Forensic Science International 175 (2008) 7982

www.elsevier.com/locate/forsciint

Case report

Fatal intoxication due to tramadol alone

Case report and review of the literature
Koen De Decker *, Jan Cordonnier b, Werner Jacobs c, Vera Coucke d,
Paul Schepens d, Philippe G. Jorens a
a

Department of Critical Care Medicine, University Hospital of Antwerp, Edegem, Belgium

b
Chemiphar Toxicology Laboratory, Bruges, Belgium
c
Department of Forensic Pathology, Antwerp University Hospital, Edegem, Belgium
d
Toxicological Centre, Antwerp University, Wilrijk, Belgium
Received 28 August 2006; received in revised form 9 July 2007; accepted 20 July 2007
Available online 17 September 2007

Abstract
Poisoning may also lead to both coma and multiple organ failure, also in youngsters without a known major medical history. As not all toxic
agents are routinely screened when a poisoning is suspected, it is useful to consider less frequently encountered poisons in certain cases.
We describe the occurrence of asystole and multiple organ failure which occurred in a young man after a suspected tramadol overdose. The
tramadol concentration on admission in the ICU was indeed 8 mg/ml (mg/l), far above the therapeutic range. Subsequently, the patient developed
severe acute liver failure, finally leading to death. Post-mortem toxicology did not reveal any other poison responsible for this unfavourable course
as only very high serum and tissue tramadol and desmethyltramadol concentrations were found.
Only a few fatal poisonings attributable to tramadol alone, as observed in our case, have been reported. An overview of these cases is presented.
# 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Tramadol; Liver failure; Poisoning; Intoxication; Overdose; Post-mortem

1. Introduction
The opioid analgesic tramadol was initially introduced in
Germany in 1977. Because of its limited abuse potential it has
been prescribed extensively, both for patients in the postoperative period and also in pain clinics for more chronic pain
syndromes [1]. Tramadol has a dual mechanism of action: a
weak agonistic effect on the m-opioid receptor as well as an
inhibition of neurotransmitter reuptake (mainly serotonin and
norepinephrine). Its analgesic potency is similar to codeine and
meperidine [1,2].
Frequently reported side effects include nausea, vomiting,
drowsiness, vertigo, constipation, headache and somnolence. In
case of poisoning however, more rare and severe complications
may occur including seizures [1]. Symptoms generally resolve

* Corresponding author at: Department of Intensive Care Medicine, Antwerp

University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
Tel.: +32 3 821 48 55; fax: +32 3 828 48 82.
E-mail address: koen.de.decker@uza.be (K. De Decker).
0379-0738/$ see front matter # 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.forsciint.2007.07.010

within 24 h and even accidental ingestions in children are well

tolerated.
We report on the case of a young patient with known
tramadol use, who was found unconscious and presented with
asystole. After a successful resuscitation, signs of multiple
organ failure and especially massive hepatic failure occurred,
finally leading to death. Blood and urine analysis revealed a
tramadol intoxication, which was confirmed at the medicolegal autopsy. We review the literature on fatal intoxications
only attributable to a tramadol overdose, which turned out to be
a rare entity.
2. Case report
A 28-year old Caucasian man, with a medical history of
Munchausens syndrome and stress incontinency, was admitted
in the evening hours at the urology ward for a series of
diagnostic examinations. He consulted a psychologist on a
regular basis and was treated with tramadol for several months
because of rather vague abdominal complaints. He was not
taking any other drugs or herbal medicines. According to the

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K. De Decker et al. / Forensic Science International 175 (2008) 7982

