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For the pharmacokinetic evaluation of Silastic capsules, ovariectomized (OVX) rats were implanted subcutaneously with this dosage form containing 17beta-estradiol (5, 10, 15, or 20% in cholesterol, where 5% 17beta-estradiol equals 0.4 mg) or progesterone (20, 40, 110, or 220 mg of crystalline progesterone). The time-course of serum 17beta-estradiol and progesterone released from these capsules in the OVX rat is characterized by an initial increase in serum hormone levels followed by a decline and then an apparent steady-state that persists from 7 to 24 days postimplant. Both hormones have large clearance values (total clearance is 97.7 L/day for 17beta-estradiol and 20.9 L/day for progesterone). For 17beta-estradiol and progesterone only, 11% of the dose was released from the implant after 24 days. Thus, the Silastic membrane represents the rate controlling barrier for these hormones. The relationship between graded doses of 17beta-estradiol or progesterone and serum concentration was linear. Neither tail flick latencies measured at 48, 52.5, and 55 degrees C nor the antinociceptive potency of morphine (ED(50) values) were altered by continuous administration to steady-state of graded doses of 17beta-estradiol or progesterone. We demonstrate how a dose-dependent analysis of some of the behavioral effects of 17beta-estradiol or progesterone can be conducted at steady-state serum hormone concentrations. PERSPECTIVE: We describe a method to obtain sustained serum levels of estrogen or progesterone and the consequences of these sustained hormone levels on acute thermal nociception and the antinociceptive response to morphine. This rat model of hormone replacement may provide insights into the role of these hormones in pathological pain states. [ABSTRACT FROM AUTHOR]

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants., Methods: In this phase 3, double-blind, placebo-controlled trial, outpatients with MDD ( DSM-5 ) were randomized to daily oral esmethadone (75 mg on day 1, followed by 25 mg daily on days 2 through 28) or placebo between December 2020 and December 2022. The primary efficacy measure was change from baseline (CFB) to day 28 in the Montgomery-Asberg Depression Rating Scale (MADRS) score. The intent-to-treat (ITT) population included all randomized participants. The per-protocol (PP) population included completers without major protocol deviations impacting assessment. Post hoc analyses included participants with severe depression (baseline MADRS score ≥35)., Results: For the ITT analysis (n = 227), mean CFB was 15.1 (SD 11.3) for esmethadone (n = 113) and 12.9 (SD 10.4) for placebo (n = 114), with a mean difference (MD) of 2.3, which was not statistically significant ( P = .154; Cohen effect size [ES] = 0.21). Remission rates were 22.1% and 13.2% ( P = .076), and response rates were 39.8% and 27.2% ( P = .044) with esmethadone and placebo, respectively. For the PP analysis (n = 198), mean CFB was 15.6 (SD 11.2) for esmethadone (n = 101) and 12.5 (SD 9.9) for placebo (n = 97), with an MD of 3.1 ( P = .051; ES =0.29). In post hoc analyses of patients with baseline MADRS ≥35 in the ITT population (n = 112), MD was 6.9; P = .0059; ES = 0.57, and for the PP population (n = 98), MD was 7.9; P = .0015; ES = 0.69. Adverse events (AEs) were predominantly mild or moderate and transient, with no significant differences between groups., Conclusions: The primary end point was not met. Esmethadone showed stronger efficacy in PP than in ITT analyses, with the discrepancy not attributable to AEs impacting treatment adherence. Significant efficacy occurred in post hoc analyses of patients with severe depression. Esmethadone was well tolerated, consistent with prior studies., Trial Registration: ClinicalTrials.gov identifier: NCT04688164., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Background and Objectives: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl- D -aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose)., Methods: Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment., Results: In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone C max and AUC 0-inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of C max and AUC 0-inf values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), C max and AUC 0-inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, C max and AUC 0-inf were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment., Conclusion: Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis., (© 2024. The Author(s).)

Background and Objective: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment., Methods: Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions., Results: Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC 50 of 9.6 μM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased C max and AUC of its metabolite 1'-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC 0-inf ) of esmethadone., Conclusions: In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs., (© 2023. The Author(s).)

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders., (© 2023. The Author(s).)

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (E max ) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS E max compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS E max (p < 0.05). In the Ketamine Study, Drug Liking VAS E max scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses., (© 2023. The Author(s).)

We have previously demonstrated that pharmacological blockade of ventral tegmental area (VTA) Ca v 1.3 L-type calcium channels (LTCCs) using Ca v 1.2 dihydropyridine insensitive (Ca v 1.2DHP -/- ) mutant mice attenuates cocaine conditioned place preference (CPP). However, the molecular mechanisms by which Ca v 1.3 channels mediate the effects of cocaine in the VTA remain largely unknown. In this study using Ca v 1.2DHP -/- male mice, we find that cocaine place preference increases CaM kinase IIα, ERK2, and CREB phosphorylation in the VTA, proteins strongly linked to cocaine behaviors. To further explore the causal role of these intracellular signaling proteins in cocaine preference, the CaM kinase II inhibitor, KN93 was directly injected into the VTA of male mice before each cocaine conditioning session. We found that KN93 attenuates conditioned preference for cocaine compared to vehicle treated mice and decreased VTA ERK2 and CREB phosphorylation. Additionally, blockade of the ERK pathway with the MEK inhibitor, U0126 or knockdown of ERK2 using siRNA, attenuated cocaine preference and VTA CREB phosphorylation but not CaMKIIα phosphorylation, suggesting that ERK is activated downstream of CaMKIIα. Examination of postsynaptic density (PSD) GluA1 subunit of AMPA receptors in the nucleus accumbens (NAc) that we have previously shown to be upregulated following long withdrawal periods, was blunted by KN93, U0126 and ERK2 siRNA when examined 30 days following cocaine CPP. Taken together, these findings demonstrate that Ca v 1.3 channels in the VTA are required for cocaine reward behavior and activation of the CaMKIIα/ERK/CREB signaling pathway in the VTA is necessary for long-lasting changes in the NAc. This article is part of the Special Issue on 'L-type calcium channel mechanisms in neuropsychiatric disorders'., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca 2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca 2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.

