Peripheral Opioid Receptor Antagonist Research Articles

Activation of Cardiac δ2-Opioid Receptors Increases Heart Tolerance to Reperfusion.

Coronary occlusion (45 min) and reperfusion (120 min) in male Wistar rats in vivo, as well as total ischemia (45 min) of an isolated rat heart followed by reperfusion (30 min) were reproduced. The selective δ2-opioid receptor agonist deltorphin II (0.12 mg/kg and 152 nmol/liter) was administered intravenously 5 min before reperfusion in vivo or added to the perfusion solution at the beginning of reperfusion of the isolated heart. The peripheral opioid receptor antagonist naloxone methiodide and δ2-opioid receptor antagonist naltriben were used in doses of 5 and 0.3 mg/kg, respectively. It was found that the infarct-limiting effect of deltorphin II is associated with the activation of δ2-opioid receptors. We have demonstrated that deltorphin II can improve the recovery of the contractility of the isolated heart after total ischemia.

Efficacy and safety of naldemedine treatment for opioid-induced constipation in gastrointestinal cancer: a retrospective analysis.

Gastrointestinal cancers are one of the most common cancer cases worldwide. Cancer treatment is multidisciplinary, which includes opioid pain management. Opioid analgesics cause opioid-induced constipation (OIC) with the onset of effect. Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in gastrointestinal cancers. We retrospectively evaluated patients with gastrointestinal cancer treated with naldemedine at ten institutions in Japan from June 2017 to August 2019. Patients with gastrointestinal cancer who initiated treatment with opioids during hospitalization and were treated with naldemedine for the first time were included in the study. The gastrointestinal cancer types included were esophageal, gastric, small bowel, and colorectal cancers. We assessed the defecation frequency before and after the initiation of naldemedine use. Responders were defined as patients who defecated three or more times/week, with an increase from the baseline of one or more bowel movements/week over seven days after starting naldemedine. Thirty-three patients were observed for one week before and after starting naldemedine. Twentyone patients had an increase in defecation frequency of at least three times per week or at least once per week above the baseline. The response rate was 63.6% (95% CI: 46.6-77.9%). The median number of bowel movements for a week before and after the initiation of naldemedine treatment was 3 (range, 0-13) and 7 (range, 1-39), respectively, in the overall population (n=33), with a significant increase in defecation frequency following naldemedine administration (Wilcoxon signed rank test, P<0.005). Diarrhea was the predominant gastrointestinal symptom, with 13 (39.4%) patients experiencing grade 1 and none experiencing grade 3 or grade 4 adverse events. The frequency of other grade 1 adverse events was low abdominal pain in two patients, nausea in two patients, and anorexia in one patient, without any grade 2-4 adverse events. The results of the study suggest that naldemedine is effective and safe in clinical practice for gastrointestinal cancer treatment.

A Retrospective Study of the Efficacy and Safety of Naldemedine for Treatment of Opioid-Induced Constipation in Patients with Hepatobiliary Pancreatic Cancer.

Background and Objectives: Opioid analgesics, which are used for cancer-related pain management, cause opioid-induced constipation (OIC). Naldemedine, a peripheral opioid receptor antagonist, is an OIC-modifying agent, but no focused efficacy and safety analysis has been conducted for its use in hepatobiliary pancreatic cancers. We performed a multi-institutional study on the efficacy and safety of naldemedine in patients with hepatobiliary pancreatic cancer using opioids in clinical practice. Materials and Methods: We retrospectively evaluated patients with hepatobiliary pancreatic cancer (including liver, biliary tract, and pancreatic cancers) treated with opioids and naldemedine during hospitalization at ten institutions in Japan from June 2017 to August 2019. We assessed the frequency of bowel movements before and after the initiation of naldemedine therapy. Responders were defined as patients who defecated ≥3 times/week, with an increase from a baseline of ≥1 defecations/week over seven days after the initiation of naldemedine administration. Results: Thirty-four patients were observed for one week before and one week after starting naldemedine. The frequency of bowel movements increased by one over the baseline frequency or to at least thrice per week in 21 patients. The response rate was 61.7% (95% confidence interval: 45.4-78.0%). The median number of weekly bowel movements before and after naldemedine treatment was 2 (range: 0-9) and 6 (range: 1-17), respectively, in the overall population (n = 34); the increase in the number of bowel movements following naldemedine administration was statistically significant (Wilcoxon signed-rank test, p < 0.0001). Diarrhea was the predominant gastrointestinal symptom, and 10 (29.4%) patients experienced grade 1, grade 2, or grade 3 adverse events. The only other adverse event included fatigue in one patient; grade 2-4 adverse events were absent. Conclusions: Naldemedine is effective, and its use may be safe in clinical practice for patients with hepatobiliary pancreatic cancer receiving opioid analgesics.

