Precipitated Opioid Withdrawal Research Articles

Buprenorphine initiation and rates of associated precipitated withdrawal in patients with fentanyl use in an urban emergency department

BackgroundFentanyl use has been linked with an increasing number of opioid-related deaths. The emergency department (ED) is a critical contact point for patients with opioid use disorder (OUD) to access basic healthcare. Little information is known about buprenorphine precipitated opioid withdrawal (BPOW). This study sought to examine the rates of BPOW in patients who used fentanyl and received buprenorphine in the ED. MethodsA retrospective cohort study was conducted in a single emergency department in an urban city and included patients who reported use of fentanyl and who received buprenorphine for opioid withdrawal. The primary outcome was occurrence of BPOW, in which we assessed for interrater reliability between data abstractors. Data extraction included patients' demographic characteristics, date of service, length of stay, Clinical Opiate Withdrawal Scale (COWS) score assessments, dosages of administered buprenorphine, occurrence of BPOW, and ED disposition. ResultsOver the course of 28 months, buprenorphine was administered 113 patients (12.5 %) who reported using fentanyl prior to their ED presentation. The majority of patients identified as White (49 %), and most patients presented with a chief complaint other than specific opioid related concerns. Fifty-one patients (45 %) had an initial COWS score documented, with a median score of 11. Three patients (2.6 %) had BPOW, two of whom required intensive care unit (ICU) admission. ConclusionsWe demonstrate that the prevalence of BPOW is low in a cohort of patients who use fentanyl. When precipitated withdrawal does occur, however, it can be severe and require intensive treatment, ICU admission, and prolonged hospital stay.

Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.

Commentary on Gregory et al.: Fear of precipitated opioid withdrawal should not prevent buprenorphine initiation.

Challenges with current diagnosis and treatment strategies for precipitated opioid withdrawal in the emergency department and the role of the pharmacist.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. To demonstrate the challenges with current diagnosis and treatment strategies for precipitated opioid withdrawal secondary to naloxone the emergency department (ED) setting and describe the role of the emergency medicine (EM) pharmacist in its management. There are no standardized criteria to define precipitated opioid withdrawal syndrome, so the diagnosis is typically based on sentinel signs and symptoms and time course. Complicating factors include a positive urine toxicology screen for nonopioid substances, comorbidities and associated medications prior to admission, medications given in the ED, and a fluctuating patient course during the ED stay that likely involves all these issues. Although buprenorphine is frequently recommended as the primary treatment for precipitated withdrawal, its use can be complicated if patients are on methadone maintenance or other long-acting opioids. The EM pharmacist plays a key role in managing patients with precipitated withdrawal. Practice changes related to the diagnosis and treatment of opioid use disorder (OUD) with precipitated withdrawal in the ED are needed. EM pharmacists as part of the interprofessional care team have an important role in the management of patients with OUD, including those patients undergoing possible precipitated withdrawal.

Effects of CB1 receptor negative allosteric modulator Org27569 on oxycodone withdrawal symptoms in mice

