Non-opioid analgesic combinations following total hip arthroplasty (RECIPE): a randomised, placebo-controlled, blinded, multicentre trial.

BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.

Inhibitory effect of berberine on morphine tolerance and hyperalgesia in mice.

OBJECTIVE: To evaluate the effect of berberine on morphine analgesia, tolerance, and hyperalgesia. METHODS: Morphine-induced acute tolerance model: mice received intraperitoneal berberine at doses of 2.5, 5.0, and 10 mg/kg; 30 min later, subcutaneous morphine 10 mg/kg was injected every hour for nine continuous h. Morphine 10 mg/kg alone was administered at 24 and 48 h. Morphine-induced chronic tolerance model: mice received intraperitoneal berberine 2.5, 5.0, and 10 mg/kg; 30 min later, 10 mg/kg morphine was injected subcutaneously for eight consecutive days. On the ninth day, morphine 10 mg/kg was given alone. Morphine-induced established tolerance model: mice were injected subcutaneously with morphine 10 mg/kg once a day for eight consecutive days. Berberine 2.5 mg/kg was administered on day one, four, and seven and morphine 10 mg/kg alone on day nine. The baseline latency (T0) and post-treatment latency (T1) were determined by the hot plate test, and the maximum possible analgesic effect (MPAE) was calculated. Nitric oxide synthase (NOS) activity and nitric oxide (NO) content in the spinal cord were measured by spectrophotometer. Verification of berberine analgesic effect by blocking N-methyl-D-aspartate (NMDA) receptor: HT-22 and HEK-293 cells transfected with NMDA plasmid were randomly divided into five groups: control group, NMDA group, berberine low-dose, medium-dose, and high-dose groups (5, 10, 20 µmol/L, respectively). Except for the control group, cells were treated with NMDA (HT-22 cells: 20 mmol/L; HEK-293 cells: 50 µmol/L). After 24 h, cell viability was detected by cell counting kit-8. The molecular mechanism between berberine and the NMDA receptor was studied by molecular docking. RESULTS: Berberine 2.5 and 5.0 mg/kg could prolong the analgesic time of morphine. In acute and chronic morphine tolerance models, berberine could inhibit the decrease of MPAE and baseline latency (0.05). In the established tolerance model, berberine could rapidly reverse the decreased MPAE (0.05). The combination of berberine and morphine on day one could effectively inhibit the morphine-induced increase of NOS activity and NO content in the spinal cord (0.05). Berberine significantly increased the cell viability of NMDA-induced nerve injury in HT-22 and HEK-293 cells (0.05). Molecular docking showed that berberine binds to the receptor pocket of NMDA. CONCLUSIONS: Berberine could effectively enhance and prolong the duration of morphine analgesia and inhibit the development of morphine-induced tolerance and hyperalgesia. Furthermore, berberine has a certain neuroprotective effect, which may be related to the inhibition of NMDA activity.

CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats.

BACKGROUND: Strong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by ß-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist. METHODS: Male Sprague-Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography). RESULTS: CYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration. CONCLUSION: Despite its lack of recruitment of ß-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than ß-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.

ß-Elemene Improves Morphine Tolerance in Bone Cancer Pain via N-Methyl-D-Aspartate Receptor 2B Subunit-Mediated µ-Opioid Receptor.

