Respiratory Effects of Biased Ligand Oliceridine in Older Volunteers: A Pharmacokinetic-Pharmacodynamic Comparison with Morphine.

BACKGROUND: Oliceridine is a G protein-biased µ-opioid, a drug class that is associated with less respiratory depression than nonbiased opioids, such as morphine. The authors quantified the respiratory effects of oliceridine and morphine in elderly volunteers. The authors hypothesized that these opioids differ in their pharmacodynamic behavior, measured as effect on ventilation at an extrapolated end-tidal Pco2 at 55 mmHg, V̇E55. METHODS: This four-arm double-blind, randomized, crossover study examined the respiratory effects of intravenous 0.5 or 2 mg oliceridine and 2 or 8 mg morphine in 18 healthy male and female volunteers, aged 55 to 89 yr, on four separate occasions. Participants' CYP2D6 genotypes were determined, hypercapnic ventilatory responses were obtained, and arterial blood samples were collected before and for 6 h after treatment. A population pharmacokinetic-pharmacodynamic analysis was performed on V̇E55, the primary endpoint; values reported are median ± standard error of the estimate. RESULTS: Oliceridine at low dose was devoid of significant respiratory effects. High-dose oliceridine and both morphine doses caused a rapid onset of respiratory depression with peak effects occurring at 0.5 to 1 h after opioid dosing. After peak effect, compared with morphine, respiratory depression induced by oliceridine returned faster to baseline. The effect-site concentrations causing a 50% depression of V̇E55 were 29.9 ± 3.5 ng/ml (oliceridine) and 21.5 ± 4.6 ng/ml (morphine), the blood effect-site equilibration half-lives differed by a factor of 5: oliceridine 44.3 ± 6.1 min and morphine 214 ± 27 min. Three poor CYP2D6 oliceridine metabolizers exhibited a significant difference in oliceridine clearance by about 50%, causing higher oliceridine plasma concentrations after both low- and high-dose oliceridine, compared with the other participants. CONCLUSIONS: Oliceridine and morphine differ in their respiratory pharmacodynamics with a more rapid onset and offset of respiratory depression for oliceridine and a smaller magnitude of respiratory depression over time.

Neurostructural Differences in Adolescents With Treatment-Resistant Depression and Treatment Effects of Transcranial Magnetic Stimulation.

BACKGROUND: Despite its morbidity and mortality, the neurobiology of treatment-resistant depression (TRD) in adolescents and the impact of treatment on this neurobiology is poorly understood. METHODS: Using automatic segmentation in FreeSurfer, we examined brain magnetic resonance imaging baseline volumetric differences among healthy adolescents (n = 30), adolescents with major depressive disorder (MDD) (n = 19), and adolescents with TRD (n = 34) based on objective antidepressant treatment rating criteria. A pooled subsample of adolescents with TRD were treated with 6 weeks of active (n = 18) or sham (n = 7) 10-Hz transcranial magnetic stimulation (TMS) applied to the left dorsolateral prefrontal cortex. Ten of the adolescents treated with active TMS were part of an open-label trial. The other adolescents treated with active (n = 8) or sham (n = 7) were participants from a randomized controlled trial. RESULTS: Adolescents with TRD and adolescents with MDD had decreased total amygdala (TRD and MDD: -5%, P = .032) and caudal anterior cingulate cortex volumes (TRD: -3%, P = .030; MDD: -.03%, P = .041) compared with healthy adolescents. Six weeks of active TMS increased total amygdala volumes (+4%, P < .001) and the volume of the stimulated left dorsolateral prefrontal cortex (+.4%, P = .026) in adolescents with TRD. CONCLUSIONS: Amygdala volumes were reduced in this sample of adolescents with MDD and TRD. TMS may normalize this volumetric finding, raising the possibility that TMS has neurostructural frontolimbic effects in adolescents with TRD. TMS also appears to have positive effects proximal to the site of stimulation.