Rationale/ObjectivesTargeting cannabinoid receptor type 1 (CB1R) has shown promise for treating opioid withdrawal symptoms. This study aimed to investigate the efficacy of a specific CB1R negative allosteric modulator (NAM), Org27569, in reducing both naloxone-precipitated and protracted withdrawal symptoms in oxycodone-dependent mice.MethodsMice received escalating doses of oxycodone (9–33 mg/kg IP) or saline twice daily for 9 days, followed by a final dose of oxycodone (33 mg/kg) or saline in the morning of day 9. In one cohort, the impact of Org27569 (3, 10, and 30 mg/kg) on naloxone (10 mg/kg IP) precipitated withdrawal symptoms was assessed. In another cohort, Org27569 (3 mg/kg) effects on the acquisition of conditioned place aversion to naloxone (0.6 mg/kg) precipitated opioid withdrawal, on behaviour following a 7–9-day abstinence period, and on naloxone (0.6 mg/kg) precipitated withdrawal-induced escape behaviour in a novel assay were assessed.ResultsAlthough Org27569 decreased opioid withdrawal-induced jumping at doses of 10 and 30 mg/kg, these effects were confounded by reduced locomotion. At all doses tested, Org27569 had a modest inhibitory effect on gastrointestinal motility. At the lower dose of 3 mg/kg, which was not confounded by locomotor effects, Org27569 did not impact naloxone-precipitated withdrawal-induced jumping, acquisition of oxycodone withdrawal-induced conditioned place aversion, or naloxone-precipitated withdrawal-induced escape behaviour in a novel assay. A clear protracted opioid withdrawal phenotype was not observed in assays of anxiety-like or social behaviour.ConclusionsOrg27569 effects on negative affective-like symptoms were confounded by locomotor effects and effects on gastrointestinal motility were not opioid withdrawal specific. Further studies are needed in a model that produces a more pronounced protracted withdrawal syndrome.

Acute Precipitated Opioid Withdrawal With Akathisia, Delirium, and Lactic Acidosis from Low-Dose Naltrexone for Chronic Pain: Case Report

BACKGROUND: Low-dose naltrexone (LDN) is an increasingly popular medication to enhance analgesia and decrease opioid reliance in patients with chronic pain. CASE REPORT: We present the case of a 66-year-old man on long-term opioids for chronic pain who was initiated on 1 mg of LDN for enhanced analgesia and subsequently went into severe precipitated opioid withdrawal (POW), a reaction understood to be rare at such low doses. CONCLUSION: LDN has been introduced into pain medicine as a safe and effective adjunct for the treatment of chronic pain conditions in both opioid-naive patients and those on concomitant opioid therapy. While this is generally considered a safe practice, LDN initiation can cause acute precipitated withdrawal in certain individuals already on opioids, even at low doses previously thought to be free from this risk. We recommend pain providers consider this effect and be prepared to manage POW when prescribing LDN. KEY WORDS: Low-dose naltrexone, LDN, chronic pain, precipitated opioid withdrawal, case report

Advanced in vitro Research on Modulation of Tumor Necrosis Factor Alpha (TNF- and #945;) by Piperine and Pirfenidone on Naloxone Precipitated Opioid Withdrawal Syndrome

Advanced in vitro Research on Modulation of Tumor Necrosis Factor Alpha (TNF- and #945;) by Piperine and Pirfenidone on Naloxone Precipitated Opioid Withdrawal Syndrome

Systematic Review of Naloxone Dosing and Adverse Events in the Emergency Department

BackgroundExperts recommend using the lowest effective dose of naloxone to balance the reversal of opioid-induced respiratory depression and avoid precipitated opioid withdrawal, however, there is no established dosing standards within the emergency department (ED). ObjectivesThe aim of this review was to determine current naloxone dosing practice in the ED and their association with adverse events. MethodsWe conducted a systematic review by searching PubMed, Cochrane, Embase, and EBSCO from 2000–2021. Articles containing patient-level data for initial ED dose and patient outcome had data abstracted by two independent reviewers. Patients were divided into subgroups depending on the initial dose of i.v. naloxone: low dose ([LD], < 0.4 mg), standard dose ([SD], 0.4–2 mg), or high dose ([HD], > 2 mg). Our outcomes were the dose range administered and adverse events per dose. We compared groups using chi-squared difference of proportions or Fisher's exact test. ResultsThe review included 13 articles with 209 patients in the results analysis: 111 patients in LD (0.04–0.1 mg), 95 in SD (0.4–2 mg), and 3 in HD (4–12 mg). At least one adverse event was reported in 37 SD patients (38.9%), compared with 14 in LD (12.6%, p < 0.0001) and 2 in HD (100.0%, p = 0.16). At least one additional dose was administered to 53 SD patients (55.8%), compared with 55 in LD (49.5%, p < 0.0001), and 3 in HD (100.0%, p = 0.48). ConclusionsLower doses of naloxone in the ED may help reduce related adverse events without increasing the need for additional doses. Future studies should evaluate the effectiveness of lower doses of naloxone to reverse opioid-induced respiratory depression without causing precipitated opioid withdrawal.