Background: Improving morphine tolerance (MT) is an urgent problem in the clinical treatment of bone cancer pain. Considering that ß-Elemene is widely used in the treatment of cancer pain, we explored the effects and mechanism of ß-Elemene in preventing MT of bone cancer pain. Method: Bone cancer pain and chronic MT rat model was established by injecting MADB106 cells and morphine (10 mg/kg). SH-SY5Y cells were treated with morphine (10 µg/mL) for 48 h to establish a cell model. The mechanical withdrawal threshold and thermal withdrawal latency of rats were detected by mechanical allodynia and thermal hyperalgesia tests, respectively. The protein expressions of µ-opioid receptor (MOPR), cyclic adenosine monophosphate (cAMP), N-methyl-D-aspartate receptor subunit 2B (NR2B), phosphorylated-calmodulin-dependent protein kinase II (p-CaMKII), and CaMKII were detected by western blot. The viability of SH-SY5Y cells was determined by the cell counting kit-8 assay. cAMP content in SH-SY5Y cells was measured by a LANCE cAMP kit. Result: Animal experiments showed that MT strengthened over time, while increased ß-Elemene dosage alleviated MT. The viability of SH-SY5Y cells was down-regulated by high-dose ß-Elemene. In the rat and cell models, long-term morphine treatment decreased the expression of MOPR and increased the cAMP and NR2B expressions and p-CaMKII/CaMKII, while ß-Elemene and siNR2B counteracted the effects of morphine treatment. In addition, siNR2B reversed the effects of ß-Elemene on related protein expressions and cAMP content in the cell model. Conclusion: ß-Elemene improved MT in bone cancer pain through the regulation of NR2B-mediated MOPR.

An infrequent cause of cholestasis: morphine-induced cholestasis / [Una causa infrecuente de colestasis extrahepática: colestasis inducida por morfina.]

Introduction: Extrahepatic cholestasis by opiates is a very rare entity of which only case reports are recorded in the literature. Methods: We present the case of a patient who developed abdominal pain and cholestasis after consumption of high doses of morphine for pain management of her underlying disease, treated by laparoscopic surgery. Results: The patient evolved favorably in the postoperative period without bilirrhage and was discharged on the fifth day with bilirubin values ​​within normal parameters. Conclusion: Sphincter of Oddi dysfunction syndrome secondary to long-term use of opioids is a very rare entity. However, it should be suspected in cases of extrahepatic cholestasis in which no stones or tumors are observed and in patients with long-term use of high-dose opiates either due to addiction or chronic pain treatment.

Introducción: La colestasis extrahepática producida por opiáceos es una entidad sumamente infrecuente de la cual solo se registran reportes de casos en la literatura. Métodos: Se presenta el caso clínico de una paciente que desarrolló dolor abdominal y colestasis luego del consumo prolongado de morfina a altas dosis, tratada por cirugía laparoscópica. Resultados: La paciente evoluciona favorablemente en el postoperatorio sin bilirragia y es dada de alta al quinto día con valores de bilirrubina dentro de los parámetros normales. Conclusión: El síndrome de disfunción del esfínter de Oddi secundario a consumo por tiempo prolongado de opioides es una entidad muy infrecuente. Sin embargo, debe sospecharse ante cuadros de colestasis extrahepáticas en los que no se observe litiasis ni tumores y en pacientes con consumo de opiáceos a altas dosis por tiempo prolongado ya sea por adicción o por tratamiento del dolor crónico.

Low-level laser acupuncture reduces postoperative pain and morphine consumption in older patients with total knee arthroplasty: A randomized placebo-controlled trial.

BACKGROUND: Patients commonly develop postoperative pain after total knee arthroplasty (TKA). Acupuncture-related techniques and low-level laser therapy could be beneficial for pain management for older individuals. OBJECTIVE: To examine the effect of low-level laser acupuncture (LA) in reducing postoperative pain, pain-related interference in daily life, morphine consumption, and morphine-related side effects in older patients with knee osteoarthritis who underwent TKA. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A single-blind randomized placebo-controlled trial was conducted. Patients (N = 82) were recruited and randomly assigned via a computer-generated list to the LA group or a placebo group. The LA group received low-level laser therapy at Sanyinjiao (SP6), Taixi (KI3), Kunlun (BL60), Fengshi (GB31), Futu (ST32) and Neiguan (PC6) after TKA, while the placebo acupuncture group received the same treatment procedure without laser energy output. MAIN OUTCOME MEASURES: The primary outcome was postoperative pain intensity, and it was measured at baseline and hours 2, 6, 10, 24, 48 and 72 after TKA. The secondary outcomes, including relative pain, postoperative pain-related interference in daily life and morphine consumption, were measured at hours 24, 48 and 72 after TKA. RESULTS: Generalized estimating equations revealed significant between-group differences in pain intensity (P = 0.01), and trend differences in pain intensity for the LA group starting at hours 10 to 72 (P < 0.05) and morphine consumption at hours 48 and 72 (P < 0.05). The changes in pain-related interference in daily life were significant (P < 0.05) at 72 h, with the exception of the parameters for worst pain, mood, and sleep. Nausea and vomiting side effects from morphine had significant between-group differences at hours 10 and 24 (P < 0.05). CONCLUSION: Low-level LA gradually reduced older patients' postoperative pain intensity and morphine consumption within the first 72 h after their TKA for osteoarthritis. Low-level LA may have benefits as an adjuvant pain management technique for clinical care. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT03995446.