Benefit and Risk Evaluation of Biased µ-Receptor Agonist Oliceridine versus Morphine.

BACKGROUND: To improve understanding of the respiratory behavior of oliceridine, a µ-opioid receptor agonist that selectively engages the G-protein-coupled signaling pathway with reduced activation of the ß-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. METHODS: Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic-pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) - P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. RESULTS: The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. CONCLUSIONS: These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range.

APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the µ-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty.

OBJECTIVES: The clinical utility of conventional IV opioids is limited by the occurrence of opioid-related adverse events. Oliceridine is a novel G protein-biased µ-opioid receptor agonist designed to provide analgesia with an improved safety and tolerability profile. This phase III, double-blind, randomized trial (APOLLO-2 [NCT02820324]) evaluated the efficacy and safety of oliceridine for acute pain following abdominoplasty. METHODS: Patients received a loading dose of either placebo, oliceridine (1.5 mg), or morphine (4 mg), followed by demand doses via patient-controlled analgesia (0.1, 0.35, or 0.5 mg oliceridine; 1 mg morphine; or placebo) with a 6-minute lockout interval. The primary endpoint was the proportion of treatment responders over 24 hours for oliceridine regimens compared to placebo. Secondary outcomes included a predefined composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs. morphine. RESULTS: A total of 401 patients were treated with study medication. Effective analgesia was observed for all oliceridine regimens, with responder rates of 61.0%, 76.3%, and 70.0% for the 0.1-, 0.35-, and 0.5-mg regimens, respectively, compared with 45.7% for placebo (all P < 0.05) and 78.3% for morphine. Oliceridine 0.35- and 0.5-mg demand dose regimens were equi-analgesic to morphine using a noninferiority analysis. RSB showed a dose-dependent increase across oliceridine regimens (mean hours [standard deviation], 0.1 mg: 0.43 [1.56]; 0.35 mg: 1.48 [3.83]; 0.5 mg: 1.59 [4.26]; all comparisons not significant at P > 0.05 vs. placebo: 0.60 [2.82]). The RSB measure for morphine was 1.72 (3.86) (P < 0.05 vs. placebo). Gastrointestinal adverse events increased in a dose-dependent manner across oliceridine demand dose regimens (0.1 mg: 49.4%; 0.35 mg: 65.8%; 0.5 mg: 78.8%; vs. placebo: 47.0%; and morphine: 79.3%). In comparison to morphine, the proportion of patients experiencing nausea or vomiting was lower with the 2 equi-analgesic dose regimens of 0.35 and 0.5 mg oliceridine. CONCLUSIONS: Oliceridine is a safe and effective IV analgesic for the relief of moderate to severe acute postoperative pain in patients undergoing abdominoplasty. Since the low-dose regimen of 0.1 mg oliceridine was superior to placebo but not as effective as the morphine regimen, safety comparisons to morphine are relevant only to the 2 equi-analgesic dose groups of 0.35 and 0.5 mg, which showed a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects compared to morphine. These findings support that oliceridine may provide a new treatment option for patients with moderate to severe acute pain where an IV opioid is warranted.

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of quality of life outcome measures in clinical practice.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective and safe therapy for major depressive disorder (MDD). This study assessed quality of life (QOL) and functional status outcomes for depressed patients after an acute course of TMS. METHODS: Forty-two, U.S.-based, clinical TMS practice sites treated 307 outpatients with a primary diagnosis of MDD and persistent symptoms despite prior adequate antidepressant pharmacotherapy. Treatment parameters were based on individual clinical considerations and followed the labeled procedures for use of the approved TMS device. Patient self-reported QOL outcomes included change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the EuroQol 5-Dimensions (EQ-5D) ratings from baseline to end of the acute treatment phase. RESULTS: Statistically significant improvement in functional status on a broad range of mental health and physical health domains was observed on the SF-36 following acute TMS treatment. Similarly, statistically significant improvement in patient-reported QOL was observed on all domains of the EQ-5D and on the General Health Perception and Health Index scores. Improvement on these measures was observed across the entire range of baseline depression symptom severity. CONCLUSION: These data confirm that TMS is effective in the acute treatment of MDD in routine clinical practice settings. This symptom benefit is accompanied by statistically and clinically meaningful improvements in patient-reported QOL and functional status outcomes.

