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Early bioavailability of paracetamol after oral or
intravenous administration
P. HOLMÉR PETTERSSON1, A. ÖWALL1 and J. JAKOBSSON2
1Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital and 2Department of Anesthesia, Sabbatsberg Day
Surgical Center, Stockholm, Sweden
Background: Paracetamol is a peripherally acting analgesic
commonly used in multimodal post-operative pain manage-
ment to reduce the need for more potent analgesics with their
unwanted side-effects. The dose and optimal galenical form for
achieving analgesic concentrations is not well defined. The
primary aim of this pilot project was to study the early bio-
availability for two fixed doses of orally administrated parace-
tamol and one dose of intravenous propacetamol, all of which
were given after minor surgery.
Methods: Thirty-five patients undergoing day surgery were
divided into five groups, seven patients each. Groups received
either 1 g of an ordinary paracetamol tablet, 2 g of an ordinary
paracetamol tablet, 1 g of a bicarbonate paracetamol tablet,
2 g of a bicarbonate paracetamol tablet or 2 g intravenously
of prodrug propacetamol. We studied the plasma concentration
of paracetamol during the first 80 min after administration.
Results: Within 40 min, intravenous propacetamol gave a
median plasma paracetamol concentration of 85 mmol/l
(range 65—161) and decreased thereafter. After oral administra-
tion, median plasma paracetamol concentration increased with
increasing dose and time, but there were huge inter-individual
differences at all time points studied. At 80 min after oral
paracetamol the median plasma concentrations were 36 and
129 mmol/l for the 1- and 2-g groups, respectively, with an
overall range between 0 and 306 mmol/l.
Conclusion: Oral administration of paracetamol as part of
multimodal pain management immediately post-operatively
resulted in a huge and unpredictable variation in plasma
concentration compared with the intravenous administration.
Accepted for publication 23 April 2004
Key words: bicarbonated formula; intravenous propa-
cetamol; pain management; paracetamol; post-operative
analgesia.
# Acta Anaesthesiologica Scandinavica 48 (2004)
PAIN management after day surgery is based on thecombination of local anesthetics and peripherally
acting analgesics such as paracetamol and nonsteroi-
dal anti-inflammatory drugs (NSAIDs). Opioids in
multimodal post-operative pain management are
reserved for rescue medication in case of insufficient
pain control (1—4). The optimal preparation and dose
for paracetamol is not well defined (5). The primary
aim of the present study was to investigate the early
bioavailability of two different fixed doses of orally
administrated paracetamol. The oral paracetamol was
administered after day surgery either as ordinary
tablets or as bicarbonated tablets. Two grams of the
intravenous prodrug propacetamol (equivalent to 1 g
of paracetamol) was used as an active reference. Para-
cetamol concentrations were measured during a
study period of 80 min as post-operative pain and
the need for treatment normally occur early after
surgery.
Materials and methods
Thirty-five ASA I—II patients, 18 men and 17 women,
undergoing day surgery procedures such as varicose
veins, arthroscopy of the knee and hernia repairs,
participated in the study after ethical committee
approval and written informed patient consent.
Patients were excluded from the study if they had
a known liver disease or any contraindication for
paracetamol.
Patients were randomly assigned (using sealed
envelopes) to one of five groups, with seven patients
in each, to receive post-operatively either:
1 1 g of ordinary paracetamol tablets (Panodil1, Glaxo
Smith Kline, Täby, Sweden);
2 2 g of ordinary paracetamol tablets (Panodil1, Glaxo
Smith Kline);
3 1 g of bicarbonated paracetamol tablets (Panodil
Zapp1, Glaxo Smith Kline);
Acta Anaesthesiol Scand 2004; 48: 867—870 Copyright # Acta Anaesthesiol Scand 2004
Printed in Denmark. All rights reserved
ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/j.1399-6576.2004.00452.x
867
4 2 g of bicarbonated paracetamol tablets (Panodil
Zapp1, Glaxo Smith Kline); and
5 2 g i.v. propacetamol (Pro-Daphalgan1 Bristol-Myers
Squibb, Bromma, Sweden).
All patients were anesthetized according to the
department routines. Patients received cyclozine
50 mg orally as premedication, and anesthesia was
induced with i.v. propofol and fentanyl (0.1 mg) fol-
lowed by the placement of a laryngeal mask airway.
