Open-label, rapid initiation pilot study for extended-release buprenorphine subcutaneous injection

Buprenorphine may be offered less frequently than indicated for treatment of opioid withdrawal in the emergency department (ED) due to patient and clinician concerns regarding precipitated withdrawal (PW). Our objective is to determine an accurate estimate of the incidence of PW following buprenorphine initiation in the ED. We performed a retrospective study of adults seen in one of the 15 EDs within the University of Maryland Medical System who received ED-initiated buprenorphine between January 1, 2019 and December 31, 2023. Patients were excluded if they were given buprenorphine to continue an established treatment regimen, had buprenorphine ordered by an inpatient clinician, or did not have a Clinical Opiate Withdrawal Scale (COWS) score recorded before treatment. PW was defined as either a ≥5-point increase in COWS score within 4 hours of buprenorphine administration or any increase in the COWS score associated with additional opioid administration within 4 hours of the first buprenorphine dose. A total of 1229 patients received buprenorphine in the ED during the study period; 990 were excluded. We identified 16 cases of PW [6.7% (95% CI: 3.5%-9.9%)]. No association was found between the development of PW and initial COWS, buprenorphine formulation, fentanyl use, or buprenorphine dose. PW was uncommon following ED-initiated buprenorphine in this cohort. However, the rate of PW was higher than reported in some prior studies. Patients should be counseled regarding the possibility of PW before treatment, and clinicians should be prepared to address symptoms of PW when they occur.

Buprenorphine is an evidence-based treatment for opioid use disorder, and the risk of precipitated withdrawal contributes to its underuse. The goal of this systematic review was to determine the incidence of buprenorphine-precipitated withdrawal in adults with opioid use disorder. This systematic review was registered on PROSPERO (CRD42023437634). We searched Medline, Embase Classic + Embase, and Cochrane CENTRAL from inception to 10 November 2023, and included original research that reported the incidence of sublingual buprenorphine-precipitated withdrawal in adults with opioid use disorder. Primary screening was completed by four independent reviewers. Full text review, data extraction and risk of bias assessments using the Newcastle Ottawa Scale and the Cochrane Risk of Bias 2 tool were completed by two independent reviewers. The primary outcome was precipitated withdrawal. Secondary outcomes were baseline opioids used, induction dose, initial Clinical Opiate Withdrawal Scale (COWS) score, location of induction, definition and severity of precipitated withdrawal and adverse events. The range of incidence of precipitated withdrawal across studies was described. Our search yielded 10 197 unique citations. Twenty-one cohort and five randomized trials met inclusion criteria (n = 4497, range 20-1293). The overall incidence of precipitated withdrawal ranged from 0 to 13.2%. Nine studies defined precipitated withdrawal; definitions were inconsistent. Most patients used heroin at baseline. The most common initial dose of buprenorphine was between 2mg and 8mg (range: 0.075 mg-24 mg). Initial minimum COWS score ranged from 5 to 13. Induction locations included home, inpatient, emergency department, pre-hospital, outpatient and residential units. Of the fifteen studies with cases of precipitated withdrawal, nine studies did not report the severity of withdrawal experienced. Other induction-related adverse events varied. The overall quality of included studies was poor. The best available evidence suggests the incidence of buprenorphine-precipitated withdrawal in adults with opioid use disorder is low and should not be a barrier to use.

