A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects.

Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucine-enkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptive-effect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.

Predictors of treatment retention and survival among methadone-maintained patients: A possible role for a functional delta opioid receptor gene variant.

BACKGROUND: Variants in the delta opioid receptor gene, OPRD1, were associated with opioid use disorder and response to treatment. The study goal was to assess whether OPRD1 variants predict survival and retention in methadone maintenance treatment (MMT). METHODS: Retention and survival time since admission (June 1993 - June 2022) until leaving treatment (for retention), or at the end of follow-up (Dec 2022) (for retention and survival) were analyzed in 488 patients. Vital data was taken from a national registry. Predictors were estimated using Kaplan-Meier and Cox regression models. RESULTS: Longer retention and survival were found for carriers of the T allele of SNP rs204076. This SNP is associated with OPRD1 expression in cortex (GTEx). Carriers of the T allele (n = 251) survived longer compared to non-carriers (24.7 vs. 20.2 years, p = 0.005) and had longer retention (11.2 vs. 8.8 years, p = 0.04). Multivariate analysis identified the T allele as an independent predictor of longer survival time (p = 0.003) and retention (p = 0.009). Additional predictors for survival were no benzodiazepine use after one year in MMT, no hepatitis C, <20 years of opioid usage, and admission at age < 30. Additional predictors for longer retention were no use of other drugs except opioids on admission, and no drugs at one year, as well as methadone dose ≥ 100mg/d at one year and axis I & II DSM-5 psychiatric diagnosis. CONCLUSIONS: The OPRD1 SNP rs204076 and non-genetic predictors contribute to survival time and retention in MMT patients.

OPRD1 rs569356 polymorphism has an effect on plasma norbuprenorphine levels and dose/kg-normalized norbuprenorphine values in individuals with opioid use disorder.

This study aimed to determine the effects of nine OPRM1, OPRD1 and OPRK1 polymorphisms on plasma BUP and norbuprenorphine (norBUP) concentrations and various treatment responses in a sample of 122 patients receiving BUP/naloxone. Plasma concentrations of BUP and norBUP were detected by LC-MS/MS. PCR-RFLP method was used to genotype polymorphisms. OPRD1 rs569356 GG had significantly lower plasma norBUP concentration (p = 0.018), dose- (p = 0.049) and dose/kg-normalized norBUP values (p = 0.036) compared with AA. Craving and withdrawal symptoms were significantly higher in OPRD1 rs569356 AG+GG relative to AA. There was a statistically significant difference between the OPRD1 rs678849 genotypes in the intensity of anxiety (13.5 for CT+TT and 7.5 for TT). OPRM1 rs648893 TT (18.8 ± 10.8) was significantly different to CC+CT (14.82 ± 11.3; p = 0.049) in view of the intensity of depression. This current study provides the first data on a prominent effect of the OPRD1 rs569356 variation on BUP pharmacology due to its metabolite norBUP.

Delta opioid receptor agonists are effective for multiple types of headache disorders.

Headaches are highly disabling and are among the most common neurological disorders worldwide. Despite the high prevalence of headache, therapeutic options are limited. We recently identified the delta opioid receptor (DOR) as an emerging therapeutic target for migraine. In this study, we examined the effectiveness of a hallmark DOR agonist, SNC80, in disease models reflecting diverse headache disorders including: chronic migraine, post-traumatic headache (PTH), medication overuse headache by triptans (MOH), and opioid-induced hyperalgesia (OIH). To model chronic migraine C57BL/6J mice received chronic intermittent treatment with the known human migraine trigger, nitroglycerin. PTH was modeled by combining the closed head weight drop model with the nitroglycerin model of chronic migraine. For MOH and OIH, mice were chronically treated with sumatriptan or morphine, respectively. The development of periorbital and peripheral allodynia was observed in all four models; and SNC80 significantly inhibited allodynia in all cases. In addition, we also determined if chronic daily treatment with SNC80 would induce MOH/OIH, and we observed limited hyperalgesia relative to sumatriptan or morphine. Together, our results indicate that DOR agonists could be effective in multiple headache disorders, despite their distinct etiology, thus presenting a novel therapeutic target for headache.