Linking disease symptoms and subtypes with personalized systems-based phenotypes: a proof of concept study.

A dynamic systems model was used to generate parameters describing a phenotype of Hypothalamic-Pituitary-Adrenal (HPA) behavior in a sample of 36 patients with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) and 36 case-matched healthy controls. Altered neuroendocrine function, particularly in relation to somatic symptoms and poor sleep quality, may contribute to the pathophysiology of these disorders. Blood plasma was assayed for cortisol and ACTH every 10 min for 24h. The dynamic model was specified with an ordinary differential equation using three parameters: (1) ACTH-adrenal signaling, (2) inhibitory feedback, and (3) non-ACTH influences. The model was "personalized" by estimating an individualized set of parameters from each participant's data. Day and nighttime parameters were assessed separately. Two nocturnal parameters (ACTH-adrenal signaling and inhibitory feedback) significantly differentiated the two patient subgroups ("fatigue-predominant" patients with CFS only versus "pain-predominant" patients with FM and comorbid chronic fatigue) from controls (all p's<.05), whereas daytime parameters and diurnal/nocturnal slopes did not. The same nocturnal parameters were significantly associated with somatic symptoms among patients (p's<.05). There was a significantly different pattern of association between nocturnal non-ACTH influences and sleep quality among patients versus controls (p<.05). Although speculative, the finding that patient somatic symptoms decreased when more cortisol was produced per unit ACTH, is consistent with cortisol's anti-inflammatory and sleep-modulatory effects. Patients' HPA systems may compensate by promoting more rapid or sustained cortisol production. Mapping "behavioral phenotypes" of stress-arousal systems onto symptom clusters may help disentangle the pathophysiology of complex disorders with frequent comorbidity.

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.

BACKGROUND: Few studies have examined the effectiveness of transcranial magnetic stimulation (TMS) in real-world clinical practice settings. METHODS: Forty-two US-based clinical TMS practice sites treated 307 outpatients with Major Depressive Disorder (MDD), and persistent symptoms despite antidepressant pharmacotherapy. Treatment was based on the labeled procedures of the approved TMS device. Assessments were performed at baseline, week 2, at the point of maximal acute benefit, and at week 6 when the acute course extended beyond 6 weeks. The primary outcome was change in the Clinician Global Impressions-Severity of Illness from baseline to end of acute phase. Secondary outcomes were change in continuous and categorical outcomes on self-report depression scales (9-Item Patient Health Questionnaire [PHQ-9], and Inventory of Depressive Symptoms-Self Report [IDS-SR]). RESULTS: Patients had a mean ± SD age of 48.6 ± 14.2 years and 66.8% were female. Patients received an average of 2.5 (± 2.4) antidepressant treatments of adequate dose and duration without satisfactory improvement in this episode. There was a significant change in CGI-S from baseline to end of treatment (-1.9 ± 1.4, P < .0001). Clinician-assessed response rate (CGI-S) was 58.0% and remission rate was 37.1%. Patient-reported response rate ranged from 56.4 to 41.5% and remission rate ranged from 28.7 to 26.5%, (PHQ-9 and IDS-SR, respectively). CONCLUSION: Outcomes demonstrated response and adherence rates similar to research populations. These data indicate that TMS is an effective treatment for those unable to benefit from initial antidepressant medication.

Budget impact and pharmacy costs with targeted use of oliceridine for postsurgical pain in patients at high risk of opioid-related adverse events.

