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To the Editor, In a randomized trial, Zamani et al. assessed the greater effectiveness and safety of buprenorphine versus naloxone to reverse methadone overdose-related respiratory depression [1]. We congratulate the authors. However, several issues may limit the accuracy of their observations and recommendation to unselectively treat opioid overdoses with buprenorphine. Usually, opioid overdose is identified in patients presenting stupor or coma (i.e., Glasgow coma score [GCS] ≤ 12), respiratory rate [RR] ≤ 12/min and miosis) [2]. Zamani’s patients were mildly poisoned with mean/median (not clear) RR of 12–15/min and GCS of 13–15. Therefore, the elevated naloxone-induced withdrawal rate clearly resulted from excessive dosage and/or inadequate titration aiming to obtain “complete arousal to normal consciousness” in mildly overdosed opioiddependent patients. Opioid-tolerant patients frequently respond to low naloxone doses, sufficient to restore breathing without provoking withdrawal [2]. Clinicians incorrectly assume that the naloxone dose required to restore respiration correlates with severity. Naloxone should be injected at 0.04 mg bolus and titrated/2 min upward to effect (i.e., RR ≥ 15/min). Naloxone-attributed complications were surprisingly frequent, not reflecting our practice, especially since patients with cardiovascular morbidities, co-ingestions, aspiration, and need for immediate intubation were excluded. ARDS onset in 15% of naloxone-treated patients without prior aspiration is unusual. Naloxone has been mistakenly implicated as a cause of pulmonary edema [2]. Using optimal regimens allows the restoration of oxygenation and prevents the postulated sympathetic surge that triggers pulmonary edema after apnea reversal. In Fig. 2, 13 apnea episodes were reported in the naloxone group, mostly reversed by naloxone boluses. Management of the 11 apnea episodes in the buprenorphine groups was not provided since only five patients were intubated. Did the patients receive buprenorphine boluses or continuous infusion? Intravenous buprenorphine should be used cautiously in opioid users who, unlike the Iranian experience, mostly co-abuse benzodiazepines and/or ethanol [3]. Drug-drug interactions and intravenous buprenorphine administration are the two well-recognized circumstances that impair buprenorphine-related ceiling effects, worsening ventilation consequently, as demonstrated experimentally [4, 5]. Because naloxone is lacking agonist activity on the mu-opioid receptor, no such risk exists. Additionally, in non-methadone abusers, buprenorphine may compete with the existing opioid on the mu-opioid receptor and, due to higher binding affinity, produce late withdrawal if the opioid exhibits shorter elimination half-life. Therefore, unless convincing data are produced, naloxone should remain the legitimate antidote to reverse opioid toxicity. Concerns that naloxone may harm opioid-dependent patients are unfounded [2]. With adequate titration, signs of naloxone-induced abstinence are unpleasant but never life-threatening.

Naloxone should remain the appropriate antidote to treat opioid overdose