Substitution treatment for opioid dependence with slow-release oral morphine: Retention rate, health status, and substance use after switching to morphine.

INTRODUCTION: Since April 2015, slow-release oral morphine (SROM) has been approved for opioid agonist treatment (OAT) in Germany. Experimental studies show that benefits of SROM over methadone include less heroin craving, better tolerability, and higher patient satisfaction and mental stability. The SROMOS study (Efficacy and Tolerability of Slow-Release Oral Morphine in Opioid Substitution Treatment) aims to investigate the long-term effects (effectiveness and safety) of morphine substitution under routine care in Germany. MATERIAL AND METHODS: This is a prospective, noninterventional, naturalistic, observational study. Between July 2016 and November 2017, this study recruited patients in OAT who decided to switch to SROM from 23 outpatient addiction treatment centers in Germany. The study collected data on mental health (Brief Symptom Inventory - BSI-18), substance use, somatic health (Opiate Treatment Index Health-Symptoms-Scale - OTI-HSS), opioid craving (visual analogue scale), and withdrawal symptoms (Short Opiate Withdrawal Scale) at baseline (t0) and after 3 (t3), 6 (t6) and 12 (t12) months. Physicians documented side effects as adverse events (AEs) and adverse drug reactions (ADRs). RESULTS: Three-quarters of the enrolled study participants (N = 180) were male. The average age was 44.4 years. Patients were opioid-dependent for 23 years and had been in OAT for almost seven years on average. After 12 months, 60.6% were still being treated with SROM. Mental health improved significantly under SROM treatment between t0 and t12. The intention-to-treat (ITT), as well as the per-protocol (PP) analysis, shows a statistically significant improvement of the mean Global Severity Index (GSI) of the BSI-18 value of 20% (ITT) and 24% (PP). Physical health also improved significantly under SROM treatment. There were no statistically significant changes in the use of cannabis, cocaine, amphetamines, and tranquillizers in the past 30 days, but heroin use, intravenous consumption, and the number of drinking days significantly decreased. CONCLUSIONS: This study provides some of the first long-term data on OAT with SROM under routine care conditions. SROM treatment is an effective alternative for a subgroup of opioid-dependent patients with an unsatisfactory course of OAT or in cases where undesirable side effects due to alternative substances have occurred. ETHICAL STATEMENT: The study protocol was approved by the Ethics Committee of the Chamber of Physicians in Hamburg in March 2016 (No. PV5222). The study was conducted by following the Declaration of Helsinki and is registered with the German Register of Clinical Trials (DRKS, ID: DRKS00010712).

D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception.

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of D-cystine diethyl ester (D-cystine diEE) or D-cystine dimethyl ester (D-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of D-cystine diEE (500 µmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO2 and sO2 accompanied by pronounced increases in pCO2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by D-cystine diME (500 µmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by D-cystine diEE. D-cystine diEE and D-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the D-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.

Sintocalmy, a Passiflora incarnata Based Herbal, Attenuates Morphine Withdrawal in Mice.

