Archives of Academic Emergency Medicine. 2020; 8(1): e16 OR I G I N A L RE S E A RC H Safety of Naloxone in Opioid-Naive Methadone Intoxicated Patients; a Case Series Study Seyed Hamid Reza Shakeri1, Hossein Hassanian-Moghaddam2,3∗, Nasim Zamani2,3 1. Department of Emergency Medicine, Mazandaran University of Medical Sciences, Sari, Iran. 2. Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Department of Clinical Toxicology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: November 2019; Accepted: December 2019; Published online: 2 March 2020 Abstract: Introduction: Studies have shown that naloxone can cause behavioral changes in naive normal volunteers. This study aimed to investigate the possible complications of naloxone in methadone-overdosed opioid-naive pa- tients. Methods: In this pilot study, a total number of 20 opioid-naive methadone-poisoned patients underwent naloxone challenge test to receive naltrexone. 0.2, 0.6, and 1.2 mg doses of naloxone were administered on min- utes 0, 5, and 15-20. The patients were followed for 30 minutes after administration of naloxone and monitored for any upsetting signs and symptoms. Patients with clinical opiate withdrawal scale (COWS) lower than 5 were considered not addicted and the severity of patients’ symptoms was calculated using subjective opiate with- drawal syndrome (SOWS). Results: 20 patients with mean age of 25.5±8.09 years were evaluated (70% female). Median ingested dose of methadone was 25 mg [IQR; 10 to 50 mg] and mean time interval between ingestion of methadone and naloxone challenge test was 7.1±4.9 hours. Fourteen patients reported some discomfort af- ter administration of a mean dose of 1.7±0.5 mg of naloxone lasting for a maximum of four hours. The most common patients’ complaints were headache (45%) followed by nausea (20%), agitation (20%), abdominal pain (20%), and flushing (20%). Two (10%) mentioned severe panic attack and sensation of near-coming death. SOWS significantly correlated with female gender (p = 0.004) and time elapsed post methadone ingestion (p = 0.001). Conclusion: It seems that naloxone is not a completely safe medication even in opioid-naive patients, and ad- ministrating adjusted doses of naloxone even in opioid-naive methadone intoxicated patients may be logical. Keywords: Naloxone; Substance Withdrawal Syndrome; Analgesics, Opioid; Drug-Related Side Effects and Adverse Reac- tions Cite this article as: Shakeri S H R, Hassanian-Moghaddam H, Zamani N. Safety of Naloxone in Opioid-Naive Methadone Intoxicated Patients; a Case Series Study. Arch Acad Emerg Med. 2020; 8(1): e16. 1. Introduction Naloxone is a safe and effective rescue medication for opi- oid overdose, a leading cause of death, worldwide. It blocks the opioid receptors for 30-90 minutes to reverse the respi- ratory depression that would otherwise lead to apnea and death. Serious side effects of naloxone are very rare. The most common side effect is opioid withdrawal in depen- dent patients, risk of which increases with larger doses of naloxone as well as the strength of drug dependency (1). ∗Corresponding Author: Hossein Hassanian-Moghaddam; Department of Clinical Toxicology, Loghman-Hakim Hospital, South Karegar Avenue, Kamali Street, Tehran 13336, Tehran, Iran. Tel/Fax: 00982155409534. E-mail: hasa- nian2000@yahoo.com; hassanian@sbmu.ac.ir Although generally regarded to be safe, naloxone may pre- cipitate rare side effects including body aches, fever, sweat- ing, sneezing, yawning, nausea/vomiting, lacrimation, rhi- norrhea, cramping, insomnia, chills, hot flashes, tachycar- dia, restlessness/irritability, tremulousness, seizure, hypo or hypertension/arrhythmias in patients with cardiac dis- orders, dizziness, headache, tremor, and pulmonary edema (2). Although much more common in dependent pa- tients, previous studies have shown that in naive normal volunteers, high-dose naloxone (2-4 mg/stat) can cause "rush" or "buzz", tingling/numbness of the extremities, dizziness, reluctance to move or initiate activities, abdom- inal pain, impaired cognitive performance, and increased tension-anxiety, anger-hostility, depression-dejection, and confusion-bewilderment subscales, which could last for This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S H R. Shakeri et al. 2 hours (3). These symptoms were then attributed to block- age of the endogenous opioids (3). Naloxone may be used to perform naloxone challenge test before administration of naltrexone, as a long term antagonist of the opioid, in opioid- naive patients (4). Since naltrexone may cause life threaten- ing conditions in opioid-dependent patients, it is essential to confirm naivety before its administration (5). While per- forming this practice, we noticed that some opioid-naive pa- tients under the effect of long-acting opioids experienced se- vere discomfort. This study aimed to investigate the possible complications of naloxone in methadone-overdosed opioid- naive patients. 