patches, may also produce unexpected delayed respiratory depression. the precise reason for sudden respiratory depression is unclear, but there are several hypotheses: saturation of the body fat compartment in people with rapid and profound body fat loss (people with cancer, cardiac or infection-induced cachexia can lose 80% of their body fat). early carbon dioxide retention causing cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces protein binding of fentanyl, releasing yet more fentanyl. reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory-depressant levels. another related complication of fentanyl overdoses includes the so-called wooden chest syndrome, which quickly induces complete respiratory failure by paralyzing the thoracic muscles, explained in more detail in the muscle rigidity section below. heart and blood vessels bradycardia: fentanyl decreases the heart rate by increasing vagal nerve tone in the brainstem, which increases the parasympathetic drive. vasodilation: it also vasodilates arterial and venous blood vessels through a central mechanism, by primarily slowing down vasomotor centers in the brainstem. to a lesser extent, it does this by directly affecting blood vessels. this is much more profound in patients who have an already increased sympathetic drive, like patients who have high blood pressure or congestive heart failure. it does not affect the contractility of the heart when regular doses are administered. muscle rigidity if high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult. the exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers. wooden chest syndrome a prominent idiosyncratic adverse effect of fentanyl also includes a sudden onset of rigidity of the abdominal muscles and the diaphragm, which induces respiratory failure; this is seen with high doses and is known as wooden chest syndrome. the syndrome is believed to be the main cause of death as a result of fentanyl overdoses. wooden chest syndrome is reversed by naloxone and is believed to be caused by a release of noradrenaline, which activates α-adrenergic receptors and also possibly via an activation of cholinergic receptors. wooden chest syndrome is unique to the most powerful opioids—which today comprise fentanyl and its analogs—while other less-powerful opioids like heroin produce mild rigidity of the respiratory muscles to a much lesser degree. overdose further information: opioid overdose and u.s. drug overdose death rates and totals over time fentanyl poses an exceptionally high overdose risk in humans. this is because the amount required to cause toxicity is unpredictable. in its pharmaceutical form most overdose deaths attributed solely to fentanyl occurring at serum concentrations at a mean of 0.025 µg/ml, with a range 0.005–0.027 µg/ml. in contexts of poly-substance use, blood fentanyl concentrations of approximately 7 ng/ml or greater have been associated with fatalities. over 85% of overdoses involved at least one other drug, and there was no clear correlation showing at which level the mixtures were fatal. the dosages of fatal mixtures varied by over three magnitudes in some cases. this extremely unpredictable volatility with other drugs makes it especially difficult to avoid fatalities. 2 mg of fentanyl, a lethal dose for most people, compared to a us penny naloxone (sold under the brand name narcan) can completely or partially reverse an opioid overdose. in july 2014, the medicines and healthcare products regulatory agency (mhra) of the uk issued a warning about the potential for life-threatening harm from accidental exposure to transdermal fentanyl patches, particularly in children, and advised that they should be folded, with the adhesive side in, before being discarded. the patches should be kept away from children, who are most at risk from fentanyl overdose. in the us, fentanyl and fentanyl analogs caused over 29,000 deaths in 2017, a large increase over the previous four years. a package of 30 lozenges, 600 mcg of fentanyl, each some increases in fentanyl deaths do not involve prescription fentanyl but are related to illicitly made fentanyl that is being mixed with or sold as heroin. death from fentanyl overdose continues to be a public health issue of national concern in canada since september 2015. in 2016, deaths from fentanyl overdoses in the province of british columbia averaged two persons per day. in 2017 the death rate rose over 100% with 368 overdose-related deaths in british columbia between january and april 2017. fentanyl has started to make its way into heroin as well as illicitly manufactured opioids and benzodiazepines. fentanyl contamination in cocaine, methamphetamine, ketamine, mdma, and other drugs is common. a kilogram of heroin laced with fentanyl may sell for more than us$100,000, but the fentanyl itself may be produced far more cheaply, for about us$6,000 per kilogram. while mexico and china are the primary source countries for fentanyl and fentanyl-related substances trafficked directly into the united states, india is emerging as a source for finished fentanyl powder and fentanyl precursor chemicals.. the united kingdom illicit drug market is no longer reliant on china, as domestic fentanyl production is replacing imports. the intravenous dose causing 50% of opioid-naive experimental subjects to die (ld50) is "3 mg/kg in rats, 1 mg/kg in cats, 14 mg/kg in dogs, and 0.03 mg/kg in monkeys." the ld50 in mice has been given as 6.9 mg/kg by intravenous administration, 17.5 mg/kg intraperitoneally, 27.8 mg/kg by oral administration. the ld50 in humans is unknown, but it is estimated that the lethal dose may be as low as 2 mg in some people depending on body size, tolerance, and past usage. false reports by police of poisonings through secondary exposure in the late 2010s, some media outlets began to report stories of police officers being hospitalised after touching powdered fentanyl, or after brushing it from their clothing. topical (or transdermal; via the skin) and inhalative exposure to fentanyl is extremely unlikely to cause intoxication or overdose (except in cases of prolonged exposure with very large quantities of fentanyl), and first responders such as paramedics and police officers are at minimal risk of fentanyl poisoning through accidental contact with intact skin. a 2020 article from the journal of medical toxicology stated that "the consensus of the scientific community remains that illness from unintentional exposures is extremely unlikely, because opioids are not efficiently absorbed through the skin and are unlikely to be carried in the air." the effects being reported in these cases, including rapid heartbeat, hyperventilation and chills, were not symptoms of a fentanyl overdose, and were more commonly associated with a panic attack. a 2021 paper expressed concern that these physical fears over fentanyl may inhibit effective emergency response to overdoses by causing responding officers to spend additional time on unnecessary precautions, and that the media coverage could also perpetuate a wider social stigma that people who use drugs are dangerous to be around. prevention public health advisories to prevent fentanyl misuse and fatal overdose have been issued by the u.s. centers for disease control (cdc). an initial han advisory, also known as a health alert network advisory ("provides vital, time-sensitive information for a specific incident or situation; warrants immediate action or attention by health officials, laboratorians, clinicians, and members of the public; and conveys the highest level of importance") was issued during october 2015. a subsequent han alert was issued in july 2018, warning of rising numbers of deaths due to fentanyl abuse and mixing with non-opioids. a december 2020 han advisory warned of: substantial increases in drug overdose deaths across the united states, primarily driven by rapid increases in overdose deaths involving... illicitly manufactured fentanyl; a concerning acceleration of the increase in drug overdose deaths, with the largest increase recorded from march 2020 to may 2020, coinciding with the implementation of widespread mitigation measures for the covid-19 pandemic; significant increases in overdose deaths involving methamphetamine. 81,230 drug overdose deaths occurred during the 12 months from may 2019 to may 2020, the largest number of drug overdoses for a 12-month interval ever recorded for the u.s. the cdc recommended the following four actions to counter this rise: local need to expand the distribution and use of naloxone and overdose prevention education, expand awareness, access, and availability of treatment for substance use disorders, intervene early with individuals at highest risk for overdose, and improve detection of overdose outbreaks to facilitate more effective response. another initiative is a social media campaign from the united states drug enforcement administration (dea) called "one pill can kill". this social media campaign's goal is to spread awareness of the prevalence of counterfeit pills that are being sold in america that are leading to the large overdose epidemic in america. this campaign also shows the difference between counterfeit pills and real pills. it also offers resources for help with drug addiction and rehabilitation. pharmacology