Paracetamol per napoli sia 2009

Paracetamol(acetaminophen)
update
C.Melloni
Libero professionista
Consulente di anestesia Villa Torri,Villa
Chiara,Gynepro
Bologna

Declaration of conflict of interest
The author is a private practitioner
He has received a fee last year from Glaxo Smith
Kline for an update on Muscle Relaxants
organized for the firm’s scientific advisors and
salesmen.
There is no conflict of interest

Systemic effects:
Antipyresis

Analgesia
Opioid sparing
Dose dependent antiaggregatory effect

General organization of topic
Mech of action
References on para
Metab and toxic implications
Side effects:hemostasis
concentration/effect considerations
Opioid sparing
Clinical application:NNT
Potency in different environments
Combination with other
drugs;codeine,tramadol,NSAIDS,oxycodone ;cochrane …..

abbreviations
NSAIDs=FANS
Coxibs=Cyclooxygenase inhibitors
Cox1=Cyclooxygenase type 1
Cox2=Cyclooxygenase type 2
Para or APAP:paracetamol or
acetaminophen

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update
Mattia C,Coluzzi F.
What anesthesiologists should
know about
paracetamol(acetaminophen)
Min.Anestesiol nov 2009 pagg 644653

Nsaids bibliography:levels of excellence

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Proportions of high levels publications in NSAIDS
bibliography


most commonly used over-the-counter medication
products were:

acetaminophen

alone, multivitamins, and
ibuprofen alone. The most commonly used
prescription-only medications across all age groups
were amoxicillin..
– Vernacchio L, Kelly JP, Kaufman DW, Mitchell AAMedication
use among children <12 years of age in the United States:
results from the Slone Survey. Pediatrics. 2009 Aug;124(2):44654.

Mechanism of action:1
lack of significant anti-inflammatory
activity of paracetamol implies a mode of
action distinct from that of non-steroidal
antiinflammatory drugs (NSAIDs)

despite years of use and research,
the mechanisms of action of
paracetamol are not fully understood.

NSAIDs act by inhibiting the activity of cyclooxygenase (COX), now recognised to
consist of two isoforms, COX-1 and COX-2, which catalyses the production of
prostaglandins responsible for pain and inflammation.

Paracetamol has previously been shown to have no
significant effects on COX-1 or COX-2 (Schwab 2003), but
is now being considered as a selective COX- 2 inhibitor
(Hinz 2008). :central???low peroxides???

Significant paracetamol-induced inhibition of
prostaglandin production has been demonstrated in
tissues in the brain, spleen, and lung (Botting 2000;
Flower 1972).

Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of
action of acetaminophen: its clinical pharmacologic characteristics reflect
its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther
2006; 79:9– 19.

Acetaminophen is an inhibitor of both
PGHS(prostaglandin H2 synthases )isoforms in
purified enzyme preparations.
highly variable capacity to inhibit PG synthesis by
different cell and tissue types;e.g. the analgesic and antipyretic
effects of acetaminophen follow its inhibition of prostaglandin E2 (PGE2)
generation within the central nervous system (CNS), whereas the failure
of acetaminophen to inhibit platelet derived thromboxane A2 synthesis
and inflammatory PGE2 synthesis accords with its weak antiplatelet and
anti-inflammatory effects.

Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of
action of acetaminophen: its clinical pharmacologic characteristics reflect
its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther
2006; 79:9– 19.

PGHS enzymes are inhibited at the level of the POX
catalytic site.
Such an inhibitory mechanism would be predicted to
exhibit a sensitivity to ambient peroxide levels
its analgesic and antipyretic effects likely follow PGHS
inhibition within vascular endothelial cells and
neurons, higher concentrations of lipid and nonlipid
hydroperoxides within activated leukocytes and
platelets prevent acetaminophen from substantially
affecting such processes as inflammation and platelet

A ’COX-3 hypothesis’ wherein the efficacy of paracetamol
is attributed to its specific inhibition of a third
cyclooxygenase isoform enzyme, COX-3 (Botting
2000;Chandrasekharan 2002;PIC 2008

) now has little credibility,

a central mode action of paracetamol is
thought to be likely (Graham 2005)
Indirect activation of cannabinoid CB1
receptor(Bertolini 2006,Hogestatt 2005)
Inhibition of plasma beta endorphins

Acetaminophem reduces plasma beta endorphin levels
in patients with symptomatic osteoarthritis. Sprott H, Shen H, Gay
S, Aeschlimann A. Acetaminophen may act through beta endorphin. Ann Rheum Dis 2005; 64:1522.

months

Pain Physician 2009; 12:269280
positive effects on the serotonergic descending
inhibitory pathways:
(endocannabinoid signaling may play a role in
APAP’s activation of the serotonergic descending
Inhibitory

interactions with :
» opioidergic systems,
» eicosanoid systems,
» nitric oxide containing pathways

Metabolism of paracetamol
glucuronide fCL was unexpectedly higher,
strongly suggesting glucuronosyltransferase
induction..

Gelotte et al .. Disposition of
acetaminophen at 4, 6, and 8 g/day for 3 days in healthy
young adults. Clin Pharmacol Ther. 2007 Jun;81(6):840-8

Utilization and enzyme inhibit.of
PGE
since GSH is a cofactor..

CYP2E1 /CYP3A4
Xenobiotica. 2009 Jan;39(1):11-21.
cetaminophen bioactivation by human cytochrome
P450 enzymes and animal microsomes..
Laine JE, Auriola S, Pasanen M, Juvonen RO

Elimination half life
.adults:2-4 hr
Children:
Newborn:4-5 hr
Premature:11 h
With severe renal impairment (GFR< 10
ml/min) dosing interval 6-8 hr.
With severe liver dysfunction do not <8
hr intervals

Hepatotoxicity
APAP overdose due to the increased metabolism of APAP
through oxidation, results in an increase in NAPQI
concentration. In case of an overdose, unconjugated NAPQI
binds to intracellular hepatic macromolecules to induce cell
necrosis and damage.
Because NAPQI is conjugated by glutathione into cysteine
metabolites, the amount of such conjugates was considered
to be a measure of the endpoint of hepatotoxicity
A new biomarker,for APAP overdose: ophthalmic acid,
indicates hepatic glutathione consumption .

Recommendations in hepatic disese:
Alcohol abusers may develop a decrease in
tolerance to paracetamol that also occurs with
starvation or intercurrent disease leading to
glutathione depletion
– Larson AM, Polson J, Fontana RJ, et al. Acetaminopheninduced acute liver failure: results of a United States
multicenter, prospective study. Hepatology 2005; 42:1364–
1372.].

When these factors are associated, or when hepatic
function is compromised, a dose of 3 g per day
should not be exceeded

Pharmacokinetics and
phrmacodynamics of PARA

Oral administration
Bioavailability:63-89%
Absorption :caffeine,metoclopramide
Renner B, Clarke G, Grattan T, et al. Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen.
Journal of Clinical Pharmacology 2007; 47: 715–26.
Nimmo J, Heading R, Tothill P, Prescott LF. Pharmacologicalmodification of astric emptying: effects of propantheline and
metoclopramide on paracetamol absorption.BMJ 1973; 1: 587–9

.

