The prevention of analgesic opioids abuse: expert opinion

Opioids are drugs of reference for the treatment of moderate to severe pain. Their proper use and a periodic assessment of the patient are crucial to prevent misuse. A multidisciplinary group suggests strategies for all stakeholders involved in the management of pain and suggests the importance of the doctor-patient relationship

Pain assessment in animal models: do we need further studies?

In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals

Finale di partita: una lettura di Altro compleanno

Tutto questo parlare di calcioper non parlare di altro(Giovanni Giudici, Viani, sociologia del calcio) Lo stadio di San Siro a fine luglio doveva allora presentarsi per quello che era da almeno vent’anni, un monolite nero e disertato, un colosso sotto il sole a picco che ne rifletteva, in una specie di sequenza luttuosa, i colori abbacinati dell’ardesia. L’uomo che lo stava fissando al crepuscolo degli anni settanta, Vittorio Sereni, abitava in via Paravia, da quelle parti, era un habitué di ..

Neonatal Abstinence Syndrome: Update on Diagnostic and Therapeutic Strategies

Substance use among pregnant women is a major public health issue. Both prescription opioid use and illicit opioid abuse have increased dramatically in recent years. Prolonged in utero drug exposure may result in neonatal abstinence syndrome (NAS), an acute multisystemic clinical entity that occurs in the first days of life. This syndrome is caused by abrupt discontinuation of fetal exposure to licit or illicit drugs chronically consumed by the mother during pregnancy and transmitted to the fetus through the placenta. It usually requires prolonged hospitalization and may have long-term effects. The interplay of many factors contributes to its clinical heterogeneity, and its pathophysiology has not been fully unveiled. The first step in NAS management consists of nonpharmacologic interventions and includes promoting breastfeeding when not contraindicated. If withdrawal signs become severe, pharmacotherapy is needed. The Finnegan scoring system supports care providers across the pharmacotherapy process from initiation through the monitoring phase, until weaning and discontinuation. However, a standardized approach to pharmacotherapy is still lacking. Morphine is usually the first-line agent to treat NAS. Methadone is a valid option, but its safety profile is not completely known. Phenobarbital, despite its lack of effect on gastrointestinal symptoms and unfavorable pharmacologic features, has been identified as a second-line agent to be used in infants unresponsive to opiates. Although buprenorphine and clonidine seem promising, their use requires further validation. Long-term developmental effects of NAS therapy call for more-comprehensive, longitudinal assessments. In this article, key points for use of recommended therapies are outlined, and directions for future research are suggested

Transient receptor potential melastatin-3 (TRPM3) mediates nociceptive-like responses in Hydra vulgaris

The ability of mammals to feel noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors, which express specific membrane receptors, such as the Transient Receptor Potential (TRP) family. Here, we show that one of the most important nociceptive-like pathways is conserved in the freshwater coelenterate Hydra vulgaris, the most primitive organism possessing a nervous system. In particular, we found that H. vulgaris expresses TRPM3, a nociceptor calcium channel involved in the detection of noxious heat in mammals. Furthermore, we detected that both heat shock and TRPM3 specific agonist (i.e., pregnenolone sulfate) induce the modulation of the heat shock protein 70 (HSP70) and the nitric oxide synthase (NOS), two genes activated by TRP-mediated heat painful stimuli in mammals. As expected, these effects are inhibited by a TRPM3 antagonist (i.e., mefenamicacid). Interestingly, the TRPM3 agonist and heat shock also induce the expression of nuclear transcription erythroid 2-related factor (Nrf2) and superoxide dismutase (SOD), known markers of oxidative stress; noteworthy gene expression was also inhibited by the TRPM3 antagonist. As a whole, our results demonstrate the presence of conserved molecular oxidative/nociceptive-like pathways at the primordial level of the animal kingdom

A Systematic Review and Meta-Analysis on the Role of Nutraceuticals in the Management of Neuropathic Pain in In Vivo Studies

The control of neuropathic pain is a leading challenge in modern medicine. Traditional medicine has, for a long time, used natural compounds such as nutraceuticals for this purpose, and extensive evidence has supported their role in controlling oxidative stress and persistent pain-related inflammation. Nutraceuticals are natural products belonging to the food sector whose consumption could be related to physiological benefits. Indeed, they are used to improve health, prevent chronic diseases, and delay the aging process. Here, we report a systematic review and meta-analysis to provide a more comprehensive report on the use of nutraceuticals in neuropathic pain, including evaluating confounding factors. A search of the literature has been conducted on principal databases (PubMed, MEDLINE, EMBASE, and Web of Science) following the PRISMA statement, and we retrieved 484 articles, 12 of which were selected for the meta-analysis. The results showed that administration of natural drugs in animals with neuropathic pain led to a significant reduction in thermal hyperalgesia, measured in both the injured paw (SMD: 1.79; 95% CI: 1.41 to 2.17; p < 0.0001) and in the two paws (SMD: −1.74; 95% CI: −3.36 to −0.11; p = 0.036), as well as a reduction in mechanical allodynia and hyperalgesia (SMD: 1.95, 95% CI: 1.08 to 2.82; p < 0.001) when compared to controls. The results of the review indicate that nutraceutical compounds could be clinically relevant for managing persistent neuropathic pain

Pain assessment in animal models: do we need further studies?

In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal-dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animal

Refractive Outcome in Preterm Newborns With ROP After Propranolol Treatment. A Retrospective Observational Cohort Study

Background: Recent explorative studies suggest that propranolol reduces retinopathy of prematurity (ROP) progression, but the short-term effects of propranolol treatment at 1 year of corrected age have not been extensively evaluated. Methods: A multi-center retrospective observational cohort study was conducted to assess the physical development and the refractive outcome of infants with prior ROP treated with propranolol. Forty-nine infants treated with propranolol were compared with an equal number of patients who did not receive any propranolol therapy and represent the control group, with comparable anthropometrical characteristics and stages of ROP. Results: The weight, length, and head circumference at 1 year of corrected age were similar between infants who had been treated, or not, with propranolol, without any statistically significant differences. Refractive evaluation at 1 year showed spherical equivalent values decreasing with the progression of ROP toward more severe stages of the disease, together with an increasing number of infants with severe myopia. On the contrary, no differences were observed between infants who had been treated with propranolol and those who had not. Conclusion: This study confirms that the progression of ROP induces an increase of refractive errors and suggests that propranolol itself does not affect the refractive outcome. Therefore, if the efficacy of propranolol in counteracting ROP progression is confirmed by further clinical trials, the conclusion will be that propranolol might indirectly improve the visual outcome, reducing the progression of ROP

The pathophisiology of retinopathy of prematurity: an update of previous and recent knowledge

Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birth weight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new anti-vasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterised for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO2 regulate the normal or abnormal production of HIF-1 and VEGF, which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF-1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF-1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti-VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and β-adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single-nucleotide polymorphisms within the β-ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using β-blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Filippi et al. Propranolol Micro-Drops for ROP Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297\u2013 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a \u3b2-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current result