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ORIGINAL RESEARCH ARTICLE
Pharmacokinetics of Oral and Intravenous Paracetamol
(Acetaminophen) When Co-Administered with Intravenous
Morphine in Healthy Adult Subjects
Robert B. Raffa
1
•Jayne Pawasauskas
2
•Joseph V. Pergolizzi Jr
3
•
Luke Lu
4
•Yin Chen
5
•Sutan Wu
5
•Brant Jarrett
4
•Randi Fain
4
•
Lawrence Hill
4
•Krishna Devarakonda
4
The Author(s) 2017. This article is an open access publication
Abstract
Background and Objective Several features favor parac-
etamol (acetaminophen) administration by the intravenous
rather than the oral route in the postoperative setting. This
study compared the pharmacokinetics and bioavailability
of oral and intravenous paracetamol when given with or
without an opioid, morphine.
Methods In this randomized, single-blind, parallel, repeat-
dose study in healthy adults, subjects received four repeat
doses of oral or intravenous 1000 mg paracetamol at 6-h
intervals, and morphine infusions (0.125 mg/kg) at the 2nd
and 3rd intervals. Comparisons of plasma pharmacokinetic
profiles were conducted before, during, and after opioid co-
administrations.
Results Twenty-two subjects were included in the phar-
macokinetic analysis. Observed paracetamol peak con-
centration (C
max
) and area under the plasma concentration-
time curve over the dosing interval (AUC
0–6
) were reduced
when oral paracetamol was co-administered with morphine
(reduced from 11.6 to 7.25 lg/mL and from 31.00 to
25.51 lgh/mL, respectively), followed by an abruptly
increased C
max
and AUC
0–6
upon discontinuation of
morphine (to 13.5 lg/mL and 52.38 lgh/mL, respec-
tively). There was also a significantly prolonged mean time
to peak plasma concentration (T
max
) after the 4th dose of
oral paracetamol (2.84 h) compared to the 1st dose
(1.48 h). However, pharmacokinetic parameters of parac-
etamol were not impacted when intravenous paracetamol
was co-administered with morphine.
Conclusions Morphine co-administration significantly
impacted the pharmacokinetics of oral but not intravenous
paracetamol. The abrupt release of accumulated paraceta-
mol at the end of morphine-mediated gastrointestinal
inhibition following oral but not intravenous administration
of paracetamol suggests that intravenous paracetamol
provides a better option for the management of postoper-
ative pain.
ClinicalTrials.gov Identifier NCT02848729.
Key Points
Morphine co-administration significantly impacts the
pharmacokinetics of oral but not intravenous
paracetamol by reducing/delaying its absorption and
substantially increasing the inter-individual
pharmacokinetic variability
Intravenous paracetamol produces more
predictable blood levels than oral paracetamol when
either are co-administered with morphine, and thus
provides a better option for the management of
postoperative pain in the context of multimodal
analgesia
&Krishna Devarakonda
krishna.devarakonda@mallinckrodt.com
1
University of Arizona College of Pharmacy, Tucson,
AZ 85718, USA
2
The University of Rhode Island College of Pharmacy,
Kingston, RI 02881, USA
3
NEMA Research, Inc., Naples, FL 34108, USA
4
Mallinckrodt Pharmaceuticals, Perryville III Corporate Park,
53 Frontage Road Third Floor, P.O. Box 9001, Hampton,
NJ 08827-9001, USA
5
Mallinckrodt Pharmaceuticals, Hazelwood, MO 63042, USA
Clin Drug Investig
https://doi.org/10.1007/s40261-017-0610-4
1 Introduction
Opioid agonists such as morphine continue to be important
analgesics in the treatment of pain in the immediate peri-
operative and critical care settings [1], although they are
associated with numerous adverse drug events [2]. In an
effort to reduce opioid exposure and thus minimize opioid-
related adverse drug events, non-opioid analgesics are
being incorporated as foundational therapy into multimodal
analgesia protocols for the management of postoperative
pain. Numerous surgical and nonsurgical medical societies
and accrediting and quality organization guidelines rec-
ommend the use of multimodal analgesia (MMA) in order
to reduce exposure to opioids [3–9]. Many also recommend
scheduled use of non-opioid analgesics (paracetamol [ac-
etaminophen], non-steroidal anti-inflammatory drugs
[NSAIDs]) as the first- line foundation of MMA.
