Risk Of Respiratory Depression Research Articles

Clinical performance of a new lateral flow immunoassay for xylazine detection.

Xylazine is a potent sedative used in veterinary medicine. Recently, recreational drugs such as fentanyl havebeen found to contain xylazine, increasing the risk of respiratory depression and death. Despite a similar presentation to opioid overdose, patients who ingest xylazine donot respond to treatment with Narcan. Therefore, rapid detection of xylazine could improve patient management and prevent adverse outcomes. We evaluated the XYL500 one-step xylazine drug of abuse test for its ability to detect xylazine in 152 urine samples from patients on chronic opioid therapy for pain management or in treatment for substance use disorder. Results were compared to LC-MS/MS as the reference method. Precision, cross-reactivity, interference and stability studies were performed. Pooled patient samples were consistently negative or positive when tested five times on the same day and over three days of testing. The diagnostic sensitivity, specificity and accuracy of the XYL500 assay were 74, 98, and 82 % respectively, as compared with LC-MS/MS. XYL500 detected 77 of the 104 LC-MS/MS positive samples identified in our initial evaluation, including some that contained low levels of xylazine (n=8), <10 ng/mL. Minimal cross-reactivity with other opioid analgesics and commonly encountered drugs was seen with only one false positive result. Interferences by common urine contaminants were negligible. Specimens were stable up to 160 days refrigerated and up to 80 days at room temperature. XYL500 allows for rapid detection of xylazine, illustrating its utility in monitoring patients who ingested recreational drugs containing the additive, xylazine, and its potential to improve patient management.

The Emergent Role of Low-Dose Naltrexone in the Symptomatic Management of Chronic Musculoskeletal and Neuropathic Pain

As a result of the intricate mechanisms of pain transmission, traditional analgesics used alone, as well as concomitantly, often do not provide consistent and/or adequate pain relief for patients suffering with chronic pain conditions. Many analgesics, as well as antineuropathic and antispastic drugs, demonstrate synergistic CNS side effects, increasing the risk of respiratory depression and overdose when used in combination. Given the steady rise of opioid-related overdose deaths in the USA, pursuit of novel treatment options, such as low dose naltrexone (LDN) regimens, are of particular interest to researchers. Although multiple reliable studies exist which demonstrate the potential for LDN in pain management, large-scale, high-quality studies are lacking, or are in progress. This review article aims to analyze the currently available literature regarding low dose naltrexone therapy in order to evaluate its potential role in the management of chronic inflammatory, neuropathic, and generalized pain symptoms. Although promising, available data is limited in its utility, warranting further research and development regarding the clinical role and place in therapy of LDN in chronic pain management.

Adverse respiratory events during treatment with gabapentin and opioids among older adults with spine-related conditions: a propensity-matched cohort study in the US Medicare population.

Recent work indicates no increased mortality risk with concurrent gabapentin and opioid use when using an active comparator control design. However, concurrent gabapentin and opioid prescriptions have been associated with greater risk of respiratory depression in some studies. To compare the risk of respiratory events among Medicare enrollees with spine-related diagnoses treated with gabapentin + opioids vs those treated with tricyclic antidepressants (TCA) or duloxetine + opioids. We hypothesized that enrollees treated with gabapentin + opioids would have increased risk of adverse respiratory events compared to those treated with an active control + opioids. Propensity score-matched cohort study with an incident user, active comparator (TCA/duloxetine) control design. The primary analysis included those who concurrently (within 30 days) filled ≥1 incident gabapentin + ≥1 opioid or ≥1 incident TCA/duloxetine + ≥1 opioid prescription. U.S. Medicare beneficiaries with spine-related diagnoses 2017-2019. People treated with gabapentin + opioids (n=66,580) were matched on demographic and clinical factors to people treated with TCAs/duloxetine + opioids (n=66,580). Time to a composite respiratory outcome consisting of mechanical ventilation, intubation, respiratory failure, pneumonia, or acute respiratory distress syndrome. Cox proportional hazard regression was used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs). Among 133,160 Medicare enrollees (median age 73.3 years; 66.7% female), 6089 (4.6%) experienced respiratory events before the end of follow-up. A total of 3297 (5.0%) of people who were treated with gabapentin + opioids (median initial dose/day of gabapentin was 338 mg) had respiratory events compared to 2792 (4.2%) of those treated with an active control + opioids. The increased risk in those treated with gabapentin + opioids was statistically significant after adjustment (HR 1.14; 95% CI 1.09, 1.20; p<0.0001). The most common respiratory events were pneumonia (3.5% of people in the gabapentin + opioids group versus 3.0% of people in the TCA/duloxetine + opioids group) and respiratory failure (2.2% in the gabapentin + opioids group versus 1.8% in the TCA/duloxetine + opioids group). Results were similar in analyses (a) restricted to ≤30-day follow-up and (b) that required ≥2 fills of each prescription. While recent work has indicated no increased mortality risk with concurrent gabapentin and opioid use, the current findings suggest clinicians should exercise caution in prescribing gabapentin to people experiencing pain who are also being treated with opioids, due to the potentially increased risk of respiratory events.

