Precipitated Withdrawal Research Articles

All rescue medications are needed in fentanyl era

Stories of overdose deaths greatly outnumber stories of withdrawal precipitated by the use of rescue medications such as naloxone. In fact, the illicit fentanyl supply is so strong that the standard dose of intranasal naloxone — 4 milligrams — is no longer enough in most cases, unless there is oxygen supplementation (see FDA urges higher naloxone doses in fentanyl era, CPU March 2024; https://onlinelibrary.wiley.com/doi/full/10.1002/cpu30843). Most reversals of overdose require at least two doses and waiting in between those doses can be fatal. Brain damage from oxygen loss can also occur. Yet the harm reduction community continues to fret about naloxone and other rescue medications causing precipitated withdrawal.

Practices and Outcomes Associated With Sublingual Buprenorphine Use in a Critically Ill Population.

Buprenorphine for opioid use disorder (OUD) is commonly used in the outpatient setting with increasing use in hospitalized patients. However, there is limited literature describing its use in critically ill populations. The primary objective was to report the practices of buprenorphine prescribing among ICU teams. We also assessed the effect of a novel initiation strategy on opioid requirements in the ICU and the incidence of precipitated withdrawal. Single-center, retrospective, descriptive study of patients receiving buprenorphine in the ICU. The main outcome was to describe the use of buprenorphine in ICU patients through indication, initiation strategy, dosing information, and time from ICU admission to the first dose. We also detailed the incidence of precipitated withdrawal overall and the difference in opioid requirements before and after a low-dose induction strategy (buprenorphine initiated while receiving full agonist opioids [5-d titration from 150 μg to 4 mg four times daily]). A total of 153 patients were included. Most patients (86.3%) received buprenorphine for treatment of OUD. Of the 75 patients taking buprenorphine before admission, 46 (61%) had it restarted within 24 hours of ICU admission. Among 95 patients requiring buprenorphine induction, 57 (60%) underwent standard induction and 38 (40%) underwent low-dose induction, with only one instance of precipitated withdrawal. Median morphine milligram equivalents (MMEs) of concomitant full agonist opioids in patients completing low-dose induction decreased from 1057.5 mg to 262.5 mg in the 24 hours before initiation compared with the 24 hours after target buprenorphine dose was reached (p < 0.005). Use of sublingual buprenorphine was most often in patients with OUD. Timely continuation of home buprenorphine in the ICU was suboptimal. Both standard and low-dose induction strategies appear to be safe with a low risk of precipitating withdrawal. When implemented appropriately, low-dose buprenorphine induction may lead to significant reduction in full agonist opioids in critically ill patients.

Overview of best practices for buprenorphine initiation in the emergency department

In recent decades, opioid overdoses have increased dramatically in the United States and peer countries. Given this, emergency medicine physicians have become adept in reversing and managing complications of acute overdose. However, many remain unfamiliar with initiating medication for opioid use disorder such as buprenorphine, a high-affinity partial opioid agonist. Emergency department-based buprenorphine initiation is supported by a significant body of literature demonstrating a marked reduction in mortality in addition to increased engagement in care. Buprenorphine initiation is also safe, given both the pharmacologic properties of buprenorphine that reduce the risk of diversion or recreational use, and previously published literature demonstrating low rates of respiratory depression, sedation, and precipitated withdrawal. Further, barriers to emergency department-based initiation have been reduced in recent years, with publicly available dosing and up-titration schedules, numerous publications overviewing best practices for managing precipitated withdrawal, and removal of USA policies previously restricting patient access and provider prescribing, with the removal of the X-waiver via the Medication Access and Training Expansion Act. Despite reductions in barriers, buprenorphine initiation in the emergency room remains underutilized. Poor uptake has been attributed to numerous individual and systemic barriers, including inadequate education, provider stigma, and insufficient access to outpatient follow-up care. The following practice innovation aims to summarize previously published evidence-based best practices and provide an accessible, user-friendly initiation guide to increase emergency physician comfortability with buprenorphine initiation going forward.