Excessive Ca 2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg 2+ , NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca 2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg 2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg 2+ , tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.

REL-1017 (esmethadone) is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist and promising rapid antidepressant candidate. Using fluorometric imaging plate reader (FLIPR) assays, we studied the effects of quinolinic acid (QA) and gentamicin, with or without L-glutamate and REL-1017, on intracellular calcium ([Ca 2+ ] in ) in recombinant cell lines expressing human GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, and GluN1-GluN2D NMDAR subtypes. There were no effects of QA on [Ca 2+ ] in in cells expressing GluN1-GluN2C subtypes. QA acted as a low-potency, subtype-selective, NMDAR partial agonist in GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D subtypes. REL-1017 reduced [Ca 2+ ] in induced by QA. In cells expressing the GluN1-GluN2D subtype, QA acted as an agonist in the presence of 0.04 μM L-glutamate and as an antagonist in the presence of 0.2 μM L-glutamate. REL-1017 reduced [Ca 2+ ] in induced by L-glutamate alone and with QA in all cell lines. In the absence of L-glutamate, gentamicin had no effect. Gentamicin was a positive modulator for GluN1-GluN2B subtypes at 10 μM L-glutamate, for GluN1-GluN2A at 0.2 μM L-glutamate, and for GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D at 0.04 μM L-glutamate. No significant changes were observed with GluN1-GluN2C NMDARs. REL-1017 reduced [Ca 2+ ] in induced by the addition of L-glutamate in all NMDAR cell lines in the presence or absence of gentamicin. In conclusion, REL-1017 reduced [Ca 2+ ] in induced by L-glutamate alone and when increased by QA and gentamicin. REL-1017 may protect cells from excessive calcium entry via NMDARs hyperactivated by endogenous and exogenous molecules.

Objective: The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel N -methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to benefit from one to three standard antidepressant treatments in their current major depressive episode. Methods: A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis. Results: Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0. Conclusions: This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.

Aim: Obesity is one of the most prevalent comorbidities associated with chronic pain, which can severely interfere with daily living and increase utilization of clinical resources. We hypothesized that a higher level of obesity, measured by BMI, would be associated with increased pain severity (intensity) and interference (pain related disability). Materials & methods: Participant data was pulled from a multisite chronic pain outpatient database and categorized based on BMI. Results: A total of 2509 patients were included in the study. We found significant differences between BMI groups for all pain severity scores (worst, least, average, current) and total pain interference score. Obese patients had significantly higher scores than normal weight patients. Conclusion: We found obesity to be associated with increased pain severity and pain interference.

This special issue is a tribute to our mentor, colleague and friend, Gavril W. Pasternak, MD, PhD. Homage to the breadth and depth of his work (~ 450 publications) over a 40 career in pharmacology and medicine cannot be captured fully in one special issue, but the 22 papers collected herein represent seven of the topics near and dear to Gav's heart, and the colleagues, friends and mentees who held him near to theirs. The seven themes include: (1) sites and mechanisms of opioid actions in vivo; (2) development of novel analgesic agents; (3) opioid tolerance, withdrawal and addiction: mechanisms and treatment; (4) opioid receptor splice variants; (5) novel research tools and approaches; (6) receptor signaling and crosstalk in vitro; and (7) mentorship. This introduction to the issue summarizes contributions and includes formal and personal remembrances of Gav that illustrate his personality, warmth, and dedication to making a difference in patient care and people's lives.

