- Email: [email protected]
Tramadol–benzodiazepines and buprenorphine–benzodiazepines: two potentially fatal cocktails?
Journal of Clinical Forensic Medicine (2003) 10, 125–128
CORRESPONDENCE
infusion of 100-mg tramadol, concentrations in plasma can be immediately detected. Elimination is slow and characterized by an elimination half-life of 5–6 h. Tramadol is mainly metabolized into two active desmethyl derivatives (O-desmethyl-tramadol and N-desmethyl-tramadol) and to several inactive compounds. A recent study demonstrated that hepatic CYP2D6 appeared to be primarily responsible for O-desmethyl-tramadol formation, whereas N-desmethyl-tramadol formation was catalyzed by CYP2B6 and CYP3A4.3 Moreover, tramadol metabolism in human liver microsomes was markedly inhibited by the CYP2D6 inhibitor quinidine and the CYP3A4 inhibitor troleandomycin, respectively. Benzodiazepines constitute a class of versatile and widely prescribed central nervous system (CNS)-depressants. Benzodiazepines are prescribed as anxiolytics, sedative hypnotics, anticonvulsants and muscle relaxants. Because of their clinical popularity, ascribed to the wide safety margin of their therapeutic index, their minimal serious adverse side-effects, these drugs are very frequently encountered in the clinical setting and forensic toxicology. Bromazepam is a benzodiazepine used as an anti-anxiety agent administrated in single oral doses of 3–12 mg. It is metabolized primarily by 3-hydroxylation and cleavage of the seven-membered ring, followed by glucuronide conjugation of the hydroxylated metabolites. The CYP3A role in the bromazepam metabolism has been demonstrated by certain authors who have reported an increase of the bromazepam plasma concentrations by fluvoxamine inhibiting CYP3A4.4 Nordiazepam is one of the metabolites of diazepam. Studies have also suggested that in the human liver, the metabolism of diazepam to nordiazepam was mediated by CYP3A4, which has been reported as the most abundant P450 form in the liver.5 The authors suggest that there is a common enzyme for tramadol and benzodiazepine (CYP3A4) which implies a potential for a pharmacokinetic drug interaction. Moreover, as described by other reported studies, this paper illustrates that tramadol overdose, especially when taken in combination with other CNS depressants, such as benzodiazepine, can be fatal, even at low dose. Although excessive CNS depression due to the combination of buprenorphine and benzodiazepine is well known and related to a pharmacokinetic interaction between the drugs, tramadol and benzodiazepine
Sir, Re: Tramadol–benzodiazepines and buprenorphine– benzodiazepines: two potentially fatal cocktails? Our two departments have been confronted in the past few months with four deaths related to tramadol overdose. In three of these four cases, benzodiazepine has been discovered in therapeutic or slightly toxic concentration (bromazepam and nordiazepam). Two cases of tramadol–benzodiazepine association did not suggest suicide. However, accidental death was suspected because of the past medical history, details surrounding the deaths and laboratory results. Tramadol blood level was systematically assessed by High Performance Liquid Chromatography with Diode Array Detection (HPLC/DAD) and measured, respectively, at 0.88, 1.9, 3.0 and 134 mg/L. According to the last Bulletin of the International Association of Forensic Toxicologists, therapeutic blood levels in adults range from 0.1 to 0.8 mg/L, the toxic level is >1 mg/L and the lethal concentration is usually considered to be >2 mg/L. Review of the literature revealed few articles concerning tramadol intoxication, particularly fatal cases and death related to tramadol alone1 (one single report). Drug-combined fatalities including tramadol frequently involved benzodiazepines and in all cases, benzodiazepines levels were in therapeutic range or slightly higher. The high frequency of benzodiazepine in tramadol fatalities therefore does not seem to be a purely random occurrence and this combined toxicity suggests a link between these drugs. Tramadol is a central analgesic used for the treatment of moderate to severe pain. It has a low affinity to opioid receptors and inhibits the reuptake of norepinephrin and serotonin producing a significant contribution to analgesic action by blocking nociceptive impulses at the spinal level.2 The drug side effects include seizures and respiratory depression. As with all other analgesic drugs, the dose of tramadol should be adjusted according to the severity of the pain and the individual sensitivity of the patient. Unless otherwise prescribed by the physician, the patient routinely receives 50–100 mg tramadol (1.5 mg/kg/day based on a 60-kg person) 3–4 times daily. Total daily dose usually does not exceed 400 mg. Following a 100-mg oral dose, a peak concentration of approximately 0.3 mg/L has been detected 2 h post-dose.2 After a single bolus 125
