Μ-opioid Agonist Research Articles

Management of eight labor and delivery patients dependent on buprenorphine (Subutex™): A retrospective chart review

Background: Opioid use during pregnancy is a growing concern in the United States. Buprenorphine has been recommended by “The American College of Obstetrics and Gynecology” as an alternative to methadone to decrease risks associated with the use of illicit opioids during pregnancy. The partial μ-opioid agonists’ unique pharmacology, including its long half time and high affinity to the μ-opioid receptor, complicates patient management in a highly kinetic, and often urgent field like obstetric anesthesia. We reviewed our management and outcomes in this medically complex population. Methods: An Institutional Review Board (IRB) approved retrospective chart review was conducted of women admitted to the University of Washington Medical Center Labor and Delivery unit from July 2012 to November 2013 using buprenorphine. All deliveries, including intrauterine fetal demise, were included. Results: Eight women were admitted during this period to our L&D floor on buprenorphine. All required peri-partum anesthetic management either for labor and/or cesarean delivery management. Analgesic management included dilaudid or fentanyl PCA and/or continued epidural infusion, and in one instance ketamine infusion, while the pre-admission buprenorphine regimen was continued. Five babies were viable, two women experienced intrauterine fetal death at 22 and 36 weeks gestational age (GSA), respectively, and one neonate died shortly after delivery due to a congenital diaphragmatic hernia. Conclusions: This case series illuminates the medical complexity of parturients using buprenorphine. Different treatment modalities in the absence of evidence-based guidelines included additional opioid administration and continued epidural analgesia. The management of post-cesarean pain in patients on partial μ-opioid agonists remains complex and variable, and evidence-based guidelines could be useful for clinicians to direct care.

Altered Signaling in the Descending Pain-modulatory System after Short-Term Infusion of the μ-Opioid Agonist Remifentanil.

μ-Opioid receptor agonists are widely used within the contemporary treatment of pain, but abrupt opioid suspension, even after short-term infusion, can paradoxically increase the sensitivity to noxious stimuli, a phenomenon that has been, for example, reported after application of the fast-acting μ-opioid receptor agonist remifentanil. To investigate the mechanisms underlying the effects of discontinuation of remifentanil application on pain processing in the human CNS, we analyzed neuronal responses to thermal stimuli before and after a short-term infusion of remifentanil (30 min 0.1 μg/kg body weight/min) compared with control in the brain, brainstem, and spinal cord in drug-naive male volunteers using fMRI. Subsequent to remifentanil suspension, we observed reduced heat pain thresholds and increased neuronal responses in pain-encoding as well as in key regions of the descending pain-modulatory system, such as the periaqueductal gray matter, the nucleus cuneiformis, and the rostral ventromedial medulla. Moreover, the spinal pain-related multivoxel activity pattern showed an opioid-specific change after drug suspension. Importantly, remifentanil suspension increased the functional coupling between the nucleus cuneiformis and the rostral anterior cingulate cortex, and the coupling strength between the rostral anterior cingulate cortex and the nucleus cuneiformis correlated negatively with the individual pain threshold after opioid suspension. These findings demonstrate that, already subsequent to a short-term infusion of the μ-opioid receptor agonist remifentanil, signaling in the descending pain-modulatory system is fundamentally altered and that these changes are directly related to the behavioral sensitivity to pain.SIGNIFICANCE STATEMENT Opioids are widely used in modern medicine, but, in addition to their known side effects, it is increasingly recognized that opioids can also increase sensitivity to pain subsequent to their use. Using the fast-acting μ-opioid receptor agonist remifentanil and fMRI in healthy male volunteers, this study demonstrates how signaling changes occur along the entire descending pain-modulatory pathway after opioid discontinuation and how these alterations are closely linked to increased behavioral pain sensitivity. Particularly by revealing modified responses in pain-modulatory brainstem regions that have been previously demonstrated to be causally involved in acute opioid withdrawal effects in rodents, the data provide a plausible neuronal mechanism by which the increased sensitivity to pain after opioid suspension is mediated in humans.