Brain-derived neurotrophic factor (BDNF), a neurotrophin widely expressed in the central nervous system, exhibits important effects on neural plasticity. BDNF has been implicated in the mechanism of action of ketamine, a N-methyl-d-aspartic acid receptor (NMDAR) antagonist with rapid anti-depressant effects in humans. REL-1017 (esmethadone), the d-optical isomer of the racemic mixture d-l-methadone, is devoid of clinically relevant opioid activity at doses expected to exert therapeutic NMDAR antagonistic activity in humans. The present study was conducted to ascertain the effects of oral administration of 25 mg of REL-1017 for 10 days on plasma BDNF in healthy subjects confined to an inpatient unit for a phase 1 clinical trial. We observed an increase in post-treatment BDNF plasma levels compared to pre-treatment levels. Post-treatment, Day 10 BDNF plasma levels ranged from 2 to 17 times pre-treatment levels in the 25 mg REL-1017 treatment group, whereas in the placebo group, BDNF plasma levels remained unchanged ( p = 0.028). Diastolic blood pressure decreased significantly in subjects treated with REL-1017, while no effect could be observed in the placebo group. In conclusion, the administration of 25 mg REL-1017 significantly increased BDNF plasma levels and significantly decreased diastolic blood pressure in healthy subjects confined to an inpatient unit for a phase 1 clinical trial., Competing Interests: SDM: Ongoing research projects sponsored by Relmada Therapeutics. NF: Relationship with Bristol-Mayers, Daiichi-Sankyo, Pharmanutra, and Amryt Pharma. SS: Consultant for Acadia, Alkermes, Allergan, AbbVie, Arbor Pharmaceuticals, Axovant, Axsome, Celgene, Concert, Clearview, EMD Serono, Eisai Pharmaceuticals, Ferring, Impel NeuroPharma, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Karuna, Lilly, Lundbeck, Merck, Otsuka, Pfizer, Relmada, Sage Therapeutics, Servier, Shire, Sunovion, Takeda, Taliaz, Teva, Tonix, Tris Pharma, and Viforpharma. Board Member: GenoMind; Served on Speakers bureaus for: Acadia, Lundbeck, Otsuka, Perrigo, Servier, Sunovion, Takeda, Teva, and Vertex; Research and/or grand support from: Acadia, Avanir, Braeburn Pharmaceuticals, Eli Lilly, Intra-Cellular Therapies, Ironshore, ISSWSH, Neurocrine, Otsuka, Shire, Sunovion, and TMS NeuroHealth Centers. CI: Consultant for and owns stock in Relmada Therapeutics. MP: Consultant for Relmada Therapeutics. ST: CEO of Relmada Therapeutics and significant stock ownership. PM: Paid consultant of Relmada Therapeutics, owns stock of Relmada and may earn Royalties from IP licensed to Relmada. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 De Martin, Gabbia, Folli, Bifari, Fiorina, Ferri, Stahl, Inturrisi, Pappagallo, Traversa and Manfredi.)

Background: Low body mass index (BMI) is suspected of being associated with low transdermal fentanyl (TDF) blood levels and worse pain relief. Clinical pain data to support this claim are lacking., Methods: Using a Chronic Pain Registry, we identified 901 cancer patients who received TDF at outpatient pain service clinics of our cancer center from 7/1/2011 to 12/1/2016. Of these, 240 patients had a BMI measure, pain intensity, and pain relief scores documented within 30 days of a TDF order. We examined associations between BMI, TDF dose, Worst and Least pain scores, and pain relief scores using standard statistical tests., Results: In cancer patients receiving TDF, low BMI (<18.5) was significantly associated with greater pain relief irrespective of TDF dose and borderline significantly associated with greater percent pain relief after controlling for age, cancer diagnoses, and pain etiology (P = .073), suggesting that low BMI may independently predict better pain relief in cancer patients. As there were no significant associations between BMI and TDF dose, we find no basis for BMI-dependent dose modification or avoiding TDF in cachectic and low BMI patients., Conclusions: When predicting percent pain relief, we conclude that there is no basis for avoiding TDF or modifying its dose in cancer patients with low BMI and cachexia., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The Memorial Sloan Kettering Pain Registry contains patient characteristics, treatments, and outcomes for a prospective cohort of 1,534 chronic pain cancer patients who were seen at outpatient pain service clinics. Average pain intensity (Brief Pain Inventory) was reported as mild by 24.6% of patients, moderate by 41.5%, and severe by 33.9%. The patient's report of average percent pain relief and health state (EuroQOL 5 dimensions) was inversely related to average pain intensity category, whereas measures of pain interference, number of worst pain locations, and physical and psychological distress were directly related to pain intensity category. Eighty-six percent of patients received an opioid at 1 or more clinic encounters. Regression analysis revealed that male sex or being younger (65 years of age or younger) was associated with a greater likelihood of an opioid ordered. Male sex nearly doubled the likelihood of a higher dose being ordered than female sex. Bivariate analysis found that patients receiving opioids reported significantly more pain relief than no-opioid patients. However, patients receiving opioids had higher pain interference scores, lower index of health state, and more physical distress than no-opioid patients Our results identify the need to consider opioid use and dosage when attempting to understand patient-reported outcomes (PROs) and factors affecting pain management., Perspective: This report describes the results of the analyses of PROs and patient-related electronic health record data collected under standard of care from cancer patients at outpatient pain management clinics of Anesthesiology and Palliative Care at the Memorial Sloan Kettering Cancer Center. Consideration of sex and age as predictors of opioid use is critical in attempting to understand PROs and their relationship to pain management., (Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

The Weill Cornell Medical College Pain Registry database contains patient characteristics, treatments, and outcomes for a prospective cohort of 1,159 chronic pain patients who were seen at the Weill Cornell Medical College Pain Medicine outpatient clinic from July 8, 2011 to December 10, 2014. Patients aged 45 to 64 years comprised 43% followed by age ≥ 65 years at 37%. Fifty-eight percent were female. Average pain intensity (Brief Pain Inventory) was reported as mild by 22.3% of patients, moderate by 34.7%, and severe by 43.0%. For each pain intensity category, patient's report of average percent pain relief and health state (EuroQOL 5 Dimensions) was inversely related to average pain intensity category, whereas measures of pain interference, number of worst pain locations, and physical and psychological distress were directly related to pain intensity category. Seventy-seven percent of patients received an opioid at 1 or more clinic encounters. Median daily opioid dose in morphine equivalents was 55 with a range from 2 to 1,145 morphine equivalents. Regression analysis revealed that being male was associated with greater likelihood of an opioid ordered and higher average dosage than being female. The registry can identify patient characteristics and treatments that provide new insights into chronic pain management., Perspective: This article describes results of analyses of patient-reported outcomes and patient-related electronic health record data collected under standard of care from a prospective cohort of chronic pain outpatients at a New York City pain management clinic. The registry provides an opportunity to learn how to improve individualized chronic pain management., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Standardization of care that is derived from analysis of outcomes data can lead to improvements in quality and efficiency of care. The outcomes data should be validated, standardized, and integrated into ongoing patient care with minimal burden on the patient and health care team. This article describes the organization and workflow of a chronic pain clinic registry designed to collect and analyze patient data for quality improvement and dissemination. Future efforts in using mobile technology and integrating patient-reported outcome data in the electronic health records have the potential to offer new and improved models of comprehensive pain management., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The μ-opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, as illustrated by the identification of an array of splice variants generated by both 5' and 3' alternative splicing. The current study reports the identification of another set of splice variants conserved across species that are generated through exon skipping or insertion that encodes proteins containing only a single transmembrane (TM) domain. Using a Tet-Off system, we demonstrated that the truncated single TM variants can dimerize with the full-length 7-TM μ-opioid receptor (MOR-1) in the endoplasmic reticulum, leading to increased expression of MOR-1 at the protein level by a chaperone-like function that minimizes endoplasmic reticulum-associated degradation. In vivo antisense studies suggested that the single TM variants play an important role in morphine analgesia, presumably through modulation of receptor expression levels. Our studies suggest the functional roles of truncated receptors in other G protein-coupled receptor families.

