Archives of Academic Emergency Medicine. 2021; 9(1): e62 OR I G I N A L RE S E A RC H Fentanyl versus Methadone in Management of Withdrawal Syndrome in Opioid Addicted Patients; a Pilot Clinical Trial Baharak Najafi1, Shahin Shadnia1, Hossein Hassanian-Moghaddam1,2, Amir Heydarian3, Arezou Mahdavinejad4, Nasim Zamani1,2∗ 1. Department of Clinical Toxicology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Department of Emergency Medicine, Loghman Hakim Hiospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Toxicological Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: July 2021; Accepted: August 2021; Published online: 13 September 2021 Abstract: Introduction: The most effective treatment for withdrawal syndrome in Opioid-dependent patients admitted to intensive care units (ICUs) remains unknown. This study aimed to compare fentanyl and methadone in this re- gard. Methods: This prospective, single-blinded, controlled pilot study was conducted on opioid-dependent in- tubated patients admitted to the toxicology ICU of Loghman Hakim Hospital, Tehran, Iran, between August 2019 and August 2020. Patients were alternately assigned to either fentanyl or methadone group after the initiation of their withdrawal syndrome. Duration and alleviation of the withdrawal signs and symptoms, ICU and hospital stay, development of complications, development of later signs/symptoms of withdrawal syndrome, and need for further administration of sedatives to treat agitation were then compared between these two groups. Results: Median age of the patients was 42 [interquartile range (IQR): 26, 56]. The two groups were similar in terms of the patients’ age (p = 0.92), sex (p = 0.632), primary Simplified Acute Physiology Score (SAPS) II (p = 0.861), and Clinical Opiate Withdrawal Score (COWS) before (p = 0.537) and 120 minutes after treatment (p = 0.136) with either methadone or fentanyl. The duration of intubation (p = 0.120), and ICU stay (p = 0.572), were also similar between the two groups. The only factor that was significantly different between the two groups was the time needed for alleviation of the withdrawal signs and symptoms after the administration of the medication, which was significantly shorter in the methadone group (30 vs. 120 minutes, p = 0.007). Conclusion: It seems that methadone treats the withdrawal signs and symptoms faster in dependent patients. However, these drugs are similarly powerful in controlling the withdrawal signs in these patients. Keywords: Methadone; Fentanyl; Substance withdrawal syndrome; Drug therapy; Intensive care units Cite this article as: Najafi B, Shadnia S, Hassanian-Moghaddam H, Heydarian A, Mahdavinejad A, Zamani N. Fentanyl versus Methadone in Management of Withdrawal Syndrome in Opioid Addicted Patients; a Pilot Clinical Trial. Arch Acad Emerg Med. 2021; 9(1): e62. https://doi.org/10.22037/aaem.v9i1.1384. 1. Introduction Substance use disorder is a common problem although its prevalence in the inpatient setting is not well-defined. In 2012, it was estimated that 11% of adult hospitalizations involved substance use disorders; however, this is proba- ∗Corresponding Author: Nasim Zamani; Department of Clinical Tox- icology Loghman Hakim Hopsital, South Karegar Street, Tehran, Iran. Tel/Fax: 00982155404241, Email: nasim.zamani@gmail.com, ORCIDs: https://orcid.org/0000-0002-2091-0197. bly an underestimation, considering the high frequency of underdiagnosis of substance use disorders (1). Withdrawal syndrome is a major problem in opioid-dependent patients when they are admitted and stay at the hospital for a rela- tively long period of time, such as when they are admitted to intensive care units (ICUs) for any reason. In toxicology ICUs, the situation is even more complicated as the depen- dent patient has already overdosed on a substance or medi- cation making the selection of the best drug/medication for treatment of withdrawal a challenge. Different medications have been proposed as substitutes 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 B. Najafi et al. 2 for opioids but it is generally accepted that the best drug/medication for treatment of withdrawal syndrome is the one the patient is dependent on (2). However, manage- ment of critically ill or injured patients who use illicit sub- stances is complicated due to both the intoxicating and the withdrawal effects of those substances. On the other hand, some medications (including tramadol, oral methadone, opium tincture, etc.) are not available in hospital settings and this may complicate the process of treatment of with- drawal syndrome in dependent patients. The complex phys- iologic responses of these patients as well as their loss of consciousness during the withdrawal may further compli- cate their management (3). In addition, poor management of withdrawal syndrome may cause severe agitation, increase the need for sedation, postpone extubation, and increase the hospital stay. Thus, finding the best medication to control withdrawal syn- drome in dependent patients admitted to the ICU is a ma- jor challenge, a fact that has been overlooked in the exist- ing literature. The aim of the current study was to compare fentanyl, as a routinely administered drug in ICUs to control both withdrawal and pain, with methadone, as a widely ac- cepted medication to treat withdrawal syndrome in hospital- admitted opioid-dependent patients. 