POSB199 Prevalence of Prurigo Nodularis in the Regional Area of Brittany (France): Estimation by Matching Two Databases

The objective of this study was to estimate the PN prevalence in Brittany and to describe treatments. We estimated the prevalence of PN by using 2 health data collection systems: - A registry data from the Brest University Hospital Center; - Medical/administrative data from the French SNDS database which links the hospitalization database (PMSI) with the outpatients claim database. Patients hospitalized between 2009-2018 with a primary or a secondary diagnosis of PN (ICD-10 code L28.1) were identified. The 2 sources were combined to identify patients that would be identified in the 2 databases as having a PN and to estimate the total number of PN patients in Brittany with the capture-recapture method. The prevalence rate was estimated by dividing the number of PN patients (capture-recapture estimate) by resident Brittany population. 63 unique patients with PN were identified: 5 patients in both sources, 21 only in the centre and 37 only in SNDS database. With the capture recapture method, the total number of unique PN cases was 218 (IC95%=[125 – 349]). As there were 3,310,000 inhabitants in Brittany, the prevalence was estimated at 0.07/1000 (IC95%=[0.04;0.11]). Among the 63 patients, 37 (58.7%) were females. Mean age was 70 years. In 2018, 61% of patients received topical corticoids, 49.2% antihistamines, 47.5% antidepressants. In 2009-2018, 93.2% of patients received topical corticoids, 96.6% antihistamines, 64% psychoanaleptics, 52.5% pregabaline. No patients received tacrolimus, pimecrolimus, capsaicin or peripheral opioid receptor antagonists. This study shows a prevalence 0.07/1000 for PN in Brittany. This prevalence appears low, but the French PN definition was very restrictive before the European one.

The active fragments of ghrelin cross the blood-brain barrier and enter the brain to produce antinociceptive effects after systemic administration.

G (1-5)-NH2, G (1-7)-NH2, and G (1-9) are the active fragments of ghrelin. The aim of this study was to investigate the antinociceptive effects, their ability to cross the blood-brain barrier, and the receptor mechanism(s) of these fragments using the tail withdrawal test in male Kunming mice. The antinociceptive effects of these fragments (2, 6, 20, and 60 nmol/mouse) were tested at 5, 10, 20, 30, 40, 50, and 60min after intravenous (i.v.) injection. These fragments induced dose- and time-related antinociceptive effects relative to saline. Using the near infrared fluorescence imaging experiments, our results showed that these fragments could cross the brain-blood barrier and enter the brain. The antinociceptive effects of these fragments were completely antagonized by naloxone (intracerebroventricular, i.c.v.); however, naloxone methiodide (intraperitoneal, i.p.), which is the peripheral restricted opioid receptor antagonist, did not antagonize these antinociceptive effects. Furthermore, the GHS-R1α antagonist [D-Lys3]-GHRP-6 (i.c.v.) completely antagonized these antinociceptive effects, too. These results suggested that these fragments induced antinociceptive effects through central opioid receptors and GHS-R1α. In conclusion, our studies indicated that these active fragments of ghrelin could cross the brain-blood barrier and enter the brain and induce antinociceptive effects through central opioid receptors and GHS-R1α after intravenous injection.

Pain Management in a Model of Interstitial Cystitis/Bladder Pain Syndrome by a Vaccinal Strategy

Current analgesic treatments for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) are limited. Here, we propose a novel antinociceptive strategy exploiting the opioid-mediated analgesic properties of T lymphocytes to relieve from bladder pain. In a chronic model of IC/BPS in rats, we show that a secondary T cell response against intravesically administered ovalbumin prevents from visceral pain in OVA-primed animals. The analgesic effect is associated with the recruitment of T lymphocytes within the inflamed mucosa and is reversed by naloxone-methiodide, a peripheral opioid receptor antagonist. Similarly, intravesical instillation of BCG or tetanus toxoid antigens in vaccinated rats protects from pain in the same model. We show opioid-dependent analgesic properties of local vaccine antigen recall in a preclinical rat model of chronic cystitis. Since BCG bladder instillation is regularly used in humans (as anticancer therapy), our results open it as a new therapeutic positioning for a pain management indication for IC/BPS patients.