Morphine,food
Kennedy J, Tyers N, Davey AK. The influence of morphine on the absorption of paracetamol from various formulations in
subjects in the supine position, as assessed by TD xmeasurement of salivery paracetamol levels. Journal of Pharmacy and
Pharmacology 2003; 55: 1345–50.

Rectal administration
Bioavailability 24-98%
» Depending from;suppositories
size,number,composition,rectal pH…..

» Lag time:120-.240 min!

Peak plasma
concentration(Cmax)
iv onset within 20 min and therapeutic conc
around 2 h

45 min p.os: abs good,but

subclinical

concentrations Early bioavailability of paracetamol after oral or intravenous
administration.P. HOLME, R PETTERSSON, A. O¨ WALL, J. JAKOBSSON,Acta Anesthesiol Scand.2006

infusion vs oral:meaningful pain relief 8 min vs
37;max pain relief 15 min vs 60 min,Equivalence at
45 min,Pain relief better with oral adm > 2 h
»

Moller P, Sindet-Pedersen S, Petersen CT, Juhl GI,Dillenschneider A, Skoglund LA. Onset of acetaminophen
analgesia: comparison of oral and intravenous routes afterthird molar surgery. British Journal of Anaesthesia 2005;
94:642–8.

Route of adminstration,onset
and duration of analgesia:II
Effervescent tablets speed up oral absorption:Tmax
27 vs 45 for ordinary tablets
»

Rygnestad T, Zahlsen K, Samdal FA. Absorption of effervescent paracetamol
tablets relative to ordinary paracetamol tablets in healthy volunteers. European
Journal of Clinical Pharmacology 2000; 56

Rectal absorption 180-270 min , slower and more
variable ,but therapeutic concentrations could be
attained with larger doses;35-45 mg/kg,with onset in
2-3 h..
Early adm!!

Plasma paracetamol levels
Minimum required for analgesia and
antipyresis: 10 microgr/ml
Anderson B, Holford N, Wollard GA, Kanagasundaram S, Mahadevan M. Perioperative pharmacodynamics of acetaminophen
analgesia in children. Anaesthesiology 1999; 90: 411–21.

Therapeutic range:10-20
microgr/ml
Threshold for potential
hepatotoxicity:150 microgr/ml

Pharmacokinetics/Pharmacodynamics of Acetaminophen Analgesia in
Japanese Patients with Chronic Pain
Shigeo SHINODA,a Takahiko AOYAMA,b Yukio AOYAMA,a Sachiko
TOMIOKA,c Yoshiaki MATSUMOTO,*,b and Yoko OHEa Biol. Pharm. Bull.
30(1) 157—161 (2007)
5 healthy volunteers,1000 mg p.os

5 patients with chronic
pain,Para 600-1000 mg p.os


B. BANNWARTH*, P. NETTER, F. LAPICQUE, P. GILLET, P. PERE, E.
BOCCARD', R. J. Royer ,Gaucher Plasma and cerebrospinal fluid
concentrations of paracetamol after a single intravenous dose of
propacetamolA.Br. J. clin. Pharmac. (1992), 34, 79-81.


AL = acetaminophen (40 mg/kg) ([black small square]), AS =
acetaminophen (20 mg/kg) ([white square]), C = combination
([black up pointing small triangle]). Plasma concentrations for the AL group were
significantly greater than for both other groups (analysis of variance, P < 0.01). From: Beck: Anesth Analg, 90(2).2000.431

acetaminophen (40 mg/kg

Acetaminophen+diclofenac

acetaminophen (20 mg/kg


20 or 40 mg/kg of rectal paracetamol after induction
of general anaesthesia. Hagemann, K.; Beck, D. H.; Schenk, M.; Scherer, R.; Kox,

W.Pharmacokinetics of higher dose rectal paracetamol (40 mg kg-1) in adult patients .Br. J. Anaesth. 1999; 82:122

Stocker ME, Montgomery JE.Serum paracetamol
concentrations in adult volunteers following rectal
administration .. Br. J. Anaesth. 2001; 87:638-640
10 healthy
adult
volunteers
increasing
doses of
rectal
paracetamo
l
(15, 25, 35,
and 45 mg
kg-1).


Suppositories and elixirAnderson et al pharmacodynamics
of acetaminophen analgesia in children.Anesthesiology. 1999 Feb;90(2):411-21.

Children undergoing outpatient tonsillectomy
orally, 0.5-1.0 h
preop (n = 20),
at induction of anesthesia
(n = 100).


Time- pain profiles for each patient, with the mean of the observations shown as a
solid line. The mean of the population predictions is shown as a dashed line. The
mean post hoc profile, based on values of the parameters for the specific individual, is
shown as a dotted line.

Anderson BJ, Holford NH, Woollard GA, Kanagasundaram S, Mahadevan M.Perioperative

pharmacodynamics of acetaminophen analgesia in children.Anesthesiology. 1999 Feb;90(2):411-21.

The relation between predicted effect compartment concentrations and
observed pain scores. The solid line is the mean observed profile, and
the dashed line is the mean predicted population profile. The mean post
hoc profile, based on values of the parameters for the specific
individual, is shown as a dotted lineAnderson BJ, Holford NH, Woollard GA,
Kanagasundaram S, Mahadevan M.Perioperative pharmacodynamics of acetaminophen
analgesia in children.Anesthesiology. 1999 Feb;90(2):411-21.

Simulation of administration of acetaminophen. A loading dose of 40
mg/kg administered orally preoperatively, supplemented by a 20mg/kg suppository 2 h later. Anderson BJ, Holford NH, Woollard GA, Kanagasundaram S,

Mahadevan M.Perioperative pharmacodynamics of acetaminophen analgesia in children.Anesthesiology.
1999 Feb;90(2):411-21.


Parameter estimates,
standardized to a 70-kg
person, are V/Foral = 60 l/70
kg, CL/Foral = 13.5 l · h- 1 · 70
kg- 1 , and Tabs = 4.5 min for
the oral elixir and Tabs = 35
min with a lag time of 40
min for the suppository.
The Frectal/oral value was 0.54.
Variability is shown using
box-and-whisker plots. The
central box represents the
fiftieth percentile.
Indentations in this box
indicate the median.
Values outside the 97.5%
percentile are shown
individually.