Chronic opioid use changes brain chemistry in areas related to reward processes, memory, decision-making, and addiction. Both neurons and astrocytes are affected, ultimately leading to dependence. Passiflora incarnata L. (Passifloraceae) is the basis of frequently used herbals to manage anxiety and insomnia, with proven central nervous system depressant effects. Anti-addiction properties of P. incarnata have been reported. The aim of this study was to investigate the effect of a commercial extract of Passiflora incarnata (Sintocalmy®, Aché Laboratory) in the naloxone-induced jumping mice model of morphine withdrawal. In addition, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) levels were assessed in the frontal cortex and hippocampus, and DNA damage was verified on blood cells. In order to improve solubilization a Sintocalmy methanol extract (SME) was used. SME is mainly composed by flavonoids isovitexin and vitexin. The effects of SME 50, 100 and 200 mg/kg (i.p.) were evaluated in the naloxone-induced withdrawal syndrome in mice. SME 50 and SME 100 mg/kg decreased naloxone-induced jumping in morphine-dependent mice without reducing locomotor activity. No alterations were found in GFAP levels, however SME 50 mg/kg prevented the S100B increase in the frontal cortex and DNA damage. This study shows anti-addiction effects for a commercial standardized extract of P. incarnata and suggests the relevance of proper clinical assessment.

Neural bases for attenuation of morphine withdrawal by Heantos-4: role of l-tetrahydropalmatine.

Severe withdrawal symptoms triggered by cessation of long-term opioid use deter many individuals from seeking treatment. Opioid substitution and α2-adrenergic agonists are the current standard of pharmacotherapy for opioid use disorder in western medicine; however, each is associated with significant complications. Heantos-4 is a non-opioid botanical formulation used to facilitate opioid detoxification in Vietnam. While ongoing clinical use continues to validate its safety and effectiveness, a mechanism of action accounting for these promising effects remains to be specified. Here, we assess the effects of Heantos-4 in a rat model of morphine-dependence and present evidence that alleviation of naloxone-precipitated somatic withdrawal signs is related to an upregulation of mesolimbic dopamine activity and a consequent reversal of a hypodopaminergic state in the nucleus accumbens, a brain region implicated in opioid withdrawal. A central dopaminergic mechanism is further supported by the identification of l-tetrahydropalmatine as a key active ingredient in Heantos-4, which crosses the blood-brain barrier and shows a therapeutic efficacy comparable to its parent formulation in attenuating withdrawal signs. The anti-hypodopaminergic effects of l-tetrahydropalmatine may be related to antagonism of the dopamine autoreceptor, thus constituting a plausible mechanism contributing to the effectiveness of Heantos-4 in facilitating opioid detoxification.

Morphine-mediated release of miR-138 in astrocyte-derived extracellular vesicles promotes microglial activation.

Opioids, such as morphine, are the mainstay for the management of postsurgical pain. Over the last decade there has been a dramatic increase in deaths related to opioid overdose. While opioid abuse has been shown to result in increased neuroinflammation, mechanism(s) underlying this process, remain less understood. In recent years, microRNAs have emerged as key mediators of gene expression regulating both paracrine signaling and cellular crosstalk. MiRNAs constitute the extracellular vesicle (EV) cargo and can shuttle from the donor to the recipient cells. Exposure of human primary astrocytes to morphine resulted in induction and release of miR-138 in the EVs isolated from conditioned media of cultured astrocytes. Released EVs were, in turn, taken up by the microglia, leading to activation of these latter cells. Interestingly, activation of microglia involved binding of the GUUGUGU motif of miR138 to the endosomal toll like receptor (TLR)7, leading, in turn, to cellular activation. These findings were further corroborated in vivo in wildtype mice wherein morphine administration resulted in increased microglial activation in the thalamus. In TLR7-/- mice on the other hand, morphine failed to induce microglial activation. These findings have ramifications for the development of EV-loaded anti-miRNAs as therapeutics for alleviating neuroinflammation in opioids abusers.

Δ9-tetrahydrocannabinol: Drug discrimination abuse liability testing in female Lister Hooded rats: Trials, tribulations and triumphs.

INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.

Maternal Poppy Seed Tea Ingestion and Ensuing Neonatal Abstinence Syndrome.

The incidence of neonatal abstinence syndrome has been rising in the USA. Nonpharmacological treatments resulting in similar withdrawal states in the newborn have also been described. We report an infant with neonatal abstinence syndrome born to a mother with daily poppy seed tea ingestion for the self-treatment of nausea. A sample of poppy seed tea was replicated using the mother's self-reported recipe. The sample was analyzed using liquid chromatography tandem mass spectrometry. This recipe produced a result of approximately 7.8 mg of morphine per serving which she reported to have drank 5-6 days per week, for an estimated 7 months during the course of her pregnancy.

Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine.

RATIONALE: Acute naloxone-precipitated morphine withdrawal (MWD) produces a conditioned place aversion (CPA) in rats even after one or two exposures to high-dose (20 mg/kg, sc) morphine followed 24-h later by naloxone (1 mg/kg, sc). However, the somatic withdrawal reactions produced by acute naloxone-precipitated MWD in rats have not been investigated. A recently discovered fatty acid amide, N-oleoylglycine (OlGly), which has been suggested to act as a fatty acid amide hydrolase (FAAH) inhibitor and as a peroxisome proliferator-activated receptor alpha (PPARα) agonist, was previously shown to interfere with a naloxone-precipitated MWD-induced CPA in rats. OBJECTIVES: The aims of these studies were to examine the somatic withdrawal responses produced by acute naloxone-precipitated MWD and determine whether OlGly can also interfere with these responses. RESULTS: Here, we report that following two exposures to morphine (20 mg/kg, sc) each followed by naloxone (1 mg/kg, sc) 24 h later, rats display nausea-like somatic reactions of lying flattened on belly, abdominal contractions and diarrhea, and display increased mouthing movements and loss of body weight. OlGly (5 mg/kg, ip) interfered with naloxone-precipitated MWD-induced abdominal contractions, lying on belly, diarrhea and mouthing movements in male Sprague-Dawley rats, by both a cannabinoid 1 (CB1) and a PPARα mechanism of action. Since these withdrawal reactions are symptomatic of nausea, we evaluated the potential of OlGly to interfere with lithium chloride (LiCl)-induced and MWD-induced conditioned gaping in rats, a selective measure of nausea; the suppression of MWD-induced gaping reactions by OlGly was both CB1 and PPARα mediated. CONCLUSION: These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly.

Birth outcomes with prescribed chronic and acute opioid exposure during pregnancy.

OBJECTIVES: To assess the effects of no, any, and acute and chronic prescription opioid exposure for pain during pregnancy on maternal and fetal outcomes. DESIGN: Retrospective cohort study. SETTING: Integrated healthcare delivery system. Information on pregnancies and their outcomes were obtained from administrative data and verified via manual chart review. PARTICIPANTS: Women ≥ 18 years of age who were pregnant between January 1, 2012 and May 31, 2015 and had chronic, acute, and no opioid exposure; defined as an ambulatory dispensing(s) of >30 (with a total of 225 morphine equivalents), 1-29, and 0 days supply of opioid, respectively, during pregnancy. MAIN OUTCOME MEASURE: Non-live birth. RESULTS: A total 13,809 pregnancies for 13,131 women were included. Pregnancies with opioid exposure had higher risk scores and more comorbid conditions. A total of 1,319 (9.6 percent) pregnancies had any documented opioid exposure during pregnancy with 125 (1.0 percent) and 1,194 (8.7 percent) pregnancies having had chronic and acute opioid exposure, respectively. Pregnancies with acute opioid exposure had a higher percentage of non-live births (3.1 percent) compared to pregnancies (1.0 percent) with no opioid exposure (adjusted odds ratio = 3.46, 95% confidence interval 2.33-5.14) but no difference compared to pregnancies with chronic (1.6 percent) opioid exposure (p > 0.05 with adjustment). CONCLUSIONS: While a dose response of opioid exposure was not identified, these results add to existing evidence that opioid exposure during pregnancy is correlated with negative outcomes. Practitioners may better serve pregnant women and their fetuses by encouraging alternate pain relief treatments.