Precision Lactobacillus reuteri therapy attenuates luminal distension-associated visceral hypersensitivity by inducing peripheral opioid receptors in the colon.

Luminal distension and abdominal pain are major clinical hallmarks of obstructive bowel disorders and functional bowel disorders linked to gut dysbiosis. Our recent studies found that chronic lumen distension increased visceral sensitivity and decreased abundance of gut commensal Lactobacillus reuteri in a rodent model of partial colon obstruction (OB). To establish causation, we performed precision microbial therapy to assess whether recolonization of L. reuteri prevents visceral hypersensitivity in lumen distension, and if so, to identify the gut-microbiota mechanism. Lumen distension was induced in Sprague-Dawley rats by implanting an OB band in the distal colon for up to 7 days. L. reuteri strains or vehicle were gavage ingested 1 × 10 colony-forming units/g daily starting 2 days before OB. L. reuteri rat strains that were able to recolonize obstructed colon significantly improved food intake and body weight in OB rats, and attenuated referred visceral hyperalgesia measured by the withdrawal response to von Frey filament applications to the abdomen. Mechanistically, L. reuteri treatment attenuated hyperexcitability of the dorsal root ganglia neurons projecting to the distended colon by promoting opioid receptor function in affected tissues. The expression of µ, δ, and κ opioid receptors was significantly downregulated in colonic muscularis externae and sensory neurons in OB rats. However, L. reuteri treatment prevented the loss of opioid receptors. Furthermore, administration of peripheral opioid receptor antagonist naloxone methiodide abolished the analgesic effect of L. reuteri in OB. In conclusion, precision L. reuteri therapy prevents lumen distension-associated visceral hypersensitivity by local bacterial induction of opioid receptors.

Antagonism of peripheral opioid receptors by methylnaltrexone does not prevent morphine tolerance in rats.

Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7days with increasing subcutaneous doses of morphine (5-30mg/kg) and were coadministered saline, MNTX (0.5 or 2mg/kg), or naltrexone (NTX; 2mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.

Endogenous control of inflammatory visceral pain by T cell-derived opioids in IL-10-deficient mice.

The opioid-mediated analgesic activity of mucosal CD4+ T lymphocytes in colitis has been reported in immunocompetent mice so far. Here, we investigated whether CD4+ T lymphocytes alleviate from inflammation-induced abdominal pain in mice with defective immune regulation. Endogenous control of visceral pain by opioids locally produced in inflamed mucosa was assessed in IL-10-deficient mice. CD4+ T lymphocytes but not F4/80+ macrophages isolated from the lamina propria of IL-10-deficient mice with colitis express enkephalin-containing opioid peptides as assessed by cytofluorometry. Colitis in IL-10-/- mice was not associated with abdominal pain. Intraperitoneal injection of naloxone-methiodide, a peripheral opioid receptor antagonist, induced abdominal hypersensitivity in IL-10-/- mice with colitis. Opioid-mediated analgesic activity of mucosal T lymphocytes remains operating in IL-10-/- mice with impaired immune regulation. The data suggest that endogenous T cell-derived opioids might reduce inflammation-induced abdominal pain in inflammatory bowel diseases associated with homozygous "loss of function mutations" in interleukin-10.

Effects of Methylnaltrexone on Ticagrelor-Induced Antiplatelet Effects in Coronary Artery Disease Patients Treated With Morphine