Serum concentrations of acetaminophen :rectal (40

mg/kg) +3 additional doses of 20 mg/kg at 6-h intervals .

rmingham P K, Tobin M J, Fisher DM, Henthorn TK, Hall SC,Coté C J. Initial and Subsequent Dosing of Rectal Acetaminophen in Children A 24-Hour
Pharmacokinetic Study of New Dose Recommendations .Anesthesiology 94:385-389, 2001

Birmingham P K, Tobin M J, Fisher DM, Henthorn TK, Hall SC,Coté C J.
Initial and Subsequent Dosing of Rectal Acetaminophen in Children A 24Hour Pharmacokinetic Study of New Dose Recommendations
.Anesthesiology 94:385-389, 2001

Rectal doses necessary to achieve the same
desired target concentrations are larger than
with oral doses.
total daily oral dose recommendations for
acetaminophen may not apply to rectal dosing.
Our rectal dosing regimen totals 100 mg/kg during the first 24
h, close to the recommended upper limits of oral dosing.

Plasma concentrations in 3 patients
following rectal admistration


Anderson BJ, Woollard GA, Holford NH.
Acetaminophen analgesia in children: placebo effect and pain
resolution after tonsillectomy. Eur J Clin Pharmacol. 2001
Oct;57(8):559-69.

: High dose acetaminophen (100 mg/kg) was no
more effective than 40 mg/kg and was associated
with increased nausea and vomiting.

A target effect compartment
concentration of 10 mg/l is expected to
produce a pain reduction of 2.6 units.
Placebo effect:1 unit……

Pharmacokinetics of rectal paracetamol after repeated dosing in
children .Hahn TW, Henneberg SW, Holm-Knudsen RJ, Eriksen
K, Rasmussen SN,Rasmussen, M.Br. J. Anaesth. 2000; 85:512-519

23 children (aged between 9 weeks and 11 yr)
paracetamol suppositories 25 mg kg-1 every 6 h
(maximum 5 days) after major surgery
serum and saliva concentrations were measured.
good correlation (r=0.91, P<0.05) between saliva and serum
concentrations.
At steady state,mean (SD) concentration was 15.2 (6.8) mg litre-1.
Mean (SD) time to reach 90% of the steady state concentration was
11.4 (8.6) h.. There was no evidence of accumulation leading to
supratherapeutic concentrations during this dosing schedule for a
mean of approximately 2–3 days.

paracetamol suppositories 25 mg kg-1 every
6 h (maximum 5 days) after major surgery


Rectal administration :
is erratic (large interindividual variability)
…
produces delayed effects..
but works at dosages with 40 mg/kg
loading followed by 20 mg/kg q.6 hr
»
Solo Tachipirina(Angelini) è in supp.da 1 gr…

Antiaggregatory effects on platelets

reaction catalyzed by COX
NSAIDs
Para
Arachidonic acid --- COXprostaglandin G2

prostaglandin G2 peroxidase
prostaglandin H2

prostaglandin H2

thromboxane synthase--

Tx2

G protein—coupled receptors on
the surface of the platelet.

:aggregation

Conclusions
Acetaminophen is a weak and reversible
inhibitor of platelet aggregation,
» …the effect is dose dependent
»

; Munsterhjelm E, Munsterhjelm N, Niemi TT, Ylikorkala , Neuvonen PJ, Rosenberg PH. Dose dependent inhibition of
platelet function by acetaminophen in healthy volunteers. Anaesthesiology 2005; 103: 712–17

.

Its combination wiyh other NSAIDS inhibits
platelet function more than the NSAID alone.
» Munsterhjelm E, Niemi TT, Syrjälä M, Ylikorkala O, Rosenberg P H. Propacetamol
augments inhibition of platelet function by diclofenac in volunteers Br. J. Anaesth. 2003;
91:357-362

This should be considered when assessing the risk of surgical bleeding .

Opioid sparing effects of
PARA

Summary of effects of paracetamol on opioid sparing
author

opioid

surgery

sparing

Side effects

comparator

Karvonen
,2008

fentanyl

Major orthop

no

=

Ketoprofen
-22%

Morton,1999

Morphine,

appendicetom
y

no

=

Sinatra,2005

morphine

Major orthop

-30%

=

propacetamol

Peduto,1998

morphine

Major orthop

-46%

-

placebo

Del Bos,1995

morphine

Knee
ligamentoplast
y

-27%

=

placebo

Remy,metanal
ysis ,2005

morphine

All major abd
& orthop

-20%

=

placebo

Lahtinen,2002

oxycodone

cardiac

-13%

NA

placebo

Hernandez
2001

morphine

Spinal fusion

-46%

NA

placebo

Ohnesorge
2009

morphine

breast

-40%

=

Placebo,meta
mizol

Twenty-four–hour morphine consumption
(in milligrams)

Anesthesiology 2005; 103:1296–1304 Does Multimodal Analgesia with Acetaminophen, Nonsteroidal Antiinflammatory Drugs, or Selective
Cyclooxygenase-2 Inhibitors and Patient-controlled Analgesia Morphine Offer Advantages over Morphine Alone? Meta-analyses of Randomized Trials
Nadia Elia, M.D.,* Christopher Lysakowski, M.D.,† Martin R. Trame` r, M.D., D.Phil.†

A weighted mean
difference (WMD) less
than 0 indicates
less morphine
consumption with active
compared with control.
When the 95%
confidence interval (CI)
does not include
0, the difference is
considered statistically
significant. COX-2
inhibitor 200 mg
celecoxib,a 50 mg
rofecoxibb; multiple high
dose valdecoxib and
parecoxib 40 mg/12 h and
parecoxib 40 mg/6 h;
multiple low dose
valdecoxib and parecoxib
20 mg/12 h.

Conclusion of metaanalysis:

Remy, C.; Marret, E.*; Bonnet, F.Effects of acetaminophen on morphine side-effects and consumption after major
surgery: meta-analysis of randomized controlled trialsBr. J. Anaesth. 2005; 94:505-513

Acetaminophen combined with PCA
morphine induced a significant
morphine-sparing effect but did not
change the incidence of morphinerelated adverse effects in the
postoperative period

Marret E, Kurdi O, Zufferey,P, Bonnet F. Effects of Nonsteroidal
Antiinflammatory Drugs on Patientcontrolled Analgesia
Morphine Side Effects.Meta-analysis of Randomized Controlled
Trials.Anesthesiology 2005; 102:1249–60
NSAIDs have a documented 30–50% sparing effect on
morphine consumption.
meta-analysis of randomized controlled trials
NSAIDs decreased significantly
»
»
»
»

postoperative nausea and vomiting by 30%
nausea alone by 12%
vomiting alone by 32%
sedation by 29%.

» Pruritus, urinary retention, and respiratory depression were

not significantly decreased by NSAIDs.