INTRODUCTIONBuprenorphine/Naloxone combination drugs such as Suboxone and Bunavail have not been reported to induce glycolimia. Two such cases are presented.METHODSCASE STUDY: Case 1: A 30-year-old, right-handed, white female with a history of opioid abuse was started on 4.2 mg buprenorphine/0.7 mg naloxone (Bunavail) BID and began sweet cravings and consumption of sweet foods. In a typical day she would eat 16 strawberry pop-tarts and 2 boxes of Little Debbie cookies. This may have provoked the 10 pound weight augmentation in the first two weeks of treatment. She denied any craving for opioids and no evidence of opioid withdrawal was present. Her Clinical Opiate Withdrawal Scale (COWS) score =4 (normal).Case 2: A 51-year-old, right-handed, male with opiate dependence, four days following the initiation of Suboxone (8 mg buprenorphine/2 mg naloxone) BID, developed strong cravings for sugary foods including donuts and ice cream, of which he was previously never inclined to eat and gained 10 pounds in one month. His COWS score= 7 (mild symptoms).DISCUSSIONThere are myriad mechanisms that may be acting to induce sugar cravings with buprenorphine/naloxone. Humans and rats acutely withdrawing from opiates, such as heroin, develop strong urges for consumption of sugary substances (Lieblich et al., 1991; Sapira, 1968; Weiss, 1982). Glycolimia in the above cases may reflect early or subclinical withdrawal, which if becoming more severe, would manifest as opioid craving. If the value of the reward system induced by sweets doesn’t meet the threshold invoked by the opioid stimulation, this “withdrawal” may lead to further sugar cravings in an attempt to reach the same reward level. In animals, certain foods and drugs share the same neurological pathway involved in the “reward system” potentially explaining why opioids influence food palatability in humans (Pelchat, 2002).Alternatively, it is possible that buprenorphine induces hypoglycemia at high doses (Bullingham et al., 1981) such that hypoglycemia may paradoxically act to enhance sugar craving similar to the Somogyi effect in insulin dependent diabetics. Another possible mechanism of action is that since buprenorphine acts to decrease glucose metabolism in the brain (Walsh et al., 1994), this may lead to a neural compensatory response by increasing sugar access to the brain behaviorally via glycolimiaand somatically reducing insulin release, thus explaining the high hemoglobin A1c observed in opioid addicts (Giugliano, 1984). Given the above presentation, complaints of sugar craving may indicate consideration to increase buprenorphine dosing and trial of this in those with glycolimia without opioid dependence may be warranted.Funding AcknowledgementsNo funding.

Objective Assess whether patients with chronic pain receiving 80 to 220 mg oral morphine sulfate equivalent of a full μ-opioid agonist could be transitioned to buccal buprenorphine at approximately 50% of their full dose without inducing opioid withdrawal or sacrificing analgesic efficacy.Methods. A randomized, double-blind, double-dummy, active-controlled, two-period crossover study in adult patients receiving around-the-clock full opioid agonist therapy and confirmed to be opioid dependent by naloxone challenge. Study doses were substituted at the time of the regular dose schedule for each patient. The primary endpoint was the proportion of patients with a maximum Clinical Opiate Withdrawal Scale score ≥ 13 (moderate withdrawal) or use of rescue medication.Results. 35 subjects on ≥ 80 mg morphine sulfate equivalent per day were evaluable for opioid withdrawal. One patient during buccal buprenorphine treatment and two during 50% full μ-opioid agonist treatment experienced opioid withdrawal of at least moderate intensity. The mean maximum Clinical Opiate Withdrawal Scale scores were similar, and numerically lower on buccal buprenorphine. There were no significant differences in pain ratings between treatments. The most frequent adverse events with buccal buprenorphine were headache (19%), vomiting (13%), nausea, diarrhea, and drug withdrawal syndrome (each 9%), and with full μ-opioid agonist were headache (16%), drug withdrawal syndrome (13%), and nausea (6%).Conclusions. Chronic pain patients treated with around-the-clock full μ-opioid agonist therapy can be switched to buccal buprenorphine (a partial μ-opioid agonist) at approximately 50% of the full μ-opioid agonist dose without an increased risk of opioid withdrawal or loss of pain control.

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.

