Drug Evaluation

Oxycodone for the treatment of

postoperative pain
Hannu Kokki†, Merja Kokki & Sari Sj€ovall
†
1. Introduction Kuopio University Hospital, Department of Anaesthesia & Operative Services, Kuopio, Finland

2. Chemistry and basic

Introduction: Pain is a likely outcome of any surgical procedure. In several
pharmacology
countries the use of oxycodone has surpassed that of morphine in postoperative
3. Clinical use pain management.
4. Oxycodone in elderly patients Areas covered: This review summarizes the recent pharmacological and clinical
5. Patient controlled analgesia data on oxycodone use for postoperative pain management. The benefits and
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 08/14/12

the impact oxycodone may have on outcome in different patient groups is

6. Intraspinal administration
addressed. As oxycodone is available on different pharmaceutical formulations
7. Adverse effects of oxycodone
and as a new combination product with naloxone, the different approaches
8. Future aspects that may be used with oxycodone in postoperative pain management are
9. Expert opinion also reviewed.
Expert opinion: The recent interest in oxycodone is based on its favorable phar-
macokinetics and pharmacodynamics, especially in the central nervous system.
Moreover, relatively high enteral bioavailability allows an easy switch from
one drug formulation to another during the course of pain management.
Oxycodone is highly effective and well tolerated in different types of surgical
procedures and patient groups, from preterm to aged patients. In the future,
For personal use only.

the use of transmucosal administration and enteral oxycodone--naloxone

controlled-release tablets is likely to increase, and an appropriate concurrent
use of different enteral drug formulations will decrease the need for more
complex administration techniques, such as intravenous patient-controlled
analgesia.

Keywords: analgesics, elderly, obstetrics, opioid, oxycodone, pain, postoperative

Expert Opin. Pharmacother. (2012) 13(7):1045-1058

1. Introduction

Pain is the most common adverse effect of surgery, and postsurgical pain is so severe
that four out of five patients need analgesics after the procedure. Sufficient pain relief
is essential not only to prevent unnecessary suffering but also to hasten recovery and
the patient’s outcome after surgery. Increasing evidence shows that severe, under-
treated acute pain may not only delay discharge and increase the need for hospitaliza-
tion after surgery, but also is a risk factor for persistent postoperative pain [1]. Severe
postoperative pain may have a significant impact on patients’ short- and long-
term quality of life and may also cause significant healthcare cost to the community
and, thus, should always be treated appropriately when it occurs. Because postopera-
tive pain is the likely outcome after surgery, proactive approaches for pain control
should be applied for all surgical patients [2].
Opioids are the most commonly used medications for the treatment of acute
severe pain. They provide effective analgesia without loss of touch, proprioception
and muscle strength. To provide adequate analgesia without severe adverse effects,
the mechanism of opioid action, adverse effects and differences among opioids
should be understood. The main constrict for effective analgesia with opioids is,
in 2012, as it was 40 years ago, an underestimation of the pain or overestimation
of the duration of action of opioids and fear of the risk of abuse [3].

10.1517/14656566.2012.677823 © 2012 Informa UK, Ltd. ISSN 1465-6566 1045

All rights reserved: reproduction in whole or in part not permitted
 H. Kokki et al.

Box 1. Drug summary.

Drug name Oxycodone hydrochloride trihydrate
Phase Postmarketing surveillance
Indication Acute moderate to severe pain, postoperative pain
Pharmacology description/ Oxycodone is mainly metabolized in the liver and only 10% of the dose is excreted
mechanism of action unchanged in urine. Majority of the metabolites are excreted in urine. The principal oxidative
metabolic pathways of oxycodone are N-demethylation (most important route, CYP3A4) to
noroxycodone and O-demethylation (CYP2D6) to oxymorphone, 6-keto reduction to oxycodol
accounts for < 10%. Oxycodone and its metabolites undergo additional 6-keto reduction and
conjugation with glucuronic acid and are secreted into the urine.
Binding to µ- opioid receptors in nerve endings in the CNS
Route of administration Oral, parenteral, transmucosal
Chemical name 6-deoxy-7,8-dihydro-14-hydroxy-3-O-methyl-6-oxomorphine
Pivotal studies [4,8,9,27,30]
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Oxycodone (6-deoxy-7, 8-dihydro-14-hydroxy-3-O-methyl-
6-oxomorphine; Box 1) is a semisynthetic thebaine derivative
µ-opioid receptor agonist, which has been in clinical use since
1917 [4]. It has been the most commonly used analgesic for
the management of postoperative and other acute pain in adults
since the 1960s in Finland [5], and over the past two decades
oxycodone use has surpassed that of morphine in several
countries [6].
Oxycodone has been administered to surgical patients by dif-
ferent administration routes: intravenous [7], intramuscular [8],
For personal use only.
derived from opium alkaloid thebaine. Oxycodone hydrochlo-
ride dissolves in water and is slightly soluble in alcohol [4].
Oxycodone has liposolubility similar to morphine; oxycodone
and morphine are both significantly less lipid soluble than fenta-
nyl. The protein binding, mainly albumin, of oxycodone
(40 -- 50%) is close to that of morphine (38%) and it is not
affected by a1-acid glycoprotein [21].
Oxycodone is an µ-opioid receptor agonist, but it has a
considerably lower µ-opioid receptor-binding affinity
than morphine and oxymorphone, one of its own metabo-