2. Methods 2.1. Study design and setting In a prospective, single-blinded, controlled pilot study, opioid-dependent intubated patients admitted to toxicology ICU of Loghman Hakim Hospital between August 2019 and August 2020 were alternately assigned to either fentanyl or methadone groups. The study was approved by our local Ethics Committee in Shahid Beheshti University of Medical Sciences under the code IR.SBMU.RETECH.REC.1398.457 and registered on Iranian registry of clinical trials (IRCT: IRCT20150110020624N2). Written consents were obtained from the patients’ relatives on ICU admission 2.2. Participants Addicted patients who were intubated and their signs and symptoms of withdrawal initiated during ICU stay were in- cluded. Any severity of withdrawal symptoms was consid- ered as the inclusion criteria (mild, moderate, and severe withdrawal symptoms). Patients with other dependencies (such as dependency to benzodiazepines) were excluded. 2.3. Interventions The patients were then alternately assigned to either methadone or fentanyl groups. Only the patients were blinded to the type of treatment they were given as they were unconscious and intubated. In the methadone group, they were put on subcutaneous methadone (Faran Shimi Com- pany, Iran) with the initial dose of 10 mg every 12 hours (20 mg/day) in the beginning. The dose was subsequently ad- justed based on the patients’ withdrawal signs and symp- toms. In the fentanyl group, the patients were put on in- travenous administration of fentanyl (Faran Shimi Company, Iran) with the initial dose of 50-100 µg/hour, which was sub- sequently adjusted based on the patients’ response. The mean dose of fentanyl was considered for analysis. For in- stance, if a patient received fentanyl with the dose 50-100 µg/hour, a mean dose of 75 µg/hour was calculated and con- sidered for analysis. Half an hour and two hours later the patients were re-visited and their Clinical Opiate Withdrawal Score (COWS) was re-calculated. Clonidine was initiated and continued in all patients with the initial dose of 0.1 mg every eight hours (0.3 mg/day) and adjusted to a maximum daily dose of 1.2 mg. 2.4. Data gathering Demographic data and severity of symptoms as well as out- comes were recorded for all cases using a predesigned check- list. N.Z was responsible for data gathering. 2.5. Outcomes The primary outcome evaluated was alleviation of the with- drawal signs and symptoms. The secondary outcomes were duration of withdrawal syndrome, duration of ICU and hos- pital stay, duration of intubation, development of later signs and symptoms of withdrawal syndrome, development of complications (bed sores, rhabdomyolysis, acute tubular necrosis, aspiration pneumonia, and acute respiratory dis- tress syndrome [ARDS] due to prolonged intubation), and need for further administration of sedatives to treat agitation. Addiction was confirmed via the history taken from the pa- tients’ next of kin, positive urine tests, and initiation of clin- ical opiate withdrawal syndrome, which was determined us- ing clinical opiate withdrawal scale (COWS). On ICU admis- sion, simplified acute physiology score (SAPS) II was calcu- lated for all patients. After the signs and symptoms of with- drawal initiated, the patients’ COWS was measured (4). 2.6. Statistical Analysis The data were recorded and transferred to statistical package for social sciences (SPSS) software version 20 and analyzed by application of Mann-Whitney U test for non-normally dis- tributed quantitative variables and Pearson Chi-Square for categorical variables. A p value less than 0.05 was considered to be statistically significant. 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. 2021; 9(1): e62 Table 1: Comparison of the study groups regarding the baseline characteristics and outcomes (n=56) Variable Methadone (n=28) Fentanyl (n=28) P* Age (year) 41 (26, 55) 44 (22, 57) 0.921 SAPS II 29 (15, 36) 24 (17, 37) 0.861 COWS at the time of withdrawal 18 (15, 21) 18 (13, 22) 0.537 COWS 30 minutes after administration 6 (18, 21) 6 (4,13) 0.967 COWS 120 minutes after administration 2 (1, 3) 0 (0, 3) 0.136 Symptom after administration (minutes) 30 (30, 60) 120 (45,120) 0.008 Midazolam (mg/hour) 30 (7, 50) 12 (5, 50) 0.427 Clonidine (mg/day) 0.30 (0.30, 0.60) 0.60 (0.34, 0.60) 0.161 Duration of intubation (day) 9 (4, 17) 5 (2, 9) 0.120 Duration of ICU stay (day) 10 (7, 14) 7 (6,14) 0.572 Data are presented as median (interquartile range). *Mann-Whitney U test; SAPS: Simplified Acute Physiology Score; COWS: clinical opiate withdrawal score; ICU: intensive care unit. 3. Results A total of 48 patients (24 in each group) were included. Me- dian age of the patients was 42 [interquartile range (IQR): 26, 56] (range: 17 to 69) years. The two groups were simi- lar in terms of the patients’ age (p = 0.92), sex (p = 0.632), primary SAPS II score (p = 0.861), and COWS before (p = 0.537) and 120 minutes after (p = 0.136) treatment with ei- ther methadone or fentanyl (Table 1). The duration of intu- bation, ICU stay, and hospital stay were also similar between the two groups. The only factor that was significantly differ- ent between the two groups was the time needed for allevia- tion of the withdrawal signs and symptoms after the admin- istration of the medication, which was significantly shorter in the methadone group (P=0.007). Median [IQR] clonidine administered was 0.30 [0.30, 0.60] and 0.60 [0.34, 0.60] in methadone and fentanyl groups, respectively (P = 0.16). Eighteen patients in the methadone groups and 22 patients in the fentanyl group developed some complication during their ICU stay although this difference was statistically in- significant (p = 0.2). Seven patients (5 in methadone and two in fentanyl group) died showing a non-significant differ- ence between the two groups (p = 0.4). Median [IQR] COWS was 18 [15, 22] (range; 3 to 27) before the administration of methadone or fentanyl, which decreased to 6 [5, 11] (range: 1 to 18) and 6 [4, 13] (range: 0 to 22) thirty and 120 minutes after administration of methadone and fentanyl, respectively (p = 0.008). 