Unlabelled: Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic-prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic-prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic-prescribing algorithms., Perspective: Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic-prescribing algorithms that could optimize opioid analgesic effectiveness and mitigate risks of opioid-related abuse and mortality., (Copyright © 2013 American Pain Society. All rights reserved.)

AMPA receptor (AMPAR) plasticity at glutamatergic synapses in the mesoaccumbal dopaminergic pathway has been implicated in persistent cocaine-induced behavioral responses; however, the precise mechanism underlying these changes remains unknown. Utilizing cocaine psychomotor sensitization, we have examined phosphorylation of GluA1 at key residues serine 845 (S845) and S831, as well as GluA1 cell surface levels in the nucleus accumbens (NAc) of cocaine-preexposed mice and the role of brain-specific Ca(v)1.2 and Ca(v)1.3 L-type Ca²⁺ channels (LTCCs), therein. We found higher basal levels of S845 phospho-GluA1 (P-GluA1) and cell surface GluA1 in the NAc following protracted withdrawal from cocaine exposure, changes that occur independently of LTCCs. In contrast, we found that a cocaine challenge that elicits expression of the cocaine-sensitized response increases S831 P-GluA1 that further increases surface GluA1 beyond the higher basal levels. Intra-NAc pharmacological manipulations indicate that the Ca(v)1.2-activated CaM kinase II (CaMKII) mediates cocaine-induced increase in S831 P-GluA1 and that both Ca(v)1.2-activated CaMKII and extracellular signal-regulated kinase 2 (ERK2) mediate the increase in GluA1 cell surface levels specific to the sensitized response. Experiments using adenoassociated viral vectors expressing Ca(v)1.3 and ERK2 siRNA further indicate that recruitment of the Ca(v)1.2 pathway in the NAc is dependent on ventral tegmental area Ca(v)1.3 LTCCs and ERK2. Together, these results identify candidate pathways that mediate cocaine-induced AMPAR plasticity in the NAc and provide a mechanism linking LTCCs and GluA1 plasticity to cocaine-induced persistent behavioral changes.

Objective: There has been a growing recognition of the need for better pharmacologic management of chronic pain among older adults. To address this need, the National Institutes of Health Pain Consortium sponsored an "Expert Panel Discussion on the Pharmacological Management of Chronic Pain in Older Adults" conference in September 2010 to identify research gaps and strategies to address them. Specific emphasis was placed on ascertaining gaps regarding use of opioid and nonsteroidal anti-inflammatory medications because of continued uncertainties regarding their risks and benefits., Design: Eighteen panel members provided oral presentations; each was followed by a multidisciplinary panel discussion. Meeting transcripts and panelists' slide presentations were reviewed to identify the gaps and the types of studies and research methods panelists suggested could best address them., Results: Fifteen gaps were identified in the areas of treatment (e.g., uncertainty regarding the long-term safety and efficacy of commonly prescribed analgesics), epidemiology (e.g., lack of knowledge regarding the course of common pain syndromes), and implementation (e.g., limited understanding of optimal strategies to translate evidence-based pain treatments into practice). Analyses of data from electronic health care databases, observational cohort studies, and ongoing cohort studies (augmented with pain and other relevant outcomes measures) were felt to be practical methods for building an age-appropriate evidence base to improve the pharmacologic management of pain in later life., Conclusion: Addressing the gaps presented in the current report was judged by the panel to have substantial potential to improve the health and well-being of older adults with chronic pain., (Wiley Periodicals, Inc.)

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation., (Copyright © 2010 Wiley-Liss, Inc.)

