Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects.

The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) µM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.

Acupuncture and laserpuncture as a therapeutic approach for nociception and inflammation: An experimental study in mice.

Inflammation and pain are consequences of injuries or diseases that affect a large number of people. This study aims to evaluate the effect of acupuncture and laserpuncture on nociception and inflammation in mice compared to the effects of morphine and dexamethasone. 140 male Swiss mice were used. Treatment with acupuncture and laserpuncture were performed at the acupoints LI11, ST36, GB34, and BL60 in mice. To evaluate the effect of acupuncture and laserpuncture on nociception, the hot plate test and intraplantar formalin injection were used. The effect of acupuncture and laserpuncture on the inflammation was evaluated through carrageenan-induced paw edema. Thermographic analysis was also applied to evaluate the anti-inflammatory effects. An antinociceptive effect (≈57%) was observed in treatments with acupuncture and laserpuncture, equivalent to the effect of morphine. Laserpuncture and acupuncture decreased paw edema by ≈25%. Acupuncture had an effect equivalent to dexamethason, basides reducing the neurogenic phase by 35% and the inflammatory phase in formalin-induced nociception by 40%, equivalent to the effects of morphine. In thermographic analysis, acupuncture, laserpuncture, morphine, and negative control had paw temperature of ≈27 °C, while formalin treatment was 31°C. Acupuncture and laserpuncture proved to be effective therapies for the treatment of inflammatory and painful processes.

Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses.

BACKGROUND: In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency. RESULTS: Morphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied. CONCLUSIONS: The current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.

Neurological excitation in a 6-week-old male infant after morphine overdose.

While respiratory depression is a known complication of morphine overdose, the neuro-excitatory side effect of the morphine metabolite morphine-3-glucuronide is less widely known. Here, we report the case of an infant with neurological excitation after morphine overdose. The neuro-excitation in this infant was probably induced by an elevated morphine-3-glucuronide concentration.

Morphine Use in the Treatment of Acute Cardiogenic Pulmonary Edema and Its Effects on Patient Outcome: A Systematic Review.

PURPOSE OF REVIEW: To analyze whether the use of morphine, as initial treatment in acute cardiogenic pulmonary edema (ACPE), has an impact in clinical outcomes and mortality. A systematic review of the literature was performed, including all the studies comparing clinical outcomes in patients with ACPE who were treated or not with morphine. RECENT FINDINGS: Seven studies were selected, none of which were a randomized trial focused on answering the aim of this systematic review. The studies consisted of clinical trial secondary analysis assessing non-invasive ventilation in ACPE, one open non-randomized trial, two propensity score evaluations from large registries, and three clinical case reviews. Most of the studies showed unfavorable results with the use of morphine in terms of adverse events and mortality, and many of them were statistically significant. Finally, the ongoing MIdazolam versus MOrphine in acute cardiogenic pulmonary edema (MIMO) trial was specifically designed to compare the results of morphine use versus midazolam. The potential hemodynamic and sedative benefit of the use of morphine for vasodilatation and dyspnea amelioration may be opposed by an increase in mortality, ICU admission, and adverse events. Until there is a randomized clinical trial, the use of morphine for ACPE should be limited.

[Analysis of the accessibility of short acting oral opioids in Hungary]. / A rövid hatású, szájon át adható morfinszármazékok hazai elérhetoségének elemzése.

Short acting oral formulas make part of optimal opioid analgesia. The use of short acting oral morphine has not widely spread in Hungary, and these drugs completely lacked from the market for three years. Since December 2015 short acting morphine-sulphate has again been commercialised. The causes of the market failure are analysed in this article. The aim of the retrospective analysis is to help the accessibility of the medicine to every patient in need. Prescription morphine use depends on the harmonised cooperation of a number of actors. Besides regulating and financing authorities and professional organisations, patients and the opinion forming media are also responsible for building up the right routine.

A conjugate vaccine attenuates morphine- and heroin-induced behavior in rats.

BACKGROUND: Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies. METHODS: A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed. RESULTS: After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse. CONCLUSION: These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.

[Cytokines level in patients with drug-induced jaw necrosis].

