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.Naloxone 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. Most of the recent 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.
This risk is higher in specific groups, like those with obstructive sleep apnea.Other factors that increase the risk of respiratory depression are:
High fentanyl doses
Sleep
Older age
Simultaneous use of CNS depressants like benzodiazepines, barbiturates, alcohol, and inhaled anesthetics
Hyperventilation
Decreased CO2 levels in the serum
Respiratory acidosis
Decreased fentanyl clearance from the body
Decreased blood flow to the liver
Renal insufficiencySustained release fentanyl preparations, such as 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.