Best Practice & Research Clinical Anaesthesiology

Vol. 16, No. 4, pp. 475488, 2002

doi:10.1053/bean.2002.0262, available online at http://www.idealibrary.com on

1
Pharmacology of systemic analgesics
Frederic Camu*

MD

Professor of Anaesthesiology and Chairman

Caroline Vanlersberghe

MD

Sta Anaesthesiologist
Department of Anaesthesiology, Flemish Free University of Brussels Medical Center, 1090 Brussels, Belgium

Systemic administration of analgesic drugs is still the most widely used method for providing
pain relief in acute painful situations. Opioids may be selected on the basis of their
physicochemical characteristics and their diusion index to the brain. But in clinical practice,
their very steep concentrationanalgesic eect relationship remains a critical aspect of opioid
therapy. Thus, small uctuations in plasma concentrations of opioids may lead to profound
uctuations in analgesic eect when their plasma and eect-site concentrations are near the
minimum eective analgesic concentration (MEAC). Combining drugs acting on dierent
mechanisms of nociceptive modulation oers benets from additive/synergistic eects and will
decrease the incidence of their adverse eects. Evidence-based reviews showed that eective
pain relief using non-opioid analgesics relied on paracetamol supplemented with non-steroidal
anti-inammatory drugs (NSAIDs). The role of COX-2 selective inhibitors (CSIs) in acute pain
relief still requires further evaluation. NSAIDs, CSIs and paracetamol share the property of
morphine sparing in situations of severe (post-operative) pain. CSIs may be benecial in patients
in whom post-operative bleeding is a major surgical risk as the eects of NSAIDs on coagulation
may last for days. Finally, low-dose ketamine infusions remain a worthwhile addition to opioid
therapy. Analgesic concentrations of ketamine are 1/5th to 1/10th the anaesthetic concentration
and exert signicant inhibition on Nmethyld-aspartate (NMDA) receptor activation.
Key words: analgesia; post-operative; analgesics; opioids; tramadol; NSAIDs; paracetamol;
dipyrone; pain; acute.

Opioids have long been the rst-line medication for relieving severe nociceptive pain.
They are considered to be highly eective although they often control dynamic pain
inadequately and elicit signicant side-eects. Moreover, dosage requirements vary
markedly between patients. Improved management of acute post-operative pain is
likely to result from combinations of agents acting additively or synergistically at
dierent sites of the nociceptive signal transmission. In this context, the non-steroidal
anti-inammatory drugs (NSAIDs) and cyclo-oxygenase-2 selective inhibitors (CSIs)
may have potential utility.
Requirements of systemic analgesics vary widely as a result of interindividual
variations in drug pharmacokinetics and pharmacodynamics, the type and extent of
*Author to whom all correspondence should be addressed.
c 2002 Elsevier Science Ltd. All rights reserved.
15216896/02/$ - see front matter *

476 F. Camu and C. Vanlersberghe

the tissue lesion, the degree of discomfort and occurrence of side-eects. In elderly
patients, the state of mind, personality, anxiety, social and ethnocultural backgrounds
can all have considerable inuence on the patient's perception of pain. Changes in
physiology, cognitive and sensory impairment and/or chronic illness may further
temper the therapeutic expectations.
MAJOR OPIOIDS
In the management of moderate to severe post-operative and inammatory pain
opioids act peripherally on injured tissues to reduce inammation, in the dorsal horn
to impede transmission of the nociceptive signal and at the supraspinal level to activate
inhibitory pathways of the spinal processing of nociception.
Morphine and pure m -receptor agonists
These drugs are the rst choice for severe pain as their analgesic ecacy is high. They
show a sigmoidal dose/eect relationship that allows their dose to be adapted to the
intensity of the acute pain perceived. When given intravenously, the peak eect is
achieved in minutes. As rst approximation a standard dose adapted to the expected
intensity of the pain could be given; however, titration of the dose to the patient's
need is essential. As an example, intravenous morphine titration with boluses of 2 or
3 mg every 5 minutes is an adequate analgesia regimen for acute pain in both young
and elderly patients1, with minimal side-eects of the m-receptor agonists. However,
increasing the dosage is often insucient to control severe pain with a visceral
component. The addition of a spasmolytic agent (e.g. hyoscine) or of a spasmolytic
analgesic (metamizole) will provide additive analgesia.
Dosing of systemic analgesic drugs is frequently based on body weight but there is
no evidence to justify this clinical practice in adults. Age, on the contrary, should
inuence the dose determination. Both pharmacokinetic and pharmacodynamic factors
are responsible for age-related dierences in analgesic needs. Indeed, the volume of
distribution and metabolic clearance of opioids and other analgesics are reduced in
elderly patients, yielding higher plasma free-drug concentrations. Age also alters the
sensitivity of the brain to opioid depressant eects.
Although the pharmacokinetic properties of morphine, pethidine and fentanyl are
relatively similar (Table 1), interpatient variability may hamper the elaboration of
therapeutic schemes. Hypothermia, hypovolaemia and hypotension aect the
absorption rate of drugs from their injection site. Hepatic disease aects the metabolic
clearance of opioids, particularly pethidine and to a lesser extent fentanyl and
morphine. Concurrent drug therapy may have marked eects. Phenytoin and
phenobarbital enhance the metabolic clearance of fentanyl, sufentanil and pethidine
while cimetidine impairs it. Cimetidine inhibits hepatic oxidative metabolism, but not
glucuronidation that is the predominant elimination process for morphine. End-stage
renal failure has no major eect on the elimination half-life of morphine but aects that
of its pharmacologically active metabolite.
Opioids are weak bases and exist in both ionized and un-ionized forms at physiological
pH. The blood levels of albumin and a1-acid glycoprotein determine the bioavailability
of the unbound, un-ionized fraction of the opioid dose. This is termed the diusible
fraction, and it amounts to 16% of plasma morphine, 2.2% of pethidine and only 1.4% of
fentanyl (Table 2). The free base form of opioid drugs diuses through the bloodbrain

Pharmacology of systemic analgesics 477

Table 1. Pharmacokinetic and pharmacodynamic characteristics of major opioids.

