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Forensic Toxicology
Published in: Forensic Toxicology 2/2021

Open Access 01-07-2021 | Naloxone | Review Article

A review on tramadol toxicity: mechanism of action, clinical presentation, and treatment

Authors: Samaneh Nakhaee, Christopher Hoyte, Richard C. Dart, Masoumeh Askari, Roland J. Lamarine, Omid Mehrpour

Published in: Forensic Toxicology | Issue 2/2021

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Abstract

Aims

As an analgesic that acts upon the central nervous system (CNS), tramadol has gained popularity in treating moderate to severe pain. Recently, it has been increasingly reported as a drug of misuse with intentional overdoses or intoxications. This review focuses on tramadol intoxication in humans and its effects on different systems.

Subject and method

This narrative review provides a comprehensive view of the pharmacokinetics, mechanism of action, and incidence of tramadol toxicity with an in-depth look at its side effects. In addition, the main approaches to the management of tramadol poisoning are described.

Results

Tramadol poisoning can affect multiple organ systems: gastrointestinal, central nervous system (seizure, CNS depression, low-grade coma, anxiety, and over time anoxic brain damage), cardiovascular system (palpitation, mild hypertension to life-threatening complications such as cardiopulmonary arrest), respiratory system, renal system (renal failure with higher doses of tramadol intoxication), musculoskeletal system (rhabdomyolysis), endocrine system (hypoglycemia), as well as, cause serotonin syndrome. Seizure, a serious nervous disturbance, is more common in tramadol intoxication than with other opioids. Fatal tramadol intoxications are uncommon, except in ingestion cases concurrent with other medications, particularly CNS depressants, most commonly benzodiazepines, and ethanol.