ObjectivesThe aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor. BackgroundMorphine delays the onset of action of oral P2Y12 receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia. MethodsIn this prospective, randomized, double-blind, placebo-controlled, crossover study, aspirin-treated patients with stable coronary artery disease (n = 30) were randomized to receive methylnaltrexone (0.3 mg/kg intravenous) or matching placebo. After methylnaltrexone or placebo administration, all patients received morphine (5 mg intravenous). This was followed 15 min later by a 180-mg loading dose of ticagrelor. Patients crossed over to the alternative study treatment after 7 ± 2 days of washout. PK and PD assessments were performed at 12 time points (6 pre- and 6 post-crossover). PK analysis included measurement of plasma levels of ticagrelor and its major active metabolite (AR-C124910XX). PD assessments included VerifyNow P2Y12, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein. ResultsOnly marginal changes in plasma levels of ticagrelor (and its major active metabolite) were observed with ticagrelor: maximum plasma concentration and area under the plasma concentration versus time curve from time 0 to the last measurable concentration were 38% and 30% higher, respectively, in patients receiving methylnaltrexone compared with those receiving placebo, but no differences in time to maximum plasma concentration were observed. There were no differences in P2Y12 reaction units by VerifyNow P2Y12 between groups at each time point, including 2 h (the primary endpoint; p = 0.261). Similarly, there were no differences in PD markers assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein. ConclusionsIn patients with coronary artery disease receiving morphine, intravenous administration of the peripheral opioid receptor antagonist methylnaltrexone leads to only marginal changes in plasma levels of ticagrelor and its major metabolite, without affecting levels of platelet reactivity. (Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine; NCT02403830)

Experimental Colitis Enhances the Rate of Antinociceptive Tolerance to Morphine via Peripheral Opioid Receptors.

Opioids are highly effective analgesics, however, their therapeutic use is limited by adverse effects that include respiratory depression, dependence, and tolerance. Inflammation has been implicated as a significant driver for the development of tolerance to opioids. Recent studies show that chronic morphine in mice results in gut microbial dysbiosis and inflammation in the colon. In the present study, we examined whether colonic inflammation results in tolerance to the antinociceptive effects of morphine. Colonic inflammation was induced in mice by intrarectal administration of 2,4,6-trinitro-benzene sulfonic acid. The development of antinociceptive tolerance was determined by warm-water tail-immersion assay in mice implanted with 25-, 50-, or 75-mg morphine pellet. Colonic inflammation significantly enhanced the rate at which tolerance developed in each cohort of chronic morphine-treated mice. At the lowest dose of morphine pellet (25 mg), antinociceptive tolerance only developed in the presence of colonic inflammation, whereas in 50- and 75-mg pelleted mice, tolerance developed faster in the inflamed animals than in the noninflamed mice. The enhanced antinociceptive tolerance was attenuated with daily administration of peripheral opioid receptor antagonist, 6β-N-heterocyclic-substituted naltrexamine derivative [17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'pyridyl)acetamido]morphinan (NAP)], irrespective of colonic inflammation. Collectively, these findings show that the rate of tolerance to morphine antinociception is exaggerated in the presence of colonic inflammation, and tolerance is prevented by a peripheral μ-opioid receptor antagonist. These studies suggest a peripheral component to the development of antinociceptive tolerance to opioids. Furthermore, peripherally selective opioid antagonists may be useful adjuncts in opioid-based pain management. SIGNIFICANCE STATEMENT: This study supports the notion that inflammation influences the development of antinociceptive tolerance to chronic morphine exposure. We found that, in the presence of colonic inflammation, the rate of development of tolerance to the antinociceptive effects of morphine increased. We also found that treatment with a peripheral opioid receptor antagonist prevented morphine antinociceptive tolerance. Increasing opioid intake during an inflammatory state would result in decreased analgesia and enhanced analgesic tolerance, which puts patients with inflammatory bowel diseases, inflammatory joint diseases, and sickle cell anemia at risk for heavy opioid use.

Identifying and Treating Opioid Side Effects: The Development of Methylnaltrexone.

Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient. To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation. Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998. Clinical research center of a university hospital. Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation. Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups. The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study. Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.

Safety and Tolerability of Naloxegol in Patients with Opioid Induced Constipation: Systematic Review and Meta-analysis