Unlabelled: This document reports the consensus of an interdisciplinary panel of research and clinical experts charged with reviewing the use of opioids for chronic noncancer pain (CNCP) and formulating guidelines for future research. Prescribing opioids for chronic noncancer pain has recently escalated in the United States. Contrasting with increasing opioid use are: 1) The lack of evidence supporting long-term effectiveness; 2) Escalating misuse of prescription opioids including abuse and diversion; and 3) Uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events (ADEs) including endocrine dysfunction, immunosuppression and infectious disease, opioid-induced hyperalgesia and xerostomia, overdose, falls and fractures, and psychosocial complications. Chief among the limitations of current evidence are: 1) Sparse evidence on long-term opioid effectiveness in chronic pain patients due to the short-term time frame of clinical trials; 2) Insufficiently comprehensive outcome assessment; and 3) Incomplete identification and quantification of ADEs. The panel called for a strategic interdisciplinary approach to the problem domain in which basic scientists and clinicians cooperate to resolve urgent issues and generate a comprehensive evidence base. It offered 4 recommendations in 3 areas: 1) A research strategy for studying the effectiveness of long-term opioid pharmacotherapy; 2) Improvements in evidence-generation methodology; and 3) Potential research topics for generating new evidence., Perspective: Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions. The need for a strong evidence base is urgent. This guideline offers a strategic approach to creating a comprehensive evidence base to guide safe and effective management of CNCP., (Copyright 2010 American Pain Society. All rights reserved.)

Several groups maintain that morphine tolerance and dependence correlate with increased activity of protein kinases ERK1/2 and P38 MAPK and PKC as well as elevated levels of the neuropeptides dynorphin (DYN), substance P (sP), and calcitonin gene-related peptide (CGRP) in spinal cord dorsal horn (SCDH). They demonstrate that tolerance and dependence can be prevented, and sometimes reversed, by constitutive genetic deletion or pharmacological inhibition of these factors. Recently, we showed that mice with a constitutive deletion of the GluR5 subunit of kainate receptors (GluR5 KO) are not different from wild type (WT) littermates with respect to baseline nociceptive thresholds as well as acute morphine antinociception, morphine physical dependence and conditioned place preference. However, unlike WT, GluR5 KO mice do not develop antinociceptive tolerance following systemic morphine administration. In this report, we examined levels of these mediators in SCDH of WT and GluR5 KO mice following subcutaneous implantation of placebo or morphine pellets. Surprisingly, spinal DYN and CGRP, along with phosphorylated ERK2 (pERK2), P38 (pP38) and PKCgamma (pPKCgamma) are elevated by deletion of GluR5. Additionally, chronic systemic morphine administration increased spinal pERK2, pP38 and pPKCgamma levels in both tolerant WT and non-tolerant GluR5 KO mice. In contrast, while morphine increased spinal DYN and CGRP in WT mice, DYN remained unchanged and CGRP was reduced in GluR5 KO mice. These observations suggest that spinal ERK2, P38 and PKCgamma are likely involved in multiple adaptive responses following systemic morphine administration, whereas DYN and CGRP may contribute selectively to the development of antinociceptive tolerance., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Following peripheral inflammation, NMDA receptor (NMDAR) activation in spinal cord dorsal horn neurons facilitates the generation of pain in response to low threshold inputs (allodynia) and signals the phosphorylation of protein kinase C (pPKC) and extracellular signal-regulated kinase 2 (pERK2). Intraplantar complete Freund's adjuvant (CFA) induces inflammatory nociception (allodynic pain) at 24 hours (h) with a concurrent increase in neuronal pPKCgamma and pERK2 but not glial pERK2. These effects are attenuated in a spatial knockout of the NMDAR (NR1 KO) confined to SCDH neurons. Although glia and proinflammatory cytokines are implicated in the maintenance of inflammatory pain and neuronal activation, the role of NMDARs and neuronal-glial-cytokine interactions that initiate and maintain inflammatory pain are not well defined. In the maintenance phase of inflammatory pain at 96h after CFA the NR1 KO mice are no longer protected from allodynia and the SCDH expression of pPKCgamma and pERK2 are increased. At 96h the expression of the proinflammatory cytokine, IL-1beta, and pERK2 are increased in astrocytes. Intrathecal IL-1 receptor antagonist (IL-1ra), acting on neuronal IL-1 receptors, completely reverses the allodynia at 96h after CFA. Deletion of NMDAR-dependent signaling in neurons protects against early CFA-induced allodynia. Subsequent NMDAR-independent signaling that involves neuronal expression of pPKCgamma and the induction of pERK2 and IL-1beta in activated astrocytes contributes to the emergence of NMDAR-independent inflammatory pain behavior at 96h after CFA. Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron-astrocyte-cytokine interactions revealed in these studies.

We have demonstrated previously that mice expressing a constitutive deletion of the kainate receptor subunit GluR5 (GluR5 KO) do not differ from wildtype (WT) littermates of a congenic C57BL/6 background with regard to both the development of morphine physical dependence as measured by naloxone-precipitated withdrawal signs and to morphine reward as revealed by the expression of conditioned place preference (CPP). However, unlike WT, GluR5 KO mice fail to develop antinociceptive tolerance following repeated systemic morphine administration. In this report, we examined the impact of GluR5 deletion on cocaine-mediated CPP and locomotor sensitization. Expression of CPP was evident in WT mice following repeated daily administration of 20mg/kg (but not 10mg/kg) i.p. cocaine. Interestingly, GluR5 KO mice exhibited enhanced cocaine preference as compared with WT mice at both 10 and 20mg/kg doses. In addition, while GluR5 KO mice did not differ from WT with respect to baseline locomotor activity, mutant mice demonstrated increased locomotor hyperactivity versus WT mice after repeated injection of 15mg/kg i.p. cocaine. Collectively, these data indicate that GluR5 appears to negatively modulate some psychostimulant and rewarding properties of cocaine, as demonstrated by heightened sensitization and salience in mutant mice., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Although morphine and heroin analgesia is mediated by mu-opioid receptors encoded by the MOR-1 gene, distinct isoforms are involved. Both opioids also induce dependence by acting at mu-opioid receptors, but which variants are utilized is not known. Here, we assayed morphine and heroin analgesia and dependence in mice treated with antisense oligodeoxynucleotides (AO) targeting MOR-1 exons 1-4. Whereas AOs targeting exons 1 and 4 blocked morphine analgesia, those targeting exons 2 and 3 blocked heroin analgesia. Neither morphine nor heroin analgesia was compromised 5 days after the last AO injection. In morphine and heroin dependent mice, only exon 1 AO significantly reduced jumping incidence during naloxone (50mg/kg) precipitated withdrawal. Neither analgesia nor withdrawal jumping was attenuated in controls pretreated with saline or a mismatch oligodeoxynucleotide control sequence. While these data confirm previous reports that morphine and heroin analgesia are not mediated by a single mu-opioid receptor, both opiates nonetheless apparently induce dependence via a mu-opioid receptor isoform containing exon 1. For heroin, the possibility that analgesia and dependence are mediated by distinct mu-opioid receptor isoforms offers the prospect of developing potent opiate analgesics possessing reduced dependence liability.

