrawal in a pediatric cardiac intensive care unit as well as impact and acceptance of acupressure as an adjunct treatment. DESIGN: Randomized pilot feasibility trial. METHODS: Acupressure stickers were applied and rotated to one ear every 1-3 days until withdrawal symptoms improved. RESULTS: There were no serious adverse events, with only one reported incident of skin irritation. Recruiting benchmarks were exceeded. Weaning phases were significantly shorter in the acupressure group (medians 6.0 vs 22.0 respectively, p = .025, d = 0.90) and the control group used skin-to-skin contact as a comfort measure significantly more than the acupressure group (42.9% vs 6.3%, p = .18). Acupressure was accepted by parents, with an overall 96.2% rating their experience as positive, as measured by the Parent Client Satisfaction Questionnaire. The majority of health care providers (n = 19) were supportive, with 71.9% agreeing or completely agreeing acupressure is an acceptable adjunct for the treatment of withdrawal symptoms; 26.8% were neutral, as measured by the Acceptability of Intervention Measure, Intervention Appropriateness Measure, and Feasibility of Intervention Measure. CONCLUSIONS: Acupressure was found to be safe, feasible, and accepted by health care providers in a pediatric cardiac intensive care setting. CLINICAL IMPLICATIONS: These findings support future research with larger sample sizes to improve clinical treatment of infants physically dependent on sedative medications.

Withdrawal during outpatient low dose buprenorphine initiation in people who use fentanyl: a retrospective cohort study.

BACKGROUND: Buprenorphine is an effective treatment for opioid use disorder (OUD); however, buprenorphine initiation can be complicated by withdrawal symptoms including precipitated withdrawal. There has been increasing interest in using low dose initiation (LDI) strategies to reduce this withdrawal risk. As there are limited data on withdrawal symptoms during LDI, we characterize withdrawal symptoms in people with daily fentanyl use who underwent initiation using these strategies as outpatients. METHODS: We conducted a retrospective chart review of patients with OUD using daily fentanyl who were prescribed 7-day or 4-day LDI at 2 substance use disorder treatment clinics in San Francisco. Two addiction medicine experts assessed extracted chart documentation for withdrawal severity and precipitated withdrawal, defined as acute worsening of withdrawal symptoms immediately after taking buprenorphine. A third expert adjudicated disagreements. Data were analyzed using descriptive statistics. RESULTS: There were 175 initiations in 126 patients. The mean age was 37 (SD 10 years). 71% were men, 26% women, and 2% non-binary. 21% identified as Black, 16% Latine, and 52% white. 60% were unstably housed and 75% had Medicaid insurance. Substance co-use included 74% who used amphetamines, 29% cocaine, 22% benzodiazepines, and 19% alcohol. Follow up was available for 118 (67%) initiations. There was deviation from protocol instructions in 22% of these initiations with follow up. 31% had any withdrawal, including 21% with mild symptoms, 8% moderate and 2% severe. Precipitated withdrawal occurred in 10 cases, or 8% of initiations with follow up. Of these, 7 had deviation from protocol instructions; thus, there were 3 cases with follow up (3%) in which precipitated withdrawal occurred without protocol deviation. CONCLUSIONS: Withdrawal was relatively common in our cohort but was mostly mild, and precipitated withdrawal was rare. Deviation from instructions, structural barriers, and varying fentanyl use characteristics may contribute to withdrawal. Clinicians should counsel patients who use fentanyl that mild withdrawal symptoms are likely during LDI, and there is still a low risk for precipitated withdrawal. Future studies should compare withdrawal across initiation types, seek ways to support patients in initiating buprenorphine, and qualitatively elicit patients' withdrawal experiences.

Probing pain aversion in rats with the "Heat Escape Threshold" paradigm.