In response to the editorial 'Sedation in endoscopy in 2016: is it safe sedation with propofol led by the endoscopist in complex situations?'

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Prevalencia y enfoque terapéutico del dolor en el servicio de urgencias de un hospital universitario / Prevalence and therapeutic management of pain in the emergency department of a university hospital

Objetivo: conocer la prevalencia de dolor y su enfoque terapéutico en un servicio de urgencias. Material y métodos: estudio transversal llevado a cabo en el Servicio de Urgencias de un hospital universitario durante 7 días consecutivos. El médico de triaje interrogó sobre la presencia de dolor a los pacientes mayores de 15 años que acudían a urgencias. Se excluyeron los pacientes atendidos en el Servicio de Psiquiatría, Obstetricia-Ginecología y aquellos cuya gravedad no permitía la valoración del dolor en el triaje. Se revisó posteriormente el tratamiento analgésico previo a la visita, la evaluación del dolor, el tratamiento analgésico aplicado durante su estancia en urgencias y el tratamiento pautado al alta. Resultados: se analizaron 668 de los 2.287 pacientes que acudieron a urgencias durante el periodo del estudio. Presentaron dolor 501 pacientes (75 %), de los que 45 ingresaron y 456 fueron dados de alta a domicilio (240 pacientes procedentes de nivel 1 y 216 de nivel 2). El 24,5 % de los 501 pacientes que manifestaron tener dolor realizaba tratamiento analgésico previo. De los 216 pacientes atendidos en el nivel 2, el 41,7 % recibió tratamiento analgésico durante su estancia [paracetamol (80,2 %), antiinflamatorios no esteroideos (AINE) (50 %), coanalgésicos (1 %), opioides débiles (20,8 %), opioides fuertes (3,1 %)]. El 32,7 % de los 196 pacientes sin registro de evaluación del dolor recibió tratamiento analgésico a demanda. En un 69,4 % de los 456 pacientes que no precisaron ingreso, al alta se pautó analgesia o se modificó el tratamiento analgésico previo [paracetamol (55 %), AINE (67 %), co-analgésicos (10 %), opioides débiles (10 %), opioides fuertes (1,1 %)]. Conclusiones: se evidencia una elevada prevalencia de dolor (75 %) en los pacientes que acuden al servicio de urgencias. El 41,7 % de los pacientes que presentaban dolor recibió tratamiento analgésico durante su estancia y en el 69,4 % de los pacientes que no precisaron ingreso se pautó analgesia al alta. Destaca la baja prescripción de opioides (AU)

Aim: To know the prevalence of pain and the therapeutic approach in an emergency department (ED). Material and methods: Cross-sectional study in the ED of a university hospital during 7 consecutive days was performed. The presence of pain was asked by a physician to patients older than 15 years admitted at ED. Patients admitted at Psychiatry, Obstetrics-Gynecology Emergency Department and those whose serious condition would not allow pain assessment in triage were excluded. The previous analgesic treatment, pain assessment, analgesic treatment in the ED and also scheduled treatment at discharge were later reviewed. Results: Six hundred and sixty-eight from 2,287 patients who were admitted at ED were analyzed. Five hundred and one patients reported pain (75 %), of which 45 were admitted and 456 were discharged at home (240 patients in level 1, 216 at level 2). The 24.5 % of the 501 patients who reported pain at admission were previously treated with analgesics. The 41.7 % of the 216 patients treated at level 2 received analgesic treatment during their stay [paracetamol (80.2 %), nonsteroidal antiinflammatory drugs (NSAIDs) (50.0 %), co-analgesics (1.0 %), weak opioids (20.8 %), strong opioids (3.1 %)]. The 32.7 % of the 196 patients without documented pain assessment received analgesic treatment as required. In 69.4 % of the 456 patients who did not require hospitalization, analgesic treatment was prescribed or modified at discharge [paracetamol (55 %), nonsteroidal anti-inflammatory drugs (NSAIDs) (67 %), co-analgesics (10 %), weak opioids (10 %), strong opioids (1.1 %)]. Conclusions: A high prevalence of pain (75 %) was found in patients admitted at ED. The 41.7 % received analgesic treatment during their stay and in 69.4 % of patients analgesia was prescribed at discharge. Low opioid prescription was detected (AU)