110 AANA Journal April 2010 Vol. 78, No. 2 www.aana.com/aanajournalonline.

aspx
We report an unusual case of respiratory depression and
prolonged apnea after a single, 50-mg intravenous dose
of tramadol. Shortly after an uneventful surgery and
anesthesia, the patient was administered intravenous
tramadol. Soon after the tramadol injection, the patient
became apneic, did not respond to verbal command,
and started exhibiting oxygen desaturation. He was
quickly administered 100% oxygen and positive pressure
ventilation via a Bain circuit, and it took 45 minutes for
the spontaneous respiration to return to regular.
The respiratory depression could be due to increased
amount of (+)enantiomer in that ampoule of tramadol.
Physiological parameters affecting the metabolism of
either enantiomer of tramadol or perioperative drugs
need to be evaluated, as do physiological changes
affecting the activity or metabolism of (+)enantiomer.
This case report demonstrates that even a small single
dose of tramadol administered intravenously in the
immediate postoperative period after general anesthe-
sia may manifest as sudden and prolonged apnea.
Keywords: Anesthesia, apnea, enantiomer, single
dose, tramadol.
Prolonged Apnea After Small Single Dose of
Intravenous Tramadol
Ravindra Pandey, MD
Lenin B. Elakkumanan, MD, DNB
Rakesh Garg, MD, DNB
Pratyush Gupta, MD
Vanlal Darlong, MD
Jyotsna Punj, MD
T
he reputation of tramadol, as an analgesic
lacking respiratory depression, has con-
tributed to its increased clinical use in intra-
operative and postoperative periods.
1
Tra-
madol has been safely used even in patients
with obstructive sleep apnea without any sedative effect
postoperatively.
2,3
Respiratory depression with tramadol
has been reported in patients with impaired renal func-
tions and CYP2D6 gene duplication.
4,5
Here we report an
unusual case of respiratory depression and prolonged
apnea after a small, single intravenous dose of tramadol.
Case Summary
A 20-year-old, 45-kg man presented to us with chief com-
plaints of bilateral nasal obstruction and nasal bleeding
for the last 2 years. He gave a history of occasional frontal
headache and excessive snoring during sleep for the same
duration. However, features suggestive of obstructive
sleep apnea were absent. The patient reported intake of no
medications. Findings of routine laboratory investiga-
tions, including serum urea nitrogen (25 mg/dL) and
serum creatinine (0.9 mg/dL), were normal. Systemic ex-
amination revealed no abnormality. Local examination re-
vealed a soft palate bulge with a soft-tissue mass filling the
left nasal cavity. Indirect laryngoscopy showed normal
and mobile cords. Biopsy revealed a benign nerve sheath
tumor, for which a left lateral rhinotomy for excision of
the mass was planned, to be performed under general
anesthesia. No sedative premedication was advised.
We used a standard anesthesia technique, with fen-
tanyl (2 mg/kg), propofol (2 g/kg), vecuronium (0.1
mg/kg), and intermittent positive pressure ventilation
(IPPV) with 100% oxygen for orotracheal intubation.
Isoflurane (1 to 1.2 minimum alveolar concentration, or
MAC) in oxygen, nitrous oxide (50:50), along with
boluses of fentanyl (0.5 g/kg each; total administered,
90 g at induction and 40 g during maintenance) and
vecuronium were used for maintenance of anesthesia.
The surgery lasted 3 hours, and intraoperative blood loss
was approximately 800 mL. The last dose of fentanyl was
administered 1 hour before completion of surgery. At the
end of the surgery, the residual neuromuscular blockade
was reversed with 2.5 mg of neostigmine and 0.4 mg of
glycopyrrolate. In view of extensive nasal, palatine, and
pharyngeal dissection and a concern for posterior pha-
ryngeal bleeding, we planned to keep the endotracheal
tube in situ overnight.
After we ensured a full recovery from neuromuscular
blockade and regular breathing, the patient was trans-
ferred to the postanesthesia care unit (PACU) and con-
nected to an oxygen supply (5 to 6 L/min) via a T-piece
system. Postoperatively he was conscious, oriented, and
maintaining vital signs (heart rate, 86/min; blood pres-
sure, 130/70 mm Hg) and normal oxygen saturation
levels as measured by pulse oximetry (SpO
2
, 99%). In the
PACU, 20 minutes later, the patient complained of pain
www.aana.com/aanajournalonline.aspx AANA Journal April 2010 Vol. 78, No. 2 111
(5 on a visual analog scale, or VAS). Thus, tramadol (50
mg) was slowly administered intravenously.