The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of novel methods focusing on affective-motivational behaviour in pain model animals. The most common tests used to assess pain aversion in animals require cognitive processes, such as associative learning, complicating the interpretation of results. To overcome this issue, studies in recent years have utilized unconditioned escape as a measure of aversion. However, the vast majority of these studies quantify jumping - a common escape behaviour in mice, but not in adult rats, thus limiting its use. Here, we present the "Heat Escape Threshold" (HET) paradigm for assessing heat aversion in rats. We demonstrate that this method can robustly and reproducibly detect the localized effects of an inflammatory pain model (intraplantar carrageenan) in male and female Sprague-Dawley rats. In males, a temperature that evoked unconditioned escape following carrageenan treatment also induced real-time place avoidance (RTPA). Systemic morphine more potently alleviated carrageenan-induced heat aversion (as measured by the HET and RTPA methods), as compared to reflexive responses to heat (as measured by the Hargreaves test), supporting previous findings. Next, we examined how blocking of excitatory transmission to the lateral parabrachial nucleus (LPBN), a key node in the ascending pain system, affects pain behaviour. Using the HET and Hargreaves tests, we show that intra-LPBN application of glutamate antagonists reverses the effects of carrageenan on both affective and reflexive pain behaviour, respectively. Finally, we employed the HET paradigm in a generalized opioid-withdrawal pain model. Withdrawal from a brief systemic administration of remifentanil resulted in a long-lasting and robust increase in heat aversion, but no change in reflexive responses to heat. Taken together, these data demonstrate the utility of the HET paradigm as a novel tool in preclinical pain research.

Association of Early Opioid Withdrawal Treatment Strategy and Patient-Directed Discharge Among Hospitalized Patients with Opioid Use Disorder.

BACKGROUND: Medical hospitalizations for people with opioid use disorder (OUD) frequently result in patient-directed discharges (PDD), often due to untreated pain and withdrawal. OBJECTIVE: To investigate the association between early opioid withdrawal management strategies and PDD. DESIGN: Retrospective cohort study using three datasets representing 362 US hospitals. PARTICIPANTS: Adult patients hospitalized between 2009 and 2015 with OUD (as identified using ICD-9-CM codes or inpatient buprenorphine administration) and no PDD on the day of admission. INTERVENTIONS: Opioid withdrawal management strategies were classified based on day-of-admission receipt of any of the following treatments: (1) medications for OUD (MOUD) including methadone or buprenorphine, (2) other opioid analgesics, (3) adjunctive symptomatic medications without opioids (e.g., clonidine), and (4) no withdrawal treatment. MAIN MEASURES: PDD was assessed as the main outcome and hospital length of stay as a secondary outcome. KEY RESULTS: Of 6,715,286 hospitalizations, 127,158 (1.9%) patients had OUD and no PDD on the day of admission, of whom 7166 (5.6%) had a later PDD and 91,051 (71.6%) patients received some early opioid withdrawal treatment (22.3% MOUD; 43.4% opioid analgesics; 5.9% adjunctive medications). Compared to no withdrawal treatment, MOUD was associated with a lower risk of PDD (adjusted odds ratio [aOR] = 0.73, 95%CI 0.68-0.8, p < .001), adjunctive treatment alone was associated with higher risk (aOR = 1.13, 95%CI: 1.01-1.26, p = .031), and treatment with opioid analgesics alone was associated with similar risk (aOR 0.95, 95%CI: 0.89-1.02, p = .148). Among those with PDD, both MOUD (adjusted incidence rate ratio [aIRR] = 1.24, 95%CI: 1.17-1.3, p < .001) and opioid analgesic treatments (aIRR = 1.39, 95%CI: 1.34-1.45, p < .001) were associated with longer hospital stays. CONCLUSIONS: MOUD was associated with decreased risk of PDD but was utilized in < 1 in 4 patients. Efforts are needed to ensure all patients with OUD have access to effective opioid withdrawal management to improve the likelihood they receive recommended hospital care.

Perinatal opioid exposure leads to decreased social play in adolescent male and female rats: Potential role of oxytocin signaling in brain regions associated with social reward.

Over the last two decades, the number of infants exposed to opioids in utero has quadrupled in the United States, with some states reporting rates as high as 55 infants per 1000 births. Clinical studies report that children previously exposed to opioids during gestation show significant deficits in social behavior, including an inability to form friendships or other social relationships. To date, the neural mechanisms whereby developmental opioid exposure disrupts social behavior remain unknown. Using a novel paradigm of perinatal opioid administration, we tested the hypothesis that chronic opioid exposure during critical developmental periods would disrupt juvenile play. As oxytocin is a major regulator of sociability, the impact of perinatal morphine exposure on oxytocin peptide expression was also examined. Juvenile play was assessed in vehicle- or morphine-exposed male and female rats at P25, P35, and P45. Classical features of juvenile play were measured, including time spent engaged in social play, time not in contact, number of pins, and number of nape attacks. We report that morphine-exposed males and females spend less time engaged in play behavior than control males and females, with a corresponding increase in time spent alone. Morphine-exposed males and females also initiated fewer pins and nape attacks. Together, these data suggest that male and female rats exposed to morphine during critical developmental periods are less motivated to participate in social play, potentially due to alterations in oxytocin-mediated reward signaling.