Conclusion

With the increasing popularity of tramadol, physicians must be aware of its adverse effects, substantial abuse potential, and drug interactions, to weigh its risk–benefit ratio for pain management. Alternative therapies might be considered in patients with a previous overdose history to reduce risks for adverse outcomes.
Literature
1.
Kaye AD (2015) Tramadol, pharmacology, side effects, and serotonin syndrome: a review. Pain Physician 18:395–400PubMedCrossRef
2.
Taghaddosinejad F, Mehrpour O, Afshari R, Seghatoleslami A, Abdollahi M, Dart RC (2011) Factors related to seizure in tramadol poisoning and its blood concentration. J Med Toxicol 7:183PubMedPubMedCentralCrossRef
3.
Rahimi HR, Soltaninejad K, Shadnia S (2014) Acute tramadol poisoning and its clinical and laboratory findings. J Res Med Sci 19:855PubMedPubMedCentral
4.
Randall C, Crane J (2014) Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012. J Forensic Leg Med 23:32–36PubMedCrossRef
5.
Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R (2017) Trends in tramadol: pharmacology, metabolism, and misuse. Anesth Analg 124:44–51PubMedCrossRef
6.
7.
Shadnia S, Soltaninejad K, Heydari K, Sasanian G, Abdollahi M (2008) Tramadol intoxication: a review of 114 cases. Hum Exp Toxicol 27:201–205PubMedCrossRef
8.
Häkkinen M, Vuori E, Ojanperä I (2014) Prescription opioid abuse based on representative postmortem toxicology. Forensic Sci Int 245:121–125PubMedCrossRef
9.
10.
Shadnia S, Brent J, Mousavi-Fatemi K, Hafezi P, Soltaninejad K (2012) Recurrent seizures in tramadol intoxication: implications for therapy based on 100 patients. Basic Clin Pharmacol Toxicol 111:133–136PubMed
11.
Ryan NM, Isbister GK (2015) Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely. Clin Toxicol 53:545–550CrossRef
12.
Lagard C, Chevillard L, Malissin I, Risède P, Callebert J, Labat L et al (2016) Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose? Toxicol Appl Pharmacol 310:108–119PubMedCrossRef
13.
Abdel-Hamid IA, Andersson K-E, Waldinger MD, Anis TH (2016) Tramadol abuse and sexual function. Sex Med Rev 4:235–246PubMedCrossRef
14.
Marquardt KA, Alsop JA, Albertson TE (2005) Tramadol exposures reported to statewide poison control system. Ann Pharmacother 39:1039–1044PubMedCrossRef
15.
Clarot F, Goulle J, Vaz E, Proust B (2003) Fatal overdoses of tramadol: is benzodiazepine a risk factor of lethality? Forensic Sci Int 134:57–61PubMedCrossRef
16.
Hassanian-Moghaddam H, Farajidana H, Sarjami S, Owliaey H (2013) Tramadol-induced apnea. Am J Emerg Med 31:26–31PubMedCrossRef
17.
Adree H, Fouad H, Waleed E, Sherief M (2018) Incidence and factors influencing acute tramadol toxicity-inducing seizures in Damietta Governorate. Mansoura J Forensic Med Clin Toxicol 26:155–167CrossRef
18.
Halawa H (2013) Clinical study of acute tramadol poisoning in the poison control center, Ain Shams University in 2012. Ain Shams J Forensic Med Clin Toxicol 21:20–26CrossRef
19.
Talaie H, Nasiri S, Gheisari M, Dadkhahfar S, Ahmadi S (2018) bservational study of dermatological manifestations in patients admitted to a tertiary poison center in Iran. Turk J Med Sci 48:136–141PubMedCrossRef
20.
Bassiony MM, Youssif UM, Hussein RA, Saeed M (2016) Psychiatric comorbidity among Egyptian patients with opioid use disorders attributed to tramadol. J Addict Med 10:262–268PubMedCrossRef
21.
Wu W, McKown L, Liao S (2002) Metabolism of the analgesic drug ULTRAM® (tramadol hydrochloride) in humans: API-MS and MS/MS characterization of metabolites. Xenobiotica 32:411–425PubMedCrossRef
22.
Barbosa J, Faria J, Queirós O, Moreira R, Carvalho F, Dinis-Oliveira RJ (2016) Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev 48:577–592PubMedCrossRef
23.
24.
Gong L, Stamer UM, Tzvetkov MV, Altman RB, Klein TE (2014) PharmGKB summary: tramadol pathway. Pharmacogenet Genom 24:374CrossRef
25.
Doostmohammadi M, Rahimi H-R (2020) ADME and toxicity considerations for tramadol: from basic research to clinical implications. Expert Opin Drug Metab Toxicol 16(7):627–640PubMedCrossRef