The degree of respiratory depression according to the effect-site concentration in remimazolam target-controlled infusion: A randomised controlled trial.

Remimazolam is not only associated with a lower incidence of respiratory depression than propofol but also in itself has the risk of respiratory depression. We investigated respiratory depression following remimazolam infusion, targeting different effect-site concentrations using target-controlled infusion. A prospective, double-blind, randomised controlled study. Tertiary hospital, Suwon, South Korea, from April 2022 to November 2022. One hundred and seven patients scheduled for general anaesthesia were randomised into three groups targeting remimazolam effect-site concentrations of 500 (RMZ-500) ( n = 36), 1000 (RMZ-1000) ( n = 35) and 1500 ng ml -1 (RMZ-1500) ( n = 36). Remimazolam was solely infused for 10 min according to target effect-site concentrations. According to the degree of SpO 2 decrease, oxygen desaturations were managed with the following respiratory supports: jaw-thrust for SpO 2 less than 97%, 100% oxygen delivery for SpO 2 less than 93% and assisted ventilation for SpO 2 less than 90%. The incidence of each respiratory support, along with respiratory variables (at baseline, 5 min and 10 min after remimazolam infusion) and loss of consciousness were observed for 10 min after remimazolam target-controlled infusion. Both RMZ-1000 and RMZ-1500 required more frequent respiratory support than RMZ-500 (both P < 0.001), with nearly identical frequencies between RMZ-1000 and RMZ-1500. In terms of respiratory support, the incidence of assisted ventilation was significantly lower in RMZ-500 (2.8%) than RMZ-1000 (48.6%) and RMZ-1500 (50%) ( P < 0.001). RMZ-1000 and RMZ-1500 achieved loss of consciousness in all patients; RMZ-500 only achieved loss of consciousness in 86.1% of patients ( P = 0.010). In patients who maintained spontaneous respiration, tidal volume decreased by 41 to 48% and respiratory rate increased by 118 to 158% at 5 and 10 min, significantly compared to baseline in all groups ( P < 0.001). Remimazolam infusion, like that of other benzodiazepines, led to respiratory depression, which was more prominent at higher target effect-site concentrations. Therefore, appropriate countermeasures should be developed to prevent oxygen desaturation. CRIS ( https://cris.nih.go.kr ), identifier: KCT0006952.

Evaluation of Postoperative Efficacy and Safety of Celecoxib in Children Hospitalized After Adenotonsillectomy.

