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The Influence of Ondansetron on the Analgesic

Effect of Acetaminophen After Laparoscopic
Hysterectomy

Article in Clinical Pharmacology &#38 Therapeutics March 2010

DOI: 10.1038/clpt.2009.281 Source: PubMed

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articles nature publishing group

The Influence of Ondansetron on the Analgesic

Effect of Acetaminophen After Laparoscopic
Hysterectomy
R Jokela1, J Ahonen1, E Seitsonen1, P Marjakangas1 and K Korttila1

The 5-HT3 antagonists tropisetron and granisetron have been shown to block the analgesic effect of acetaminophen
in healthy volunteers. To study the interaction between ondansetron and acetaminophen in women undergoing
laparoscopic hysterectomy, we randomized 134 patients into three groups to receive acetaminophenplacebo (AP),
acetaminophenondansetron (AO), or placeboplacebo (PP). One gram of intravenous acetaminophen or placebo
was administered at the induction of anesthesia and every 6h thereafter for 24h, and 4mg of ondansetron or placebo
was administered at the end of surgery. Pain control was provided by patient-controlled analgesia (PCA)-oxycodone.
Acetaminophen (as compared to placebo) in periodic doses starting at induction of anesthesia reduced the total
dosage of oxycodone required over 024h (P = 0.031), but ondansetron given at the end of the surgery had no impact
on the analgesic effect of acetaminophen (P = 0.723). The Numeric Rating Scale (NRS) scores for pain were similar
whether ondansetron or placebo was administered at the end of the surgery. Therefore, it may be concluded that in
women undergoing laparoscopic hysterectomy, the administration of periodic doses of intravenous acetaminophen
(as compared to placebo) starting at induction of anesthesia reduces the total dose requirement of oxycodone, and
a concomitant dose ofa 5-HT3 antagonist such as ondansetron at the end of the surgery does not block the analgesic
effectof acetaminophen.

Acetaminophen is one of the most commonly used analgesic
antipyretic drugs worldwide. It has also gained increased popu-
larity in the treatment of postsurgical pain because it has little
or no toxic effect on the gastrointestinal tract and is less likely
to interfere with a patients comedication, coagulation, or renal
function as compared with nonsteroidal anti-inflammatory
drugs.1,2 During the first few days after surgery, acetaminophen
or nonsteroidal anti-inflammatory drugs are usually not suf-
ficient to control postoperative pain. They are nevertheless
used to reduce the need for opioids and to improve patient
satisfaction.
Despite the widespread use of acetaminophen and its fre-
quent concomitant administration with other drugs, very few
clinically significant drug interactions involving this drug have
been documented.1 Recently, Pickering et al.3 showed in healthy
volunteers that coadministration of tropisetron or granisetron
with acetaminophen completely blocks the analgesic effect of the
latter. However, given that the plasma concentrations of acetami-
nophen were unchanged when either tropisetron or granisetron
was given concomitantly, the antagonism of analgesia could not
have been caused by a pharmacokinetic interaction. The effect
of these 5-HT3 antagonists, leading to the reversal of acetami-
nophen analgesia, was due to a pharmacodynamic interaction.
This was demonstrated using an electrical3 as well as a mechani-
cal stimulus.4
Laboratory studies on pain have limitations, and the results
must be extrapolated cautiously to clinical practice. We therefore
decided to study the interaction between ondansetron, a 5-HT3
antagonist, and acetaminophen in women undergoing laparo-
scopic hysterectomy. Our primary aim was to evaluate the effect
of ondansetron on the analgesic effect of acetaminophen. Our
secondary aim was to compare the analgesic effect of acetami-
nophen with that of a placebo.
Results
The study was carried out in the operating theater and the gyne-
cology ward of Helsinki University Hospital (Helsinki, Finland).
A total of 134 patients were randomized into the study, 132 of

1Department of Anesthesia and Intensive Care Medicine, Helsinki University Hospital, Helsinki, Finland. Correspondence:R Jokela (ritva.m.jokela@hus.fi)

Received 7 July 2009; accepted 20 November 2009; advance online publication 10 March 2010. doi:10.1038/clpt.2009.281

