Review of Opioid Abuse-Deterrent Formulations: Impact and Barriers to Access.

The misuse and abuse of opioid analgesics continue to pose a serious public health concern, but for some patients, opioids remain an important analgesic option. Extended-release (ER) opioid formulations are effective for treating chronic pain and are supported by multiple 12-week efficacy studies. ER opioids often contain a high opioid content, and similar to immediate-release (IR) formulations, are subject to abuse, misuse, and diversion. Unintentional misuse may also occur when ER formulations are manipulated for medicinal administration, such as crushing a dose for easier oral intake. As part of a multipronged strategy designed to fight the opioid epidemic, abuse-deterrent formulations (ADFs) were developed to deter misuse, abuse, and diversion of opioids by making manipulation more difficult and nonoral routes of administration less rewarding. Although ADF opioids have been shown to decrease rates of abuse and diversion, they are not equally effective in terms of deterring manipulation for abuse or misuse. Xtampza ER utilizes DETERx technology, which allows it to retain ER characteristics when chewed or crushed, making it the only ER opioid without a boxed warning against these types of manipulation. OxyContin was also developed as an ADF but uses RESISTEC technology, making the tablet hard to crush and viscous in aqueous solutions. ADF utilization has been hampered by patient access issues, including high prices due to lack of insurance coverage. Postmarket real-world studies demonstrate lower rates of abuse, misuse, and diversion for ADF ER opioids compared with non-ADF formulations. However, similar studies comparing abuse-related effectiveness and health care costs for ADF opioids are warranted if clinicians are expected to utilize these potentially safer opioid formulations. These studies would support further education surrounding the benefits and utilization of ADFs and manipulation potential of different ADFs.

Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone.

An open-label, randomized, crossover study in healthy volunteers compared the reversal of remifentanil-induced respiratory depression by intranasal (IN) naloxone hydrochloride (4 mg) to IN nalmefene (2.7 mg) (NCT04828005). Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight-fitting mask for an initial period of 46 min prior to a series of mask "holidays" introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time-dependent reversal of remifentanil-induced reductions in MV measured 2.5-20 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L/min) were nearly twice that produced by naloxone (3.01 L/min) (P < .0009); the point estimate favors nalmefene, demonstrating non-inferiority and superiority. In this model of opioid-induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose.

The effects of virtual reality neuroscience-based therapy on clinical and neuroimaging outcomes in patients with chronic back pain: a randomized clinical trial.

ABSTRACT: Chronic pain remains poorly managed. The integration of immersive technologies (ie, virtual reality [VR]) with neuroscience-based principles may provide effective pain treatment by targeting cognitive and affective neural processes that maintain pain and therefore potentially changing neurobiological circuits associated with pain chronification and amplification. We tested the effectiveness of a novel VR neuroscience-based therapy (VRNT) to improve pain-related outcomes in n = 31 participants with chronic back pain, evaluated against usual care (waitlist control; n = 30) in a 2-arm randomized clinical trial (NCT04468074). We also conducted pre-treatment and post-treatment MRI to test whether VRNT affects brain networks previously linked to chronic pain and treatment effects. Compared with the control condition, VRNT led to significantly reduced pain intensity (g = 0.63) and pain interference (g = 0.84) at post-treatment vs pre-treatment, with effects persisting at 2-week follow-up. These improvements were partially mediated by reduced kinesiophobia and pain catastrophizing. Several secondary clinical outcomes were also improved by VRNT, including disability, quality of life, sleep, and fatigue. In addition, VRNT was associated with increases in dorsomedial prefrontal functional connectivity with the superior somatomotor, anterior prefrontal and visual cortices, and decreased white matter fractional anisotropy in the corpus callosum adjacent to the anterior cingulate, relative to the control condition. Thus, VRNT showed preliminary efficacy in significantly reducing pain and improving overall functioning, possibly through changes in somatosensory and prefrontal brain networks.

Three recent court decisions reframe what constitutes criminal conduct in prescribing controlled substances.

