Are high doses of naloxone required for Nitazene overdoses?
Date First Published:
January 5, 2026
Last Updated:
January 5, 2026
Report by:
Isobel Blanksby1 and Lucie Harrison2, Medical student's (University of Manchester)
Search checked by:
Daniel Darbyshire, Doctor
Three-Part Question:
In [Emergency department patients with suspected nitazenes overdose] are [high doses of naloxone] required to [treat the overdose]?
Clinical Scenario:
A 27-year-old patient is brought into the emergency department (ED) after being found unconscious by a passerby. On clinical examination, the patient has reduced consciousness, pinpoint pupils, evident track marks and a reduced work of breathing. The patient is known to misuse nitazenes, a highly potent synthetic opioid. You suspect a possible nitazene overdose. You are aware that naloxone is first-line at reversing the effects of synthetic opioid overdoses. Still, you are wondering whether you need to use a high dose of naloxone to treat this patient’s overdose due to the higher potency of nitazenes.
Search Strategy:
Using the OVID interface, the search was conducted on two major databases, MEDLINE (1946-2025) and EMBASE (1980-2025). After breaking down the research question, the keywords and synonyms (including brand names for the drugs) were identified.
Combining keywords and synonyms enabled the creation of a thorough search formula: (Nitazene.mp. OR benzimidazole.mp. or benzimidazoles/ OR isotonitazene.mp. OR metonitazene.mp. OR etonitazene.mp. OR protonitazene.mp.) AND (exp Naloxone/ OR naloxone.mp. OR Narcan.mp. OR Evzio.mp. OR Kloxxado.mp. OR Naloxone hydrochloride.mp. OR Naloxonum.mp. OR Nyxoid.mp. OR Rextovy.mp. OR Suboxone.mp. OR Targin.mp. OR Targiniq.mp. OR Zimhi.mp. OR Zubsolv.mp. OR Rezenopy.mp. OR RiVive.mp.).
The search results were de-duplicated in the OVID interface and exported to a Microsoft Excel spreadsheet for title and abstract screening. Title and abstract screening led to the removal of a further duplicate paper. The remaining papers underwent a full text review.
A Google Scholar search was conducted using the search question “In Emergency department patients with suspected nitazenes overdose are high doses of naloxone required to treat the overdose?”.
Reference lists of each eligible paper were screened. We excluded reviews but screened the papers within them.
Citations of the eligible papers were reviewed for additional papers.
Combining keywords and synonyms enabled the creation of a thorough search formula: (Nitazene.mp. OR benzimidazole.mp. or benzimidazoles/ OR isotonitazene.mp. OR metonitazene.mp. OR etonitazene.mp. OR protonitazene.mp.) AND (exp Naloxone/ OR naloxone.mp. OR Narcan.mp. OR Evzio.mp. OR Kloxxado.mp. OR Naloxone hydrochloride.mp. OR Naloxonum.mp. OR Nyxoid.mp. OR Rextovy.mp. OR Suboxone.mp. OR Targin.mp. OR Targiniq.mp. OR Zimhi.mp. OR Zubsolv.mp. OR Rezenopy.mp. OR RiVive.mp.).
The search results were de-duplicated in the OVID interface and exported to a Microsoft Excel spreadsheet for title and abstract screening. Title and abstract screening led to the removal of a further duplicate paper. The remaining papers underwent a full text review.
A Google Scholar search was conducted using the search question “In Emergency department patients with suspected nitazenes overdose are high doses of naloxone required to treat the overdose?”.
Reference lists of each eligible paper were screened. We excluded reviews but screened the papers within them.
Citations of the eligible papers were reviewed for additional papers.
Outcome:
The MEDLINE and EMBASE database search resulted in 232 results. OVID de-duplication removed 37 papers, with one further duplicate manually removed. This left 194 results for title and abstract screening.
Title and abstract screening removed 184 ineligible papers. This included the removal of conference abstracts, letters and comments. This resulted in 10 papers for full-text review. During this process, seven papers were removed and deemed ineligible due to being review papers (n=4), being lab-based (n=1) and due to naloxone being administered pre-hospital only (n=2).
Reference screening yielded 1 additional paper1. Citation screening did not yield any addition papers.
The Google Scholar search yielded 1 addition paper 2.
5 papers met the inclusion exclusion criteria; one multi-centre prospective series3, two cohort studies 2,4, one case series5 and one case report1. These papers and their outcomes are summarised in the Table below.