The study included 15 patients with purulent inflammatory diseases of maxillofacial area and 25 patients with facial bone necrosis induced by synthetic drugs. Pro- and anti-inflammatory cytokines levels in saliva and wound fluid were analyzed in two groups. The results proved cytokines to play important role in jaw necrosis induced by drugs containing red phosphorus.

Comparison of the Centers for Disease Control (CDC) recommendations and the risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) tool for guiding naloxone coprescribing.

PURPOSE: Patients treated with ongoing opioid therapy may be at an increased risk of respiratory depression or death, which may be mitigated through prompt administration of naloxone. The Centers for Disease Control (CDC) guidelines for prescribing opioids in primary care settings recommend patients treated with ongoing opioid analgesic therapy be offered a coprescription of naloxone based on total oral morphine milligram equivalents per day or concurrent benzodiazepine therapy. Opioid overdose risk is dose-dependent, yet other patient-specific factors contribute to this risk. The risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) incorporates additional risk factors to assess the risk of overdose or clinically relevant respiratory depression. OBJECTIVES: This study compared the frequency of meeting CDC, Veterans' Health Administration (VA) RIOSORD, or civilian RIOSORD criteria for naloxone coprescribing. METHODS: A retrospective chart review of 42 Federally Qualified Health Centers in Illinois was conducted for all CII-CIV opioid analgesic prescriptions. Ongoing opioid therapy was defined as patients who received seven or more CII-CIV opioid analgesic prescriptions during the 1-year study period. Patients aged 18-89, receiving opioids for nonmalignant pain, and meeting the criteria of ongoing opioid therapy were included in the analysis. RESULTS: A total of 41,777 controlled substance analgesic prescriptions were prescribed during the study period. Data from 651 individual patient charts were evaluated. Of those, 606 patients met inclusion criteria. From these data, 57.9 percent of patients (N = 351) met civilian RIOSORD criteria, 36.5 percent (N = 221) met VA RIOSORD criteria, and 22.8 percent (N = 138) met CDC guideline recommendations for naloxone coprescribing. The percentage of patients who met RIOSORD criteria compared to CDC criteria was significantly higher (p < 0.001). Of all patients meeting ongoing opioid therapy criteria, only seven had been coprescribed naloxone. CONCLUSION: Coprescribing of naloxone is significantly underutilized in patients treated with opioid therapy for nonmalignant chronic pain and should not solely be based on total oral morphine milligram equivalents per day or concurrent benzodiazepine therapy. As risk assessment improves, consideration of other risk-conferring variables, such as gabapentinoids, skeletal muscle relaxants, and sleep hypnotics, should be considered.

Chemical composition and antinociceptive and anti-inflammatory activity of the essential oil of Hyptis crenata Pohl ex Benth. from the Brazilian Amazon.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaf tea of Hyptis crenata has its practical use in the Brazilian Amazon for treating gastrointestinal and liver disorders, sweating induction, and as an anti-inflammatory. AIM OF THE STUDY: Evaluation of the chemical composition, acute oral toxicity, and antinociceptive and anti-inflammatory activities of the H. crenata essential oil. MATERIAL AND METHODS: The essential oil was hydrodistilled and analyzed by GC and GC-MS. The antinociceptive action in mice was evaluated for the peripheral and central analgesic activity (abdominal contortion and hot plate tests), and the xylene-induced ear swelling was carried out for the nociception test. RESULTS: Oxygenated monoterpenes (53.0%) and monoterpene hydrocarbons (38.9%) predominated in the H. crenata oil, being 1,8-cineo1e (35.9%), α-pinene (20.8%), camphor (10.0%), and ß-pinene (7.3%) their primary constituents. The oral oil administration in the mice did not display changes in behavior patterns or animal mortality at 300 and 2000 mg/kg doses. The control group's biochemical parameters (ALP, AST, ALT) displayed a statistical difference from the treated group, unlike the renal parameters, which showed no variation between the groups. Oil reduced the abdominal contortions at doses of 100 (79.5%) and 300 mg/kg (44.4%), while with endodontacin, the dose was 5 mg/kg (75.2%). In addition, the oil could not decrease the paw licking/biting time at doses of 30, 100, and 300 mg/kg. However, it showed a significant antinociceptive effect on the second phase in the formalin test inhibiting licking time, with a reduction of 50.8% (30 mg/kg), 63.4% (100 mg/kg), 58.0% (300 mg/kg), and morphine (4 mg/kg, 78.3%). The oil administration produced significant inhibition of ear edema at all tested doses, with a better effect produced at 30 mg/kg (64.0% inhibition). CONCLUSION: The oil of Hyptis crenata, rich in 1,8-cineole, camphor, α-pinene, and ß-pinene, totaling 74%, displayed low acute toxicity and significant anti-inflammatory activity, with peripheral and no central antinociceptive action. Thus, these results show an actual perspective on using H. crenata oil in developing a phytotherapeutic product.