Morphine-related adverse effects

Anesthesiology 2005; 103:1296–1304 Does Multimodal Analgesia with Acetaminophen, Nonsteroidal Antiinflammatory Drugs,
or Selective Cyclooxygenase-2 Inhibitors and Patient-controlled Analgesia Morphine Offer Advantages over Morphine Alone?
Meta-analyses of Randomized Trials Nadia Elia,* Christopher Lysakowski, Martin R. Trame` r

A relative risk (RR) less
than 1 indicates less
morphine-related adverse
effects with active
compared with control.
When the 95% confidence
interval (CI) does not
include 1, the difference
is considered statistically
significant. * Sedation or
drowsiness or
somnolence. ** Ileus or
constipation or intestinal
obstruction.
Meta-analyses were
performed when data
from at least three trials or

Mean pain relief

Sinatra R S; Jahr JS., Reynolds L, Viscusi E, Groudine SB,

Payen-Champenois C. Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous
Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic Surgery
Anesthesiology 102:822-31, 2005

Major orthopedic surgery lower extremity joint replacement
surgery,151 pats., reporting moderate to severe pain

Propacet 2 gr
Para 1 gr
placebo


Mean pain intensity differenc es

Sinatra R S; Jahr JS., Reynolds L, Viscusi E, Groudine SB, Payen-Champenois C. Efficacy and Safety of Single
and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain
Management after Major Orthopedic Surgery Anesthesiology 102:822-31, 2005

placebo


Time to Ist rescue medication
la
p

bo
ce

total morphine doses received over 24 h:
38.3 ± 35.1 mg for i.v.acetaminophen
40.8 ± 30.2 mg for propacetamol,
57. 4 ± 52.3 mg for placebo.


Sinatra R S; Jahr JS., Reynolds L, Viscusi E, Groudine SB, Payen-Champenois C.
Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous
Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic
Surgery Anesthesiology 102:822-31, 2005

12
10
8

para
propara
placebo

6
4
2
0
-2

totpar

spid

sprid

Mean scores of pain relief

Moller PL, Juhl GI, Payen-Champenois C, Skoglund LA Intravenous Acetaminophen (Paracetamol): Comparable Analgesic
Efficacy, but Better Local Safety than Its Prodrug, Propacetamol, for Postoperative Pain After Third Molar Surgery Anesth
Analg 2005; 101:90-6

patients with moderate-to-severe pain after third molar
surgery.

propacetamol

acetaminophen

Mean scores of PID

Moller PL, Juhl GI, Payen-Champenois C, Skoglund LA Intravenous Acetaminophen (Paracetamol): Comparable
Analgesic Efficacy, but Better Local Safety than Its Prodrug, Propacetamol, for Postoperative Pain After Third
Molar Surgery Anesth Analg 2005; 101:90-6

Advantages of Nsaids
significant opioid-sparing effect
lack of sedation
Lack of respiratory depression
low abuse potential
no interference with bowel or bladder
function
Comparable efficacy for both pain at rest
and with movement

Disadvantages of Nsaids
Ceiling effect
Insufficient analgesia following major
surgery
Danger of platelet inhibition
Danger of renal damage
Danger of GI bleeding

Advantages of PARA
Low technology interventions :such as oral
paracetamol administration, used appropriately, have
the potential to reduce unnecessary pain.
Paracetamol is the analgesic of choice for adult
patients in whom salicylates or other NSAIDs are
contraindicated.
» asthmatics, those with salicylate allergies, those with a
history of peptic ulcer.

children with febrile viral illnesses, in whom aspirin is

contraindicated due to the risk of Reye’s syndrome (swelling of the
brain that may lead to coma and death).

Paracetamol indications
» Opioid sparing
» Patients at risk for bleeding
Patients in whom salycilates are contraindicated

» Asthmatics
» Allergic
» Peptic ulcer
» Children with febrile viral ilnesses

A comparison between Paracetamol
and selective COX 2 I
action
Pain

paracetamol
active

Selective COX 2 Inhib
active

fever

active

active

inflammation

inactive

active

platelets

active,but rapidly inactive
reversible

Rheumatoid arthritis

(inactive)?

active

Intestinal damage

inactive

inactive

Decreased Na renal

inactive

active

a few good supporters
of para…….

Scottish Intercollegiate guidelines network.Control of
pain in adults with cancer.Nov 2008

Pag 18:
“Patients at all stages of WHO
ladder should be prescribed
paracetamol and /or NSAID unless
contraindicated “

[Update on current care guidelines. Safe use of non-steroidal
anti-inflammatory drugs]
Karvonen AL, Hakala M, Helin-Salmivaara A,
Kankaanranta H, Kivilaakso E, Kunnamo I, Lehtola J, Martio J
.

“…Pain medication should be based on patient's needs and risk profile. Age > 65 years,
prior ulcer, co-morbidities, large daily dose, Helicobacter pylori infection, concurrent use of
glucocorticoids, serotonin re-uptake inhibitors, or warfarin increase the risk of upper
gastrointestinal bleeds. As a preventive strategy the use of concurrent proton pump inhibitors
with non-selective NSAIDs is recommended. It is also possible to use COX-2 selective
NSAIDs but they are contraindicated for persons with atherosclerotic diseases and special
consideration is required for persons with risk factors of heart diseases.

Paracetamol is the drug of choice
for pain.”

ASA reference:
Ashburn MA, Caplan RA, Carr DB, et al. Practice
guidelines for acute pain management in the
perioperative setting: an updated report by the
American Society of Anesthesiologists Task Force on
Acute Pain Management.
American Society of Anesthesiologists Task Force on
Acute Pain Management. Practice guidelines for
acute pain management in the perioperative setting:
an updated report by the American Society of
Anesthesiologists Task Force on Acute Pain

Practice guidelines for acute pain management in the perioperative setting: an updated report by the
American Society of Anesthesiologists Task Force on Acute Pain Management.
American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute
pain management in the perioperative setting: an updated report by the American Society of
Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2004 Jun;100(6):1573-81.

Multimodal Techniques for Pain Management

Whenever possible, anesthesiologists should
employ multimodal pain management therapy.
Unless contraindicated, all patients should
receive an around-the-clock regimen of nonsteroidal anti-inflammatory drugs (NSAIDs),
cyclooxygenase-2 inhibitors (COXIBs), or

acetaminophen. ….

Pharmacodynamics
Most drug effects can be described by the
so called Emax model:

» E=EmaxC/Ec50+C
»
»
»
»

E:effect
C:drug concentration
E max:maximum effect
EC 50 ;concentrtion producing 50% of the maximum
effect

Emax pharmacodynamic model
The line represents
the effect at
different effect site
concentrations.
EC 50 is the
concentration at
which 50% of the
maximum effect
(Emax) is achieved

90%

Ec90

Concentration effect curves for drugs with
different steepness of the curve:gamma:γ
Drugs with little
Variability between
concentration
And effect have steep
Curves and large γ;drugs
with More variability
have more gently sloping
curves and lower γs


E and E max
E=EmaxCγ/Ecγ50+Cγ
Where

γ is the Hill coefficient ,that
describes how steep the
increasing portion of the curve
is.