Anesthesia was maintained with oxygen in nitrous
oxide (1:2) and sevoflurane was titrated to clinical
needs. No muscle relaxants were used. At the end
of surgery, anesthetic gases were discontinued and
replaced by oxygen 100% until patients’ regained
consciousness. Patients were transferred to the recov-
ery room and when awake given the allocated form of
paracetamol. All patients were also given an NSAID,
lornoxicam 8 mg (Xefo1 Nycomed, Lidingö, Sweden)
orally and were encouraged to drink and eat as soon
as possible.
The visual analog scale (VAS) for grading experi-
enced pain from 0 to 10, where 0 represented no pain
and 10 represented the worst pain imaginable was
used post-operatively and the VAS-values were noted
and documented. Pain was treated when VAS> 4.
Side-effects such as nausea and vomiting were also
noted and treated accordingly.
Blood samples for analysis of plasma concentrations
of paracetamol were taken prior to paracetamol
administration (baseline) and at 20, 40 and 80 min
after the administration. The blood samples, contain-
ing 5 ml each, were taken at predetermined time
points, centrifuged, and stored at �20�C until analy-
sis. Plasma paracetamol concentrations were deter-
mined by fluorescent polarization immunoassay
(AxSym from Abbott Scandinavia, Solna, Sweden).
The dynamic range of the assay was 6.6—1320mmol/l.
The lower concentration limit of detection was
6.6mmol/l and the coefficient of variation was 6% at
100mmol/l.
Statistics
Data are shown as median and range. Differences
between groups were analyzed by Kruskal—Wallis
ANOVA and Friedman ANOVA. Categorical data
were analyzed using Fisher’s exact test.
Results
Patient characteristics and the amount of paraceta-
mol/kg given are shown in Table 1.
Plasma paracetamol concentrations after i.v. propa-
cetamol administration peaked within 40 min and
decreased thereafter with a seemingly small variabil-
ity (Table 2).
Plasma paracetamol concentration did not differ
between ordinary and bicarbonated tablets (Table 2).
The median plasma concentration after orally admin-
istrated paracetamol increased with dose and time.
Concentrations after the 1-g dose increased from
median 0 (0—64) at 20 min to 36 (0—90) at 80 min and
after the 2-g dose from 5 (0—186) to 129 (21—306) at 20
and 80 min, respectively.
There were large interindividual differences in
plasma concentrations at the three time points studied
(Table 2, Fig. 1). In the patients given paracetamol
orally, 11 out of 28 patients showed undetectable
plasma concentrations of paracetamol after 40 min.
After 80 min, 3 out of 14 patients who received 1 g
had a plasma paracetamol concentration less than
10mmol/l. One patient who received 2 g orally
reached 306mmol/l at 80 min
Two patients, both orally treated, experienced a
short period of nausea that responded to metoclopra-
mide. Pain was well controlled in all patients.
Table 1
Patient characteristics: number of patients, age, weight and the dose of paracetamol (mg/kg).
Ordinary tablet Bicarbonated tablet i.v. propacetamol
1 g (n¼ 7) 2 g (n¼ 7) 1 g (n¼ 7) 2 g (n¼ 7) 2 g (n¼ 7)
Age 55 (48—72) 65 (44—73) 55 (37—61) 53 (43—68) 46 (41—59)
(Median and range)
Weight 77 (58—99) 75 (64—84) 85 (73—95) 80 (65—95) 82 (62—94)
(Median and range)
Male/female 4/3 3/4 3/4 4/3 4/3
Paracetamol dose/kg 13 (10—17) 27 (24—31) 12 (11—14) 25 (21—31) 12 (11—16)*
(Median and range)
*Two grams of propacetamol equivalent to 1 g of paracetamol.
P. Holmér Pettersson et al.
868
DiscussionThe main finding of the present study was that
plasma paracetamol concentrations after oral admin-
istration of 1- or 2-g paracetamol tablets were highly
variable and unpredictable, while 2 g of i.v. propace-
tamol gave rise to seemingly more predictable early
plasma paracetamol concentrations.
The paracetamol plasma concentration required
for adequate analgesia is not well defined. The thera-
peutic antipyretic plasma concentration is considered
to be 66—132mmol/l or 10—20mg/ml (5). While the
threshold concentration for analgesic effect is prob-
ably greater than for the antipyretic effect, both higher
and lower values have been suggested (6—10).