Additive and subadditive antiallodynic interactions between μ-opioid agonists and N-methyl D-aspartate antagonists in male rhesus monkeys.

μ-Opioid agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception and N-methyl D-aspartate (NMDA) receptor antagonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate the undesirable effects of μ-opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of μ-agonists in preclinical models of thermal hypersensitivity (i.e. capsaicin-induced thermal allodynia) are unknown. The present study determined the behavioral effects of racemic ketamine, (+)-MK-801, (-)-nalbuphine, and (-)-oxycodone alone and in fixed proportion mixtures in assays of capsaicin-induced thermal allodynia and schedule-controlled responding in rhesus monkeys. Ketamine, nalbuphine, and oxycodone produced dose-dependent antiallodynia. MK-801 was inactive up to doses that produced undesirable effects. Ketamine, but not MK-801, enhanced the potency of μ-agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or subadditive depending on the mixture. Furthermore, oxycodone and MK-801 interactions were subadditive on antiallodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antagonists as adjuncts to μ-opioid agonists for thermal allodynic pain states.

Management of eight labor and delivery patients dependent on buprenorphine (Subutex™): A retrospective chart review

Background: Opioid use during pregnancy is a growing concern in the United States. Buprenorphine has been recommended by “The American College of Obstetrics and Gynecology” as an alternative to methadone to decrease risks associated with the use of illicit opioids during pregnancy. The partial μ-opioid agonists’ unique pharmacology, including its long half time and high affinity to the μ-opioid receptor, complicates patient management in a highly kinetic, and often urgent field like obstetric anesthesia. We reviewed our management and outcomes in this medically complex population. Methods: An Institutional Review Board (IRB) approved retrospective chart review was conducted of women admitted to the University of Washington Medical Center Labor and Delivery unit from July 2012 to November 2013 using buprenorphine. All deliveries, including intrauterine fetal demise, were included. Results: Eight women were admitted during this period to our L&D floor on buprenorphine. All required peri-partum anesthetic management either for labor and/or cesarean delivery management. Analgesic management included dilaudid or fentanyl PCA and/or continued epidural infusion, and in one instance ketamine infusion, while the pre-admission buprenorphine regimen was continued. Five babies were viable, two women experienced intrauterine fetal death at 22 and 36 weeks gestational age (GSA), respectively, and one neonate died shortly after delivery due to a congenital diaphragmatic hernia. Conclusions: This case series illuminates the medical complexity of parturients using buprenorphine. Different treatment modalities in the absence of evidence-based guidelines included additional opioid administration and continued epidural analgesia. The management of post-cesarean pain in patients on partial μ-opioid agonists remains complex and variable, and evidence-based guidelines could be useful for clinicians to direct care.

Management of eight labor and delivery patients dependent on buprenorphine (Subutex™): A retrospective chart review.

Background: Opioid use during pregnancy is a growing concern in the United States. Buprenorphine has been recommended by "The American College of Obstetrics and Gynecology" as an alternative to methadone to decrease risks associated with the use of illicit opioids during pregnancy. The partial μ-opioid agonists' unique pharmacology, including its long half time and high affinity to the μ-opioid receptor, complicates patient management in a highly kinetic, and often urgent field like obstetric anesthesia. We reviewed our management and outcomes in this medically complex population. Methods: An Institutional Review Board (IRB) approved retrospective chart review was conducted of women admitted to the University of Washington Medical Center Labor and Delivery unit from July 2012 to November 2013 using buprenorphine. All deliveries, including intrauterine fetal demise, were included. Results: Eight women were admitted during this period to our L&D floor on buprenorphine. All required peri-partum anesthetic management either for labor and/or cesarean delivery management. Analgesic management included dilaudid or fentanyl PCA and/or continued epidural infusion, and in one instance ketamine infusion, while the pre-admission buprenorphine regimen was continued. Five babies were viable, two women experienced intrauterine fetal death at 22 and 36 weeks gestational age (GSA), respectively, and one neonate died shortly after delivery due to a congenital diaphragmatic hernia. Conclusions: This case series illuminates the medical complexity of parturients using buprenorphine. Different treatment modalities in the absence of evidence-based guidelines included additional opioid administration and continued epidural analgesia. The management of post-cesarean pain in patients on partial μ-opioid agonists remains complex and variable, and evidence-based guidelines could be useful for clinicians to direct care.

