Therapeutic Follow-Up of Postoperative
Patients on Tramadol in the Intensive Care
Unit a Tertiary African Hospital: A Cohort Study
Metogo Mbengono JA1, Owono Etoundi Paul2, Amengle Albert Ludovic2, Nguidjoe EM3, Metogo Ntsama JA4, Tsafack E3, Tochie Noutakdie Joel2* and Ze Minkande J2
1Department of Surgery and Specialties, University of Douala, Africa
2Department of Surgery and Specialties, University of Yaoundé I, Africa
3Department of Pharmacotoxicology and Pharmacokinetics, University of Yaoundé I, Africa
4Department of Gynecology and Obstetrics, University of Yaoundé I, Africa
Submission: July 25, 2019; Published: August 19, 2019
*Corresponding author: Joel Noutakdie T, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Cameroon, Africa
How to cite this article: Metogo M J, Owono E P, Amengle A L, Tochie Noutakdie Joel, et al. Therapeutic Follow-Up of Postoperative Patients on Tramadol
in the Intensive Care Unit a Tertiary African Hospital: A Cohort Study. J Anest & Inten Care Med. 2019; 9(2): 555760. DOI: 10.19080/JAICM.2019.09.555760
Objectives: Tramadol is an analgesic which can be used to relief of moderate to severe postoperative pain. It is a prodrug that requires bioactivation through cytochrome P450 enzymes (CYP450) to obtain O-desmethyltramadol(M1) with is its most potent analgesic metabolite. However, little is known about the pharmacogenetic profile Africans with regards to tramadol metabolism. Hence, we aimed to study the biological efficacy of tramadol in an African population.
Patients and methods: This was a prospective cohort study over a 3-month period carried out at intensive care unit (ICU) of a tertiary hospital in Cameroon. We enrolled all consecutive consenting patients who had a moderate-to-severe pain surgery, who were fully conscious, and had not been administered drugs metabolized by CYP450.We studied their socio-demographic data, the type of surgery they underwent, and the technique of anesthesia used. Immediately after surgery, tramadol was administered at a dose of 2mg/kg slow intravenously every 6 hours. Pain was evaluated using the Visual Analog Scale (VAS) on ICU admission and then at the 20th minute, 3rd hour, 6th hour, 12th hour, and 24th hour respectively, following tramadol administration. Vital signs and side effects were also recorded. Plasma samples were collected at 3rd and 6th hours after tramadol administration to assay tramadol and M1 using HPLC-UV.
Results: We enrolled 30 patients with a mean age of 32 years operated for caesarean section, exploratory laparotomy and cancer surgery, mainly under spinal anesthesia and general anesthesia. Before administration of tramadol, the VAS was about 6/10. The VAS progressively decreased 4/10 at the 3rd hour, 1/10 at the 6th hour. The vital sign that varied the most was the respiratory rate with a reduction of 3 breath cycles per minute as early as the 6th hour. The most common side effects were nausea and vomiting. Samples from 13 patients were analyzed. M1 was found in all patients; of which 4 had a slow metabolism and 3 had a faster metabolism. Overall, there was good correlation between clinical and biological findings.
Conclusion: Overall, there was good correlation between the clinical and biological analgesic efficacy of tramadol.
Postoperative Pain is considered an undesirable and expected effect of surgery; hence, an effective postoperative analgesia regimen is considered indisputable. Tramadol is an effective analgesic for the relief of moderate to severe postoperative pain . It has an original action profile on both weak opioid agonist on μ receptors, and as a reuptake inhibitor of norepinephrine and serotonin . Tramadol is a prodrug that requires bioactivation
to obtain O-desmethyltramadol which has the analgesic effects
of tramadol. This bioactivation is done through the hepatic enzyme (CYP2D6) of the cytochrome P450 family which has genetic polymorphisms. In the Caucasian population, 10% of people do not have CYP2D6 activity. Thus, tramadol will have no analgesic effect on them [3-5]. However, the pharmacokinetic and pharmacodynamic profiling of drugs ensures their rational use, providing a precise description of the dose-concentration- effect-toxicity relationships . In our setting, few studies have
been conducted on the clinical and pharmacological monitoring of
analgesic drugs. Hence, we carried out this study on the therapeutic
follow-up of tramadol in patients admitted in the postoperative
period, in the intensive care unit (ICU) of the Yaoundé Gynecoobstetrics
and Pediatric Hospital (HGOPY).
This was a prospective cohort study conducted over a 3-month
period in the ICU of HGOPY, as well as in two laboratories. Sampling
was consecutive and non-exhaustive. We included patients who
underwent surgeries of moderate to severe pain, without altered
consciousness, with no notion prior administration of drugs
metabolised by CYP450 enzymes and with no hepatic or renal
Sociodemographic data, the type of surgery and the technique
of anesthesia were studied. Tramadol was administered over
15 minutes at a dose of 2mg/kg intravenously diluted in 100ml
of infusion every 6h. Pain assessment with the Visual Analogue
Scale. (VAS) was done at admission into the ICU and then at
the 20thmin, 3rdh, 6thh, 12thh& 24thh respectively, following
tramadol administration. Clinical parameters and side effects
were recorded. We collected 3-5ml of blood sample in EDTA tubes
at the 3rd & 6th hour after administration of tramadol.
