High-dose naloxone formulations are not as essential as we thought.

Naloxone is an effective FDA-approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review investigates the adequacy of two doses of standard IM or IN naloxone in reversing fentanyl overdoses compared to newer high-dose naloxone formulations. Moreover, our initiative incorporates the experiences of people who use drugs, enabling a more practical and contextually-grounded analysis. The evidence indicates that the vast majority of fentanyl overdoses can be successfully reversed using two standard IM or IN dosages. Exceptions include cases of carfentanil overdose, which necessitates ≥ 3 doses for reversal. Multiple studies documented the risk of precipitated withdrawal using ≥ 2 doses of naloxone, notably including the possibility of recurring overdose symptoms after resuscitation, contingent upon the half-life of the specific opioid involved. We recommend distributing multiple doses of standard IM or IN naloxone to bystanders and educating individuals on the adequacy of two doses in reversing fentanyl overdoses. Individuals should continue administration until the recipient is revived, ensuring appropriate intervals between each dose along with rescue breaths, and calling emergency medical services if the individual is unresponsive after two doses. We do not recommend high-dose naloxone formulations as a substitute for four doses of IM or IN naloxone due to the higher cost, risk of precipitated withdrawal, and limited evidence compared to standard doses. Future research must take into consideration lived and living experience, scientific evidence, conflicts of interest, and the bodily autonomy of people who use drugs.

High-Dose Naloxone Formulations Are Not as Essential as We Thought.

Naloxone is a U.S. Food and Drug Administration (FDA) approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public, and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review aimed to improve understanding regarding the adequacy of the regularly distributed two doses of low-dose IM or IN naloxone in effectively reversing fentanyl overdoses and whether high-dose naloxone formulations (HDNF) formulations are an optimal solution to this problem. Moreover, our initiative incorporated the perspectives and experiences of people who use drugs (PWUD), enabling a more practical and contextually-grounded analysis. We began by discussing the knowledge and perspectives of Tennessee Harm Reduction, a small peer-led harm reduction organization. A comprehensive literature review was then conducted to gather relevant scholarly works on the subject matter. The evidence indicates that, although higher doses of naloxone have been administered in both clinical and community settings, the vast majority of fentanyl overdoses can be successfully reversed using standard IM dosages with the exception of carfentanil overdoses and other more potent fentanyl analogs, which necessitate three or more doses for effective reversal. Multiple studies documented the risk of precipitated withdrawal using high doses of naloxone. Notably, the possibility of recurring overdose symptoms after resuscitation exists, contingent upon the half-life of the specific opioid. Considering these findings and the current community practice of distributing multiple doses, we recommend providing at least four standard doses of IN or IM naloxone to each potential bystander, and training them to continue administration until the recipient achieves stability, ensuring appropriate intervals between each dose. Based on the evidence, we do not recommend HDNF in the place of providing four doses of standard naloxone due to the higher cost, risk of precipitated withdrawal and limited evidence compared to standard IN and IM. All results must be taken into consideration with the inclusion of the lived experiences, individual requirements, and consent of PWUD as crucial factors. It is imperative to refrain from formulating decisions concerning PWUD in their absence, as their participation and voices should be integral to the decision-making process.

Spectrum of sublytic astrocytopathy in neuromyelitis optica.

Neuromyelitis optica is an autoimmune inflammatory disorder targeting aquaporin-4 water channels in CNS astrocytes. Histopathological descriptions of astrocytic lesions reported in neuromyelitis optica so far have emphasized a characteristic loss of aquaporin-4, with deposition of IgG and complement and lysis of astrocytes, but sublytic reactions have been underappreciated. We performed a multi-modality study of 23 neuromyelitis optica autopsy cases (clinically and/or pathologically confirmed; 337 tissue blocks). By evaluating astrocytic morphology, immunohistochemistry and AQP4 RNA transcripts, and their associations with demyelinating activity, we documented a spectrum of astrocytopathy in addition to complement deposition, microglial reaction, granulocyte infiltration and regenerating activity. Within advanced demyelinating lesions, and in periplaque areas, there was remarkable hypertrophic astrogliosis, more subtle than astrocytic lysis. A degenerative component was suggested by 'dystrophic' morphology, cytoplasmic vacuolation, Rosenthal fibres and associated stress protein markers. The abundance of AQP4 mRNA transcripts in sublytic reactive astrocytes devoid of aquaporin-4 protein supported in vivo restoration following IgG-induced aquaporin-4 endocytosis/degradation. Astrocytic alterations extending beyond demyelinating lesions speak to astrocytopathy being an early and primary event in the evolving neuromyelitis optica lesion. Focal astrocytopathy observed without aquaporin-4 loss or lytic complement component deposition verifies that astrocytic reactions in neuromyelitis optica are not solely dependent on IgG-mediated aquaporin-4 loss or lysis by complement or by IgG-dependent leucocyte mediators. We conclude that neuromyelitis optica reflects a global astrocytopathy, initiated by binding of IgG to aquaporin-4 and not simply definable by demyelination and astrocytic lysis. The spectrum of astrocytic morphological changes in neuromyelitis optica attests to the complexity of factors influencing the range of astrocytic physiological responses to a targeted attack by aquaporin-4-specific IgG. Sublytic astrocytic reactions are no doubt an important determinant of the lesion's evolution and potential for repair. Pharmacological manipulation of the astrocytic stress response may offer new avenues for therapeutic intervention.

Family Functioning, Substance Use and Related Problem Behaviors: Hispanic vs. Anglo Runaway Youths.

Runaway youths represent a neglected clinical group, and few studies have examined ethnicity differences within this population. Substance use, family functioning and related problem behaviors were examined in a sample of Hispanic and Anglo runaway youths with substance abuse diagnoses (N = 145). Youths, aged 12-17, were recruited from two urban, southwestern runaway shelters. Within single-parent families, Anglo youths reported more marijuana use, and, regardless of family constitution, reported more tobacco use than did Hispanic youths. Overall, Anglo youths reported more externalizing problems and more conflict tactics used in resolving disagreements with their primary caretaker while Hispanic youths reported higher depression and familism scores. Given the differences found between Hispanic and Anglo youths, the findings argue that culturally sensitive interventions for runaway youths and families are warranted.