Tapentadol: what every doctor needs to know about this new drug

ABSTRACT BACKGROUND AND OBJECTIVES: Acute and chronic pain is a major problem with repercussion in our society, causing impairment in the quality of life of patients as well as socioeconomic losses, due to work absenteeism. This review aims to analyze the use of tapentadol, an analgesic not yet available in Brazil, with a dual mechanism of action, in the treatment of acute and chronic pain syndromes. CONTENTS: A review about this new drug was made on the Pubmed database using the keywords tapentadol and opioids, evaluating its pharmacological and clinical aspects comparing with other current drugs in pain treatment, as well as its indications and contraindications in the management of patients with pain disorders. CONCLUSION: Tapentadol has been shown to be effective in the treatment of acute and chronic pain, with potency equivalent to the opioids currently used. In addition, it developed less tolerance, less adverse effects and better therapeutic response in chronic neuropathic pain when compared to pure µ-opioid receptors agonists.

Tapentadol: what every doctor needs to know about this new drug

ABSTRACT BACKGROUND AND OBJECTIVES: Acute and chronic pain is a major problem with repercussion in our society, causing impairment in the quality of life of patients as well as socioeconomic losses, due to work absenteeism. This review aims to analyze the use of tapentadol, an analgesic not yet available in Brazil, with a dual mechanism of action, in the treatment of acute and chronic pain syndromes. CONTENTS: A review about this new drug was made on the Pubmed database using the keywords tapentadol and opioids, evaluating its pharmacological and clinical aspects comparing with other current drugs in pain treatment, as well as its indications and contraindications in the management of patients with pain disorders. CONCLUSION: Tapentadol has been shown to be effective in the treatment of acute and chronic pain, with potency equivalent to the opioids currently used. In addition, it developed less tolerance, less adverse effects and better therapeutic response in chronic neuropathic pain when compared to pure µ-opioid receptors agonists.

The effect of µ-opioid receptor activation on GABAergic neurons in the spinal dorsal horn.

The superficial dorsal horn of the spinal cord plays an important role in pain transmission and opioid activity. Several studies have demonstrated that opioids modulate pain transmission, and the activation of µ-opioid receptors (MORs) by opioids contributes to analgesic effects in the spinal cord. However, the effect of the activation of MORs on GABAergic interneurons and the contribution to the analgesic effect are much less clear. In this study, using transgenic mice, which allow the identification of GABAergic interneurons, we investigated how the activation of MORs affects the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive afferent and GABAergic interneurons. We found that a selective µ-opioid agonist, [D-Ala2, NMe-Phe4, Gly-ol]-enkephanlin (DAMGO), induced an outward current mediated by K+ channels in GABAergic interneurons. In addition, DAMGO reduced the amplitude of evoked excitatory postsynaptic currents (EPSCs) of GABAergic interneurons which receive monosynaptic inputs from primary nociceptive C fibers. Taken together, we found that DAMGO reduced the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive C fibers and GABAergic interneurons. These results suggest one possibility that suppression of GABAergic interneurons by DMAGO may reduce the inhibition on secondary GABAergic interneurons, which increase the inhibition of the secondary GABAergic interneurons to excitatory neurons in the spinal dorsal horn. In this circumstance, the sum of excitation of the entire spinal network will control the pain transmission.