26.
Gan SH, Ismail R, Adnan WAW, Zulmi W (2007) Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics. Mol Diagn Ther 11:171–181PubMedCrossRef
27.
Stamer U, Stüber F (2007) Codeine and tramadol analgesic efficacy and respiratory effects are influenced by CYP2D6 genotype. Anaesthesia 62:1294–1295PubMedCrossRef
28.
Halling J, Weihe P, Brosen K (2008) CYP2D6 polymorphism in relation to tramadol metabolism: a study of faroese patients. Ther Drug Monit 30:271–275PubMedCrossRef
29.
Haufroid V, Hantson P (2015) CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants. Clin Toxicol 53:501–510CrossRef
30.
Raffa RB (2008) Basic pharmacology relevant to drug abuse assessment: tramadol as example. J Clin Pharm Ther 33:101–108PubMedCrossRef
31.
Raffa RB, Stone DJ (2008) Unexceptional seizure potential of tramadol or its enantiomers or metabolites in mice. J Pharmacol Exp Ther 325:500–506PubMedCrossRef
32.
Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A (2012) Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care 16:R136PubMedPubMedCentralCrossRef
33.
Ingelman-Sundberg M, Oscarson M, McLellan RA (1999) Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 20:342–349PubMedCrossRef
34.
Jovanović-Čupić V, Martinović Ž, Nešić N (2006) Seizures associated with intoxication and abuse of tramadol. Clin Toxicol 44:143–146CrossRef
35.
Pedersen RS, Damkier P, Brosen K (2005) Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clin Pharmacol Ther 77:458–467PubMedCrossRef
36.
De Decker K, Cordonnier J, Jacobs W, Coucke V, Schepens P, Jorens PG (2008) Fatal intoxication due to tramadol alone: case report and review of the literature. Forensic Sci Int 175:79–82PubMedCrossRef
37.
Gillen C, Haurand M, Kobelt DJ, Wnendt S (2000) Affinity, potency and efficacy of tramadol and its metabolites at the cloned human µ-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 362:116–121PubMedCrossRef
38.
Enggaard TP, Poulsen L, Arendt-Nielsen L, Brøsen K, Ossig J, Sindrup SH (2006) The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 102:146–150PubMedCrossRef
39.
Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL et al (1993) Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 267:331–340PubMed
40.
Raffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM et al (2012) Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother 13:1437–1449PubMedCrossRef
41.
Goeringer KE, Logan BK, Christian GD (1997) Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers. J Anal Toxicol 21:529–537PubMedCrossRef
42.
43.
Gibson TP (1996) Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl. Am J Med 101:S47–S53CrossRef
44.
Costa I, Oliveira A, de Pinho PG, Teixeira HM, Moreira R, Carvalho F et al (2013) Postmortem redistribution of tramadol and O-desmethyltramadol. J Anal Toxicol 37:670–675PubMedCrossRef
45.
Mehrpour O, Sharifi M, Zamani N (2015) Tramadol poisoning. In: Andreazza AC, Scola G (ed) Toxicology studies—cells, drugs and environment: BoD, Books on Demand
46.
Tsutaoka BT, Ho RY, Fung SM, Kearney TE (2015) Comparative toxicity of tapentadol and tramadol utilizing data reported to the national poison data system. Ann Pharmacother 49:1311–1316PubMedCrossRef
47.
Dhagudu NK, Erravalli A, Sarkar S, Chadda RK (2019) Tramadol-related adverse drug reactions at an addiction psychiatry setting: a cross-sectional analysis. Indian J Psychol Med 41:593PubMedPubMedCentralCrossRef
48.
Pedersen RS, Damkier P, Christensen MMH, Brosen K (2013) A cytochrome P450 phenotyping cocktail causing unexpected adverse reactions in female volunteers. Eur J Clin Pharmacol 69:1997–1999PubMedCrossRef
49.
Ghamsari AA, Dadpour B, Najari F (2016) Frequency of electrocardiographic abnormalities in tramadol poisoned patients; a brief report. Emerg 4:151
50.
Spiller HA, Gorman SE, Villalobos D, Benson BE, Ruskosky DR, Stancavage MM et al (1997) Prospective multicenter evaluation of tramadol exposure. Clin Toxicol 35:361–364