NY needs all rescue medications in formulary in fentanyl era

Stories of overdose deaths greatly outnumber stories of withdrawal precipitated by the use of rescue medications such as naloxone. In fact, the illicit fentanyl supply is so strong that the standard dose of intranasal naloxone — 4 milligrams — is no longer enough in most cases, unless there is oxygen supplementation (see FDA urges reevaluating naloxone dosing in fentanyl era, ADAW Jan. 29; https://onlinelibrary.wiley.com/doi/10.1002/adaw.34010). Most reversals of overdose require at least two doses and waiting in between those doses can be fatal. Brain damage from oxygen loss can also occur. Yet the harm reduction community continues to fret about naloxone and other rescue medications causing precipitated withdrawal.

Novel Uses of Methadone Under the "72-Hour Rule" to Facilitate Transitions of Care and Low-Dose Buprenorphine Induction in an Outpatient Bridge Clinic.

Federal regulations restrict methadone for opioid use disorder (OUD) treatment to licensed opioid treatment programs (OTPs). However, providers in other settings can administer methadone for opioid withdrawal under the "72-hour rule" while linking to further care. Prior work has demonstrated that methadone initiation in a low-barrier bridge clinic is associated with high OTP linkage and 1-month retention rates. We describe 2 other novel applications of the 72-hour rule in which methadone withdrawal management facilitated linkage to inpatient hospitalization and outpatient buprenorphine induction. Patient 1 was a 46-year-old woman with OUD complicated by serious injection-related infections. Severe opioid withdrawal limited her ability to tolerate emergency department wait times and receive inpatient care. We administered methadone for opioid withdrawal in an outpatient bridge clinic immediately before emergency department referral; this enabled hospital admission for intravenous antibiotics and anticoagulation. Patient 2 was a 36-year-old man with OUD desiring buprenorphine treatment. He had been unable to complete traditional buprenorphine induction without experiencing precipitated withdrawal. Thus, we recommended a low-dose buprenorphine induction overlapping with a full opioid agonist. Given the patient's preference to stop using fentanyl immediately, he received 72 hours of methadone for withdrawal treatment during the induction phase and successfully transitioned to buprenorphine without significant concomitant fentanyl use. In addition to facilitating OTP linkage, on-demand 72-hour methadone administration for opioid withdrawal can reduce barriers to acute medical care and buprenorphine treatment.

Preferences and decisional considerations relating to opioid agonist therapy among Ukrainian people who use drugs: A conjoint analysis survey.

Scaling up opioid agonist therapies (OAT) is the most effective strategy to control combined HIV and opioid epidemics, especially in Eastern Europe and Central Asia (EECA), where HIV incidence and mortality continue to increase. Patient concerns about OAT, however, have undermined scale-up. The objective of this study is to understand Ukrainian opioid use disorder patient preferences about OAT to guide the development of an evidence-informed decision aid for clinical decision-making. We conducted a conjoint-based choice (CBC) survey. Participants were asked to about their preferences relating to 7 attributes of OAT (cost, dosing frequency, concerns about withdrawal symptoms, adverse side effects, improvements in quality of life, precipitation of withdrawal and legislative requirements to be registered as a drug dependent person) and 20 attribute levels for receiving OAT under differing potential treatment constraints. Data were analyzed using Hierarchical Bayesian models. Using respondent-driven sampling and random sampling, we recruited 2,028 people who inject drugs with opioid use disorder. Relative importance (RIS) and partial-worth utility scores (PWUS) were used to assess preferences for attributes and thresholds within each attribute. Cost and dosing frequency were the most important attributes (RIS = 39.2% and RIS = 25.2%, respectively) to potential patients, followed by concerns about withdrawal symptoms (RIS = 10.8%), adverse side effects (RIS = 9.0%), quality-of-life improvement (RIS = 7.5%), precipitation of euphoria (5.2%) and requirement to be registered as a drug- dependent person (RIS = 3.1%). The monthly cost-threshold for willingness-to-pay was 1,900 UAH ($70 USD). In Ukraine, where both governmental and private OAT clinics have emerged and provide markedly different delivery strategies, preferences are mostly driven by out-of-pocket expenses, despite many patients being willing to pay for OAT. Programmatic demands (flexibility and ease of acquiring medications) remain an important consideration while for a minority, clinical concerns about withdrawal symptoms, adverse side effects and OAT impact on life play a smaller role.