Three recent opinions issued by the United States (US) Supreme Court suggest the possibility of a new interpretation of key drug enforcement provisions in the Controlled Substances Act of 19701 (CSA) affecting prescribers of controlled sub-stances. Applying the Court's holdings in Xiulu Ruan v. US,2 Dobbs v. Jackson Women's Health Organization,3 and West Virginia v. Environmental Protection Agency4 to the Department of Justice's and the Drug Enforcement Administration's overreaching enforcement of the CSA, this paper contends that Congress should amend the CSA and rectify the broad misapplication of the law to the practice of medicine.

The Effects of Virtual Reality Neuroscience-based Therapy on Clinical and Neuroimaging Outcomes in Patients with Chronic Back Pain: A Randomized Clinical Trial.

Chronic pain remains poorly managed. The integration of innovative immersive technologies (i.e., virtual reality (VR)) with recent neuroscience-based principles that position the brain as the key organ of chronic pain may provide a more effective pain treatment than traditional behavioral therapies. By targeting cognitive and affective processes that maintain pain and potentially directly changing neurobiological circuits associated with pain chronification and amplification, VR-based pain treatment has the potential for significant and long-lasting pain relief. We tested the effectiveness of a novel VR neuroscience-based therapy (VRNT) to improve pain-related outcomes in n = 31 participants with chronic back pain, evaluated against usual care (n = 30) in a 2-arm randomized clinical trial ( NCT04468074) . We also conducted pre- and post-treatment MRI to test whether VRNT affects brain networks previously linked to chronic pain and treatment effects. Compared to the control condition, VRNT led to significantly reduced pain intensity (g = 0.63) and pain interference (g = 0.84) at post-treatment vs. pre-treatment, with effects persisting at 2-week follow-up. The improvements were partially mediated by reduced kinesiophobia and pain catastrophizing. Several secondary clinical outcomes were also improved, including disability, quality of life, sleep, and fatigue. In addition, VRNT was associated with modest increases in functional connectivity of the somatomotor and default mode networks and decreased white matter fractional anisotropy in the corpus callosum adjacent to anterior cingula, relative to the control condition. This, VRNT showed preliminary efficacy in significantly reducing pain and improving overall functioning, possibly via changes in somatosensory and prefrontal brain networks.

Reductions in All-Cause Mortality Associated with the Use of Methylnaltrexone for Opioid-Induced Bowel Disorders: A Pooled Analysis.

OBJECTIVE: Preclinical and clinical studies suggest that activation of the µ-opioid receptor may reduce overall survival and increase the risk for all-cause mortality in patients with cancer and noncancer pain. Methylnaltrexone, a selective, peripherally acting µ-opioid receptor antagonist, has demonstrated efficacy for the treatment of opioid-induced constipation. This retrospective analysis of 12 randomized, double-blind, placebo-controlled studies of methylnaltrexone evaluated the treatment of opioid-induced bowel disorders in patients with advanced illness or noncancer pain. METHODS: The risk of all-cause mortality within 30 days after the last dose of study medication during the double-blind phase was compared between methylnaltrexone and placebo groups. The data were further stratified by cancer vs noncancer, age, gender, and acute vs chronic diagnoses. RESULTS: Pooled data included 2,526 methylnaltrexone-treated patients of which 33 died, and 1,192 placebo-treated patients of which 35 died. The mortality rate was 17.8 deaths/100 person-years of exposure in the methylnaltrexone group and 49.5 deaths/100 person-years of exposure for the placebo group. The all-cause mortality risk was significantly lower among patients receiving methylnaltrexone compared with placebo (hazard ratio: 0.399, 95% confidence interval: 0.25, 0.64; P = .0002), corresponding to a 60% risk reduction. Significant risk reductions were observed for those receiving methylnaltrexone who had cancer or chronic diagnoses. Methylnaltrexone-treated patients had a significantly reduced mortality risk compared with placebo regardless of age or gender. CONCLUSIONS: Methylnaltrexone reduced all-cause mortality vs placebo treatment across multiple trials, suggesting methylnaltrexone may confer survival benefits in patients with opioid-induced bowel disorders taking opioids for cancer-related or chronic noncancer pain.

Oral, intranasal, and intravenous abuse potential of serdexmethylphenidate, a novel prodrug of d-methylphenidate.