672 VOLUME 87 NUMBER 6 | June 2010 | www.nature.com/cpt

 articles

whom received the study drug. In the final analysis, data from
120 patients were available relating to the first 24h after surgery.
The flow of patients through the trial, including the reasons for
exclusion, is presented in Figure1.
The patient characteristics did not differ among the three
study groups (Table1). Several patients were taking regular
medications, but the various medications were distributed
evenly in each study group (data not shown). The distribution
of the differences in laparoscopic procedures was similar in the
three groups, as was the duration of anesthesia and surgery.
The amounts of remifentanil and propofol administered were
equal, and the average state entropy (Entropy; General Electrics
Healthcare, Helsinki, Finland) values did not differ between the
groups.
The times to the first rescue analgesic dose were equal in
the three study groups (Table2). The total dose of oxycodone
(024h after surgery) in the acetaminophenplacebo group
(AP) was smaller than in the placeboplacebo group (PP) (P =
0.031, one-way analysis of variance (ANOVA); P = 0.028, post
hoc test using Tukeys adjustment) but did not differ from the
acetaminophenondansetron group (AO) (P = 0.723, a post hoc
test using Tukeys adjustment) (Table2, Figure2). The doses of
oxycodone in the AP group during hours 06, 612, and 1218
were smaller than in the PP group but equal to those in the
AO group (P = 0.040, repeated measures ANOVA; P=0.039
(PP vs.AP), P = 0.794 (AP vs. AO); pairwise comparison using
Sidaks correction) (Table2). The Numeric Rating Scale (NRS)
scores for pain at rest (Figure3), while raising the leg, and
while coughing (data not shown) were similar in the three study
groups during the whole recovery period. Satisfaction with the
anesthesia and pain medication was equal in all three groups.
The incidence of postoperative nausea and vomiting (PONV)
and postoperative vomiting (Table3), as well as the number of
patients needing rescue antiemetics (data not shown), did not
differ in the three study groups. Of the side effects, the incidence
of dizziness, headache, lack of concentration, and pruritus did
not differ between the three groups (Table3).
Discussion
We have shown that, in women undergoing laparoscopic hys-
terectomy, intravenous administration of acetaminophen
(ascompared with placebo) significantly reduced the need
for patient-controlled analgesia with oxycodone during the
first 24h after surgery. Furthermore, unlike in healthy vol-
unteers, a concomitant single dose of a 5-HT3 antagonist did
not block the analgesic effect of acetaminophen. However, we
also found that the administration of acetaminophen did not
reduce the side effects typical for opioids (oxycodone) and that
the patients in the placebo group were equally satisfied with the
pain medication.

220 Assessed for eligibility

86 Patients excluded
14 Not meeting inclusion
criteria
14 Refused to participate
58 For logistic reasons

134 Randomized

45 Allocated to 45 Allocated to 44 Allocated to

placebo + placebo acetaminophen + placebo acetaminophen + ondansetron
45 Received study drugs 1 Operation canceled 1 Received acetaminophen
44 Received study drugs orally before anesthesia
43 Received study drugs

5 Patients withdrawn 4 Patients withdrawn 3 Patients withdrawn

4 Laparoscopies converted 4 Laparoscopies converted 3 Laparoscopies converted
to hysterectomy to hysterectomy to hysterectomy
1 Hysterectomy extended
to lymphadenectomy

40 Completed protocol 40 Completed protocol 40 Completed protocol

40 Included in efficacy 40 Included in efficacy 40 Included in efficacy

analysis analysis analysis

Figure 1 Flow of patients through the trial.

Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 6 | june 2010 673

articles

Table 1Characteristics of the patients and surgical procedures in the three study groups
PP (n = 40) AP (n = 40) AO (n = 40) Significance
Age (years) 49 (8) 48 (9) 49 (7) 0.833
BMI (kg/m2) 24 (4) 25 (3) 25 (3) 0.450
ASA I/II/III 15/24/1 (38/60/3) 16/24/0 (40/60/0) 20/20/0 (50/50/0) 0.510
Risk of PONV according to Apfel et al.14 (%) 65 (13) 68 (13) 65 (15) 0.629
Type of surgery
LH 20 (50) 23 (58) 24 (60)
LH with salpingo-oophorectomy 19 (48) 16 (40) 16 (40) 0.783
LAVH 1 (3) 1 (3) 0
Duration of anesthesia (min) 141 (38) 122 (38) 140 (45) 0.054
Duration of surgery (min) 114 (37) 96 (36) 113 (43) 0.079
Propofol during anesthesia (mg/kg/min) 0.10 (0.02) 0.10 (0.02) 0.11 (0.03) 0.204
Remifentanil during anesthesia (g/kg/min) 0.10 (0.03) 0.11 (0.03) 0.11 (0.03) 0.440
Average SE value during anesthesia 43 (6) 44 (5) 45 (4) 0.344
Values are mean (SD) or n (%). The PP group received placebo at the induction of anesthesia and placebo at the end of surgery, the AP group received acetaminophen 1g i.v. at the
induction of anesthesia and placebo at the end of surgery, and the AO group received acetaminophen 1g i.v. at the induction of anesthesia and ondansetron 4mg i.v. at the end
of surgery. Placebo was repeated after 6, 12, and 18h in group PP. Acetaminophen 1g i.v. was repeated after 6, 12, and 18h in groups AP and AO.
AO, acetaminophenondansetron; AP, acetaminophenplacebo; ASA, American Society of Anesthesiologists; BMI, body mass index; LH, laparoscopic hysterectomy;
LAVH,laparoscopically assisted vaginal hysterectomy; PONV, postoperative nausea and vomiting; PP, placeboplacebo; SE, state entropy.

Table 2Times to the first rescue analgesic, amounts of postoperative rescue analgesics, and satisfaction with pain medication
and anesthesia in the three study groups
Significance Significance
PP (n = 40) AP (n = 40) AO (n = 40) Significance (PPAP) (APAO)
Time to the first dose of 21 (11) 24 (16) 24 (12) 0.514
oxycodone (min)a
Oxycodone dose (mg/kg)
During hours 06 0.24 (0.10) 0.21 (0.08) 0.23 (0.09)
after surgeryb
During hours 612 0.09 (0.06) 0.06 (0.04) 0.07 (0.05) 0.040* 0.039* 0.794
after surgery
During hours 1218 0.10 (0.07) 0.07 (0.05) 0.07 (0.05)
after surgery
Total dose of 0.43 (0.18) 0.34 (0.15) 0.37 (0.16) 0.031* 0.028* 0.723
oxycodone (mg/kg)a
Satisfaction with pain 36/3/1 (90/8/3) 31/6/0 (84/16/0) 29/7/0 (81/19/0) 0.392
medication (excellent/
good/moderate)c
Satisfaction with anesthesia 35/5/0 (88/13/0) 32/4/1 (87/11/3) 29/7/0 (81/19/0) 0.516
(excellent/good/moderate)c
Values are mean (SD), or n (%). For explanations see Table4.
AO, acetaminophenondansetron; AP, acetaminophenplacebo; PP, placeboplacebo.
aOne-way analysis of variance (ANOVA), post hoc test with Tukeys adjustment. bRepeated measures ANOVA, pairwise comparison between the groups using Sidaks correction.
c2-test.

*P < 0.05 is considered to show a significant difference.

The precise mode of action of acetaminophen is still unclear.
Acetaminophen is generally considered a weak inhibitor of the
synthesis of prostaglandins, and its in vivo effects are similar
to those of the selective cyclooxygenase-2 inhibitors. However,
acetaminophen does not suppress the severe inflammation
present in rheumatoid arthritis.5 In addition to its inhibition of
prostaglandin synthesis, there is considerable evidence that the
analgesic effect of acetaminophen acts centrally and is caused by
the activation of descending serotonergic pathways.69 In healthy
volunteers, the analgesic effect of acetaminophen was completely
inhibited by tropisetron and granisetron, two 5-HT3 antagonists
that are devoid of any intrinsic effect on pain thresholds.3 In a
similar laboratory model of pain in humans, acetaminophen was
seen as reinforcing the central descending pain-inhibiting path-
ways. This reinforcement suggests a supraspinal site of action
of acetaminophen as well as a heightened effect of the drug in