Introduction: Naloxegol is the first oral peripheral mu opioid receptor antagonist approved for opioid induced constipation. In clinical trials, patients reported shorter times to first spontaneous bowel movement. However, studies have also reported numerous gastrointestinal and non-gastrointestinal side effects. Hence, we performed a systematic review and meta-analysis to assess the safety and tolerability of 25 mg Naloxegol compared to placebo. Methods: All randomized controlled trials enrolling adult patients that reported clinical safety and tolerability of Naloxegol were identified from PubMed, MEDLINE, Embase & Cochrane Central Register of Controlled Trials through May 30, 2016. Four randomized controlled trials were identified. Primary outcome of our study was mortality. Secondary outcomes studied were nausea, vomiting, upper abdominal pain, abdominal pain, flatulence, diarrhea, headache, and back pain. Random effects model was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) using Cochrane Collaborative software, RevMan 5.3. Measure of heterogeneity between the studies was assessed using the chi square test and was considered significant if I2 > 50%. Results: We included 4 RCTs with a total of 1,750 participants in our analysis, of which 1,009 received 25 mg Naloxegol and 741 received a placebo. No statistical significant difference in the primary outcome of mortality (OR=0.50, 95% CI 0.03 - 8.10) was observed in our study. There was an increased risk of adverse effects in Naloxegol group as compared to placebo: nausea (8.9% versus 4.8%, OR 1.90, 95% CI 1.26-2.87; Number Needed to Harm 24.6), upper abdominal pain (4.6% versus 1.5%, OR - 3.10, 95% CI 1.56 - 6.15; NNH 31.9), abdominal pain (17.3% versus 4.8%, OR 4.08, 95% CI 2.68- 6.21; NNH 7.9), flatulence (6.4% versus 2.1%, OR - 2.86, 95% CI 1.45 - 5.64; NNH 23.35), diarrhea (11.3% versus 4.8%, OR - 2.35, 95% CI 1.59 - 3.48; NNH=15.53), headache (6.9% versus 3.5%, OR - 1.83, 95% CI 1.14 - 2.96; NNH=29.09) and back pain (6.8% versus 3%, OR - 2.01, 95% CI 1.22 - 3.31; NNH=26.6). No statistical significant difference in vomiting was observed between the two groups (OR - 1.29, 95% CI 0.70 - 2.39). Conclusion: Use of Naloxegol was associated with an increased risk of gastrointestinal side effects, headache, and back pain without increased risk of mortality as compared to placebo. As with all medications, a discussion with patients regarding the risks and benefits of this treatment is advised.Figure 1

Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in mice

Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral μ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate–dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by μ-opioid antagonist β-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment.

The Effect of Methylnaltrexone on the Side Effects of Intrathecal Morphine after Orthopedic Surgery under Spinal Anesthesia

Methylnaltrexone is a peripheral opioid receptor antagonist that does not cross the blood-brain barrier; so without interference with pain relief, it could reverse the peripheral opioid side effects such as constipation, pruritus, postoperative ileus, and urinary retention. This study has been designed to evaluate the effect of methylnaltrexone on postoperative side effects of intrathecal morphine. In seventy-two 18- to 55-year-old patients scheduled for elective orthopedic operations under spinal anesthesia, neuraxial blockade was achieved using 10mg 0.5% hyperbaric bupivacaine and 0.1mg preservative-free morphine sulfate. The first group (M) received 12mg methylnaltrexone, while the second group (P) received normal saline, subcutaneously, immediately after spinal block in a randomized, double-blind fashion. There was a significant decrease in the rate of nausea and vomiting in group M, but there was no significant difference in the rate of pruritus or urinary retention between the two groups. Pain score was significantly lower in group M. Respiratory depression or decreased level of consciousness was not reported in any patient. Subcutaneous administration of methylnaltrexone was not effective in decreasing postoperative urinary retention and pruritus, but lowered the rate of nausea and vomiting and pain score after intrathecal bupivacaine and morphine.

Effects of remifentanil on the esophagogastric junction and swallowing

A recent study demonstrated that reflux is associated with impaired pressure augmentation in the esophagogastric junction (EGJ), caused by diaphragmal contractions during inspiration. It is unknown whether this augmentation is influenced by opioids. Swallowing difficulties can be a poorly recognised side effect of remifentanil. Here, we investigated whether remifentanil influences inspiratory EGJ augmentation and evaluated subjective swallowing difficulties induced by remifentanil. We also used the peripheral opioid receptor antagonist methylnaltrexone to evaluate whether these effects are centrally or peripherally mediated. Ten healthy volunteers participated in a double-blind, randomised, cross-over trial at the University Hospital in Örebro, Sweden. They were studied on two different occasions, during which they were randomly assigned to receive either methylnaltrexone 0.15 mg/kg or saline subcutaneously 30 min before the target-controlled infusion of remifentanil of 3 ng/mL. EGJ pressures were measured by high-resolution manometry. Swallowing difficulties were assessed when volunteers performed dry swallows. The outcomes were the differences in EGJ pressures at baseline and during remifentanil infusion and with methylnaltrexone vs. placebo. Differences in swallowing difficulties before and during remifentanil, and with methylnaltrexone vs. placebo were also recorded. Remifentanil decreased the inspiratory EGJ augmentation and induced swallowing difficulties. No statistically significant differences between methylnaltrexone and placebo occasions were found. Remifentanil may increase risk for gastroesophageal reflux by decreasing the inspiratory EGJ augmentation. The clinical significance of remifentanil-induced swallowing difficulties is to be studied further. Given the limited sample size, it cannot be concluded whether these effects are centrally or peripherally mediated.