Soon after the tramadol injection, the patient became
apneic, did not respond to verbal command, and started
exhibiting oxygen desaturation (SpO
2
, 89% to 90%). He
was quickly administered 100% oxygen and positive
pressure ventilation via a Bain circuit. It took 45 minutes
for the spontaneous respiration to return to regular. He
was kept under observation overnight and extubated the
next morning after we checked for evidence of no poste-
rior pharyngeal bleeding. He subsequently made an un-
eventful recovery.
Discussion
Tramadol is a centrally acting synthetic 4-phenylpiperi-
dine analogue of codeine, which is an analgesic agent
acting as both a weak opioid agonist and an inhibitor of
monoamine neurotransmitter reuptake for the treatment
of moderate to severe pain. The efficacy of tramadol has
been confirmed in postoperative, neuropathic, and os-
teoarthritic pain. Unlike other opioids, it is well tolerated
and has no clinically relevant effects on cardiovascular pa-
rameters. The marketed product is a racemate mixture
containing 50% of a (+)enantiomer and 50% of a ()enan-
tiomer. The analgesic effect of tramadol is mediated
through 2 distinct but complimentary mechanisms of
action. It acts as an opioid agonist with selectivity for the
-opioid receptor and binds weakly to the - and -opioid
receptor. The (+) and ()enantiomers differentially con-
tribute to the analgesic effect of racemic tramadol, which
is the clinically used form of the drug. The (+)enantiomer
has a greater affinity for the -receptor and is a more ef-
fective inhibitor of serotonin reuptake, whereas the
()enantiomer is a more effective inhibitor of norepineph-
rine reuptake and increases norepinephrine release by au-
toreceptor activation.
6
In a pilot study, Grond et al,
7
using
patient-controlled analgesia with tramadol, concluded
that the (+)enantiomer and racemate of tramadol were
more potent analgesics than ()enantiomer, whereas the
incidence of adverse events was higher in patients receiv-
ing (+)enantiomer than with racemate.
The analgesic and antinociceptive effects of tramadol
are only partially antagonized by the opioid antagonist
naloxone, which suggests that nonopioid mechanisms
are also involved.
8
Plasma concentrations of tramadol, its
enantiomers and O-desmethyltramadol have been found
to show considerable interindividual variations.
6
The polymorphic cytochrome P450 2D6 (CYP2D6)
appears to be a major enzyme involved in the metabolism
of tramadol enantiomers. Tramadol undergoes biotrans-
formation in the liver and is excreted via the kidneys. Of
11 known metabolites, only the O-desmethyltramadol is
pharmacologically active and has a greater affinity at the
-receptor than its parent compound.
6,9
It also has sig-
nificant opiate side effects (100 times more than those of
tramadol isomers by themselves).
10
To our knowledge, no case has been reported where
such a small single dose of tramadol is associated with
prolonged apnea. Our patient did not have any history of
renal dysfunction, as results of kidney function tests were
normal. Although we could not obtain an evaluation for
the CYP2D6 gene, we think that the respiratory depres-
sion could be due to an increased amount of (+)enan-
tiomer in that ampoule of tramadol. Physiological param-
eters affecting the metabolism of either of the enantiomers
of tramadol or perioperative drugs, and physiological
changes affecting the activity or metabolism of (+)enan-
tiomer, need to be evaluated. Through this case report, we
want to emphasize that even a small single dose of tra-
madol administered intravenously in the immediate post-
operative period after general anesthesia may manifest as
sudden and prolonged apnea.
Hence, we recommend that tramadol should be used
only in a monitored environment and that even a small
single intravenous dose may not be safe. Caution should
be exercised in this regard, especially where adequate facil-
ities for postoperative monitoring are not fully developed.
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AUTHORS
Ravindra Pandey, MD, is an assistant professor, Department of Anaesthesi-
ology and Intensive Care, All India Institute of Medical Sciences, Ansari
Nagar, New Delhi, India.
Lenin B. Elakkumanan, MD, DNB, is a senior resident, Department of
Anaesthesiology and Intensive Care, All India Institute of Medical Sciences.
112 AANA Journal April 2010 Vol. 78, No. 2 www.aana.com/aanajournalonline.aspx
Rakesh Garg, MD, DNB, is a senior resident, Department of Anaesthe-
siology and Intensive Care, All India Institute of Medical Sciences. Email:
[email protected].
Pratyush Gupta, MD, is a senior resident, Department of Anaesthesiol-
ogy and Intensive Care, All India Institute of Medical Sciences.
Vanlal Darlong, MD, is an assistant professor, Department of Anaes-
thesiology and Intensive Care, All India Institute of Medical Sciences.
Jyotsna Punj, MD, is an assistant professor, Department of Anaesthesi-
ology and Intensive Care, All India Institute of Medical Sciences.