Differential disruption of response alternation by precipitated Δ9-THC withdrawal and subsequent Δ9-THC abstinence in mice

In addition to overt somatic symptoms, cannabinoid withdrawal can also manifest as disruptions in motivation and attention. Experimental animal models using operant-conditioning approaches reveal these differences, in either antagonist-precipitated or spontaneous withdrawal models. However, these processes have yet to be characterized in the same subjects simultaneously. To differentiate between motivational and attentional processes disrupted in cannabinoid withdrawal, the current study used a response alternation task in which a fixed-ratio (FR) schedule repeatedly alternated between two spatially distinct response options throughout daily training sessions. This task yielded traditional measures of motivation (e.g., response latency) as well as attention (e.g., responses to the incorrect side). After two weeks of training, male and female C57BL/6 J mice either received vehicle or Δ9-THC (10 mg/kg, s.c.) twice daily for 5 days. On the 6th day, all mice received their final injection of vehicle or Δ9-THC followed 30 min later by injection of the CB1 receptor selective inverse agonist rimonabant (2 mg/kg, i.p.) to precipitate withdrawal. Testing continued for 3 days post-rimonabant to assess how THC abstinence impacted task performance. Whereas rimonabant decreased response rates to equal degrees in THC-treated and vehicle-treated mice, THC-treated mice showed longer session times, longer response latencies, and more errors per reinforcer. Only THC-treated mice showed a longer latency to switch after committing an error reflecting that precipitated withdrawal impacted measures of both motivation and attention. During the 3-day abstinence window, performance of vehicle-treated mice returned to baseline, but THC-treated mice continued to show disruptions in motivational measures. Importantly, attentional measures (errors and latency to switch after an error) were unaffected by THC abstinence. These data suggest that precipitated and “spontaneous” cannabinoid withdrawal may be qualitatively and quantitatively distinct withdrawal conditions with precipitated withdrawal disrupting both attentional and motivational processes, while abstinence may only affect motivation.

Characterizing Opioid Withdrawal Experiences and Consequences Among a Community Sample of People Who Use Opioids

Background Opioid withdrawal symptoms are a highly salient and consequential health condition experienced by people who use opioids (PWUO). This study utilized qualitative interviews to explore opioid withdrawal experiences and consequences among PWUO in Los Angeles County, USA. Methods Semi-structured qualitative interviews were conducted with 22 PWUO (aged 27–63 years) between May 2021 and May 2022. Participants self-reported opioid and injection drug use in the last 30 days. We employed an inductive thematic approach to systematically code and synthesize textual interview data. Results Participants experienced withdrawal symptoms frequently, with many going to great lengths to avoid them. Withdrawal pain was described as incapacitating and interfered with PWUO’s ability to sustain regular employment and ensure stable housing. Avoiding withdrawal was described as influential in driving decisions to continue using opioids. Mechanisms for managing withdrawal included using other substances to the point of sedation. PWUO who transitioned from heroin to fentanyl use revealed more frequent, painful, and faster onset of withdrawal symptoms. Adverse withdrawal experiences and fear of precipitated withdrawal from buprenorphine were barriers to treatment initiation and continuation. Conclusion Withdrawal symptoms among PWUO increase health risk. Improved strategies to treat opioid withdrawal are urgently needed. Solutions such as safe supply and intentional opioid withdrawal interventions (educational trainings, withdrawal comfort kits) are needed to improve withdrawal management and reduce opioid-related harm.

