Disulfiram Abrogates Morphine Tolerance-A Possible Role of µ-Opioid Receptor-Related G-Protein Activation in the Striatum.

One of the key strategies for effective pain management involves delaying analgesic tolerance. Early clinical reports indicate an extraordinary effectiveness of off-label disulfiram-an agent designed for alcohol use disorder-in potentiating opioid analgesia and abrogation of tolerance. Our study aimed to determine whether sustained µ-opioid signaling upon disulfiram exposure contributes to these phenomena. Wistar rats were exposed to acute and chronic disulfiram and morphine cotreatment. Nociceptive thresholds were assessed with the mechanical Randal-Selitto and thermal tail-flick tests. µ-opioid receptor activation in brain structures important for pain processing was carried out with the [35S]GTPγS assay. The results suggest that disulfiram (12.5-50 mg/kg i.g.) augmented morphine antinociception and diminished morphine (25 mg/kg, i.g.) tolerance in a supraspinal, opioid-dependent manner. Disulfiram (25 mg/kg, i.g.) induced a transient enhancement of µ-opioid receptor activation in the periaqueductal gray matter (PAG), rostral ventromedial medulla (RVM), hypothalamus, prefrontal cortex and the dorsal striatum at day 1 of morphine treatment. Disulfiram rescued µ-opioid receptor signaling in the nucleus accumbens and caudate-putamen 14 days following morphine and disulfiram cotreatment. The results of this study suggest that striatal µ-opioid receptors may contribute to the abolition of morphine tolerance following concomitant treatment with disulfiram.

Evaluation of tramadol human pharmacokinetics and safety after co-administration of magnesium ions in randomized, single- and multiple-dose studies.

BACKGROUND: Magnesium ions (Mg2+) increase and prolong opioid analgesia in chronic and acute pain. The nature of this synergistic analgesic interaction has not yet been explained. Our aim was to investigate whether Mg2+ alter tramadol pharmacokinetics. Our secondary goal was to assess the safety of the combination. METHODS: Tramadol was administered to healthy Caucasian subjects with and without Mg2+ as (1) single 100-mg and (2) multiple 50-mg oral doses. Mg2+ was administered orally at doses of 150 mg and 75 mg per tramadol dosing in a single- and multiple-dose study, respectively. Both studies were randomized, open label, laboratory-blinded, two-period, two-treatment, crossover trials. The plasma concentrations of tramadol and its active metabolite, O-desmethyltramadol, were measured. RESULTS: A total of 25 and 26 subjects completed the single- and multiple-dose study, respectively. Both primary and secondary pharmacokinetic parameters were similar. The 90% confidence intervals for Cmax and AUC0-t geometric mean ratios for tramadol were 91.95-102.40% and 93.22-102.76%. The 90% confidence intervals for Cmax,ss and AUC0-τ geometric mean ratios for tramadol were 93.85-103.31% and 99.04-105.27%. The 90% confidence intervals for primary pharmacokinetic parameters were within the acceptance range. ANOVA did not show any statistically significant contribution of the formulation factor (p > 0.05) in either study. Adverse events and clinical safety were similar in the presence and absence of Mg2+. CONCLUSIONS: The absence of Mg2+ interaction with tramadol pharmacokinetics and safety suggests that this combination may be used in the clinical practice for the pharmacotherapy of pain.

Novel opioid-neurotensin-based hybrid peptide with spinal long-lasting antinociceptive activity and a propensity to delay tolerance development.

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration (in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics.

Genetic Predisposition for Osteoporosis and Fractures in Postmenopausal Women.

Osteoporosis is a disease with complex etiology where the genetic factors may account for as much as 50-85% of the risk of its development in postmenopausal women. The polymorphism of estrogen receptor genes (ESR1, ESR2) seems essential among the genetic factors. The goal of this study was to analyze polymorphisms of selected genes in a population of postmenopausal women treated for osteoporosis and to evaluate the influence of genetic and nongenetic factors on the estimated 10-year risk of fracture. The study group consisted of 214 women hospitalized for treatment of postmenopausal osteoporosis. We investigated the presence of ESR1, ESR2, LRP5, and WNT16 genetic polymorphisms and the risk of fracture in each woman. The main finding was that of significant differences in the polymorphisms of the WNT16 rs2908004 genetic variant, notably, the less frequent presence of TC allele in women with a greater risk of osteoporotic fractures. We conclude that the polymorphism of the WNT16 gene seems highly relevant in the pathogenesis of osteoporosis, which makes it a promising object for further research on the genetic background of fracture risk.

Autologous Platelet-Rich Plasma Reduces Healing Time of Chronic Venous Leg Ulcers: A Prospective Observational Study.