In 500μg of plasma, we added a drop of 0.1mol/L NaOH. The
mixture was vortexed for one minute. We added 1ml of extracted
solvent which was made of ethylacetate + cyclohexane in the ratio
of 1:4. The mixture was vortexed a second time for one minute
and then centrifuged at 400rpm for 15 minutes. The organic
phase obtained was then transferred to vials to be introduced into
We used an HPLC-UV chain with RP C18 tubes with 5μm
particles, 250x4.6mm PHENOMENEX® brand. The eluent or
mobile phase was acetonitrile/phosphate buffer (KH2PO4 0.01M
solution) in proportions: 30/70 which was then mixed with
triethylamine at a concentration of 0.1% TEA. The pH of this
mobile phase was adjusted to 3. The injection volume was 10μl
with a flow rate of 1ml/min and a separation time of 7 minutes.
The detection was set at 218nm UV at room temperature.
The data obtained was analyzed on the software SPSS version
20 and EPI INFO version 3.5.4. The statistical study was descriptive
with the study of proportions and means.
We recruited 30 patients with a mean age of 32.8±10.26 years.
ASA 1 patients (60%) were the most represented. Caesarean
section was the most performed surgical procedure (80%),
followed by laparotomies (ectopic pregnancy and pelviperitonitis)
and gynecological oncological surgeries. Spinal anesthesia (RA)
was the most commonly performed anesthesia technique (54%)
followed by general anesthesia with orotracheal intubation (AG +
IOT) in 43% of patients.
When evaluating the pain intensity of patients prior to
tramadol administration, the mean VAS was 5,933±1,257. The
intensity of the pain was higher in patients who underwent
exploratory laparotomy (6.3/10) (Figure 1). When the vital signs
were taken, the respiratory rate was the only slightly elevated
parameter varying up to 25 cycles/min (Table 1).
After administration of tramadol, a reduction in pain intensity
was observed as early as the 20th minute. This reduction was 2
points or around 3/10 for all patients at the 3rdh compared to the intensity of the pain before the administration of tramadol. From
the 24thh, the VAS was about 1/10 (Figure 2).
During the evaluation of the parameters, a decrease in
systolic blood pressure of 20mmHg was observed at the 3rdh
& 6thh respectively for patients who underwent an exploratory
laparotomy and a carcinological surgery. Concomitantly, a
regression of 10mmHg was recorded for diastolic blood pressure.
We observed a regression of 2 to 3 respiratory cycles per minute
for all patients and 10 beats per minute reduction in pulse rate.
The main adverse effects of tramadol concerned mainly
the gastrointestinal tract (30% of nausea cases and 13.30% of
vomiting cases), followed by cholinergic effects (dryness of mouth
in 16.7% of cases) and neurological effects especially vertigo
When we performed the plasma determination of 13 patients.
We found the active metabolite of tramadol: O-desmethyltramadol
(M1). Overall, there was good agreement between clinical and
laboratory data (Figure 3). However:
Four patients had a slower metabolism (Table 2)
Three patients had a faster metabolism (Table 3)
The average age of our patients was 32.8±10.26 years, which
corresponds to the generally young age of the Cameroonian and
African population. Caesarean sections were most performed
surgical procedures explained by the fact that the study setting
is a hospital specialized only in the management of mother and
Paracetamol was the main analgesic used in combination with
tramadol. In effect, the pain after caesarean section, exploratory
laparotomy or cancer surgery is classified as strong in the first
48 hours according to the WHO . As such, it seems logical to
propose tramadol as part of a balanced intravenous analgesic
regimen . In addition, with respect to the combination of
tramadol + paracetamol, a meta-analysis of randomized clinical
trials conducted on postoperative dental, orthopedic and
gynecological pain showed the analgesic superiority of tramadolparacetamol
compared to the either analgesic effect tramadol or
The mean VAS before tramadol administration was
5.933±1.257/10, explained by the fact that preemptive analgesia
was started during the intraoperative period. A significant
reduction in pain intensity was observed for all patients at the
3rdh compared to the intensity of the pain before administration
of tramadol. This reduction is more than 50% at the 24thh
compared to the baseline VAS before administration of tramadol.
This threshold significance was proposed in 2003. These data
seem to agree with the pharmacokinetic data with respect to the
time of action, the half-life and the plasma peak of tramadol .
With regards to the side effects of tramadol, we mainly
found the gastrointestinal (nausea, vomiting), cholinergic
effects (dryness of mouth) and vertigo. This finding concurs
with that of the literature . Of the 30 patients enrolled, 13
had postoperative biological monitoring of the concentration of
tramadol and O-desmethyltramadol or M1 at the 3rd & 6thh after
administration of tramadol. Overall, there was good agreement
between clinical and biological parameters. An African study in
Ethiopia  was previously performed without the biological
assay of tramadol. Our results are in line with this study as far as
patient satisfaction is concerned.
We wanted to go further than this by testing the hypothesis
that patient satisfaction using VAS may be consistent to some
extent with the biology of tramadol and O-desmethyltramadol. We
found that those who metabolize slowly have better satisfaction
with the analgesic effect. On the other hand, in those who seemed
to metabolize rapidly, the VAS decreased but remained generally
at levels of moderate pain values. This is in good correspondence
with the literature on the subject .
We will have been able to have more samples tested, to
measure more specific pharmacokinetic parameters such as
the area under the curve, the plasma clearance and the half-life,
for example . Nevertheless, our results allow us to know
the metabolism profiles (CYP 2D6) of our patients indirectly. In
addition, tramadol + paracetamol combination could compensate
for the effect of tramadol on VAS values, if tramadol shows low
plasma concentrations at the same time.
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