126 Journal of Clinical Forensic Medicine interactions have never been previously reported in the literature. Therefore, we hypothesize that buprenorphine and tramadol could present similarities, which may explain their potential interactions with benzodiazepines. In fact, it is possible to affirm that both have a l-opioid receptors affinity, are modulated by naloxone and undergo extensive oxidative metabolism by P450 cytochrome and inhibit the CYP3A. It is therefore possible to suggest that tramadol could interact pharmacokinetically with benzodiazepine in a similar manner as buprenorphine. Furthermore, this interaction could produce an addictive or synergic effect of tramadol and benzodiazepine on the CNS. This hypothesis would explain that death could occur even at low blood concentrations and even with non-lethal dose. To our knowledge, an interaction between tramadol and benzodiazepines has not been previously reported. Both drugs are already in widespread clinical use and are prescribed by general practitioners as well as in several other specialties. This pharmacokinetic drug interaction warrants further clinical investigation. Consequently, we suggest that physicians should be more aware when prescribing tramadol and benzodiazepines concomitantly. REFERENCES
2. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic potential in acute and chronic pain states. Drugs 1993; 46: 313–340. 3. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001; 29(8): 1146–1155. 4. Ono S, Hatanaka T, Miyazawa S, Tsutsui M, Aoyama T, Gonzalez FJ, Satoh T. Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily. Xenobiotica 1996; 26(11): 1155–1166. 5. Sproule BA, Naranjo CA, Brenmer KE, Hassan PC. Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin Pharmacokinet 1997; 33(6): 454–471.
Franck Clarot Bernard Proust E. Vaz Department of Forensic Medicine Rouen University Hospital Rouen 76031, France E-mail address: [email protected] Jean Pierre Goulle Pharmakinetic and Toxicology Laboratory Jacques Monod Hospital 76083 Le Havre, France
1. Musshoff F, Madea B. Fatality due to ingestion of tramadol alone. Forensic Sci Int 2001; 116: 197–199.
Ó 2003 Elsevier Science Ltd and APS. All rights reserved. doi:10.1016/S1353-1131(03)00039-7
Sir,
behaviour and then only in the highest dose level of the drug. However, FIT of the volunteers resulted in subjects being declared ‘‘unfit’’ on 11 occasions out of 56 (8 subjects). Therefore, using a simulated driving test, it was not possible to show any major impairment of driving ability and yet the FIT procedure would have failed 8 out of the 14 drivers on at least one occasion. The reason for this is highlighted in a recent study of marijuana and alcohol, separately and combined.3 The investigators concluded that cannabis impaired balance without detrimentally affecting a simulated driving task but that the impaired balance may trigger a false positive on a FIT. In the UK ‘‘impairment’’ to drive is not defined in law. The use of FIT and whether or not a subject ‘‘passes’’ or ‘‘fails’’ the tests is being used by the police as evidence of impairment. However, we have no evidence of how the performance on the various tests relates to driving ability or on how the performance of
Re: Drugs, driving and sobriety tests In their article ‘‘Drugs, driving and sobriety tests – review of recent developments’’ Stark et al.1 suggest that field impairment testing (FIT) is a suitable method for the detection of impaired driving due to drugs. The authors cite evidence that FIT can reliably identify drug use and can even identify the class of drug use in 90% of cases. However, they present no evidence that there is any correlation between a persons performance on any aspect of the battery of tests used in FIT and that persons ability to drive. The problem is illustrated by the Transport Research Laboratory study2 on the effects of cannabis on driving. In this study the investigators were only able to show that cannabis had a small detrimental impact on a single aspect of simulated driving
