Archives of Academic Emergency Medicine. 2022; 10(1): e34 OR I G I N A L RE S E A RC H Demographic and Clinical Characteristics of 907 Cases with Naltrexone Intoxication; a 14-Year Cross-Sectional Study Mitra Rahimi1, Alireza Kargar2, Delara Hazegh Fetratjoo3, Sayed Masoud Hosseini1, Arezou Mahdavinejad1, Shahin Shadnia1∗ 1. Toxicological Research Center, Excellence Center of Clinical Toxicology, Department of Clinical Toxicology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Student Research Committee, Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Received: February 2022; Accepted: March 2022; Published online: 1 May 2022 Abstract: Introduction: Opioids have been the leading cause of death from poisoning in Iran for several years. This study aimed to evaluate the clinical and para-clinical presentations of naltrexone intoxication, its toxic dose, and its epidemiological properties. Methods: This retrospective cross-sectional study was conducted on medical records of patients presenting to Toxicology Department of Loghman Hakim Hospital, Tehran, Iran, following naltrexone intoxication, from 2002 to 2016. Patients’ demographic and laboratory data, clinical signs, supposed ingested dose, and intent of naltrexone consumption were collected, analyzed, and then interpreted. Results: 907 patients with the mean age of 36.6 ±11.7 years were evaluated (94.3% male). The mean amount of naltrex- one consumed by the intoxicated patients reported in the medical records was 105.8 ± 267.8 mg. One hundred thirty patients (14.3%) used naltrexone to treat substance use disorder. Two hundred eighty-seven poisoned pa- tients (31.6%) were current opium users who intentionally or unintentionally used naltrexone concomitantly. The most common symptoms observed in these patients were agitation (41.8%), vomiting (16.4%), and nau- sea (14.8%). Among patients with naltrexone poisoning, 25 patients were intubated (2.8%), and three passed away. Aspartate aminotransferase (AST) levels were significantly higher in patients intoxicated with naltrexone who needed intubation (p = 0.02). Conclusion: The probability of intubation of cases with naltrexone intoxica- tion was associated with AST elevation. It seems that, the number of intensive care unit (ICU) admissions and mortality rates are not high among these patients. Keywords: Naltrexone; poisoning; aspartate aminotransferases; cross-sectional studies; retrospective studies Cite this article as: Rahimi M, Kargar A, Hazegh Fetratjoo D, Hosseini SM, Mahdavinejad A, Shadnia S. Demographic and Clinical Characteristics of 907 Cases with Naltrexone Intoxication; a 14-Year Cross-Sectional Study. Arch Acad Emerg Med. 2022; 10(1): e34. https://doi.org/10.22037/aaem.v10i1.1554. 1. Introduction Naltrexone is a long-acting, pure opioid antagonist that blocks mu-receptors and is used in various disorders such as opioid and alcohol use disorder (1). Iran is among the coun- tries with the highest prevalence of opioid use disorder, and ∗Corresponding Author: Shahin Shadnia; Department of Clinical Toxicology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: Shahin1380@gmail.com, https://orcid.org/0000-0002- 9401-0781. opium is the most common substance among these patients (2). Afghanistan is the number one producer of opiates glob- ally, which might lead to Iran’s highest number of seized opi- ates in 2018. In addition, opioids have been the leading cause of death from poisoning in Iran for several years (3-5). Con- sequently, many opioids and naltrexone poisoning cases are referred to Loghman Hakim Hospital, the most crowded re- ferral poisoning center globally (6). The reduced opioid tolerance caused by naltrexone makes patients vulnerable to opioid overdose after missed doses or discontinuation of treatment (7). Three possible causes of death related to naltrexone have been suggested: Opioid 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 M. Rahimi et al. 2 overdose during naltrexone treatment, opioid overdose after naltrexone treatment discontinuation, and intoxication with naltrexone in patients with opioid use disorder (8). The most common side effects of naltrexone are gastroin- testinal (GI) complaints such as diarrhea and abdominal cramping. These adverse effects are analogous to the symp- toms of opioid withdrawal, as