51.
52.
Atici S, Cinel I, Cinel L, Doruk N, Eskandari G, Oral U (2005) Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model. J Biosci 30:245–252PubMedCrossRef
53.
54.
Eizadi-Mood N, Ozcan D, Sabzghabaee AM, Mirmoghtadaee P, Hedaiaty M (2014) Does naloxone prevent seizure in tramadol intoxicated patients? Int J Prev Med 5:302PubMedPubMedCentral
55.
56.
Taheri MS, Noori M, Shakiba M, Jalali AH (2011) Brain CT-scan findings in unconscious patients after poisoning. Int J Biomed Sci 7:1PubMedPubMedCentral
57.
Afshari R, Ghooshkhanehee H (2009) Tramadol overdose induced seizure, dramatic rise of CPK and acute renal failure. J Pak Med Assoc 59:178PubMed
58.
Bekjarovski N, Chaparoska D, Radulovikj-Bekjarovska S (2012) Seizures after use and abuse of tramadol. Contributions of Macedonian Academy of Sciences & Arts, p. 33
59.
Farajidana H, Hassanian-Moghaddam H, Zamani N, Sanaei-Zadeh H (2012) Tramadol-induced seizures and trauma. Eur Rev Med Pharmacol Sci 16:34–37PubMed
60.
Farzaneh E, Mostafazadeh B, Mehrpour O (2012) Seizurogenic effects of low-dose naloxone in tramadol overdose. Iran J Pharmacol Ther 11:6
61.
Gardner JS, Blough D, Drinkard CR, Shatin D, Anderson G, Graham D et al (2000) Tramadol and seizures: a surveillance study in a managed care population. Pharmacother 20:1423–1431CrossRef
62.
Goodarzi F, Mehrpour O, Eizadi-Mood N (2011) A study to evaluate factors associated with seizure in tramadol poisoning in Iran. Indian J Med Forensic Med Toxicol 5:66–69
63.
Mazor SS, Feldman KW, Sugar NF, Sotero M (2008) Pediatric tramadol ingestion resulting in seizurelike activity: a case series. Pediatr Emerg Care 24:380–381PubMedCrossRef
64.
Mehrpour M (2005) Intravenous tramadol-induced seizure: two case reports. Iran J Pharmacol Ther 4:146
65.
Mehrpour O, Taghaddosi-Nejad F, Seghatoleslami A, Chalaki N, Afshari R (2010) Tramadol poisoning induced seizure. Toxicol Lett 196:S79–S80CrossRef
66.
Petramfar P, Haghighi AB (2010) Tramadol induced seizure: report of 106 patients. Iran Red Crescent Med J 12:49
67.
Nakhaee S, Amirabadizadeh A, Brent J, Miri-Moghaddam E, Foadoddini M, Farrokhfall K et al (2019) Tramadol and the occurrence of seizures: a systematic review and meta-analysis. Crit Rev Toxicol 49:710–723PubMedCrossRef
68.
Rezk NN, Khater AS, Sarhan NM (2012) Tramadol induced seizures; in relation to patient criteria and tramadol dose. Egypt J Forensic Sci Appl Toxicol 220:1–9
69.
Thundiyil JG, Kearney TE, Olson KR (2007) Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System. J Med Toxicol 3:15–19PubMedPubMedCentralCrossRef
70.
Grosek S, Mozina M, Grabnar I, Primozic J (2009) Diagnostic and therapeutic value of naloxone after intoxication with tramadol in a young girl. Pediatr Int 51:842–843PubMedCrossRef
71.
Correia MS, Whitehead E, Cantrell FL, Lasoff DR, Minns AB (2019) A 10-year review of single medication double-dose ingestions in the nation’s largest poison control system. Clin Toxicol 57:31–35CrossRef
72.
Abuelfadl AA, El-Ebiary AA, Soliman MA (2016) Tramadol blood level and prediction of seizures in patients with acute tramadol poisoning. Mansoura J Forensic Med Clin Toxicol 24:35–47CrossRef
73.
Mohammadpour A, Ashkezari MD, Farahmand B, Shokrzadeh M (2019) Demographic characteristics and functional performance of the kidneys and hearts of patients with acute tramadol toxicity. Drug Res 69:207–210CrossRef
74.
Nasr MA, Mahmoud SF, Mohammed MA, El-samie HSA (2018) A study of clinical and laboratory picture of acute tramadol toxicity in Damietta governorate. Mansoura J Forensic Med Clin Toxicol 26:143–153CrossRef
75.
Lagard C, Malissin I, Indja W, Risède P, Chevillard L, Mégarbane B (2018) Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat. Clin Toxicol 56:737–743CrossRef
76.
Hara K, Minami K, Sata T (2005) The effects of tramadol and its metabolite on glycine, γ-aminobutyric AcidA, and N-methyl-d-aspartate receptors expressed in Xenopus oocytes. Anesth Analg 100:1400–1405PubMedCrossRef
