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In this trial comparing methadone with buprenorphine in opioid-dependent pregnant women, neonates exposed to buprenorphine required less morphine to treat neonatal abstinence syndrome (NAS) and had a significantly shorter duration of hospitalization and of treatment for NAS. Opioid dependence during pregnancy is compounded by multiple risk factors contributing to adverse maternal, neonatal, and long-term developmental consequences. 1 – 6 Improved treatment options should reduce the public health and medical costs associated with the treatment of neonates exposed to opioids, which in 2009 was estimated at $70.6 million to $112.6 million in the United States alone. 7 Just as the use of methadone in nonpregnant patients with opioid dependence improves patient outcomes, 8 its use as part of a comprehensive approach to the care of pregnant women improves maternal and neonatal outcomes, as compared with no treatment and with medication-assisted withdrawal. 4 , . . .

Background: Morphine sulfate/sequestered naltrexone hydrochloride (HCl) (MS-sNT) extended-release fixed-dose combination capsules, approved by the US Food and Drug Administration (FDA) in August 2009 for chronic moderate to severe pain, contain extended-release morphine pellets with a sequestered core of the opioid antagonist naltrexone. MS-sNT was designed so that if the product is tampered with by crushing, the naltrexone becomes bioavailable to mitigate morphine-induced subjective effects, rendering the product less attractive for tampering. Objectives: The primary aim of this study was to compare the oral bioavailability of naltrexone and its metabolite 6-β-naltrexol, derived from crushed pellets from MS-sNT capsules, to naltrexone solution. This study also assessed the relative bioavailability of morphine from crushed pellets from MS-sNT capsules and that from the whole, intact product. Methods: This single-dose, randomized-sequence, open-label, 3-period, 3-treatment crossover trial was conducted in healthy volunteers. Adults admitted to the study center underwent a 10-hour overnight fast before study drug administration. Each subject received all 3 of the following treatments, 1 per session, separated by a 14-day washout: tampered pellets (crushed for ≥2 minutes with a mortar and pestle) from a 60-mg MS-sNT capsule (60 mg morphine/2.4 mg naltrexone); 60-mg whole, intact MS-sNT capsule; and oral naltrexone HCl (2.4 mg) solution. Plasma concentrations of naltrexone and 6-β-naltrexol were measured 0 to 168 hours after administration. Morphine pharmaco-kinetics of crushed and whole pellets were determined 0 to 72 hours after administration. The analysis of relative bioavailability was based on conventional FDA criteria for assuming bioequivalence; that is, 90% CIs for ratios of geometric means (natural logarithm [In]-transformed C max and AUC) fell within the range of 80% to 125%. Subjects underwent physical examinations, clinical laboratory tests, and ECG at screening and study discharge and were monitored for adverse events (AEs) throughout the study. Results: Of the 24 subjects enrolled in the study, 23 completed it. Most subjects were white (79%) and male (63%); the mean (SD) age was 39.3 (11.2) years and the mean weight was 77.6 (13.5) kg (range, 55.0102.5 kg). Plasma C max and AUC 0-t of naltrexone after the administration of crushed pellets of MS-sNT (579 pg/mL and 1811 h · pg/mL, respectively) and naltrexone solution (584 pg/mL and 1954 h · pg/mL) were not significantly different; 90% CIs were 83.8% to 116% and 83.3% to 102%, meeting the regulatory requirements for assuming bioequivalence in this study population. Plasma naltrexone concentration was below the lower limit of quantitation (4.0 pg/mL) in 23 of 24 subjects (96%) after whole MS-sNT administration. Morphine AUC 0-t was not significantly different whether MS-sNT was crushed (163 h · ng/mL) or administered whole (174 h · ng/mL), but C max was numerically higher (24.5 vs 7.7 ng/mL) and T max was numerically shorter (2.00 vs 7.03 hours) with MS-sNT crushed versus whole. The most commonly reported AEs were nausea (8/23 [35%], 10/24 [42%], and 3/23 [13%] subjects in the crushed, whole, and naltrexone groups, respectively) and emesis (6 [26%], 7 [29%], and 2 [9%]). Conclusions: In this single-dose study, when pellets from MS-sNT were crushed, naltrexone appeared to be completely released and available to mitigate morphine-induced effects. When MS-sNT was administered whole, morphine was released in an extended-release fashion while naltrexone remained sequestered.

