The role of spinal inhibitory neuroreceptors in the antihyperalgesic effect of warm water immersion therapy.

OBJECTIVE: Warm water immersion therapy (WWIT) has been widely used in the treatment of various clinical conditions, with analgesic and anti-inflammatory effects. However, its mechanism of action has not been fully investigated. The present study analyzed the role of spinal inhibitory neuroreceptors in the antihyperalgesic effect of WWIT in an experimental model of inflammatory pain. METHODS: Mice were injected with complete Freund's adjuvant (CFA; intraplantar [i.pl.]). Paw withdrawal frequency to mechanical stimuli (von Frey test) was used to determine: (1) the effect of intrathecal (i.t.) preadministration of naloxone (a non-selective opioid receptor antagonist; 5 µg/5 µl), (2); AM281 (a selective cannabinoid receptor type 1 [CB1] antagonist; 2 µg/5 µl), (3); and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; a selective adenosine A1 receptor antagonist; 10 nmol/5 µl), on the antihyperalgesic (pain-relieving) effect of WWIT against CFA-induced hyperalgesia. RESULTS: Intrathecal naloxone, AM281, and DPCPX significantly prevented the antihyperalgesic effect of WWIT. This study suggests the involvement of spinal (central) receptors in the antihyperalgesic effect of WWIT in a model of inflammatory pain. CONCLUSIONS: Taken together, these results suggest that opioid, CB1, and A1 spinal receptors might contribute to the pain-relieving effect of WWIT.

Brand-to-Generic Substitution of Buprenorphine/Naloxone Sublingual Film in Puerto Rico: A Case Study.

A 56-year-old patient with a 1-year history of stable maintenance treatment with Suboxone for opioid use disorder (OUD) was switched to a generic formulation in May of 2019. The patient reported experiencing-over the course of the following 3 months-withdrawal symptoms when switched to the Alvogen-produced generic formulation in May of 2019 and then to the Sandoz-produced version in July of that same year, she also was positive for fentanyl during that time. As a result, the buprenorphine dose was increased, and the patient was stable at this new dose using the generic versions. Blood levels pre- and post-change (not reported in previous case reports) showed maximum buprenorphine concentration being reached more quickly when the brand-name drug was used. Additionally, the area under the curve (AUC) values indicate that the generic formulation had higher exposures than the brand-name drug. Based on the clinical impact of the brand-to generic switch in this patient, further research in this area is warranted. In the meantime, clinicians should carefully monitor their patients so that, if warranted, dose adjustments can be made quickly and safely to minimize negatively impacting the OUD therapy outcomes of patients.

Opioids for restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a distressing and common neurological disorder that may have a huge impact in the quality of life of those with frequent and intense symptoms. Patients complain of unpleasant sensations in the legs, at or before bedtime, and feel an urge to move the legs, which improves with movement, such as walking. Symptoms start with the patient at rest (e.g. sitting or lying down), and follow a circadian pattern, increasing during the evening or at night. Many pharmacological intervention are available for RLS, including drugs used to treat Parkinson's disease (L-Dopa and dopaminergic agonists), epilepsy (anticonvulsants), anxiety (benzodiazepines), and pain (opioids). Dopaminergic drugs are those most frequently used for treatment of RLS, but some patients do not respond effectively and require other medication. Opioids, a class of medications used to treat severe pain, seem to be effective in treating RLS symptoms, and are recommended for patients with severe symptoms, because RLS and pain appear to share the same mechanism in the central nervous system. All available drugs are associated to some degree with side effects, which can impede treatment. Opioids are associated with adverse events such as constipation, tolerance, and dependence. This justifies the conduct of a systematic review to ascertain whether opioids are safe and effective for treatment of RLS. OBJECTIVES: To asses the effects of opioids compared to placebo treatment for restless legs syndrome in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled trials, CENTRAL 2016, issue 4 and MEDLINE, EMBASE, and LILACS up to April 2016, using a search strategy adapted by Cochraneto identify randomised clinical trials. We checked the references of each study and established personal communication with other authors to identify any additional studies. We considered publications in all languages. SELECTION CRITERIA: Randomised controlled clinical trials of opioid treatment in adults with idiopathic RLS. DATA COLLECTION AND ANALYSIS: Two review authors independently screened articles, independently extracted data into a standard form, and assessed for risk of bias. If necessary, they discussed discrepancies with a third researcher to resolve any doubts. MAIN RESULTS: We included one randomised clinical trial (N = 304 randomised; 204 completed; 276 analysed) that evaluated opioids (prolonged release oxycodone/naloxone) versus placebo. After 12 weeks, RSL symptoms had improved more in the drug group than in the placebo group (using the IRLSSS: MD -7.0; 95% CI -9.69 to -4.31 and the CGI: MD -1.11; 95% CI -1.49 to -0.73). More patients in the drug group than in the placebo group were drug responders (using the IRLSSS: RR 1.82; 95% CI 1.37 to 2.42 and the CGI: RR1.92; 95% ICI 1.49 to 2.48). The proportion of remitters was greater in the drug group than in the placebo group (using the IRLSSS: RR 2.14; 95% CI 1.45 to 3.16). Quality of life scores also improved more in the drug group than in the placebo group (MD -0.73; 95% CI -1.1 to -0.36). Quality of sleep was improved more in the drug group measured by sleep adequacy (MD -0.74; 95% CI -1.15 to -0.33), and sleep quantity (MD 0.89; 95% CI 0.52 to 1.26).There was no difference between groups for daytime somnolence, trouble staying awake during the day, or naps during the day. More adverse events were reported in the drug group (RR 1.22; 95% CI 1.07 to 1.39). The major adverse events were gastrointestinal problems, fatigue, and headache. AUTHORS' CONCLUSIONS: Opioids seem to be effective for treating RLS symptoms, but there are no definitive data regarding the important problem of safety. This conclusion is based on only one study with a high dropout rate (moderate quality evidence).