other patients on the ward, he had ingested a benzodiazepine

before going to sleep and snored all night. In the morning, one
of his fellow patients witnessed apnea and alerted the nurses
and the medical team. On arrival, asystole was observed and
advanced life support was started. An arterial blood gas taken
during CPR showed extreme acidosis and hypoglycaemia
(5 mg/dl, normal value 75110 mg/dl), for which hypertonic
glucose and sodium bicarbonate were administered. Cardiac
output was restored within 10 min and the patient was admitted
to the intensive care ward. On arrival the Glasgow Coma Scale
score was 3/15, no pupillary reactions neither reflexes could be
found. An ECG showed sinus tachycardia and a transthoracic
echocardiography showed no abnormalities. A chest X-ray
revealed a consolidation of the left lower lobe necessitating a
bronchoscopy.
Blood-, urine- and gastric lavage samples were taken for
clinical toxicological screening. An arterial blood gas
reconfirmed an extreme metabolic acidosis and the lab
results suggested acute hepatic as well as acute renal failure.
Routine clinical toxicological screening of both serum and
urine revealed neither the presence of potentially toxic drugs
nor high or toxic levels of other drugs. An extensive GCMS
(gas chromatographymass spectrometry) analysis of the
serum on admission at the ICU showed only the presence of
tramadol. In view of a proposed availability of arsenic by the
family, arsenic poisoning was considered. This was excluded
by the absence of toxic arsenic serum and urinary levels. A
pulmonary artery catheter was inserted to guide fluid and
inotropic therapy. The patient was ventilated in a pressurecontrolled mode.
Because of progressive hepatic failure, with ammonia levels
as high as 175 IU/l, a liver biopsy was performed the next day,
showing both steatosis and centrolobular necrosis.
Therapy was mainly supportive including the initiation of
antibiotics, pulmonary artery catheter guided fluid management, inotropics and vasopressor therapy, enemas with
lactulose because of high ammonia levels as well as correction
of coagulation abnormalities. Nevertheless, we were unable to
prevent acute renal failure, progressing to multiple organ failure
of which the patient died two days later.
3. Methods and materials
Systematic toxicological analysis was performed on the post-mortem
samples to investigate for illegal and prescribed drugs, alcohol, volatile substances and other poisons. Screening for the presence of drugs of abuse in urine
and serum was carried out using fluorescence polarization immunoassay (FPIA)
on an Abbott ADx analyzer. Radioimmunoassay (RIA) was used to screen for
LSD in urine and benzodiazepines in blood. Presumptive colour tests (according
to the manufacturers specifications) were used to detect salicylates, paracetamol, phenothiazines and imipramines. UV spectrophotometry was used for
quantification of carbon monoxide and cyanide in blood. Thin layer chromatography (TLC) was used to screen for the presence of acidic (blood), neutral
(blood) and basic drugs (urine and stomach content). Screening for the presence
of basic drugs in urine and stomach content was performed by GCMS and in
blood by HPLC-DAD. The presence of alcohol in blood and urine and of other
volatile substances in blood was performed by gas chromatography and static
headspace gas chromatography with flame ionization detector (HS-GC/FID),
respectively. Screening for the presence of basic drugs in urine and stomach
content was performed by GCMS and in blood by HPLC-DAD.

4. Results
An autopsy revealed pulmonary edema, diffuse hemorrhagic
mucosa of the gastrointestinal tract and a shock liver.
Microscopy findings were all characteristic of multiple organ
failure: alveolar hemorrhages in the lung, pericentral ischemia
of the liver and acute tubular necrosis of the kidneys.
Toxicological analysis of serum and gastric lavage specimens,
obtained on admission at the ICU revealed a tramadol
concentration of 8 and 400 mg/l, respectively. Post-mortem
analysis by GCMS (liver and kidney) and HPLC-DAD (blood)
analysis [3,4] detected both tramadol and metabolite
N-desmethyltramadol in the blood, liver and kidney; tramadol
concentrations were 5.2 mg/l, 6.5 mg/g tissue 4.5 mg/g tissue
respectively; N-desmethyltramadol was not quantitated.

5. Discussion
The central acting analgesic tramadol has been used
increasingly the last two decades because of its low abuse
potential and because less respiratory depression is observed in
comparison with the classical opioid analgesics, such as
morphine. It provides relief from moderate to severe pain at oral
doses of 50100 mg QID. Thirty per cent of the drug is excreted
through the kidneys in an unchanged manner, while the
remaining is metabolised by N- and O-demethylation, followed
by conjugation with glucuronic acid and sulphate [5]. The peak
serum level is reached after 23 h. The active metabolite,
O-monodesmethyltramadol, has a longer half-life and is
apparently two to six times more potent than the parent drug
[5,6]. This metabolite is also believed to cause some of the toxic
side effects of the drug [6].
Tramadol levels can be determined by both gas chromatographymass spectrometry and HPLC-DAD [24,6]. Therapeutic blood levels in adults are believed to range from 100 to
300 ng/ml [5,7,8]. In lethal cases, additional tissue sampling
may add proof of tramadol intoxication.
Initially the manufacturer claimed a low incidence of typical
opioid side effects. Indeed, in view of the (+)-enantiomers low
affinity for the m-opioid receptor, tramadol was also originally
thought to have a low potential for abuse, tolerance and
dependence [6,9].
Nevertheless, recent reports describe the potential for abuse
and the occurrence of seizures and anaphylactoid reactions.
Currently tramadol is not recommended for patients with past
or present histories of addiction to or dependency on opioids, in
patients with allergies to tramadol or other opioids, and in
patients taking concomitant drugs that may reduce the seizure
threshold (such as tricyclic antidepressants and selective
serotonin reuptake inhibitors). Another possible side effect,
that has received little attention, is hypoglycaemia. This was
particularly demonstrated in rats: the activation of opioid
m-receptors by tramadol, increased the utilization of glucose
and/or decreases the hepatic gluconeogenesis causing low
plasma glucose levels in diabetic rats [10]. After repeated oral
administration in humans [11], the main sings of intoxication

