The ALERRT® instrument: a quantitative measure of the effort required to compromise prescription opioid abuse-deterrent tablets

Background: US FDA guidance recommends measuring the degree of effort needed to manipulate abuse-deterrent (AD) opioids. The ALERRT^® instrument (PinneyAssociates; Bethesda, MD) uses visual analog scales to assess the labor, effort, and resources necessary to physically compromise AD product candidates in standardized settings. Objective: Use the ALERRT^® instrument for testing morphine abuse-deterrent, extended-release, injection-molded tablets (ADER-IMT) 60 and 100 mg and the comparators immediate-release (IR) morphine sulfate 30 mg and extended-release (ER) morphine sulfate 60 mg. Methods: Four technicians tested the products using 10 household tools. The ALERRT instrument quantified effort (all tools) and time (3 preselected tools) required for manipulation. Results: Morphine-ADER-IMT 60 and 100 mg were difficult to manipulate, as demonstrated by high scores (mean range, 71.0?99.0 and 77.0?99.5, respectively). IR and ER morphine sulfate were easy to manipulate (low scores; mean range, 2.0?14.8 and 2.3?17.5, respectively). Statistically significant mean differences between morphine-ADER-IMT and comparators’ ALERRT scores were observed. Manipulations of morphine-ADER-IMT 60 and 100 mg for 300 seconds failed to produce substantial powdering. Manipulations of IR morphine sulfate (mean range, 65.5?175.8 seconds) and ER morphine sulfate (49.3?163.0 seconds) produced substantial to complete powdering in 92% of tablets. Conclusions: Morphine-ADER-IMT was extremely difficult to manipulate versus non-AD formulations of morphine. The ALERRT system differentiated the degree of effort for manipulation of morphine-ADER-IMT and non-AD morphine formulations, indicating sensitivity of this instrument as part of Category 1 testing. By measuring the degree of effort required for manipulation, the ALERRT instrument provides an empirical assessment into the relative difficulty of manipulating opioid analgesics for abuse.     

In Utero Exposure to Opioids: An Observational Study of Mothers Involved in the Child Welfare System

Background: Women are underrepresented in the current substance abuse research; however, women are a particularly vulnerable population when it comes to opioid use and abuse. Pregnant women are even more so, because of the potential that exists for in utero exposure (IUE) to substances. Objectives: To identify trends in IUE to opioids in order to ensure that resources are allocated effectively to address the current opioid epidemic and to assist the populations most affected by it. Methods: This study draws on 15 years' worth of clinical assessment data collected from 3598 child welfare-involved mothers to assess for trends in IUE to substances over time. Data from the last 5 year period (N = 852) are then analyzed to identify recent demographic correlates associated with IUE to opioid substances. Results: A substantial increase in the rates of IUE to opioids over the past 15 years is observed among child welfare-involved mothers. Moreover, we find that race is a significant correlate of IUE to opioids. Conclusion: Study findings are consistent with other recent research that demonstrates racial differences in the populations that are most affected by the opioid epidemic; however, more research is needed to determine how these racial differences in rates of IUE to opioids affect child welfare outcomes.     

Economic and clinical burden of opioid-induced nausea and vomiting

Opioids are the standard of care for treating moderate-to-severe pain; however, their efficacy can be limited by adverse events (AEs), including nausea and vomiting. Opioid-induced nausea and vomiting (OINV) is an inherent adverse effect of opioid treatment, exerting effects centrally and peripherally. Opioid-related AEs can impact treatment adherence and discontinuation, which can result in inadequate pain management. OINV may persist long-term, negatively affecting patient functional outcomes, physical and mental health, patient satisfaction, and overall costs of treatment. Multiple factors may contribute to OINV, including activation of opioid receptors in the chemoreceptor trigger zone, vestibular apparatus, and gastrointestinal tract. Prophylactic or early treatment with antiemetics may be appropriate for patients who are at high risk for OINV.     

Connecting the dots: an association between opioids and acute hippocampal injury

Acute hippocampal injury represents a relatively rare cause of amnesia. Interestingly however, between 2012 and 2017, 18 patients were reported at hospitals in Massachusetts with sudden-onset amnesia in the setting of complete diffusion-weighted hyperintensity of both hippocampi on magnetic resonance imaging. Notably, 17 of the 18 patients tested positive for opioids or had a recorded history of opioid use. This observation suggests an association between opioids and acute hippocampal injury. With particular attention to the Massachusetts cluster and data on fentanyl and its congeners, the epidemiological and pathophysiological evidence that supports this hypothesis is presented, as are potential underlying mechanisms.     

Labor Pain Management Other Than Neuraxial: What Do We Know and Where Do We Go Next?