Operational definition of precipitated opioid withdrawal.

Opioid withdrawal can be expressed as both a spontaneous and precipitated syndrome. Although spontaneous withdrawal is well-characterized, there is no operational definition of precipitated opioid withdrawal. People (N = 106) with opioid use disorder maintained on morphine received 0.4 mg intramuscular naloxone and completed self-report (Subjective Opiate Withdrawal Scale, SOWS), visual analog scale (VAS), Bad Effects and Sick, and observer ratings (Clinical Opiate Withdrawal Scale, COWS). Time to peak severity and minimal clinically important difference (MCID) in withdrawal severity were calculated. Principal component analysis (PCA) during peak severity were conducted and analyzed with repeated measures analyses of variance (ANOVA). Within 60 min, 89% of people reported peak SOWS ratings and 90% of people had peak COWS scores as made by raters. Self-reported signs of eyes tearing, yawning, nose running, perspiring, hot flashes, and observed changes in pupil diameter and rhinorrhea/lacrimation were uniquely associated with precipitated withdrawal. VAS ratings of Bad Effect and Sick served as statistically significant severity categories (0, 1-40, 41-80, and 81-100) for MCID evaluations and revealed participants' identification with an increase of 10 [SOWS; 15% maximum percent effect (MPE)] and 6 (COWS; 12% MPE) points as meaningful shifts in withdrawal severity indicative of precipitated withdrawal. Data suggested that a change of 10 (15% MPE) and 6 (12% MPE) points on the SOWS and COWS, respectively, that occurred within 60 min of antagonist administration was identified by participants as a clinically meaningful increase in symptom severity. These data provide a method to begin examining precipitated opioid withdrawal.

Precipitated Opioid Withdrawal Treated With Ketamine in a Hospitalized Patient: A Case Report.

Although initiating buprenorphine in the presence of full opioid agonists has always been a clinical dilemma, the transition to primarily fentanyl in the drug supply has increased the urgency to find appropriate treatments for precipitated opioid withdrawal (POW). Although rare, lack of evidence on how to best treat POW threatens clinician and patient comfort in initiating life-saving medication for opioid use disorder. Ketamine has been used in emergency department settings to treat POW; this is the first case report of ketamine use in a hospitalized patient. A 38-year-old male patient with severe opioid use disorder presented to the emergency department with suicidality and opioid withdrawal 24 hours after last fentanyl use. In the first 24 hours of admission, he received sublingual buprenorphine-naloxone (BNX) 16-4 mg, resulting in Clinical Opiate Withdrawal Scale score increasing from 13 to over 36. The patient was admitted, and addiction medicine was consulted. The patient was diagnosed with POW, started on ketamine infusion, and given additional BNX 8-2 mg. Twelve hours after the ketamine infusion, the patient's Clinical Opiate Withdrawal Scale score improved to 18 but remained elevated. He received a second ketamine infusion plus additional BNX with complete resolution of symptoms within 8 hours, and he was stabilized and discharged on BNX 24-6 mg daily. Ketamine is a promising treatment for POW due to its potentiation of μ-opioid receptor-mediated signaling. This is the first case to describe POW in the inpatient hospital setting. More research is needed to establish the effectiveness and feasibility of ketamine as treatment for POW.