The choice of optimal analgesia following an adenotonsillectomy is a clinical issue because of the risk of respiratory depression and bleeding. The objective of this study was to assess the effect of celecoxib on opioid use and pain scores in children hospitalized after adenotonsillectomy and to document its adverse effects. This retrospective study was conducted in a tertiary care pediatric hospital. We compared a group of subjects aged 1 to 17 years who were prescribed celecoxib and opioids between January 2017 and June 2020 following an adenotonsillectomy during a 3-day or less hospitalization to a group of matched controls for sex, age, and length of stay who were prescribed opioids. A total of 228 patients were identified (76 in the celecoxib + opioids group, 152 in the control group). Opioid use, in oral morphine equivalent daily dose, was lower in the celecoxib + opioids group at 0 to 24 hours of hospitalization (0.15 vs 0.20 mg/kg/day, p = 0.05). Initiating celecoxib within 24 hours of surgery (n = 60) significantly reduced opioid requirement for up to 48 hours compared with controls (0-24 hours: 0.12 vs 0.20 mg/kg/day, p = 0.002; 25-48 hours: 0.02 vs 0.09 mg/kg/day, p = 0.001). A shorter length of stay was observed for patients receiving celecoxib + opioids during the first 24-hour post--operative period (27 vs 32 hours, p = 0.01). With celecoxib use, no significant change in pain scores and occurrence of adverse effects including bleeding was found. Using celecoxib early after an adenotonsillectomy has reduced both opioid use and duration of hospital stay without increasing adverse effects or bleeding.

Association of Opioid and Concurrent Benzodiazepine, Skeletal Muscle Relaxant, and Gabapentinoid Usage on Healthcare Expenditure and Resource Utilization: A Serial Cross-Sectional Study, 2009 to 2019.

Healthcare providers may be utilizing central nervous system (CNS) depressants to reduce opioid use due to recent changes in public policy. Combination use of these agents with opioids increases the risk of respiratory depression and death. Healthcare expenditures by individuals using these drug combinations have not been previously quantified. We sought to characterize healthcare costs and expenditures associated with a population reporting concurrent CNS depressants and opioid use compared with nonopioid analgesics in the United States from 2009 to 2019. A serial cross-sectional design was used to compare the healthcare expenditures of adult Medical Expenditure Panel Survey respondents who were prescribed nonopioid analgesics, opioids only, opioids/benzodiazepines (BZD), opioids/BZD/skeletal muscle relaxants (SMR), or opioids/gabapentin (gaba) using pooled data from 2009 to 2019. Expenditure (cost and resource utilization) categories included inpatient, outpatient, office-based, and prescription medicine. Average marginal effects were used to compare survey-weighted annual costs and resource utilizations across the groups as compared to nonopioid analgesic respondents, adjusted for covariates. A weighted total of 34 241 838 individuals were identified. Most were opioid-only respondents (46.5%), followed by nonopioid analgesic (43.4%), opioid/BZD (5.3%), opioid-gaba (3.5%), and opioid/BZD/SMR respondents (1.3%). In comparison to the study groups with nonopioid analgesics, opioid-gaba users had the highest significant incremental cost difference among the different pairings (+$11 684, P < .001). Opioid-gaba, opioid/BZD, and opioid/BZD/SMR respondents had significantly higher inpatient, emergency department, and prescription drug costs and use compared to nonopioid analgesic respondents. Opioid-only respondents had higher outpatient and office-based costs and visits compared to nonopioid analgesic respondents. As healthcare providers seek to utilize fewer opioids for pain management, attention must be paid to ensuring safe and effective use of concurrent CNS depressants to mitigate high healthcare costs and burden.

Respiratory Effects of Benzodiazepine in Patients with Advanced-Stage Cancer Receiving Opioid Analgesics: A Prospective Observational Study.

Despite the risk of respiratory depression, benzodiazepines are often prescribed to patients receiving palliative care owing to their efficacy in symptom control. Opioids, which also cause respiratory depression, are often administered to patients with advanced-stage cancer. However, the additive effect of the two drugs has not been systematically analyzed. This prospective observational study aimed to determine the respiratory effects of coadministration of benzodiazepines and opioids in terminally ill patients with cancer. The respiratory variables (primary endpoint) and activity index (ACI) (secondary endpoint) of 24 patients were assessed using a continuous noncontact, nonrestraining vital sign monitor placed under the legs of the bed. The respiratory rate (RR) changed from 12.0 ± 3.9/min to 10.3 ± 3.3/min (n = 24, p = 0.0005) following administration of the first dose of benzodiazepine in addition to regular opioid treatment, indicating no difference (p > 0.83) from the decrease in the RR observed on the previous day at the same time (12.1 ± 3.3/min to 10.3 ± 3.4/min). No increase in apnea-hypopnea frequency and respiratory irregularity or no decrease in respiratory size was observed. The ACI showed a significant decrease following the administration of benzodiazepine, suggesting remission of the symptoms. The effect of five repeated doses of benzodiazepines in nine patients showed no significant change in the respiratory variables compared with the first dose. Addition of single or consecutive benzodiazepine-type drugs at clinically useful dose in patients receiving palliative care for cancer with opioid analgesics, readily exposed to respiratory depression, was observed with a decreased RR similar to the decrease observed during sleep with opioid alone.