Low-dose buprenorphine infusion to prevent postoperative hyperalgesia in patients undergoing major lung surgery and remifentanil infusion: a double-blind, randomized, active-controlled trial

BackgroundPostoperative secondary hyperalgesia arises from central sensitization due to pain pathways facilitation and/or acute opioid exposure. The latter is also known as opioid-induced hyperalgesia (OIH). Remifentanil, a potent μ-opioid agonist, reportedly induces postoperative hyperalgesia and increases postoperative pain scores and opioid consumption. The pathophysiology underlying secondary hyperalgesia involves N-methyl-D-aspartate (NMDA)-mediated pain pathways. In this study, we investigated whether perioperatively infusing low-dose buprenorphine, an opioid with anti-NMDA activity, in patients receiving remifentanil infusion prevents postoperative secondary hyperalgesia. MethodsSixty-four patients, undergoing remifentanil infusion during general anaesthesia and major lung surgery, were randomly assigned to receive either buprenorphine i.v. infusion (25 μg h−1 for 24 h) or morphine (equianalgesic dose) perioperatively. The presence and extent of punctuate hyperalgesia were assessed one day postoperatively. Secondary outcome variables included postoperative pain scores, opioid consumption and postoperative neuropathic pain assessed one and three months postoperatively. ResultsA distinct area of hyperalgesia or allodynia around the surgical incision was found in more patients in the control group than in the treated group. Mean time from extubation to first morphine rescue dose was twice as long in the buprenorphine-treated group than in the morphine-treated group: 18 vs 9 min (P=0.002). At 30 min postoperatively, patients receiving morphine had a higher hazard ratio for the first analgesic rescue dose than those treated with buprenorphine (P=0.009). At three months, no differences between groups were noted. ConclusionsLow-dose buprenorphine infusion prevents the development of secondary hyperalgesia around the surgical incision but shows no long-term efficacy at three months follow-up.

Chronic morphine reduces the readily releasable pool of GABA, a presynaptic mechanism of opioid tolerance.

Chronic treatment with opioids, such as morphine, leads to analgesic tolerance. While postsynaptic opioid tolerance is well documented, the involvement of presynaptic mechanisms remains unclear. We show that chronic morphine reduces the ability of periaqueductal grey (PAG) neurons to maintain GABAergic transmission. This depression of GABAergic transmission was due to a reduction in the effective size of the readily releasable pool. This also led to a reduction in opioid presynaptic inhibition; these presynaptic adaptations need to be considered in the development of strategies to reduce opioid tolerance. The midbrain periaqueductal grey (PAG) plays a critical role in tolerance to the analgesic actions of opioids such as morphine. While numerous studies have identified the postsynaptic adaptations induced by chronic morphine treatment in this and other brain regions, the presence of presynaptic adaptations remains uncertain. We examined GABAergic synaptic transmission within rat PAG brain slices from animals which underwent a low dose morphine treatment protocol which produces tolerance, but not withdrawal. Evoked GABAergic IPSCs (inhibitory postsynaptic currents) were less in morphine compared to control saline treated animals. Postsynaptic GABAA receptor mediated currents and desensitization, presynaptic release probability (Pr ), and inhibition by endogenous neurotransmitters were similar in morphine and saline treated animals. By contrast, the effective size of the readily releasable pool (RRP) was smaller in morphine treated animals. While the μ-opioid agonist DAMGO produced a reduction in Pr and RRP size in saline treated animals, it only reduced Pr in morphine treated animals. Consequently, DAMGO-induced inhibition of evoked IPSCs during short burst stimulation was less in morphine, compared to saline treated animals. These results indicate that low dose chronic morphine treatment reduces presynaptic μ-opioid inhibition by reducing the size of the pool of vesicles available for action potential dependent release. This novel presynaptic adaptation may provide important insights into the development of efficacious pain therapies that can circumvent the development of opioid tolerance.

Effects of remifentanil on esophageal and esophagogastric junction (EGJ) bolus transit in healthy volunteers using novel pressure-flow analysis.