Operational definition of precipitated opioid withdrawal

Operational definition of precipitated opioid withdrawal

343EMF Identifying and Addressing Barriers to Emergency Department Buprenorphine Use Across a Health Care System

343EMF Identifying and Addressing Barriers to Emergency Department Buprenorphine Use Across a Health Care System

57 Buprenorphine Initiation for Pregnant Patients With Opioid Use Disorder: A Multicenter Observational Study of California Bridge Sites

57 Buprenorphine Initiation for Pregnant Patients With Opioid Use Disorder: A Multicenter Observational Study of California Bridge Sites

Case Report: Buprenorphine-precipitated fentanyl withdrawal treated with high-dose buprenorphine

Background: Buprenorphine, a partial agonist of the mu-opioid receptor, is an increasingly prescribed medication for maintenance treatment of opioid use disorder. When this medication is taken in the context of active opioid use, precipitated withdrawal can occur, leading to acute onset of opioid withdrawal symptoms. Fentanyl complicates use of buprenorphine, as it slowly releases from body stores and can lead to higher risk of precipitated withdrawal. Objectives: Describe the successful management of buprenorphine precipitated opioid withdrawal from fentanyl with high doses of buprenorphine. We seek to highlight how no adverse effects occurred in this patient and illustrate his stable transition to outpatient treatment. Case report: We present the case of a patient with severe opioid use disorder who presented in moderately severe opioid withdrawal after taking non-prescribed buprenorphine-naloxone which precipitated opioid withdrawal from daily fentanyl use. He was treated with high doses of buprenorphine, 148 mg over the first 48 hours, averaging 63 mg per day over four days. The patient reported rapid improvement in withdrawal symptoms without noted side effects and was able to successfully taper to 16 mg twice daily by discharge. Conclusions: This case demonstrates the safety and effectiveness of buprenorphine at high doses for treatment of precipitated withdrawal. While other options include symptomatic withdrawal management, initiating methadone or less researched options like ketamine, utilizing buprenorphine can preserve or re-establish confidence in this life-saving medication. This case also increases the previously documented upper boundary on buprenorphine dosing for withdrawal and should provide additional confidence in its use.

Reddit discussions about buprenorphine associated precipitated withdrawal in the era of fentanyl

Background Induction of buprenorphine, an evidence-based treatment for opioid use disorder (OUD), has been reported to be difficult for people with heavy use of fentanyl, the most prevalent opioid in many areas of the country. In this population, precipitated opioid withdrawal (POW) may occur even after individuals have completed a period of opioid abstinence prior to induction. Our objective was to study potential associations between fentanyl, buprenorphine induction, and POW, using social media data. Methods This is a mixed methods study of data from seven opioid-related forums (subreddits) on Reddit. We retrieved publicly available data from the subreddits via an application programming interface, and applied natural language processing to identify subsets of posts relevant to buprenorphine induction, POW, and fentanyl and analogs (F&A). We computed mention frequencies for keywords/phrases of interest specified by our medical toxicology experts. We further conducted manual, qualitative, and thematic analyses of automatically identified posts to characterize the information presented. Results: In 267,136 retrieved posts, substantial increases in mentions of F&A (3 in 2013 to 3870 in 2020) and POW (2 in 2012 to 332 in 2020) were observed. F&A mentions from 2013 to 2021 were strongly correlated with mentions of POW (Spearman’s ρ: 0.882; p = .0016), and mentions of the Bernese method (BM), a microdosing induction strategy (Spearman’s ρ: 0.917; p = .0005). Manual review of 384 POW- and 106 BM-mentioning posts revealed that common discussion themes included “specific triggers of POW” (55.1%), “buprenorphine dosing strategies” (38.2%) and “experiences of OUD” (36.1%). Many reported experiencing POW despite prolonged opioid abstinence periods, and recommended induction via microdosing, including specifically via the BM. Conclusions Reddit subscribers often associate POW with F&A use and describe self-managed buprenorphine induction strategies involving microdosing to avoid POW. Further objective studies in patients with fentanyl use and OUD initiating buprenorphine are needed to corroborate these findings. HIGHLIGHTS Increase in mentions of precipitated opioid withdrawal (POW) on Reddit from 2012 to 2021 was associated with the increase in fentanyl and analog mentions. Experiences of precipitated opioid withdrawal (POW) were described by individuals despite reporting prolonged periods of abstinence compared to standard buprenorphine induction protocols. People with Opioid Use Disorder (OUD) on Reddit are using and recommending microdosing strategies with buprenorphine to avoid POW. People who used fentanyl report experiencing POW following statistically longer periods of abstinence than people who use heroin.