Concentration effect
relationship
The curves represent
The concentration effect
relationship Between 3
hypothetical drugs
with different Values of
EC50 ,i.e. the
concentration at which
50% of the maximum
effect is achieved..
The higher the EC 50,the
lower the potebcy


4
fent
para
(da dati di Anderson)

analgesia
0

15

20 30

Choice criteria from bibliography and efficacy analysis

Oxford league table of analgesics in acute
pain
This league table was constructed for analgesics in acute
pain.
Information was from systematic reviews of randomised,
double-blind, single-dose studies,placebo controlled.
in patients with moderate to severe pain.
For each review the outcome was identical - that is at least
50% pain relief over 4-6 hours.
The pain measurements were standardised, and have been
validated.

Scientific evidence
High trial quality ;double blind randomized placebo-controlled clinical
trials of paracetamol for acute postoperative pain in adults.
Area under the “pain relief versus time” curve was used to
derive the proportion of participants with paracetamol or
placebo experiencing at least 50% pain relief over four to
six hours, using validated equations.
Number-needed-to-treat-to-benefit (NNT) was calculated,
with 95% confidence intervals (CI).
The proportion of participants using rescue analgesia over
a specified time period, and time to use, were sought as
measures of duration of analgesia.
Information on adverse events and withdrawals was also
collected.

NNT
A measure of analgesic efficacy

Number of patients who need to receive
the active drug for one to achieve at
least 50% relief of pain compared with
placebo over a 4-6 h treatment period
The most effective drugs have a low NNT,i.e. just
over 2
The NNT is drug,dose,context specific

Numbers Needed to Treat
Two other sources of information on
NNTs are Bandolier , and the
Centre for Evidence-Based Medicine

.

Using Numerical Results from
Systematic Reviews in Clinical Practice
Annals of Internal Medicine 1 May 1997. 126:712-720.
Henry J. McQuay, DM, and R. Andrew Moore, DSc
ACADEMIA AND CLINIC

Calculating NNT
»Active
Total
improved

NNt=

Ta
IA

1
---------------(Ia/Ta)-(Ic/Tc)

control
Ca
Ic

Number needed to treat (NNT) for at least 50% pain relief over 4-6
hours in patients with moderate to severe pain, all oral analgesics
except IM morphine and pethidine and ketorolac.Bandolier 2004


2007 League table of number needed to treat (NNT) for at least 50%
pain relief over 4-6 hours in patients with moderate to severe pain,
all oral analgesics except IM morphine


NNTs for paracetamol at different doses

But.....League table considered only
NSAIDS or COxibs against
placebo......in DENTAL SURGERY…
in minor surgery ..
What about comparison between
NSAIDS and Coxibs?

Moreover:1…
the analgesic efficacy of drugs varies between
different types of surgery: e.g. the analgesic efficacy
of paracetamol is twofold less in orthopaedic
procedures compared with dental procedures
– . Gray A, Kehlet H, Bonnet F et al. Predicting postoperative
analgesia outcomes: NNT league tables or procedure-specific
evidence? British Journal of Anaesthesia 2005; 94: 710e714 .,

Moreover 2:
the difference in analgesic efficacy between
NSAIDS and paracetamol has been demonstrated
to depend on the magnitude of surgery.
– Hyllested M, Jones S, Pedersen JL et al. Comparative effect of
paracetamol, NSAIDs or their combination
in postoperative
pain management: a qualitative review. British Journal of
Anaesthesia 2002; 88:199e214

MOREOVER :3
a 50% decrease in pain may have a
different clinical relevance depending on

whether pain decreases from 40
to 20 or from 80 to 40 on a
hundred-point visual analogue
scale.

Therefore ……….
PROSPECT: evidencebased,procedure-specific
postoperative pain management
» Best Practice & Research Clinical Anaesthesiology Vol. 21,
No. 1, pp. 149e159, 2007.
»

doi:10.1016/j.bpa.2006.12.001

Henrik Kehlet ,Roseanne C. Wilkinson , Barrie J. Fischer ,Frederic
Camu .

Superiority of NSAIDs vs paracetamol:osteoarthritis
Lee C, Straus WL, Balshaw R, Barlas S, Vogel S, Schnitzer TJ.A comparison of the
efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in
the treatment of osteoarthritis: a meta-analysis. Arthritis Rheum 2004;51:746-754.
» NSAIDS statistically > paracetamol in treating osteoarthritis pain
Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of
osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis
2004;63:901-907
» NSAIDS and paracetamol =in treating osteoarthtic pain,but NSAIDS + in pain
relief,patient preferences,patient response
Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen
for osteoarthritis. Cochrane Database Syst Rev 2006;(1):CD004257 .

» NSAIDS + effective in controlling pain at rest and at night with
a trend toward superiority in controlling pain after activity.
However, the risk of adverse gastrointestinal events associated with NSAID
use was greater than for acetaminophen, resulting in a benefit-to-risk ratio
that favored acetaminophen in certain pain conditions.

Other works on NSAIDs superiority
In the field d of postpartum pain due to
caesarean,episiotomy,repair of vaginal tears Nsaids
offered superior analgesia with less side effects vs
the association paracetamol+codein. Nauta M, Landsmeer ML,
Koren G.Codeine-acetaminophen versus nonsteroidal anti-inflammatory drugs in the
treatment of post-abdominal surgery pain: a systematic review of randomized trials.
Am J Surg. 2009 Aug;198(2):256-61.

Superiority of Ibuprofen vs paracetamol in relieving
pain after 3 rd molar extraction surgery Daniels S, Reader S,
Berry P, Goulder M. Onset of analgesia with sodium ibuprofen, ibuprofen acid
incorporating poloxamer and acetaminophen--a single-dose, double-blind, placebocontrolled study in patients with post-operative dental pain. Eur J Clin Pharmacol. 2009
Apr;65(4):343-53.

Visual analog scale (VAS) score for pain intensity at
rest at 24 h (0–10 cm).
Anesthesiology 2005; 103:1296–1304 Does Multimodal Analgesia with Acetaminophen,

Nonsteroidal Antiinflammatory Drugs, or Selective Cyclooxygenase-2 Inhibitors and Patient-controlled Analgesia Morphine Offer Advantages
over Morphine Alone? Meta-analyses of Randomized Trials . Elia N, Lysakowski C, Trame` r MC

A weighted mean difference (WMD) less than 0 indicates less pain with active compared with control.
When the 95% confidence interval (CI) does not include 0, the difference is considered atistically
significant. Meta-analyses were performed when data from at least three trials or more than 100 patients
could be combined; this was not the case for cyclooxygenase-2 inhibitors. NSAID nonsteroidal
antiinflammatory drug.