A recent review [10] and the American Society of
Anesthesiologists (ASA) guidelines [11] have suggested
there is inadequate differentiation of intravenous and oral
paracetamol to warrant the higher acquisition cost and
longer time to administer the intravenous formulation.
Given that opioids remain a key component of post-
operative pain management, it is important to note that
opioids, along with surgical stress may have a negative
impact on orally administered drugs. Opioids inhibit gas-
trointestinal motility, including delaying gastric emptying
[12] and thus the route of administration of analgesics used
in multimodal regimens may be an important considera-
tion. Specifically, absorption of orally administered
paracetamol may be compromised in patients receiving
opioids, which could reduce efficacy. Furthermore, delayed
absorption of orally administered paracetamol in patients
receiving opioids could result in gastric accumulation of
paracetamol, thereby markedly changing the pharmacoki-
netic profile during and after opioid administration.
Paracetamol can significantly reduce the use of opioid
analgesics when concomitantly administered for the treat-
ment of acute pain [13]. The use of intravenous paraceta-
mol concomitantly with opioids has gained increased
popularity for postsurgical pain relief over orally admin-
istered paracetamol because it provides an immediate peak
plasma concentration [14] and is thought to provide a faster
analgesic effect. Bioavailability of intravenous paracetamol
is 100%, whereas the oral bioavailability of paracetamol
can be as low as 79% [15]. In a study comparing the
pharmacokinetics of paracetamol 1 g administered via
intravenous, oral, or rectal routes, cerebrospinal fluid (CSF)
area under the concentration-time curve from 0 to 6 h
(AUC
0–6
) was 24.9, 14.2, and 10.3 lgh/mL, respectively.
Absorption phase, variability in plasma and CSF were
greater with oral and rectal administration than with
intravenous administration [14].
Furthermore, in patients receiving opioids, the absorp-
tion of orally administered paracetamol may be delayed
and could result in gastric accumulation of paracetamol,
thereby markedly changing the pharmacokinetic profile.
Opioid-induced inhibition of gastrointestinal function
would not be expected to affect intravenous paracetamol
pharmacokinetics.
To assess potential interaction, the current study evalu-
ated whether an opioid, intravenous morphine, commonly
used to treat postsurgical pain, affects the absorption of
oral or intravenous paracetamol and results in altered
pharmacokinetics during and after co-administration in
healthy subjects.
2 Methods
This was an institutional review board (IRB)-approved,
randomized, single-blind, parallel, single-site, repeat-dose
study (NCT02848729) in healthy adult subjects from 18 to
55 years of age (inclusive). The study was completed with
four cohorts of subjects: both males and non-pregnant
females were enrolled in Cohort 1, and male subjects only
in Cohorts 2–4. Subjects were randomly assigned to 1 of 2
parallel groups: 4 repeat doses of 1000 mg oral paraceta-
mol (2 tablets, 500 mg/tablet; Mallinckrodt Inc., Hazel-
wood, Missouri, USA) at hours 0, 6, 12, and 18, and a
dummy 15-min intravenous infusion of saline at the same
time points, or 4 doses of intravenous paracetamol (1000
mg/100 mL; Ofirmev
, Mallinckrodt Inc., Hazelwood,
Missouri, USA) delivered as an infusion at hours 0, 6, 12,
and 18, and 2 placebo tablets at the same time points.
Intravenous morphine infusions (0.125 mg/kg in 100 mL
saline, approximately 15 min; morphine sulfate injection
10 mg/mL, 1 mL, West-Ward Pharmaceutical Corp.,
Eatontown, New Jersey, USA) occurred at hours 6 and 12
for all subjects. The total study duration for each subject
was approximately 38 days. A drop-out rate of 50% was
anticipated due to the required discontinuation of subjects
who experienced emesis and the known association
between morphine and emesis.