77.
Raimundo JM, Sudo RT, Pontes LB, Antunes F, Trachez MM, Zapata-Sudo G (2006) In vitro and in vivo vasodilator activity of racemic tramadol and its enantiomers in Wistar rats. Eur J Pharmacol 530:117–123PubMedCrossRef
78.
Faria J, Barbosa J, Leal S, Afonso LP, Lobo J, Moreira R et al (2017) Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats. Toxicol 385:38–47CrossRef
79.
Medei E, Raimundo JM, Nascimento JHM, Trachez MM, Sudo RT, Zapata-Sudo G (2011) Inhibition of L-type calcium current by tramadol and enantiomers in cardiac myocytes from rats. Arq Bras Cardiol 97:324–331PubMedCrossRef
80.
Perdreau E, Iriart X, Mouton J-B, Jalal Z, Thambo J-B (2015) Cardiogenic shock due to acute tramadol intoxication. Cardiovasc Toxicol 15:100–103PubMedCrossRef
81.
Belin N, Clairet A-L, Chocron S, Capellier G, Piton G (2017) Refractory cardiogenic shock during tramadol poisoning: a case report. Cardiovasc Toxicol 17:219–222PubMedCrossRef
82.
Garrett P (2004) Tramadol overdose and serotonin syndrome manifesting as acute right heart dysfunction. Anaesth Intensive Care 32:575–577PubMedCrossRef
83.
Elkalioubie A, Allorge D, Robriquet L, Wiart J-F, Garat A, Broly F et al (2011) Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer. Eur J Clin Pharmacol 67:855–858PubMedCrossRef
84.
Daubin C, Quentin C, Goullé J-P, Guillotin D, Lehoux P, Lepage O et al (2007) Refractory shock and asystole related to tramadol overdose. Clin Toxicol 45:961–964CrossRef
85.
Cole JB, Sattiraju S, Bilden EF, Asinger RW, Bertog SC (2012) Isolated tramadol overdose associated with Brugada ECG pattern. Pacing Clin Electrophysiol 35:e219–e221PubMedCrossRef
86.
Emamhadi M, Sanaei-Zadeh H, Nikniya M, Zamani N, Dart RC (2012) Electrocardiographic manifestations of tramadol toxicity with special reference to their ability for prediction of seizures. Am J Emerg Med 30:1481–1485PubMedCrossRef
87.
Hassanian-Moghaddam H (2013) Oral pure tramadol exposure like other opioids can cause apnea-why not be careful? Am J Emerg Med 31:410–411PubMedCrossRef
88.
Hassanian-Moghaddam H, Farnaghi F, Rahimi M (2015) Tramadol overdose and apnea in hospitalized children, a review of 20 cases. Res Pharm Sci 10:544PubMedPubMedCentral
89.
Stamer UM, Stüber F, Muders T, Musshoff F (2008) Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107:926–929PubMedCrossRef
90.
Wang S-Q, Li C-S, Song Y-G (2009) Multiply organ dysfunction syndrome due to tramadol intoxication alone. Am J Emerg Med 27:903.e5-903.e7CrossRef
91.
Gioia S, Lancia M, Bacci M, Suadoni F (2017) Two fatal intoxications due to tramadol alone: autopsy case reports and review of the literature. Am J Forensic Med Pathol 38:345–348PubMedCrossRef
92.
Teppema LJ, Nieuwenhuijs D, Olievier CN, Dahan A (2003) Respiratory depression by tramadol in the catinvolvement of opioid receptors. Anesthesiology 98:420–427PubMedCrossRef
93.
Nieuwenhuijs D, Bruce J, Drummond G, Warren P, Dahan A (2001) Influence of oral tramadol on the dynamic ventilatory response to carbon dioxide in healthy volunteers. Br J Anaesth 87:860–865PubMedCrossRef
94.
Tashakori A, Afshari R (2010) Tramadol overdose as a cause of serotonin syndrome: a case series. Clin Toxicol 48:337–341CrossRef
95.
Khan FY, Yousef H, Errayes M (2010) Tramadol toxicity-induced rhabdomyolysis. J Emerg Trauma Shock 3:421CrossRef
96.
Sanaei-Zadeh H (2013) Tramadol intoxication and tongue laceration. N Z Med J 126:113–114PubMed
97.
Mugunthan N, Davoren P (2012) Danger of hypoglycemia due to acute tramadol poisoning. Endocr Pract 18:e151–e152PubMedCrossRef
98.
Nasouhi S, Talaie H, Pajoumand A, Aghapour S, Rahimi M, Khorasani AG et al (2015) Hypo and hyperglycemia among tramadol overdose patients in Loghman Hakim Hospital, Tehran. Iran Pak J Pharm Sci 28:1959–1963PubMed
99.
Abadie D, Durrieu G, Roussin A, Montastruc J-L (2013) “Serious” adverse drug reactions with tramadol: a 2010–2011 pharmacovigilance survey in France. Therapie 68:77–84PubMedCrossRef
100.