The intravenous prodrug propacetamol is quickly
hydrolyzed to paracetamol in the blood. Two grams of
propacetamol i.v. results in 1 g of paracetamol and
reaches a maximum mean plasma concentration of
86mmol/l (13 mg /l) within 30 min (11). These data
correspond well to our results with a rapid onset
and median concentration of 87mmol/l at 40 min.
The i.v. plasma concentrations showed a tendency to
decrease after 40 min.
Oral paracetamol administration showed slow and
unpredictable absorption. Although plasma concen-
trations increased during the 80-min study period,
huge individual variability was seen. Some patients
achieved remarkably high plasma concentrations
while others did not even reach a detectable plasma
concentration within the 80-min study period.
There are a number of factors that should be
considered regarding our findings. We studied only
a limited number of patients and only during the first
80 min after administration. Our patients were
encouraged to drink and eat when adequately awake
which may have affected the absorption of paracetamol
(12—14). Furthermore, we are not able to say when and
at what concentration orally administrated para-
cetamol concentrations peak. It seems reasonable
to conclude that increasing the oral dose does not
guarantee an adequate therapeutic plasma concentra-
tion in patients during the early post-operative period.
Doubling the oral dose to 2 g did not provide
paracetamol concentrations in even the antipyretic
effect range within 80 min in more than 9 out of
14 patients.
The optimal formulation for oral administration of
paracetamol is not entirely clear. Although peak con-
centrations may not differ to a major extent, the time
to reach maximum absorption has been shown to
differ between different formulations (15, 16). It has
been demonstrated that bicarbonate formulations of
paracetamol are absorbed faster than ordinary tablets
(14, 17). The time to analgesic onset has been shown to
vary between different formulations with a slower
onset for ordinary tablets (18). We could not see any
major difference in plasma concentration pattern
between the two formulations of oral paracetamol
studied, but the low number of patients and sample
times should of course be considered.
The study period included only the first 80 min after
paracetamol intake. This is a limitation that precludes
knowing whether delayed uptake would have taken
place in the patients who demonstrated low concen-
trations during the time window studied. Our aim
was to study the early bioavailability for paracetamol
Table 2
Concentrations of paracetamol, mmol/l (median and range) after 1- or 2-g ordinary tablets or 1 or 2 g of bicarbonated formula or
2 g of intravenous propacetamol.
Ordinary tablet Bicarbonated tablet i.v. propacetamol
1 g (n¼ 7) 2 g (n¼ 7) 1 g (n¼ 7) 2 g (n¼ 7) 2 g (n¼ 7)
20 min 0 (0—49) 23 (0—85) 0 (0—64) 0 (0—186) 85 (65—161)
40 min 18 (0—109) 89 (0—293) 7 (0—48) 54 (0—179) 87 (42—90)
80 min 32 (0—90) 151 (21—306) 40 (0—84) 106 (22—176) 64 (43—81)
µm
ol
/l
0
50
100
150
200
250
300
350
0.005 0.01 0.015 0.02 0.025 0.03 0.0350
Paracetamol/kg
Fig. 1. The paracetamol plasma concentration at 80 min after
taking 1- or 2-g tablet vs. the paracetamol dose (g/kg). ^: 1 g of
ordinary paracetamol tablets or bicarbonated formula; ^: 2 g of
ordinary paracetamol tablets or bicarbonated formula.
Early bioavailability of paracetamol
869
when used as a part of a multimodal approach for
pain management after day surgery, combining low
dose opioid, NSAID and paracetamol in the clinical
setting.
To conclude, as apart of a multimodal pain
approach in day surgery intravenously administered
propacetamol produces a rapid and predictable
plasma paracetamol concentration, in contrast to orally
administrated paracetamol that leads to low and
highly variable plasma concentrations. Even doub-
ling the oral dose to 2 g resulted in huge range of
individual plasma concentrations with a number of
patients having only limited absorption within 80 min
after administration.
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Address:
Pia Holmér Pettersson
Department of Cardiothoracic Surgery and Anesthesiology
Karolinska University Hospital
S-171 76 Stockholm
Sweden
e-mail: pia.holmer-pettersson@ks.se
P. Holmér Pettersson et al.
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