Unlabelled: NMDA receptors in the spinal cord dorsal horn (SCDH) mediate some inflammatory pain behaviors. Here, we used rAAV vectors expressing an active small interfering RNA (siRNA) (vector 6) targeting the essential NR1 subunit of the NMDA receptor or a mismatch siRNA (vector MM-6) sequence to determine the consequences of RNAi-mediated knockdown of NR1 expression on NMDA receptor levels and formalin-induced pain behaviors in adult rats. Three weeks after intraparenchymal administration of the vector 6 into the right lumbar SCDH, NR1 mRNA and protein levels were significantly reduced (P < .01) in the ipsilateral SCDH compared with the contralateral SCDH but not in vector MM-6 or non-vector control animals. Formalin-induced phase 2 nociceptive response was significantly reduced (P < .05) in vector 6 animals compared with controls. Although neither vector affected normal mechanical threshold, vector 6 provided protection from the mechanical allodynia seen in controls at 24 hours after intraplantar formalin. Vector 6 also prevented the increase in phosphorylated NR1 levels seen in the ipsilateral SCDH of control rats 45 minutes after formalin. These results indicate that vector-derived siRNAs can effectively produce spatial knockdown of NR1 gene expression, and this knockdown selectively attenuates in vivo NMDA receptor-mediated formalin behaviors and NR1 phosphorylation in the rat., Perspective: This study reveals that a single administration of an siRNA-expressing viral vector produces significant knockdown of the NR1 gene in the SCDH of adult rats. This preclinical study demonstrates the use of RNAi to target the expression of genes mediating pain and the therapeutic potential of this approach.

Previous reports utilizing pharmacological antagonists implicate kainate receptor (KAR) activation in the development of morphine tolerance, dependence, conditioned place preference (CPP), and locomotor sensitization, but the role of glutamate receptor (GluR) 5-containing KAR in these effects remains unclear because of limited selectivity of the inhibitors employed. Therefore, we examined responses to systemic morphine treatment in mice expressing a constitutive deletion of GluR5 [GluR5 knockout (KO)]. Unlike wild-type (WT) littermates, GluR5 KO mice do not develop tolerance after repeated morphine administration by subcutaneous injection or via subcutaneous pellet implantation. In contrast, GluR5 KO mice do not differ from WT with respect to thermal or mechanical nociceptive thresholds, acute morphine antinociception, morphine disposition in the central nervous system (CNS), morphine physical dependence as revealed by naloxone-precipitated withdrawal or development of place preference and locomotor hyperresponsiveness after chronic morphine administration. It is surprising that continuous subcutaneous infusion of the GluR2/GluR5-preferring antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] decreased the number of naloxone-precipitated jumps to a similar extent in WT and GluR5 KO mice. We observed opioid-induced hypersensitivity in both groups during morphine withdrawal as demonstrated by equivalent reductions in thermal and mechanical thresholds; however, this hypersensitivity was not evident during continuous systemic morphine infusion. These data collectively indicate that KARs containing the GluR5 subunit contribute to the development of morphine tolerance without affecting nociceptive thresholds, morphine analgesia, or disposition in CNS of morphine and its metabolite morphine-3-glucuronide. In addition, constitutive deletion of GluR5 does not alter the morphine-induced increase in locomotor activity or the acquisition of morphine reward as measured by a CPP paradigm.

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 signaling in the spinal cord dorsal horn (SCDH) has been implicated in injury-induced pain hypersensitivity. Available ERK pathway inhibitors cannot distinguish between ERK1 and ERK2, nor can they differentially target the expression of neuronal or glial ERK1/2. We selectively inhibited the expression of ERK2 in neurons of the adult mouse SCDH by use of an ERK2 small interfering RNA (siRNA) delivered by a neurotropic adenoassociated viral vector. In situ hybridization revealed a siRNA vector-induced decrease in ERK2 mRNA in the ipsilateral SCDH. Immunohistochemistry showed a decreased neuronal phospho-ERK1/2 (pERK1/2), and Western blot analysis revealed that both ERK2 expression and phosphorylation were reduced by the siRNA vector. In contrast, basal ERK1 expression was not affected, although pERK1 was slightly increased. The siRNA vector-induced knockdown of ERK2 expression in the SCDH did not alter the baseline mechanical or thermal paw withdrawal thresholds. Hindpaw intraplantar injection of complete Freund's adjuvant (CFA) produced peripheral inflammation, mechanical allodynia, and thermal hyperalgesia in vector control animals that persisted for at least 96 h. It also caused an increase in SCDH ERK1 and ERK2 levels at 96 h and pERK1 and pERK2 levels at 1 and 96 h. The ERK2 siRNA vector prevented changes in ERK1, ERK2, and pERK2. In addition, the siRNA vector protected the animals from developing mechanical allodynia and thermal hyperalgesia throughout the 96 h after CFA. These findings indicate that ERK2 in the SCDH neurons is critical for the development of inflammatory pain hypersensitivity.