In this prospective study, we compared the efficacy and side effects of indomethacin, ibuprofen, and paracetamol in patent ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm neonates with hemodynamically significant PDA (hs-PDA) admitted at our neonatal intensive care unit were enrolled in the study. They were randomized into three groups. Group I (paracetamol group) received 15 mg/kg/6 h IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg IV ibuprofen infusion followed by 5 mg/kg/day for 2 days. Group III (indomethacin group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses. Laboratory investigations such as renal function test, liver function test, complete blood count, and blood gases were conducted in addition to echocardiographic examinations. All investigations were done before and 3 days after treatment. There was no significant difference between all groups regarding efficacy of PDA closure ( P  = 0.868). There was a significant increase in serum creatinine levels and serum blood urea nitrogen (BUN) in the ibuprofen and indomethacin groups ( P  < 0.001). There was a significant reduction in platelet count and urine output (UOP) in both ibuprofen and indomethacin groups ( P  < 0.001). There was a significant increase in bilirubin levels in only the ibuprofen group ( P  = 0.003). No significant difference of hemoglobin (HB) level or liver enzymes in all groups ( P  > 0.05). Ventilatory settings improved significantly in patients with successful closure of PDA than those with failed PDA closure ( P  < 0.001). Conclusion : Paracetamol is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates and has less side effects mainly on renal function, platelet count, and GIT bleeding. What is Known: • Hemodynamically significant patent ductus arteriosus has many complications for preterm and low birth weight neonates and better to be closed. Many drugs were used for medical closure of PDA e.g. indomethacin, ibuprofen and recently paracetamol. Many studies compare safety and efficacy of paracetamol with either indomethacin or ibuprofen. What is New: • It is the first large study that compares the efficacy and side effects of the three drugs in one study.

ObjectiveAnaesthesiology guidelines suggest that opioids worsen obstructive sleep apnoea (OSA) despite no randomised controlled trial evidence. We therefore conducted a randomised controlled trial to evaluate the effects of a common clinical dose of morphine on OSA, and to identify clinical phenotype and genotype vulnerability to opioid-respiratory depression.MethodsUnder a double-blind, randomised, crossover design, 60 male patients with OSA attended two visits to the hospital sleep laboratory, at least 1 week apart. Either 40 mg controlled-release oral morphine or placebo was administered. Awake ventilatory chemoreflex tests were performed post dose and prior to overnight polysomnography monitoring. Blood was sampled before sleep and the next morning for toxicology and genotype analyses. Sleep time with oxygen saturation (SpO2) <90% (T90) was the primary outcome.ResultsDespite a large inter-individual variability, 40 mg morphine did not worsen T90 and apnoea–hypopnoea index, and only decreased the SpO2 nadir by 1.3%. In patients with severe OSA, a lower baseline CO2ventilatory response threshold correlated with the worsening of T90, apnoea–hypopnoea index and oxygen desaturation index with morphine use. Patients with OSA and the A118G OPRM1 polymorphism of A/A and A/G had a significantly different morphine effect on awake ventilatory chemosensitivity and T90 during sleep.Conclusions40 mg oral controlled-release morphine did not worsen OSA in men, challenging traditional thinking that OSA will be worsened by opioids. Individual opioid response in patients with OSA may relate to baseline CO2 response threshold and OPRM1 genotype. Our study findings may pave the way for a precision medicine approach to avoid opioid-related risks.Trial registration numberThe Australian and New Zealand Clinical Trial Registry, ACTRN12613000858796.

Background Biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) 7.5/325-mg tablets are formulated with gastroretentive ER drug delivery technology that has been associated with clinically meaningful food effects in other approved products. Two phase 1 studies evaluated potential effects of food on single-dose pharmacokinetics of IR/ER HB/APAP tablets. Methods These were single-center, open-label, randomized, single-dose, 3-period crossover studies in healthy volunteers (aged 18–55 years). IR/ER HB/APAP was administered as a single 2-tablet dose (study 1) or 3-tablet dose (study 2) under fed (high- and low-fat) and fasted conditions. Area under the plasma concentration-time curve from 0 h to time t (AUC 0–t ) and from time 0 extrapolated to infinity (AUC 0–inf ) and maximum observed plasma concentration (C max ) of hydrocodone and APAP under fed versus fasted conditions were compared using analysis of variance. A 90 % confidence interval of the geometric least squares mean ratio fully contained within 80 to 125 % indicated no treatment difference. Safety and tolerability were assessed. Results Forty of 48 participants in study 1 and 21 of 30 in study 2 completed all treatments. In both studies, under fed (high- or low-fat meal) versus fasted conditions, 90 % CIs for AUC 0–t and AUC 0–inf for both hydrocodone and APAP were entirely contained within the bioequivalent range (80–125 %), indicating that high- and low-fat meals did not affect the extent of exposure. In both studies, a high-fat meal did not affect the C max for hydrocodone. Hydrocodone C max was not affected by a low-fat meal in study 1 but increased by approximately 19 % in study 2. A high-fat meal decreased APAP C max by approximately 20 % (study 1) and 13 % (study 2); a low-fat meal decreased APAP C max by 22 % (study 1) and 21 % (study 2). Approximately 50 % of participants in both studies reported ≥1 treatment-emergent adverse event (TEAE), with no notable difference based on food intake. There were no serious or severe AEs. The most common TEAEs were nausea, vomiting, and dizziness. Conclusions Pharmacokinetic and safety findings were similar regardless of food intake. TEAEs were consistent with those reported with low-dose combination opioids. IR/ER HB/APAP can be administered without regard to food. Trial registration ClinicalTrials.gov NCT02561650 and NCT02561741 .

The release of ATP from spinal microglia via pannexin-1 channels is required for withdrawal symptoms after termination of chronic opioid treatment in rodents, and pharmacological blockade of pannexin-1 channels reduces the severity of withdrawal without affecting opiate analgesia. Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates 1 , 2 , 3 , 4 . Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP 5 , 6 . We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide ( 10 panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.