CORRESPONDENCE
infusion of 100-mg tramadol, concentrations in plasma can be immediately detected. Elimination is slow and characterized by an elimination half-life of 5–6 h. Tramadol is mainly metabolized into two active desmethyl derivatives (O-desmethyl-tramadol and N-desmethyl-tramadol) and to several inactive compounds. A recent study demonstrated that hepatic CYP2D6 appeared to be primarily responsible for O-desmethyl-tramadol formation, whereas N-desmethyl-tramadol formation was catalyzed by CYP2B6 and CYP3A4.3 Moreover, tramadol metabolism in human liver microsomes was markedly inhibited by the CYP2D6 inhibitor quinidine and the CYP3A4 inhibitor troleandomycin, respectively. Benzodiazepines constitute a class of versatile and widely prescribed central nervous system (CNS)-depressants. Benzodiazepines are prescribed as anxiolytics, sedative hypnotics, anticonvulsants and muscle relaxants. Because of their clinical popularity, ascribed to the wide safety margin of their therapeutic index, their minimal serious adverse side-effects, these drugs are very frequently encountered in the clinical setting and forensic toxicology. Bromazepam is a benzodiazepine used as an anti-anxiety agent administrated in single oral doses of 3–12 mg. It is metabolized primarily by 3-hydroxylation and cleavage of the seven-membered ring, followed by glucuronide conjugation of the hydroxylated metabolites. The CYP3A role in the bromazepam metabolism has been demonstrated by certain authors who have reported an increase of the bromazepam plasma concentrations by fluvoxamine inhibiting CYP3A4.4 Nordiazepam is one of the metabolites of diazepam. Studies have also suggested that in the human liver, the metabolism of diazepam to nordiazepam was mediated by CYP3A4, which has been reported as the most abundant P450 form in the liver.5 The authors suggest that there is a common enzyme for tramadol and benzodiazepine (CYP3A4) which implies a potential for a pharmacokinetic drug interaction. Moreover, as described by other reported studies, this paper illustrates that tramadol overdose, especially when taken in combination with other CNS depressants, such as benzodiazepine, can be fatal, even at low dose. Although excessive CNS depression due to the combination of buprenorphine and benzodiazepine is well known and related to a pharmacokinetic interaction between the drugs, tramadol and benzodiazepine
Sir, Re: Tramadol–benzodiazepines and buprenorphine– benzodiazepines: two potentially fatal cocktails? Our two departments have been confronted in the past few months with four deaths related to tramadol overdose. In three of these four cases, benzodiazepine has been discovered in therapeutic or slightly toxic concentration (bromazepam and nordiazepam). Two cases of tramadol–benzodiazepine association did not suggest suicide. However, accidental death was suspected because of the past medical history, details surrounding the deaths and laboratory results. Tramadol blood level was systematically assessed by High Performance Liquid Chromatography with Diode Array Detection (HPLC/DAD) and measured, respectively, at 0.88, 1.9, 3.0 and 134 mg/L. According to the last Bulletin of the International Association of Forensic Toxicologists, therapeutic blood levels in adults range from 0.1 to 0.8 mg/L, the toxic level is >1 mg/L and the lethal concentration is usually considered to be >2 mg/L. Review of the literature revealed few articles concerning tramadol intoxication, particularly fatal cases and death related to tramadol alone1 (one single report). Drug-combined fatalities including tramadol frequently involved benzodiazepines and in all cases, benzodiazepines levels were in therapeutic range or slightly higher. The high frequency of benzodiazepine in tramadol fatalities therefore does not seem to be a purely random occurrence and this combined toxicity suggests a link between these drugs. Tramadol is a central analgesic used for the treatment of moderate to severe pain. It has a low affinity to opioid receptors and inhibits the reuptake of norepinephrin and serotonin producing a significant contribution to analgesic action by blocking nociceptive impulses at the spinal level.2 The drug side effects include seizures and respiratory depression. As with all other analgesic drugs, the dose of tramadol should be adjusted according to the severity of the pain and the individual sensitivity of the patient. Unless otherwise prescribed by the physician, the patient routinely receives 50–100 mg tramadol (1.5 mg/kg/day based on a 60-kg person) 3–4 times daily. Total daily dose usually does not exceed 400 mg. Following a 100-mg oral dose, a peak concentration of approximately 0.3 mg/L has been detected 2 h post-dose.2 After a single bolus 125