Remifentanil is associated with subjective dysphagia and an objective increase in aspiration risk. Studies of opioid effects have shown decreased lower esophageal sphincter relaxation. We assessed bolus transit through the esophagus and esophagogastric junction (EGJ) during remifentanil administration using objective pressure-flow analysis. Data from 11 healthy young participants (23±3years, 7M) were assessed for bolus flow through the esophagus and EGJ using high-resolution impedance manometry (Manoscan™, Sierra Scientific Instruments, Inc., LES Angeles, CA, USA) with 36 pressure and 18 impedance segments. Data were analyzed for esophageal pressure topography and pressure-flow analysis using custom Matlab analyses (Mathworks, Natick, USA). Paired t tests were performed with a P-value of <.05 regarded as significant. Duration of bolus flow through (remifentanil/R 3.0±0.3 vs baseline/B 5.0±0.4seconds; P<.001) and presence at the EGJ (R 5.1±0.5 vs B 7.1±0.5seconds; P=.001) both decreased during remifentanil administration. Distal latency (R 5.2±0.4 vs B 7.5±0.2seconds; P<.001) and distal esophageal distension-contraction latency (R 3.5±0.1 vs B 4.7±0.2seconds; P<.001) were both reduced. Intrabolus pressures were increased in both the proximal (R 5.3±0.9 vs B 2.6±1.3mmHg; P=.01) and distal esophagus (R 8.6±1.7 vs B 3.1±0.8mmHg; P=.001). There was no evidence of increased esophageal bolus residue. Remifentanil-induced effects were different for proximal and distal esophagus, with a reduced time for trans-sphincteric bolus flow at the EGJ, suggestive of central and peripheral μ-opioid agonism. There were no functional consequences in healthy subjects.

Advances in the delivery of buprenorphine for opioid dependence.

Opioid use disorders (OUDs) have long been a global problem, but the prevalence rates have increased over 20 years to epidemic proportions in the US, with concomitant increases in morbidity and all-cause mortality, but especially opioid overdose. These increases are in part attributable to a several-fold expansion in the prescription of opioid pain medications over the same time period. Opioid detoxification and psychosocial treatments alone have each not yielded sufficient efficacy for OUD, but μ-opioid receptor agonist, partial agonist, and antagonist medications have demonstrated the greatest overall benefit in OUD treatment. Buprenorphine, a μ-opioid receptor partial agonist, has been used successfully on an international basis for several decades in sublingual tablet and film preparations for the treatment of OUD, but the nature of formulation, which is typically self-administered, renders it susceptible to nonadherence, diversion, and accidental exposure. This article reviews the clinical trial data for novel buprenorphine delivery systems in the form of subcutaneous depot injections, transdermal patches, and subdermal implants for the treatment of OUD and discusses both the clinical efficacy of longer-acting formulations through increasing consistent medication exposure and their potential utility in reducing diversion. These new delivery systems also offer new dosing opportunities for buprenorphine and strategies for dosing intervals in the treatment of OUD.

Safety and effectiveness of once-daily Hysingla extended-release tablets in patients with baseline depression or anxiety.

Long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone bitartrate (HYD) for the treatment of moderate to severe noncancer and nonneuropathic pain among patients with and without concurrent depression/anxiety at baseline. Post hoc analysis. HYD demonstrated a safety profile consistent with μ-opioid agonists: Serious adverse events in 12% patients with depression/anxiety including four deaths; 6% without depression/anxiety including one death. All pain scores declined by ≥2 points and mean daily HYD dose remained stable in both subgroups. More serious adverse events occurred among patients with comorbid depression/anxiety at baseline than among those without. HYD provided stable and effective analgesia for 52 weeks among chronic pain patients with and without comorbid depression/anxiety at baseline.

The Hypnotic, Anxiolytic, and Antinociceptive Profile of a Novel µ-Opioid Agonist.