Remimazolam for anesthesia and sedation in cardiac surgery and for cardiac patients undergoing non-cardiac surgery: a systematic-narrative hybrid review.

Remimazolam, an ultra-short-acting benzodiazepine recognized and approved as an anesthetic and sedative in multiple countries, offers a distinctive pharmacokinetic profile, boasting advantages such as rapid onset, short action duration, and rapid recovery. These attributes may contribute to enhanced hemodynamic stability and a diminished risk of respiratory depression compared to other sedatives. We conducted the first comprehensive systematically structured narrative review to evaluate the role and potential application of remimazolam in cardiac surgery. Twenty-one studies published from 2021 to 2023 delved into remimazolam's application in open cardiac surgery, cardiac catheterization or electrophysiology laboratories, and high-risk cardiovascular patients undergoing non-cardiac surgery. Overall, remimazolam usage was apparently linked to potentially superior hemodynamic stability compared to other hypnotic drugs. However, findings regarding the reduction in postoperative delirium incidence with remimazolam and the doses of remimazolam for anesthesia induction and maintenance were inconsistent across the studies. Though remimazolam has demonstrated potential safety, efficacy, and ease-of-use for both anesthesia induction and maintenance in cardiac surgery patients and high-risk cardiovascular patients undergoing non-cardiac surgery, further research is imperative to delve into specific patient subgroups (e.g., the elderly or emergent procedures) so as to ascertain optimal dose ranges to suit diverse clinical scenarios.

Pro-Con Debate: Universal Versus Selective Continuous Monitoring of Postoperative Patients.

In this Pro-Con commentary article, we discuss use of continuous physiologic monitoring for clinical deterioration, specifically respiratory depression in the postoperative population. The Pro position advocates for 24/7 continuous surveillance monitoring of all patients starting in the postanesthesia care unit until discharge from the hospital. The strongest arguments for universal monitoring relate to inadequate assessment and algorithms for patient risk. We argue that the need for hospitalization in and of itself is a sufficient predictor of an individual's risk for unexpected respiratory deterioration. In addition, general care units carry the added risk that even the most severe respiratory events will not be recognized in a timely fashion, largely due to higher patient to nurse staffing ratios and limited intermittent vital signs assessments (e.g., every 4 hours). Continuous monitoring configured properly using a "surveillance model" can adequately detect patients' respiratory deterioration while minimizing alarm fatigue and the costs of the surveillance systems. The Con position advocates for a mixed approach of time-limited continuous pulse oximetry monitoring for all patients receiving opioids, with additional remote pulse oximetry monitoring for patients identified as having a high risk of respiratory depression. Alarm fatigue, clinical resource limitations, and cost are the strongest arguments for selective monitoring, which is a more targeted approach. The proponents of the con position acknowledge that postoperative respiratory monitoring is certainly indicated for all patients, but not all patients need the same level of monitoring. The analysis and discussion of each point of view describes who, when, where, and how continuous monitoring should be implemented. Consideration of various system-level factors are addressed, including clinical resource availability, alarm design, system costs, patient and staff acceptance, risk-assessment algorithms, and respiratory event detection. Literature is reviewed, findings are described, and recommendations for design of monitoring systems and implementation of monitoring are described for the pro and con positions.

Physiologically based modeling reveals different risk of respiratory depression after fentanyl overdose between adults and children.

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose-dependent impact of opioids on respiratory depression in children, the leading cause of opioid-associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age-dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen-related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric-specific factors may need to be considered.