Pain relief scores after propacetamol 2 gr, ketorolac 15mg,
ketorolac 30 mg .PCA Morhine in use Zhou TJ, Tang J, White PF: Propacetamol versus
ketorolac for treatment of acute postoperative pain after total hip or knee replacement. Anesth Analg 92:1569-75, 2001

comple
te
A lot

moderate

Ketor 30
Paracet 1 gr

Ketor 15
A little

patients undergoing total hip or knee replacement
first morning after major joint replacement surgery
164 patients experiencing moderate-to-severe pain

Pain intensity differences after propacetamol 2 gr,
ketorolac 15mg, ketorolac 30 mg .PCA Morhine in use

Ketor 30
Ketor 15
propacet


Time to onset of analgesia,rescue medication(Morphine) Zhou
TJ, Tang J, White PF: Propacetamol versus ketorolac for treatment of acute postoperative pain after total hip or
knee replacement. Anesth Analg 92:1569-75, 2001

Beaussier M, Weickmans H,Paugam C,Lavazais S,Baechle JP,Goater P
Buffin ,Loriferne JF,Perier JF,Didelot JP,Mosbah A,Said R, Lienhart A.A
Randomized, Double-Blind Comparison Between Parecoxib Sodium and
Propacetamol for Parenteral Postoperative Analgesia After Inguinal
Hernia Repair in Adult Patients Anesth Analg 2005; 100:1309-15

inguinal hernia repair under general anesthesia
single injection of 40 mg parecoxib or
2 injections of 2 g propacetamol within the first 12 h after surgery.

Rawal N, Allvin R,Amilon A,Ohlsson T,Hallén J
Postoperative Analgesia at Home After Ambulatory Hand Surgery: A
Controlled Comparison of Tramadol, Metamizol, and Paracetamol
Anesthesia and Analgesia 2001; 92:347-351.

prospective, randomized, double-blinded
120 ASA I and II patients
ambulatory hand surgery with IV regional anesthesia.
At discharge, oral analgesic tablets were prescribed
as follows: tramadol 100 mg every 6 h, metamizol 1 g
every 6 h, and paracetamol (acetaminophen) 1 g
every 6 h.
Rescue medication consisted of oral
dextropropoxyphene 100 mg on demand.

Postoperative Analgesia at Home After Ambulatory Hand
Surgery: A Controlled Comparison of Tramadol, Metamizol,
and Paracetamol

Analgesic efficacy was evaluated by self-assessment
of pain intensity by visual analog score at six different
time intervals during the 48-h study period.
Patients also recorded global pain relief on a 5-grade
scale, total number of study and rescue analgesic
tablets, frequency and severity of adverse effects,
sleep pattern, and overall satisfaction.

Postoperative Analgesia at Home After Ambulatory
Hand Surgery: A Controlled Comparison of Tramadol,
Metamizol, and Paracetamol
None of the study drugs alone provided effective analgesia in all
patients.
% of patients who required supplementary analgesics was 23% with
tramadol, 31% with metamizol, and 42% with acetaminophen.
Tramadol was the most effective analgesic, as evidenced by low pain
scores, least rescue medication, and fewest number of patients with
sleep disturbance. However, the incidence of side effects was also
increased with tramadol. Seven patients (17.5%) withdrew from the
study because of the severity of nausea and dizziness associated with
the use of tramadol. Metamizol and acetaminophen provided good
analgesia in about 70% and 60% of patients, respectively, with a
decreased incidence of side effects.

Postoperative Analgesia at Home After Ambulatory
Hand Surgery: A Controlled Comparison of Tramadol,
Metamizol, and Paracetamol
Despite receiving oral analgesic medication, up to 40% of
patients undergoing hand surgery experienced inadequate
analgesia in this controlled trial.
Although tramadol was more effective, its use was associated
with the highest frequency and intensity of adverse effects
and the most patient dissatisfaction. Metamizol and
acetaminophen provided good analgesia with a small
incidence of side effects. For patients undergoing ambulatory hand
surgery, postoperative pain can last longer than 2–3 days, and there is a
need for both better education before the procedure and oral analgesic
therapy at home.

Anesthesia and Analgesia 2001; 92:347-351.

Anesthesia and Analgesia 2001; 92:347-351


Studies with paracetamol
Cochrane review
3rd Molar removal (Bony Impacted)or other
teeth
» Bentley 1987, Cooper 1980 ,Cooper 1981,Cooper1986,Cooper 1988, Cooper
1989,Cooper1991a, Cooper 1998 , Forbes 1982 , Forbes 1984 , Forbes 1989 ,Forbes
1990a , Forbes 1990b , Hersch 2000 , Kiersch 1994 , Lehnert 1990 , Mehlisch 1995 ,
Moller 2000 , Seymour 1996 , Sunshine 1986 ,

Oral surgery (involving bone removal)
» Mehlisch 1984, Mehlisch 1990 , Winter 1983

Dental, gynaecologic and orthopaedic pain patients
» Edwards 2002

General, Gynaecological or orthopaedic surgery)
»

Forbes 1984b,F orbes 1983, Jain 1986

Studies with paracetamol Cochrane
review
Episiotomy
» Bhounsule 1990, Berry 1975 , Sunshine 1989

Caesarean section
» Bjune 1996, Sunshine 1993

Post partum (post episiotomy and post-surgical)
» Laska 1983 (Study 3), Rubin 1984, Schachtel 1989

Elective orthopaedic surgery
» McQuay 1988, Sakata 1986 , Santos Pereira 1986 , Winnem 1981

Tonsillectomy
» Pinto 1984

Urological
» Rubinstein 1986

However NNTs cannot be
viewed in isolation…………
Effects of analgesics may vary with
different pain models…
» Gray A, Kehlet H, Bonnet F, Rawal N. Predicting
postoperative
analgesia outcomes: NNT league
tables or procedure-specific evidence? British
Journal of Anaesthesia 2005;94: 710–4.

Forest plot and graphical
information
One attraction of meta-analysis is that the results can
be summarised using a graphical plot such as a forest
plot, in which each study is represented by a square
indicating the point estimate of the effect size and a
horizontal line indicating the confidence interval
around that estimate. The pooled estimate of the
effect size and its confidence interval are represented
by a diamond at the bottom of the figure.Forest plots
thereby provide a compact, visually striking overview
of the essential data from each individual study and

Cochrane conclusions:
There was no significant difference in the relative
benefit or NNT for at least 50% pain relief by dose .

Values for NNT were 3.5 (2.7 to 4.8) for 500mg, 4.6 (3.9 to 5.5) for 600 to
650mg , and 3.6 (3.2 to 4.1) for 975 to 1000mg.

About half of participants treated with paracetamol at
standard doses achieved at least 50%pain relief over
four to six hours, compared with about 20%treated
with placebo.
The differences between dental and other postsurgical pain
have been noted before (Barden 2004c).
Consistently lower placebo responses in the dental pain model do not
effect the NNT as a measurement of efficacy. Dose response may be more
sensitively determined using trials that directly compare two doses, as has
been done for paracetamol 1000 mg compared with 500 mg (McQuay
2007).

Randomised, double-blind, placebo-controlled
trials of paracetamol plus codeine, compared
with placebo or the same dose of paracetamol
alone, for relief of acute postoperative pain in
adults.

NNTs for paracetamol +codeine at
different doses

Conclusion PARA+Codeine
Addition of codeine increased proportion of
participants achieving at least 50% pain relief over
four-to-six hours by 10 to 15%
,increased time to use of rescue medication by
about one hour, and reduced proportion of
participants needing rescue medication by
about 15% (NNT to prevent remedication 6.9 (4.2 to
19). Adverse events were mainly mild to moderate in
severity and incidence did not differ between
groups.