Somatic and anxiety-like behaviors in male and female rats during withdrawal from the non-selective cannabinoid agonist WIN 55,212–2

Synthetic cannabinoids are associated with higher risk of dependence and more intense withdrawal symptoms than plant-derived Δ9-tetrahydrocannabinol (THC). Avoidance of withdrawal symptoms, including anxiogenic effects, can contribute to continued cannabinoid use. Adult male and female Long-Evans rats were given escalating doses of WIN 55,212–2 (WIN) via twice daily intrajugular infusions. Precipitated withdrawal was elicited with SR 141716 (rimonabant) 4 h after the final infusion. Global withdrawal scores (GWS) were compiled by summing z-scores of observed somatic behaviors over a 30-min period with locomotor activity simultaneously collected via beam breaks. Rimonabant precipitated withdrawal in female and male rats at 3 or 10 mg/kg, respectively, but the individual behaviors contributing to GWS were not identical. 3 mg/kg rimonabant did not impact locomotor behavior in females, but 10 mg/kg decreased locomotion in male controls. Spontaneous withdrawal observed between 6 and 96 h after the final infusion was quantifiable up to 24 h following WIN administration. Individual behaviors contributing to GWS varied by sex and time point. Males undergoing spontaneous withdrawal engaged in more locomotion than females undergoing withdrawal. Separate groups of rats were subjected to a battery of anxiety-like behavioral tests (elevated plus maze, open field test, and marble burying test) one or two weeks after WIN or vehicle infusions. At one week abstinence, sex-related effects were noted in marble burying and the open field test but were unrelated to drug treatment. At two weeks abstinence, females undergoing withdrawal spent more time grooming during marble burying and performed more marble manipulations than their male counterparts. WIN infusions did not impact estrous cycling, and GWS scores were not correlated with estrous at withdrawal. Collectively, these results show qualitative sex differences in behaviors contributing to the behavioral experience of cannabinoid withdrawal supporting clinical findings from THC.

Sex differences in nicotine intake and relapse behavior in nicotine-dependent adult wistar rats.

Tobacco use is highly addictive and the leading cause of premature mortality in the world. Long-access nicotine self-administration procedures in rats closely model human smoking behavior. However, significant gaps remain in our understanding of sex differences in the development of dependence and relapse in adult rats. In the present study, we investigated operant responding for both nicotine and saline and the development of dependence in adult rats of both sexes. The rats had daily access to nicotine or saline for 6h per day, 7days per week. Dependence was assessed by evaluating precipitated and spontaneous somatic withdrawal signs, measuring locomotor activity in the small open field test, and assessing anxiety-like behavior in the large open field and elevated plus maze test. The sucrose preference test was used to determine if cessation of nicotine intake leads to anhedonia. It was also investigated if a period of forced abstinence affects nicotine-seeking behavior. This study showed that nicotine intake is higher in females than in males when given daily long access to nicotine. Daily nicotine self-administration led to more precipitated and spontaneous somatic withdrawal signs compared to saline self-administration, with no sex differences observed. In addition, cessation of nicotine intake led to a similar increase in activity in both males and females in the small open field test. However, cessation of nicotine intake did not increase anxiety-like behavior or cause anhedonia in either males or females. A time course analysis revealed that the nicotinic acetylcholine receptor antagonist mecamylamine affected nicotine intake differently in males and females, increasing intake in males and decreasing intake in females. Three weeks of forced abstinence led to an increase in nicotine and saline-seeking behavior. The rats exhibited more nicotine than saline seeking, and the females displayed more nicotine seeking than the males. The present findings demonstrate that females self-administer more nicotine and display more nicotine-seeking behavior than males. Furthermore, there were no sex differences in somatic withdrawal signs or activity during abstinence from nicotine. This work underscores the importance of considering sex differences across various aspects of addiction, including intake and relapse, when developing novel treatments for tobacco use disorder.