Title and abstract screening removed 184 ineligible papers. This included the removal of conference abstracts, letters and comments. This resulted in 10 papers for full-text review. During this process, seven papers were removed and deemed ineligible due to being review papers (n=4), being lab-based (n=1) and due to naloxone being administered pre-hospital only (n=2).
Reference screening yielded 1 additional paper1. Citation screening did not yield any addition papers.
The Google Scholar search yielded 1 addition paper 2.
5 papers met the inclusion exclusion criteria; one multi-centre prospective series3, two cohort studies 2,4, one case series5 and one case report1. These papers and their outcomes are summarised in the Table below.
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| Clinical toxicity of nitazene detections in two Australian emergency department toxicosurveillance systems (3) Isoardi KZ et al 2024 Australia | Adults (n=32) presenting to the ED after nitazene ingestion. 9 received treated only in the hospital setting. Mean age 31 72% male 28% female | Multi-centre prospective series. Level 4 |
Total dose of IV naloxone given within 1h post-hospital presentation. | Standard dosing regimens of naloxone appeared effective in most cases. | Aim of study was to describe nitazene-related presentations, not to compare naloxone dosage. Naloxone was only administered to 47% of included patients in hospital setting – unclear which of those had also received pre-hospital naloxone. More than half of patients had co-exposure to methamphetamine. No control group. |
| Median total dose of IV naloxone within 1h post hospital presentation of 400 μg (range 100-1400). | |||||
| 4 patients required additional naloxone infusion. | |||||
| Naloxone Use in Novel Potent Opioid and Fentanyl Overdoses in Emergency Department Patients (4) Amaducci A et al 2023 United States of America | Adults (n=9) presenting to the ED who tested positive for novel potent opioids (NPOs). 7 consumed nitazenes. Ages 20-57 44.4% male 55.6% female | Cohort study Level 3 |
Total cumulative naloxone doses administered for NPO overdose compared to fentanyl overdose. | The NPO group received a similar total cumulative naloxone dose (4.40mg) compared to the fentanyl group (6.41mg). | Retrospective data collection may introduce recall bias. Data was extracted from wider TOxIC study database which has 10 participating sites, it is unclear how many of these were included in this sub-analysis. The NPO and fentanyl overdose groups may not be directly comparable as the mean age of the NPO group was 15 years older than the fentanyl group. |
| Identification of a novel opioid, N-piperidinyl etonitazene (etonitazepipne), in patients with suspected opioid overdose (5) Calello DP et al. 2022 United States of America | Adult patients (n=3) that tested positive for N-piperidinyl etonitazene at time of ED presentation. Ages 33-55 66.7% male 33.3% female | Case series Level 4 |
Naloxone dose administered to achieve clinical response. | The patient in case 3 who received hospital naloxone (unlike the other 2 patients) required 0.68mg naloxone prior to discharge. | Case series with retrospective information gathered as part of multicentre ToxIC study – not stated where patient details gathered from. Small sample size of 3pts – limited generalisability. 100% of patients had ingested other substances as well as nitazenes. Naloxone administration method varied per patient, unclear whether they received any other interventions. No control group. |
| Clinical and biochemical profile of a patient with acute metonitazene intoxication (2) Abu Rumeileh et al 2024 Germany | Adult patient (n=1) that was admitted to ED after consuming Metonitazene. Age 19 Male | Case report Level 4 |
Naloxone dose administered to achieve clinical improvement. | Patient was given a total of 0.6mg. | Case report of a single patient – lacks generalisability. Clinical condition clearly reported but no comparator/control group – no way to establish cause and effect. Flumazenil given in addition to naloxone – unable to establish whether clinical recovery due to naloxone alone. |
| Clinical Experiences With the Nitazene Class of Synthetic Opioids: A Cohort Study (2) Darren M. Roberts et al 2025 Australia | Adults (n = 27) that had laboratory confirmed nitazene exposures, 16 of which presented acutely. Ages 22 – 31 85% male 15% female | Cohort study Level 3 |
Parenteral naloxone dose needed to effectively reverse nitazene overdose, particularly hypoventilation. | Naloxone was effective with a median parenteral reversal dose of 400μg (range 200-1800 μg). | Retrospective nature of the study introduces selection bias and recall bias. No control over confounding variables.. Most patients had co-exposure to other substances such as cannabis and MDMA; impossible to tell how this influenced both clinical presentation and outcomes. Naloxone was not the only intervention given. Naloxone was given via varying routes: intranasal by bystanders, infusions, various doses. No control/comparator. |
| 5 patients required repeated doses, 3 of which were infusions. |
Author Commentary:
The multi-centre prospective series study3 found that a median dose of 0.4mg (0.1-1.4mg) of naloxone was adequate for reversal of nitazene overdoses within the first hour post hospital presentation, but 4 patients required additional naloxone infusions. Likewise, the 2025 cohort study2 found that naloxone was effective with a median parenteral reversal dose of 400μg (range 200-1,800 μg). Conversely, the cohort study4 found that patients who consumed NPOs in fact needed less naloxone (4.40mg) compared to patients who consumed fentanyl (6.41mg). The case series study5 found that their patient required 0.68mg of naloxone to reverse the effects of the nitazenes; similarly, the case report study1 found that their patient required 0.6mg of naloxone.