The study investigated whether the application of dressings with autologous platelet-rich plasma (PRP) would reduce the healing time in patients with chronic venous leg ulcers. This is a prospective observational study that included 100 patients diagnosed with lower extremity venous insufficiency complicated by ulceration of a leg or foot, who had been after angioplasty of stenotic artery. Patients were divided into two groups of 50 each: treated with PRP (study group) and treated with conventional hydrocolloid dressings (control group). We followed the wound changes at Day 10, Day 20, and Day 30 of treatment and compared them with the baseline appearance at Day 0. We evaluated the appearance, area, and depths of wounds with ultrasound. The granulation process was examined histologically to document skin formation and wound tissue neovascularization. The findings were that treatment with PRP dressings resulted in a significant progressive reduction in ulcer size, irrespective of the ulcer's initial size, compared to treatment with conventional dressings. Further, the best effect of PRP was noticed in the category of largest wounds. After a month of treatment with PRP dressings, more than 50% of all ulcers were completely healed. The young epidermis appeared together with the granulation tissue, and the formation of dermis took shape after 20 days of treatment. We conclude that the use of PRP dressings is a safe, nonsurgical adjunctive procedure for treating chronic venous leg ulcers. The potential benefit of PRP dressings over conventional ulcer treatment requires further in-depth exploration.

Does Patient-Specific Instrumentation Improve Femoral and Tibial Component Alignment in Total Knee Arthroplasty? A Prospective Randomized Study.

Alignment of the prosthesis is one of the most significant factors that affect the long-term clinical outcome following total knee arthroplasty (TKA). There is conflicting evidence whether patient-specific instrumentation (PSI) for TKA improves the component position compared to standard instrumentation. This study aimed to compare the rotational alignment of the femoral and tibial components in TKA patients when performed with either conventional or PSI. Sixty patients with primary knee osteoarthritis were randomly divided into two groups treated surgically with TKA: one with conventional instrumentation and the other with the Visionaire PSI system (Smith and Nephew, Memphis, TN). Computerized tomography (CT) and X-ray imaging were performed preoperatively and 12 weeks after surgery. The rotational alignment of the femoral and tibial component in all patients was assessed postsurgically using CT imaging according to the Berger protocol. Both groups were clinically assessed in a blinded fashion using the Knee Society Score (KSS) and a visual analog scale (VAS). Fifty-eight patients were prospectively assessed. The mean postsurgical follow-up was 3.0 ± 0.4 months. CT images did not reveal any significant improvement in the rotational alignment of the implant components between the groups. X-rays revealed a significant improvement in the deviation from the optimal alignment range of the femoral component in the coronal plane in both groups. Patients operated with Visionaire PSI assistance had poorer functional outcomes. We conclude that there were no improvements in clinical outcomes or knee component alignment in patients treated with PSI compared with those treated with standard instruments. In addition, clinical and functional assessment showed inferior results in terms of KSS and VAS scores at the midterm follow-up in patients treated with PSI.

Tapentadol and nitric oxide synthase systems.

Tapentadol, a new analgesic drug with a dual mechanism of action (µ-opioid receptor agonism and norepinephrine reuptake inhibition), is indicated for the treatment of moderate to severe acute and chronic pain. In this paper, the possible additional involvement of the nitric oxide synthase (NOS) system in the antinociceptive activity of tapentadol was investigated using an unspecific inhibitor of NOS, L-NOArg, a relatively specific inhibitor of neuronal NOS, 7-NI, a relatively selective inhibitor of inducible NOS, L-NIL, and a potent inhibitor of endothelial NOS, L-NIO. Tapentadol (1-10 mg/kg, intraperitoneal) increased the threshold for mechanical (Randall-Selitto test) and thermal (tail-flick test) nociceptive stimuli in a dose-dependent manner. All four NOS inhibitors, administered intraperitoneally in the dose range 0.1-10 mg/kg, potentiated the analgesic action of tapentadol at a low dose of 2 mg/kg in both models of pain. We conclude that NOS systems participate in tapentadol analgesia.

Dry needling as a method of tendinopathy treatment.

Tendinopathy is a broad concept that describes any painful condition that occurs in or around a tendon.The ideal treatment for tendinopathy is still nebulous. Dry needling is a treatment method in which a special needle is placed into the focus of tendinosis. The aim of this procedure is to form fenestrations which may initiateadvantageous bleeding and thus bring about the influx of growth factors (activating healing and regeneration). Relevant clinical studies have often combineddry needling with autologous blood injection therapy. Results from these studies are encouraging. This review of English-language literature aims to present this noteworthy method of tendino- and enthesopathytreatmentm by describing the results of several trials, hypotheses explaining the underlying mechanism and the application of dry needling in other fields of medicine.