Preclinical behavioral pharmacological and neuropharmacological evidence indicates that the NMDA receptor plays an important role in opioid dependence, however, the neural substrates subserving these actions are poorly understood. The central nucleus of the amygdala (CeA) is a critical coordinator of autonomic, behavioral, and emotional systems impacted by opioids, however there is no evidence that the essential NMDA-NR1 (NR1) subunit gene in the amygdala plays a role in opioid dependence. To determine the role of the NR1 subunit gene in the amygdala with respect to physical and psychological opioid withdrawal, a spatial-temporal deletion of this gene was produced by microinjecting a recombinant adeno-associated virus (rAAV) expressing the GFP reporter and Cre recombinase (rAAV-GFP-Cre) into the CeA of adult "floxed" NR1 mice (fNR1). Amygdala microinjection of rAAV-GFP-Cre produced a decrease in NR1 gene expression and protein immunolabeling in postsynaptic sites of neurons without signs of compromised ultrastructural neuronal morphology. Amygdala NR1 gene deletion also did not affect locomotor, somatosensory, or sensory-motor behaviors. In addition, bilateral local NR1 gene deletion did not impact somatic or visceral withdrawal symptoms precipitated by naloxone in morphine-dependent mice. However, there was a significant deficit in the expression of an opioid withdrawal-induced conditioned place aversion in mice with amygdala NR1 deletion. These results indicate that functional amygdala NMDA receptors are involved in aversive psychological processes associated with opioid withdrawal. More generally, spatial-temporal deletion of the NR1 subunit by Cre-loxP technology is an effective means to elucidate the neurogenetic substrates of complex phenotypes associated with drug abuse.

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0-104 and 0-142 jumps, respectively) and substantial heritability (h(2)=0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated (r=0.75-0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.

The N-methyl-d-aspartate (NMDA) receptor in the spinal cord dorsal horn (SCDH) is one of the mechanisms involved in central sensitization during chronic pain. Previously, this laboratory created a spatio-temporal knockout (KO) of the N-methyl-d-aspartate receptor I (NR1) subunit in the mouse SCDH. The NR1 KO completely blocks NR1 gene and subsequent NMDA receptor expression and function in SCDH neurons. In the NR1 KO mice, the mechanical and cold allodynia induced at 24 h after complete Freund's adjuvant (CFA) was reduced. However, the protective effects of KO were transient and were not seen at 48 h after CFA. These observations suggest the presence of NMDA-independent pathways that contribute to CFA-induced pain. CFA induces the activation of several signaling cascades in the SCDH, including protein kinase C (PKC)gamma and extracellular signal-regulated kinases (ERK1/2). The phosphorylation of PKCgamma and ERK1/2 was inhibited in the SCDH of NR1 KO mice up to 48 h after CFA treatment, suggesting that these pathways are NMDA receptor-dependent. Interestingly, neuronal cyclooxygenase (COX) -2 expression and microglial p38 phosphorylation were induced in the SCDH of the NR1 KO at 48 h after CFA. Our findings provide evidence that inflammatory reactions are responsible for the recurrence of pain after NR1 KO in the SCDH.

Opioid and excitatory amino acid receptors contribute to morphine dependence, but there are no studies of their role in heroin dependence. Thus, mice injected with acute or chronic heroin doses in the present study were pretreated with one of the following selective antagonists: 7-benzylidenenaltrexone (BNTX), naltriben (NTB), nor-binaltorphimine (nor-BNI; delta1, delta2, and kappa opioid receptors, respectively), MK-801, or LY293558 (NMDA and AMPA excitatory amino acid receptors, respectively). Naloxone-precipitated withdrawal jumping frequency, shown here to be a reliable index of heroin dependence magnitude, was reduced by BNTX or NTB in mice injected with both acute and chronic heroin doses. In contrast, nor-BNI did not alter jumping frequencies in mice injected with an acute heroin dose but significantly increased them in mice receiving chronic heroin injections. Continuous MK-801 or LY293558 infusion, but not injection, reduced jumping frequencies during withdrawal from acute heroin treatment. Their delivery by injection was nonetheless effective against chronic heroin dependence, suggesting mechanisms not simply attributable to NMDA or AMPA blockade. These data indicate that whereas delta1, delta2, NMDA, and AMPA receptors enable acute and chronic heroin dependence, kappa receptor activity limits the dependence liability of chronic heroin. With the exception of delta1 receptors, the apparent role of these receptors to heroin dependence is consistent with their contribution to morphine dependence, indicating that there is substantial physiological commonality underlying dependence to both heroin and morphine. The ability of kappa receptor blockade to differentially alter acute and chronic dependence supports previous assertions from studies with other opioids that acute and chronic opioid dependence are, at least in part, mechanistically distinct. Elucidating the substrates contributing to heroin dependence, and identifying their similarities and differences with those of other opioids such as morphine, may yield effective treatment strategies to the problem of heroin dependency.