2.1 Bioanalytical Method to Determine Plasma
Concentration of Paracetamol
Venous blood was collected by venipuncture in K
2
EDTA-
containing tubes, and plasma was separated and stored at
-80 C. Quantification of paracetamol in plasma was
performed via high-performance liquid chromatography
(HPLC) with paired mass spectrometry (MS/MS). Analysis
of human plasma samples began on 16 March 2016 and
R. B. Raffa et al.
was completed on 01 April 2016. Plasma samples were
analyzed with a lower limit of quantitation of 0.100 lg/mL
and upper limit of quantitation of 50.0 lg/mL. Each cali-
bration curve was calculated using a linear (1/concentra-
tion
2
weighted) least-squares regression algorithm.
Precision and accuracy were evaluated by replicate anal-
yses of human plasma quality control pools prepared at five
concentrations spanning the calibration range. To demon-
strate reproducible quantitation of incurred subject sam-
ples, approximately 10% of the study samples were re-
assayed. Incurred sample repeats were considered accept-
able if the original and re-assay values from two-thirds of
the repeated samples had a relative percent difference of
B20%. The results of the incurred sample repeats met the
acceptance criteria.
2.2 Pharmacokinetics
Venous blood samples (6 mL each) for measuring parac-
etamol concentrations were collected at the following
times:
•up to 30 min prior to the administration of the first dose
of paracetamol;
•at 15, 30, and 45 min (±2 min), 1, 2, 3, 4, 6 h (±5 min
for hours 1, 2, 3, and 4; ±10 min for hour 6) after the
first paracetamol dose;
•at 30 min (±2 min), 1, 2, 3, 4 and 6 h (±5 min for
hours 1, 2, 3, and 4; ±10 min for hour 6) after both
second and third paracetamol doses;
•and at 15, 30, and 45 min (±2 min), 1, 2, 3, 4, 6, 8, 10,
12, and 18 h (±5 min for hours 1, 2, 3, 4, 8, 10, 12 and
18; ±10 min for hour 6) after the fourth dose of
paracetamol.
Blood draws at 6 h after the first, second, and third
paracetamol doses were collected before the next parac-
etamol dose that was to be administered.
A total of 33 blood samples were collected for each
subject. The schedules for blood samples collection were
the same for all study groups.
Approximately 200 mL of blood for determination of
plasma concentrations of paracetamol was collected, and
18 mL was collected for clinical laboratory tests at the
screening visit and check-in. The time (24-h clock) and
date of collection for each sample was recorded.
2.3 Safety
The following safety assessments were evaluated: medi-
cal/surgical history, physical examination, pregnancy test-
ing (Cohort 1 female subjects only) electrocardiogram,
vital signs, clinical laboratory testing (including standard
assessment of renal and hepatic function), pulse oximetry,
concomitant medication use, and assessment of adverse
events (AEs).
2.4 Statistical Analysis
This study was regarded as exploratory and thus sample
size was not determined by power analysis. Two popula-
tions were identified and analyzed in this study. The safety
population comprised subjects enrolled in the study that
received any quantity of study drug. The per-protocol
population comprised subjects who received all study drug
doses and provided all 33 protocol-specified blood samples
within required time frames without any major protocol
deviations.
Pharmacokinetic simulations were performed to predict
the paracetamol concentrations after the second, third, and
fourth doses of paracetamol assuming no co-administration
of morphine. The simulations were based on the observed
pharmacokinetic values after the first dose of orally or
intravenously administered paracetamol. Simulations were
performed using Phoenix
WinNonlin
V 6.4 (Certara,
Princeton, NJ).
Descriptive statistics for continuous variables included
number of values (N), mean, standard deviation (SD),
median, minimum, and maximum, unless otherwise noted.
Frequency and percentages were calculated for categorical
variables. In anticipation of having a limited number of
subjects available for final analysis (due to a high rate of
emesis-related drop-outs), the paired t-test was used in
comparisons within the oral paracetamol group or within
the intravenous paracetamol group, across paracetamol
doses, and the two-sample t-test was used in comparisons
across the oral and intravenous paracetamol groups. To
control for multiple comparisons, both raw pvalues from
the paired t-test and Hochberg adjusted pvalues were
calculated, and only the adjusted pvalues were presented.
All statistical significance testing was 2-tailed using
a=0.05.