Biological sex influences sleep phenotype in mice experiencing spontaneous opioid withdrawal.

Aversive symptoms, including insomnia experienced during opioid withdrawal, are a major drive to relapse; however, withdrawal-associated sleep symptomatology has been little explored in preclinical models. We describe here a model of opioid withdrawal in mice that resembles the sleep phenotype characteristic of withdrawal in humans. Male and female C57BL/6 mice were instrumented with telemeters to record electroencephalogram, electromyogram, activity and subcutaneous temperature. All mice received two treatments separated by a 16-day washout period: (1) saline (volume: 10 ml kg-1 ); or (2) ascending doses of morphine (5, 10, 20, 40 and 80 mg kg-1 ; volume: 10 ml kg-1 ) for 5 days at Zeitgeber time 1 and Zeitgeber time 13. Recordings for the first 71 hr after treatment discontinuation (withdrawal days 1-3) and for 24 hr on withdrawal days 5 and 7 were scored for sleep/wake state, and sleep architecture and electroencephalogram spectral data were analysed. Morphine was acutely wake- and activity-promoting, and non-rapid eye movement and rapid eye movement sleep were increased during the dark phase on withdrawal day 2 in both sexes. While non-rapid eye movement delta power (0.5-4.0 Hz), a measure of sleep intensity, was reduced during the light phase on withdrawal day 1 and the dark phase on withdrawal day 2 in both sexes, female mice also exhibited changes in the duration and the number of bouts of sleep/wake states. These observations of fragmented sleep on withdrawal days 1-3 suggest poorer sleep consolidation and a more pronounced withdrawal-associated sleep phenotype in female than in male mice. These data may indicate a greater sensitivity to morphine, a more distinct aversive sleep phenotype and/or a faster escalation to dependence in female mice.

Assessing Neonatal Opioid Withdrawal Syndrome Severity as a Function of Maternal Buprenorphine Dose and Umbilical Cord Tissue Concentrations.

BACKGROUND: Infants born to mothers with opioid use disorder (OUD) and prenatally treated with buprenorphine have a significantly lower incidence of neonatal opioid withdrawal syndrome (NOWS), its treatment duration, and hospital length of stay compared with methadone. However, risk of NOWS remains and clinicians continue to lack an objective methodology to predict NOWS severity among these infants. OBJECTIVE: The purpose of this study was to assess the relationship between buprenorphine exposure, umbilical cord tissue (UCT) concentrations, and NOWS development and severity. METHODS: A single-center retrospective observational cohort study from March 2018 through June 2020 of newborns exposed to buprenorphine in utero. Associations between quantified buprenorphine exposure, neonatal UCT concentrations, NOWS diagnosis, and severity were made using regression analyses. RESULTS: A total of 24 mothers and 25 neonates were included. Length of maternal buprenorphine therapy (months) positively correlated to norbuprenorphine (r2 = 0.234, P = 0.019) and buprenorphine + norbuprenorphine UCT concentrations (r2 = 0.203, P = 0.031). A positive relationship was seen between active metabolite concentrations and cumulative morphine dose (mg/kg) for treatment of severe NOWS (r2 = 0.471, P = 0.007). A 0.36 ng/g buprenorphine + norbuprenorphine UCT (CI = 0.002-0.72, P = 0.049) equated in a 1-point increase in modified peak Finnegan score. CONCLUSION AND RELEVANCE: Buprenorphine and norbuprenorphine UCT concentrations can allow for quantification of in utero fetal exposure and demonstrate an association with a longer duration of exposure with the severity and treatment of NOWS in exposed infants.

Buprenorphine-naloxone, buprenorphine, and methadone throughout pregnancy in maternal opioid use disorder.

