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Research · Medication

Naloxone and nalmefene

Two systematic reviews of observational studies linked take-home and bystander naloxone to fewer overdose deaths and more recoveries. Nasal and injected naloxone succeeded about equally in a meta-analysis, while blinded trials of lower nasal doses found injection worked faster. An 8 mg dose did not raise survival over 4 mg. Sudden opioid withdrawal after naloxone was common.

Add to Bio HackChecked 2026-11-14
Status
Narcan 4 mg naloxone nasal spray was approved by FDA for over-the-counter sale on March 29, 2023, the first naloxone product sold without a prescription, and generic over-the-counter versions followed. Other naloxone formulations and doses, including the 8 mg Kloxxado nasal spray and Zimhi and other injections, remain prescription drugs. Nalmefene is a prescription drug, as Opvee nasal spray and the Zurnai auto-injector, for ages 12 and older. All are FDA approved for emergency treatment of known or suspected opioid overdose.
Also called
naloxone, naloxone hydrochloride, Narcan, Narcan nasal spray, Kloxxado, Zimhi, naloxone injection, opioid overdose reversal, opioid antagonist, nalmefene, nalmefene hydrochloride, Opvee, Zurnai
Taken for
opioid overdose, fentanyl overdose, reversing an overdose, restoring breathing, heroin overdose, overdose prevention kits

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help1

Reported risks5

What people take it for, and what was found

Shown to help1

Strong

Survival of opioid overdose with take-home and bystander naloxone

Linked to fewer overdose deaths and higher odds of recovery, about 8.6 times, in two systematic reviews of observational studies of take-home and bystander naloxone.

Compared with no naloxone given by a bystander [1]; comparisons the review abstract does not describe [2]; communities without naloxone programs [3]

The numbers and sources
Effect
Pooling four studies, naloxone given by bystanders was associated with higher odds of recovery than no naloxone (OR 8.58, 95% CI 3.90 to 13.25), and trained people scored higher on overdose recognition and response tests (SMD 1.35) [1]. A review of 22 observational studies found take-home naloxone met all nine Bradford Hill criteria for causation. Even with naloxone given, 1 in 123 overdoses was fatal (0.8%, 95% CI 0.4 to 1.2) [2]. In Massachusetts, communities that trained more than 100 people per 100,000 in overdose response with nasal naloxone had lower overdose death rates than communities without the program (adjusted rate ratio 0.54, 95% CI 0.39 to 0.76) [3]. FDA states these medicines can be given by people without medical training and have no abuse potential [4].
Population
4 studies of bystander naloxone and 5 of overdose education [1]; 22 observational studies [2]; 19 Massachusetts communities, 2002 to 2009, with 2,912 trained bystanders reporting 327 rescues [3].
Sources
[1], [2], [3]
Caveats
No randomized trials, since withholding naloxone in an overdose is not ethical. The programs combined naloxone with training and calls to emergency services [3].

Mixed results2

Moderate

Nasal against injected naloxone

Mixed results: a meta-analysis found nasal and injected naloxone succeeded about equally, while two blinded trials of lower nasal doses found injection restored breathing faster with fewer rescue doses.

Compared with intramuscular or intravenous naloxone [5]; intramuscular naloxone 800 µg [6][7]

The numbers and sources
Effect
In prehospital studies, success rates were 82.5% for nasal and 80.4% for injected naloxone (OR 1.01, 95% CI 0.42 to 2.43). Nasal naloxone acted slightly more slowly (SMD 0.63) and needed a rescue dose more often (OR 2.17, 95% CI 1.53 to 3.09) [5]. In a supervised injecting facility, a rescue dose was needed after 8.6% of intramuscular and 23.1% of nasal doses of 800 µg (OR 0.35) [6]. In ambulance care, adequate breathing returned within 10 minutes after one dose in 97.2% on intramuscular 0.8 mg and 79.6% on nasal 1.4 mg, a difference of 17.5% [7].
Population
6 prehospital studies [5]; 197 adults who inject drugs, 88% men, in Sydney [6]; 201 adults treated by ambulance staff in Norway, 82% men, mostly suspected heroin [7].
Sources
[5], [6], [7]
Caveats
The blinded trials used nasal doses lower than the 4 mg over-the-counter spray [6][7]. Heroin, not fentanyl, was the main opioid in the trials [7].
Limited

Nalmefene against naloxone

Mixed results: one emergency department trial found nalmefene and naloxone gave similar improvements, while a volunteer study found faster breathing recovery on nalmefene at 5 minutes.