Morphine
Pethidine
Fentanyl
Alfentanil
Sufentanil

Intravenous
potency ratio

Vc (l)

Vdss (l)

Clm (l/min) T1/2b (h)

1
0.53
292
73
4521

23
88
13
4.1
14

224
305
335
34
339

1.05
1.02
0.6
0.36
0.92

T1/2ke0
(min)

1.44
37
25
1.33.3
2.54

30
6.4
0.9
6.2

Vc volume of central compartment; Vdss volume of distribution at steady-state; Clm metabolic

clearance; T1/2b elimination half-life; T1/2ke0 equilibration half-time between plasma and brain
concentrations.

barrier in proportion to their lipophilicity and the concentration gradient. Within the
brain, binding to receptors depends on the anity of the drug for the receptor and the
extent of binding to non-receptor sites, such as brain lipids, which is again dependent on
lipid solubility. The hydrophilic morphine, for example, penetrates the bloodbrain
barrier slowly but its low lipid solubility results in a large mass of drug reaching the
receptor sites where it binds with high anity to the m-receptor.
The analgesic eects of opioids are related to their plasma concentration. Either mean
eective concentration (MEC) or minimum eective analgesic concentration (MEAC) is
used for assessing concentrationeect relationships. MEC is the concentration at the
time re-medication is required. MEAC can be determined with the use of constant rate
infusions of the opioid until steady-state concentrations are reached. At that moment,
drug concentrations will have equilibrated between plasma and eect-site compartment
with its receptors, and the drug concentration eliciting analgesia can be determined.
The eective plasma concentration associated with analgesia may vary four- to vefold
between patients and is presented in Table 2. Pharmacodynamic variability may also be
related to endogenous pain modulation. The relationship between concentrations of
pethidine in the cerebrospinal uid (CSF) and the pre-operative CSF concentration of
endorphins demonstrated this.2
Hepatic metabolism of opioids may produce pharmacologically active metabolites.
Morphine-6-glucuronide (M6G) is 20 to 40 times more potent than morphine. As the
Table 2. Diusion of opioids to the brain.

pKa
Fu (%)
F non-ionized (%)
F diusible (%)
Vc (l)
Octanol/water partition
coecient
Diusion index
MEAC (ng/ml)

Morphine

Pethidine

Alfentanil

Fentanyl

Sufentanil

7.9
70
23
16
23
6

8.5
30
7.4
2.2
88
525

6.5
9
89
8
4.1
128

8.4
16
9
1.4
13
813

8
7
20
1.4
14
1778

4
1540

13
455

250
4060

88
0.61

178
0.030.04

Fu fraction of dose not bound to proteins; F non-ionized fraction of dose un-ionized;

F diusible fraction of dose diusible to brain; Vc volume of central compartment; MEAC minimum
eective analgesic concentration.
F diusible (Fu  F non-ionized)/100.
Diusion index (F diusible  liposolubility)/Vc.

478 F. Camu and C. Vanlersberghe

elimination half-life of morphine is very short (approximately 90 minutes), the much

longer elimination half-life of M6G may explain the prolonged and intense analgesic
eect of morphine observed after its post-operative administration.3 M6G excretion by
the kidney is directly related to calculated creatinine clearance. In patients with
impaired renal function, M6G may accumulate in blood and CSF. Pethidine, sufentanil
and tramadol are other examples of opioids with pharmacologically active metabolites.
Piritramide, a 3,3-diphenylpropylamine derivative, has a potency about two-thirds
that of morphine. Its dipiperidine structure gives it a clinical prole with fewer
side-eects (nausea, vomiting, obstipation and respiratory depression) than morphine;
however, sedation is more common. Onset of eect is rapid, with the peak analgesic
eect occurring 15 to 20 minutes after intramuscular or subcutaneous injection. The
duration of analgesia is 4 to 6 hours. Current dosing for intramuscular use is 0.2 to
0.3 mg/kg in adults and 0.25 mg/kg in children.
Methadone, a very lipophilic synthetic opioid, has comparable potency to morphine
but much longer duration of action. In contrast to morphine, methadone is converted
to two pharmacologically inactive metabolites. Several studies conrmed the existence
of a concentrationeect relationship for methadone in humans. MEC values
varied between 30 and 58 ng/ml, depending on dosing regimens.4 With repeated
administration, methadone becomes several times more potent than morphine. This
relates to the very long half-life of methadone (range 13100 hours), which makes
titration dicult. Despite its long half-life, many patients require administration at a
4- to 8-hour interval to maintain analgesic eect.5
The phenylpiperidine analgesics (fentanyl, sufentanil, and alfentanil) are potent
m-receptor agonists with moderate (alfentanil) to high lipid solubility (sufentanil). They
diuse rapidly through lipid membranes. The major pharmacodynamic dierences
between these drugs are potency and rate of equilibration between plasma and eect
site (ke0). Alfentanil has a pKa that is lower than the plasma pH and thus remains
mainly un-ionized at physiological pH. Its high diusible fraction results in a large
concentration gradient and fast diusion of the un-ionized molecules to the eect site
with fast onset of drug eect (Table 2). Despite its lipophilicity, the diusion of
sufentanil to tissues is slower because the un-ionized fraction not bound to plasma
proteins at physiological pH is smaller than for alfentanil. Sufentanil is the most potent
opioid clinically available. It is 625 times more potent than morphine and twelve times
more potent than fentanyl, while fentanyl is 60 times more potent than alfentanil.
Onset of analgesia is almost immediate when sufentanil is administered intravenously,
and the peak analgesic eect is observed after 8 minutes. Fentanyl has high potency
and lipophilicity. Plasma fentanyl PK-PD relationships for post-operative pain relief
suggest a Css50 (concentration required to produce 50% eect) of 0.63 + 0.25 ng/ml.6
Its elimination half-life is about 7 hours. Its respiratory depressant eect is seldom
clinically important at plasma concentrations of less than 3 ng/ml. No phenylpiperidine
analgesic induces histamine release, contrary to morphine and pethidine.
Drug distribution in elderly patients is inuenced by the reduction in lean body mass
and total body water (1015%) and the increase in adipose tissue (35% in men, 48% in
women). Therefore, the volumes of distribution of lipophilic analgesic drugs (pethidine,
fentanyl) increase relative to hydrophilic drugs, and such dierences would be expected
to be more marked in elderly female patients. On the contrary, higher plasma
concentrations must be expected with hydrophilic drugs (morphine) due to the
reduced total body water and lean mass. This may increase the risk of toxic eects7,8 and
mandates reduction of dosing. Furthermore, hepatic blood ow decreases from 1400 to
800 ml/minute by the age of 75 years. For drugs with high hepatic extraction ratios, such