126 Journal of Clinical Forensic Medicine interactions have never been previously reported in the literature. Therefore, we hypothesize that buprenorphine and tramadol could present similarities, which may explain their potential interactions with benzodiazepines. In fact, it is possible to affirm that both have a l-opioid receptors affinity, are modulated by naloxone and undergo extensive oxidative metabolism by P450 cytochrome and inhibit the CYP3A. It is therefore possible to suggest that tramadol could interact pharmacokinetically with benzodiazepine in a similar manner as buprenorphine. Furthermore, this interaction could produce an addictive or synergic effect of tramadol and benzodiazepine on the CNS. This hypothesis would explain that death could occur even at low blood concentrations and even with non-lethal dose. To our knowledge, an interaction between tramadol and benzodiazepines has not been previously reported. Both drugs are already in widespread clinical use and are prescribed by general practitioners as well as in several other specialties. This pharmacokinetic drug interaction warrants further clinical investigation. Consequently, we suggest that physicians should be more aware when prescribing tramadol and benzodiazepines concomitantly. REFERENCES
2. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic potential in acute and chronic pain states. Drugs 1993; 46: 313–340. 3. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG. Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 2001; 29(8): 1146–1155. 4. Ono S, Hatanaka T, Miyazawa S, Tsutsui M, Aoyama T, Gonzalez FJ, Satoh T. Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily. Xenobiotica 1996; 26(11): 1155–1166. 5. Sproule BA, Naranjo CA, Brenmer KE, Hassan PC. Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin Pharmacokinet 1997; 33(6): 454–471.
Franck Clarot Bernard Proust E. Vaz Department of Forensic Medicine Rouen University Hospital Rouen 76031, France E-mail address: [email protected] Jean Pierre Goulle Pharmakinetic and Toxicology Laboratory Jacques Monod Hospital 76083 Le Havre, France
1. Musshoff F, Madea B. Fatality due to ingestion of tramadol alone. Forensic Sci Int 2001; 116: 197–199.
Ó 2003 Elsevier Science Ltd and APS. All rights reserved. doi:10.1016/S1353-1131(03)00039-7
Sir,
behaviour and then only in the highest dose level of the drug. However, FIT of the volunteers resulted in subjects being declared ‘‘unfit’’ on 11 occasions out of 56 (8 subjects). Therefore, using a simulated driving test, it was not possible to show any major impairment of driving ability and yet the FIT procedure would have failed 8 out of the 14 drivers on at least one occasion. The reason for this is highlighted in a recent study of marijuana and alcohol, separately and combined.3 The investigators concluded that cannabis impaired balance without detrimentally affecting a simulated driving task but that the impaired balance may trigger a false positive on a FIT. In the UK ‘‘impairment’’ to drive is not defined in law. The use of FIT and whether or not a subject ‘‘passes’’ or ‘‘fails’’ the tests is being used by the police as evidence of impairment. However, we have no evidence of how the performance on the various tests relates to driving ability or on how the performance of
Re: Drugs, driving and sobriety tests In their article ‘‘Drugs, driving and sobriety tests – review of recent developments’’ Stark et al.1 suggest that field impairment testing (FIT) is a suitable method for the detection of impaired driving due to drugs. The authors cite evidence that FIT can reliably identify drug use and can even identify the class of drug use in 90% of cases. However, they present no evidence that there is any correlation between a persons performance on any aspect of the battery of tests used in FIT and that persons ability to drive. The problem is illustrated by the Transport Research Laboratory study2 on the effects of cannabis on driving. In this study the investigators were only able to show that cannabis had a small detrimental impact on a single aspect of simulated driving