Aliyu I, Kyari F, Ibrahim Z (2016) Hypoglycemia in a child with tramadol poisoning. Saudi J Med Med Sci 4:35PubMedCrossRef
101.
Cheng J-T, Liu I-M, Chi T-C, Tzeng T-F, Lu F-H, Chang CJ (2001) Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes 50:2815–2821PubMedCrossRef
102.
Fouad S, Hassan N, Nassief N, El-Halawany F, Hussien R (2015) Critical score as a predictor for progression of tramadol intoxication. J Clin Toxicol 5(2161–0495):1000249
103.
Kara H, Karci A, Gümüştekin M, Örmen M, Taşdöğen A, Elar Z (2013) The effect of tramadol on blood glucose levels in rats. Open J Anesthesiol 3:18CrossRef
104.
Nakhaee S, Brent J, Hoyte C, Farrokhfall K, Shirazi M, Askari M et al (2020) The effect of tramadol on blood glucose concentrations: a systematic review. Expert Rev Clin Pharmacol 13(5):531–543PubMedCrossRef
105.
Mansouripour SM, Afshari R (2013) Chlordiazepoxide preventive effect on tramadol overdose induced serotonin syndrome evaluated by Hunter and Radomski criteria: a clinical trial. Toxicol Int 20:126PubMedPubMedCentralCrossRef
106.
Maréchal C, Honorat R, Claudet I (2011) Serotonin syndrome induced by tramadol intoxication in an 8-month-old infant. Pediatr Neurol 44:72–74PubMedCrossRef
107.
Fujimoto Y, Funao T, Suehiro K, Takahashi R, Mori T, Nishikawa K (2015) Brain serotonin content regulates the manifestation of tramadol-induced seizures in ratsdisparity between tramadol-induced seizure and serotonin syndrome. Anesthesiology 122:178–189PubMedCrossRef
108.
Iravani FS, Akhgari M, Jokar F, Bahmanabadi L (2010) Current trends in tramadol-related fatalities, Tehran, Iran 2005–2008. Subst Use Misuse 45:2162–2171PubMedCrossRef
109.
Häkkinen M, Launiainen T, Vuori E, Ojanperä I (2012) Comparison of fatal poisonings by prescription opioids. Forensic Sci Int 222:327–331PubMedCrossRef
110.
Hawton K, Ferrey A, Casey D, Wells C, Fuller A, Bankhead C et al (2019) Relative toxicity of analgesics commonly used for intentional self-poisoning: a study of case fatality based on fatal and non-fatal overdoses. J Affect Disord 246:814–819PubMedCrossRef
111.
Kim E, Park Y, Ha H, Chung H (2016) Patterns of drugs & poisons in southern area of South Korea in 2014. Forensic Sci Int 269:50–55PubMedCrossRef
112.
Alinejad S, Zamani N, Abdollahi M, Mehrpour O (2017) A narrative review of acute adult poisoning in Iran. Iran J Med Sci 42:327PubMedPubMedCentral
113.
Handley S, Flanagan R (2014) Drugs and other chemicals involved in fatal poisoning in England and Wales during 2000–2011. Clin Toxicol 52:1–12CrossRef
114.
Tjäderborn M, Jönsson AK, Hägg S, Ahlner J (2007) Fatal unintentional intoxications with tramadol during 1995–2005. Forensic Sci Int 173:107–111PubMedCrossRef
115.
Clarkson JE, Lacy JM, Fligner CL, Thiersch N, Howard J, Harruff RC et al (2004) Tramadol (Ultram®) concentrations in death investigation and impaired driving cases and their significance. Iran J Med Sci 49:1101–1105
116.
Loughrey M, Loughrey C, Johnston S, O’Rourke D (2003) Fatal hepatic failure following accidental tramadol overdose. Forensic Sci Int 134:232–233PubMedCrossRef
117.
Moore KA, Cina SJ, Jones R, Selby DM, Levine B, Smith ML (1999) Tissue distribution of tramadol and metabolites in an overdose fatality. Am J Forensic Med Pathol 20:98–100PubMedCrossRef
118.
Musshoff F, Madea B (2001) Fatality due to ingestion of tramadol alone. Forensic Sci Int 116:197–199PubMedCrossRef
119.
De Backer B, Renardy F, Denooz R, Charlier C (2010) Quantification in postmortem blood and identification in urine of tramadol and its two main metabolites in two cases of lethal tramadol intoxication. J Anal Toxicol 34:599–604PubMedCrossRef
120.
121.
Ripple MG, Pestaner JP, Levine BS, Smialek JE (2000) Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol 21:370–374PubMedCrossRef
122.
Wiergowski M, Schetz D, Jankowski Z, Sumińska-Zuminska B, Sein JA (2015) Intoxication of female patient with generalised cancer in hospital–a case report. Przegl Lek 72:485–487PubMed
123.