Pharmacology of systemic analgesics 479

as opioids, an age-related decline in clearance must be anticipated. Alfentanil, fentanyl,

morphine and pethidine were all shown to have decreased plasma clearance in the
elderly.
Mixed agonistantagonist opioids
All opioids with mixed agonistantagonist activity (pentazocine, nalbuphine and
butorphanol) have limited exibility in dosing in comparison with pure agonists, and
they show ceiling eects for analgesia and respiratory depression. Assessed for their
ecacy in post-operative pain, agents with a marked ceiling eect to respiratory
depression produced usually inadequate analgesia for severe pain. Their maximal
analgesic eect was obtained with relatively low doses and a further increase of the
dosing induced a larger incidence of side-eects. These compounds do not allow an
adaptation of the dosing to the clinical need comparable with that of the pure
m-receptor agonists and have little to oer with regard to the variability of
post-operative pain.
Partial agonist opioids
The partial agonist buprenorphine shows high anity for the m-receptor but with low
intrinsic activity at this receptor (ecacy). Its doseresponse curve exhibits a ceiling
eect at less than the maximal eect produced by a full agonist. Therefore,
buprenorphine does not provide better analgesia than morphine, but may produce
fewer respiratory, gastrointestinal or urinary side-eects. Buprenorphine dissociates
very slowly from the m-receptor. When administered together with a pure m-receptor
agonist, displacement of the agonist can cause a net reduction in analgesic action.
Buprenorphine has poor oral bioavailability (16%) and is most often used by the
parenteral or sublingual routes. Its half-life is long (3045 hours).
WEAK OPIOIDS
Weak opioids include tramadol, codeine, dihydrocodeine, dextropropoxyphene and
tilidine. They are typically prescribed in low-dose formulations in combination with
either an NSAID or paracetamol. All of these drugs have a short half-life and their
duration of action is 2 to 4 hours.
Codeine has almost no analgesic eect by itself, except at doses above 90 mg, but its
metabolism leads to the production of morphine and M6G. Dextropropoxyphene, a
congener of methadone, has a very limited role in post-operative analgesia, as its
analgesic ecacy is not better than that of aspirin. Its major metabolite, norpropoxyphene, has a long half-life and is associated with excitatory eects, including
seizures.
Tramadol, a weak m- and k-receptor agonist, is available as an injectable formulation. It
acts at the monoamine receptors of the autonomous nervous system where it prevents
noradrenaline (norepinephrine) re-uptake and displaces stored 5-HT from nerve
endings. This eect on the descending antinociceptive pathways is complemented by a
moderate activity on opioid receptors.9 a2-adrenergic antagonists antagonize its spinal
modulating eects on pain. The synergy of monoaminergic and opioid activities achieves
analgesic eects.10 Approximately 1/10th as potent as morphine, continuous intravenous
infusions provide ecient post-operative analgesia. The maximum daily dose is

480 F. Camu and C. Vanlersberghe

500600 mg. Combined administration with NSAIDs or metamizole may be very useful
for relieving spastic visceral pain.11 If respiratory depression is extremely uncommon,
pronounced sedative eects with decreased motor activity may occur in elderly patients
and high-risk patients. Other side-eects include nausea, vomiting, dry mouth, dizziness,
headache, hypotension and sweating, but occur less frequently when the initial dose (1
1.5 mg/kg) is administered as a 1520-minute infusion. Tramadol provides inappropriate
control of dynamic pain, but may be useful in the late post-operative phase. Its use is
contraindicated in patients treated with MAO inhibitors or serotoninergic blocking
agents.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND COX-2

SELECTIVE INHIBITORS
NSAIDS or mixed COX-1/COX-2 inhibitors
Considered to be antipyretic and peripheral analgesics, they combine central and
peripheral eects. Their analgesic action results from inhibition of the cyclo-oxygenase
(COX) enzymes that synthesize prostaglandin E2 (PGE2) in the traumatized and
inamed areas, thereby increasing the threshold of activation of the nociceptors.
NSAIDs have also spinal mechanisms of action. The expression of COX-2 enzyme in
the spinal neurones is believed to contribute to neuronal plasticity and central
sensitization.12 This suggests that NSAIDs should have new and more active roles in
the treatment of clinical pain syndromes involving pathological pain after tissue injury
(post-operative, trauma) or nerve injury (neurogenic pain). NSAIDs are used today for
the treatment of post-operative pain, with or without supplemental opioid agents, in
surgeries where the inammatory component forms a major contribution to the
pain sensation (e.g. orthopaedics, ENT, stomatology, urology).
Information on the distribution and pharmacokinetic behaviour of NSAIDs helps in
the understanding of their eects. The anti-inammatory eects of NSAIDs rely on
their acidic character and their extensive protein binding. Inammation causes
capillary leakage of plasma proteins and acidic pH value in the extracellular space of
inamed tissues. The decrease of local pH will raise the concentration of un-ionized
NSAID, depending on the pKa of the molecule (pKa between 3.5 and 5), and yield high
concentrations in inamed tissues. Consequently, they inhibit prostaglandin synthesis
rst of all in inamed tissues. This tissue accumulation explains their generally longer
duration of action than would be expected from their plasma elimination half-life.
Pharmacodynamic modelling provides information on the tissue kinetics and
concentrationeect relationships of several NSAIDs. For aspirin, the half-time of
equilibration between plasma and eect site compartments (t1/2 ke0) was 20 minutes with
a Css50 of 5.3 mg/ml. The sigmoidicity (slope) factor of 1.35 indicates limited variability
between patients.13 The time course of analgesia is delayed relative to the change in
plasma drug concentration, especially after intravenous administration. For example, the
t1/2 ke0 for analgesia is fastest with paracetamol (7 to 13 minutes) and aspirin (20 minutes)
and longest with ibuprofen (460 minutes). Analgesic concentrations of NSAIDs have
been sparsely documented. In human experimental pain, concentrations of 40 mg/ml
were necessary for adequate analgesia with diunisal, a uorinated derivative of salicylic
acid.14 Clinical trials for ibuprofen treatment of post-operative pain after dental surgery
indicated a Css50 of 30 mg/ml, while at concentrations of 60 mg/ml 90% of patients would
be free of pain.15 Thus, increased plasma ibuprofen concentrations were associated with