BACKGROUND: Oliceridine, a new class of µ-opioid receptor agonist, may be associated with fewer opioid-related adverse events (ORAEs) due to its unique mechanism of action. Thus, it may provide a cost-effective alternative to conventional opioids such as morphine. PATIENTS AND METHODS: Using a decision tree with a 24-hour time horizon, we calculated costs for medication and management of the three most common AEs (oxygen saturation <90%, vomiting, somnolence) following postoperative oliceridine or morphine in high-risk patients. Costs were enumerated as differences in cost of analgesics and resource utilization in the first 24 hours post-surgery. An economic model compared expected AEs and costs in a blended cohort where elderly/obese patients at higher risk for ORAEs received oliceridine while those presumed to be at lower risk received morphine with a cohort that received morphine alone. RESULTS: In high-risk patients, use of oliceridine resulted in overall savings of $363,944 (in 1,000 patients). Implementing a targeted approach of oliceridine utilization in patients with high risk for ORAEs can save a typical hospital system $122,296 in total cost of care. CONCLUSION: Use of oliceridine in postoperative care among patients at high risk provides a favorable health economic benefit compared to the use of morphine.

Oliceridine, a new class of opioid analgesics, administered directly into a vein, is a unique medication in that it provides pain relief equivalent to morphine and may have less costly side effects. It is given in a hospital/clinic or surgery center for the treatment of postoperative pain and can reduce costs compared to other opioid analgesics, possibly due to less side effects. An economic model was developed that compares morphine to oliceridine in patients more likely to experience sides effects due to traditional pain medications, comparing common side effects and pain relief following surgery. Although oliceridine costs more than morphine, in our economic model, the use of oliceridine resulted in cost savings ($363,944 US 2020 Dollars in 1,000 patients), and a positive return of investment of over 7 times, when compared to morphine.

Cost-effectiveness and cost-benefit analysis of oliceridine in the treatment of acute pain.

Aim: Oliceridine, a new class of µ-opioid receptor agonist, is selective for G-protein signaling (analgesia) with limited recruitment of ß-arrestin (associated with adverse outcomes) and may provide a cost-effective alternative versus conventional opioid morphine for postoperative pain. Patients & methods: Using a decision tree with a 24-h time horizon, we calculated costs for medication and management of three most common adverse events (AEs; oxygen saturation <90%, vomiting and somnolence) following postoperative oliceridine or morphine use. Results: Using oliceridine, the cost for managing AEs was US$528,424 versus $852,429 for morphine, with a net cost savings of $324,005. Conclusion: Oliceridine has a favorable overall impact on the total cost of postoperative care compared with the use of the conventional opioid morphine.

Lay abstract Oliceridine, a new class of opioid pain medication, given in a vein, is a unique medication in that it provides pain relief comparable to morphine and may have less costly side effects. It is given in a hospital or surgery center for the treatment of postoperative pain and can save money compared with other opioid pain medicines due to fewer side effects. An economic model was developed to compare morphine to oliceridine for common side effects and pain relief following surgery. Oliceridine use resulted in a cost saving (US$324,005; 2020 US dollars) when compared with morphine.

Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials.

