Rates have remained at least 2.5 times higher among males since 2016 . This is among the first national investigations to examine reasons for fentanyl exposure in a nuanced manner. With respect to route of administration, dermal use decreased, and injection and inhalation in particular increased. Inhalation not only increased over four-fold, but this route was a risk factor for patients experiencing a major effect or death. This is the first national report on the increase in inhalation as a route of illicit fentanyl use. These results are difficult to compare to various other studies that queried route of administration but only reported injecting behavior . In addition, a limitation of Poison Control data is that we often cannot differentiate types of use that constitute inhalation; specifically, we cannot determine whether the patients insufflated, i.e., snorted, or smoked the substance. Our results appear to add to a national cross-sectional study of fentanyl-related deaths in 2016 which found evidence for snorting and smoking the drug in 52.4% and 17.9% of cases, respectively . A recent study in San Francisco found that there was a shift between injecting heroin to smoking fentanyl . This shift appeared to be largely rooted in harm reduction behavior; e.g., avoiding injection related risks of skin and soft tissue infections. Further, injection is associated with increased risk of overdose , although in our multi-variable model, injection only approached significance as a risk factor for a major adverse outcome or death. Deaths involving opioids as recorded by the State Unintentional Drug Overdose Reporting System in the first half of 2019 suggest that among deaths with a reported specific route of administration, injection was most common, followed by ingestion , snorting/sniffing , and smoking . Indeed, snorting or smoking fentanyl is less common than injecting , but these methods appear to be becoming more prevalent among those who want to avoid injection or its associated risks . As such,how to cure cannabis research needs to continue to monitor shifts in route of administration as well as real or perceived changes in risk related to route.
Many Poison Control studies that examine drug exposures combine “abuse” and misuse into a single category, but we chose not to aggregate these reasons, which resulted in a more nuanced analysis. The proportion of cases involving “abuse” increased over time and represented the majority of cases in 2021. “Abuse” was also a major risk factor for patients experiencing a major effect or death. Misuse, which implies improper use of a legitimate medication, slightly decreased over time, and was actually inversely associated with patients experiencing a major effect or death. We believe this suggests higher call volume indicating use of illicitly manufactured fentanyl as opposed to use of pharmaceutical product. These results demonstrate the complexity of reasons for use which cannot be delineated in other datasets. Also, with respect to reasons for use, suspected suicide attempts decreased, although these cases were associated with higher risk of a major effect or death, possibly due to intentional high doses. Therapeutic error and adverse reactions decreased which we believe suggests stricter or more careful medical oversight of prescribed fentanyl in recent years. With regard to polydrug use, the proportion of cases involving methamphetamine and cocaine increased from 669.0% and 374.0%, respectively. This corroborates literature suggesting that co-use of fentanyl with stimulants is becoming more common , so much that it has been suggested that co-use of fentanyl and stimulants is now the “fourth wave” of the opioid overdose crisis . Despite increased co-use of methamphetamine, we found that this was actually a protective factor against experiencing a major adverse effect or death. The extent to which the drugs were directly combined, used en tandem, or merely used within the same day, is unknown. Given that some people use methamphetamine in attempt to prevent or reverse effects of opioids or other depressants and others use in attempt to alleviate opioid withdrawal , more research is needed to determine contexts of such co-use in relation to severity of overdose risk. While the proportion of patients co-using heroin increased, we found that co-use of prescription opioids decreased.
This finding adds to findings from mortality data which suggests that while deaths involving both prescription opioids and synthetic opioids increased from 2013 to 2017, deaths then leveled off from 2017 to 2019 . This decrease may be indicative of the decline of the “first wave” of the opioid crisis which was largely driven by prescription opioid use . Further, nationally, non-medical prescription opioid use and misuse has also been decreasing in the US . Although recent studies have found increasing rates of benzodiazepine use being involved in fentanyl-related deaths , we found that co-use of benzodiazepines actually decreased. A recent finding of a serious rise in seizures of counterfeit pills containing fentanyl highlights concern about unbeknownst co-use. The highest proportion of exposures occurred in the West, which is in contrast with other studies finding that most related deaths have occurred in the Northeast . With regard to the origin of calls, the proportion of calls to Poison Control centers increased from hospital centers and the proportion of calls made “on site,” typically referring to where the poisoning occurred, decreased. This suggests that it is primarily medical staff that call PCCs regarding fentanyl exposures, not patients or their caretakers. This perhaps demonstrates that while 911 emergency services are often called to respond to fentanyl overdoses, the public rarely calls PCCs for such cases. We also found that on site cases were less likely to experience a major outcome or death, although SUDORS data from the first half of 2019 suggest that the majority of fentanyl-related deaths occur at the decedent’s home followed by someone else’s home . Therefore, on site calls appear to be lacking using these data so more research is needed to focus on circumstances of nonfatal overdoses that occur in homes. The increase in poisonings found in this study highlight the rising risk environment due to illicitly manufactured fentanyl and point to the need for better prevention efforts. Improved drug supply surveillance is needed to better elucidate exposure risk and this could include crime lab data , or data from the High Intensity Drug Trafficking Areas Performance Monitoring Program .