Comparison of nalbuphine and morphine as intrathecal adjuvant to 0.5% bupivacaine for post-operative analgesia in lower abdominal surgeries – A randomized and control study

Background: The use of a higher volume of 0.5% bupivacaine, however, is associated with hemodynamic instability. Adjuvants such as morphine and other opioids are added in with the local anesthetic to reduce this adverse effect and extend the duration of sensory block, hence extending the length of analgesia. However, opiates are associated with a high risk of respiratory depression and other side effects. Nalbuphine has been used to counteract these adverse effects. Thus, we decided to compare the analgesic effect of intrathecal (IT) nalbuphine with IT morphine. Aims and Objectives: The aim of the study was to compare IT morphine with nalbuphine as adjuvant to a spinal anesthetic agent. The primary objective was to compare between the time of onset of sensory and motor blockade and the post-operative analgesic duration between the two adjuvants, while hemodynamic variables and side effects were studied as secondary variables. Materials and Methods: This randomized controlled study was conducted after Ethical Committee approval for a period of 1 year on 100 patients who fulfilled the inclusion criteria. They were randomized into two groups to receive sub-arachnoid block: Group A: 3 mL of 0.5% Hyperbaric Bupivacaine and 0.2 mg morphine and Group B:3 mL of 0.5% Hyperbaric Bupivacaine and 0.5 mg nalbuphine. The following parameters were monitored – Height, Weight, blood pressure, American Society of Anesthesiologists grading, time of onset, maximum duration and regression of Motor and sensory blocks, and total duration of analgesia. Results: The onset of sensory blockade was comparable in both groups while the onset of motor blockade was significantly longer in the morphine group (P≤0.001). The duration of analgesia in the morphine group was longer as compared to nalbuphine group and was statistically significant (P&lt;0.05). The incidence of side effects was 26% in the morphine group and 6% in the nalbuphine group, which was statistically significant (P&lt;0.05). Fourteen patients in the morphine group had pruritus and four patients in the nalbuphine group experienced nausea. Conclusion: IT nalbuphine with 0.5% bupivacaine produces rapid onset of anesthesia and early post-operative analgesia with minimal side effects, but the total analgesic duration was more with IT morphine.

Hyperlipidemia Increases Nalbuphine Brain Accumulation with Multiple Dosing without Affecting Its Analgesic Response-Its Respiratory Depression Potential Should Be Investigated in Future Studies.

Nalbuphine is associated with a significant risk of respiratory depression. Its central nervous system entry is hindered by P-glycoproteins, and lower P-glycoprotein activity is a risk factor for respiratory depression. We assessed the effect of hyperlipidemia on nalbuphine pharmacokinetics, brain and liver uptake, and analgesic response following single (2.5 mg/kg) and multiple (2.5 mg/kg/day for three days) doses in normolipidemic and hyperlipidemic rats. Trends of reduction and increase in nalbuphine Cmax and Vdss/F were observed, respectively, in hyperlipidemic rats. Negative correlations were observed between Cmax and serum lipoproteins. Serum-normalized brain and liver levels at 1 h post-dose were lower in hyperlipidemic rats, with brain and liver levels being negatively and positively correlated with TG and HDL, respectively. At steady state, marked nalbuphine accumulation was observed in hyperlipidemic rat brains (R = 1.6) compared with normolipidemic rats (R = 1.1). Nalbuphine analgesic response was not altered by hyperlipidemia at steady state. Caution should be exercised since greater brain accumulation in hyperlipidemic patients treated with nalbuphine could increase their risk of respiratory depression. Our study highlights an unexpected role of lipoproteins in drug absorption and tissue uptake. We also propose a model for reduced nalbuphine absorption based on interaction with intestinal HDL-3.

Inter-Semispinalis Plane Block Versus General Anesthesia for Postoperative Analgesia in Posterior Cervical Spine Surgery: A Randomized Controlled Trial.