Transdermal buprenorphine for in-hospital transition from full agonist opioids to sublingual buprenorphine: a retrospective observational cohort study

Introduction Patients with opioid use disorder may have difficulty transitioning from full-agonist opioids to sublingual buprenorphine due to the risk of precipitated opioid withdrawal. Novel strategies have been developed to facilitate this transition, including the use of micro-dosing with transdermal buprenorphine. We began using a transdermal buprenorphine transition strategy at our hospital in 2019. Methods We performed a retrospective observational cohort study of patients treated with transdermal buprenorphine to facilitate transition from full-agonist opioids (prescribed or recreational) while hospitalized between January 2019 and December 2020. Patients were excluded if transdermal buprenorphine was given for pain, if they did not receive at least one dose of sublingual buprenorphine while hospitalized, or if their clinical course precluded analysis of their tolerance of the transition protocol. Data on the doses and timing of medications, symptoms during transition, and hospital outcomes were abstracted from the electronic medical record. Results We identified 41 cases that satisfied inclusion and exclusion criteria. Thirty-five cases involved a transition from medically indicated opioids; of these, 8 cases involved a transition from methadone. Six cases involved a transition from illicit opioids used prior to hospital presentation. For patient transitioning from medically indicated opioids, the median milligram morphine equivalent (MME) on the day prior to transdermal buprenorphine application was 63.8 (range 0-900, IQR 153.8) and the median MME on the day of transdermal buprenorphine application was 34.5 (range 0-600, IQR 65.3). The median initial dose of sublingual buprenorphine administered was 8 mg (range 2-8mg, IQR 6mg), the median total first-day dose was 16mg (range 2-24mg, IQR 16mg), and the median total daily dose on the last day of follow-up was 16mg (range 2-24mg, IQR 16mg). In 38 cases, patients completed the transition to sublingual buprenorphine and were still taking buprenorphine at the time they left the hospital. The transition protocol was fairly well-tolerated, with 59% of cases tolerating it well and 32% tolerating it fairly. Discussion Our findings suggest that the use of transdermal buprenorphine to facilitate transition to sublingual buprenorphine is generally well-tolerated, and may be helpful in hospitalized patients. We identified several areas for improvement in future practice by reviewing the clinical courses of patients who tolerated transition poorly. Limitations of the study include its retrospective chart review design, the lack of a standardized transition protocol during the study period, and the lack of standardized data in the medical record regarding patients' tolerance of the transition protocol. Future research should include prospective studies using a standardized protocol and structured, pre-planned assessments of opioid withdrawal during the transition period. Conclusion The use of transdermal buprenorphine to facilitate induction of sublingual buprenorphine therapy in hospitalized patients with OUD was generally well-tolerated in this single-center retrospective observational study. Further prospective research is needed to demonstrate efficacy and optimize treatment protocols.

Low Dose Initiation of Buprenorphine: A Narrative Review and Practical Approach.