BackgroundPoverty, unemployment and substance abuse are inter-related problems. This study evaluated the effectiveness of abstinence-contingent wage supplements in promoting drug abstinence and employment in unemployed adults in outpatient treatment for opioid use disorder.MethodsA randomised controlled trial was conducted in Baltimore, MD, from 2014 to 2019. After a 3-month abstinence initiation and training period, participants (n=91) were randomly assigned to a usual care control group that received employment services or to an abstinence-contingent wage supplement group that received employment services plus abstinence-contingent wage supplements. All participants were invited to work with an employment specialist to seek employment in a community job for 12 months. Abstinence-contingent wage supplement participants could earn training stipends for working with the employment specialist and wage supplements for working in a community job, but had to provide opiate and cocaine-negative urine samples to maximise pay.ResultsAbstinence-contingent wage supplement participants provided significantly more opiate and cocaine-negative urine samples than usual care control participants (65% vs 45%; OR=2.29, 95% CI 1.22 to 4.30, p=0.01) during the 12-month intervention. Abstinence-contingent wage supplement participants were significantly more likely to have obtained employment (59% vs 28%; OR=3.88, 95% CI 1.60 to 9.41, p=0.004) and lived out of poverty (61% vs 30%; OR=3.77, 95% CI 1.57 to 9.04, p=0.004) by the end of the 12-month intervention than usual care control participants.ConclusionAbstinence-contingent wage supplements can promote drug abstinence and employment.Trial registration numberClinicalTrials.gov NCT02487745.

Objectives To compare the efficacy and safety of single versus combination non-prescription oral analgesics in community-derived people aged 40 years and older with chronic knee pain. Methods A randomised, double-blind, four-arm, parallel-group, active controlled trial investigating short-term (day 10) and long-term (week 13) benefits and side-effects of four regimens, each taken three times a day: ibuprofen (400 mg); paracetamol (1000 mg); one fixed-dose combination tablet (ibuprofen 200 mg/paracetamol 500 mg); two fixed-dose combination tablets (ibuprofen 400 mg/paracetamol 1000 mg). Results There were 892 participants (mean age 60.6, range 40–84 years); 63% had radiographic knee osteoarthritis and 85% fulfilled American College of Rheumatology criteria for osteoarthritis. At day 10, two combination tablets were superior to paracetamol (p<0.01) for pain relief (determined by mean change from baseline in WOMAC pain; n=786). At 13 weeks, significantly more participants taking one or two combination tablets rated their treatment as excellent/good compared with paracetamol (p=0.015, p=0.0002, respectively; n=615). The frequency of adverse events was comparable between groups. However, by 13 weeks, decreases in haemoglobin (≥1 g/dl) were observed in some participants in all groups. Twice as many participants taking two combination tablets had this decrease compared with those on monotherapy (p<0.001; paracetamol, 20.3%; ibuprofen, 19.6%; one or two combination tablets, 24.1%, 38.4%, respectively). Conclusions Ibuprofen/paracetamol combination analgesia, at non-prescription doses, confers modest short-term benefits for knee pain/osteoarthritis. However, in this population, paracetamol 3 g/day may cause similar degrees of blood loss as ibuprofen 1200 mg/day, and the combination of the two appears to be additive. Study no ISRCTN77199439

Opioid-induced constipation (OIC) is one of the major side effects in patients receiving methadone maintenance treatment (MMT). Quite often, constipation becomes a factor significantly affecting therapeutic options and choices. Currently used approaches are symptomatic and in many cases ineffective. At the same time, it is well known that the gastrointestinal system is a subject for psychosomatic influences. In this case report, we describe an unexpected outcome of placebo administration in a patient suffering from OIC since her participation in MMT. The patient participated in a triple-blind randomised placebo-controlled trial of naloxone for treatment of OIC. As part of the study crossover design, the patient received 1 week of placebo followed by 1 week of naloxone, and had significant improvement in her bowel functioning when receiving placebo, then returned to baseline during the second week of the study.

Acetaminophen, an effective and popular over-the-counter pain reliever (e.g., the active ingredient in Tylenol), has recently been shown to blunt individuals' reactivity to a range of negative stimuli in addition to physical pain. Because accumulating research has shown that individuals' reactivity to both negative and positive stimuli can be influenced by a single factor (an idea known as differential susceptibility), we conducted two experiments testing whether acetaminophen blunted individuals' evaluations of and emotional reactions to both negative and positive images from the International Affective Picture System. Participants who took acetaminophen evaluated unpleasant stimuli less negatively and pleasant stimuli less positively, compared with participants who took a placebo. Participants in the acetaminophen condition also rated both negative and positive stimuli as less emotionally arousing than did participants in the placebo condition (Studies 1 and 2), whereas nonevaluative ratings (extent of color saturation in each image; Study 2) were not affected by drug condition. These findings suggest that acetaminophen has a general blunting effect on individuals' evaluative and emotional processing, irrespective of negative or positive valence.