Postoperative pain management is crucial for improving patient outcomes following posterior cervical spine surgery. Opioids are effective but carry a risk of respiratory depression. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used but may not provide adequate pain relief and have potential complications. The inter-semispinalis plane (ISPB) block is a novel technique for postoperative analgesia in cervical spine surgery. This study aims to evaluate and compare the efficacy of the ISPB with general anesthesia in terms of analgesia, postoperative Visual Analog Scale (VAS) pain scores, patient-surgeon satisfaction levels, and the occurrence of postoperative complications. This double-blind, randomized controlled trial was blinded to both the patient and the assessor. Fifty adult patients (18 - 60 years old) undergoing elective posterior cervical spine surgery were enrolled. The participants were divided into 2 groups: The ISPB group (receiving bilateral ultrasound-guided ISPB at the C5 level) and the control group (receiving general anesthesia only), with each group comprising 25 patients. The study assessed intraoperative fentanyl use, postoperative VAS pain levels, the need for rescue analgesia, and complications. The ISPB group showed significantly lower intraoperative fentanyl consumption (median 100 vs. 100 - 150 μg, P = 0.022) and lower postoperative pain scores at 1, 8, 12, and 48 hours (P = 0.016, 0.009, 0.005, 0.016). Additionally, the ISPB group required less postoperative pethidine (20% vs. 64%, P = 0.002) and had a longer delay before requesting pethidine (hazard ratio 0.215, P = 0.001). Surgeon satisfaction was significantly higher in the ISPB group (P = 0.003). These results suggest that the ISPB can effectively reduce pain and analgesic requirements. The ISPB is an effective analgesic technique for posterior cervical spine surgery, reducing opioid consumption, providing better pain control, and enhancing surgeon satisfaction without increasing complications. This approach has the potential to improve postoperative care and patient outcomes in this surgical population.

Risk Factors for Respiratory Depression Associated with Tramadol Based on the Global Pharmacovigilance Database (VigiBase).

Tramadol, a weak μ-opioid receptor agonist, has been used worldwide for pain management. It is considered to have a favorable safety profile without serious adverse events; however, safety issues of respiratory depression were proposed by regulatory governments. We aimed to examine the risk and contributing factors associated with tramadol-related respiratory depression using a real-world database, VigiBase. Disproportionality analysis of tramadol and tramadol/paracetamol was performed using proportional reporting ratios, reporting odds ratios, and information components for all drugs and opioids. Factors related to respiratory depression, including sex, age, presence of abuse, death, and various concomitant medications, were evaluated. Among 140,721 tramadol reports, respiratory depression was reported in 1126 cases, 81.3% of which were deemed serious. Five adverse events were detected as signals of tramadol-related acute central respiratory depression (ACRD) in 882 reports. A higher proportion of ACRD cases in children and adolescents was observed than all adverse events cases of tramadol. Concomitant users of CYP2D6 inhibitors, opioids, benzodiazepines, and anti-depressant drugs showed a higher proportion in ACRD cases than non-ACRD cases. ACRD was related to drug abuse and death. This pharmacovigilance study, using VigiBase, confirmed a high risk of respiratory depression (a serious, potentially fatal adverse event) secondary to the use of tramadol, especially in pediatric patients, drug abusers, or during concomitant use of opioids, benzodiazepines, or antidepressants.

Opioid-Associated Emergencies: A Review of Their Management and the Utility of Naloxone.

Although pain is most effectively treated through a multimodal approach, opioids remain a mainstay of treatment for chronic pain despite their considerable adverse effect profile and associated risks. Through modulation of the μ-opioid receptors, opioids can cause respiratory depression, which may result in death if not treated. When used in conjunction with other sedative substances, the risk of respiratory depression is potentiated. If an opioid emergency is suspected, responders should activate the emergency response system as outlined by the American Heart Association. Prompt and appropriate naloxone administration is vital to appropriate emergency care. As a preventative measure, naloxone should be recommended to individuals who are at higher risk of an opioid overdose. Naloxone is available at most pharmacies, can be billed through an individual's insurance, and is now available over the counter without a prescription.