INTRODUCTION: In the management of postoperative acute moderate-to-severe pain, opioids remain an important component. However, conventional opioids have a narrow therapeutic index and are associated with dose-limiting opioid-related adverse events (ORAEs) that can result in worse patient outcomes. Oliceridine, a new intravenous µ-opioid receptor agonist, is shown in nonclinical studies to be biased for G protein signaling (achieving analgesia) with limited recruitment of ß-arrestin (associated with ORAEs). In two phase 3 randomized controlled studies of patients with moderate-to-severe acute pain following hard or soft tissue surgery, in which analgesia was measured using Sum of Pain Intensity Differences (SPID) from baseline over 48 and 24 h (SPID-48 and -24 respectively, oliceridine at demand doses of 0.1, 0.35, or 0.5 mg was highly effective compared to placebo, with a favorable safety profile compared to morphine. This exploratory analysis was conducted to determine whether the safety benefits seen with oliceridine persisted when adjusted for equal levels of analgesia compared to morphine. METHODS: Presence of at least one treatment-emergent ORAE (based on Medical Dictionary for Regulatory Activities [MedDRA]-coded events: hypoxemia, nausea, vomiting, sedation, pruritus, or dizziness) was used as the composite safety endpoint. A logistic regression model was utilized to compare oliceridine (pooled regimens) versus morphine, after controlling for analgesia (using SPID-48 or SPID-24 with pre-rescue scores carried forward 6 h). This analysis excluded patients receiving placebo and was repeated for each study and for pooled data. RESULTS: At a given level of SPID-48 or SPID-24, patients receiving oliceridine were less likely to experience the composite safety endpoint. Although not statistically significant at the 0.05 level in the soft tissue model, the odds ratio (OR) showed a consistent numerical trend for oliceridine, being approximately half that observed with morphine in both the hard (OR 0.499; 95% confidence interval [CI] 0.255, 0.976; p = 0.042) and soft (OR 0.542; 95% CI 0.250, 1.175; p = 0.121) tissue studies. Results from the pooled data were consistent with those observed in the individual studies (OR 0.507; 95% CI 0.304, 0.844; p = 0.009). CONCLUSION: Findings from this exploratory analysis suggest that at comparable levels of analgesia, patients receiving oliceridine were less likely to experience the composite safety endpoint consisting of ORAEs compared to patients treated with morphine. Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials- A Video (MP4 99188 kb).

Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk.

BACKGROUND: Oliceridine is a biased ligand at the µ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. OBJECTIVE: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. METHODS: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. RESULTS: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 µM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. CONCLUSION: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.

Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial.

Treatment-resistant depression (TRD) is prevalent and associated with a substantial psychosocial burden and mortality. There are few prior studies of interventions for TRD in adolescents. This was the largest study to date examining the feasibility, safety, and efficacy of 10-Hz transcranial magnetic stimulation (TMS) for adolescents with TRD. Adolescents with TRD (aged 12-21 years) were enrolled in a randomized, sham-controlled trial of TMS across 13 sites. Treatment resistance was defined as an antidepressant treatment record level of 1 to 4 in a current episode of depression. Intention-to-treat patients (n = 103) included those randomly assigned to active NeuroStar TMS monotherapy (n = 48) or sham TMS (n = 55) for 30 daily treatments over 6 weeks. The primary outcome measure was change in the Hamilton Depression Rating Scale (HAM-D-24) score. After 6 weeks of blinded treatment, improvement in the least-squares mean (SE) HAM-D-24 scores were similar between the active (-11.1 [2.03]) and sham groups (-10.6 [2.00]; P = 0.8; difference [95% CI], - 0.5 [-4.2 to 3.3]). Response rates were 41.7% in the active group and 36.4% in the sham group (P = 0.6). Remission rates were 29.2% in the active group and 29.0% in the sham group (P = 0.95). There were no new tolerability or safety signals in adolescents. Although TMS treatment produced a clinically meaningful change in depressive symptom severity, this did not differ from sham treatment. Future studies should focus on strategies to reduce the placebo response and examine the optimal dosing of TMS for adolescents with TRD.

Low Incidence of Opioid-Induced Respiratory Depression Observed with Oliceridine Regardless of Age or Body Mass Index: Exploratory Analysis from a Phase 3 Open-Label Trial in Postsurgical Pain.