Pharmacology of systemic analgesics 481

increased analgesia. In contrast, anti-inammatory eects may be better controlled with

low doses of sustained-release NSAIDs.
NSAIDs are useful during the pre-, intra- and post-operative periods for achieving
balanced analgesia given the multiplicity of mechanisms involved in pain.16 All share
analgesic, anti-inammatory, anti-oedematous and antipyretic eects to dierent
degrees. Ketorolac, indomethacin and diclofenac have potent analgesic activity while
the oxicams show more pronounced anti-inammatory eects. However, there is no
clear evidence for the clinical superiority of any individual NSAID for post-operative
use, and the choice may therefore depend on desired route of administration
(intravenous, oral, rectal), duration of eect, side-eect prole and cost. However,
meloxicam shows pronounced anti-inammatory activity with a large therapeutic
margin in comparison with standard NSAIDs.17
Small doses of NSAIDs are not ecient for acute pain relief, and therefore the
maximum daily dose should be prescribed, divided over several administrations given at
xed time intervals in relation to the mean duration of eect of these agents. The
average duration of clinical analgesia is 46 hours for ibuprofen and aspirin and 8 hours
for diclofenac, ketorolac, naproxen and diunisal. Additional opioids are required when
post-operative pain is severe. When given concurrently with opioids, NSAIDs reduced
post-operative opioid consumption by 1740%1821 and patients beneted from an
earlier return of post-operative bowel function and a lower incidence of bladder
spasm.22 Severe visceral pains are, on the contrary, less amenable to NSAID treatment.
Combination of NSAIDs with spasmolytic agents and with opioids may achieve good
results.
NSAIDs are enzyme inhibitors and their onset of eect is slower than that of
opioids. Their delayed analgesic eect could represent the time needed to block the
arachidonic acid cascade. Several clinical studies suggested that the opioid-sparing
eect of NSAIDs was not apparent until 45 hours after administration.2325 Thus, it
may be clinically relevant to administer NSAIDs before surgery to enhance pain
relief and opioid-sparing eect in the immediate post-operative period. When
compared to placebo treatments the pre-operative administration of NSAIDs
resulted in signicantly improved pain relief in the early post-operative period.2629
However, such treatments showed no pre-emptive analgesic eect of NSAIDs as the
reduction in opioid requirements was small and limited to the rst post-operative
hours.30,31
NSAIDs should be used cautiously in elderly patients. While it has not been
demonstrated that side-eects are more common in elderly patients in the context of
post-operative analgesia, the risk of serious complications of peptic ulcer disease
increased two- to vefold in the elderly receiving NSAID therapy.7 One should also be
concerned about the possibility of acute renal impairment. In elderly patients, 35% of
the nephrons are lost and renal blood ow decreases by 4553%. Also, sodium and
water retention may occur with prolonged NSAID therapy and may lead to an
additional cardiovascular risk. NSAIDs with long half-lives, such as piroxicam and
tenoxicam, may accumulate in elderly patient as both hepatic and renal functions
decline.
COX-2 selective inhibitors (CSIs)
The COX-2 expression during various pathological conditions suggests new potential
therapeutic indications for CSIs, including neuronal injury and pain. This class of drugs
includes rofecoxib, celecoxib, etoricoxib, parecoxib and valdecoxib. CSIs exert

482 F. Camu and C. Vanlersberghe

anti-inammatory activity while keeping gastric and coagulation side-eects to a

minimum. CSIs demonstrated clinical ecacy equivalent to that of conventional
NSAIDs in treating acute pain and inammation associated with surgery.32
As surgical patients often cannot tolerate post-operative oral medication, and as
pre-operative administration of oral medication is not indicated for most surgical
procedures, there is a need for novel parenteral CSIs. Parecoxib sodium is the rst
injectable COX-2 selective inhibitor that has been developed for the management of
post-operative pain.
Parecoxib sodium, the injectable prodrug of valdecoxib, a highly specic COX-2
inhibitor, is rapidly and completely hydrolysed in the liver to valdecoxib that reaches
its maximal concentration within 16 minutes. Valdecoxib is slowly cleared from the
plasma with an elimination half-life of about 8 hours.33 Parecoxib had a rapid onset of
action (713 minutes) in oral, orthopaedic and abdominal surgical pain models, and
demonstrated analgesic ecacy that was equivalent to ketorolac 1530 mg intravenous
or 60 mg intramuscular and superior to a single dose of morphine 4 mg.34
Furthermore, the duration of action of a single dose of parecoxib was longer than
that of either ketorolac or morphine. Parecoxib and valdecoxib reduced morphine
requirements by approximately 2040% when administered in combination with
patient-controlled analgesia morphine as part of a multimodal treatment strategy.35
Importantly, despite reduced morphine intake, patients receiving combined parecoxib
or valdecoxib and morphine therapy experienced superior pain relief compared with
patients receiving morphine alone. Signicant opioid-sparing eects and improved
analgesia when combined with morphine indicate that CSIs will prove useful in the
multimodal management of post-operative pain.