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain.

PURPOSE: Our aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days. METHODS: Forty-two cancer patients with pain and/or opioid side effects were assessed in this randomised trial. Trough serum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days 1, 2, 3, 4, 7, and 14. Primary outcome was number of patients with methadone concentrations in apparent C(SS) on day 4. Secondary outcomes were exposure to opioids during the first 3 days, interindividual variation of opioid concentrations, and correlation between methadone concentrations and pain intensity (PI) day 3. RESULTS: Thirty-five patients received methadone (16 in the SAG group, 19 in the 3DS group). The median preswitch morphine equivalent doses were 620 (range 350-2000) mg/day in the SAG group and 800 (range 90-3600) mg/day in the 3DS group (p = 0.43);42% reached C(SS) for methadone in the SAG group on day 4 compared with 22% in the 3DS group (p = 0.42). The SAG group was significantly less exposed to morphine/M6G/oxycodone and significantly more exposed to methadone in the first 3 days. Methadone showed a low correlation with PI. More patients dropped out after intervention in the SAG group than in the 3DS group (38% vs. 5%; p = 0.032). One SAG patient suffered from respiratory depression on day 5. CONCLUSION: The SAG group was initially more exposed to methadone and less to the replaced opioids but without observed clinical benefit and with a higher dropout rate. Patients switched to methadone should be followed closely for the first 5 days, regardless of switching strategy.

"Krokodil":revival of an old drug with new problems.

In order to summarize current knowledge about the drug "Krokodil" a systematic review including a literature search of the databases PubMed, Embase, Scopus, and Google was conducted in December 2011. According to information acquired, "Krokodil" is a mixture of several substances and was first reported to have been used in Russia in 2003. The core agent of "Krokodil" is desomorphine, an opioid-analogue that can be easily and cheaply manufactured by oneself. Self-production results in a contaminated suspension that is injected intravenously. Due to its pharmacologic features, desomorphine shows a high potential to cause dependence. Against the background of first possible cases of "Krokodil" use in Western Europe, it appears advisable to provide information regarding the fatal consequences of "Krokodil."

Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study.

BACKGROUND: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers. METHODS: Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data. RESULTS: Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration. CONCLUSIONS: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.

[Treatment of epidural morphine induced pruritus with butorphanol].

BACKGROUND: Epidural morphine has been used to provide postoperative analgesia. However, one of the most common side effects of epidural morphine is pruritus. The incidence may or may not be related to the dose of morphine administered. First, we examined whether epidural morphine induced a dose-related increase in pruritus or not. Secondly, the purpose of this study was to evaluate the relief of pruritus when a combination of epidural morphine (a mu-receptor agonist) and butorphanol (a mu-receptor antagonist and kappa-receptor agonist) was administered. METHODS: The incidence of pruritus, in 100 patients after abdominal surgery receiving continuous epidural analgesia with 0.2% ropivacaine + morphine, was retrospectively evaluated. Secondly, 60 adult patients undergoing abdominal surgery were randomly assigned to receive one of three epidural regimens; (1) continuous infusion of 0.2% ropivacaine with morphine 3.3 mg x day(-1) + butorphanol 2 mg x day(-1) (group MB), (2) morphine 3.3 mg x day(-1) alone (group M), or (3) butorphanol 2 mg x day(-1) alone (group B) at a rate of 4 ml x hr(-1), for 75 hours. RESULTS: Continuous epidural morphine at more than 3 mg x day(-1) caused a dose-related increase in pruritus. Pruritus was 0% in group B and group MB, but 55% in group M. CONCLUSIONS: Butorphanol 2 mg x day(-1) was effective in preventing pruritus associated with continuous epidural infusion of morphine 3.3 mg x day(-1).