Compared with intravenous naloxone 2 mg [9]; nasal naloxone 4 mg [10]

The numbers and sources
Effect
In emergency patients with altered consciousness, intravenous nalmefene 1 or 2 mg and naloxone 2 mg gave similar improvements in breathing rate and alertness, with no differences in efficacy or withdrawal [9]. In healthy volunteers given remifentanil, minute ventilation 5 minutes after nasal nalmefene 2.7 mg rose 5.75 L/min against 3.01 L/min after nasal naloxone 4 mg, and naloxone took 20 minutes to match it [10]. FDA approved nalmefene nasal spray on pharmacokinetic studies bridging to the injection and one volunteer study, stating that efficacy trials in overdose are neither ethical nor feasible [11].
Population
176 emergency department adults with suspected opioid overdose at 9 centers, 77 opioid-positive [9]; healthy volunteers in an open-label crossover study [10]; FDA review [11].
Sources
[9], [10], [11]
Caveats
In [9], 75% of opioid-positive patients also had other sedating drugs. The volunteer model used remifentanil, not fentanyl, and was open-label [10].

Not shown to help1

Limited

Higher-dose 8 mg naloxone against 4 mg

One observational study of police responses found 8 mg nasal naloxone did not raise survival or lower repeat doses against 4 mg, and withdrawal was 2.5 times as likely.

Compared with 4 mg nasal naloxone [8]

The numbers and sources
Effect
Survival, mean number of doses, most signs after naloxone, anger or combativeness, and refusal of hospital transport did not differ between 8 mg and 4 mg recipients. Opioid withdrawal signs, including vomiting, were 2.51 times as likely after 8 mg (95% CI 1.51 to 4.18) [8].
Population
People given nasal naloxone for suspected overdose by New York State Police troops, March 2022 to August 2023 [8].
Sources
[8]
Caveats
Troops, not people, were assigned the product, and it was not randomized [8].

Doses studied

FDA approved the 4 mg Narcan spray for over-the-counter use after the maker showed consumers could use it as labeled without a health professional, and kept other formulations and doses prescription only [12]. The over-the-counter Narcan spray delivers naloxone 4 mg per device, with a dose every 2 to 3 minutes until the person wakes [13]. The 8 mg Kloxxado spray [14] and the 5 mg Zimhi injection [15] are prescription forms. The blinded route trials used 800 µg nasal or intramuscular [6] and 1.4 mg nasal against 0.8 mg intramuscular [7]. The police study compared 8 mg and 4 mg nasal sprays [8]. The emergency department trial gave intravenous nalmefene 1 or 2 mg or naloxone 2 mg every 5 minutes as needed, up to 4 doses [9]. Opvee delivers nalmefene 2.7 mg per spray [16], and the Zurnai auto-injector nalmefene 1.5 mg [17]. The pulmonary complications study defined a high dose as more than 4.4 mg in total [18].

Risks

Reported risks5

LimitedVery common

Sudden opioid withdrawal

The labels warn naloxone can set off sudden opioid withdrawal in people dependent on opioids. In one emergency medical services cohort, 46% met proxy criteria for it.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
The labels list body aches, diarrhea, fast heart rate, fever, runny nose, sneezing, goose bumps, sweating, nausea or vomiting, restlessness or irritability, shivering, cramps and raised blood pressure, and state that risk and severity rise with naloxone exposure. In newborns, withdrawal may be life-threatening [14][19]. The over-the-counter label says people may wake shaking, sweating, nauseated or angry [13]. Of 4,561 people given naloxone by one emergency medical services system, 2,124 (46.2%) met proxy criteria for precipitated withdrawal, more often after several doses (RR 1.2) [20]. In a blinded trial, withdrawal reactions were 6.8 percentage points more frequent on intramuscular 0.8 mg than nasal 1.4 mg in a post hoc analysis [7].
Population
Labeling statements [13][14][19]; 4,561 prehospital patients, 2019 to 2023 [20]; 201 ambulance patients [7].
Sources
[13], [14], [19], [20], [7]
Caveats
The cohort used proxy markers such as persistent fast heart rate, which overdose itself can cause [20].
LimitedVery common