5′-4-Alkyl/aryl-1H-1,2,3-triazole derivatives PILAB 1–12 were synthesized and a pharmacological screening of these derivatives was performed to identify a possible effect on the Central Nervous System (CNS) and to explore the associated mechanisms of action. The mice received a peritoneal injection (100 µmol/kg) of each of the 12 PILAB derivatives 10 min prior to the injection of pentobarbital and the mean hypnosis times were recorded. The mean hypnosis time increased for the mice treated with PILAB 8, which was prevented when mice were administered CTOP, a µ-opioid antagonist. Locomotor and motor activities were not affected by PILAB 8. The anxiolytic effect of PILAB 8 was evaluated next in an elevated-plus maze apparatus. PILAB 8 and midazolam increased a percentage of entries and spent time in the open arms of the apparatus compared with the control group. Conversely, a decrease in the percentages of entries and time spent in the closed arms were observed. Pretreatment with naloxone, a non-specific opioid antagonist, prior to administration of PILAB 8 exhibited a reverted anxiolytic effect. PILAB 8 exhibited antinociceptive activity in the hot plate test, and reduced reactivity to formalin in the neurogenic and the inflammatory phases. These data suggest that PILAB 8 can activate µ-opioid receptors to provoke antinociceptive and anti-inflammatory effects in mice.

PD50-09 A POTENTIAL NEW TARGET FOR STRESS URINARY INCONTINENCE: A μ-OPIOID RECEPTOR IN THE SPINAL CORD BY TRAMADOL, IN RATS

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Female Incontinence: Therapy II1 Apr 2017PD50-09 A POTENTIAL NEW TARGET FOR STRESS URINARY INCONTINENCE: A μ-OPIOID RECEPTOR IN THE SPINAL CORD BY TRAMADOL, IN RATS Asuka Ashikari, Minoru Miyazato, Takuma Oshiro, and Seiichi Saito Asuka AshikariAsuka Ashikari More articles by this author , Minoru MiyazatoMinoru Miyazato More articles by this author , Takuma OshiroTakuma Oshiro More articles by this author , and Seiichi SaitoSeiichi Saito More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2221AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Stress urinary incontinence (SUI) is the most common type of urinary incontinence in women. As the efficacy of pharmacotherapy for SUI is generally unsatisfactory, surgery seems to be the best option for achieving long-term continence. Thus, new effective drugs for SUI should be developed. Tramadol is widely used as an analgesic. It combines the effects of μ-opioid receptors with inhibition of serotonin and noradrenaline reuptake inhibitors. Both effects may be useful for treatment of SUI, but the efficacy of tramadol for SUI has not been examined yet. We previously established a rat model that can be used for examining the active urethral closure mechanism during sneezing. We therefore investigated the effect of tramadol on urethral continence reflex by using this model. METHODS Healthy female rats and rats with SUI induced by vaginal distension (VD) were used. (1) The effects of tramadol on tilt leak point pressure (tilt LPP) were examined before and after intravenous (i.v.) injection of tramadol under urethane anesthesia in both rats. (2) To investigate the effect of tramadol on mid-urethral responses during sneezing, the amplitude of the urethral responses during sneezing (A-URS) and urethral baseline pressure (UBP) were measured by inserting a microtip transducer catheter in the middle urethra in both rats. (3) To confirm the effects of tramadol on μ-opioid receptors in the spinal cord, the effect of tramadol in the presence of intrathecal (i.t.) cyprodime, a selective μ-opioid receptor antagonist, was examined in the healthy rats. RESULTS (1) Tilt LPP was lower in the VD rats than in the healthy rats (43.9 vs 48.6 cmH2O). Tramadol (i.v.) significantly increased the tilt LPP by 25.9% and 21.2% in the healthy and VD rats, respectively. (2) In the healthy rats, tramadol (i.v.) enhanced the A-URS and UBP by 37.0% and 74.9%, respectively. In the VD rats, tramadol administration also enhanced UBP by 11.1% but did not affect A-URS. (3) Administration of cyprodime alone (i.t.) did not affect A-URS and UBP. However, in the presence of cyprodime, tramadol-induced increases in A-URS were suppressed, while UBP was elevated significantly. CONCLUSIONS These results indicate that tramadol, a μ-opioid agonist, is effective for enhancing the active urethral continence reflex during sneezing at the spinal level (a microtip transducer catheter measurement), thereby preventing SUI (a LPP measurement). Therefore, activation of μ-opioid receptors in the spinal cord may be a new candidate treatment for SUI in humans. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e982-e983 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Asuka Ashikari More articles by this author Minoru Miyazato More articles by this author Takuma Oshiro More articles by this author Seiichi Saito More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