INTRODUCTION: Advanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m2) patients and analyzed risk factors of OIRD. METHODS: Patients aged ≥ 18 years with a score ≥ 4 on an 11-point numeric pain rating scale (NPRS) received IV oliceridine as needed via bolus dosing and/or patient-controlled analgesia (PCA). OIRD occurring within 48 h of last dose of oliceridine was defined using two established definitions: (1) naloxone use, (2) respiratory rate < 10 breaths per minute and/or oxygen saturation < 90%. RESULTS: A total of 724 surgical patients with a mean age of 54.5 ± 15.9 years and a mean NRS score of 6.2 ± 2.1 were included in this analysis; 33.3% (241/724) were ≥ 65 years of age and 46.3% (335/724) had BMI (body mass index) ≥ 30 kg/m2. The overall OIRD incidence was 13.7% with no patients requiring naloxone. The OIRD incidence was similar in the elderly and younger adults' cohorts [10.8 vs. 15.1%, OR 0.68 (0.42, 1.1), p = 0.11], and in obese and non-obese groups [14.0 vs. 13.4%, OR 1.06 (0.69, 1.62), p = 0.80]. In patients that were both elderly and obese (n = 120), the incidence was 10.8%. The multivariate analysis identified baseline NRS ≥ 6 [OR 1.6 (1.0, 2.4), p = 0.0499], PCA administration [OR 1.9 (1.2, 3.1), p = 0.005], and concomitant use of benzodiazepines and/or gabapentinoids [OR 1.6 (1.0, 2.6), p = 0.045], as being associated with OIRD. CONCLUSIONS: Postoperative oliceridine use in patients with advanced age and/or increased BMI was not associated with increased risk of OIRD.

Oliceridine is Associated with Reduced Risk of Vomiting and Need for Rescue Antiemetics Compared to Morphine: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials.

INTRODUCTION: Use of parenteral opioids is a major risk factor for postoperative nausea and vomiting. Conventional opioids bind to µ-opioid receptors (MOR), stimulate both the G-protein signaling (achieving analgesia); and the ß-arrestin pathway (associated with opioid-related adverse effects). Oliceridine, a next-generation IV opioid, is a G-protein selective MOR agonist, with limited recruitment of ß-arrestin. In two randomized, placebo- and morphine-controlled phase 3 studies of patients with moderate-to-severe acute pain following bunionectomy or abdominoplasty, oliceridine at demand doses of 0.1, 0.35, and 0.5 mg provided rapid and sustained analgesia vs. placebo with favorable gastrointestinal (GI) tolerability. In this exploratory analysis, we utilized a clinical endpoint assessing gastrointestinal tolerability, "complete GI response" defined as the proportion of patients with no vomiting and no use of rescue antiemetic to characterize the GI tolerability profile of oliceridine vs. morphine. METHODS: A logistic regression model was utilized to compare oliceridine (pooled regimens) vs. morphine, after controlling for analgesia (using the sum of pain intensity difference [SPID]-48/24 [bunionectomy/abdominoplasty] with pre-rescue scores carried forward for 6 h). This analysis excluded patients receiving placebo and was performed for each study separately and for pooled data from both studies. RESULTS: In the unadjusted analysis, a significantly greater proportion of patients in the placebo (76.4%), oliceridine 0.1 mg (68.0%), and 0.35 mg (46.2%) demand dose achieved complete GI response vs. morphine 1 mg (30.8%), p ≤ 0.005. In the adjusted analysis, after controlling for analgesia, the odds ratio of experiencing a complete GI response with oliceridine (pooled regimens) vs. morphine was 3.14 (95% CI: 1.78, 5.56; p < 0.0001) in bunionectomy study and 1.92 (95% CI: 1.09, 3.36; p = 0.024) in abdominoplasty study. CONCLUSIONS: When controlled for the analgesic effects (constant SPID-48/24), the odds ratio for complete GI response was higher with oliceridine than morphine, suggesting better GI tolerability with oliceridine.

Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

BACKGROUND AND OBJECTIVE: Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective µ-agonist with limited activity on ß-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. METHODS: Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. RESULTS: Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.

A Phase I, Randomized, Single­Blind, Placebo­Controlled, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of Subcutaneous and Oral TRV250, a G Protein-Selective Delta Receptor Agonist, in Healthy Subjects.