intranasal [7], transmucosal [9], subcutaneous [10], rectal [11], epi-
dural [12] and oral [8,10,13,14]. For oral administration immediate-
release solutions and immediate- and controlled-release tablets
and capsules are available.
The main pharmacological effects of oxycodone and other
opioids are mediated via opioid receptors in the cell membranes
of presynaptic nerve endings in the CNS. These opioid recep-
tors belong to G-protein-coupled receptor family (µ-, d- and
k- opioid) receptors [15].
Intravenous oxycodone has been considered to have a similar
potency to intravenous morphine in patients undergoing super-
ficial or orthopedic surgery [16,17]; and in visceral pain less intra-
venous oxycodone than morphine is needed for sufficient
analgesia in patients undergoing intra-abdominal surgery [18].
The potent opioid effect is also confirmed in children [19,20].
Clinical data indicate that, although there is a significant
interindividual variation in oxycodone need in postoperative
pain management, most patients may have sufficient analgesia
after major surgery with 40 -- 60 mg oxycodone i.v. (enteral:
60 -- 100 mg) during the first 24 h after surgery. After moderate
surgery, 20 -- 30 mg i.v. (enteral: 25 -- 50 mg) is often sufficient
and in minor surgery one, two or three doses of 2 -- 3 mg i.v.
(enteral dose: 5 -- 20 mg) should be sufficient (Table 1).
The purpose of this review is to summarize the recent phar-
macological and clinical data on oxycodone use in postoperative
pain management.
2. Chemistry and basic pharmacology
The oxycodone molecule consists of two planar and two
aliphatic rings (Figure 1). It is a white, odorless crystalline powder
lites. Oxycodone also binds to k-opioid and d-opioid
receptors, but with a lower affinity than to µ-receptors. The
effects of oxycodone may be mediated by not only µ-receptors
but also k-opioid receptors, but this is still controversial
issue [22].
2.1 Pharmacokinetics
Oxycodone is extensively metabolized in the liver. The prin-
cipal oxidative metabolic pathways of oxycodone are
N-demethylation to noroxycodone and O-demethylation to
oxymorphone; 6-keto reduction to oxycodol accounts
for < 10%. N-demethylation is quantitatively the most impor-
tant route (ca 50%), but the metabolite noroxycodone has
only a weak antinociceptive effect. O-demethylation accounts
11% of oxycodone metabolism, but it provides pharmacolo-
gically active metabolite oxymorphone. Noroxycodone and
oxymorphone are further metabolized to noroxymorphone,
which is also an active metabolite. Oxymorphone is a potent
opioid with 10 -- 40 times higher µ-opioid receptor affinity
than oxycodone parent compound. However, the active
metabolites do not contribute markedly to analgesic action
as these metabolites are even less lipophilic than oxycodone
which limits their uptake into the CNS [23].
These methylations are catalyzed by the liver enzyme cyto-
chrome P450 3A (CYP3A4/5) and 2D6 (CYP2D6). Because
of a genetic polymorphism of CYP2D6, the population can
be divided into four groups according to the CYP2D6 geno-
type: poor, intermediate, extensive and ultrarapid metaboli-
zers. In the caucasian population, the two clinically
significant CYP2D6 phenotypes are poor metabolizers (8%
of population) with a lack of CYP2D6 activity and extensive

1046 Expert Opin. Pharmacother. (2012) 13(7)

 Oxycodone hydrochloride trihydrate

CH3 CH3

N N

HO HO

OH
O O O O O
H H O
CH3 CH3

Oxycodone Oxycodol
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CH3 CH3
CH3
N N
N

HO HO
HO

OH
O O O O O
HO O H H O
H O
CH3 CH3
For personal use only.

Oxymorphone Noroxycodone Noroxycodol

CH3

N NH

HO HO

OH
HO O HO O O
H O H

Oxymorphol Noroxymorphone

Figure 1. Oxycodone metabolism.

metabolizers (‡ 90%) [24] with highly variable CYP2D6
function [25,26]. However, in postoperative pain management
polymorphism of CYP2D6 seems not to affect the analgesic
efficacy of oxycodone [27].
After methylation, oxycodone and its metabolites undergo
more 6-keto reduction and conjugation with glucuronic acid.
Most oxycodone and noroxycodone is excreted in the urine as
a free (unconjugated) form, but oxymorphone is mainly
excreted in a conjugated form [8]. Oxycodone is extensively
metabolized and only 8 -- 14% is excreted unchanged or
conjugated to urine as a parent compound [14]. The amount
of first-pass metabolism in the intestinal mucosa is minimal.
The volume of distribution of oxycodone is 2 -- 3 liters/kg,
the clearance 0.7 -- 0.8 liters/min and the elimination half-
life (t1/2) 2 -- 3 h after intravenous administration. After
immediate-release tablets, t1/2 is 3 h and after controlled-
release tablets 4 -- 5 h. The maximum plasma concentra-
tion (Cmax) is reached within 1.3 and 2.6 h after immediate-
and controlled-release tablets, respectively. The maximum
concentrations after immediate-release tablets are twice as