OBJECTIVES: Serdexmethylphenidate (SDX) chloride (Cl) is a novel prodrug of d-methylphenidate (d-MPH). These studies evaluated the abuse potential of SDX Cl when administered orally, intranasally (IN), and intravenously (IV). METHODS: Three randomized, double-blind, placebo- and active-controlled crossover studies were conducted in recreational drug users to evaluate the abuse-related effects of oral SDX (120 and 240 mg) vs. extended-release (ER) d-MPH (80 mg) and phentermine (60 mg); IN SDX (80 mg) vs. d-MPH (40 mg), and IV SDX (30 mg) vs. d-MPH (15 mg). Abuse-related subjective measures, pharmacokinetics, and safety were assessed. RESULTS: The primary endpoint of maximum (Emax) Drug Liking (DL) (0-100-point scale) was significantly higher following d-MPH vs. placebo, validating the studies. In the oral study, DL Emax was significantly higher following 80 mg ER d-MPH (Emax = 81.5) than 120 mg SDX (Emax = 62.8, p < .001) and 240 mg SDX (Emax = 63.8, p = .006); and following 60 mg phentermine (Emax = 80.2) than 120 mg SDX (p = .0195), but not 240 mg SDX (p = .0665). DL Emax scores were significantly higher following IN d-MPH vs SDX (Emax = 93.2 vs. 71.0, p < .0001) and following IV d-MPH vs. SDX (Emax = 84.3 vs. 56.6, p = .001). Intravenous SDX was non-inferior to placebo (p = .001) for DL Emax. Secondary endpoints (e.g. Take Drug Again) were generally consistent with the primary endpoint. Maximal and overall d-MPH exposure was lower for SDX than d-MPH for all routes. Adverse events typical of stimulants were more frequent with d-MPH than SDX. CONCLUSIONS: These findings indicate that the novel d-MPH prodrug, SDX, has lower abuse potential than d-MPH and support its classification as a C-IV controlled substance.

Pharmacokinetics of Buprenorphine Buccal Film and Orally-administered Oxycodone in a Respiratory Study: An Analysis of Secondary Outcomes from a Randomized Controlled Trial.

OBJECTIVE: To evaluate pharmacokinetic (PK) parameters and oxygen saturation as markers of abuse potential after administration of buprenorphine buccal film (BBF) and immediate-release (IR) oxycodone. METHODS: This was a secondary analysis of data from a phase I randomized controlled trial. A total of 19 healthy subjects who self-identified as recreational opioid users were enrolled, with 15 completing the study. Subjects were administered 300, 600, and 900 µg BBF; 30 and 60 mg orally-administered oxycodone; and placebo. For PK analysis, blood samples were collected before dosing and at 0.5, 1, 2, 3, 4, and 6 h postdose. Respiratory drive/ventilatory response to hypercapnia and oxygen saturation were evaluated before dosing and up to 8 h after administration of test drugs. RESULTS: Median time to maximum concentration (Tmax) was 2.17 h for 900 µg BBF and 1.17 h for 60 mg oxycodone and was similar across all doses for each drug. Mean maximum concentration (Cmax) was 1.06 ng/mL for 900 µg BBF and 132 ng/mL for 60 mg oxycodone. The abuse quotient, defined as Cmax/Tmax, was substantially higher for oxycodone compared to BBF. Respiratory depression (maximum decrease in minute ventilation) was similar for all 3 doses of BBF, consistent with a potential ceiling effect. In addition, respiratory depression occurred sooner with oxycodone vs BBF, and a greater mean decrease in oxygen saturation was observed for oxycodone 30- and 60-mg doses, compared with BBF. CONCLUSION: These results indicate that BBF may have a decreased risk of abuse and respiratory depression compared with the full µ-opioid receptor agonist oxycodone. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03996694.

Effects of buprenorphine buccal film and oral oxycodone on pupil diameter in a respiratory study.