Efecto de la Naloxona sobre la secreción pulsátil de la hormona luteinizante en vacas de doble propósito con doble ordeño y amamantamiento / Effect of Naloxone over the secretion of the Luteinizing Hormone on double purpose cows with double milking and suckling

Se examinó el efecto de cero, una y tres inyecciones de naloxona (NX; 500 mg) el día 30 posparto a intervalos de 1 h, sobre la liberación de la hormona luteinizante (LH), en vacas de doble propósito en anestro: ¾ Europeo x » Cebú (n = 18). Las vacas pastorearon en zacate Estrella de África (Cynodon plectostachyus) y gramas nativas (Axonopus y Paspalum spp.) con un consumo de 5 kg de alimento balaceado diariamente (16 % de PC). El ordeño fue mecánico dos veces al día y se realizó amamantamiento de las crías después del ordeño (30 min). Las vacas y las crías permanecieron separadas, excepto durante el amamantamiento. Se colectó una muestra de sangre cada 2 días desde el parto hasta el día 30 posparto y se cuantificó la progesterona (P) sérica por RIA. El anestro fue indicado por P < 1 ng/ml. El día 30 posparto se tomaron muestras de sangre cada 15 min durante 3 horas: una hora después de cada inyección de NX o solución salina fisiológica y se cuantificó la LH sérica por RIA. Las variables de respuesta fueron: concentración media (MLH) y basal (BLH), número (NP), amplitud (AP) y duración (DP) de pulsos de LH. Se usó un ANDEVA con parcelas divididas, parcela mayor = tratamiento y subparcela = período de muestreo. No hubo efectos (p >0.05) de tratamiento, período y sus interacciones en las variables de respuesta. En vacas de doble propósito con doble ordeño y amamantamiento, la naloxona no cambió la secreción de la LH en el día 30 posparto.

This study determined the effect of zero, one and three intramuscular injection of naloxone (NX, 500 mg) on 30 postpartum day for 1 hour intervals over the release of the luteinizing hormone in dual purpose cows in anestrous (¾ Europe x » Zebu) cows (n =18). The cows grazed on African Star grass (Cynodon plectostachyus) and native grass (Axonopus and Paspalum spp) and ate daily 5 kg of balanced food (16% crude protein). The cows were mechanically milked twice a day and after that their calves were allowed to suck for 30 minutes. A blood sample was collected every two days, from the delivery until 30 days postpartum for the quantification of progesterone (P) by RIA. In this blood anestrous was indicated by P< 1 ng/ml. On day 30 postpartum blood samples were drawn every 15 min during 3 hours: one hour after each naloxone injection or saline solution and Luteinising Hormone (LH) was measured by RIA. The response variables were mean (MLH) and basal concentration (BLH), number (PN), amplitude (PA) and pulse duration (PD) of LH. The statistic analysis was divided plot; principal plot was the treatment and secondary plot was the samples period. There were not effects (p>0.05) of treatment, samples period and its interactions on response variables. In double purpose cows with double milking and suckling naloxona did not affect the LH secretion at 30 day pospartum.

Cardiorespiratory and endocrine effects of endogenous opioid antagonism by naloxone in ponies anaesthetised with halothane.