the mu receptor blockade will increase GI motility. Naltrexone has been reported to cause liver damage (when given at doses higher than recom- mended). It carries an FDA boxed warning for this rare side effect. Naltrexone may induce a withdrawal syndrome lasting up to 72 hours. It is recommended that the patients spend a pe- riod of seven to ten days of opioid abstinence before naltrex- one treatment to avoid withdrawal symptoms, such as agita- tion and restlessness, altered level of consciousness, nausea and vomiting, abdominal pain, diarrhea, myalgia, tachycar- dia, and dilated pupils (9). This retrospective cross-sectional study aimed to evaluate the clinical and para-clinical presentations of naltrexone in- toxication during 14 years in Loghman Hakim Hospital. 2. Methods 2.1. Study design and setting This research is a retrospective cross-sectional study on med- ical records of 907 patients with naltrexone intoxication from April 2002 to March 2016 in Loghman Hakim Hospital, in which trained clinical toxicologists record patients’ history and trend of management, as well as their vital signs. This study has been approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences (Ethics Code: IR.SBMU.REC.1394.149). All patients’ data were anonymous and identified by the file numbers to preserve patients’ con- fidentiality. 2.2. Participants All the patients who referred to Loghman Hakim Hospital with naltrexone poisoning, both opioid dependent and non- dependent, and also all patients with intentional or acciden- tal poisoning were included in this study. All cases of multi- ple drug toxicity were excluded. Since there is no laboratory method in the world to confirm the use of naltrexone, we also relied on the patient’s history of using this drug. 2.3. Data gathering Demographic data were collected, including age, sex, history and type of drug use disorder, and history of alcohol use dis- order. Other background data included the amount of nal- trexone consumed, clinical characteristics, and lab data. In addition, withdrawal symptoms, electrocardiograms (ECG), arterial blood gases (ABG), venous blood gases (VBG), blood electrolytes, and liver and kidney function tests were evalu- ated. Mortality rate, cause of death, and duration of intensive care unit (ICU) admission were also analyzed. Moreover, the effect of each variable, including demographic and other background data, on need for intubation and du- ration of hospitalization was assessed. 2.4. Statistical analysis The present study used SPSS 26.0 for Windows for data anal- ysis. Normality was then examined using the Kolmogorov- Smirnov and Shapiro-Wilk tests. In addition, quantita- tive variables were reported as median and interquartile range (IQR). Qualitative variables were also presented as fre- quency (percentage). Additionally, Mann-Whitney U test and Kruskal-Wallis test were used to evaluate data with non- normal distribution, and Chi-square test was used to com- pare categorical variables. The relationship between the du- ration of hospitalization and other independent quantitative variables was analyzed using Spearman correlation analysis. P-values less than 0.05 were considered statistically signifi- cant. 3. Results 3.1. Baseline characteristics of patients Medical records of 907 patients with the diagnosis of naltrex- one intoxication were studied. The majority of cases were male (855 cases, 94.3%) with a mean age of 36.6 ±11.7 years. The mean amount of naltrexone consumed by the intoxi- cated patients reported in the medical records was 105.8 ± 267.8 mg. One hundred thirty patients (14.3%) used naltrex- one to treat substance use disorder. Two hundred eighty- seven poisoned patients (31.6%) were current opium users who intentionally or unintentionally used naltrexone con- comitantly. The most common symptoms observed in these patients were agitation (41.8%), vomiting (16.4%), and nau- sea (14.8%). Baseline characteristics of patients are pre- sented in Table 1. Table 2 summarizes the laboratory finding of patients. 3.2. ECG findings Among 612 patients whose ECG was examined, 523 patients had normal ECG, 27 patients had right axis deviation, 37 pa- tients had left axis deviation, and one patient experienced ST depression. One patient experienced ST elevation. Two pa- tients had T-flat, and two patients experienced T-invert. 