2. Methods 2.1. Study design and setting In this case series study, opioid-naive methadone-poisoned patients who were referred to emergency department of Loghman Hakim Hospital, Tehran, Iran, and underwent naloxone challenge test to receive naltrexone during a 3- month period between March and June 2019 were evalu- ated. The experiment was conducted with the informed con- sent of the human subject. Ethical approval for the study was given by Shahid Beheshti University of Medical Science Ethics Committee (Ethic code:). 2.2. Participants Patients who claimed not to be opioid dependent and had ac- cidentally or intentionally (suicidal or recreational) ingested methadone (based on the obtained history), were included. The participants were those who needed opioid-antagonist administration for long times due to persistent respiratory acidosis (pH<7.2 and PCO2 >52) (5). All had signs and symp- toms of acute opioid toxicity and urine test results returned to be positive only for methadone. Those with active liver dis- ease and increased level of transaminases (twice the normal range), acute poisoning with complications developed be- fore presentation (aspiration pneumonia, brain trauma, and acute lung injury), and those discharged against medical ad- vice were excluded. 2.3. Procedure In our center, the routine protocol to manage these patients is administration of naltrexone instead of naloxone to avoid long naloxone infusions and hospital stay. However, before administration of naltrexone it is necessary to make sure the patient is not opioid-dependent as he/she may not give the correct history on being naive. We administered 0.2, 0.6, and 1.2 mg doses of naloxone in minutes 0, 5, and 15-20 (6, 7). The patient was followed for 30 minutes after administration of naloxone doses and monitored for signs and symptoms in- cluding nausea and vomiting, agitation, flushing, abdominal pain and cramp, anxiety and restlessness, muscle and bone pain, and panic attack. 2.4. Data gathering Possible side effects as well as the patients’ characteristics (age and gender), amount of the ingested methadone, dura- tion of the symptoms lasting after administration of nalox- one, total naloxone dose administered, and treatments given were recorded by a toxicology fellow using a predesigned checklist. To confirm that the patient was not addicted, clin- ical opiate withdrawal scale (COWS) was determined (8) and scores lower than 5 were considered not addicted. To deter- mine the severity of patients’ symptoms, subjective opiate withdrawal syndrome (SOWS) was calculated (9). 2.5. Statistical Analysis The data was analyzed using statistical package for social sci- ences (SPSS) version 20 using Kolmogorov-Smirnov test, t- test, Mann-Whitney U test, and Spearman test. P < 0.05 was considered significant. Data are presented as mean ± stan- dard deviation, median and inter quartile range (IQR), or fre- quency (%). 3. Results 3.1. Baseline characteristics of studied patients 20 patients with the mean age of 25.5±8.09 (range; 17 to 46) years were evaluated (70% female). Thirteen (75%) had overdosed on methadone syrup and 7 (35%) had consumed methadone tablets. Median ingested dose of methadone was 25 mg [IQR; 10 to 50 mg] and mean time between ingestion of methadone and naloxone challenge test was 7.1±4.9 (range; 2 to 24) hours. 18 (90%) patients had referred with loss of con- sciousness and 9 (45%) had respiratory acidosis on presenta- tion (pH < 7.3 and PCO2 > 54mmHg). Mean pH and PCO2 on admission were 7.2 ± 0.05 (range; 7.12 to 7.38) and 51.4 ± 3.5 (range; 46 to 58) mmHg, respectively. 3.2. Side effects 14 (70%) patients reported some discomfort after adminis- tration of a mean dose of 1.7 ± 0.5 mg of naloxone (0.2 to 2 mg). Their symptoms lasted for a maximum of four hours posttest. The most common symptom the patients com- plained about was headache (45%) followed by nausea (20%), agitation (20%), abdominal pain (20%), and flushing (20%). 2 (10%) cases mentioned severe panic attack and sensation of near-coming death. Mean COWS and SOWS scores were 2.4±1.9 and 2.4±2.4, respectively. SOWS significantly corre- lated with female gender (t test; p = 0.004) and time elapsed post methadone ingestion (spearman rho test; p=0.001; Fig- ure 1). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2020; 8(1): e16 Figure 1: Scatter plot showing the relationship between time post methadone ingestion and severity of subjective opiate withdrawal syn- drome (SOWS). 4. Discussion Naloxone is a derivative of natural plant alkaloid and is sim- ilar to oxymorphone. Naloxone, however, is a competitive antagonist of the opiate receptors and has particularly high affinity for the Îij opiate receptor and can displace morphine and other full agonists, thereby reversing their effects (10). In 2015 the American Association of Poison Control Centers reported no fatalities due to naloxone other than buprenor- phine/naloxone combinations (11). Although post nalox- one administration complications had been previously re- ported in opioid-naive normal volunteers (3), these symp- toms were mainly behavioral and had been attributed to the effect of the endo-morphines. This is the first study re- porting complications after administration of naloxone in methadone-overdosed opioid-naive patients. The low COWS score shows that our patients were not really opioid depen- dent. However, they showed a series of inadvertent reactions after naloxone administration. This may be due to mu recep- tors developing tolerance during the time elapsed between methadone ingestion and naloxone administration. In fact, it seems that the receptors have justified themselves to the high methadone concentration, while administration of naloxone reverses this transient tolerance and causes patient discom- fort. This may show that despite what was previously alluded naloxone is not a very safe medication even in opioid-naive patients. Therefore, administrating adjusted doses of nalox- one even in naive patients seems logical. We had a small sam- ple size because we ran a pilot on only 20 patients. Future studies on larger sample sizes are warranted to better eluci- date the effect of naloxone on opioid-naive patients. 5. Conclusion It seems that naloxone is not a completely safe medication even in opioid-naive patients, and administrating adjusted doses of naloxone even in opioid-naive methadone intoxi- cated patients may be logical. 6. Declarations 6.1. Acknowledgements None. 6.2. Author contribution All the authors meet the standard criteria of authorship based on recommendations of the international committee of medical journal editors. Authors ORCIDs Seyed Hamid Reza Shakeri: 0000-0002-2111-1522 Hossein Hassanian-Moghaddam: 0000-0003-4370-0544 Nasim Zamani: 0000-0002-2091-0197 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem S H R. Shakeri et al. 4 6.3. Funding/Support None. 6.4. Conflict of interest None. References 1. Naloxone: Frequently Asked Question. Available from: http://naloxoneinfo.org/sites/default/files/Frequently %20Asked%20Questions-Naloxone_EN.pdf. 2. Naloxone Side Effects. Available from: https://www.drugs.com/sfx/naloxone-side-effects.html. 3. Cohen M, Cohen R, Pickar D, Weingartner H, Murphy D, Bunney JR W. Behavioural effects after high dose nalox- one administration to normal volunteers. The Lancet. 1981;318(8255):1110. 4. Aghabiklooei A, Hassanian-Moghaddam H, Zamani N, Shadnia S, Mashayekhian M, Rahimi M, et al. Effective- ness of naltrexone in the prevention of delayed respi- ratory arrest in opioid-naive methadone-intoxicated pa- tients. BioMed Research International. 2013;2013. 5. Hamdi H, Hassanian-Moghaddam H, Hamdi A, Za- hed NS. Acid-base disturbances in acute poisoning and their association with survival. Journal of critical care. 2016;35:84-9. 6. Khosravi N, Zamani N, Hassanian-Moghaddam H, Os- tadi A, Rahimi M, Kabir A. Comparison of Two Naloxone Regimens in Opioid-dependent Methadone-overdosed Patients: A Clinical Trial Study. Current clinical pharma- cology. 2017;12(4):259-65. 7. Ostadi A, Zamani N, Hassanian-Moghaddam H, Khos- ravi N, Shadnia S. Comparison of 2 Naltrexone Regi- mens in the Maintenance Therapy of Acute Methadone Overdose in Opioid-naive Patients: A Randomized Con- trolled Trial. Crescent Journal of Medical and Biological Sciences. 2019;6(1):1-5. 8. Clinical opiate withdrawal scale. Available from: https://www.drugabuse.gov/sites/default/files/files/ ClinicalOpiateWithdrawalScale.pdf. 9. Subjective opiate withdrawal scale. Available from: https://www.asam.org/docs/default-source/education- docs/sows_8-28-2017.pdf?sfvrsn=f30540c2_2. 10. Naloxone. Available from: https://livertox.nih.gov/ Naloxone.htm. 11. Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Asso- ciation of Poison Control Centers’ National Poison Data System (NPDS): 33rd Annual Report. Clinical Toxicology. 2016;54(10):924-1109. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Conclusion Declarations References