OBJECTIVE: Evaluate the pupillary-constricting effects following administration of buprenorphine buccal film (BBF) and immediate-release (IR) oxycodone. DESIGN: A double-blind, double-dummy, six-treatment, six-period, placebo-controlled, randomized crossover study. SETTING: Single-center, phase 1 exploratory pharmacodynamics. PARTICIPANTS: Healthy individuals who self-identify as recreational opioid users, confirmed via a naloxone challenge test on day 1. INTERVENTIONS: Placebo: BBF 300, 600, and 900 mcg and IR oxycodone 30 and 60 mg. MAIN OUTCOME MEASURE: Minute ventilation (measured by the ventilatory response to hypercapnia) and pupil diameter (determined via standard pupillometry) were assessed predose and at 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours post-dose. RESULTS: Change from baseline in minute ventilation was moderately correlated with change from baseline in pupil diameter during treatment with BBF (Pearson's r = 0.38-0.40; p ≤ 0.0011) or oxycodone (Pearson's r = 0.34-0.37; p ≤ 0.005). The initial onset of significant (p < 0.05) pupil constriction relative to placebo occurred at 2, 1.5, and 1 hour after dosing with BBF 300, 600, and 900 mcg, respectively, and at 0.5 hours after dosing with oxycodone 30 or 60 mg. CONCLUSIONS: Although BBF and IR oxycodone achieved similar levels of pupil constriction, there was a delayed miosis seen with BBF relative to that found with oxycodone.

Establishing Minimal Clinically Important Differences in Quality of Life Measures in Opioid-Induced Constipation.

BACKGROUND & AIMS: Opioids have a role in chronic pain management. However, opioid-induced constipation may cause patients to skip or reduce opioid doses, leading to inadequate pain relief and negatively impacting quality of life. We sought to establish a minimal clinically important difference to understand whether changes in quality of life scores are of value to patients. METHODS: Integrated data from the double-blind, controlled, phase 3 COMPOSE-1 and COMPOSE-2 trials of naldemedine in chronic noncancer pain and opioid-induced constipation were used to determine minimal clinically important differences using Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. Patients completed the questionnaires (5-point Likert scale; predose, Weeks 2, 4, and 12), kept a daily log of Bowel Movement and Constipation Assessment, and rated satisfaction at end of study. Minimal clinically important differences were computed using an anchor-based method with 6 anchors: 5 from the Bowel Movement and Constipation Assessment and 1 from patient satisfaction. Threshold values for each anchor were set to define responders versus nonresponders based on score definitions. Clinically meaningful cutoff values for changes in PAC-SYM and PAC-QOL scores were determined using receiver operating characteristic curves. RESULTS: Data from 1095 patients (549, naldemedine; 546, placebo) were analyzed. The area under the curve for the receiver operating characteristic curves (ranges, 0.719 to 0.798 for PAC-SYM and 0.734 to 0.833 for PAC-QOL) indicated that both instruments can discriminate responders and nonresponders for each anchor. PAC-SYM cutoff values ranged from -1.04 to -0.83; PAC-QOL cutoff values ranged from -0.93 to -0.82. CONCLUSIONS: Based on data derived from the anchor method, reductions in PAC-SYM and PAC-QOL scores of >1.0 in patients with chronic noncancer pain and opioid-induced constipation are clinically meaningful. CLINICALTRIALS: gov Registration: NCT01965158; NCT01993940.

Ventilatory Response to Hypercapnia as Experimental Model to Study Effects of Oxycodone on Respiratory Depression.

BACKGROUND: Opioid analgesics used to treat pain can cause respiratory depression. However, this effect has not been extensively studied, and life-threatening, opioid-induced respiratory depression remains difficult to predict. We tested the ventilatory response to hypercapnia for evaluating the pharmacodynamic effect of a drug on respiratory depression. METHODS: We conducted a randomized, placebo-controlled, double-blind, crossover study on 12 healthy adult males. Subjects received 2 treatments (placebo and immediate-release oxycodone 30 mg) separated by a 24-hour washout period. Subjects inhaled a mixture of 7% carbon dioxide, 21% oxygen, and 72% nitrogen for 5 minutes to assess respiratory depression. Minute ventilation, respiratory rate, tidal volume, flow rate, end-tidal CO2, and oxygen saturation were recorded continuously at pre-dose and 30, 60, 120, and 180 minutes post-dose. The primary endpoint was the effect on the ventilatory response to hypercapnia at 60 minutes post-dose, as assessed by the slope of the linear relationship between minute ventilation and end-tidal CO2. RESULTS: At 60 minutes post-dose, subjects had a mean slope of 2.4 in the oxycodone crossover period, compared to 0.1 in the placebo period (mean difference, 2.3; 95% CI: 0.2 to 4.5; p = 0.035). Statistical significance was likewise achieved at the secondary time points (30, 120, and 180 minutes post-dose, p <0.05). CONCLUSIONS: This model for testing ventilatory response to hypercapnia discriminated the effect of 30 mg of oxycodone vs. placebo for up to 3 hours after a single dose. It may serve as a method to predict the relative effect of a drug on respiratory depression.