Side-eects
In general, NSAIDs whose inhibitory potency against COX-1 is higher than that
against COX-2 have more potential to induce severe side-eects.36,37 The major
side-eects of long-term treatments with NSAIDs are well documented and include
gastropathy, impaired haemostasis, asthma and bronchospasm, and depression of renal
function. The incidence of such side-eects is very small when these agents are used in
the context of short-term treatments for post-operative pain.38
Compounds that inhibit COX-1 and COX-2 isoenzymes with similar potency, such
as diclofenac and ketorolac, show a lesser incidence of gastrointestinal (GI) ulcers than
do compounds that are clearly more selective for COX-1, such as indomethacin,
aspirin and piroxicam.39 Improved side-eect proles of meloxicam and nimesulide,
both COX-2 inhibitors, over standard NSAIDs, were reported in endoscopy studies.40
The risk of upper gastrointestinal bleeding increases with old age, female gender, prior
peptic ulcer disease, concomitant steroid usage, smoking and excessive alcohol intake,
particularly with chronic use of oral NSAIDs. However, controlled studies found no
evidence that short-term (51 week) NSAID treatment for post-operative analgesia
induced signicant unwanted gastric eects36,41, but the risk of upper GI bleeding
seems related to dose.
Due to their COX-1-sparing nature, COX-2-specic inhibitors can be used to treat
pain and inammation eectively without associated bleeding risks and GI complications.42 Parecoxib and valdecoxib have little or no eect on platelet aggregation,
bleeding times and serum thromboxane A2 levels (assayed by its metabolite TXB2)
levels.43 The incidence of GI ulceration during treatment was similar to that with

Pharmacology of systemic analgesics 483

placebo. The improved platelet and GI safety of parecoxib and valdecoxib is observed
consistently in both young and elderly healthy adults.42
DIPYRONE AND PARACETAMOL
Generally considered as belonging to the NSAID family, metamizole (dipyrone),
paracetamol and its prodrug propacetamol do not inhibit the cyclo-oxygenase enzyme
at the concentrations used in pain therapy and have no anti-inammatory activity.
They therefore do not present the typical side-eects of NSAIDs on the gastric mucosa
and blood platelets. They are alternatives when there are contraindications to the use
of NSAIDs. The modes of action of metamizole and paracetamol have not been fully
elucidated but they have central antinociceptive eects involving serotonin and the
serotoninergic descending inhibitory pathways.44,45 Metamizole has an elimination
half-life of 7 hours and an average duration of clinical analgesia of 46 hours. The risk of
agranulocytosis after metamizole is minimal and mortality is probably not higher than
the paracetamol-related mortality.46
The peak plasma concentration of paracetamol is reached in less than 90 minutes after
oral administration and after 23 hours following rectal administration. The volume of
distribution is large (127 l) and its metabolic clearance 440 ml/minute. Its elimination
half-life is 3.3 hours. Experimental and clinical data support a direct relationship
between paracetamol plasma concentrations and its analgesic eect, which followed a
sigmoidal model. Analgesia was associated with a target plasma concentration of at least
10 mg/ml.47 The analgesic eect depended on the peak blood concentration. No
signicant analgesia was detected during continuous intravenous infusions of
paracetamol compared to a bolus-type regimen, which did produce analgesia despite
similar plasma concentration proles after both regimens.48 Taken together with the
elimination half-life, rapid release paracetamol should be administered at xed time
intervals of 46 hours. The initial minimum eective dose for adults is 1 g given orally,
and its maximal eect is obtained with doses of 1.5 to 2 g. Maintenance doses given
every 68 hours are unlikely to have a useful clinical impact because the target
concentrations for analgesia may not be reached. The daily dose limit is xed at between
60 and 90 mg/kg. Dosing should be reduced by 30 to 50% in chronic alcoholics and in
patients treated with isoniazide.
Propacetamol, the prodrug of paracetamol, is completely hydrolysed to paracetamol
by plasma esterases within 7 minutes after intravenous injection. One gram of
propacetamol yields 500 mg paracetamol. Most studies showed improved pain relief
after administration of propacetamol in comparison with placebo. Propacetamol also
signicantly reduced consumption of supplementary analgesics by 3650%.49 As
paracetamol-induced analgesia is partly centrally mediated, it is interesting to note that
propacetamol yields rapidly signicant concentrations of paracetamol in the CSF with a
peak concentration at 4 hours.50 Both the negligible binding of paracetamol to plasma
proteins and the relatively high lipid solubility of the drug contribute to these high
CSF concentrations.
Paracetamol, when given alone, provided generally better analgesia than placebo. Its
analgesic activity was inferior to that of NSAIDs following minor surgery, but the
ecacy of NSAIDs and paracetamol were comparable in post-operative pain from
major surgery.51 Adding an NSAID to paracetamol further improved post-operative
pain but, on the contrary, adding paracetamol to NSAIDs had no benecial eect on
analgesia.49

Nephrectomy

Intradermal Capsaicin

11
9
10

12
12
19
12

0.15 mg/kg i.v. (preop.)

2 mg/kg i.v. (preop.)

20 mg/kg/min (periop.)

0.5 mg/kg (preop.)

2 mg/kg/min (periop.)
2 mg/kg/min (1st day postop.)
1 mg/kg/min (2nd3rd days postop.)
10 mg/kg/min after 0.07 mg/kg bolus i.v.

0.15 mg/kg i.v.

0.30 mg/kg i.v.

9 mg/kg/min after 0.5 mg/kg bolus i.v.

# signicantly reduced; * not signicantly changed.

Electrical

Local burn
injury
Local burn injury

Abdominal
hysterectomy

Cholecystectomy

Dose/administration route

Type of
noxious
stimulation

# Intensity of ongoing pain (4 hours)

# Morphine consumption (24 hours)
* Intensity of ongoing pain (48 hours)
# Wound hyperalgesia (48 hours)
* Intensity of movement-associated pain (48 hours)
# Intensity of ongoing pain (1 hour)
# Wind-up-like pain (3 days)
# Area of wound hyperalgesia (7 days)
# Morphine consumption (6 hours)
# Intensity of spontaneous pain
# Area/magnitude of secondary hyperalgesia (pinprick stimuli)
* Allodynia
# Area of secondary hyperalgesia (punctuate and brush stimuli)
# Temporal summation (mechanical stimuli)
# Intensity of spontaneous pain
# Area of secondary hyperalgesia (punctuate and brush stimuli)
# Intensity of spontaneous pain
# Temporal summation (electrical stimuli)

Pain characteristics inhibited

Table 3. Results of randomized, double-blind, placebo-controlled studies on the analgesic eect of ketamine.