Data summary and analyses were performed with SAS
9.2 or higher.
3 Results
3.1 Subject Disposition
A total of 50 subjects were enrolled in the study, 23 sub-
jects (46.0%) completed, and 27 subjects (54.0%) were
discontinued early. Twenty-six subjects (52.0%) discon-
tinued due to emesis and 1 subject withdrew consent to
participate in the study; no subjects discontinued due to any
other treatment-emergent adverse event (TEAE). A total of
22 subjects were included in the per-protocol population
PK of Oral and IV Paracetamol When Co-administered with IV Morphine
and used in the pharmacokinetic analysis. One subject
completed the study but did not provide all pharmacoki-
netic samples and thus was excluded from the per-protocol
population. No data imputation was performed.
3.2 Demographic and Baseline Characteristics
Of the 50 subjects enrolled, 34 (68%) were white and 16
(32%) were black or African American. The majority
(64%; 32/50) were not Hispanic or Latino in ethnicity.
Across all enrolled subjects, the mean age was 32.8 years
(range 18–55 years), and the mean body mass index was
27.78 kg/m
2
. There were 41 (82%) male and 9 (18%)
female subjects.
Of the 22 subjects included in the per-protocol popula-
tion, the majority were white (16 of 22 subjects; 72.7%),
and other subjects (6 of 22 subjects; 27.3%) were black or
African American. Subjects in the per-protocol population
had a mean age of 32.8 years (range 18–55 years), and had
a mean body mass index of 28.03 kg/m
2
. There were 21
male subjects (95.5%) and 1 female subject (4.5%).
3.3 Pharmacokinetics
Mean plasma pharmacokinetic parameters of oral parac-
etamol administered before, during, and after morphine
administration are presented in Table 1.
Observed paracetamol peak concentration (C
max
) and
area under the plasma concentration-time curve over the
6-h dosing interval (AUC
0–6
) for paracetamol following
oral administration were reduced when co-administered
with morphine, and increased after morphine was discon-
tinued. The mean AUC
0–6
was decreased from 31.00 lgh/
mL after the second dose (28.51 lgh/mL) and third dose
(25.31 lgh/mL) of oral paracetamol, and then sharply
increased following the fourth dose (52.38 lgh/mL),
resulting in statistically significant increases between
fourth and first dose (p\0.001), and fourth and third dose
(p=0.004). The mean C
max
followed a similar trend,
decreasing from 11.6 lg/mL after the first dose to 7.29 lg/
mL after the second dose and 7.25 lg/mL after the third
dose of paracetamol, and then increasing significantly after
the fourth dose (13.5 lg/mL, p=0.019, when compared
with the third dose).
Time to peak plasma concentration (T
max
) for oral
paracetamol was prolonged during and after co-adminis-
tration of morphine. Significantly prolonged mean T
max
(i.e., delayed C
max
) values were also observed after the
fourth (2.84 h, p=0.031) dose of oral paracetamol when
compared to the first dose (1.48 h).
Concomitant use of morphine also resulted in greater
variability in orally administered paracetamol exposures,
plasma concentrations, and T
max
(Table 1; Figs. 1and 2a).
The SDs of the pharmacokinetic parameters, AUC
0–6
,
C
max
, plasma concentration at 6 h (C
6
), and T
max
, after the
third and fourth doses of oral paracetamol, in most cases,
were greater than those after the first and second doses,
indicating greater inter-subject variability as a result of
interaction with co-administered morphine (Table 1).
Additionally, the concentration of the drug that produces
50% of the maximal effect (EC
50
), which for paracetamol
is purported to be in the range of 10–15 lg/mL [16,17],
was rarely reached following oral administration (Fig. 3a).
In contrast, the values of all critical pharmacokinetic
parameters after each intravenous dose of paracetamol,
administered before, during, and after morphine adminis-
tration, were found to be very similar (Fig. 2b). Further-
more, following intravenous administration of paracetamol,
EC
50
was reliably met in subjects following each dose
(Fig. 3b).