Overall, studies suggested 0.4mg – 4.40mg doses of naloxone are needed to treat nitazenes overdoses. The results did not suggest that a dramatic increase in naloxone dose was needed to treat nitazene overdoses. Most patients responded to standard dosing regimens, but the patient response was determined by many independent variables.
A key weakness of this review is the limited number of studies on nitazene. The studies included in this review are limited to a small sample of patients, which limits the reliability of the data extracted and the conclusions drawn. Grey literature, such as Rapid Action Drug Alerts and Response (RADAR) Alerts from Public Health Scotland6 were not accessed using our methodology.
Future research should focus on tracking naloxone doses administered in the pre-hospital environment (whether by bystanders or ambulance staff) against those administered in the hospital environment, as this will provide an overview of all naloxone doses, administration routes, and patient responses. It may be that dose frequency is more important than increasing nitazene doses, as suggested in a 2025 RADAR report 6, and studies assessing this would be beneficial. Four of the five studies mention the use of naloxone infusions for multiple patients; further studies into the use of naloxone infusions for nitazene overdoses, and which patients meet the criteria for these infusions, would be helpful. It would be beneficial to record the patient observations at first contact to track the patient’s clinical improvement after naloxone administration.
Overall, studies suggested 0.4mg – 4.40mg doses of naloxone are needed to treat nitazenes overdoses. The results did not suggest that a dramatic increase in naloxone dose was needed to treat nitazene overdoses. Most patients responded to standard dosing regimens, but the patient response was determined by many independent variables.
A key weakness of this review is the limited number of studies on nitazene. The studies included in this review are limited to a small sample of patients, which limits the reliability of the data extracted and the conclusions drawn. Grey literature, such as Rapid Action Drug Alerts and Response (RADAR) Alerts from Public Health Scotland6 were not accessed using our methodology.
Future research should focus on tracking naloxone doses administered in the pre-hospital environment (whether by bystanders or ambulance staff) against those administered in the hospital environment, as this will provide an overview of all naloxone doses, administration routes, and patient responses. It may be that dose frequency is more important than increasing nitazene doses, as suggested in a 2025 RADAR report 6, and studies assessing this would be beneficial. Four of the five studies mention the use of naloxone infusions for multiple patients; further studies into the use of naloxone infusions for nitazene overdoses, and which patients meet the criteria for these infusions, would be helpful. It would be beneficial to record the patient observations at first contact to track the patient’s clinical improvement after naloxone administration.
Bottom Line:
- In patients presenting to the emergency department with a suspected nitazene overdose a range of 0.4 – 4.40mg naloxone is usually sufficient to stabilise the patient.
- There was no evidence to suggest that increased doses of naloxone are beneficial for nitazene overdoses.
- There was no evidence to suggest that increased doses of naloxone are beneficial for nitazene overdoses.
Level of Evidence:
Level 3: Small numbers of small studies or great heterogeneity or very different population
References:
- Isoardi KZ et al. Clinical toxicity of nitazene detections in two Australian emergency department toxicosurveillance systems (3)
- Amaducci A et al. Naloxone Use in Novel Potent Opioid and Fentanyl Overdoses in Emergency Department Patients (4)
- Calello DP et al.. Identification of a novel opioid, N-piperidinyl etonitazene (etonitazepipne), in patients with suspected opioid overdose (5)
- Abu Rumeileh et al. Clinical and biochemical profile of a patient with acute metonitazene intoxication (2)
- Darren M. Roberts et al. Clinical Experiences With the Nitazene Class of Synthetic Opioids: A Cohort Study (2)