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1.00 6
* Study group
Place + placebo

5 Acetominophen + placebo
0.80
Acetominophen + ondansetron
Oxycodone dose mg/kg

Mean NRS pain at rest

0.60

3
0.40

2
0.20

1
0.00

Placebo + Acetaminophen + Acetaminophen + 0

placebo placebo ondansetron
Study group 1 2 4 6 8 18 24
Hours after surgery
Figure 2 Oxycodone consumption (mg/kg) during hours 024 after Error bars: 95% CI
surgery in the placeboplacebo (PP), acetaminophenplacebo (AP), and
acetaminophenondansetron (AO) groups. (*P = 0.031, one-way ANOVA; Figure 3 NRS for pain at rest (mean, 95% CI) during hours 124 after
P=0.028, post hoc test using Tukeys adjustment). ANOVA, analysis of variance. surgery in the placeboplacebo (PP), acetaminophenplacebo (AP),
andacetaminophenondansetron (AO) groups. (No difference; repeated
measures ANOVA.) ANOVA, analysis of variance; CI, confidence interval;
Table 3The incidence of side effects in the three study groups NRS,Numeric Rating Scale.
PP AP AO
n = 40 n = 40 n = 40 Significance pain than in a laboratory model, and 5-HT3 antagonists are
PONV therefore unable to significantly block the analgesic effect of
02h 4 (10) 4 (10) 0 0.117 acetaminophen. Furthermore, studies in animals have suggested
224h 12 (30) 8 (20) 6 (15) 0.253 that the opioid system has an indirect action on the serotonergic
pathways, because supraspinal opioid mechanisms are involved
Vomiting
in the stimulation of descending serotonergic transmission
02h 0 0 0
by noxious stimuli in animals.10 Therefore, the concomitant
224h 4 (10) 2 (5) 0 0.122 administration of opioids and acetaminophen may lessen the
Dizziness inhibitory effect of 5-HT3 antagonists on the analgesic effect of
024h after surgery 23 (58) 21 (53) 27 (68) 0.381 acetaminophen.
Headache Pickering et al.3 have suggested that 5-HT3 serotonin recep-
tors might not be involved in producing the effects seen with
024h after surgery 10 (25) 5 (13) 10 (25) 0.283
acetaminophen because there is evidence that a non-5-HT3
Lack of concentration
receptor plays a role in its antinociceptive effect.11 There are
024h after surgery 30 (75) 34 (85) 28 (70) 0.271 differences between the 5-HT3 antagonists in their abilities to
Pruritus inhibit the antinociceptive effect of serotonin or acetaminophen.
024h after surgery 3 (8) 8 (20) 6 (15) 0.272 Tropisetron was shown to be more potent than granisetron; the
Values are n (%). For explanations see Table4. latter inhibited the antinociceptive effect only when given in
AO, acetaminophenondansetron; AP, acetaminophenplacebo; PONV, postoperative high doses.12,13 Tropisetron showed a high affinity for this non-
nausea and vomiting; PP, placeboplacebo. 5-HT3 receptor, whereas granisetron is required to be admin-
istered in higher doses in order to interact with the receptor.3
pathological conditions in which inhibitory pain control could We decided to use ondansetron because there is considerable
be activated.4 evidence about the efficacy of this 5-HT3 antagonist in the pre-
Unlike in human studies with a laboratory model of pain, a vention and treatment of PONV14 and it has been used at our
5-HT3 antagonist (ondansetron) did not significantly block the hospital for many years. In their study with healthy volunteers,
analgesic effect of acetaminophen in our patients undergoing Pickering et al.3 used 5mg of tropisetron and 3mg of grani-
laparoscopic hysterectomy. One important explanation could setron, which are the typical recommended doses for prevent-
be that laboratory models of pain do not induce tissue injury or ing and treating chemotherapy-induced nausea and vomiting.
subsequent alterations in the organization of the serotonergic However, the recommended doses for preventing PONV are
input in the dorsal horn, including sprouting of serotonergic smaller, i.e., 2mg of tropisetron, 1mg of granisetron, and 4mg
terminals.4 The inhibitory effect of acetaminophen on prosta of ondansetron. These smaller doses, especially with granisetron
glandin synthesis may play a more important role in postsurgical and ondansetron,11 may be less effective in blocking the analgesic

Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 6 | june 2010 675

articles
Table 4 Flowchart of the study protocol
Group Induction of anesthesia End of surgery
PP Placebo (saline 100ml) Placebo (saline 2ml)
AP Acetaminophen 1g Placebo (saline 2ml)
AO Acetaminophen 1g Ondansetron 4mg
AO, acetaminophenondansetron; AP, acetaminophenplacebo; PP, placeboplacebo.
effect of acetaminophen and thereby make this interaction
unimportant in the prevention and treatment of PONV.
We did not determine the plasma concentrations of ondanset-
ron or acetaminophen. Pickering et al.3 showed that, as com-
pared with placebo, neither tropisetron nor granisetron affected
the plasma concentrations of acetaminophen. Ondansetron is
metabolized by cytochrome P450 (CYP) enzymes CYP1A2,
CYP2D6, and the CYP3A family, and to a lesser extent by
CYP1A1; tropisetron is metabolized by CYP2D6 and theCYP3A
family; and granisetron is metabolized solely by the CYP3A
family.15 However, ~90% of acetaminophen is metabolized by
glucuronidation and sulfation to form nontoxic metabolites,
whereas only ~10% is oxidized by CYP1A2, CYP2E1, and
CYP3A4.1 Therefore, it is unlikely that ondansetron has any
impact on the plasma concentrations of acetaminophen.
With the exceptions of dexamethasone and ondansetron,
none of the medications used during anesthesia in this study
is a known inducer or inhibitor of CYP1A2, CYP2D6, or the
CYP3A family,16 nor did any of the women stay on a medica-
tion that would affect the activity of these isozymes. A smaller
dose of dexamethasone (1.5mg/day for 4 days) did not have a
statistically significant effect on the pharmacokinetics of tria-
zolam, a CYP3A4 substrate,17 and a higher dose (16mg/day for
5 days) increased CYP3A4 activity by only ~26%.18 Accordingly,
in a factorial trial of six interventions for the prevention of
PONV, 4mg of dexamethasone and 4mg of ondansetron acted
independently; i.e., the concomitant use of dexamethasone
and ondansetron did not reduce the antiemetic potency of
ondansetron.14
Ondansetron was recently shown to inhibit the CYP2D sub-
family and CYP3A1/2-mediated metabolism of tamoxifen in
rats.19 In humans, oxycodone is eliminated mainly by metabo-
lism and <10% is excreted unchanged in urine. CYP3A-mediated
N-demethylation to noroxycodone accounts for the major part
of its oxidative metabolism. A smaller fraction of oxycodone is
O-demethylated to oxymorphone by CYP2D6.20 Although the
metabolites show variable pharmacokinetic activity, it is the
parent oxycodone that seems to be responsible for the central
effects.21 Quinidine is a potent inhibitor of CYP2D6, and it was
shown to block the production of oxymorphone from oxyco-
done. Although the production of oxymorphone was nearly com-
pletely blocked, the concentrations of oxycodone were essentially
unchanged, as were the central effects of oxycodone.22 In our
study, several patients took regular medications, but there were
only a few patients on each of these medications. Furthermore,
the various medications were distributed evenly among the
676
Time of administration
6h after induction 12h after induction 18h after induction
of anesthesia of anesthesia of anesthesia
Placebo (saline 100ml) Placebo (saline 100ml) Placebo (saline 100ml)
Acetaminophen 1g Acetaminophen 1g Acetaminophen 1g
Acetaminophen 1g Acetaminophen 1g Acetaminophen 1g
study groups. It is therefore unlikely that pharmacokinetic drug
interactions had any impact on our results.16
We decided to administer acetaminophen intravenously
because we wanted to achieve effective and reliable plasma
concentrations of acetaminophen. This trial was not designed
to assess the cost-effectiveness of intravenous acetaminophen.
However, it must be noted that at our hospital the cost of four
doses of 1g of intravenous acetaminophen amounts to $43,
whereas the cost of 50mg of oxycodone and the PCA (CADD
Legacy; SIMS Deltec, St Paul, MN) cassette reservoir plus the
extension set is $38 (in April 2009). Almost all the patients in
our trial required only one cassette reservoir of oxycodone
each. The cost-effectiveness of intravenous acetaminophen in
this patient population should be questioned, because the use
of acetaminophen did not reduce the side effects typically asso-
ciated with opioids, and, furthermore, the patients in the pla-
cebo group were equally satisfied with their pain medication.
Oral administration of acetaminophen is much more economi-
cal than the use of the intravenous preparation. However, the
intestinal absorption of acetaminophen is dependent on gastric
emptying.1 The simultaneous presence of other drugs, as well as
various types of surgery, can alter gastric emptying and change
the pharmacokinetics of acetaminophen, thereby impairing its
analgesic effect.
Pickering et al.3 have shown that, in healthy volunteers, the
coadministration of tropisetron or granisetronat doses rec-
ommended for preventing and treating chemotherapy-induced
nausea and vomitingwith acetaminophen completely blocks
the analgesic effect of acetaminophen. For routine prophylaxis
of PONV, only one (smaller) dose of a 5-HT3 antagonist is used
at the end of the surgery. In this study, we wanted to evaluate the
interaction between a widely used 5-HT3 antagonist, ondanset-
ron14 and acetaminophen in everyday clinical practice.
In conclusion, we have shown that, in women undergo-
ing laparoscopic hysterectomy, intravenous acetaminophen
(ascompared to placebo) significantly reduced the total dose
of PCA oxycodone required during the first 24h after sur-
gery. Unlike in healthy volunteers, a concomitant single dose
of a 5-HT3 antagonist did not significantly block the analgesic
effect of acetaminophen. Further studies are needed to evaluate
whether our results can be generalized as being applicable to the
concomitant use of these medications in other types of surgery.
Methods
After the study design was approved by the ethics committee of Helsinki
University Hospital and the National Agency of Medicines, we obtained
written informed consent from 134 Finnish-speaking women with
VOLUME 87 NUMBER 6 | June 2010 | www.nature.com/cpt