Adverse immune reactions and non-immune medications for perioperative use. / Reacciones adversas inmunitarias y no inmunitarias a fármacos de uso perioperatorio.

Reactions to medications can occur through a mechanism mediated by immunoglobulin or otherwise, not both. Drug allergy is a type of adverse reaction to the drug and comprises a range of hypersensitivity reactions mediated by different immunological mechanisms with diverse clinical manifestations. A rate of 3.2 fatal cases of anaphylaxis associated with drugs per 100,000 inhabitants per year is estimated, which seems to be approximately 10 times higher in hospitalized patients. The incidence of perioperative anaphylactic reactions is estimated at 1 in 10,000-20,000 anesthetic procedures. The diagnosis is based on a careful clinical history and physical examination. In some cases, skin tests, progressive challenges and methods to induce tolerance to the medication may be required. In hospitalized patients and at perioperative intervals, muscle relaxants, neuroleptics and morphinomimetics are frequently used and adverse reactions may occur to these drugs. This review shows a general description of the reactions of these medications, emphasizes allergic reactions and analyzes strategies for the diagnosis and treatment of these reactions.

Las reacciones a medicamentos pueden ocurrir por mecanismos mediados o no por imunoglobulina E. La alergia a fármacos es un tipo de interacción adversa y comprende una gama de reacciones de hipersensibilidad mediadas por distintos mecanismos inmunológicos con diversas manifestaciones clínicas. Se estima una tasa anual de 3.2 casos fatales de anafilaxia asociados con los fármacos por cada 100 000 habitantes, que parece ser aproximadamente 10 veces mayor en los pacientes hospitalizados. La incidencia de reacciones anafilácticas perioperatorias se estima en uno de cada 10 000-20 000 procedimientos anestésicos. El diagnóstico se basa en una cuidadosa historia clínica y en el examen físico. En algunos casos pueden requerirse pruebas cutáneas, pruebas de retos progresivos y procedimientos de inducción de tolerancia al medicamento. En los pacientes hospitalizados y en el intervalo perioperatorio frecuentemente se emplean relajantes musculares, neurolépticos y morfinomiméticos, por lo que pueden presentarse respuestas adversas a estos fármacos. En esta revisión se hace énfasis en las reacciones alérgicas a los medicamentos y se abordan estrategias para su diagnóstico y manejo.

Morphine-6-glucuronide, an active morphine metabolite for the potential treatment of post-operative pain.

Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is being developed by CeNeS Pharmaceuticals as an alternative to morphine (the most commonly used opioid) for the management of postoperative pain. M6G is currently undergoing phase III clinical trials in patients with postoperative pain.

Characteristics of opioid-maintained clients smoking fentanyl patches: The importance of confirmatory drug analysis illustrated by a case series and mini-review.

The increase in opioid prescribing in many European countries over the last decade has raised concerns about associated diversion, overdose, and mortality. Fentanyl is one of these synthetic opioids that is typically prescribed as a transdermal patch for pain that requires continuous pain relief and has been the focus of investigation due to reports of overdose and death. We report a case series of 14 drug addiction treatment entrants, who entered treatment in a service located in the region of Southern Denmark from August 2015 to December 2015 for smoking fentanyl patches. Clients presented with difficulties breathing and pains in the lungs. The clients had a history of past opioid use, including heroin. Relapses resulted in treatment disengagement. Immunoassays for fentanyl were used in the service. In some cases, false negative results occurred. Clients' urine samples were subsequently analysed in a collaborating laboratory. Seven clients tested positive for fentanyl. One client was positive for both fentanyl and heroin. Analyses were also positive for other opioids and metabolites in 6 clients, predominantly codeine and oxycodone. Results from confirmatory analysis contributed to clearer insights into clients' drug histories, which facilitated personalised care plans consisting of opioid agonist therapy informed by confirmed drug use. In Denmark, prescription levels of fentanyl are high, which has been accompanied by observations of diversion and smoking in a smaller population. In addition to revision of inappropriate prescribing to reduce diversion, we recommend increased reliance upon confirmatory drug analysis in the addiction treatment sector in Denmark.