Expert Opin. Pharmacother. (2012) 13(7) 1047

 H. Kokki et al.
Table 1. Oxycodone administration routes and doses used in authors’ institutions.
Variable i.v. bolus dosing i.v. PCA (conc.: oxycodone Transmucosal
(dosing interval 2 mg/ml, droperidol
10 -- 15 min) 0.05 mg/ml; lockout:
6 -- 10 min)
Adolescents: 0.05 -- 0.1 mg/kg 0.02 mg/kg
12 -- 17 years
Adults*: 18 -- 65 years 3 mg 1 -- 2 mg
Elderly: > 65 years 2 mg 1 mg
Aged: > 80 years 1 mg 1 mg
*Typical doses during the first 24 h after surgery in adults: minor surgery: i.v. 5 mg/enteral 10 mg; moderate surgery: i.v. 20 -- 30 mg/enteral 25 -- 50 mg; major
surgery: i.v. 40 -- 60 mg/enteral 60 -- 100 mg.
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conc.: Concentration; CR: Controlled-release; IR: Immediate-release; i.v.: intravenous.
high as those observed following equivalent doses of
controlled-release tablets [14,28].
Oxycodone has a relatively high oral bioavailability
(between 45 and 87%) [8,9,28]. Transmucosal administration
is also an attractive administration route in acute pain man-
agement with oxycodone. Bioavailability is less after intranasal
dosing of oxycodone than that after oral transmucosal
administration: the intranasal bioavailability of oxycodone
was 46% with a high interindividual variation [7] and 55%
For personal use only.
after oral transmucosal administration [9,29]. Oral administra-
tion is a feasible route because oxycodone has a neutral taste
and thus is easily accepted by patients [29].
Gender seems to affect the pharmacokinetics of oxycodone.
In healthy female volunteers, the clearance is 25% slower than
that in male volunteers. The exposure of oxycodone is the
greatest in elderly women and lowest in young men [30].
In patients with renal failure the elimination of oxycodone
and its metabolites is impaired, the clearance is significantly
smaller and volume of distribution is greater than in healthy
volunteers with normal renal function [31]. In end-stage renal
failure the interindividual variability of oxycodone exposure is
great and, thus, in these patients, lower doses should be used,
and close follow-up is needed when repeated doses are used.
Because oxycodone is metabolized in the liver, hepatic
function has a significant impact on the pharmacokinetics
and pharmacodynamics of oxycodone. In hepatic insuffi-
ciency, volume of distribution is higher and clearance of
oxycodone is lower than in healthy subjects with normal liver
function. In end-stage liver disease the t1/2 of oxycodone
could be > 12 h and pharmacodynamic responses (sedation,
respiratory depression) more distinctive than in healthy peers.
Thus, the doses of oxycodone should be carefully titrated
in patients with any alteration in metabolic function of
oxycodone [32].
As the analgesic action of oxycodone is mainly due to the
parent compound rather than its metabolites, drugs affecting
the CYP3A and 2D6-mediated metabolism have important
effects on the pharmacokinetics of oxycodone, but the phar-
macodynamic effects of oxycodone may not alter. Rifampicin
induces CYP3A4 and can increase the metabolism of
1048 Expert Opin. Pharmacother. (2012) 13(7)
IR oxycodone tablet CR tablet
(dosing interval or oral liquid (dosing
15 -- 30 min) interval 30 -- 60 min)
5 -- 10 mg 5 -- 10 mg 10 -- 20 mg b.i.d.
10 mg 5 -- 10 mg 20 mg b.i.d.
5 mg 5 mg 5 -- 10 mg b.i.d.
5 mg 5 mg 5 mg b.i.d.
oxycodone and decrease its efficacy as an analgesic [33]. On
the other hand, drugs that block the CYP3A4-mediated
metabolism of oxycodone (e.g., voriconazole), can, at least
in theory, increase the effects of oxycodone [34].
3. Clinical use
3.1 Efficacy in acute postoperative pain
Intravenous oxycodone is an effective treatment for acute
postoperative pain. In one of the earliest studies comparing
morphine and oxycodone in patients with corrective breast or
lumbar spinal surgery in which patients used intravenous
patient-controlled analgesia (PCA) for postoperative pain relief,
a similar amount of morphine and oxycodone was needed for
sufficient analgesia [17]. In a subsequent study in patients sched-
uled for the abdominal surgery, intravenous oxycodone pro-
vided faster pain relief with smaller doses than morphine,
indicating a potency ratio of oxycodone and morphine of
2:3 [18]. In a recent study in patients with laparoscopic hysterec-
tomy, similar intravenous PCA opioid consumption, pain
scores and adverse-effect profile were found in patients ran-
domized to oxycodone or morphine [35]. This indicates that
not only the type of surgery but also the extent of surgery
may affect the comparison of different opioid analgesics.
A Cochrane review has evaluated the efficacy of single-dose,
immediate-release oxycodone in postoperative pain manage-
ment. It was concluded that oxycodone is an effective analge-
sic in acute postoperative pain and that oxycodone is two to
three times stronger than codeine. Moreover, the efficacy of
oxycodone was found to increase when combined with
paracetamol [36].
The efficacy of controlled-release oxycodone in postopera-
tive pain has been demonstrated in several studies [37,38].
However, the use of prolonged-release oxycodone in postop-
erative pain should be qualified, and controlled-release tablets
are not recommended for preoperative use or for the first 24 h
postoperatively, firstly because the gastrointestinal function
during the immediate perioperative period is altered and, sec-
ondly, in acute pain controlled-release tablets are not a
feasible dosage form for the dose titration.