A Study on the Mechanism of Cinobufagin in the Treatment of Paw Cancer Pain by Modulating Localβ-Endorphin ExpressionIn Vivo

Background. Cinobufagin has been widely used in the treatment of carcinoma and plays an important role in the relief of cancer pain. But the involved mechanism remains unknown. Aim. To investigate the changes in thermal and mechanical hyperalgesia in paw cancer pain in mice and the action mechanism of cinobufagin using a paw cancer pain model. Methods. 60 female mice were randomly divided into 5 groups: control group, model group, cinobufagin group, cinobufagin +NAL-M group, and morphine group; except ones in control group, mice were inoculated with H22 hepatoma cells in the right hind paw. From the 9th day after inoculation, mice were administrated drug once daily lasting for 8 days. The pain behavior was determined on the 2nd, 4th, 6th, and 8th days before and after administration. On the last day, they were sacrificed. The levels of β-END, CRF, and IL-1β were analyzed by ELISA; immunohistochemistry was performed to detect the expressions of β-END, POMC, and μ-OR in the tumor and adjacent tissue. Results. The thresholds of thermal pain and mechanical pain were significantly increased by cinobufagin. Moreover, the expressions of β-END, CRF, POMC, and μ-OR were significantly upregulated by cinobufagin. The analgesic effect of cinobufagin was blocked by the peripheral opioid receptor antagonist NAL-M. Conclusions. Cinobufagin significantly relieved cancer pain in mice and raised their pain threshold, mainly upregulating the expression levels of β-END and μ-OR in the hind paw tumor and adjacent tissue.

Non-Analgesic Effects of Opioids: Management of Opioid-Induced Constipation by Peripheral Opioid Receptor Antagonists: Prevention or Withdrawal?

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

Activation of opioid μ-receptors, but not δ- or κ-receptors, switches pulmonary C-fiber-mediated rapid shallow breathing into an apnea in anesthetized rats

Rapid shallow breathing (RSB) is mainly mediated by bronchopulmonary C-fibers (PCFs). We asked whether this RSB could be modulated by opioids. In anesthetized rats right atrial bolus injection of phenylbiguanide (PBG) to evoke RSB was repeated after: (1) intravenously giving fentanyl (μ-receptor agonist), DPDPE (δ-receptor agonist), or U-50488H (κ-receptor agonist); (2) fentanyl (iv) following naloxone methiodide, a peripheral opioid receptor antagonist; (3) bilateral microinjection of fentanyl into the nodose ganglia; (4) fentanyl (iv) with pre-blocking histamine H1 and H2 receptors by diphenhydramine and ranitidine. Systemic fentanyl challenge, but not DPDPE or U-50488H, switched the PBG-induced RSB to a long lasting apnea. This switch was blocked by naloxone methiodide rather than diphenhydramine and ranitidine. After microinjecting fentanyl into the nodose ganglia, PBG also produced an apnea. Our results suggest that activating μ-receptors is capable of turning the PCF-mediated RSB into an apnea, at least partly, via facilitating PCFs’ activity and this switching effect appears independent of the released histamine.

ADL5945, a potent orally bioavailable peripheral opioid receptor antagonist, improves bowel motility w/a low incidence/severity of GI AEs in a dose-dependent manner: results of 2 Ph 2 trials in opioid-induced constipation pts (45CL242 and 45CL243)

Opioids are a mainstay for managing chronic pain, however central and peripheral adverse effects often limit their utility. Mu opioid receptor (MOR) binding is primarily responsible for opioid-induced constipation (OIC) and gastrointestinal (GI) symptoms; the delta OR (DOR) may also play a role. ADL5945, a MOR and DOR antagonist, is under development for OIC and associated abdominal symptoms in patients on chronic opioid therapy for persistent noncancer pain. Randomized, double blind, placebo controlled, Phase 2 studies compared ADL5945 dosed once- (0.25mg QD) or twice-daily (0.1mg BID and 0.25mg BID) with placebo based on spontaneous bowel movement (SBM) change over treatment weeks 1-4.