BACKGROUND: The delta opioid receptor (DOR) has been identified as a therapeutic target for migraine, with DOR agonists exhibiting low abuse potential compared with conventional µ-opioid agonists. TRV250 is a novel small molecule agonist of the DOR that is preferentially selective for G-protein signaling, with relatively little activation of the ß-arrestin2 post-receptor signaling pathway. This selectivity provides reduced susceptibility to proconvulsant activity seen with non-selective DOR agonists. TRV250 significantly reduced nitroglycerin-evoked hyperalgesia in rodents, indicating a potential utility in acute migraine without the risk of seizure activity or abuse potential. OBJECTIVE: This trial evaluated the safety, tolerability, and pharmacokinetics of ascending dose levels of TRV250 administered subcutaneously (SC) and the relative bioavailability of TRV250 administered orally compared with SC administration. METHODS: This was a two-part, single ascending dose study. Part A included four cohorts of healthy adults (N = 38). Each cohort was dosed on three occasions (placebo and two different dose levels of TRV250, allocated in randomized order and administered by SC route). In Part B, a single cohort of nine subjects received an oral dose of either TRV250 (n = 7) or placebo (n = 2) in a fed or fasted state. Serial blood samples were obtained for pharmacokinetic determination across a 24-h post-dose period. Safety assessments included clinical laboratory measures, vital signs, 12-lead electrocardiogram (ECG), and electroencephalogram (EEG) pre- and post-dosing. RESULTS: TRV250 was well tolerated. There were no serious adverse events (SAEs), and all AEs were mild in severity. Injection-site reactions and headache were the most common AEs. One subject was withdrawn from the study due to a TRV250-related AE of postural orthostatic tachycardia. There were no clinically relevant changes in physical examination, hematology, clinical chemistry, urinalysis, suicidal ideation, or vital signs, with the exception of orthostatic changes in some subjects. No subject experienced abnormalities in EEGs or experienced a change from baseline in heart-rate-corrected QT interval (QTcF) > 60 ms, or an absolute QTcF interval > 480 ms at any post-dosing observation. Peak and total plasma exposure to TRV250 increased in a dose-proportional manner following 0.1-30 mg SC doses, with the mean half-life ranging from 2.39 to 3.76 h. Oral bioavailability of TRV250 ranged from 14% (fasting) to 19% (fed) relative to SC dosing, while administration with food increased the AUC but decreased the rate of absorption as reflected by a modest delay in median time to maximum concentration and a slight reduction in maximum concentration. CONCLUSION: The findings from the first-in-human study support further evaluation of TRV250, a G-protein selective DOR agonist, in the treatment of acute migraine.

Treatment-Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance.

Objective: To describe the clinical characteristics of adolescents with antidepressant treatment-resistant major depressive disorder (MDD) and to examine the utility of the Antidepressant Treatment Record (ATR) in categorizing treatment resistance in this population. Methods: Adolescents with treatment-resistant MDD enrolled in an interventional study underwent a baseline evaluation with the ATR, Children's Depression Rating Scale-Revised (CDRS-R), and Clinical Global Impressions-Severity (CGI-S) scales. Demographic and clinical characteristics were examined with regard to ATR-defined level of resistance (level 1 to ≥3) using analysis of variance and χ2 tests. Results: In adolescents with treatment-resistant MDD (N = 97), aged 12-21 years, most were female (65%), white (89%), and had recurrent illness (78%). Patients were severely ill (median CGI-S score of 5), had a mean CDRS-R score of 63 ± 10, and 17.5% had been hospitalized for depression-related symptoms. Fifty-two patients were classified as ATR 1, whereas 32 were classified as ATR level 2 and 13 patients as ≥3, respectively. For increasing ATR-defined levels, illness duration increased from 12.0 (range: 1.5-31.9) to 14.8 (range: 1.8-31.7) to 19.5 (range: 2.5-36.2) months and the likelihood of treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs) similarly increased (p = 0.006 for both SNRIs and DNRIs) as did the likelihood of treatment with mixed dopamine serotonin receptor antagonists (χ2 = 17, p < 0.001). Conclusions: This study underscores the morbidity and chronicity of treatment-resistant MDD in adolescents. The present characterization of related clinical features describes the use of nonselective serotonin reuptake inhibitors in adolescents with treatment-resistant depression and raises the possibility that those with the greatest medication treatment resistance are less likely to have had recurrent episodes. The study also demonstrates the utility of the ATR in categorizing treatment resistance in adolescents with MDD.

Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis.

Background: Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the µ-opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of ß-arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolerability profile at equianalgesic doses to morphine. The phase 3, open-label, single-arm, multicenter ATHENA trial demonstrated the safety, tolerability, and effectiveness of oliceridine in moderate to severe acute pain in a broad range of patients undergoing surgery or with painful medical conditions warranting use of an IV opioid. This retrospective, observational chart review study compared respiratory depression events associated with oliceridine administration as found in the ATHENA trial to a control cohort treated with conventional opioids. Methods: Patients at 18 years of age or older, who underwent colorectal, orthopedic, cardiothoracic, bariatric, or general surgeries between June 2015 and May 2017 in 11 sites participating in the ATHENA trial who received postoperative analgesia either with IV oliceridine or with IV conventional opioids (e.g., morphine alone or in combination with other opioids) (CO cohort); and had a hospital stay >48 hours, were included in this retrospective analysis. Data from the ATHENA trial was used for the oliceridine cohort; and additional baseline characteristics were collected from medical charts. Data from medical charts were collected for all CO cohort patients. The two cohorts were balanced using an inverse probability weighting method. The primary outcome was the incidence of operationally defined opioid-induced respiratory depression (OIRD) in the two cohorts. Secondary outcomes included between-group comparison of the incidence of OIRD events among a subset of high-risk patients. Results: OIRD was significantly less in the oliceridine cohort compared to the CO cohort (8.0% vs. 30.7%; odds ratio: 0.139) (95% confidence interval [CI] 0.09-0.22; P < 0.0001). Likewise, the incidence of OIRD was lower among high-risk patients in the oliceridine cohort (9.1% vs. 34.7%; odds ratio: 0.136) (95% CI [0.09-0.22]; P < 0.0001) compared to the CO cohort. Conclusion: In this retrospective chart review study, patients receiving IV oliceridine for moderate to severe acute pain demonstrated a lower incidence of treatment emergent OIRD compared to patients who were treated with IV morphine either alone or with concomitant administration of other opioids.

The assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form (ATHF-SF).

There is considerable diversity in how treatment-resistant depression (TRD) is defined. However, every definition incorporates the concept that patients with TRD have not benefited sufficiently from one or more adequate trials of antidepressant treatment. This review examines the issues fundamental to the systematic evaluation of antidepressant treatment adequacy and resistance. These issues include the domains of interventions deemed effective in treatment of major depressive episodes (e.g., pharmacotherapy, brain stimulation, and psychotherapy), the subgroups of patients for whom distinct adequacy criteria are needed (e.g., bipolar vs. unipolar depression, psychotic vs. nonpsychotic depression), whether trials should be rated dichotomously as adequate or inadequate or on a potency continuum, whether combination and augmentation strategies require specific consideration, and the criteria used to evaluate the adequacy of treatment delivery (e.g., dose, duration), trial adherence, and clinical outcome. This review also presents the Antidepressant Treatment History Form: Short-Form (ATHF-SF), a completely revised version of an earlier instrument, and details how these fundamental issues were addressed in the ATHF-SF.

Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.

BACKGROUND: We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. METHODS: In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. RESULTS: Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. CONCLUSIONS: Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.