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

Low-dose buprenorphine initiation and treatment continuation among hospitalized patients with opioid dependence: A retrospective cohort study

BackgroundBuprenorphine is an effective treatment for both opioid use disorder (OUD) and chronic pain, but buprenorphine's pharmacology complicates treatment initiation for some patients. Low-dose buprenorphine initiation is a novel strategy that may reduce precipitated withdrawal. Few studies describe what patient populations benefit most from low-dose initiations and the clinical parameters that impact treatment continuation. This study aimed to 1) describe experiences with low-dose buprenorphine initiation, including both successes and failures among hospitalized patients in an urban underserved community; 2) identify patient- and treatment-related characteristics associated with unsuccessful initiation and treatment discontinuation; and 3) assess buprenorphine treatment continuation after discharge. MethodsThis is a retrospective cohort study with opioid-dependent (meaning OUD or receiving long-term opioid therapy for chronic pain) patients who underwent low-dose buprenorphine initiation during hospital admission from October 2021 through April 2022. The primary outcome was successful completion of low-dose initiation. Bivariate analysis identified patient- and treatment-related factors associated with unsuccessful initiation. Secondary outcomes were buprenorphine treatment discontinuation at post-discharge follow-up, 30- and 90-days. ResultsOf 28 patients who underwent low-dose buprenorphine initiation, 68 % successfully completed initiation. Unsuccessful initiation was associated with receipt of methadone during admission and higher morphine milligram equivalents (MME) of supplemental opioids. Of 22 patients with OUD, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 46 %, 36 %, and 36 %. Of 6 patients with chronic pain, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 100 %, 100 %, and 83 %. ConclusionLow-dose buprenorphine initiation can be successful in opioid-dependent hospitalized patients. Patients taking methadone or requiring higher MME of supplemental opioids may have more difficulty with the low-dose buprenorphine initiation approach, but these findings should be replicated in larger studies. This study suggests patient- and treatment-related factors that clinicians could consider when determining the optimal treatment strategy for patients wishing to transition to buprenorphine.

Factors influencing JUUL e-cigarette nicotine vapour-induced reward, withdrawal, pharmacokinetics and brain connectivity in rats: sex matters

Though vaping likely represents a safer alternative to smoking, it is not without risks, many of which are not well understood, especially for vulnerable populations. Here we evaluate the sex- and age-dependent effects of JUUL nicotine vapour in rats. Following passive nicotine vapour exposures (from 59 mg/ml JUUL nicotine pods), rats were evaluated for reward-like behaviour, locomotion, and precipitated withdrawal. Pharmacokinetics of nicotine and its metabolites in brain and plasma and the long-term impact of nicotine vapour exposure on functional magnetic resonance imaging-based brain connectivity were assessed. Adult female rats acquired conditioned place preference (CPP) at a high dose (600 s of exposure) of nicotine vapour while female adolescents, as well as male adults and adolescents did not. Adult and adolescent male rats displayed nicotine vapour-induced precipitated withdrawal and hyperlocomotion, while both adult and adolescent female rats did not. Adult females showed higher venous and arterial plasma and brain nicotine and nicotine metabolite concentrations compared to adult males and adolescent females. Adolescent females showed higher brain nicotine concentration compared to adolescent males. Both network-based statistics and between-component group connectivity analyses uncovered reduced connectivity in nicotine-exposed rats, with a significant group by sex interaction observed in both analyses. The short- and long-term effects of nicotine vapour are affected by sex and age, with distinct behavioural, pharmacokinetic, and altered network connectivity outcomes dependent on these variables.

Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell-derived secretome in preclinical models of morphine dependence.

Morphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine-induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti-inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress. Two animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC-derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini-pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC-derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC-derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation. In both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine-induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens. Data presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.