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81

Table 1
Summary of eight case reports of severe tramadol overdose, attributable to tramadol ingestion alone
References

Gender/age

Tramadol levels (in mg/l for fluids, mg/g for tissue)

Presenting symptoms

HB

PB

Clarkson et al. [3]

Male, 43
Male, 28
Male, 43

Autoingestion, found dead

Found dead
Cardiac arrest while working

De Decker et al.

Male, 28

Coma, hypoglycemia, metabolic

acidosis, liver and renal failure

5.2

Loughrey et al. [15]

Male, 67

Dyspnoea, cyanotic and hypotensive,

cardiorespirator arrest, short after ER admission

3.7

UR

Outcome

1.6
7.9
13.9

Death
Death
Death
6.5

4.5

Death
Death

Lusthof et al. [13]

Male, 49

Previous suicide attempts, autoingestion, found dead

Moore et al. [14]

Female, 23

History of depression autoingestion, found dead

19.7

15.1

13
110.2

68.9

Death

Musshoff et al. [8]

Male, 26

Found dead

13.1

9.6

46

6.2

46.1

37.5

Death

3.1

Death

NT: no therapy; HB: heart blood; PB: peripheral blood; B: bile; K: kidney; L: liver; UR: urine. The normal therapeutic range is 0.10.3 mg/l [13].

include central nervous symptoms, from vomiting to convulsions or eventually anoxic brain damage [12].
Fatal reports after tramadol poisoning and overdose have
been seldomly reported. Moreover, the number of patients in
whom death could be attributed to tramadol poisoning alone is
limited to 8, including this case, as summarized in Table 1
[3,8,1315]. In only one other case than ours, the clinical course
before death was known [15]. As blood concentrations in
tramadol-associated deaths overlap with subjects arrested for
tramadol-associated impaired driving [3], in moderate excess
the drug might not be a principle cause of death in suicidal or
accidental cases.
Indeed, virtually all reported fatal tramadol poisonings have
been reported in conjunction with the detection of other drugs,
such as propanolol, trazodone, alcohol and especially central
nervous system depressants, particularly benzodiazepines,
barbiturates and drugs with serotonin effects [2,4,6,1618].
Clarkson et al. reviewed a very large series of 66 deaths in
which tramadol was detected in the decedents blood, in order
to assess the role tramadol was determined to have played [3].
Tramadol was consistently found together with other analgesics, muscle relaxants or CNS depressant drugs, apart from the
cases summarized in Table 1.
Our patient died as a consequence of multiple organ failure,
including hepatic insufficiency as revealed by hepatic failure
during the ICU observation and massive hepatic necrosis at
autopsy [19]. Liver failure following accidental tramadol
poisoning has been reported once [5]. Management in our
patient was mainly supportive and no literature is available on
the usefulness of molecular absorbent recirculating systems or
liver transplantation in tramadol-associated liver failure.
Although many of the clinical as well as pathological features
in this patient might have been the consequence of multiple
organ failure as observed after resuscitation, we believe this
case report provides a full description of one of the scanty cases
of a lethal poisoning attributable to an overdose of tramadol
alone.
In conclusion, after its introduction in the 70s, tramadol
gained great interest because of its low abuse potential, but in

rare cases overingestion may lead to fatal complications.