Mean plasma pharmacokinetic parameters of intra-
venous paracetamol are presented in Table 2. Because no
blood samples were collected at 0.25 h after intravenous
paracetamol, doses 2 and 3, C
max
and T
max
values reflect
the lack of sample collection before 0.25 h. Concentrations
at 0.5 h after each dose were measured, which were com-
parable across all four doses of paracetamol. Therefore,
C
0.5
is more relevant in representing the early phase of the
paracetamol concentrations when inter-dose comparison is
needed. Overall, the values of all critical pharmacokinetic
parameters after each intravenous dose of paracetamol
were found to be similar. The AUC
0–6
, AUC
0.5–6
,C
0.5
, and
C
6
for doses 2, 3, and 4 are within the bioequivalence limits
compared to the first dose but demonstrated a trend toward
small increases with each additional dose. This is consis-
tent with drug accumulation as expected in multi-dose
paracetamol administration.
3.4 Safety
Overall, 39 subjects (78.0%) experienced at least 1 TEAE,
all of which were mild or moderate in severity. The most
frequently reported TEAEs (experienced by C10% of
subjects) were vomiting (26 subjects, 52.0%), nausea
(22 subjects, 44.0%), dizziness (8 subjects, 16.0%), and
somnolence (5 subjects, 10.0%). No other TEAEs were
reported in more than 4 subjects. Although statistical
comparisons were not performed, there were fewer subjects
with TEAEs after receiving intravenous paracetamol
(73.9%) than after receiving oral paracetamol (81.5%).
There were fewer subjects who experienced the TEAE of
vomiting after receiving intravenous paracetamol (47.8%)
than after receiving oral paracetamol (55.6%). A total of 26
subjects discontinued the study due to emesis. Ten of the
26 subjects discontinued due to emesis after receiving their
first dose of morphine following their second paracetamol
R. B. Raffa et al.
dose and the remaining 16 subjects discontinued after the
second dose of morphine. Of the 10 subjects who discon-
tinued due to emesis after receiving their first dose of
morphine, 8 had previously received two doses of oral
paracetamol and 2 had received intravenous paracetamol
doses.
4 Discussion
Overall, this study demonstrated a substantial impact on the
pharmacokinetic profile of oral paracetamol, but not
intravenous paracetamol, when co-administered with
morphine. Greater pharmacokinetic variability was seen
following administration of paracetamol orally compared
to intravenously, particularly after subjects were exposed to
morphine. This variability could be attributed multiple
factors: (1) much of the inter-individual inherent physio-
logic variability could be contributing to higher variance in
absorption, (2) the uptake of paracetamol from the small
intestine is much faster than from the stomach due to the
greater surface area. An important consequence was that
the absorption would be determined by the rate at which
the drug was transferred from the stomach to the site of
rapid absorption in the upper small intestine, (3) absorption
also involved the process of dissolution from an orally
administered solid dosage form and either the rate of transit
from stomach or dissolution could be rate-limiting. Head-
ing and colleagues [18] found that rapid gastric emptying
in 14 convalescent patients was associated with the early
appearance of high peak plasma paracetamol concentra-
tions, whereas peak concentrations were low and appeared
late when gastric emptying was slow.
Observed peak paracetamol concentration (C
max
) and
area under the plasma concentration-time curve over the
6-h dosing interval (AUC
0–6
) were reduced in this study
when oral paracetamol was co-administered with mor-
phine, followed by an abruptly increased C
max
and AUC
0–6
upon the discontinuation of morphine, indicating the
absorption of the accumulated paracetamol entering the
small intestine after the effect of morphine dissipated.
Noticeable changes were also observed for time to reach
maximum drug concentration (T
max
) after the 3rd and 4th
doses. Variability in C
max
, AUC
0–6
,C
6
(paracetamol con-
centration before the following dosing time), as well as
T
max
around 3rd dose was significantly higher than that of
first two doses, indicating the impact of morphine on oral
paracetamol absorption varies substantially among indi-
vidual subjects. In contrast, intravenous paracetamol
demonstrated more predictable pharmacokinetics in the
setting of concomitant opioid use.