Sir, Tramadol is a synthetic 4-phenyl-piperidine analog of codeine, and it is effective in mild-to-moderate analgesia. Tramadol acts on μ-opioid receptor mainly and to a lesser extent on δ-opioid receptor and κ-opioid receptor. It also has action as a serotonin and norepinephrine reuptake inhibitor.[1] In addition to typical withdrawals of opiate, tramadol can also have atypical withdrawals in the form of anxiety, paranoia, depersonalization, derealization, and auditory hallucinations.[1] Tramadol has relatively less potential for abuse and dependency than morphine.[2] In literature, there is handful of case reports of psychosis emerging from tramadol withdrawal which were managed with antipsychotic and without antipsychotic.[34] Here, the authors have reported a case of tramadol withdrawal having predominant auditory hallucinations and responded to the management of opioid withdrawals without use of antipsychotic. CASE REPORT A 42-year-old male presented with acute onset of symptoms of aggressive behavior, difficulty in sleeping, self-muttering, severe and diffuse leg pain for the past 3 days. The patient accepted that he could hear the voices of his demised father and grandfather. He would hear these voices 8–10 times throughout the day, from outer objective space. The patient had a history of opioid dependence and was treated with tablet tramadol. However, he continued to use tablet tramadol 50 mg, 5–10 tablets per day in a dependent fashion continuously for the last 3 years, and the last dose was 36–48 h before onset of current complaints. There is no history of delirium or seizure and no history of psychiatric illness. General physical examination and neurological examination were within normal limits. Mental status examination revealed second-person auditory hallucinations, and higher mental functions were within normal limits and absent insight. All routine blood investigations and contrast-enhanced computed tomography of the head were within normal limit. Urine screening with poly-kit for substance was positive for tramadol (>100 ng/ml). However, it was negative for benzodiazepines and cannabis. Baseline clinical opiate withdrawal scale (COWS)[5] score was 19 and subjective opiate withdrawal scale[6] was 30. The patient was managed for opioid withdrawal with tablet clonidine, benzodiazepines, and painkillers and the COWS score came down to 6 within a week. Auditory hallucination disappeared completely in 2 weeks of abstinence. Naranjo scale for causality assessment score came out to be 9 which suggests a definite correlation.[7] The patient is coming for follow-up and maintaining abstinent from tramadol and free from auditory hallucination. Since tramadol binds to opioid μ-receptors, it is expected that its cessation after chronic use causes withdrawal symptoms and signs like the other opioid drugs. However, there are instances in which tramadol withdrawal symptoms are similar to serotonin reuptake inhibitor withdrawal symptoms.[18] This has a direct correlation to tramadol's mechanism of action as a serotonin and norepinephrine reuptake blocker, which explains the auditory hallucinations in the index case. Index case was managed without use of antipsychotic which is similar to another case report[3] but contrary to the case report by Lakhal et al.[4] Hence, atypical withdrawal of tramadol can appear in the form of psychosis, and one should manage such patients solely by treating the opioid withdrawal and do not require the addition of an antipsychotic. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Impact of Administering Buprenorphine to Overdose Survivors Using Emergency Medical Services.

To examine patient satisfaction with long-acting injectable buprenorphine (LAIB) as opioid agonist therapy (OAT) during custody, the effect on prisoner behavior and illicit drug use in custody, and the impact on healthcare utilization within OAT programs in Scottish prisons. This observational, service evaluation included 134 adult patients (≥18 years) with opioid dependence. Clinically appropriate patients were stabilized on monthly LAIB. The following outcomes were evaluated at 12, 24, and 52weeks: patient satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM), patient-reported craving using a 100 mm visual analog scale (VAS), and opioid withdrawal using the Clinical Opiate Withdrawal Scale (COWS). Patient-reported illicit drug use and disciplinary actions were recorded. Retention on LAIB for 12 months or until release/transfer was 93.8%. Patient satisfaction with LAIB was high, with median global TSQM scores >80 at all timepoints in the whole population and in those transferred after reduction from high-dose methadone (>30 mg/day). Compared with the first 4weeks, craving significantly decreased at Weeks 12 and 24; the decrease at Week 52 was not statistically significant. COWS scores were also significantly lower at all timepoints. Levels of illicit drug use and disciplinary actions were low throughout. Healthcare worker contact time saved with LAIB versus methadone was estimated at ~100minutes per patient monthly. As of June 30, 2024, ~228hours in total are estimated to have been saved per month across the Forth Valley prison estate. This service evaluation demonstrates high levels of patient satisfaction with LAIB in the prison setting, with minimal disruption to patient comfort or behavior even during treatment transition. Provision of LAIB has reduced healthcare hours required to deliver OAT medication in the Forth Valley prison estate, allowing the reprioritization of some healthcare resources toward other health-promoting goals.