3.3. Outcomes Among the 907 patients with naltrexone intoxication, evalu- ated in this study, 759 (83.7%) patients were discharged af- ter completion of the treatment course, 145 (16.0%) patients were discharged against medical advice. Three patients were 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. 2022; 10(1): e34 Table 1: Baseline characteristics of patients with naltrexone intoxication Variable N Values Age (year) 878 36.64 ± 11.75 Sex Male 907 855 (94.3) Female 52 (5.7) Intoxication characteristics Naltrexone Dosage (mg) 710 105.83 ± 267.77 Time elapsed to presentation 706 4.82 ± 6.31 Vital signs Temperature (c) 483 36.93 ± 0.3 Pulse rate (beats/minute) 839 81.84 ± 11.93 Diastolic blood pressure (mmHg) 842 75.64 ± 10.2 Systolic blood pressure (mmHg) 852 117.9 ± 15.8 Oxygen Saturation (%) 26 93.95 ± 7.9 Glasgow coma scale 96 13.08 ± 1.92 Presenting symptoms Vomiting 149 (16.4) Nausea 134 (14.8) Diarrhea 907 70 (7.7) Agitation 379 (41.8) Seizure 24 (2.6) Outcome Intubation 25 (2.8) Hospitalization (hour) 27.88 ± 28.8 ICU admission 907 56 (6.2) ICU Stay (hour) 4.82 ± 2.8 Mortality 3 (0.3) Data are presented as mean ± standard deviation or frequency (%). ICU: intensive care unit. N: number of data available regarding that variable on the patients’ profile. deceased (one patient died because of cardiopulmonary ar- rest, one due to acute tubular necrosis (ATN), and the third patient died due to coagulation disorder). There was a significant difference between patients who needed intubation and those who did not in terms of age range (mean rank; 560.58 vs 432.99; p = 0.014), aspartate aminotransferase (AST) level (mean rank; 129.39 vs 96.51; p = 0.02), atrial HCO3 (mean rank; 36.5 vs 24; p = 0.049), dose of drug used (less than 100mg vs more than 100 mg; Pearson Chi-Square: 14.5; p = 0.021), and intention of nal- trexone use (suicide vs other; Pearson Chi-Square: 4.72; p = 0.03). The duration of hospitalization in patients who con- sumed more than 100 mg naltrexone was significantly higher than patients who consumed less than 100 mg naltrexone (p = 0.001). 4. Discussion In this study, it was shown that naltrexone poisoning was not associated with serious adverse events or high mortality rate, contrary to previous assumptions. Naltrexone is a pure competitive opioid antagonist at the mu (µ), kappa (K), and delta (δ) receptors. Naltrexone is used orally for patients following opioid detoxification to maintain opioid abstinence and as an adjunct to achieve ethanol ab- stinence. However, naltrexone should not be administered to an opioid-tolerant patient (10). Naltrexone may induce a withdrawal syndrome lasting up to 72 hours (11). Hassanian et al. conducted a study from December 2007 to March 2008 in Loghman-Hakim Hospital. Among 132 pa- tients who were evaluated, agitation was the most prominent presentation with 96.2% prevalence, followed by altered level of consciousness, nausea, vomiting, abdominal pain, diar- rhea, bone and muscle pain, tachycardia, and dilated pupils. Except for agitation, no relationship was found between the presence of these symptoms and the dose of naltrexone used (9). Furthermore, another cross-sectional study was performed on patients hospitalized with a history of naltrexone use co- inciding with opioid substances at Razi Hospital, Rasht, Iran, during 2007- 2008. The collected data were demographic in- formation, drug use disorder information, clinical signs and symptoms, laboratory findings, and the therapeutic mea- sures taken. The mean age of the patients was 33.7 ± 10.2 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 M. Rahimi et al. 4 Table 2: Laboratory findings of patients with naltrexone intoxication Variable N Values Arterial blood gas analysis PH 56 7.41 ± 0.11 PCO2 (mmHg) 51 39.65 ± 34.61 PO2 (mmHg) 49 93.69 ± 112.19 HCO3 (mEq/L) 50 24.14 ± 10.7 Base excess (mEq/L) 51 0.98 ± 5.47 Venous blood gas analysis PH 214 7.3938 ± 0.23 PCO2 (mmHg) 214 40.709 ± 27.7 PO2 (mmHg) 202 41.000 ± 21.38 HCO3 (mEq/L) 215 24.714 ± 4.57 Base excess (mEq/L) 203 2.073 ± 6.55 Other laboratory data Sodium (mEq/L) 763 141.1 ± 4.5 Potassium (mEq/L) 756 4.2 ± 0.6 Blood Sugar (mg/dL) 773 108 ± 36.6 Hemoglobin (g/dL) 706 13.9 ± 1.7 Blood urea nitrogen (mg/dL) 757 30 ± 10.8 Creatinine (mg/dL) 758 1 ± 0.4 Aspartate Transaminase (IU/L) 199 36.2 ± 37.3 Alanine Transaminase (IU/L) 197 27.1 ± 22 Alkaline Phosphatase (IU/L) 205 211.7 ± 82.5 Creatine phosphokinase (IU/L) 142 767.3 ± 1571.6 Lactate dehydrogenase (IU/L) 143 653.7 ± 488.8 Data are presented as mean ± standard deviation. PCO2: Partial Pressure of Carbon Dioxide; pH: Potential of Hydrogen; PO2: Partial Pressure of Oxygen. years. The majority of the cases were male (95.6%) and urban (96.7%). The leading cause of withdrawal symptoms in 91.1% of the patients was inappropriate naltrexone usage. In 80% of the cases, the only poisoning agent consumed was nal- trexone. The major clinical features were nausea, vomiting, and agitation. In addition, the primary therapeutic measures were supportive intravenous fluids and methadone adminis- tration. The mean hospitalization period was 21.8 ± 18 hours (12). The current study was consistent with the previous studies in terms of general characteristics. The median age of pa- tients was 35, and the male was the dominant sex among pa- tients with naltrexone intoxication. Contrary to the primary hypothesis, there was no significant difference between the various age groups regarding clinical consequences. This is probably due to the high prevalence of addiction among this population (13). In accordance with the previous studies, the main clinical presentations among the studied population were agitation, vomiting, nausea, and diarrhea. Some cases experienced seizures. These manifestations were mainly due to the withdrawal syndrome caused by naltrexone exposure in opioid-tolerant patients. In another study conducted in Australia from 2000 to 2003, the severity and duration of withdrawal symptoms due to ac- cidental or intentional naltrexone abuse were suggested to be variable and unpredictable. Oral naltrexone was estimated to have a mortality rate four times greater than methadone in treating patients with opioid use disorder (8). In this study, results revealed that the risk of intubation in patients who were intoxicated with naltrexone with suicidal intention was significantly higher than the patients who were intoxicated due to other reasons (accidental or to quit addiction). Anal- ysis revealed that patients who consumed more than 100 mg naltrexone were those who committed suicide. In other words, patients with naltrexone intoxication and suicidal in- tention were more likely to consume naltrexone more than 100 mg (Pearson Chi-square=4.5; p<0.03). Thus, increased odds of intubation in patients with suicidal intention are probably due to the higher dose of naltrexone exposure in these patients. There are contradictions about naltrexone hepatotoxicity and it does not appear to increase hepatic enzymes at ther- apeutic doses (14-17). Some studies have shown that high doses of naltrexone (up to 400 mg/day) do not affect liver en- zyme levels (17). On the contrary, other studies have shown that naltrexone may increase hepatic transaminases at a 300 mg/day dose (18, 19). The present study shows that high levels of AST were asso- 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 5 Archives of Academic Emergency Medicine. 2022; 10(1): e34 ciated with greater need for intubation and more extended hospital stays among patients with naltrexone poisoning. It is recommended to pay more attention to the relationship be- tween elevated AST and the clinical consequences of naltrex- one poisoning in future studies. Considering that Loghman Hakim Hospital is the scientific center of clinical toxicology and the referral center in Iran, so the findings of the study can be generalized, at least, to Iran. For future studies, we recommend a prospective study with pre-designed forms to facilitate data entry and prevent missing data in order to aid in preparing a comprehensive and practical protocol for management of naltrexone intoxi- cation. 5. Limitations Due to the type of research, this study has poor internal va- lidity, which may be negligible due to the importance of the subject and the number of cases studied. Moreover, as men- tioned above, several cases had missing information regard- ing the doses of naltrexone, patients’ ages, and their intention for consuming naltrexone. 