Table 1 Plasma pharmacokinetic parameters of oral paracetamol
Parameter Paracetamol dose
a
pvalue
c
First (before
b
) Second (during
b
) Third (during
b
) Fourth (after
b
)
n11 11 11 11
AUC
0–6
(lgh/mL)
d
Mean (SD) 31.00 (5.11) 28.51 (5.96) 25.31 (11.59) 52.38 (13.48) \0.001
CV% 16.5% 20.9% 45.8% 25.7%
AUC
0–18
(lgh/mL) Mean (SD) 82.50 (23.28)
C
max
(lg/mL) Mean (SD) 11.6 (4.11) 7.29 (1.82) 7.25 (3.95) 13.5 (3.31) 0.188
CV% 35.5% 25.0% 54.5% 24.6%
C
6
(lg/mL) Mean (SD) 2.93 (0.633) 3.71 (0.694) 4.83 (1.97) 6.83 (2.22) \0.001
CV% 21.6% 18.7% 40.8% 32.5%
T
max
(h) Mean (SD) 1.48 (0.61) 1.64 (0.78) 3.26 (2.30) 2.84 (1.05) 0.031
CV% 40.9% 47.5% 70.5% 37.0%
K
el
(/h) Mean (SD) 0.1904 (0.0171)
t
1/2
(h) Mean (SD) 3.67 (0.33)
CV coefficient of variation, AUC area under the plasma concentration-time curve, C
max
peak plasma concentration, C
6
plasma concentration at 6
h, T
max
time to peak plasma concentration, K
el
elimination rate constant, t
1/2
plasma half-life, SD standard deviation
a
Treatment A: first paracetamol dose: 1000 mg oral paracetamol (2 9500 mg tablets) and an intravenous infusion of saline at hour 0 (before
morphine). Second and third paracetamol doses: 1000 mg oral paracetamol (2 9500 mg tablets) and an intravenous infusion of saline at hours 6
and 12 (during morphine). Fourth paracetamol dose: 1000 mg oral paracetamol (2 9500 mg tablets) and an intravenous infusion of saline at hour
18 (after morphine)
b
Before, during, or after are relative to morphine administration
c
Treatment comparison: fourth/first paracetamol dose
d
AUC following each dose of paracetamol
PK of Oral and IV Paracetamol When Co-administered with IV Morphine
In this study, only two 0.125 mg/kg doses of morphine
were given, whereas in clinical practice, patients may need
more than two doses, which could have an even greater
impact on gastric emptying and gut motility, resulting in
greater accumulation of paracetamol following repeat oral
dose administration. Once gastric function is restored upon
the discontinuation of morphine, there is an abrupt release
of unabsorbed paracetamol that enters the small intestine
[19]. We observed a resultant approximate doubling in
AUC (after the 4th dose of oral paracetamol), which may
produce significant changes in paracetamol metabolism, as
common pathways such as glucuronidation/sulfation get
Fig. 1 Individual plasma concentration-time profiles of oral parac-
etamol showing large inter-subject variability. Subjects received
Treatment A, i.e., 4 repeat doses of 1000 mg oral paracetamol (2 9
500 mg tablets) and an intravenous infusion of saline every 6 h [hours
0, 6, 12, and 18 (blue arrows)], and 2 infusions of intravenous
morphine (0.125 mg/kg) at hours 6 and 12 (black arrows)
R. B. Raffa et al.
saturated and more drug is converted into the free radical
metabolite N-acetyl-p-benzoquinone imine (NAPQI),
which binds to and causes death of hepatocytes.
In general, the pharmacokinetic profile of paracetamol
following oral administration is known to exhibit consid-
erable inter-subject variability due to differences in normal
physiologic factors such as gastrointestinal movement [18].
The plasma concentrations of paracetamol and its absorp-
tion are apparently related to the rate of gastric emptying
since faster gastric emptying is associated with the rapid
appearance of high peak plasma concentrations, while the
peaks occur late and are lower in patients with delayed
gastric emptying. Gastric emptying likely influences
paracetamol absorption directly by controlling the rate at
which the drug is delivered to the small intestine. Consis-
tent with the high inter-subject variability in pharmacoki-
netic profiles seen in the current study in subjects who
received oral paracetamol, individual variation in the rate
of drug absorption may be due largely to differences in the
rate of gastric emptying [18]. Furthermore, concomitant
use of morphine in the current study introduced even
greater variability in orally administered paracetamol
exposures, plasma concentrations, and T
max
.