58

57

59

56

66

64

60

Reference

484 F. Camu and C. Vanlersberghe

Pharmacology of systemic analgesics 485

KETAMINE
Animal studies suggest that the spinal dorsal horn NMDA-receptor has an important
role in mechanisms underlying central sensitization.52,53 NMDA-receptor antagonists
lessen the hyperactivity of dorsal horn neurones following prolonged activation of
primary aerent neurones and inhibit nociceptive behaviour induced by peripheral
tissue or nerve injury.
Ketamine, a non-competitive NMDA-receptor antagonist, acts at the phencyclidine
(PCP) binding site in the NMDA-receptor channel.54 Both isomers of ketamine have
marked anity for the NMDA channel. Inhibition of pain by ketamine occurs at serum
concentrations below 1 mM/l55 with a highly signicant correlation between pain relief
and serum concentrations of ketamine. Analgesia is obtained with 1/10th to 1/5th of an
anaesthetic dose.
Several randomized, placebo-controlled trials showed that ketamine inhibited acute
pain caused by dierent noxious stimuli, including ischaemic, chemical56, heat57 and
electrical stimuli58 and the area of secondary hyperalgesia induced by chemical56 or
heat stimuli57,59 (Table 3). Ketamine-induced NMDA-receptor block also inhibited
temporal summation of repeated mechanical and electrical stimuli.58,59 Thus, clinical
evidence demonstrates that ketamine inhibits central sensitization. Pre- and
perioperative treatment with low-dose ketamine reduced post-operative morphine
consumption, although the intensity of ongoing post-operative pain was less aected.60
However, many other clinical studies on acute post-operative pain could not conrm
this nding.6163 Wound hyperalgesia may be a more sensitive measure of pain relief
than assessment of post-operative pain intensity.64,65 Stubhaug et al66 demonstrated
that the area of wound hyperalgesia was reduced for 4 days after low-dose ketamine
infusion, whereas ongoing pain was reduced for only 1 hour.
Controlled studies further demonstrated that ketamine signicantly inhibited
spontaneous ongoing pain in patients with dierent types of chronic pain, including
peripheral and central neuropathic pains, bromyalgia and chronic ischaemic pain.67
Ketamine also reduced allodynia in patients with neuropathic pain55,68 and the eect
may last longer than the pharmacological action as mechanical allodynia diminished

Practice points
. key factors for improving pain management include:
mechanism-based rather than symptomatic treatment of pain
administering the appropriate drugs according to their pharmacokinetic
prole
combining drugs acting on dierent mechanisms of nociceptive modulation to
enhance additive/synergistic eects
. signicant interpatient variation in the plasma concentration of opioid drugs
required to achieve adequate pain relief exists. Thus, dosing must be adjusted to
achieve the desired therapeutic endpoint
. the non-opioid analgesics act as antihyperalgesics/analgesics and as antiinammatory agents. The time course of analgesia is delayed relative to the
change in plasma drug concentration. The duration of analgesia may be dierent
from the duration of the anti-inammatory eect

486 F. Camu and C. Vanlersberghe

Research agenda
. well-controlled randomized clinical trials are needed for determining the most
ecient drug dosages in combination therapies in acute post-operative pain and
acute exacerbations of neuropathic pain
. clinical studies should evaluate the functional outcome of the morphine dose
reductions in combined analgesic therapies that document a morphine-sparing
eect
. studies should address the relevance of pharmacokinetic covariates (age, body
mass index, gender) for dierent systemic analgesics in specic pain models

considerably during the 3-month period of intermittent ketamine administration once

or twice daily during wound dressing.

REFERENCES
1. Aubrun F, Monsel S, Langeron O et al. Postoperative titration of intravenous morphine in the elderly
patient. Anesthesiology 2002; 96: 1723.
2. Tamsen A, Hartvig P, Fagerlund C & Dahlstrom B. Patient-controlled analgesic therapy. Part II.
Individual analgesic demand and analgesic plasma concentrations of pethidine in postoperative pain.
Clinical Pharmacokinetics 1982; 7: 164175.
3. Portenoy RK, Thaler HT, Inturrisi CE et al. The metabolite morphine-6-glucuronide contributes to the
analgesia produced by morphine infusion in patients with pain and normal renal function. Clinical
Pharmacology and Therapeutics 1992; 51: 422431.
4. Gourlay GK, Willis RJ & Wilson PR. Postoperative pain control with methadone: inuence of
supplementary methadone doses and blood-concentration response relationships. Anesthesiology 1984; 61:
1926.
5. Groshow L, Sheidler V, Grossman S et al. Does intravenous methadone provide longer lasting analgesia
than intravenous morphine? A randomized double-blind study. Pain 1989; 38: 151157.
6. Gourlay GK, Kowalski SR, Plummer JL et al. Fentanyl blood concentration analgesic response
relationship in the treatment of postoperative pain. Anesthesia and Analgesia 1988; 67: 320324.
* 7. Johnson AG & Day RO. The problems and pitfalls of NSAID therapy in the elderly (Part 1). Drugs &
Aging 1991; 1: 130143.
* 8. Mangat PS & Jones JG. Postoperative pain control in the elderly. Bailliere's Clinical Anaesthesiology 1993; 7:
169193.
9. Lee CR, McTavish D & Sorkin EM. Tramadol. A preliminary review of its pharmacodynamic and
pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993; 46:
313340.
10. Raa RB, Friderichs E, Reimann W et al. Opioid and nonopioid components independently contribute to
the mechanism of action of tramadol, an `atypical' opioid analgesic. Journal of Pharmacology and
Experimental Therapeutics 1992; 260: 275285.
11. Lehmann KA. Tramadol for the management of acute pain. Drugs 1994; 47 (supplement 1): 1932.
*12. Woolf CJ & Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288: 17651769.
13. Velegapudi R, Harter JG, Brueckner R & Peck CC. Pharmacokinetic pharmacodynamic models in
analgesic study design. Advances in Pain Research and Therapy 1991; 18: 559562.
14. Paalzow L, Edman P, Eekman A & Lindstrom B. The activity of diunisal and dextropropoxyphene on
experimental pain in man: relationships between plasma levels and analgesia. In Huskisson EC &
Caldwell AD (eds) Diunisal: New Perspectives in Analgesia, p 27. London: Academic Press, 1979.
15. Laska EM, Sunshine A, Marrero I et al. The correlation between blood levels of ibuprofen and clinical
analgesic response. Clinical Pharmacology and Therapeutics 1986; 40: 15.
16. Kehlet H & Dahl JB. The value of multimodal or `balanced analgesia' in postoperative pain treatment.
Anesthesia and Analgesia 1993; 77: 10481056.