Fewer data are available on spinal use of oxycodone and the
data are inconsistent. When oxycodone or morphine were
administered epidurally to surgical patients, the final epidural
dose ratio between morphine and oxycodone was 1:9 to pro-
vide comparable analgesia, indicating less intraspinal potency
than morphine. During the infusion, plasma concentrations
of oxycodone were similar with intravenous and epidural
administration [12]. A more recent study in patients undergo-
ing gynecological surgery indicates that oxycodone may have
some efficacy in epidural use. In that study, an epidural bolus
dose of oxycodone 4 mg followed by a continuous epidural
infusion of 12 mg/24 h was found equally efficacious to mor-
phine 2 + 6 mg/24 h, but at a 2 + 6 mg/24 h dose oxycodone
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was inferior to epidural morphine. However, safety was better
with oxycodone and adverse effects were less common with
epidural oxycodone than with morphine [39].
3.2 Ear, nose and throat surgery
In ear, nose and throat (ENT) surgery perioperative bleeding is a
main concern and in patients with nasal polyposis and ASA (Ace-
tylsalicylic acid)-induced asthma nonsteroidal anti-inflammatory
analgesic drugs (NSAIDs) are contraindicated. Paracetamol
affects thrombocyte function, though to a lesser extent than
NSAIDs. In risky operations and in at-risk patients NSAIDs
For personal use only.
and paracetamol should be given only after primary hemostasis
has been developed. Thus, opioids are often the first-line analge-
sics in postoperative pain management in ENT surgery.
Oxycodone has been used in a variety of ENT procedures;
after myringotomy and adenoidectomy one or two doses of
0.05 mg/kg i.v. may be sufficient, but after tonsillectomy
postoperative pain is more severe and the need for opioid
analgesics is higher [40]. Endoscopic sinus surgery causes less
pain than throat surgery. If nonopioid analgesics are contrain-
dicated, most patients need one or two 2-mg i.v. doses of
oxycodone during the first hours after surgery [41].
Oxycodone need during the first 24 h after tonsillectomy is
0.25 -- 0.3 mg/kg of body weight. Nonopioid analgesics
improve analgesia both at rest and during swallowing and
have a significant opioid-sparing efficacy. In patients with
scheduled nonopioid analgesics for background analgesia,
the need for oxycodone during the first 24 postoperative
hours is 0.15 -- 0.2 mg/kg i.v. [42,43].
Most tonsillectomies are performed as day cases. Typical
doses of oxycodone in adult patients during the first 6 h after
tonsillectomy are i) up to 10 mg i.v. (i.e., 0.1 -- 0.15 mg/kg) if
no background analgesia has been used; ii) 5 -- 6 mg i.v. in
conjunct with either paracetamol or NSAID; and
iii) 2 -- 3 mg i.v. with a combination of paracetamol and
NSAID [42-46].
In tonsillectomy patients not only background analgesia
but also the surgical technique may affect the need for
rescue oxycodone. In patients with a recently launched tissue
welding technique, only one or two 2-mg i.v. doses of
oxycodone may provide sufficient postoperative analgesia after
tonsillectomy [47].
Expert Opin. Pharmacother. (2012) 13(7)
Oxycodone hydrochloride trihydrate
3.3 Thyroid surgery
Oxycodone has performed well in superficial surgery like thy-
roid surgery. In most of these studies oxycodone has been
used as a part of a multimodal approach. In a placebo-con-
trolled, double-blinded study the need for oxycodone during
the first 24 h after thyroid surgery was 10 -- 12 mg both in
the active group -- cyclo-oxygenase-2-inhibitor etoricoxib
120 mg was given by mouth 60 min before anesthesia -- and
in the placebo group [48]. In another recent study with no
background nonopioid analgesia, the oxycodone consump-
tion was similar. In contrast to the study hypothesis, the
need for oxycodone was not higher in poor metabolizers for
CYP2D6 (13 mg/24 h) than that in extensive metabolizers
(16 mg/24 h). This indicates that in acute pain management
the analgesic action is from the parent compound and the
active metabolites do not have any clinically meaningful
impact on analgesic efficacy [27].
In an earlier study the mean of oxycodone consumption
during the first 24 h after thyroid surgery was higher
(0.33 -- 0.35 mg/kg) [48]. In the Jokela et al. study [49], a con-
ventional open surgical technique was used, while in the
Smirnov et al. study [48], ultrasonography scissors were used
for tissue preparation. Thus, the twofold higher need for
oxycodone in the Jokela et al. study [49] indicates that that
the surgical technique may have a significant impact on
patient recovery and need for postoperative opioids.
3.4 Breast surgery
The analgesic efficacy of oxycodone has been compared
with that of tramadol in patients with breast surgery. Patients
were randomized to receive either oxycodone 20 mg or
tramadol 200 mg controlled-release tablets on a 12-h
schedule. Pain scores at rest and during coughing, and the
incidence of postoperative nausea and vomiting (PONV)
were similar with both drugs during the first 24 h after sur-
gery. In numeric values the need for rescue analgesia was less
in the oxycodone group, but because of a small sample size
the difference was not statistically significant. Based on the
results, a potency ratio of 1:10 was estimated for oxycodone:
tramadol [50]. In an earlier study in patients with maxillo-
facial surgery a potency ratio of 1:8 for oxycodone:tramadol
was reported by Silvasti et al. [51]. A most important finding
was that oxycodone was associated with significantly
less PONV than tramadol, indicating that oxycodone is
better tolerated.
In a multimodal pain treatment model, in which patients
in the intervention group were provided a single paravertebral
injection of bupivacaine, the need for oxycodone during the
first hours after surgery was significantly less than that in the
no-injection group, 5 vs 9 mg, respectively [52].
3.5Gastrointestinal surgery
Gastrointestinal surgery is associated with both wound pain
and visceral pain, and oxycodone has been shown to have
highly potent analgesic action in these cases.
1049
 H. Kokki et al.