κ-,δ-,μ-オピオイドペプチドレセプター作動薬脳室内投与によるラット摂食行動亢進効果

κ-,δ-,μ-オピオイドペプチドレセプター作動薬脳室内投与によるラット摂食行動亢進効果

Mechanisms of inhibitory action of TRK-130 (Naltalimide), a μ-opioid receptor partial agonist, on the micturition reflex.

To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex. The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats. TRK-130 (0.001-0.01mg/kg, iv) dose-dependently inhibited RBCs, which was dose-dependently antagonized by naloxone; however, the antagonism susceptibility was different from morphine (1mg/kg, iv). The minimum effective dose (0.003mg/kg) of TRK-130 remained similar in spinal cord-transected animals. TRK-130 (0.0025mg/kg, iv) increased bladder capacity without changing the voiding efficiency, maximum flow rate, and intravesical pressure at the maximum flow rate, whereas oxybutynin (1mg/kg, iv) increased the bladder capacity but affected the other parameters. TRK-130 (0.005mg/kg, iv) did not produce significant changes on the bladder contractions induced by peripheral stimulation of the pelvic nerve, while oxybutynin (1mg/kg, iv) significantly suppressed the bladder contractions. These results suggest that TRK-130 enhances the bladder storage function by modulating the afferent limb of the micturition reflex through µ-opioid receptors in the spinal cord. TRK-130 could be a more effective and safer therapeutic agent with a different fashion from antimuscarinics and conventional opioids for overactive bladder.

Hysingla® ER, a once-daily, single-entity hydrocodone with abuse-deterrent properties in treating chronic nonmalignant and nonneuropathic pain in patients with osteoarthritis

ABSTRACTObjectives: Osteoarthritis (OA)-related chronic pain is associated with physical and psychosocial impairment as well as poorer quality of life. There is limited literature on long-term opioid therapy in OA patients. This post hoc analysis of OA patients assessed the long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone (HYD) with abuse-deterrent properties for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which other treatment options are inadequate.Methods: This is a post hoc analysis of the 307 patients with OA pain from a primary open-label study. Following screening and dose titration, patients who achieved a stable HYD dose continued into a 52-week maintenance period. Supplemental non-opioid or short-acting opioid analgesics were allowed throughout the study. Safety was monitored. Effectiveness evaluations included “average pain over the last 24 hours” scores, “pain right now” scores, Brief Pain Inventory-Short Form and treatment satisfaction questionnaire.Results: No new or unexpected safety concerns emerged during treatment with HYD. HYD demonstrated a safety profile consistent with other µ-opioid agonists with 22% discontinuations of treatment due to adverse events, a majority of which were related to the study drug. Clinically meaningful analgesia was achieved as mean “average pain over the last 24 hours”; scores decreased by 2.9 points from baseline to the end of maintenance. During the maintenance period, pain severity declined 2.7 points and interference by 2.5 points from baseline. Mean “pain right now” scores were similar at dosing and 12 hours later. A majority of patients reported satisfaction with HYD.Conclusion: In OA patients, long-term HYD treatment was generally well tolerated and provided clinically important analgesia.

In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD™ prodrug of oxycodone.