Pharmacology of systemic analgesics 487

17. Engelhardt G, Homma D, Schlegel K et al. Anti-inammatory, analgesic, antipyretic and related
properties of meloxicam, a new nonsteroidal anti-inammatory agent with favourable gastrointestinal
tolerance. Inammation Research 1995; 44: 423433.
18. Tigerstedt I, Tammisto T & Neuvonen PJ. The ecacy of intravenous indomethacin in prevention of
postoperative pain. Acta Anaesthesiologica Scandinavica 1991; 35: 535540.
19. Merry AF, Wardall GJ, Cameron RJ et al. Prospective controlled double-blind study of intravenous
tenoxicam for analgesia after thoracotomy. British Journal of Anaesthesia 1992; 69: 9294.
20. Perttunen K, Kalso E, Heinonen J & Salo J. Intravenous diclofenac in postthoracotomy pain. British Journal
of Anaesthesia 1992; 68: 474480.
*21. Joris J. Ecacy of nonsteroidal anti-inammatory drugs in postoperative pain. Acta Anaesthesiologica
Belgica 1996; 47: 115123.
22. Grass JA, Sakima NT, Valley M et al. Assessment of ketorolac as an adjuvant to fentanyl patientcontrolled epidural analgesia after radical retropubic prostatectomy. Anesthesiology 1993; 78: 642648.
23. Segstro R, Morley-Forster PK & Lu G. Indomethacin as a postoperative analgesic for total hip
arthroplasty. Canadian Journal of Anaesthesia 1991; 38: 578581.
24. Claeys M, Camu F & Maes V. Prophylactic diclofenac infusions in major orthopedic surgery: eects on
analgesia and acute phase proteins. Acta Anaesthesiologica Scandinavica 1992; 36: 270275.
25. Laitinen J & Nuutinen L. Intravenous diclofenac coupled with PCA fentanyl for pain relief after total hip
replacement. Anesthesiology 1992; 76: 194198.
26. Vogel RI, Desjardins PJ & Major KVO. Comparison of presurgical and immediate postsurgical ibuprofen
on postoperative periodontal pain. Journal of Periodontology 1992; 63: 914918.
27. Gillberg LE, Harsten AS & Stahl LB. Preoperative diclofenac sodium reduces postlaparoscopy pain.
Canadian Journal of Anaesthesia 1993; 40: 406408.
28. Code WE, Yip RW, Rodney ME et al. Preoperative naproxen sodium reduces postoperative pain
following arthroscopic knee surgery. Canadian Journal of Anaesthesia 1994; 41: 98101.
29. Camu F, Vanlersberghe C & Lauwers MH. Timing of perioperative nonsteroidal anti-inammatory drug
treatment. Acta Anaesthesiologica Belgica 1996; 47: 125128.
30. Murphy DF & Medley C. Preoperative indomethacin for pain relief after thoracotomy. Comparison with
postoperative indomethacin. British Journal of Anaesthesia 1993; 70: 298300.
31. Vanlersberghe C, Lauwers MH & Camu F. Preoperative ketorolac administration has no pre-emptive
analgesic eect for minor orthopedic surgery. Acta Anaesthesiologica Scandinavica 1996; 40: 948952.
32. Reicin A, Brown J, Jove M et al. Ecacy of single-dose and multidose rofecoxib in the treatment of postorthopedic surgery pain. American Journal of Orthopedics 2001; 30: 4048.
33. Karim A, Laurent A, Slater M et al. A pharmacokinetic study of intramuscular (IM) parecoxib sodium in
normal subjects. Journal of Clinical Pharmacology 2001; 41: 11111119.
34. Daniels S, Grossman E, Kuss M et al. A double-blind, randomized comparison of intramuscularly and
intravenously administered parecoxib sodium versus ketorolac and placebo in a post-oral surgery pain
model. Clinical Therapeutics 2001; 23: 10181031.
35. Camu F, Beecher T, Recker DP & Verburg KM. Valdecoxib, a COX-2 specic inhibitor, is an ecacious,
opioid-sparing analgesic in patients undergoing hip arthroplasty. American Journal of Therapeutics 2002; 9:
4351.
36. Kehlet H & Dahl JB. Are perioperative non-steroidal anti-inammatory drugs ulcerogenic in the short
term? Drugs 1992; 44 (supplement 5): 3841.
*37. Souter AJ, Fredman B & White PF. Controversies in the perioperative use of nonsteroidal antiinammatory drugs. Anesthesiology 1994; 79: 11781190.
*38. Forrest JB, Camu F, Greer IA et al. Ketorolac, diclofenac and ketoprofen are equally safe for pain relief
after major surgery. British Journal of Anaesthesia 2002; 88: 227233.
39. Kaufman DW, Kelly JP, Sherman JE et al. Nonsteroidal anti-inammatory drug use in relation to major
upper gastrointestinal bleeding. Clinical Pharmacology and Therapeutics 1993; 53: 484494.
40. Cipollini F, Mecozzi V & Altilia F. Endoscopic assessment of the eects of nimesulide on the gastric
mucosa: comparison with indomethacin. Current Therapeutic Research 1989; 45: 10421048.
41. Strom BL, Berlin JA, Kinman JL et al. Parenteral ketorolac and risk of gastrointestinal and operative site
bleeding. A postmarketing surveillance study. Journal of the American Medical Association 1996; 275:
376382.
42. Harris S, Kuss M, Hubbard RC et al. Upper gastrointestinal tolerability evaluation of parecoxib sodium, a
new parenteral COX-2 specic inhibitor, as compared to ketorolac, naproxen or placebo. Clinical
Therapeutics 2001; 23: 14221428.
*43. Noveck RJ, Laurent A, Kuss M et al. The COX-2 specic inhibitor parecoxib sodium does not impair
platelet function in healthy elderly and nonelderly subjects: two randomized, controlled trials. Clinical
Drug Investigations 2001; 21: 465476.