Evaluation of the abuse potential of difelikefalin, a selective kappa-opioid receptor agonist, in recreational polydrug users.

Difelikefalin, a selective kappa-opioid receptor agonist with limited central nervous system penetration, is being developed for the treatment of chronic pruritic conditions. This randomized, double-blind, active- and placebo-controlled, four-way crossover study was designed to evaluate the abuse potential of difelikefalin in healthy recreational polydrug users. Using a 4 × 4 Williams design, nondependent adult users of opioids and hallucinogens (N = 44) were randomized to receive single intravenous (i.v.) injections of difelikefalin at supratherapeutic doses (5 and 15 mcg/kg); pentazocine (0.5 mg/kg), a schedule IV mu-opioid partial agonist and kappa-opioid receptor agonist; and placebo. The abuse potential of difelikefalin was compared with pentazocine and placebo using the maximal score (maximum effect [Emax ]) of the Drug Liking visual analog scale (VAS; primary end point), along with multiple secondary end points of subject-rated measures and pupillometry. Difelikefalin produced significantly lower Drug Liking VAS Emax , and lower peak positive, sedative, and perceptual effects compared with pentazocine. These effects of difelikefalin were small, brief, and not dose-dependent, although marginally greater than those observed with placebo. Neither dose of difelikefalin elicited significant negative or hallucinogenic effects. On end-of-session measures of overall drug liking and willingness to take the drug again, difelikefalin did not differ from placebo, indicating subjects neither liked nor disliked the effects overall and did not feel motivated to take the drug again. Consistent with its lack of mu agonist activity, difelikefalin did not induce miosis compared with pentazocine. All treatments were generally well-tolerated. This study indicates that difelikefalin presents a low potential for abuse.

Atypical opioids and their effect on respiratory drive.

Opioids are an important tool in the treatment of pain, but opioid overdose has become a serious health issue. Most opioid-related deaths are caused by respiratory depression, and the risk of respiratory depression is compounded because of the risks of abuse and diversion, which makes the need for safer opioids even more urgent. However, the atypical opioids (buprenorphine, tramadol, and tapentadol), with mechanisms of action not purely driven by µ-opioid receptor agonism, may be safer than conventional opioids, eg, morphine, oxycodone, and fentanyl. The purpose of this narrative review is to describe the clinical and experimental evidence regarding opioid-induced respiratory depression in the context of the mechanisms of action of the atypical opioids. Among the atypical opioids, tramadol has an advantage of being a Schedule IV drug, and thus having a relatively low abuse potential-but its effects, including its effect on respiratory drive, are dependent on cytochrome P450 2D6 metabolizer status. Tapentadol appears to affect respiratory drive, but this has not been well investigated. Buprenorphine is a Schedule III drug, thus having less abuse potential than the majority of opioids. Experimentally, a ceiling effect on the respiratory depression has been reported with intravenous buprenorphine. In addition, experimental hypercapnic stress in healthy volunteers demonstrated no respiratory depression following the administration of a single dose of the buccal film formulation of buprenorphine when compared with placebo. Overall, the data suggest that atypical opioids may be a safer option than conventional opioids for the treatment of pain.

Wooden Chest syndrome: The atypical pharmacology of fentanyl overdose.

WHAT IS KNOWN AND OBJECTIVE: A large percentage of opioid overdose fatalities involve fentanyl or one of its legal or illegal analogs (F/FAs). Is there something about the pharmacology of these drugs that make them unusually dangerous in an overdose? COMMENT: Some of the reasons for the dangers of overdose of F/FAs is their high potency and low cost (that leads to wide distribution). But it is rarely asked if the basic pharmacology of F/FAs differ in some fundamental way from conventional opioids such as morphine and heroin. In addition to centrally mediated respiratory depression via opioid receptors, F/FAs cause rigidity in the key respiratory muscles of the chest, upper airway and diaphragm ("wooden chest syndrome," WCS) by a non-opioid mechanism. WHAT IS NEW AND CONCLUSION: WCS is an atypical pharmacology of F/FAs. Because of its rapid onset and non-opioid mechanism, WCS makes F/FA overdose particularly dangerous.