National Institutes of Health consensus and state-of-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of (1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality (AHRQ), (2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session, (3) questions and statements from conference attendees during open discussion periods that are part of the public session, and (4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the NIH or the U.S. Government.The statement reflects the panel's assessment of medical knowledge available at the time the statement was written. Thus, it provides a "snapshot in time" of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research.

Recent case reports have raised concerns about the potential for methadone to prolong the QTc interval (QT corrected for heart rate) and predispose patients to torsade de pointes (TdP), a life-threatening arrhythmia. We present a case report that describes the successful use of parenteral and oral methadone in a patient with uncontrolled cancer pain and a history of QTc prolongation. We describe an approach to the use of methadone in this patient and review both case reports and recent prospective studies that have evaluated the risk of TdP and the long-term outcome with respect to the development of TdP in patients receiving methadone for chronic pain or addiction.

NR1 is an essential subunit of the N-methyl-D-aspartate (NMDA) receptor, which at the spinal level is involved in injury-induced pain hypersensitivity and morphine tolerance. An in vitro luciferase assay was used to identify candidate and control (inactive) short interfering RNA (siRNA) sequences that are expressed by a recombinant adeno-associated virus (rAAV) plasmid. rAAV vectors targeting the NR1 subunit were prepared that express active or control (mismatch) siRNA sequences and injected into the mouse spinal cord dorsal horn (SCDH). Three weeks after vector administration, green fluorescent protein labeling of the ipsilateral SCDH confirmed the spatial localization of the viral transduction. Active siRNAs resulted in a 60 to 75% knockdown of NR1 mRNA and protein in the area of the virus injection. The spatial knockdown persisted for at least 6 months after a single administration of the vector. Neither the active nor the mismatch siRNAs resulted in cellular toxicity as measured by nuclear staining and cell integrity. The vector-derived knockdown of NR1 expression in SCDH did not alter acute thermal or mechanical stimulus paw-withdrawal thresholds. However, the vector-derived siRNA prevented the mechanical allodynia measured at 24 and 48 h after injection into the paw of the inflammatory agent, Complete Freund's adjuvant. These results demonstrate that vector-derived siRNAs can be used to produce an in vivo spatial knockdown of the expression and function of the NMDA receptor that is confined to the ipsilateral SCDH. Vector-derived siRNAs may have therapeutic potential for the management of injury-induced pain resulting from the activation of NMDA receptors in the SCDH.

Unlabelled: A subcutaneous implant of 17beta-estradiol or progesterone provides steady-state serum hormone levels from 7 to 24 days after implantation and allows the evaluation of the effects of the replacement with these hormones on phase 1 and phase 2 formalin-induced behaviors in ovariectomized (OVX) rats. Graded doses of 17beta-estradiol (5% to 40%) reduce formalin-induced behavior by 35% to 49% during phase 2 but not during phase 1, as measured with an automated formalin apparatus. The maximal response is seen with 20% 17beta-estradiol. The antihyperalgesic effect of 20% 17beta-estradiol is significant at 8 days after implantation and persists at 21 days. In contrast, graded doses of progesterone have no effect on either phase of formalin. The estrogen receptor antagonist tamoxifen completely prevents the antihyperalgesic effect of the 20% 17beta-estradiol implant. Formalin-induced behaviors during phase 2 are significantly less in proestrus females and OVX rats given 20% 17beta-estradiol compared with OVX control rats. Also, the formalin-induced increase in serum corticosterone is attenuated in OVX control rats compared with proestrus females and OVX rats given 20% 17beta-estradiol. These results indicate that estrogen replacement in OVX rats restores the maximal corticosterone response to tonic pain and, by an estrogen receptor-mediated process, inhibits tonic pain., Perspective: Hormone replacement (HR) therapy remains a widely used modality. We used a pharmacokinetically based rat HR model that results in continuous physiological levels of 17beta-estradiol to demonstrate the analgesic (antihyperalgesic) effects of estrogen replacement in an inflammatory pain model (formalin). These results suggest a potentially important consequence of HR therapy.

Clinical and preclinical studies have found sex-specific differences in the discrimination and perception of inflammatory stimuli. The emerging picture suggests that the biological basis of these differences resides in the regulatory activity of gonadal hormones in the central nervous system. This study describes the effects of ovarian hormones in inflammatory pain processes. Ovariectomized rats received estradiol and/or progesterone, and the number of paw flinches was measured after 1, 2.5 or 5% formalin administration. Both estradiol and progesterone altered the number of flinches only after 1% formalin administration. Estradiol significantly reduced the overall number of flinches during Phase II of the formalin nociceptive response while progesterone attenuated Phase I of the response. After co-administration of estradiol and progesterone, progesterone reversed estradiol's analgesic effect in Phase II, however, estradiol did not reverse progesterone's analgesic activity in Phase I. To determine if estradiol effects are receptor-mediated, tamoxifen (selective estrogen receptor mediator, 15 mg/kg) or alpha-estradiol (an inactive isomer of estradiol, 20 microg) were utilized. Tamoxifen decreased the number of formalin-induced flinches during Phase II while alpha-estradiol did not affect any formalin-induced responses. When co-administered with estradiol, tamoxifen failed to reverse estradiol's effect, suggesting both tamoxifen and estradiol activate similar intracellular mechanisms. Although Western blot analysis detected the presence of estradiol alpha and beta and progesterone B receptors in the spinal cord, hormone replacement treatments had no effects on the levels of these receptors. We postulate that the mechanisms by which estradiol and progesterone induce analgesia occur through the activation of their receptor at the spinal cord level.