Hernandez AF, Montero MN, Pla A, Villanueva E (1995) Fatal moclobemide overdose or death caused by serotonin syndrome? J Forensic Sci 40:128–130PubMedCrossRef
124.
Solarino B, Rießelmann B, Buschmann CT, Tsokos M (2010) Multidrug poisoning involving nicotine and tramadol. Forensic Sci Int 194:e17–e19PubMedCrossRef
125.
Mannocchi G, Napoleoni F, Napoletano S, Pantano F, Santoni M, Tittarelli R et al (2013) Fatal self administration of tramadol and propofol: a case report. J Forensic Leg Med 20:715–719PubMedCrossRef
126.
Zhang S, Guan D, Wang L, Wang H, Zhang G, Zhao R et al (2011) The expression of GABA (A) receptor alpha1 and GABA (B) receptor 1 in medulla oblongata solitary nucleus and ambiguous nucleus in the cases of tramadol intoxication. Fa Yi Xue Za Zhi 27:401–404PubMed
127.
Barbera N, Fisichella M, Bosco A, Indorato F, Spadaro G, Romano G (2013) A suicidal poisoning due to tramadol. A metabolic approach to death investigation. J Forensic Leg Med 20:555–558PubMedCrossRef
128.
Afshari R, Afshar R, Mégarbane B (2011) Tramadol overdose: review of the literature. Réanimation 20:436CrossRef
129.
130.
Raffa RB, Wu C, Stone DJ Jr, Borenstein MR, Codd EE, Coogan TP (2000) Determination of the adsorption of tramadol hydrochloride by activated charcoal in vitro and in vivo. J Pharmacol Toxicol Methods 43:205–210PubMedCrossRef
131.
Bianchetti M, Beutler A, Ferrier P (1988) Acute poisoning with a narcotic (tramadol) in an infant of five weeks. Helv Paediatr Acta 43:241–244PubMed
132.
Riedel F, von Stockhausen H-B (1984) Severe cerebral depression after intoxication with tramadol in a 6-month-old infant. Eur J Clin Pharmacol 26:631–632PubMedCrossRef
133.
Lagard C, Malissin I, Indja W, Risède P, Chevillard L, Mégarbane B (2017) Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat. Clin Toxicol 56(8):737–743CrossRef
134.
Saidi H, Ghadiri M, Abbasi S, Ahmadi S-F (2010) Efficacy and safety of naloxone in the management of postseizure complaints of tramadol intoxicated patients: a self-controlled study. Emerg Med J 27:928–930PubMedCrossRef
135.
Vahabzadeh M, Moshiri M, Mohammadpour AH, Hosseinzadeh H (2013) Promising effects of intravenous lipid emulsion as an antidote in acute tramadol poisoning. Reg Anesth Pain Med 38:425–430PubMedCrossRef
136.
Abbasi B, Hafezimoghadam P, Ansari Nejad N, Sarvari M, Ramim T (2015) Assessment of time interval between tramadol intake and seizure and second drug-induced attack. Tehran Univ Med J 73:592–599
137.
Mood NE, Sabzghabaee AM, Safdari A, Yaraghi A (2011) Clinical signs, hospitalization duration and outcome of tramadol intoxication. J Isfahan Med Sch 28
138.
Farzaneh E, Samadzadeh M, Shahbazzadegan B, Sayadrezai I, Mostafazadeh B, Sarbandi Farahani A, et al (2012) Comparing the frequency of seizure in patients intoxicated with tramadol treated with or without naloxone. J Isfahan Med Sch 30
139.
Ahmadimanesh M, Shadnia S, Rouini MR, Sheikholeslami B, Nasab SA, Ghazi-Khansari M (2018) Correlation between plasma concentrations of tramadol and its metabolites and the incidence of seizure in tramadol-intoxicated patients. Drug Metab Pers Ther 33:75–83PubMedCrossRef
140.
Ahmadi H, Hosseini J, Rezaei M (2008) Epidemiology of tramadol overdose in Imam Khomeini hospital, Kermanshah, Iran (2008). J Kermanshah Univ Med Sci 15
141.
Murray BP, Carpenter JE, Dunkley CA, Moran TP, Alfaifi M, Alsukaiti WS et al (2019) Seizures in tramadol overdoses reported in the ToxIC registry: predisposing factors and the role of naloxone. Clin Toxicol 57(8):692–696CrossRef
Metadata
Title
A review on tramadol toxicity: mechanism of action, clinical presentation, and treatment
Authors
Samaneh Nakhaee
Christopher Hoyte
Richard C. Dart
Masoumeh Askari
Roland J. Lamarine
Omid Mehrpour
Publication date
01-07-2021
Publisher
Springer Singapore
Published in
Forensic Toxicology / Issue 2/2021
Print ISSN: 1860-8965
Electronic ISSN: 1860-8973
DOI
https://doi.org/10.1007/s11419-020-00569-0

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