INTRODUCTION: Current WHO guidelines recommend using methadone or buprenorphine as maintenance treatments for maternal opioid use disorder. However, buprenorphine-naloxone, with a lower abuse risk than buprenorphine monotherapy or methadone, offers a potentially beneficial alternative, but scientific evidence on its effects on pregnancies, fetuses, and newborns is scarce. This paper compares the outcomes of the pregnancies, deliveries, and newborns of women on buprenorphine-naloxone, buprenorphine, or methadone maintenance treatments. According to the hypothesis, as a maintenance treatment, buprenorphine-naloxone does not have more adverse effects than buprenorphine, whereas methadone is more complicated. MATERIAL AND METHODS: In this population-based study, 172 pregnant women on medical-assisted treatments were followed-up at Helsinki University Women's Hospital (Finland). Women receiving the same opioid maintenance treatment from conception to delivery and their newborns were included. Consequently, 67 mother-child dyads met the final inclusion criteria. They were divided into three groups based on their opioid pharmacotherapy. The outcomes were compared among the groups and, where applicable, with the Finnish population. RESULTS: The buprenorphine-naloxone and buprenorphine groups showed similar outcomes and did not significantly differ from each other in terms of maternal health during pregnancies, deliveries, or newborns. Illicit drug use during the pregnancy was common in all groups, but in the methadone group it was most common (p = 0.001). Most neonates (96%) were born full-term with good Apgar scores. They were of relatively small birth size, with those in the methadone group tending to be the smallest. Of the neonates 63% needed pharmacological treatment for neonatal opioid withdrawal syndrome. The need was lower in the buprenorphine-based groups than in the methadone group (p = 0.029). CONCLUSIONS: Buprenorphine-naloxone seems to be as safe for pharmacotherapy for maternal opioid use disorder as buprenorphine monotherapy for both mother and newborn. Hence it could be a choice for oral opioid maintenance treatment during pregnancy, but larger studies are needed before changing the official recommendations. Women on methadone treatment carry multifactorial risks and require particularly cautious follow up. Furthermore, illicit drug use is common in all treatment groups and needs to be considered for all patients with opioid use disorder.

Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratory rhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

An individualised tapering protocol reduces opioid use 1 year after spine surgery: A randomised controlled trial of patients with preoperative opioid use.

BACKGROUND: Persistent opioid use following surgery is common especially in patients with preoperative opioid use. This study aims to determine the long-term effect of an individualised opioid tapering plan versus standard of care in patients with a preoperative opioid use undergoing spine surgery at Aarhus University Hospital, Denmark. METHODS: This is the 1-year follow-up of a prospective, single-centre, randomised trial of 110 patients who underwent elective spine surgery for degenerative disease. The intervention was an individualised tapering plan at discharge and telephone counselling 1 week after discharge, compared to standard of care. Postoperative outcomes after 1 year include opioid use, reasons for opioid use and pain intensity. RESULTS: The overall response rate to the 1-year follow-up questionnaire was 94% (intervention group 52/55 patients and control group 51/55 patients). Forty-two patients (proportion = 0.81, 95% CI 0.67-0.89) in the intervention group compared to 31 (0.61, 95% CI 0.47-0.73; p = .026) patients in the control group succeeded in tapering to zero 1 year after discharge (p = .026). One patient (0.02, 95% CI 0.01-0.13) in the intervention group compared to seven patients (0.14, 95% CI 0.07-0.26) in the control group were unable to taper to their preoperative dose 1 year after discharge (p = .025). Back/neck and radicular pain intensity was similar between study groups. CONCLUSION: These results suggest that an individualised tapering plan at discharge combined with telephone counselling 1 week after discharge can reduce opioid use 1 year after spine surgery.

Adrenoceptors: A Focus on Psychiatric Disorders and Their Treatments.

Research into the involvement of adrenoceptor subtypes in the cause(s) of psychiatric disorders is particularly challenging. This is partly because of difficulties in developing animal models that recapitulate the human condition but also because no evidence for any causal links has emerged from studies of patients. These, and other obstacles, are outlined in this chapter. Nevertheless, many drugs that are used to treat psychiatric disorders bind to adrenoceptors to some extent. Direct or indirect modulation of the function of specific adrenoceptor subtypes mediates all or part of the therapeutic actions of drugs in various psychiatric disorders. On the other hand, interactions with central or peripheral adrenoceptors can also explain their side effects. This chapter discusses both aspects of the field, focusing on disorders that are prevalent: depression, schizophrenia, anxiety, attention-deficit hyperactivity disorder, binge-eating disorder, and substance use disorder. In so doing, we highlight some unanswered questions that need to be resolved before it will be feasible to explain how changes in the function of any adrenoceptor subtype affect mood and behavior in humans and other animals.