Contrary to common belief, the need for opioid analgesics
in the early recovery period after cholecystectomy is not less
after laparoscopic surgery than after open surgery [52-54]. Later
in recovery opioid consumption is significantly less in patients
having had laparoscopic surgery than in those having had
open cholecystectomy [55].
Recent studies support existing data that there is a signifi-
cant interindividual variation in the need for oxycodone for
sufficient analgesia [53,54]. Preoperative patient history also
seems to affect the need for opioid analgesics. In a recent
study the need for oxycodone was two times higher in patients
who had surgery due to chronic cholecystitis compared with
patients having minilaparotomy cholecystectomy due to
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simple gallstone disease [56]. Consistent with Harju et al. [53],
in another study in patients with laparoscopic cholecystec-
tomy there was a high interindividual variation for the need
for oxycodone: for some patients oxycodone 10 mg i.v. was
sufficient, while some needed 40 mg i.v. [57].
Different combinations of background analgesics did not
affect significantly the oxycodone consumption during the
early phase of recovery after laparoscopic cholecystectomy.
The mean dose of oxycodone was between 18 and 22 mg
in patients with coxib, paracetamol or dexamethasone, or
different combinations of these three drugs [58].
For personal use only.
3.6 Orthopedic surgery
High analgesic efficacy of oxycodone has been shown also in
orthopedic surgery. Postoperative pain after bone surgery is
often severe. In patients with first metatarsal bone osteotomy
and paracetamol 1 g t.i.d. for background analgesia, the
mean oxycodone consumption during the first 72 h after
surgery was 59 mg in patients with dexamethasone 9 mg by
mouth and 83 mg in patients with no dexamethasone
supplementation [59].
Intravenous oxycodone has been found to be a highly effec-
tive mode to treat early pain after more extensive orthopedic
surgery; a high analgesic efficacy has been demonstrated in
acromioplasty [60], spine surgery [61,62] and knee [63] and hip
arthroplasty [38]. In lumbar disc surgery, controlled-release
oxycodone 20 mg b.i.d. by mouth reduced the need for intra-
venous PCA morphine during the first 24 h after surgery
(26, vs 52 mg in the placebo group); and a similar
morphine-sparing efficacy was found also for the 25 -- 48 h
postsurgery (i.v. PCA morphine 13 mg in the patients with
oxycodone vs 33 mg in the placebo group). In both groups,
the patients had paracetamol 1 g i.v. every 6 h for background
analgesia. In patients with oxycodone the incidence of PONV
was lower, bowel function recovered earlier and the patient
satisfaction with pain management was higher than in the
control group [62].
3.7 Eye surgery
In contrast to efficacy comparison in patients with breast
surgery, in which the analgesic oxycodone-to-tramadol ratio
was 1:8 -- 1:10 [50,51], in eye surgery oxycodone seems to be
1050 Expert Opin. Pharmacother. (2012) 13(7)
more effective. In retinal surgery, controlled-release oxyco-
done 10-mg tablets were compared with a drug combination
of tramadol 100 mg/metamizol 1 g i.v. The oxycodone-
treated patients rated quality of analgesia significantly higher
than the tramadol/metamizol-treated patients. The incidence
of adverse effects and number of patients discontinuing study
medication were less with oxycodone, indicating that in eye
surgery oxycodone could be superior to tramadol [64].
3.8 Gynecological surgery
Women report more severe pain and have greater analgesic
responses to opioids than men, indicating that there are sex
differences in nociceptive responses and pain perception [65].
However, in postoperative pain perception and opioid con-
sumption, gender seems not to be as important a predictor
as traditionally believed [66].
Oxycodone has been evaluated in gynecological surgery and
caesarean section most often combined with paracetamol or
NSAIDs. The theoretical background behind oxycodone use
as part of multimodal analgesia [67] is that higher doses of
opioids increase the risk for opioid-induced hyperalgesia and
other adverse effects [68].
In North America oxycodone is commonly used as a combi-
nation product with ibuprofen or paracetamol. Both oxycodone
5 mg/ibuprofen 400-mg tablets and oxycodone 5 mg/
paracetamol 325-mg tablets provide enhanced analgesic action
compared with pure opioid-based analgesia in women undergo-
ing abdominal or pelvic surgery [69-71]. In one study in
60 women undergoing elective laparoscopic surgery, preopera-
tive administration of oxycodone 15 mg by mouth did not
enhance analgesia achieved with ibuprofen 800 mg [72]. How-
ever, the mean of oxycodone’s Cmax was low at 10.0 ng/ml
(range 4.6 -- 14.7 ng/ml) and Tmax was 4.8 h (range 2 -- 8 h),
indicating that in most patients subtherapeutic concentrations
were achieved [19] and that peroral administration was not opti-
mal in this indication, because PONV, anesthesia and surgery
delay and decrease the absorption of peroral medicines [9,49].
In laparoscopic hysterectomy consistent effects of different
types of adjuvant analgesics on oxycodone need have been
shown. In three studies in which a similar protocol was
used, oxycodone was administered by intravenous PCA
pump (oxycodone 1 mg/ml and droperidol 0.05 mg/ml, oxy-
codone i.v.-bolus dose 0.04 mg/kg and a lockout time of
8 -- 10 min). In the control groups the total dose of oxycodone
during the first 24 h after surgery was 0.45 -- 0.55 mg/kg.
Paracetamol 1 g every 6 h [73], pregabalin 600 mg by mouth
before surgery [74] and dexamethasone 15 mg i.v. [75] provided
a similar opioid-sparing efficacy; the total dose of oxycodone
was 0.34 mg/kg/24 h in all three studies. However, the inter-
individual variation in oxycodone need was significant, and
the need for intravenous PCA oxycodone varied more than
10-fold, being between 0.1 and 1.3 mg/kg/24 h.
An early finding that after major abdominal surgery less
oxycodone than morphine is needed for pain relief [18] has
been confirmed recently by Lenz and colleagues [35] in