6. Conclusion This study showed that there are many cases of poisoning with naltrexone in Iran. The probability of intubation was as- sociated with AST elevation, which may be due to liver dam- age caused by high doses of naltrexone. It seems that, the number of ICU admissions and mortality rates are not high among patients with naltrexone intoxication. 7. Declarations 7.1. Acknowledgments The authors thank Dr Maral. Ramezani for her kind support. 7.2. Authors’ contributions Each author’s contribution is in the analytical search for sci- entific publications, writing the article, and approving the content. 7.3. Funding and supports Toxicological Research Center,Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences. 7.4. Conflict of interest The authors declare that they have no competing interests. References 1. Kirchmayer U, Davoli M, Verster A. Naltrexone main- tenance treatment for opioid dependence. Cochrane Database Syst Rev. 2003(2). 2. Amin-Esmaeili M, Rahimi-Movaghar A, Sharifi V, Hajebi A, Radgoodarzi R, Mojtabai R, et al. Epidemiology of il- licit drug use disorders in Iran: prevalence, correlates, co- morbidity and service utilization results from the Iranian Mental Health Survey. Addiction. 2016;111(10):1836-47. 3. Shadnia S, Esmaily H, Sasanian G, Pajoumand A, Hassanian-Moghaddam H, Abdollahi M. Pattern of acute poisoning in Tehran-Iran in 2003. Hum Exp Toxicol. 2007;26(9):753-6. 4. Ghane T, Zamani N, Hassanian-Moghaddam H, Beyrami A, Noroozi A. Lead poisoning outbreak among opium users in the Islamic Republic of Iran, 2016–2017. Bull World Health Organ. 2018;96(3):165. 5. Merz F. United Nations Office on Drugs and Crime: World Drug Report 2017. 2017. SIRIUS. 2018;2(1):85-6. 6. Hassanian-Moghaddam H. An educational and research opportunity for the largest university hospital poison control centers; Tehran and Cairo. Egypt J Forensic Sci. 2013;2(3):64-5. 7. Strang J, McCambridge J, Best D, Beswick T, Bearn J, Rees S, et al. Loss of tolerance and overdose mortality af- ter inpatient opiate detoxification: follow up study. Bmj. 2003;326(7396):959-60. 8. Gibson AE, Degenhardt LJ. Mortality related to phar- macotherapies for opioid dependence: a compara- tive analysis of coronial records. Drug alcohol Rev. 2007;26(4):405-10. 9. Hassanian-Moghaddam H, Afzali S, Pooya A. Withdrawal syndrome caused by naltrexone in opioid abusers. Hum Exp Toxicol. 2014;33(6):561-7. 10. Nelson L, Howland M, Lewin N, Smith S, Goldfrank L, Hoffman R. Chapter 4: Principles of Managing the Acutely Poisoned or Overdosed Patient. Goldfrank’s Tox- icologic Emergencies, 11th ed New York, NY: McGraw- Hill Education Online edition Accessed September. 2019;25:2021. 11. Pope JF. Clinical Management of Poisoning and Drug Overdose. Clin Pediatr. 1998;37(7):457. 12. Rahbar M, Badsar AR, Mahmanzar Ch, Fallah M. The Study of the Demographic and Clinical and Laboratory Findings in Naltrexone Poisoning Patients Admitted to Razi Hospital, Rasht, During 2007-08. Iran J Toxicol. 2012;17(6):649-654. 13. Mokri A. Brief overview of the status of drug abuse in Iran. Arch Iran Med. 2002;5(3):184-190. 14. Yen M-H, Ko H-C, Tang F-I, Lu R-B, Hong J-S. Study of hepatotoxicity of naltrexone in the treatment of alco- holism. Alcohol. 2006;38(2):117-20. 15. Vagenas P, Di Paola A, Herme M, Lincoln T, Skiest DJ, Altice FL, et al. An evaluation of hepatic enzyme ele- vations among HIV-infected released prisoners enrolled 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 M. Rahimi et al. 6 in two randomized placebo-controlled trials of extended release naltrexone. J Subst Abuse Treat. 2014;47(1):35-40. 16. Brewer C, Wong VS. Naltrexone: report of lack of hepato- toxicity in acute viral hepatitis, with a review of the liter- ature. Addict biol. 2004;9(1):81-7. 17. Marrazzi MA, Wroblewski JM, Kinzie J, Luby ED. High- dose naltrexone and liver function safety. Am J Addict. 1997;6(1):21-9. 18. Mitchell JE, Morley JE, Levine AS, Hatsukami D, Gannon M, Pfohl D. High-dose naltrexone therapy and dietary counseling for obesity. Biol psychiatry. 1987;22(1):35-42. 19. Pfohl DN, Allen JI, Atkinson RL, Knopman DS, Mal- colm RJ, Mitchell JE, et al. Naltrexone hydrochloride (Trexan): a review of serum transaminase elevations at high dosage. NIDA Res Monogr. 1986;67:66-72. 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 Limitations Conclusion Declarations References