Buprenorphine is a highly effective medication for the treatment of opioid use disorder, but it can cause precipitated withdrawal (PW) from opioids. Incidence, risk factors, and best approaches to management of PW are not well understood. Our objective was to describe adverse outcomes after buprenorphine administration among emergency department (ED) patients and assess whether they met the criteria for PW. This study is a case series using retrospective chart review in a convenience sample of patients from 3 hospitals in an urban academic health system. This study included patients who were reported by clinicians as potential cases of PW. Relevant clinical data were abstracted from the electronic health record using a structured retrospective chart review instrument. A total of 13 cases were included and classified into the following 3 categories: (1) PW after buprenorphine administration consistent with guidelines (n=5), (2) PW after deviating from guidelines (n=4), and (3) protracted opioid withdrawal with no increase in Clinical Opiate Withdrawal Scale score (n=4). A total of 11 patients had urine drug testing positive for fentanyl, and 11 patients received additional doses of buprenorphine for symptom management. Of the patients, 5 had self-directed hospital discharges, and 6 were ultimately discharged with prescriptions for buprenorphine. Cases of adverse outcomes after buprenorphine administration in the ED and hospital meet criteria for PW, although some cases may have represented protracted opioid withdrawal. Further investigation into the incidence, risk factors, management of PW as well as patient perspectives is needed to expand and sustain the use of buprenorphine in EDs and hospitals.

ABSTRACTIntroduction: Nalmefene, a long-acting µ-opioid antagonist approved to treat alcohol use disorder, is occasionally mistakenly prescribed to opiate-dependent or opioid-treated patients. We review recent literature on drug-drug interactions between nalmefene and opioids that lead to precipitated opioid withdrawal, and focus on its management and planning for care at discharge.Areas covered: This article provides a brief and comprehensive review of management of precipitated opioid withdrawal syndrome when nalmefene is associated with an opioid, whether misused or legally prescribed.Expert opinion: When treating an opiate-dependent patient with co-occurring alcohol use disorder, both conditions need to be a focus of clinical attention. New drugs for alcohol use disorder have been approved, but must be given cautiously and with a full understanding of their potential drug-drug interactions with opioid medications. Opiate-dependent patients should be intensively monitored for risk factors of alcohol use disorder and should be continuously motivated for treatment maintenance. When nalmefene is administered to opiate-dependent patients, acute opioid withdrawal syndrome may occur. Management of precipitated acute opioid withdrawal may include short or long-acting µ-opioid agonists during hospitalization, in addition to supportive treatment. The best management of polydrug abusers is based on a multidisciplinary approach, which should be pursued and improved through continuing medical education.

Utilization of full-agonist therapy for severe precipitated opioid withdrawal: A case series and retrospective analysis.

Buprenorphine precipitated opioid withdrawal: Prevention and management in the ED setting

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.

Support and safety measures are essential for Veterans admitted to acute psychiatric units with co-occurring posttraumatic stress disorder (PTSD) and opioid use disorder (OUD) to avoid unpleasant withdrawal symptoms. A human patient simulator was used to train clinicians to recognize opioid withdrawal symptoms. Clinicians were educated to assess for opioid withdrawal symptoms using the Clinical Opiate Withdrawal Scale. Knowledge was evaluated via pre/posttest. All participants' (N = 12) posttest scores improved. Participants self-rated their perception of clinical knowledge and practice skills as higher postintervention. Veterans indicated decreased concern about opioid withdrawal symptoms and increased perception that symptoms were adequately evaluated and treated by clinicians. Overall, the intervention appeared to enhance the provision of quality care in Veterans with OUD and co-occurring PTSD on an acute inpatient psychiatric unit. [Journal of Psychosocial Nursing and Mental Health Services, 56(6), 36-42.].

Low dose intramuscular methadone for acute mild to moderate opioid withdrawal syndrome