The most common adverse effects of naloxone are symptoms of acute opioid withdrawal, not side effects of the drug itself. When naloxone reverses an opioid overdose, it rapidly displaces opioids from receptors in the brain, which can trigger a cascade of withdrawal symptoms including nausea, vomiting, agitation, confusion, and increased heart rate. In one large observational study of nearly 1,200 naloxone administrations, adverse events were reported in 45% of cases, with confusion (32% of all reported events) and headache (22%) topping the list.
Why Withdrawal Is the Main Side Effect
Naloxone works by knocking opioids off the receptors they’ve latched onto in the brain. In someone who isn’t opioid-dependent, this process causes virtually no symptoms. But in someone whose body has adapted to regular opioid use, the sudden absence of opioid activity creates a deficit the nervous system isn’t prepared for. The result is precipitated withdrawal: a rapid-onset version of the same withdrawal syndrome that develops naturally when someone stops using opioids, but compressed into minutes rather than days.
Unlike spontaneous withdrawal, which builds gradually over hours, precipitated withdrawal hits fast and can feel intensely unpleasant. Characteristic early signs include eyes tearing, nose running, yawning, sweating, and hot flashes. These symptoms are so reliably linked to precipitated withdrawal that clinicians use them as markers to distinguish it from other causes of distress.
How Often Specific Symptoms Occur
The frequency of individual symptoms varies across studies, partly because different settings capture different populations. In a study tracking bystander-administered naloxone from 2003 to 2009, vomiting occurred in 13% of cases and anger or discomfort in 9%. A separate study from 2014 to 2015 found that 27% of recipients were confused afterward, 11% were angry, and 7% were nauseous. A large Norwegian observational study broke adverse events down further: confusion was most common, followed by headache, nausea and vomiting, aggressiveness, rapid heart rate, and seizures (about 4% of reported events).
Agitation and combativeness deserve special attention because they create real challenges for first responders. In a study of 597 law enforcement-administered naloxone cases, about 10% of patients were irritable or combative after receiving the drug. Suspected fentanyl exposure made this significantly more likely, with combativeness rates roughly four times higher in those cases compared to other opioids.
Nausea and Vomiting
Nausea and vomiting are among the most consistently reported effects across all naloxone studies. They stem from the abrupt shift in the gut’s opioid receptors, which play a role in slowing digestion. When naloxone strips those receptors clean, the digestive system essentially lurches back into full activity. Vomiting is particularly concerning in someone still partially sedated because of the risk of inhaling stomach contents into the lungs, which is why placing a person in the recovery position after naloxone administration matters.
Cardiovascular Effects
Naloxone can cause a spike in sympathetic nervous system activity, the body’s “fight or flight” response. This happens because opioids suppress that system, and when naloxone suddenly removes the suppression, heart rate and blood pressure can surge. Rapid heart rates of 160 to 180 beats per minute have been documented in case reports, and elevated blood pressure is common enough to be considered a standard feature of precipitated withdrawal.
Serious cardiovascular complications are rare but documented. These include dangerous heart rhythm disturbances and, in very uncommon cases, cardiac arrest. Most reported cases of severe cardiac events have involved patients recovering from surgical anesthesia rather than street overdose reversal, and they occurred across a range of doses. For the typical overdose reversal scenario, cardiovascular symptoms are usually limited to temporarily elevated heart rate and blood pressure that resolve on their own.
Pulmonary Edema
One rare but well-known complication is fluid buildup in the lungs, a condition called noncardiogenic pulmonary edema. Estimates put this at roughly 0.2% to 3.6% of patients who receive naloxone and end up in the emergency department. A study of 639 patients found a 2% rate of pulmonary complications. Despite longstanding concern among healthcare providers, the same study found no significant difference in complication rates between patients who received low, moderate, or high doses. The fear that larger doses cause more lung problems appears to be unfounded based on current evidence.
Nasal Spray vs. Injectable Forms
Naloxone is available as a nasal spray and as an injection (into muscle or a vein). A systematic review comparing these routes found no meaningful difference in the rate of serious side effects. Major complications were essentially zero for nasal spray and 0.05% for injection. Minor side effects, the nausea, vomiting, agitation, and sweating that come with withdrawal, occurred at roughly similar rates regardless of how the naloxone was delivered: about 7% for nasal and 13.5% for injection, though the difference wasn’t statistically significant. Only one case of a grand mal seizure was reported across the studies reviewed, and it occurred with an intramuscular injection.
How Long the Effects Last
Naloxone wears off faster than most opioids. Its effects typically last 30 to 90 minutes, while many opioids remain active for much longer. This mismatch creates two practical realities. First, withdrawal symptoms triggered by naloxone are usually short-lived, resolving as the naloxone clears the body and opioids re-occupy their receptors. Second, the original overdose can return once naloxone wears off, which is why medical observation after reversal is important. The unpleasant withdrawal symptoms often lead people to leave the scene or refuse transport, which increases the risk of a recurrent overdose going untreated.
Special Risk in Newborns
Naloxone carries a distinct risk for babies born to mothers who used opioids during pregnancy. Because these infants are already physically dependent on opioids, naloxone can trigger precipitated withdrawal that includes seizures. The American Academy of Pediatrics has specifically advised against giving naloxone to opioid-exposed newborns for this reason, and no clinical trials have been conducted in this population due to the seizure risk.