Electroacupuncture alleviates morphine­induced hyperalgesia by regulating spinal CB1 receptors and ERK1/2 activity.

Electroacupuncture (EA), a traditional Chinese therapeutic technique, is considered an effective method for treating certain painful neuropathies induced by various neuropathological damage. The current study investigated the effect of EA on intrathecal (IT) morphine­induced hyperalgesia (MIH) and examined the hypothesis that activation of cannabinoid receptor 1 (CB1) could enhance the antinociceptive effect of EA on MIH via regulation of the extracellular signal­regulated kinase 1/2 (ERK1/2) signaling pathway. Using a rat model of IT MIH, mechanical and thermal hyperalgesia were evaluated by an electronic von Frey filament and hotplate at baseline (1 day before IT administration) and at days 1, 3, 5 and 7 after IT administration. Rats received IT normal saline, IT morphine or IT morphine + EA at ST36­GB34. The protein levels of ERK1/2, phosphorylated (p)­ERK1/2 and CB1 in the spinal cord were assayed by western blotting. Furthermore, the effect of IT injection of the CB1 agonist WIN 55,212­2 and the CB1 antagonist SR141716 on the antinociceptive effect of EA in rats with MIH was investigated. Nociceptive behavior and ERK1/2, phosphorylated (p)­ERK1/2 and CB1 protein levels were evaluated as mentioned above. The results revealed that chronic IT injections of morphine induced a significant decrease in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) accompanied with remarkable upregulation of p­ERK1/2 in the spinal cord, which could be attenuated by EA at the ST36­GB34 acupoints. In the rat model of MIH, IT injection of WIN 55,212­2 combined with EA induced a significant increase in MWT and TWL accompanied with a significant decrease in p­ERK1/2 and a significant increase in CB1 protein level compared with EA alone, while SR141716 induced the opposite results. The present study suggests that EA alleviates hyperalgesia induced by IT injection of morphine partially through the inhibition of ERK1/2 activation. Activation of the CB1 receptor enhances the antinociceptive effect of EA in rats with MIH partly through the regulation of the spinal CB1­ERK1/2 signaling pathway.

Systematic review of interventions for the prevention and treatment of postoperative urinary retention.

Background: Postoperative urinary retention (PO-UR) is an acute and painful inability to void after surgery that can lead to complications and delayed hospital discharge. Standard treatment with a urinary catheter is associated with a risk of infection and can be distressing, undignified and uncomfortable. This systematic review aimed to identify effective interventions for the prevention and treatment of PO-UR that might be alternatives to urinary catheterization. Methods: Electronic databases were searched from inception to September 2017. Randomized trials of interventions for the prevention or treatment of PO-UR were eligible for inclusion. Studies were assessed for risk of bias using the Cochrane (2.0) tool. Two reviewers were involved at all review stages. Where possible, data were pooled using random-effects meta-analysis. The overall quality of the body of evidence was rated using the GRADE approach. Results: Some 48 studies involving 5644 participants were included. Most interventions were pharmacological strategies to prevent PO-UR. Based on GRADE, there was high-certainty evidence to support replacing morphine in a regional anaesthetic regimen, using alpha-blockers (number needed to treat to prevent one case of PO-UR (NNT) 5, 95 per cent c.i. 5 to 7), the antispasmodic drug drotaverine (NNT 9, 7 to 30) and early postoperative mobilization (NNT 5, 4 to 8) for prevention, and employing hot packs or gauze soaked in warm water for treatment (NNT 2, 2 to 4). Very few studies reported on secondary outcomes of pain, incidence of urinary tract infection or duration of hospital stay. Conclusion: Promising interventions exist for PO-UR, but they need to be evaluated in randomized trials investigating comparative clinical and cost effectiveness, and acceptability to patients.

Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner.

Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine-threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a µ opioid receptor (MOR)-dependent manner. Levo-corydalmine (l-CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l-CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l-CDL also inhibited tolerance induced by the MOR agonist DAMGO. l-CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l-CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt-dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance.

Acupuncture for reducing pruritus induced by intrathecal morphine at elective cesarean delivery: a placebo-controlled, randomized, double-blind trial.

BACKGROUND: Intrathecal morphine is a standard postoperative analgesic administered after cesarean delivery, but frequently causes pruritus. Acupuncture reportedly resolves refractory pruritus in certain patients. The aim of the study was to investigate the effectiveness of acupuncture in preventing pruritus induced by intrathecal morphine. METHODS: Thirty parturients received intrathecal hyperbaric bupivacaine (12 mg), fentanyl (10 µg), and morphine (150 µg) for spinal anesthesia at elective cesarean delivery at term. Patients were randomly divided into the acupuncture group (n=15) and the control group (n=15). In the acupuncture and control groups, certified acupuncturists inserted either indwelling press needles or sham needles, into Hegu (LI4), Neiguan (PC6), Quchi (LI11), and Zhigou (SJ6) on both arms the day before surgery. Needles were removed 48 hours postoperatively. The primary outcome was the incidence of postoperative pruritus. Adverse effects including nausea and vomiting were also investigated. RESULTS: There were no significant differences between the acupuncture group and the control group in the incidence of pruritus (67% vs. 67%, P=1.000, RR 1.0 [95% CI 0.60 to 1.66]) or the requirement for antipruritic therapy (6.7% vs. 20.0%, P=0.283, RR 0.33 [95% CI 0.04 to 2.85]). The incidence of postoperative nausea in the acupuncture group versus control group was 40.0% vs. 13.3%, P=0.099, RR 3.0 [95% CI 0.72 to 12.6]). The postoperative analgesic effect was comparable. CONCLUSION: Preoperatively administered acupuncture using press needles did not decrease intrathecal morphine-induced pruritus or the requirement for treatment.

Effect of Adding Magnesium Sulphate to Epidural Bupivacaine and Morphine on Post-Thoracotomy Pain Management: A Randomized, Double-Blind, Clinical Trial.

Post-thoracotomy pain is very severe and may cause pulmonary complications. Thoracic epidural analgesia can greatly decrease the pain experience and its consequences. However, finding new methods to decrease the amount of administered opioids is an important issue of research. We aimed to evaluate the effect of adding epidural magnesium sulphate to bupivacaine and morphine on pain control and the amount of opioid consumption after thoracotomy. Eighty patients undergoing thoracotomy at a tertiary cardiothoracic referral centre were enrolled in a randomized, double-blind trial. Patients were randomly allocated to two groups. Bupivacaine (12.5 mg) and morphine (2 mg) were administered epidurally to all patients at the end of operation. Patients in the magnesium (Mg) group received epidural magnesium sulphate (50 mg), and patients in the control (C) group received normal saline as an adjuvant. Visual analogue scale (VAS) score and the amount of morphine consumption were measured during 24 hr post-operation. Thirty-nine patients in the Mg group and 41 patients in the C group completed the study. Patients in the Mg group had significantly less VAS score at recovery time (p < 0.05), 2 hr (p < 0.01) and 4 hr (p < 0.05) after surgery. The patient-controlled analgesia pump was started earlier in the C group than in the Mg group (p < 0.05). The amount of morphine needed in the Mg group was significantly lower than in the C group (5.64 ± 1.69 mg/24 hr versus 8.44 ± 3.98 mg/24 hr; p < 0.001). Pruritus was seen in the C group (9.7%) and absent in the Mg group (p < 0.05). Co-administration of magnesium sulphate with bupivacaine and morphine for thoracic epidural analgesia after thoracotomy leads to a reduction in post-operative pain score and the need for opioid administration.