The interaction between morphine and orally adminis-
tered paracetamol could be even more pronounced in
postsurgical patients where factors such as concomitant
medications and surgical trauma may further impair gastric
function. This may result in inadequate pain control from
orally administered paracetamol during opioid co-treat-
ment and subsequent absorption of accumulated paraceta-
mol upon cessation of opioid treatment.
The results from this study are consistent with the
pharmacokinetic results of the study by Singla et al 2012
[14]. With respect to efficacy, plasma and CSF levels need
Fig. 2 Predicted (solid blue) and observed (dashed red) pharmacoki-
netic profiles for aoral and bintravenous paracetamol. Subjects
received Treatment A, i.e., 4 repeat doses of 1000 mg oral
paracetamol (2 9500 mg tablets) and an intravenous infusion of
saline every 6 h (hours 0, 6, 12, and 18), and 2 infusions of
intravenous morphine (0.125 mg/kg) at hours 6 and 12 Fig. 3 Paracetamol concentration-time profiles following aoral and
bintravenous paracetamol administration
PK of Oral and IV Paracetamol When Co-administered with IV Morphine
to be considered, though it is difficult to correlate parac-
etamol CSF levels with efficacy, —i.e., paracetamol has a
central effect but concentrations in CSF are not predictive
of (i.e., linearly related to) efficacy [20]. This is a limitation
of the study by Singla et al [14]. The ‘‘effect compartment’’
is unknown and could be multiple locations (e.g., brain and
spinal cord) [21]. Paracetamol conversion to the active
metabolite AM404 may result in active analgesia [22].
Low plasma concentrations following oral administra-
tion of paracetamol could impact efficacy relative to the
intravenous route of administration. Plasma C
max
may be a
better predictor of efficacy than AUC, in that the passive
diffusion of paracetamol into the CNS is highly dependent
on the concentration gradient across the blood brain barrier
[14]. Post-operative intravenous paracetamol previously
has been demonstrated to provide faster onset of analgesia
than a similar dose given orally [23] and, more recently,
that only two-thirds of patients given an oral dose of 1 g
paracetamol preoperatively achieved therapeutic plasma
concentrations at any point compared to 96% in those
given an intravenous dose of 1 g preoperatively [24].
In the context of multimodal analgesia, when choosing
medications to administer, increased efficacy, decreased
adverse effects, and opioid reduction are the primary
objectives [25]. Therefore, selection of non-opioids is
imperative, and route of administration should be factored
in, given opioid impact on gut motility, which impacts the
pharmacokinetics of agents administered orally; substantial
inter-subject variability could be the result of morphine’s
effect, or first- pass metabolism, or both.
Results of this study suggest intravenous paracetamol is
a better choice than oral paracetamol in patients receiving
concomitant opioids until normal gut function can be
demonstrated. A future study should evaluate the extent of
the ‘‘burst effect’’ (i.e., the abrupt release of accumulated
paracetamol at the end of morphine-mediated GI inhibition
following oral administration), to evaluate both pharma-
cokinetics and safety (in particular, the impact on liver
enzyme levels). The study should also aim to measure
metabolites to determine the extent of NAPQI formation
following the burst effect.