Halothane depresses cardiorespiratory function and activates the pituitary-adrenal axis, increasing beta endorphin. In horses, beta endorphin may enhance the anaesthetic-associated cardiorespiratory depression and mortality risk. The authors studied endogenous opioid effects on cardiorespiratory function and pituitary-adrenal activity in halothane-anaesthetised ponies by investigating opioid antagonism by naloxone. Six ponies were anaesthetised three times (crossover design). Anaesthesia was induced with thiopentone and maintained with 1.2 per cent halothane for 2 hours. Immediately after induction, naloxone was administered either intravenously (0.5 mg kg(-1)bolus then 0.25 mg kg(-1)hour(-1)for 2 hours) or intrathecally (0.5 mg) or was replaced by saline as control. Pulse and respiratory rates, arterial blood gases, cardiac output and plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations were measured. All groups developed cardiorespiratory depression (40 per cent decrease in cardiac output) and plasma cortisol increased. Plasma ACTH concentration was higher in ponies treated with intrathecal naloxone. Endogenous opioids may inhibit ACTH secretion, attenuating the stress response to halothane anaesthesia in equidae.

Edema pulmonar agudo después de la administración de naloxona / Acute pulmonary edema following administration of naloxone

La administración de opiaceos provoca depresión respiratoria, que puede prolongarse en el periodo postoperatorio por lo que es conveniente la vigilancia estrecha del paciente o la administración de drogas antagonistas tales como la naloxona. Se presenta un caso de edema agudo pulmonar posterior a la administración de naloxona en un paciente femenino de 36 años de edad y aparentemente sin antecedentes patológicos predisponentes para esta complicación. La paciente fue programada para polipectomia nasal, la cual se realizó bajo anestesia general endovenosa. Durante el procedimiento fueron utilizados, propofol en infusión como anestésico, vecuronio como relajante muscular y fentanyl como analgésico. Al terminar la cirugía, la paciente presentó depresión respiratoria y miosis, por lo que se decidió antagonizar los efectos del opiaceo con dosis relativamente bajas de naloxona. Cinco minutos depués de haber ingresado a la sala de recuperación la paciente presenta datos compatibles con edema agudo pulmonar, por lo que, se inicia el tratamiento antiedema y treinta minutos después, la paciente presenta mejoría. Posteriormente continúa su tratamiento en la Terapia Intensiva de donde es egresada dos días después en completa mejoría y continúa su observación en la consulta externa de su clínica.

Antagonismo de los efectos disociados de la Ketamina con Naloxona / Antagonism of the dissociative ketamine effects with naloxone

Se estudia la acción de la naloxona sobre los efectos disociativos de la ketamina, con el objeto de poder establecer la participación del sistema opioide endógeno en la génesis de dichos efectos, para lo cual se estudiaron 30 pacientes adultos del sexo femenino, siguiendo un procedimiento simple ciego y dos paradigmas farmacológicos diferentes con cuatro condiciones consecutivas cada uno: 1. Control inicial (C), ketamina (K), solución salina isotónica (S) y control final (C'). 2. C, K, naloxona (N) y C'. La naloxona disminuyó significativamente el tiempo de recuperación y nistagmus, y antagonizó la analgesia y efectos cardiovasculares de la ketamina. Se concluye que los efectos de la ketamina son medidos en gran parte por el sistema opiode endógeno, ya que dosis bajas de un antagonista específico revierte significativamente tales efectos.

Efecto de los antagonistas opiaceos en el choque / Effects of the narcotic antagonists in the shock

I. Administración de naloxona en choque hipovolémico, provocado en una rata. En las distintas variedades de choque se ha documentado experimental y clinicamente la participación de opiáceos endógenos contribuyendo a la hipotensión y a la parálisis de la regulación de la presión arteriual, la cual explica la utilidad de la naloxona en el tratamineto clínico de algunas formas de choque. Aun cuando se ha documentado la efectividad de estos compuestos en variedades ebdotóxicas e hipovolémicas de choque, la utilidad de naloxona tiene inconvenientes relacionados con la capacidad de bloqueo del efecto analgésico de los opiáceos que resulta en hiperalgesía, lo cual ha estimulado a la búsqueda de otros antagonistas parciales que preserven el efecto analgésico de la morfina y el efecto antishock de la naloxona. En este trabajo se presenta evidencia experimental de los efectos de la naloxona en un modelo de shock hipovolémico en rata derpierta, modelo que permitira el estudio de otros compuestos que reúnan las características mencionadas .