American Society of Anesthesiologists physical status I/II/III and body
mass index <35kg/m2 who were scheduled for laparoscopic hysterec-
tomy with or without salpingooophorectomy. The study period lasted
13 months, starting in December 2007. The exclusion criteria were liver
disease or contraindication to the use of any of the study medications.
The hospital pharmacy performed the randomization using a
computer-generated random number table. Each consenting patient
received a consecutive random number. The study medication was
prepared according to the instructions by a person not involved with
the perioperative or postoperative care of the patient. Patients in the PP
group received 100ml of saline at induction of anesthesia and 2ml of
saline at the end of surgery; the AP group received acetaminophen 1g
(10mg/ml) at induction of anesthesia and 2ml of saline at the end of
surgery; and the AO group received acetaminophen 1g (10mg/ml) at
induction of anesthesia and 4mg of ondansetron at the end of surgery.
Administration of saline 100ml or acetaminophen 1g was repeated at 6,
12, and 18h after induction of anesthesia (Table4).
The study patients were premedicated orally with diazepam 10mg
1h before surgery. In the operating theater standard monitoring was
started, and the study medication (saline 100ml or acetaminophen
1g in identical 100ml bottles masked with aluminum foil and an
opaque plastic bag) was administered in a double-blind fashion as
soon as intravenous (i.v.) access was established. Anesthesia was
induced immediately afterward using a target-controlled infusion
pump (Orchestra Base Primea; Fresenius Vial, Brezins, France) with
a target of 68g/kg for propofol and 3ng/kg for remifentanil. Tra-
cheal intubation was facilitated with rocuronium 0.6mg/kg, and the
patients were mechanically ventilated with a mixture of oxygen and
nitrous oxide (0.5:0.5l) to keep end tidal CO2 at the level of 4.55.0%.
After intubation, a gastric tube was inserted to deflate the stomach;
the tube was aspirated and removed before extubation. The propofol
infusion was adjusted to maintain the level of hypnosis at a fixed level;
state entropy was used for monitoring hypnosis to keep it between 45
and 55. The remifentanil infusion was adjusted to maintain noninva-
sive blood pressure at 15 to +15% of the baseline value 20mmHg.
To prevent PONV, all patients received dexamethasone 5mg at the
induction of anesthesia and droperidol 10g/kg (0.50.75mg) i.v. at
the end of surgery. The study medication (saline 2ml or ondansetron
4mg in a 2ml syringe masked with aluminum foil) was administered
in a double-blind fashion. When the operation was completed, the
remifentanil infusion was discontinued, and a 0.07mg/kg i.v. bolus of
oxycodone was given. During the closure of skin, the propofol infusion
was stopped, and neostigmine 2.5mg with glycopyrrolate 0.5mg i.v.
was applied to reverse neuromuscular blockade. The total amounts
of remifentanil and propofol infused and the average values of state
entropy during the anesthesia were recorded.
In the postanesthesia care unit, patients requesting analgesia or report-
ing pain of NRS 4 received 0.04mg/kg doses of oxycodone i.v. When
the patients were alert, PCA with oxycodone 1mg/ml was initiated
(oxycodone 100mg in combination with droperidol 5mg diluted with
saline) using a 0.04mg/kg bolus of oxycodone and a lock-out time of