The goal is timely data that can serve as an early warning system. Likewise, PCC data, with potentially timelier outcome data, can complement mortality data and aid in surveillance efforts. Drug checking for fentanyl, an intimate form of drug surveillance, is being explored to reduce the risk imposed by fentanyl . Further, wider distribution of naloxone is needed for more rapid response to fentanyl related overdose. For better household coverage, the US Food and Drug Administration is working on over-the-counter status for naloxone . We do not know definitively which cases involved prescribed, unprescribed, and/or illicitly manufactured fentanyl, although misuse tends to be associated with prescribed fentanyl . We did not present data on form of fentanyl reportedly used as this variable was missing for 64% of cases. However, results from a sub-analysis do indicate that 87.7% of patients who reported dermal use used fentanyl in patch form, suggesting that the vast majority of dermal use was in fact via patches. These data rely on caller or other contact information which may or may not include the patient. Some cases may rely on secondhand reporting, though this is not likely to have changed significantly over time and unlikely to have significantly biased trend estimates. Toxicology testing was not always conducted to confirm exposure to fentanyl or its analogs. Relatedly, given that fentanyl is a common adulterant in or replacement for drugs such as heroin, fentanyl exposures were likely underreported when people were unknowingly exposed. In fact, reporting of poisonings related to fentanyl is relatively rare compared to mortality studies. This is because calls to Poison Control are dependent on a patient or medical professional calling to report the poisoning or to ask for medical advice to treat a case. As such, these data are not generalizable to all poisonings; they are however, useful in informing other national studies. Exposures are also not generalizable to use or nonfatal overdose in the population as most cases reported involve adverse effects related to exposure and reporting exposures to PCCs is only voluntary. Finally,trimming cannabis it is possible for medical outcomes to be misclassified, but in at least three quarters of cases involving fentanyl, exposure information is obtained from medical facilities that monitor patients and PCC staff follows up on cases to obtain the most accurate information possible before closing a case .However, HIV-associated neurocognitive disorders remain highly prevalent, particularly in milder forms and even in PWH on suppressive ART . The most prominent neurocognitive deficits in the ART era tend to be observed in the domains of learning and executive function, though many PWH are also impaired in delayed recall, processing speed, working memory, and motor skills . Significant heterogeneity exists with regard to severity and profile of neurocognitive impairment in PWH and this is also reflected in neuroimaging and neuropathological studies. One explanation for this heterogeneity is that there may be subtypes of HAND with distinct underlying mechanisms, risk factors,and consequences. Identifying sub-types of HAND may improve our understanding of the etiology, nature, course, and treatment of HAND.
Multiple factors contribute to NCI in virally suppressed PWH , including viral persistence in the CNS , cellular and epigenetic factors , ART toxicity , comorbidities, and coinfections. A unifying factor across these mechanisms is chronic immune activation and inflammation. ART reduces, but does not normalize immune activation, in most PWH. Soluble biomarkers of immune activation and inflammation are elevated in PWH despite viral suppression and in PWH with HAND . This persistent level of low-grade chronic immune activation and inflammation, which induces neuroinflammation and neurovascular complications , is considered a key element of pathogenesis of NCI in ART-treated PWH. Chronic inflammation in ART-treated PWH can also lead to endothelial dysfunction , which is a key mechanism underlying the development of atherosclerosis and subsequent cardiovascular disease . During the immune response to infection, pro-inflammatory cytokines released from immune cells activate endothelial cells, triggering the expression of cellular adhesion molecules . Cell adhesion molecules interact with other molecules to promote the recruitment, adherence, and migration of leukocytes to and across the vascular endothelium . Chronic and sustained activation of immune and endothelial cells leads to increased adhesion molecule expression, vascular permeability, and immune cell migration, which further propogates the inflammatory response and can lead to endothelial dysfunction or damage . CVD is among the most prevalent of age-associated non-infectious conditions in PWH , may occur at earlier ages relative to age-matched people without HIV , and is further exacerbated by the increased incidence of traditional and non-traditional risk factors . In the general population, CVD, particularly in mid-life, is among the strongest risk factors for vascular, Alzheimer’s, and mixed dementia types . Studies of PWH, including those who are virally suppressed, have found adverse independent effects of CVD and/or its risk factors on NCI , brain inflammation, vascular abnormalities, and neural injury . As the HIV population grows older, CVD and its risk factors are increasingly recognized for their role in HAND. Recent studies have also found evidence of endothelial dysfunction and blood-brain barrier impairment in ART-treated and virally suppressed PWH . The BBB, composed of specialized endothelial cells and tight junctions and surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons , is a primary target of HIV-associated neural injury and a central neuropathological factor underlying HAND . The BBB is also altered by CVD, further contributing to dysfunction . Increased BBB permeability is a key mechanism in cognitive impairment due to cerebrovascular disease, which is similar to HAND in terms of risk factors and often has similar underlying pathological processes given evidence of overlapping neuroimaging and neurocognitive phenotypes . Cerebrovascular-related cognitive deficits depend on the location and characteristics of the particular lesion, though these lesions are often distributed throughout fronto-subcortical and fronto-parietal white matter tracts important for processing speed and executive functioning . These domains are also linked to subclinical CVD and atherosclerosis in PWH , and similar patterns of diffuse white matter pathology are found in HAND .