Low dose buprenorphine initiation, is an alternative method of initiating buprenorphine in which the starting dose is very low and gradually increased to therapeutic levels over a period of days. This method takes advantage of slow displacement of the full opioid agonist from mu-opioid receptors, avoiding the need for a person with opioid use disorder to experience opioid withdrawal symptoms before initiating buprenorphine, while also minimizing the risk of precipitated opioid withdrawal. With this initiation method, full opioid agonists can be continued as buprenorphine is initiated, expanding the population to which buprenorphine can be offered. To date, the literature on low dose initiation is primarily case-based but rapidly growing. While evidence emerges, guidance for the use of low dose initiation is clearly desired and urgently needed in the context of an increasingly risky and contaminated opioid drug supply, particularly with high potency synthetic opioids, driving overdose deaths. Despite limited evidence, several principles to guide low dose initiation have been identified including: (1) choosing the appropriate clinical situation, (2) initiating at a low buprenorphine dose, (3) titrating the buprenorphine dose gradually, (4) continuing the full opioid agonist even if it is nonmedical, (5) communicating clearly with frequent monitoring, (6) pausing or delaying buprenorphine dose changes if opioid withdrawal symptoms occur, and (7) prioritizing care coordination. We review a practical approach to low dose initiation in hospital-based and outpatient settings guided by the current evidence.

Challenges with buprenorphine inductions in the context of the fentanyl overdose crisis: A case series.

North America is currently experiencing an epidemic of opioid overdose deaths, driven by the proliferation of fentanyl in the street drug market. Although buprenorphine/naloxone (BUP/NX) is an evidence-based, first-line opioid agonist for the management of opioid use disorder, a key challenge in its prescribing lies in the fact that it can precipitate opioid withdrawal during its initial induction process. At this time, there is minimal literature on the BUP/NX induction process in individuals who use illicit fentanyl regularly. A case series from a Vancouver, Canada addiction medicine clinic of three fentanyl-exposed patients who experienced unexpected, precipitated withdrawal when initiating BUP/NX. These cases describe incidents of precipitated opioid withdrawal occurring after unusually long periods of fentanyl abstention. Although fentanyl is experienced as a short-acting opioid, the drug persists much longer in the body's peripheral tissues. Here, we highlight the new challenges fentanyl may pose to current BUP/NX induction strategies, and explore the possibility of a long-acting pharmacokinetic effect of fentanyl in the setting of repeated illicit use.

Evaluation of Buprenorphine Rotation in Patients Receiving Long-term Opioids for Chronic Pain

Individuals with chronic pain who use long-term opioid therapy (LTOT) are at risk of opioid use disorder and other harmful outcomes. Rotation to buprenorphine may be considered, but the outcomes of such rotation in this population have not been systematically reviewed. To synthesize the evidence on rotation to buprenorphine from full μ-opioid receptor agonists among individuals with chronic pain who were receiving LTOT, including the outcomes of precipitated opioid withdrawal, pain intensity, pain interference, treatment success, adverse events or adverse effects, mental health condition, and health care use. PubMed, CINAHL, Embase, and PsycInfo were searched from inception through November 3, 2020, for peer-reviewed original English-language research that reported the prespecified outcomes of rotation from prescribed long-term opioids to buprenorphine among individuals with chronic pain. Two independent reviewers extracted data as well as assessed risk of bias and study quality according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Quality of evidence was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. A total of 22 studies were analyzed, of which 5 (22.7%) were randomized clinical trials, 7 (31.8%) were case-control or cohort studies, and 10 (45.5%) were uncontrolled pre-post studies, which involved 1616 unique participants (675 female [41.8%] and 941 male [58.2%] individuals). Six of the 22 studies (27.3%) were primary or secondary analyses of a large randomized clinical trial. Participants had diverse pain and opioid use histories. Rationale for buprenorphine rotation included inadequate analgesia, intolerable adverse effects, risky opioid regimens (eg, high dose and/or sedative coprescriptions), and aberrant opioid use. Most protocols were adapted from protocols for initiating treatment in patients with opioid use disorder and used buccal or sublingual buprenorphine. Very low-quality evidence suggested that buprenorphine rotation was associated with maintained or improved analgesia, with a low risk of precipitating opioid withdrawal. Steady-dose buprenorphine was better tolerated than tapered-dose buprenorphine. Adverse effects were manageable, and severe adverse events were rare. Only 2 studies evaluated mental health outcomes, but none evaluated health care use. Limitations included a high risk of bias in most studies. In this systematic review, buprenorphine was associated with reduced chronic pain intensity without precipitating opioid withdrawal in individuals with chronic pain who were receiving LTOT. Future studies are necessary to ascertain the ideal starting dose, formulation, and administration frequency of buprenorphine as well as the best approach to buprenorphine rotation.