Naldemedine Improves Patient-Reported Outcomes of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain in the COMPOSE Phase 3 Studies.

OBJECTIVE: Opioid-induced constipation is among the most common side effects associated with opioid use in patients with chronic non-cancer pain, and it can have a significant negative impact on health-related quality of life (QOL). This analysis evaluated the effect of naldemedine 0.2 mg on patient-reported outcomes in three phase 3 clinical studies. METHODS: COMPOSE-1 and COMPOSE-2 were identical randomized, double-blind, placebo-controlled, parallel-group studies of 12 weeks' duration, allowing data to be integrated (n=1095). COMPOSE-3 was similar in design, but of 52 weeks' duration (n=1241). Patients were adults with chronic non-cancer pain who had been treated with opioid analgesics for ≥3 months and experiencing opioid-induced constipation. Patient-reported outcomes included Patient Assessment of Constipation Symptoms (PAC-SYM; 12 questions assessed on a 5-point Likert scale), PAC-QOL (28 questions assessed on a 5-point Likert scale), and Subject Global Satisfaction (measured on a 7-point Likert scale). The proportion of patients achieving a ≥1.5 improvement in PAC-SYM and PAC-QOL was calculated. The correlation between change in PAC-SYM and PAC-QOL scores and frequency of bowel movements was also explored. RESULTS: The proportion of PAC-SYM and PAC-QOL responders was significantly higher for naldemedine than for placebo at all assessed time points in COMPOSE-1/COMPOSE-2 (p<0.005 for both) and COMPOSE-3 (p<0.005 and p<0.0001, respectively). There was a statistically significant correlation between improvement in PAC-SYM/PAC-QOL and frequency of bowel movements at all time points (p≤0.0002). The majority of patients treated with naldemedine reported markedly or moderately improved satisfaction with constipation and abdominal symptoms on the Subject Global Satisfaction questionnaire. DISCUSSION: Naldemedine treatment was associated with a rapid and sustained clinically relevant improvement in patient-reported outcomes, indicating improvement in opioid-induced constipation-related symptoms and QOL. CLINICALTRIALSGOV REGISTRATION: NCT01965158, NCT01993940, NCT01965652.

Accelerating and de-risking CMC development with transposon-derived manufacturing cell lines.

The development of highly productive, genetically stable manufacturing cell lines is on the critical path to IND filing for protein-based biologic drugs. Here, we describe the Leap-In Transposase® platform, a novel transposon-based mammalian (e.g., Chinese hamster ovary) cell line development system that produces high-titer stable pools with productivity and product quality attributes that are highly comparable to clones that are subsequently derived therefrom. The productivity distributions of clones are strongly biased toward high producers, and genetic and expression stability is consistently high. By avoiding the poor integration rates, concatemer formation, detrimental transgene recombination, low average expression level, unpredictable product quality, and inconsistent genetic stability characteristic of nonhomologous recombination methods, Leap-In provides several opportunities to de-risk programs early and reduce timelines and resources.

Open-Label Adhesion Performance Studies of a New Lidocaine Topical System 1.8% versus Lidocaine Patches 5% and Lidocaine Medicated Plaster 5% in Healthy Subjects.