5 Conclusion
This study demonstrated that morphine co-administration
significantly impacted the pharmacokinetics of oral
paracetamol, but not intravenous paracetamol, by
Table 2 Plasma pharmacokinetic parameters of intravenous paracetamol
Parameter Paracetamol dose
a
pvalue
c
First (before
b
) Second (during
b
) Third (during
b
) Fourth (after
b
)
n11 11 11 11
AUC
0–6
(lgh/mL)
d
Mean (SD) 42.56 (3.94) 44.37 (4.46) 43.59 (4.21) 49.05 (3.95) \0.001
CV% 9.2% 10.1% 9.7% 8.1%
AUC
0–18
(lgh/mL) Mean (SD) 63.58 (6.74)
C
max
(lg/mL Mean (SD) 22.6 (3.83) 17.0
e
(1.48) 17.5
e
(1.93) 28.5 (4.31) \0.001
CV% 17.0% 8.7% 11.0% 15.1%
C
0.5
(lg/mL) Mean (SD) 16.1 (1.41) 17.0 (1.48) 17.5 (1.93) 17.2 (1.60) 0.1054
C
6
(lg/mL) Mean (SD) 2.53 (0.659) 2.95 (0.621) 2.78 (0.544) 2.88 (0.616) 0.0465
CV% 24.7% 20.0% 18.8% 20.3%
T
max
(h) Mean (SD) 0.25 (0.01) 0.50 (0.00) 0.51 (0.02) 0.25 (0.01)
CV% 2.0% 0.0% 4.0% 4.0%
K
el
(/h) Mean (SD) 0.1704 (0.0193)
t
1/2
(h) Mean (SD) 4.11 (0.46)
AUC area under the plasma concentration-time curve, C
max
peak plasma concentration, C
6
plasma concentration at 6 h, T
max
time to peak plasma
concentration, K
el
elimination rate constant, t
1/2
plasma half-life, SD standard deviation
a
Treatment B: first paracetamol dose: intravenous infusion of paracetamol (1000 mg/100 mL) and 2 placebo tablets hour 0 (before morphine).
Second and third paracetamol doses: intravenous infusion of paracetamol (1000 mg/100 mL) and 2 placebo tablets at hours 6 and 12 (during
morphine). Fourth paracetamol dose: intravenous infusion of paracetamol (1000 mg/100 mL) and 2 placebo tablets at hour 18 (after morphine)
b
Before, during, or after are relative to morphine administration
c
Treatment comparison: fourth/first paracetamol dose
d
AUC following each dose of paracetamol
e
Concentration at first measured time point (0.5 h) post-dose
R. B. Raffa et al.
significantly reducing/delaying its absorption and substan-
tially increasing the inter-individual pharmacokinetic
variability. The abrupt release of the accumulated parac-
etamol at the end of morphine-mediated gastrointestinal
inhibition following oral administration of paracetamol is a
safety concern, particularly given that additional postsur-
gical patient factors may impact gastric function. Intra-
venous paracetamol thus provides a better option for the
management of postoperative pain in the context of mul-
timodal analgesia.
Compliance with Ethical Standards
Funding This study was funded by Mallinckrodt Pharmaceuticals.
These data were presented in part at the 15th Annual Pain Medicine
Meeting of the American Society of Regional Anesthesia and Pain
Medicine (ASRA), November 17–19, 2016, San Deigo, California.
Author contribution Michael G. Baker, PhD of Samorn Bio-
sciences, Inc., provided assistance with writing/formatting/proof
reading collation of the author comments and this assistance was
funded by Mallinckrodt Pharmaceuticals.
Conflict of interest Robert B. Raffa is a former employee of Johnson
& Johnson (1986–1996); he has received basic science laboratory
analgesics research funding from pharmaceutical companies; he
consults/presents on analgesics for several pharmaceutical companies,
including Mallinckrodt, but he receives no royalties for sales of any
products. Jayne Pawasauskas is a consultant to Mallinckrodt Phar-
maceuticals Inc., Joseph V Pergolizzi Jr. is a consultant/ speaker and/
or researcher for: Inspirion, Mallinckrodt, Collegium, Purdue Pharma
LLP, Grunenthal GmhB, Inspirion, ENDO Pharmaceuticals Iroko,
DepoMed and Mundipharma. Krishna Devarakonda, Jia Lu, Yin
Chen, Sutan Wu, Lawrence Hill, Brant Jarrett, and Randi Fain are
employees of Mallinckrodt Pharmaceuticals Inc.
Ethical approval Prior to initiation of this single-center study, the
protocol was reviewed and approved by the institutional review board
IntegReview, Austin, Texas. All procedures performed in studies
involving human participants were in accordance with the ethical
standards of the institutional and/or national research committee and
with the 1964 Helsinki declaration and its later amendments or
comparable ethical standards.
Informed consent Informed consent was obtained from all individ-
ual participants included in the study. Additional informed consent
was obtained from all individual participants for whom identifying
information is included in this article.
Open Access This article is distributed under the terms of the
Creative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
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