14-Methoxymetopon, a highly potent mu opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats.

RATIONALE: Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective micro opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index. OBJECTIVE: To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats. METHODS: Male sP rats with continuous 2-bottle choice access to ethanol (10% v/v) or water were subjects. The effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 micro/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 micro/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 micro/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 micro/kg, s.c.) on self-administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1 g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003-100 ng, i.c.v.) on 4-h ethanol intake were evaluated. RESULTS: Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer-lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrexone-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose-response function, increasing it at a 10 pg dose, while suppressing it at a 10,000-fold higher dose. CONCLUSIONS: The novel mu analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain mu opioid receptor stimulation on ethanol intake.

Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: a 12-week, randomized, double-blind, placebo-controlled study.

UNLABELLED: Opioid-experienced (N = 250) patients with chronic, moderate to severe low back pain (LBP) were converted from their prestudy opioid(s) to an approximately equianalgesic dose of OPANA ER (oxymorphone extended release). Patients continued slow titration, with 56% stabilized within 1 month to a dose of OPANA ER that reduced average pain to <40 mm on a visual analog scale with good tolerability. Stabilized patients (n = 143) were randomized to placebo or their stabilized dose of OPANA ER every 12 hours for a 12-week double-blind period. Pain intensity increased significantly more for patients randomized to placebo than for patients who continued their stabilized dose of OPANA ER; the increase from baseline (at randomization) to final visit was 31.6 mm for placebo versus 8.7 mm with OPANA ER (P < .0001). During double-blind treatment, placebo patients were approximately 8-fold more likely than OPANA ER patients to discontinue because of lack of efficacy (P < .001). Discontinuations as a result of adverse events were similar between groups, 10% with placebo and 11% with OPANA ER. Opioid-related adverse events included constipation (6%), somnolence (3%), and nausea (3%). Fifty-seven percent of opioid-experienced patients with chronic, moderate to severe LBP achieved a stable dose of OPANA ER that was efficacious and generally well-tolerated for up to 12 weeks. PERSPECTIVE: In a 12-week, double-blind, randomized, placebo-controlled trial in opioid-experienced patients with chronic, moderate to severe LBP, OPANA ER provided efficacious, long-term analgesia and was generally well-tolerated. OPANA ER may provide clinicians with a new treatment option for patients experiencing suboptimal analgesic responses or poor tolerability with other opioids.

Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review.

CONTEXT: Opioid use and abuse have increased dramatically in recent years, particularly among women. OBJECTIVES: We conducted a systematic review to evaluate the association between prenatal opioid use and congenital malformations. DATA SOURCES: We searched Medline and Embase for studies published from 1946 to 2016 and reviewed reference lists to identify additional relevant studies. STUDY SELECTION: We included studies that were full-text journal articles and reported the results of original epidemiologic research on prenatal opioid exposure and congenital malformations. We assessed study eligibility in multiple phases using a standardized, duplicate review process. DATA EXTRACTION: Data on study characteristics, opioid exposure, timing of exposure during pregnancy, congenital malformations (collectively or as individual subtypes), length of follow-up, and main findings were extracted from eligible studies. RESULTS: Of the 68 studies that met our inclusion criteria, 46 had an unexposed comparison group; of those, 30 performed statistical tests to measure associations between maternal opioid use during pregnancy and congenital malformations. Seventeen of these (10 of 12 case-control and 7 of 18 cohort studies) documented statistically significant positive associations. Among the case-control studies, associations with oral clefts and ventricular septal defects/atrial septal defects were the most frequently reported specific malformations. Among the cohort studies, clubfoot was the most frequently reported specific malformation. LIMITATIONS: Variabilities in study design, poor study quality, and weaknesses with outcome and exposure measurement. CONCLUSIONS: Uncertainty remains regarding the teratogenicity of opioids; a careful assessment of risks and benefits is warranted when considering opioid treatment for women of reproductive age.