Therefore, early diagnosis is very important. As no data on
urgent liver transplantation are available, the management of
this intoxication associated liver failure is limited to supportive
interventions.
Acknowledgement
We thank Mr. Thys K., investigating magistrate in Antwerp,
for giving the permission to reproduce data from the legal file.
References
[1] K.A. Marquardt, J.A. Alsop, T.E. Alberton, Tramadol exposures reported
to statewide poison control system, Ann. Pharmacother. 39 (2005) 1039
1044.
[2] M.G. Ripple, J.P. Pestaner, B.S. Levine, J.E. Smialek, Lethal combination
of tramadol and multiple drugs affecting serotonin, Am. J. Forensic Med.
Pathol. 21 (2000) 370374.
[3] J.E. Clarkson, J.M. Lacy, et al., Tramadol (UltramR) concentrations in
death investigation and impaired driving cases and their significance, J.
Forensic Sci. 49 (2004) 15.
[4] F. Clarot, J.P. Goulle, E. Vaz, B. Proust, Fatal overdoses of tramadol: is
benzodiazepine a risk factor of lethality? Forensic Sci. Int. 134 (2003) 57
61.
[5] H.B. Gutstein, H. Akil, Opioid analgesics, in: J.G. Hardman, L.E. Linobird
(Eds.), Goodman & Gilmans The Pharmacological Basis of Therapeutics,
McGraw-Hill, New York, 2001, pp. 569620.
[6] K.E. Goeringer, B.K. Logan, G.D. Christian, Identification of tramadol
and its metabolites in blood from drug-related deaths and drug-impaired
drivers, J. Anal. Toxicol. 21 (1997) 529537.
[7] F. Riedel, H.B. von Stockhausen, Severe cerebral depression after intoxication with tramadol in a 6-month old infant, Eur. J. Clin. Pharmacol. 26
(1984) 632642.
[8] F. Musshoff, B. Madea, Fatality due to ingestion of tramadol alone,
Forensic Sci. Int. 116 (2001) 197199.
[9] C.R. Lee, D. McTavish, E.M. Sorkin, Tramadol. A preliminary review of
its pharmacodynamic and pharmacokinetic properties, and therapeutic
potential in acute and chronic pain states, Drugs 46 (1993) 313340.
[10] J.T. Cheng, I.M. Liu, T.C. Chi, T.F. Tzeng, F.H. Lu, C.J. Chang, Plasmaglucose-lowering effect of tramadol in streptozotocin-induced diabetic
rats, Diabetes 50 (2001) 28152821.
[11] T. Matthiesen, T. Wohrmann, T.P. Coogan, H. Uragg, The experimental
toxicology of tramadol: an overview, Toxicol. Lett. 95 (1998) 6371.

82

K. De Decker et al. / Forensic Science International 175 (2008) 7982

[12] H.A. Spiller, S.E. Gorman, D. Villalobos, B.E. Benson, D.R. Ruskosky,
M.M. Stancavage, D.L. Anderson, Prospective multicenter evaluation of
tramadol exposure, J. Toxicol. Clin. Toxicol. 35 (1997) 361364.
[13] K.J. Lusthof, P.G. Zweipfenning, Suicide by tramadol overdose, J. Anal.
Toxicol. 22 (1998) 260.
[14] K.A. Moore, S.J. Cina, R. Jones, D.M. Selby, B. Levine, M.L. Smith,
Tissue distribution of tramadol and metabolites in an overdose fatality,
Am. J. Forensic Med. Pathol. 20 (2000) 98100.
[15] M.B. Loughrey, C.M. Loughrey, S. Johnston, D. ORourke, Fatal hepatic
failure following accidental tramadol overdose, Forensic Sci. Int. 134
(2003) 232233.

[16] N.D. Bynum, J.L. Poklis, M. Gaffney-Kraft, D. Garside, J.D. RoperoMiller, Post-mortem distribution of tramadol, amitriptyline, and their
metabolites in a suicidal overdose, J. Anal. Toxicol. 29 (2005) 401406.
[17] K. Michaud, M. Augsburger, N. Romain, C. Giroud, P. Mangin, Fatal
overdose of tramadol and alprazolam, Forensic Sci. Int. 105 (1999) 185
189.
[18] B. Levine, V. Ramcharitar, J.E. Smialek, Tramadol distribution in four
post-mortem cases, Forensic Sci. Int. 86 (1997) 4348.
[19] J. Henrion, M. Schapira, R. Luwaert, L. Colin, A. Delannoy, F.R. Heller,
Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive
cases, Medicine 82 (2003) 392406.