Analgesia and coping with labor pain can prevent suffering during childbirth. Nonpharmacologic methods help women manage labor pain. Strong evidence is available for the efficacy of continuous one‐to‐one support from a woman trained to provide nonmedical care during labor, immersion in warm water during first‐stage labor, and sterile water injected intracutaneously or subcutaneously at locations near a woman's lumbosacral spine to reduce back‐labor pain. Sterile water injections also reduce the incidence of cesarean deliveries. Nitrous oxide labor analgesia is not potent, but helps women relax, gives them a sense of control, and reduces and distracts their perception of pain. It is inexpensive; can be administered and discontinued safely, simply, and quickly; has no adverse effects on the normal physiology and progress of labor; and does not require intensive monitoring or co‐interventions. Parenteral opioids provide mild‐to‐moderate labor pain relief, but cause side effects. Although observational studies have found associations between maternal use of opioids and neonatal complications, little higher level evidence is available except that meperidine is associated with low Apgar scores. Patient‐controlled intravenous administration of remifentanil provides better analgesia and satisfaction than other opioids, but can cause severe side effects; continuous monitoring of arterial oxygen saturation, anesthesia supervision, one‐to‐one nursing, and availability of oxygen are recommended. The demand for inexpensive, simple, safe but effective labor pain management for women will undoubtedly increase in places that lack wide access to it now. (BIRTH 39:4 December 2012)     

Complications of Psychotropic and Pain Medications in an Ultrarapid Metabolizer Patient at the Upper 1% of Cytochrome P450 (CYP450) Function Quantified by Combinatorial CYP450 Genotyping

A 44-year-old Caucasian woman presented with a history of empirical treatment with 20 pain and psychotropic medications, as well as dual comorbidity of intractable pain and depression. A multiple gain-of-function profile in the CYP450 family of cytochrome P450 (CYP450) drug metabolism isoenzymes was discovered. The patient was a homozygote of suprafunctional alleles for both CYP2D6 (^*35/^*35) and CYP2C19 (^*17/^*17) genes and functional alleles for CYP2C9 (^*1/^*1), which account for aggregate drug metabolism function at the upper 1% of the population. The patient improved clinically with discontinuation of psychotropics and pain medications that were substrates of CYP2D6 and/or CYP2C19, suggesting that much of her symptomatology was drug induced. Combinatorial genotyping of CYP450 genes is diagnostically useful in individuals with histories of multiple side effects or drug resistance, which could be avoided by genetically informed therapeutics in behavioral health.     

丙泊酚复合不同阿片类药物在老年人结肠镜检查中的镇静效果

目的 探讨丙泊酚复合不同阿片类药物应用于老年人结肠镜检查镇静的效果.方法 60例老年结肠镜受检者随机分为3组,均采用靶控输注方法给予丙泊酚,其中20例单次推注芬太尼(芬太尼组),靶控输注舒芬太尼(舒芬太尼组)、瑞芬太尼(瑞芬太尼组)各20例.记录患者血流动力学改变、镇静深度和不良事件.结果 3组受检患者一般情况、血流动力学改变、镇静深度和不良事件比较差异无统计学意义(均P＞0.05).检查后恢复时间芬太尼组[(21.3±4.6)min]长于舒芬太尼组[(19.9±3.3)min]和瑞芬太尼组[(15.9±1.8)min],且与瑞芬太尼组比较差异有统计学意义(均P＜0.05).结论 丙泊酚复合3种阿片类药物均可安全有效地用于老年人结肠镜检查,但使用瑞芬太尼受检者恢复更为迅速.

Abstract：

Objective To explore the feasibility and safety of fentanyl, sufentanil or remifentanil combined with target-controlled infusion (TCI) of propofol for sedation in the elderly undergoing colonoscopy. Methods In this prospective randomized study, 60 patients undergoing colonoscopy and propofol TCI were randomly assigned to group F (fentanyl), group S (sufentanil) and group R (remifentanil)(each n=20). Patients in group F received a single bolus of fentanyl, while those in group S and group R received TCI sufentanil and remifentanil separately. The blood pressure, heart rate, blood oxygen content and Bispectral index (BIS) were monitored, and all the complications were recorded. Results All patients were adequately sedated. There were no significant differences in general conditions, hemodynamics changes, sedation depth and adverse event among the three groups (all P＞0.05). Time for recovery was longer in group F [(21.3±4.6) min] than in group S [(19.9±3.3) min] and group R [(15.9±1.8) min, P＜0.05]. Conclusions For the elderly undergoing colonoscopy, sedation with fentanyl, sufentanil or remifentanil combined with propofol TCI is feasible and safe. It is more excellent for the remifentanil group at shorter discharge time.