The need for pain medication which will not lead to abuse is well recognized. Ensysce has designed prodrug analogs of the commonly used pain medications including hydromorphone, oxycodone (OC), hydrocodone, and morphine that limit their use to oral delivery, two of which are in clinical development. This study was undertaken to demonstrate that PF614, an extended-release prodrug of OC, allows the release of OC as designed when delivered orally, yet it resists ex vivo extraction with household chemicals and is pharmacologically inactive when administered by nonoral routes (nasal and parenteral), thereby substantially reducing its intravenous (IV) and intranasal abuse potential. In vitro and in vivo methods were used to determine release of OC from PF614 and to show potential µ-opioid receptor activity. Plasma and cerebral spinal fluid levels of OC were evaluated following in vivo IV administration of PF614 in rats. In vitro extraction of OC from PF614 was explored using enzymes, common solvents, and household chemicals at room temperature and elevated temperature over time to determine release of OC from the prodrug. PF614 was stable with in vitro exposure to human plasma, saliva, and liver microsomes or culinary enzyme preparations. PF614 was stable (≥90 percent remaining as intact prodrug) under all room temperature conditions evaluated for 24 hours. At 80°C for 1 hour, no OC was released. Incubation at 80°C for 24 hours in vinegar or vodka produced a conversion to OC of 6 percent. Incubation with trypsin at 37°C converted PF614 approximately stoichiometric to OC with half-life of 4 hours. PF614's penetration of the central nervous system was 83-fold lower than OC and it had a 6.5-fold reduced potency as a µ-opioid agonist. Finally, oral PF614 delivers OC into plasma with an extended-release profile in dogs (reduced Cmax; delayed Tmax). The Bio-Activated Molecular Delivery prodrug design limits the use of PF614 to the intended oral route of delivery with reduced potential for IV or nasal abuse, as it cannot be activated intravenously or nasally to provide an active opioid. Unlike existing opioid formulations, the extended-release profile of PF614 cannot be accelerated by chewing or ex vivo extraction to pharmacologically active substances.

Thalidomide attenuates the development and expression of antinociceptive tolerance to μ-opioid agonist morphine through l-arginine-iNOS and nitric oxide pathway

Morphine is a μ-opioid analgesic drug which is used in the treatment and management of chronic pain. However, due to development of antinociceptive tolerance its clinical use is limited. Thalidomide is an old glutamic acid derivative which recently reemerged because of its potential to counteract a number of disorders including neurodegenerative disorders. The potential underlying mechanisms and effects of thalidomide on morphine-induced antinociceptive tolerance is still elusive. Hence, the present study was designed to explore the effect of thalidomide on the development and expression of morphine antinociceptive tolerance targeting l-arginine-nitric oxide (NO) pathway in mice and T98G human glioblastoma cell line. When thalidomide was administered in a dose of 17.5mg/kg before each dose of morphine chronically for 5days it prevented the development of antinociceptive tolerance. Also, a single dose of thalidomide 20mg/kg attenuated the expression phase of antinociceptive tolerance. The protective effect of thalidomide was augmented in development phase when co-administration with NOS inhibitors like L-NAME (non- selective NOS inhibitor; 2mg/kg) or aminoguanidine (selective inducible NOS inhibitor; 50mg/kg). Also, the reversal effect of thalidomide in expression phase was potentiated when concomitantly administrated with L-NAME (5mg/kg) or aminoguanidine (100mg/kg). Co-administration of ODQ (a guanylyl cyclase inhibitor) 10mg/kg in developmental phase or 20mg/kg in expression phase also progressively increased the pain threshold. In addition, thalidomide (20μM) also significantly inhibited the overexpression of iNOS gene induced by morphine (2.5μM) in T98G cell line. Hence, our findings suggest that thalidomide has protective effect both in the development and expression phases of morphine antinociceptive tolerance. It is also evident that this effect of thalidomide is induced by the inhibition of NOS enzyme predominantly iNOS.