patients with laparoscopic hysterectomy. The consumption
of oxycodone with intravenous PCA (13 mg/24 h) was
significantly less than that of morphine (22 mg/24 h).
3.9 Thoracic and cardiac surgery
Opioids are a basis in the treatment of postoperative pain after
thoracic surgery. However, adverse effects of opioids such as
sedation, respiratory depression, biliary spasm, gastrointesti-
nal dysfunction and PONV necessitate the use of adjuvant
analgesics to reduce opioid consumption and adverse effects.
In coronary artery bypass grafting (CABG) surgery patients
the mean need for intravenous PCA oxycodone is 50 -- 60 mg
during the first 24 postoperative hours and it decreases on the
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 08/14/12
following days. As in other indications, in CABG surgery
interindividual variation in opioid need is significant. In a
recent study, the range of intravenous oxycodone need for ini-
tial titration for comfort in the ICU was 0 -- 16 mg; intrave-
nous PCA oxycodone consumption during the first 24 h
between 6 and 94 mg, and for postoperative hours
25 -- 48 between 8 and 110 mg; the cumulative consumption
during the first 48 h was between 14 and 239 mg [76]. In
another study S-ketamine provided only a modest
oxycodone-sparing efficacy: mean intravenous PCA oxyco-
done consumption was 103 mg/48 h in the S-ketamine group
For personal use only.
and that in the placebo group 125 mg/48 h [77]. In another
study, contrary to the study hypothesis, the choice of intrao-
perative opioid did not affect postoperative oxycodone need;
oxycodone consumption in patients with intraoperative sufen-
tanil ranged between 42 and 219 mg/48 h and in patients
with remifentanil between 29 and 166 mg/48 h [78].
Cardiothoracic surgery, like gastrointestinal surgery, is a
condition in which the switch from parenteral administration
to enteral dosage forms should be carefully considered. Once
patients are able to tolerate analgesics by mouth, the oral route
is preferred because it is more convenient, noninvasive and
less expensive. However, when oxycodone or any other
opioids are swallowed soon after surgery, first delayed and
then abrupt absorption of an increased amount of opioids
when gastrointestinal function is restored should be taken in
account. During the first 48 h after cardiac surgery absorption
of oral drugs is low [79], and thus the use of tablets should be
postponed after that period. Later, when gastrointestinal func-
tion is restored, peroral preparations may perform suffi-
ciently [80]. Use of oxycodone by mouth for postoperative
pain management after cardiothoracic surgery warrants addi-
tional studies, and oral transmucosal administration should
be tested also in this patient population.
3.10 Neurosurgery
Pain following craniotomy is common and often moderate or
severe; 60% of patients have significant pain after craniotomy [81].
In some institutions opioids are avoided in craniotomy
patients because of their risk to cause respiratory depression,
PONV and sedation, which may interfere with the neurolog-
ical examination [80]. However, lower doses of oxycodone
Expert Opin. Pharmacother. (2012) 13(7)
Oxycodone hydrochloride trihydrate
have been well tolerated also in neurosurgery. In one study
in adult patients, intravenous oxycodone with PCA-device
settings of bolus dose 0.03 mg/kg, lockout time 10 mins, no
background infusion and a maximum of three boluses/
hour provides an effective and well-tolerated analgesia. Less
oxycodone was used during the first 24 h after cranial surgery
in patients with ketoprofen 100 mg i.v. t.i.d. (20 mg/24 h)
than those with paracetamol 1 g t.i.d. (37 mg/24 h), respec-
tively. No severe or serious drug-related adverse effects were
reported [82]. In another small study, the need for oxycodone
5 mg/paracetamol 325 mg tablets was less in patients with
COX-2-inhibitor rofecoxib (mean dose of oxycodone 32 mg
by mouth) than that in those with no rofecoxib (68 mg) [83].
These results indicate that small doses of opioids can pro-
vide safe and effective pain relief also in craniotomy patients.
However, more studies in intracranial surgical patients are
needed, because sample sizes in the published studies have
been small.
4. Oxycodone in elderly patients
The average age of the population is increasing in all coun-
tries, and the number of aged (‡ 80 years) surgical patients
is the fastest-growing patient group. Pain management in
aged patients is complicated owing to age-related changes
in pharmacokinetics, and multipharmacy, which is common
in the elderly [84].
Age affects the pharmacokinetics of oxycodone. In the
elderly, oxycodone exposure is up to 80% greater and clear-
ance is 30% lower than in young adults and, thus, at 8 h after
oxycodone administration plasma oxycodone concentration is
twofold higher in aged subjects than in young adults [30,54,85].
Multipharmacy is an issue because concomitant medica-
tions may alter oxycodone pharmacokinetics. CYP3A4
inhibitors (e.g., clarithromycin, itraconazole, ritonavir and
grapefruit juice) have been evaluated in young healthy adults
and in the elderly. CYP3A4 inhibition increases exposure to
oxycodone and its active metabolite, oxymorphone, in the
two age groups in a similar manner. However, neither age
nor CYP3A4 inhibition influence oxycodone effects in cold
pain threshold, cold pain intensity, self-rated behavioral meas-
urements, pupil size, Maddox wing test or the digit-symbol
substitution test [86]. CYP3A4 inductors, such as rifampicin
and St John’s Wort, enhance elimination and decrease oxyco-
done exposure. Similar to CYP3A4 inhibition, CYP2D6 inhi-
bition (e.g., paroxetine) prolongs oxycodone elimination
twofold and increases oxycodone exposure twofold, but with
no pharmacodynamic consequences when single doses are
used in acute pain management.
Intravenous oxycodone is a feasible opioid analgesic for
postoperative pain management in the elderly. In cardiac
surgery patients, the mean effective analgesic concentration
of oxycodone is similar in young adults and in the elderly.
In a recent study, three doses of oxycodone 0.05 mg/kg i.v.
were given for patients recovering from cardiac surgery. The
1051
 H. Kokki et al.