Low-dose Induction of Buprenorphine in Pregnancy: A Case Series.

Because of a risk of precipitated withdrawal occurring from buprenorphine induction in people who use fentanyl, low-dose inductions are becoming increasingly common. However, little evidence exists on the use of this method in pregnant people. We conducted a case series of all pregnant people treated for opioid use disorder with low-dose buprenorphine induction at the University of Maryland Medical Center between January 1, 2021, and August 22, 2022. Primary outcome was completion of induction regimen. Secondary outcomes were self-report of withdrawal, continuation of buprenorphine until delivery, and return to or continuation of illicit opioid use. Six pregnant people were prescribed a total of 10 buprenorphine inductions. Five of the 6 pregnant people (83.3%) completed at least 1 induction, none of whom experienced precipitated withdrawal. Two of 6 (33.3%) continued buprenorphine until the time of delivery, and 1 of 6 (16.7%) abstained from illicit opioid use. The low-dose buprenorphine induction regimen described was successful in 5 of 6 pregnant individuals. Further research, particularly regarding continuation rates, is needed.

Evaluation of Low-dose Buprenorphine Initiation With Buprenorphine Buccal Films in Hospitalized Patients: A Retrospective Cohort Study.

Low-dose buprenorphine initiation (LDBI) strategies to transition patients from full opioid agonists to buprenorphine have previously been described using sublingual films, intravenous solution, transdermal patches, and, more recently, buccal films. The objective of this study was to describe the effectiveness of LDBI using novel titration schedules with buccal films. This is a retrospective cohort study of hospitalized patients with opioid use disorder (OUD) or physiologic dependence to opioids who underwent LDBI with buprenorphine buccal films at NYU Langone Health. Two LDBI protocols were evaluated, including a short titration schedule over 4 days and a long schedule over 7 days. The primary outcomes of interest included LDBI completion rates and incidence of opioid withdrawal. Forty-two patients underwent 46 LDBIs at NYU Langone Health between October 2020 and April 2022. The cohort comprised patients with OUD (57%), chronic pain with OUD (33%), and chronic pain without OUD (10%). Indications for LDBI most commonly included co-occurring pain precluding discontinuation of full opioid agonists (72%), prior history of precipitated withdrawal (30%), and methadone use (23%). The overall completion rate of LDBI was 78%. Withdrawal was encountered in 33% of patients; however, only 2 patients required LDBI discontinuation as a result. On multivariate analysis, a diagnosis of OUD was independently associated with withdrawal during LDBI. Buprenorphine buccal films can successfully be used off-label to facilitate LDBI in the hospital setting. We present 4- and 7-day titration protocols, which were well-tolerated, and provide practical considerations for use.

The End of the X-waiver: Excitement, Apprehension, and Opportunity.

With the passage of the MAT act (Mainstreaming Addiction Treatment) and the MATE Act (Medication Training and Expansion), the Drug Enforcement Agency "X-waiver" program governing the office-based prescription of buprenorphine for opioid use disorder has been immediately eliminated. The move was championed by vocal organizations with a rightful concern about buprenorphine access but was opposed by most physicians. Nonetheless, buprenorphine can now be prescribed like any schedule 3 medication. Studies show that despite rising opioid overdoses, buprenorphine prescription increases have been slow to rise and are particularly absent in rural communities. The elimination of the X-waiver may theoretically improve buprenorphine prescribing rates for opioid use disorder in rural areas, by nurse practitioners and physician assistants, and by resident physicians in teaching programs. It may also help decrease discrimination against individuals with opioid use disorder in postacute-care settings like nursing homes, physical rehabilitation centers, and in prisons and jails. Concerns include the elimination of the only focused opioid use disorder education many physicians receive (X-waiver courses) and a literature base showing that interest, rather than the X-waiver itself, remains the biggest barrier to recruiting more buprenorphine prescribers. Concerns also exist over the harms of precipitated withdrawal when buprenorphine is initiated inappropriately. The change of the elimination of the X-waiver brings about a new opportunity for Family Medicine and its parent organizations to champion the inclusion of opioid use disorder treatment within the chronic disease care models well-known to our integrated care settings.