4. Discussion Our results showed that application of methadone and fen- tanyl controlled the withdrawal signs and symptoms with similar long-term effects, complications, hospital stay, and final outcome. The only significant difference between the groups in our study was the time needed for the medica- tions to take effect. Patients in methadone group responded to methadone faster, although the severity of COWS was the same between the two groups after treatment. Opiate withdrawal occurs when opioid concentrations de- crease in the central nervous system of tolerant individuals (5). The mainstay of treatment of withdrawal syndrome is replacing the opiate with an opioid with less chance of be- ing abused. Adrenergic agonists, such as clonidine, may also be required to gain control over vital functions. General re- suscitation and supportive measures are necessary for treat- ment in any withdrawal syndrome. A thorough history of the patient’s substance use/abuse/abuse patterns should be ob- tained from the patient, if possible, or from the family. Fentanyl is the preferred opioid used in many ICUs (6, 7) be- cause of its potency and not inducing histamine release, re- sulting in a low risk of hemodynamic instability. However, the short duration of action of this medication often requires a continuous infusion making the weaning process more dif- ficult (8). The use of continuous infusion sedation is associ- ated with prolongation of mechanical ventilation and longer hospital and ICU stays (9). Introduction of long-acting opioids via enteral administra- tion to prevent opioid withdrawal syndrome was first de- scribed in 1965 with the use of methadone for the rehabili- tation of heroin users and has been practiced in the United States since 1970 (10). We could not find any study in the literature that compared methadone and fentanyl in alleviation of withdrawal syn- drome in dependent patients. In a similar study that com- pared opium tincture and methadone for controlling with- drawal syndrome in ICU-admitted dependent patients, it was concluded that a lower dose of methadone could bet- ter control the patients’ agitation (11). However, the authors claimed that the two drugs controlled the patients’ signs and symptoms fairly similar. We can claim the same because our patients showed similar results in the two groups, but re- ceived lower doses of methadone compared to the contin- 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 B. Najafi et al. 4 uous infusions of fentanyl. However, it should be borne in mind that considering the equivalent doses of fentanyl and methadone, it seems that even the received doses were prac- tically similar and methadone is only superior to fentanyl since it is administered twice a day and causes less drowsi- ness. 5. Limitations Most of our patients were methadone users. This may be a potential source of bias because it is generally considered that the best treatment for withdrawal syndrome is the same drug that has caused it. Thus, it seems that in these pa- tients, methadone has been a better substitute from the be- ginning. This is a potential limitation of the current study, which should be considered and taken into account in future studies in this regard. The limited number of studied cases is another limitation. Future studies on more cases are war- ranted to further elucidate the superiority of methadone to fentanyl in dependent patients admitted to the ICUs. 6. Conclusion Methadone seems to treat the withdrawal signs and symp- toms faster compared to fentanyl. However, these drugs seem to similarly control withdrawal signs. Further double- blinded, randomized studies with larger sample sizes are warranted to clearly determine superiority or similarity of these two medications in treatment of dependent patients in the ICUs. 7. Declarations 7.1. Acknowledgments None. 7.2. Funding and supports This study was funded by Shahid Beheshti University of Med- ical Sciences. 7.3. Author contribution All authors met the four criteria for authorship contribution based on the recommendations of the international commit- tee of medical journal editors. SS gave the idea. BN, AM, and AH collected the data. HHM analyzed the data. NZ drafted and finalized the manuscript. 7.4. Competing interest None. 7.5. Consent for publication Not applicable. 7.6. Availability of data Data is available upon request. References 1. Heslin KC, Elixhauser A, Steiner CA. Hospitalizations involving mental and substance use disorders among adults, 2012: statistical brief# 191. 2015. 2. Organization WH. Training manual for clinical guidelines for withdrawal management and treatment of drug de- pendence in closed settings: Manila: WHO Regional Of- fice for the Western Pacific; 2009. 3. Donroe JH, Tetrault JM. Substance use, intoxication, and withdrawal in the critical care setting. Critical care clin- ics. 2017;33(3):543-58. 4. Nelson KL, Stenehjem D, Driscoll M, Gilcrease GW. 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Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declarations References