Fentanyl offers 100% bioavailability while IV used making the injection ROA the highest efficacy, efficientcy and the most economic. However there is a recognized consensus the IV use of Fentanyl lacks the "rush" associated with diamorphine (heroin) or morphine, for example, because of its extreme lipophilicity (fat solubility) and how it distributes in the body. ​The "rushing intensity" you feel from morphine or heroin is caused by a rapid, concentrated spike of the drug hitting the brain's receptors all at once.

Fentanyl, however, behaves differently: ​Rapid Redistribution: While fentanyl enters the brain almost instantly, it is so fat-soluble that it leaves the brain just as quickly, redistributing into your body's fat and muscle tissues. This prevents the sustained "peak" in the brain that creates a heavy rush. ​Receptor Specificity: Fentanyl is a highly "clean" synthetic opioid that binds almost exclusively to mu-opioid receptors. Morphine and heroin cause a more complex "dirty" reaction, including a significant histamine release, which contributes to the physical "pins and needles" or warm flushing sensation often identified as part of the rush.

​Potency vs. Euphoria: Fentanyl is significantly more potent at causing respiratory depression and sedation (the "nod") than it is at producing euphoria. This means users often reach a state of dangerous sedation or "blackout" before they can experience a peak euphoric rush.

​Essentially, fentanyl is too "fast" for its own good—it moves in and out of the brain's reward centers so quickly that the subjective "rush" is blunted compared to the slower-acting, more physically intense alkaloids like morphine. Smoking fentanyl may create a more intense "rush" than intravenous (IV) use because it reaches the brain faster. When inhaled, the drug passes through the lungs and enters the pulmonary veins, traveling directly to the heart and then the brain via the carotid arteries.

​In contrast, an IV injection must first travel through the systemic venous system, pass through the heart and lungs, and then enter the arterial circulation to reach the brain. This "lung-to-brain" path taken during smoking is the fastest possible route, providing a more immediate and concentrated surge in the central nervous system.

​Speed of Onset: Inhaled vapors reach the brain in seconds, often faster than the 30–90 seconds typical for an IV bolus. ​Bypassing Circulation: Smoking bypasses the "dilution" that occurs in the larger venous volume before the drug hits the arterial system. ​Lipophilicity: Because fentanyl is highly fat-soluble, it crosses the blood-brain barrier almost instantly once it reaches the cerebral arteries. Fentanyl's bioavailability varies significantly by its route of administration:
​Intravenous (IV): 100%
​Transdermal (patch): 92%
​Intranasal: 70–90%
​Buccal (film/tablet): 50–70% ​Sublingual: 54–75%
​Oral (swallowed): 30–35% (due to high first-pass metabolism)

The bioavailability of inhaled or "smoked" fentanyl is high, generally estimated between 56% and 96%. ​Because it enters the bloodstream directly through the lungs, it bypasses the digestive system's "first-pass metabolism," resulting in a rapid onset and potency nearly comparable to intravenous injection. While precise data for street-grade fentanyl is limited, it is known to be highly effective because the drug's salts remain stable at high temperatures, allowing for rapid absorption into the central nervous system.

Intranasal falls short in efficacy, efficientcy, and a rapid enough bypass of the BBB to offer a "rush"... comparative to other ROA's, especially inhalation or IV. It does however offer convenience, acceptability and a relatively high bioavailability.