488 F. Camu and C. Vanlersberghe

44. Weithmann KU & Alpermann HG. Biochemical and pharmacological eects of dipyrone and its
metabolites in model systems related to arachidonic acid cascade. Drug Research 1985; 35: 947952.
45. Carlsson KH, Helmreich J & Jurna I. Activation of inhibition from the periaqueductal grey matter
mediates central analgesic eect of metamizol (dipyrone). Pain 1987; 27: 373390.
46. Andrade SE, Martinez C & Walker AM. Comparative safety evaluation of non-narcotic analgesics. Journal
of Clinical Epidemiology 1998; 51: 13571365.
47. Schuitmaker M, Anderson BJ, Holford NH & Woollard GA. Pharmacokinetics of paracetamol in adults
after cardiac surgery. Anaesthesia and Intensive Care 1999; 27: 615622.
48. Luthy CS, Collart L & Dayer P. Administration prole controls acetaminophen analgesia. Clinical
Pharmacology and Therapeutics 1993; 53: 171176.
49. Rmsing J, Moiniche S & Dahl JB. Rectal and parenteral paracetamol in combination with NSAIDs, for
postoperative analgesia. British Journal of Anaesthesia 2002; 88: 215226.
50. Bannwarth B, Netter P, Lapicque F et al. Plasma and cerebrospinal uid concentrations of paracetamol
after a single intravenous dose of propacetamol. British Journal of Clinical Pharmacology 1992; 34: 7981.
*51. Hyllested M, Jones S, Pedersen JL & Kehlet H. Comparative eect of paracetamol, NSAIDs or their
combination in postoperative pain management: a qualitative review. British Journal of Anaesthesia 2002;
88: 199214.
*52. Coderre TJ, Katz J, Vaccarino AL & Melzack R. Contribution of central neuroplasticity to pathological
pain: review of clinical and experimental evidence. Pain 1993; 52: 259285.
53. Dickenson A. Mechanisms of central hypersensitivity: excitatory amino acid mechanisms and their
control. In Dickenson A & Besson JM (eds) The Pharmacology of Pain, pp 167210. Berlin: Springer Verlag,
1997.
54. Anis NA, Berry SC, Burton NR & Lodge D. The dissociative anaesthetics, ketamine and phencyclidine,
selectively reduce excitation of central mammalian neurones by N-methylaspartate. British Journal of
Pharmacology 1993; 79: 565575.
55. Eide PK, Stubhaug A, ye I & Breivik H. Continuous subcutaneous administration of the N-methyl-Daspartic acid (NMDA) receptor antagonist ketamine in the treatment of postherpetic neuralgia. Pain
1995; 61: 221228.
56. Park KM, Max MB, Robinovitz E et al. Eects of intravenous ketamine, alfentanil, or placebo on pain,
pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects. Pain 1995; 63:
163172.
57. Ilkjaer S, Petersen KL, Brennum J et al. Eect of systemic N-methyl-D-aspartate receptor antagonist
(ketamine) on primary and secondary hyperalgesia in humans. British Journal of Anaesthesia 1996; 76:
829834.
58. Arendt-Nielsen L, Petersen-Felix S, Fischer M et al. The eect of N-methyl-D-aspartate antagonist
(ketamine) on single and repeated nociceptive stimuli: a placebo-controlled experimental human study.
Anesthesia and Analgesia 1995; 81: 6368.
59. Warncke T, Stubhaug A & Jorum E. Ketamine, an NMDA receptor antagonist, suppresses spatial and
temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over
comparison with morphine and placebo. Pain 1997; 72: 99106.
60. Roytblat L, Korotkoruchko A, Katz J et al. Postoperative pain: the eect of low-dose ketamine in
addition to general anesthesia. Anesthesia and Analgesia 1993; 50: 454457.
61. Reeves M, Lindholm DE, Myles PS et al. Adding ketamine to morphine for patient controlled analgesia
after major abdominal surgery: a double-blinded randomized controlled trial. Anesthesia and Analgesia
2001; 93: 116120.
62. Burstal R, Danjoux G, Hayes C & Lantry G. PCA ketamine and morphine after abdominal hysterectomy.
Anaesthesia and Intensive Care 2001; 29: 246251.
63. Murdoch CJ, Crooks BA & Miller CD. Eect of the addition of ketamine to morphine in patient
controlled analgesia. Anaesthesia 2002; 57: 484488.
64. Tverskoy M, Oz Y, Isakson A et al. Preemptive eect of fentanyl and ketamine on postoperative pain and
wound hyperalgesia. Anesthesia and Analgesia 1994; 78: 205209.
65. De Kock M, Lavand'homme P & Waterloos H. Balanced analgesia in the perioperative period: is there a
place for ketamine? Pain 2001; 92: 373380.
*66. Stubhaug A, Breivik H, Eide PK et al. Mapping of punctuate hyperalgesia around a surgical incision
demonstrates that ketamine is a powerful suppresser of central sensitization to pain following surgery.
Acta Anaesthesiologica Scandinavica 1997; 41: 11241132.
67. Persson J, Hasselstrom J, Wiklund B et al. The analgesic eect of racemic ketamine in patients with
chronic ischemic pain due to lower extremity arteriosclerosis obliterans. Acta Anaesthesiologica
Scandinavica 1998; 42: 750758.
68. Backonja M, Arndt G, Gombar KA et al. Response of chronic neuropathic pain syndromes to ketamine: a
preliminary study. Pain 1994; 56: 5157.