Nasal and other side effects in volunteer studies

In volunteer studies, nasal nalmefene caused nasal discomfort in 29% and headache in 27%. Narcan's study listed raised blood pressure, headache and nasal effects.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
Across 150 healthy adults given nalmefene 2.7 mg nasal spray, nasal discomfort occurred in 28.7%, headache in 26.7%, dizziness in 9.3%, nasal congestion in 4.0% and throat irritation in 4.0% [16]. In a study of 30 healthy adults given Narcan, the most common reactions were increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, swelling, congestion and inflammation [19]. With Kloxxado 8 mg, abdominal pain, weakness, dizziness, headache, nasal discomfort and near-fainting each occurred in 2 of 47 volunteers [14].
Population
Healthy adult volunteers in pharmacokinetic and pharmacodynamic studies [16][19][14].
Sources
[16], [19], [14]
Caveats
These studies had no placebo group, and the volunteers were not opioid dependent, so withdrawal is not captured here.
LimitedHow often is not known

Return of overdose after naloxone wears off

The labels warn that most opioids last longer than naloxone, so breathing problems can return after a first response, and further doses may be needed.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The prescribing information states the duration of action of most opioids may exceed that of naloxone, causing a return of breathing and central nervous system depression after initial improvement, and directs repeat doses and continued watching until help arrives [14]. The over-the-counter label directs another dose if the person becomes very sleepy again and to stay until the ambulance arrives [13]. Even with take-home naloxone, 0.8% of overdoses were fatal [2].
Population
Labeling statements [13][14]; 22 observational studies [2].
Sources
[14], [13], [2]
Caveats
No rate of recurrence is given on the labels.
LimitedHow often is not known

Lung complications at higher doses

Linked to more lung complications after overdose when total prehospital naloxone exceeded 4.4 mg, 42% against 26%, in one observational study. Pulmonary edema occurred in 1.1%.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Pulmonary complications, including pulmonary edema and aspiration, occurred in 42% of patients given more than 4.4 mg and 26% of those given less (OR 2.14, adjusted OR 1.85, 95% CI 1.12 to 3.04). An initial dose above 0.4 mg was linked to 27% against 13% (OR 2.57). Pulmonary edema occurred in 1.1% overall [18]. The labels report pulmonary edema, abnormal heart rhythms and cardiac arrest after abrupt reversal of opioid effects after surgery, mostly in people with heart disease or on other drugs with similar effects [14][19].
Population
1,831 patients treated with naloxone by Pittsburgh emergency medical services [18]; postmarketing reports [14][19].
Sources
[18], [14], [19]
Caveats
Observational. Overdose itself causes lung injury, and people needing more naloxone may have had more severe overdoses [18].
LimitedHow often is not known

Weaker effect against buprenorphine

The label warns that reversal of breathing depression from buprenorphine and other partial agonists may be incomplete, and larger or repeat doses may be needed.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The prescribing information states that reversal of respiratory depression by partial agonists or mixed agonist-antagonists such as buprenorphine and pentazocine may be incomplete, and that larger or repeat doses may be required because buprenorphine has a long duration of action [14].
Population
Labeling statement [14].
Sources
[14]
Caveats
No rate is given.

Checked, no increase found2

Limited

Adverse events, nalmefene against naloxone

One emergency department trial found adverse events in 30.9% on nalmefene 2 mg and 15.5% on naloxone, a difference that was not significant, none linked to lasting harm.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Adverse events occurred in 30.9% on intravenous nalmefene 2 mg, 15.9% on nalmefene 1 mg and 15.5% on naloxone 2 mg, with no significant difference and none associated with morbidity. Withdrawal scores did not differ [9]. The nalmefene labels carry the same warning of severe precipitated withdrawal as naloxone [16].
Population
176 emergency department adults with suspected opioid overdose [9].
Sources
[9], [16]
Caveats
One trial, with most patients needing one dose [9].
LimitedStudied in pregnancy

Pregnancy

The label states retrospective cohort studies have not identified a risk of birth defects or miscarriage with naloxone, while it may set off withdrawal in the mother and fetus.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The Kloxxado label states available data from retrospective cohort studies have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, and that naloxone may precipitate opioid withdrawal in the pregnant woman and fetus [14]. The Narcan label states naloxone crosses the placenta and directs that the fetus be evaluated for distress after use [19].
Population
Labeling statements drawing on retrospective cohorts [14][19].
Sources
[14], [19]
Caveats
The labels do not give study sizes.