PURPOSE: The primary objective was to evaluate adhesion performance of the lidocaine topical system 1.8% for 12 hours in healthy human subjects in three studies: as a single product (Study 1) and versus other lidocaine topical products (lidocaine patch 5% and lidocaine medicated plaster 5% [Study 2] and generic lidocaine patch 5% [Study 3]). Safety of the lidocaine topical system 1.8%, with a skin irritation focus, was a secondary objective. PATIENTS AND METHODS: All three studies were open-label, randomized, Phase 1 adhesion performance studies in healthy adult volunteers (N=125). Lidocaine topical products were applied for 12 hours per test, per study arm. Adhesion of all test products was scored at 0, 3, 6, 9, and 12 hours post-application. Skin irritation was scored after product removal or when a product detached. RESULTS: Overall, the majority (≥75%) of subjects treated with the lidocaine topical system 1.8% demonstrated ≥90% adhesion (FDA adhesion score 0) throughout the 12-hour administration period versus 13.6% of subjects treated with lidocaine patch 5%, 15.9% of subjects treated with lidocaine medicated plaster 5%, and 0% of subjects treated with the generic lidocaine patch 5%. There were no complete detachments with the lidocaine topical system 1.8%, whereas 4.5% of lidocaine patch 5% and lidocaine medicated plaster 5% detached, and 29% of generic lidocaine patch 5% detached. Minimal skin irritation was observed with each lidocaine topical product. CONCLUSION: Across three studies, lidocaine topical system 1.8% demonstrated superior adhesion performance versus the three other products tested. Skin irritation was minimal across products and studies. CLINICALTRIALSGOV: NCT04312750, NCT04320173, NCT04319926.

The Physiology and Maintenance of Respiration: A Narrative Review.

Chronic pain is one of the most common reasons adults seek medical care and is often managed with opioid analgesics; however, opioids may cause respiratory depression by suppressing various components of respiration. Respiration is the physiological process that facilitates gas exchange and is mediated through the proper function of and communication among central neural control (respiratory drive), sensory input systems, the lungs, and the muscles involved in respiration. Normal respiratory function can be dampened with the use of central nervous system (CNS) depressants and/or underlying health conditions. Patients with chronic pain are often exposed to CNS depressants other than opioids, including benzodiazepines, barbiturates, nonbenzodiazepine sedative-hypnotics, and ethanol, which can function synergistically with opioids to increase the risk of respiratory depression. Some patients may also have underlying health issues, such as obstructive sleep apnea, that can be exacerbated with the use of opioids and other CNS depressants and further contribute to respiratory depression. Clinicians should have a thorough understanding of respiration, recognize how various CNS depressants suppress it, and take necessary steps to mitigate the risk of opioid-induced respiratory depression by collaborating with a multidisciplinary team (i.e., sleep and pain specialists), choosing appropriate medications, and educating patients on the proper use and storage of opioids.

A Phase I Placebo-Controlled Trial Comparing the Effects of Buprenorphine Buccal Film and Oral Oxycodone Hydrochloride Administration on Respiratory Drive.

INTRODUCTION: Buprenorphine is a partial µ-opioid receptor agonist that, unlike full µ-opioid receptor agonists, has been shown to have a ceiling effect on respiratory depression. Buprenorphine buccal film (BBF) is approved by the US Food and Drug Administration for use in patients with chronic pain severe enough to require daily, around-the-clock, long-term opioid treatment and for whom alternative treatment options are inadequate. This study was conducted to compare the effects of BBF and immediate-release oral oxycodone hydrochloride administration on respiratory drive, as measured by the ventilatory response to hypercapnia (VRH) after drug administration. METHODS: Subjects (N = 19) were men and women, ages 27-41 years, self-identifying as recreational opioid users who were not physically dependent on opioids as determined via a Naloxone Challenge Test. Respiratory drive was evaluated by measuring VRH through the assessment of the maximum decrease in minute ventilation (Emax) after administration of each treatment. The treatments utilized in this study included 300, 600, and 900 µg BBF; 30 and 60 mg orally administered oxycodone; and placebo (each separated by a 7-day washout period). Effects on respiratory drive were assessed using a double-blind, double-dummy, six-treatment, six-period, placebo-controlled, randomized crossover design. Statistical analyses were performed using a linear mixed-effects model. RESULTS: The least squares mean differences in minute volume Emax (L/min, versus placebo) were as follows: 300 µg BBF (+ 1.24, P = 0.529), 600 µg BBF (+ 0.23, P = 0.908), 900 µg BBF (+ 0.93, P = 0.637), 30 mg oxycodone (- 0.79, P = 0.687), and 60 mg oxycodone (- 5.23, P = 0.010). CONCLUSIONS: BBF did not significantly reduce respiratory drive at any dose compared with placebo, including at the maximum available prescription dose of 900 µg. Administration of oxycodone resulted in a significant dose-dependent decrease in respiratory drive. These data suggest that BBF may be a safer treatment option than full µ-opioid receptor agonists for patients with chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03996694.