Duration of action of the combination Paracetamol+
codeine
The median time to use of rescue medication varied greatly
between trials, particularly for the active treatment arms, but
was generally longer for paracetamol plus codeine than
for placebo or paracetamol alone.
The weighted mean of the median time to use of rescue
medication (all doses of paracetamol plus codeine) at 4.3
hours is equal to or shorter than most non-selective NSAIDs
(diclofenac 50 mg 3.8 hours, ibuprofen 400 mg 5.3 hours,
naproxen 9.8 hours) and much shorter than etoricoxib 120 mg
and rofecoxib 50mg (20 hours ormore).
The addition of codeine to paracetamol extended the duration
of action by about one hour

Rees J,Moore RA,McQuay HJ, Derry S, Gaskell H. Single dose
oral oxycodone and oxycodone plus
paracetamol (acetominophen) for acute postoperative pain in
adults. Cochrane Database of Systematic Reviews 2000, Issue 2

Seventy-seven reports were identified. Seven reports
met the inclusion criteria; all assessed oral
oxycodone.
For efficacy, a significant benefit of active drug over
placebo was shown for all doses of oxycodone and
oxycodone plus paracetamol, except oxycodone 5
mg.

Rees J,Moore RA,McQuay HJ, Derry S, Gaskell H. Single dose oral
oxycodone and oxycodone plus
paracetamol (acetominophen) for acute postoperative pain in adults.
Cochrane Database of Systematic Reviews 2000, Issue 2

adverse effects
:significantly more adverse effects with active drug than with
placebo were shown for all doses, except oxycodone 5 mg
and its combination with paracetamol 325 mg. This was also
shown for drowsiness/somnolence. Significantly

more nausea, vomiting and
dizziness/lightheadedness were reported
with oxycodone 10 mg plus paracetamol
(650 mg and 1000 mg) than with placebo.

PLAINLANGUAGESUMMARY
Single dose oxycodone and oxycodone plus paracetamol
(acetaminophen) for acute postoperative pain
Insufficient evidence that single-dose oxycodone and
oxycodone plus paracetamol provides effective analgesia
in adults with acute postoperative pain. This review assessed
the efficacy of single-dose oral oxycodone and oxycodone plus
paracetamol in adults with moderate/severe postoperative pain using
information from randomised placebo-controlled trials. The results were
based on few data and were not robust. The implication was that these
drugs were effective, providing similar analgesia to intramuscular
morphine 10mg and non-steroidal anti-inflammatory drugs. A doseresponse relationship was not shown with increased doses of
oxycodone or paracetamol. This may be due to the paucity of
information. Drowsiness, dizziness, nausea and vomiting were
commonly reported.

Trattamento del dolore acuto post-operatorio in chirurgia ortopedica
maggiore
Acute pain management after major orthopaedic surgery
R. Troglio,M. Berti,G. Danelli,C. Consigli

Mattia C, Coluzzi F, Sarzi Puttini P, Viganó R.

Paracetamol/Tramadol association: the easy
solution for mild-moderate pain. Minerva Med. 2008
Aug;99(4):369-90

Analysis of the combination of paracetamol
(325 mg) and tramadol (37.5 mg)
9 double-blind,acute painful flares of
chronic-degenerative pathologies, trauma or
subjected to surgery
» duration of treatment was 1-10 days and, in
total, 2 537 patients were admitted, affected by
The mean daily dose of paracetamol/tramadol
most frequently used was 4.3-4.5 tablets/day.

Paracetamol/Tramadol association: the easy solution
for mild-moderate pain
chronic pain;
» 6 studies considered the duration of treatment was 4-13
weeks and a total of 1 890 patients, affected by chronic
musculoskeletal pain.
» The mean daily dose of paracetamol/tramadol was
between 3.5 and 4.2 tab.

In conclusion, the fixed association
paracetamol/tramadol is a new therapeutic option,
particularly useful in mild-moderate pain where
paracetamol is inadequate.

Paracetamol+tramadol vs tramadol alone in low back pain
patients : Patients were randomized and treated for 10 days with PIT (325 mg/37.5
mg) or T (50 mg

).

. Perrot S, Krause D, Crozes P, Naïm C; GRTF-ZAL-1 Study Group. Efficacy and tolerability of paracetamol/tramadol (325
mg/37.5 mg) combination treatment compared with tramadol (50 mg) monotherapy in patients with subacute low back pain:
a multicenter, randomized, double-blind, parallel-group, 10-day treatment studyClin Ther. 2006 Oct;28(10):1592-606.

Pracetamol+tramadol Tramadol alone
Adequate pain relief % 81.6

82.9

Overall patient
satisfaction %

72.5

72.9

Total tramadol mg

172.5

227.3

,nausea,
dizziness/vertigo,
sleepiness/drowsiness,
constipation, vomiting

-

+

Smith AB, Ravikumar TS, Kamin M, Jordan D, Xiang J,
Rosenthal N; CAPSS-115 Study Group. Combination
tramadol plus acetaminophen for postsurgical pain Am J Surg.
2004 Apr;187(4):521-7
multicenter, randomized, double-blind, active- and placebocontrolled trial
Moderate and severe post orthopedic and abdominal
pain
2* 37.5 mg tramadol + 325 mg APAP vs 2*codeine 30 mg
+APAP 300 mg vs placebo

tramadol + APAP> codeine + APAP
AE:8.2% of tramadol plus APAP, 10.1% of codeine plus APAP,
and 3.0% of placebo patients.
constipation (4.1% tramadol plus APAP vs 10.1% codeine
plus APAP) and vomiting (9.2% vs 14.7%, respectively),

Fricke JR Jr, Karim R, Jordan D, Rosenthal N.. A double-blind, single-dose comparison
of the analgesic efficacy of tramadol/acetaminophen combination tablets,
hydrocodone/acetaminophen combination tablets, and placebo after oral surgery. Clin
Ther 2002; 24:953-68

after extraction of > or =2 impacted third molars,a
comparison between 1 or 2 37.5 mg tramadol/325
mg acetaminophen tablets (T/APAP), 10 mg
hydrocodone bitartrate/650 mg acetaminophen
tablets (HC/APAP), and placebo in the treatment of
postoperative dental pain demonstrated comparable
analgesia with better tolerability in the group T/APAP

Filitz J, Ihmsen H, Günther W, Tröster A, Schwilden H,
Schüttler J, Koppert W. Supra-additive effects of tramadol
and acetaminophen in a human pain modelPain. 2008
Jun;136(3):262-70. 20.
Department of Anesthesiology, University Hospital Erlangen, Krankenhausstrasse 12,
D-91054 Erlangen, Germany. Joerg.Filitz@kfa.med.uni-erlangen.de

17 healthy volunteers were enrolled in this double-blind and placebocontrolled study in a cross-over design.
Transcutaneous electrical stimulation at high current densities (29.6+/16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct
areas of hyperalgesia for painful mechanical stimuli (pinprickhyperalgesia). Pain intensities as well as the extent of the areas of
hyperalgesia were assessed before, during and 150 min after a 15 min
lasting intravenous infusion of acetaminophen (650 mg),

tramadol (75 mg), a combination of both (325 mg
acetaminophen and 37.5mg tramadol), or saline 0.9%.