Cell-type specific expression and behavioral impact of galanin and GalR1 in the locus coeruleus during opioid withdrawal.

The neuropeptide galanin is reported to attenuate opioid withdrawal symptoms, potentially by reducing neuronal hyperactivity in the noradrenergic locus coeruleus (LC) via galanin receptor 1 (GalR1). We evaluated this mechanism by using RNAscope in situ hybridization to characterize GalR1 mRNA distribution in the dorsal pons and to compare galanin and GalR1 mRNA expression in tyrosine hydroxylase-positive (TH+) LC cells at baseline and following chronic morphine or precipitated withdrawal. We then used genetically altered mouse lines and pharmacology to test whether noradrenergic galanin (NE-Gal) modulates withdrawal symptoms. RNAscope revealed that, while GalR1 signal was evident in the dorsal pons, 80.7% of the signal was attributable to TH- neurons outside the LC. Galanin and TH mRNA were abundant in LC cells at baseline and were further increased by withdrawal, whereas low basal GalR1 mRNA expression was unaltered by chronic morphine or withdrawal. Naloxone-precipitated withdrawal symptoms in mice lacking NE-Gal (GalcKO-Dbh ) were largely similar to WT littermates, indicating that loss of NE-Gal does not exacerbate withdrawal. Complementary experiments using NE-Gal overexpressor mice (NE-Gal OX) and systemic administration of the galanin receptor agonist galnon revealed that increasing galanin signaling also failed to alter behavioral withdrawal, while suppressing noradrenergic transmission with the alpha-2 adrenergic receptor agonist clonidine attenuated multiple symptoms. These results indicate that galanin does not acutely attenuate precipitated opioid withdrawal via an LC-specific mechanism, which has important implications for the general role of galanin in regulation of somatic and affective opioid responses and LC activity.

Automated quantification of opioid withdrawal in neonatal rat pups using Ethovision® XT software

Chronic prenatal exposure to opioids often causes fetal opioid dependence that leads to neonatal opioid withdrawal syndrome (NOWS) shortly after delivery. Rat models of NOWS often require quantifying neonatal withdrawal behaviors using time-consuming, labor-intensive manual scoring methods. The goal of this study was to automate quantification of opioid withdrawal in neonatal rat pups. Accordingly, we used the animal behavior software Ethovision® XT to analyze archived videos of rat pups subjected to precipitated opioid withdrawal testing on postnatal day 0. We compared results obtained from Ethovision® XT with those previously obtained from manual scoring. Two endpoints reported by Ethovision® XT, Distance Moved (cm) and Movement Duration (s), had strong positive linear relationships with manually derived global withdrawal scores (GWS; R2 > 0.73). Sensitivity and specificity of each endpoint to discriminate presence and absence of low-grade withdrawal were assessed by receiver operator characteristic curve analysis, which indicated that Distance Moved and Movement Duration had excellent accuracy (AUC > 0.90). Finally, we analyzed main and interaction effects of prenatal treatment (with vehicle or mu opioid receptor full agonists) and postnatal challenge (with saline or an opioid receptor antagonist) on each endpoint and determined they were similar for the manual and automated methods. These results show that Ethovision® XT software can reliably quantify opioid withdrawal in neonatal rat pups with non-inferiority to manual scoring even in videos that were not originally purposed and optimized for Ethovision® XT analysis. This faster and less labor-intensive method of analysis is expected to accelerate progress in preclinical studies of NOWS.