older patients had less pain but were more sedated after the
third oxycodone dose than the younger patients. However,
fentanyl concentrations were significantly higher in the elderly
for several hours after surgery, and in that study this is the
most likely cause for the greater sedative effect observed [87].
Oxycodone by mouth has been evaluated in the elderly for
postoperative pain management after knee or hip arthroplasty.
In one study, oxycodone controlled-release tablets were
equally effective with intravenous PCA morphine in patients
with hip and knee arthroplasty. Although pain scores were
similar in the two groups the amount of rescue analgesics dur-
ing the hospital stay was lower and the duration of hospital
stay was shorter (5.5 vs 6.4 days) with controlled-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 08/14/12
release oxycodone tablets than with intravenous PCA mor-
phine. Adverse effects, somnolence and constipation, were
more common with oxycodone, but PONV was more com-
mon with morphine [88]. In a recent study in 114 elderly
patients, 20-mg oxycodone controlled-release tablets b.i.d.
with immediate-release oxycodone for rescue analgesia was
compared with intravenous PCA morphine after total hip
arthroplasty. There were no differences in pain scores at dur-
ing the first 72 h after surgery. Patients taking intravenous
PCA morphine received more antiemetics than patients
taking oxycodone [38].
For personal use only.
Pain relief with oxycodone 10 mg b.i.d. by mouth as part of
a multimodal approach was as effective as epidural ropiva-
caine in patients after radical retrobupic prostatectomy. How-
ever, the safety profile of oxycodone was better than that of
epidural ropivacaine. Epidural infusion was terminated before
the end of the planned 3-day study period in 8/20 patients,
with adverse effects, loss of sensory function, hypotension or
poor efficacy being the most common reasons [89].
Although oxycodone can be used in elderly patients, post-
operative pain management approaches in frail elderly
patients have not been established and more studies are
needed on the use of oxycodone in this special patient group.
5. Patient controlled analgesia
Oxycodone is the drug of choice for PCA opioid administra-
tion in Finland [5]. The common starting doses for opioid-
naive patients are a bolus dose of 0.02 -- 0.03 mg/kg with a
lockout time of 10 min and a maximum of four doses in an
hour. Patient preference for intravenous PCA is higher com-
pared with conventional regimens. However, evidence does
not support the common belief that intravenous opioid PCA
would provide better analgesia than other opioid regimens.
If there is enough nursing staff, and appropriate use and com-
bination of different oxycodone formulations is applied in
multimodal analgesia, the superiority of intravenous PCA oxy-
codone may be less evident. Also, the evidence regarding PCA
opioid consumption is contradictory; both no change and an
increase in consumption have been reported [90].
In a multimodal analgesia, oxycodone controlled-release
tablets provide similar or slightly more effective analgesia
1052 Expert Opin. Pharmacother. (2012) 13(7)
than intravenous opioid PCA. In a recent study in patients
with hip arthroplasty, oral oxycodone, as a component of
multimodal pain management, at a mean dose of
103 mg/50 h, provides similar pain relief and outcome as
intravenous PCA with morphine [38]. The feasibility of oral
multimodal pain management with controlled-release
oxycodone tablets has been shown also in patients with spine
surgery. In a recent study, the need for intravenous PCA
morphine was less and the pain-related interface with walking,
coughing and deep breathing was also less in patients using a
multimodal approach than that in patients with intravenous
morphine [61].
Oxycodone intravenous PCA is a feasible mode for exam-
ple in orthopedic surgery. Recently it has been evaluated in
45 patients with acromioplasty. For concomitant analgesia
these patients received one of a single-injection interscalene
plexus block, a subacromial bursa block or placebo. Oxyco-
done consumption was greatest in the placebo (27 mg) and
subacromial block (24 mg) groups, but with plexus block
the need for oxycodone was significantly less (6 mg i.v.) [60].
Intravenous PCA oxycodone with or without concomitant
NSAIDs (ketoprofen or diclofenac) was evaluated in
64 knee arthroplasty patients. Both NSAIDs had an
oxycodone-sparing efficacy: oxycodone consumption in the
ketoprofen group was 43 mg, in the diclofenac group 45 mg
and in the placebo group 61 mg [63].
Respiratory depression is a major concern with opioid anal-
gesics. An important safety issue for oxycodone is fast onset of
action after intravenous administration. Olkkola et al. [19]
have shown that after oxycodone 0.1 mg/kg i.v. the maximum
mean end-tidal carbon dioxide concentration and minimum
mean ventilatory rate occurs within 8 min after oxycodone
administration, and that the minimum mean peripheral
arteriolar oxygen saturation occurs even earlier, at 4 min
after oxycodone dosing in children recovering from deep-
inhalation anesthesia. There are other isolated reports sugges-
ting that, besides a faster onset of intrinsic antinociceptive
effect, oxycodone administration also demonstrates a rapid
onset of its respiratory effects, if any, compared with some
other opioids. This has been shown also in healthy adult
volunteers having stable inhalation anesthesia. In a recent
study, oxycodone produced dose-dependent respiratory
depression across the doses evaluated [91].
One of the main safety issues with PCA systems is the
stability of compounds in the syringes and the reservoirs.
The microbial and physicochemical stability of oxycodone
hydrochloride solutions in PCA reservoirs have been noted
for different diluted solutions [92].
The complex programming processes in setting up and
potential technical errors in using the equipment are risk fac-
tors for medication errors when PCA-pumps are used for
intravenous administration of opioids. Based on recent studies
in postoperative analgesia with controlled-release oxycodone
tablets which show equal efficacy with fewer adverse effects
and technical problems than with opioid PCA, the use of