Buprenorphine/naloxone micro-induction in a tertiary care hospital: a retrospective cohort analysis

Objectives To describe the use of buprenorphine/naloxone micro-inductions in hospitalized patients and characterize the success rate of these inductions. Methods We conducted a retrospective chart review of hospitalized patients receiving a buprenorphine/naloxone micro-induction for opioid use disorder in a tertiary care hospital from Jan 2020–Dec 2020. The primary outcome was a description of the micro-induction prescribing patterns used. The secondary outcomes were a description of the demographic characteristics of patients, the estimated frequency of withdrawal symptoms experienced by patients undergoing a micro-induction, and the overall success rate of the micro-inductions defined as retention on buprenorphine/naloxone therapy with no precipitated withdrawal experienced. Results Thirty-three patients were included in the analysis. Three main micro-induction regimens were identified, including rapid micro-inductions (8 patients), 0.5 mg SL BID initiations (6 patients), and 0.5 mg SL daily initiations (19 patients). Twenty-four patients (73%) met the criteria for a successful micro-induction, defined as being retained in buprenorphine/naloxone therapy with no precipitated withdrawal experienced. The most common reason for micro-induction failure was patient request to discontinue buprenorphine/naloxone therapy due to perceived adverse effects or personal preference. Conclusion Buprenorphine/naloxone micro-induction in hospitalized patients resulted in a majority of patients being successfully initiated on buprenorphine/naloxone therapy without requiring opioid abstinence prior to induction. Dosing regimens were variable, and the ideal regimen remains unclear.

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.

0027 Ravaged Rat Rhythms: Circadian Rhythm Influence on Mecamylamine-Induced Nicotine Withdrawal

Abstract Introduction Mecamylamine (Mec) is a nicotinic acetylcholine receptor (nAChR) antagonist, serving as an important piece of nicotine addiction cessation therapies. When co-administered with nicotine, Mec blocks the positive reinforcing effects of the substance of abuse and may promote a lessened desire to perpetuate an addictive cycle. On the other hand, the magnitude of the withdrawal symptoms caused by this co-administration may reinforce addiction as users can choose to terminate the process of quitting. Methods The present study uses Sprague-Dawley rats to examine if the time of withdrawal onset in relation to circadian rhythms impacts the magnitude of the relevant aversive symptoms. We hypothesized that Mec injected during the rat’s dark period show significantly less aversive symptoms when compared to when it’s done during their light period. For this, we injected rats (n=3 per group) twice a day for thirteen days subcutaneously, with either saline or nicotine, a validated protocol to induce addiction. To measure aversive symptoms of nicotine precipitated withdrawal in light vs dark periods, we used a conditioned place aversion (CPA) behavioral assay in which the rats were either tested mid-light or mid-dark periods. In CPA, the rats were first introduced to the two distinct chambers and allowed to freely move in between them (day 10, for 15 minutes), while time spent in each one was analyzed. Then, they were conditioned to associate one chamber with saline and the other with Mec (days 11-12, for 30 minutes each). Finally, they were placed again in freedom, and the time spent in the mecamylamine-paired chamber was detracted from pre-conditioning to give us the results of aversion (day 13, for 15 minutes). Results We predicted that in the aftermath, the light-period rats on nicotine addiction schedule would show the shortest change in time in Mec-paired chamber, while saline-scheduled rats across both periods would show a change of zero—or no impact of Mec. Results indicated no significant differences between group averages for time spent in the Mec-paired chamber, but they showed saline-scheduled rats to be similarly aversive to it. Conclusion This result indicates the potential need for a study with a more selective nicotine blocker. Support (if any)