Claims tested and not found

  1. That a higher 8 mg naloxone dose saves more lives than 4 mg. In New York State Police responses, survival and doses needed did not differ, and withdrawal was more likely after 8 mg [8].
  2. That nalmefene gives better clinical outcomes than naloxone in overdose. In an emergency department trial, breathing, alertness and withdrawal did not differ [9].

Sources

  1. Giglio RE, Li G, DiMaggio CJ. Effectiveness of bystander naloxone administration and overdose education programs: a meta-analysis. Injury Epidemiology. 2015. https://doi.org/10.1186/s40621-015-0041-8
  2. McDonald R, Strang J. Are take-home naloxone programmes effective? Systematic review utilizing application of the Bradford Hill criteria. Addiction. 2016. https://doi.org/10.1111/add.13326
  3. Walley AY, Xuan Z, Hackman HH, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ. 2013. https://doi.org/10.1136/bmj.f174
  4. U.S. Food and Drug Administration. Opioid Overdose Reversal Medications. Accessed 2026. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-about-naloxone
  5. Yousefifard M, Vazirizadeh-Mahabadi MH, Neishaboori AM, et al. Intranasal versus Intramuscular/Intravenous Naloxone for Pre-hospital Opioid Overdose: A Systematic Review and Meta-analysis. Advanced Journal of Emergency Medicine. 2020. https://pubmed.ncbi.nlm.nih.gov/32322795/
  6. Dietze P, Jauncey M, Salmon A, et al. Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial. JAMA Network Open. 2019. https://doi.org/10.1001/jamanetworkopen.2019.14977
  7. Skulberg AK, Tylleskär I, Valberg M, et al. Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double-dummy, randomised, controlled trial. Addiction. 2022. https://doi.org/10.1111/add.15806
  8. Payne ER, Stancliff S, Rowe K, Christie JA, Dailey MW. Comparison of Administration of 8-Milligram and 4-Milligram Intranasal Naloxone by Law Enforcement During Response to Suspected Opioid Overdose, New York, March 2022 to August 2023. MMWR Morbidity and Mortality Weekly Report. 2024. https://doi.org/10.15585/mmwr.mm7305a4
  9. Kaplan JL, Marx JA, Calabro JJ, et al. Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Annals of Emergency Medicine. 1999. https://doi.org/10.1016/s0196-0644(99)70270-2
  10. Ellison M, Hutton E, Webster L, Skolnick P. Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone. Journal of Clinical Pharmacology. 2024. https://doi.org/10.1002/jcph.2421
  11. Nallani SC, Li Z, Florian J, et al. FDA Approval Summary: Nalmefene Nasal Spray for the Emergency Treatment of Known or Suspected Opioid Overdose. Clinical Pharmacology & Therapeutics. 2025. https://doi.org/10.1002/cpt.3514
  12. U.S. Food and Drug Administration. FDA Approves First Over-the-Counter Naloxone Nasal Spray. Press announcement. 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray
  13. U.S. Food and Drug Administration. NARCAN (naloxone hydrochloride) nasal spray 4 mg, drug facts label. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0ebc83d-2892-40de-bc0a-775ce90b30db
  14. U.S. Food and Drug Administration. KLOXXADO (naloxone hydrochloride) nasal spray, prescribing information. 2025. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ebf0f833-c1c0-487c-8f29-01fa8c61b6cb
  15. U.S. Food and Drug Administration. ZIMHI (naloxone hydrochloride) injection, prescribing information. 2025. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=523c0909-bff6-4010-988a-53de18b7cb3f
  16. U.S. Food and Drug Administration. OPVEE (nalmefene hydrochloride) nasal spray, prescribing information. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=999a4269-9e54-4801-b2ac-2a7276f0b94f
  17. U.S. Food and Drug Administration. ZURNAI (nalmefene hydrochloride) injection, prescribing information. 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a59a5847-9fe4-4341-a203-be0a5e6d3e36
  18. Farkas A, Lynch MJ, Westover R, et al. Pulmonary Complications of Opioid Overdose Treated With Naloxone. Annals of Emergency Medicine. 2020. https://doi.org/10.1016/j.annemergmed.2019.04.006
  19. U.S. Food and Drug Administration. NARCAN (naloxone hydrochloride) nasal spray, prescribing information. 2025. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=724df050-5332-4d0a-9a5f-17bf08a547e1
  20. Vandergrift LA, Rice AD, Primeau K, et al. Precipitated Withdrawal Induced by Prehospital Naloxone Administration. Prehospital Emergency Care. 2025. https://doi.org/10.1080/10903127.2024.2449505

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