controlled-release oxycodone as part of multimodal analgesia
is recommended.
6. Intraspinal administration
Neuraxial opioids are commonly used in postoperative pain
management, and both intrathecal [93] and epidural
opioids [94] have been shown to provide potent analgesic
efficacy either alone or combined with local anesthetics.
There are no reports of intrathecal efficacy of oxycodone, and
only two studies have evaluated epidural use of oxycodone -- with
contradictory results. In the first study, in patients after major
abdominal surgery, no advantage was found in epidural admin-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 08/14/12
istration of oxycodone (dose: 65 mg/24 h) compared with intra-
venous oxycodone (dose: 72 mg/24 h). In the control group,
epidural morphine provided significant analgesic efficacy with
a total dose of 8 mg/24 h. There were no differences with pain
scores at rest but dynamic pain, pain during coughing, was better
controlled with epidural oxycodone than with morphine. The
adverse-effect profiles were similar in the three study groups [12].
A more recent study indicates that oxycodone may have
analgesic efficacy also when administered into the epidural
space. Yanadigate et al. [39] studied epidural oxycodone in
patients undergoing gynecological surgery. Postoperative
For personal use only.
pain was treated with: i) oxycodone 2-mg epidural bolus fol-
lowed by continuous epidural infusion of 6 mg/24 h;
ii) oxycodone 4-mg epidural bolus followed by 12 mg/24 h
infusion; and iii), in the control group, morphine 2-mg bolus
and 6 mg/24 h infusion. Oxycodone 4 + 12 mg was equally
efficacious, but oxycodone 2 + 6 mg was inferior to morphine
2 + 6 mg. Safety was better with oxycodone and adverse
effects were less common with epidural oxycodone [39].
More clinical studies of epidural and intrathecal use are
warranted, as oxycodone may have more favorable CNS
pharmacokinetics than other opioids [95,96].
7. Adverse effects of oxycodone
Adverse effects of oxycodone are typical of opioid agonists, with
CNS depression and gastrointestinal dysfunction the most
commonly reported. In acute pain management, appropriate
patient monitoring may detect potential adverse reactions early.
However, in significant overdoses, respiratory depression and
cardiovascular collapse may result, and prompt treatment
should be initiated to establish open airway, assisted ventilation
and circulatory support. Repeated doses of naloxone 0.4 -- 2 mg
i.v. may be administered. In acute pain management, if the
patient is not monitored, the outcome after opioid-induced
respiratory depression can be fatal [97] (H Kokki, personal
communication).
One of the most common adverse effects of opioids is gas-
trointestinal dysfunction including constipation, abdominal
fullness and sense of incomplete bowel emptying, which are
often associated also with urinary disorders. These adverse
effects are thought to be mediated by stimulation of opioid
Expert Opin. Pharmacother. (2012) 13(7)
Oxycodone hydrochloride trihydrate
receptors in the gastrointestinal tract and in the bladder [98].
Constipation may be prevented with laxatives, but constipa-
tion may persist despite appropriate laxative use. In chronic
pain management there is good evidence that oral naloxone
could reverse oxycodone-associated bowel dysfunction [99],
and our initial experiences in acute pain management are
encouraging on both bowel and bladder dysfunction reversal.
There seem to be some differences in adverse drug reactions
associated with different opioids. Several reports indicate that
oxycodone may cause fewer hallucinations and nightmares
than morphine [10,100,101]. Oxycodone decreases arterial blood
pressure less compared with morphine in equianalgesic
doses [18]. This may be related to the fact that oxycodone
does not release significant amounts of histamine as does
morphine. Lesser release of histamine may explain also why
itching is less common with oxycodone compared with mor-
phine, although other mechanisms are also involved [13,102].
An in vitro study indicated that oxycodone may not suppress
the immune system as much as morphine [103]. However, the
clinical significance of this finding remains unclear in acute
postoperative pain management. In acute use, physical depen-
dence and withdrawal syndrome are not common but should
be taken in account if the need for oxycodone is prolonged.
Oxycodone is extensively metabolized by CYP2D6 and
CYP3A enzymes and it is thus prone to drug interactions. The
inhibition of metabolizing enzymes may lead to clinically rele-
vant increase in oxycodone concentrations, and inhibition of
these enzymes decreases oxycodone exposure. Whether these
interactions are associated with any safety concerns in clinical
practice remains an open question because in acute postopera-
tive pain management oxycodone should always be titrated to
the effect [104]. Because the lipophilicity of oxycodone is rela-
tively low, its penetration into the CNS is limited. Simultaneous
use of other drugs affecting the CNS or CNS drug penetration
may potentiate the effects of oxycodone [13,105].
Opiates are the main problem drugs among persons receiving
treatment for drug abuse in Europe, as they are in many coun-
tries [6]. Oxycodone is a pure opioid agonist and it is associated
with abuse potential. In 2010 in the USA, there were just under
600000 new nonmedical users of oxycodone [6]. Abuse poten-
tial should be taken in account when prescribing oxycodone
for patients with known abuse risks. Formulations that pro-
vided stable concentrations or are combined with opioid antag-
onist naloxone should be safer in acute pain management in risk
patients. Oxycodone is most often abused intravenously or by
snorting [106]. In the future there will be new tamper-
resistant oxycodone formulations available for clinical use which
should decrease the risk for oxycodone abuse.
8. Future aspects
Enteral bioavailability of oxycodone is relatively high and thus it
is likely that in the future enteral administration will be the most
popular route to administer oxycodone for postoperative pain.
The indications to use intravenous PCA for oxycodone
1053
 H. Kokki et al.
administration will decrease and focus more on major surgery.
Emerging data seem to indicate that optimal pain control can
be achieved by combining a scheduled controlled-release
formulation with immediate-release oxycodone as needed for
rescue analgesia, pointing to a new standard for the near future.
In all postoperative patients, the gastrointestinal tract does
not function optimally for oral administration of analgesics.
Recently, an orodispersible tablet, approved in some countries,
provides a promising option for oxycodone administration in
this situation. Transmucosal use of oxycodone facilitates the
optimal dose titration with orodispersible tablets in the early
phase of recovery and is a feasible formulation for rescue
analgesia in the later course of recovery. Moreover, some
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Sanofi Synthelabo on 08/14/12
patients cannot or are not allowed to swallow drugs (PONV,
gastrointestinal surgery patients with gastric suction, children,
the elderly, etc.), and in these patients oral transmucosal
administration should be an optimal route.
Experimental studies indicate that a sublingual spray solution
dosage form with adjusted pH may provide fast onset of pain
relief. The pH of the solution is important because it affects
transmucosal absorption. In the future, oxycodone spray solu-
tion may provide an easy and economical way for postoperative
pain treatment in the early phase of recovery [87].
Opioids are associated with high incidence of adverse
For personal use only.
effects. In the first hours after surgery respiratory depression
and risk for PONV are the two most common concerns.
Thus, close monitoring and an appropriate combination of
nonopioid analgesics as a part of multimodal approach will
decrease the need for oxycodone and are likely to reduce the
risk of serious complications. Later in the course of recovery,
bowel dysfunction is the most harmful adverse effect for
patients. In this instance, the new controlled-released combi-
nation depot tablet, containing oxycodone and naloxone in
a 2:1 ratio, is promising. Our own initial experiences in acute
pain management have been encouraging so far. In our qua-
lity assurance project in pain management we found that in
patients on opioids before spine surgery switching to oxyco-
done--naloxone improved not only bowel function but also
bladder function (data not shown). Additional studies are
needed to show how well the oxycodone--naloxone product
will fit with postoperative pain management protocol.
Opioids are associated with abuse risk, and this should be
taken in account also in postoperative pain management while
prescribing oxycodone. Oxycodone formulations less prone to
abuse are under development.
9. Expert opinion
In Finland, oxycodone has been the most popular opioid in
acute pain management for the last 50 years, and in pediatric
pain management we have 30 years’ experience with oxycodone.
During the last decade the use of oxycodone has surpassed that
of morphine in several other countries [6], and it is likely to
increase in the future. The new interest in oxycodone is based
on the favorable pharmacokinetics and pharmacodynamics of
1054 Expert Opin. Pharmacother. (2012) 13(7)
oxycodone especially in the target site, in the CNS. The analge-
sic efficacy of parenteral oxycodone is similar to that of mor-
phine in somatic pain and superior in visceral pain. Moreover,
the onset of analgesic action is relatively fast and the relatively
high enteral bioavailability allows an easy switch from one
drug formulation to another during the course of pain manage-
ment. Other reasons why oxycodone use is increasing in postop-
erative pain management is that oxycodone does not release
histamine, and the risk for some other adverse effects such as
nightmares and hallucinations is low.
Oxycodone is highly effective and well tolerated in different
types of surgical procedure and in different patient groups. Its
use is relatively safe also in special patient groups and in
patients with renal or hepatic failure, and age is no contrain-
dication for oxycodone -- it is used both in preterm neonates
and in elderly patients.
In future the use of oral transmucosal administration and
swallowed oxycodone--naloxone controlled-release tablets is
likely to increase. Appropriate concurrent use of these drug for-
mulations will decrease the need for more complex administra-
tion techniques, such as intravenous PCA. The transmucosal
bioavailability of oxycodone is high and new transmucosal
formulations, orodispersible tablets and pH-adjusted liquids
should provide feasible options for effective pain management
in patients with impaired gastrointestinal function and in
patients who should not or do not swallow drugs. A new com-
bination product, a controlled-released oxycodone--naloxone
tablet, may make it possible to overcome some of the harmful
adverse effect of opioids, for example bowel and bladder
dysfunction. The oxycodone--naloxone combination should
be useful also in surgical patients because anesthesia, periopera-
tive bed rest and surgery itself impair bowel and bladder
function. Controlled-release tablets will provide a constant
background oxycodone concentration and a immediate-
release transmucosal formulation may offer a fast-acting option
for rescue analgesia.
The use of these new products in postoperative pain manage-
ment warrants additional studies. More data are needed in phar-
macokinetic--pharmacodynamic interactions of oxycodone with
other analgesics and perioperative medications. For effective
and safe use of oxycodone, and for other opioids as well, it is
important to know the analgesic concentrations at the target
sites. We need to know the minimal analgesic concentrations
for different types of surgery and different type of analgesic
combination. For example, ketamine, an N-methyl-D-alanine
receptor antagonist, is a useful concomitant compound with
some other opioids in postoperative pain management.
Whether this is the case with oxycodone should be evaluated.
More data are needed also on intraspinal use of oxycodone
because our current knowledge is sparse and controversial.
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.

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Affiliation
Hannu Kokki†1,2 MD, Prof.,
Merja Kokki 1,2 MD, PhD &
Sari Sj€ovall 3 MD, PhD
†
Author for correspondence
1
Kuopio University Hospital,
Department of Anaesthesia & Operative Services,
Puijonlaaksontie 2, FI-70211 Kuopio, Finland
Tel: + 358 17 17 3311;
Fax: +358 17 17 3443;
E-mail: hannu.kokki@kuh.fi
2
University of Eastern Finland,
Department of Anaesthesiology & Intensive Care,
School of Medicine, Kuopio, Finland
3
Central Hospital of Satakunta,
Department of Surgery & Anaesthesia,
Pori, Finland