Brain PET imaging using 11C-flumazenil and 11C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

Among opioids, buprenorphine presents a favorable safety profile with a limited risk of respiratory depression. However, fatalities have been reported when buprenorphine is combined to a benzodiazepine. Potentiation of buprenorphine interaction with opioid receptors (ORs) with benzodiazepines, and/or vice versa, is hypothesized to explain this drug-drug interaction (DDI). The mutual DDI between buprenorphine and benzodiazepines was investigated at the neuroreceptor level in nonhuman primates (n = 4 individuals) using brain PET imaging and kinetic modelling. The binding potential (BPND) of benzodiazepine receptor (BzR) was assessed using 11C-flumazenil PET imaging before and after administration of buprenorphine (0.2 mg, i.v.). Moreover, the brain kinetics and receptor binding of buprenorphine were investigated in the same individuals using 11C-buprenorphine PET imaging before and after administration of diazepam (10 mg, i.v.). Outcome parameters were compared using a two-way ANOVA. Buprenorphine did not impact the plasma nor brain kinetics of 11C-flumazenil. 11C-flumazenil BPND was unchanged following buprenorphine exposure, in any brain region (p > 0.05). Similarly, diazepam did not impact the plasma or brain kinetics of 11C-buprenorphine. 11C-buprenorphine volume of distribution (VT) was unchanged following diazepam exposure, in any brain region (p > 0.05). To conclude, our PET imaging findings do not support a neuropharmacokinetic or neuroreceptor-related mechanism of the buprenorphine/benzodiazepine interaction.

Initiation and rapid titration of methadone and slow-release oral morphine (SROM) in an acute care, inpatient setting: a case series

BackgroundMethadone titration in an outpatient setting typically involves initiation with subtherapeutic doses with slow titration to mitigate the risks of respiratory depression and overdose. In pregnancy, and generally, subtherapeutic doses of methadone and slow titrations are associated with poorer outcomes in terms of treatment retention and ongoing illicit opioid use. We aim to describe rapid titration of OAT in an inpatient setting for pregnant injection opioid users with high opioid tolerance secondary to a fentanyl-based illicit drug supply.MethodsRetrospective case series of patients admitted to a tertiary center with a primary indication of opioid withdrawal and treatment for severe opioid use disorder in pregnancy. ResultsTwelve women received rapid methadone titrations with or without slow-release oral morphine for opioid use disorder during a total of fifteen hospital admissions. All women included in the study were active fentanyl users (12/12). Methadone dosing was increased rapidly with no adverse events with a median dose at day 7 of 65 mg (IQR 60–70 mg) and median discharge dose of 85 mg (IQR 70–92.5 mg) during their admission for titration. Slow-release oral morphine was used in half of the titration admissions (8/15) with a median dose of 340 mg (IQR 187.5–425 mg) at discharge. The median length of admission was 12 days (IQR 9.5–15).ConclusionsA rapid titration of methadone was completed in an inpatient setting with or without slow-release oral morphine, without adverse events showing feasibility of this protocol for a pregnant population in an inpatient setting. Patients achieved therapeutic doses of methadone (and/or SROM) faster than outpatient counterparts with no known adverse events.

Safety and Efficacy of Oral Nalbuphine on Postoperative Pain in Hemorrhoidectomy Patients: A Randomized, Double-blind, Placebo-controlled, Pivotal Trial.

Severe postoperative pain requiring opioid treatment has been reported in 20-40% of hemorrhoidectomy patients. Compared to morphine, nalbuphine offers better hemodynamic stability, a lower risk of respiratory depression, and a lower potential for addiction. Nalbuphine was developed from intravenous form into an oral form (PHN131) to alleviate moderate-to-severe pain. A randomized, double-blind, placebo-controlled, multiple-dose, parallel-design trial was conducted to evaluate the safety and efficacy of PHN131 in patients undergoing hemorrhoidectomy. Eligible patients were randomly assigned to receive either PHN131 soft capsules containing nalbuphine hydrochloride 60mg or placebo capsules. Intramuscular diclofenac was the rescue analgesic. Pain was measured by the area under the curve of mean Visual Analog Scale (VAS) pain intensity scores. VAS results in patients receiving PHN131 were significantly lower than placebo group scores through 48 hours postoperatively (149.2±75.52 vs. 179.6±65.97; P=0.0301). According to Brief Pain Inventory Short Form scores, the impact of pain on quality of life was significantly smaller for the PHN131 group than for the placebo group. Time to the first use of diclofenac postoperatively was significantly longer in the PHN131 group than in the placebo group. The cumulative dosage of diclofenac in the PHN131 group was only around half of that in the placebo group (P<0.0001). Drug-related adverse events were mild-to-moderate and resolved by treatment end. No drug-related severe adverse events were observed. Our findings demonstrate that PHN131 is effective and well-tolerated in the treatment of moderate-to-severe pain and may provide another option for patients to control their pain.