810min. The next morning, the PCA was discontinued, and the total
amount of oxycodone consumed was recorded. Before stopping the PCA,
regular oral pain medication was started with ibuprofen 800mg twice a
day. While the patients still had an i.v. line, the rescue antiemetic medica-
tion used was droperidol 0.5mg i.v.
On an 11-point NRS, which the patients had been trained to use before
premedication was administered, postoperative pain in each patient
was assessed in three situations: (i) at rest, (ii) while raising a leg, and
(iii)while coughing. In addition to pain scores (0 = no pain; 10 = most
severe pain imaginable), NRS scores for side effects including PONV,
dizziness, headache, lack of concentration, and itching, as well as the
number of episodes of postoperative vomiting, were recorded at 1, 2, 4,
6, 8, 12, 18, and 24h after surgery.
Power analysis. A power analysis was performed using a power of
90% and an of 0.05. On the basis of data from our earlier study,23 the
Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 6 | june 2010
articles
consumption of oxycodone was assessed to be 0.50mg/kg after periopera-
tive administration of placebo or acetaminophen with ondansetron, and
0.35mg/kg after perioperative administration of acetaminophen alone,
with an SD of 0.20mg/kg. Based on these assumptions, a sample size of
37 patients per group was required. When we estimated the sample size
using NRS scores, we assumed a pain score of 3 after administration of
placebo or acetaminophen with ondansetron and a pain score of 1 after
perioperative administration of acetaminophen. With an SD of 3, the
sample size was calculated to be 35 patients per study group. Using these
two calculations, we randomized 45 patients into each group to allow for
the possibility of dropouts.
Statistical analysis. The patients demographic data, including American
Society of Anesthesiologists physical status classification, smoking hab-
its, and history of PONV or motion sickness, characteristics of the sur-
gery (including different types of surgery), and the incidence of side
effects were analyzed using a 2-test. The demographic data, includ-
ing age and body mass index, and clinical data, including duration of
anesthesia and surgery, doses of remifentanil and propofol, and average
state entropy value during anesthesia, were compared using ANOVA.
A post hoc analysis was performed using Tukeys adjustment. The times
to the first dose of rescue analgesic were evaluated using ANOVA, and
the amounts of postoperative analgesics and the NRS scores for pain
and side effects were compared using repeated measures ANOVA. The
pairwise comparison between the groups was performed using Sidaks
correction. The statistical analysis was performed using the Statistical
Package for Social Sciences, Windows versions 14.0, 16.0, and 17.0
(SPSS, Chicago, IL).
Acknowledgments
We thank Antti Nevanlinna of the IT Department of the University of Helsinki
for statistical advice. We are also grateful to Olli Erkola, Aulikki Korpinen,
Maija Parvio, Minna Kaiponen, and Eija Ruoppa, as well as the entire staff of
the operating theaters and gynecology wards in Womens Hospital, Helsinki
University Hospital, for taking excellent care of our patients.
Conflict of Interest
The authors declared no conflict of interest.
2010 American Society for Clinical Pharmacology and Therapeutics
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