Comparison of Remimazolam–Flumazenil versus Propofol for Recovery from General Anesthesia: A Systematic Review and Meta-Analysis

(1) Purpose: to systematically evaluate the recovery following sedation and anesthesia with remimazolam combined with flumazenil in comparison to propofol. (2) Methods: Electronic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, were systematically searched from their inception up to 22 October 2023. Included in this analysis were randomized controlled trials (RCT) that compared remimazolam–flumazenil with propofol for the recovery from sedation and anesthesia in adults. The risk of bias was assessed using the Cochrane risk of bias tool. Pooled risk ratios (RR) or mean differences (MD) along with their corresponding 95% confidence intervals (CI) were calculated using either fixed-effects or random-effects models, and the results were visualized in forest plots. (3) Results: Nine RCTs involving 745 patients who underwent general anesthesia in three different countries were included. Compared to propofol, the remimazolam–flumazenil combination shortened the emergence time (MD = −4.34 min, 95% CI = [−6.88, −1.81], p = 0.0008, low certainty), extubation time (MD = −4.26 min, 95% CI = [−6.81, −1.7], p = 0.0011, low certainty), and the post-anesthesia care unit (PACU) stay (MD = −4.42 min, 95% CI = [−7.45, −1.38], p = 0.0044, low certainty), while reducing the incidence of respiratory depression (RR = 0.2, 95% CI = [0.04, 0.89], p = 0.03, high certainty) after general anesthesia. However, this combination was associated with a higher incidence of re-sedation (RR = 4.15, 95% CI = [1.31, 13.13], p = 0.01, moderate certainty). (4) Conclusions: Based on the existing evidence, the combination of remimazolam and flumazenil accelerates recovery from general anesthesia and lowers the risk of respiratory depression compared to propofol. However, it is important to consider the higher risk of re-sedation when using this combination in clinical practice. Due to limitations in the quality of the evidence, it is advisable to interpret the results of meta-analyses with caution.

Should Buprenorphine Be Considered a First-Line Opioid for the Treatment of Moderate to Severe Cancer Pain?

Cancer pain remains a significant problem worldwide, affecting more than half of patients receiving anti-cancer treatment and most patients with advanced disease. Opioids remain the cornerstone of therapy, and morphine, given its availability, multiple formulations, price, and evidence base, is typically considered the first-line treatment for moderate to severe cancer pain. Buprenorphine has emerged in recent decades as an alternative opioid for treating chronic pain and substance use disorder (SUD). However, it remains controversial whether buprenorphine should be considered a first-line opioid for moderate to severe cancer pain. In this "Controversies in Palliative Care" article, three expert clinicians independently answer this question. Specifically, each group provides a synopsis of the key studies that inform their thought process, share practical advice on their clinical approach, and highlight the opportunities for future research. All three groups agree that there is a place for the use of buprenorphine as a first-line opioid in cancer pain. Specifically, they mention populations of elderly patients, patients with renal failure, and those with (SUD). They also underscore many unique and favorable characteristics of buprenorphine, such as the low risk for respiratory depression, lack of adverse effects on testosterone levels in men, no risk of serotonin syndrome when combined with antidepressants, and ease of use given its transdermal, transmucosal, and sublingual formulations. However, further studies are needed to guide the use of buprenorphine for cancer pain-primarily randomized clinical trials (RCTs) comparing buprenorphine with other opioids in various pain syndromes.