Filitz J, Ihmsen H, Günther W, Tröster A, Schwilden H,
Schüttler J, Koppert W. Supra-additive effects of tramadol
and acetaminophen in a human pain modelPain. 2008
Jun;136(3):262-70. 20.
Paracetam Paracetam Tramadol 75
ol 650
ol+tramado
l(325+37.5)
a maximum pain
reduction

9.8+/4.4%),

15.2+/-5.7% 11.7+/-4.2%

antyhyperalgesic 34.5+/-14.0 41.1+/-14.3 no

Tramadol alone produces significant analgesia but no
reduction of hyperalgesia
Pain ratings

Areas of pin prick
hyperalgesia

Placebo corrected reduction of analgesia and
hyperalgesia

Dose response curves and ED50 of acetaminophen
a:for analgesia

b:for antihyperalgesia

Supraadditive effects of tramadol and acetaminophen
Supraadditive effect for
analgesia

Supraadditive effect for
hyperanalgesia

Sen H, Kulahci Y, Bicerer E, Ozkan S, Dagli G, Turan AThe
analgesic effect of paracetamol when added to lidocaine for
intravenous regional anesthesia. Anesth Analg. 2009
Oct;109(4):1327-30.

IVRA with lidocaine alone or with paracetamol(300
mg) added.
addition of paracetamol during IVRA with lidocaine
decreased tourniquet pain, increased anesthesia
quality, and decreased postoperative analgesic
consumption

McQuay H, Edwards JMeta-analysis of single dose
oral tramadol plus acetaminophen in acute
postoperative pain.
The tramadol/acetaminophen combination was more effective
than either of its two components administered alone. For
dental patients, who formed the bulk of the population, the
combination formulation also had a significantly lower (better )

NNT (approximately 3) than the components al
one (approximately 8-12), comparable to ibuprofen
400 mg. The adverse effects associated with
tramadol/acetaminophen were similar to those
associated with the components alone. The commonest
were dizziness, drowsiness, nausea, vomiting and
headache.

JE Edwards

et al. Combination analgesic efficacy: Individual patient data
meta-analysis of single dose oral tramadol plus acetaminophen in acute
postoperative pain. Journal of Pain and Symptom Management 2002
23:121-30.

At least half pain relief,
number/total
(%)
Pain model/dosage

Paracetamol plus
Placebo
tramadol

NNT
(95% CI)

Dental pain:
Paracetamol 650 mg + 145/340 (43)
tramadol 75 mg

14/339 (4)

2.6 (2.3 to 3.0)

Postsurgical pain:
Paracetamol 975 mg + 61/101 (60)
tramadol 112.5 mg

25/100 (25)

2.8 (2.1 to 4.4)


Cochrane on paracetamol+tramadol
More patients reported adverse events with
paracetamol plus tramadol than with placebo in
an analysis of dental pain patients. There were
more patients experiencing any adverse effect
(NNH 5.4), and dizziness (NNH 23), nausea
(NNH 7) and vomiting (NNH 6) with paracetamol
plus tramadol.

Comparison of Para vs PARA+NSAID
from Romsing BJA 2002)

Author()

Nsaid

surgery

Effect on
pain score

Consumption Time to
of analgesics rescue

Breivik

diclofenac

dental

+

+

Fletcher

ketoprofen

Lumbar disc

+

-

Matthews

diclofenac

dental

+

-

-

Beck

diclofenac

abdominal

+

-

-

Montgomery

diclofenac

Abdominal
gynecological

-

-

Mather

ketorolac

tonsillectomy

-

-

Morton

diclofenac

appendectomy

-

-

-

Fassolt

suprofen

various

-

-

-

Lancker

tenoxicam

Arthroscopy

-

-

-

Comparison of NSAID vs NSAID+PARA
(from Romsing Bja 2002)

Author()

Nsaid

surgery

Effect on pain
score

Consumption
of analgesics

Time to rescue

Breivik

diclofenac

dental

+

Fletcher

ketoprofen

Lumbar disc

+

-

-

Montgomery

diclofenac

Abdominal
gynecological

-

-

-

Morton

diclofenac

appendectomy -

-

-

Matthews

diclofenac

dental

-

-

-

Lancker

tenoxicam

Arthroscopy

-

-

-

+

Paracetamol dosages
And treatment schemes

Postoperative analgesia in infants and children
P.-A. Lo¨nnqvist,N. S. Morton.Br J Anaesth 2005; 95: 59–68


Route of adminstration,onset and duration of
analgesia:III:benefits of high dosage?ceiling effect ?
» NO:No diff in vas and rescue alfentanil between diff
dosages of propacetamol iv
Hahn T, Morgensen C, et al. Analgesic effect of i.v. paracetamol: possible ceiling effect of paracetamol in postoperative
pain. Acta Anaesthesiologica Scandinavica 2003; 47: 138–45

.

» Yes:i.v.2 gr> 1 gr in pain relief and duration of pain
relief >8 hr after 3rd molar surgery.
»

Juhl G, Norholt S, Tonnesen E, Hiesse-Provost O,

Jensen TS. Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2 g starting dose
following 3rd molar surgery. European Journal of Pain 2006; 10: 371–7

» 2 gr iv paracetamol > 1 gr in onset,efficacy and duration
after 3° molar surgery.
»

Juhl GI, Norholt SE, Tonnesen E, Hiesse-Provost O, Jensen TS. Analgesic efficacy and safety of intravenous
paracetamol (acetaminophen) administered as a 2 g starting dose following third molar surgery. Eur J Pain.
2006 May;10(4):371-7.

Costs (da Guida all’Uso dei Farmaci 2008)
Os.cp eff.1000 mg: eur 5-8.34
Tab 500 ;eur 5.10-5.51-6.7 RR(ric med);16 cp,0.52
euro/1 gr
Iv 12 fl. :eur 63.47,i.e 5.33 euro/gr iv.
Sciroppo :2.4-2.5%,cioè 2.5 gr in 100 ml,ossia 25
mg/ml
Supp?
classe C
SOP:senza obbligo prescrizione
Sip.:senza indicazione prezzo

Elia N, Lysakowski C, Trame` r MR.Does Multimodal Analgesia with
Acetaminophen, Nonsteroidal Antiinflammatory Drugs, or Selective
Cyclooxygenase-2 Inhibitors and Patient-controlled Analgesia Morphine
Offer Advantages over Morphine Alone? Meta-analyses of Randomized
TrialsAnesthesiology 2005; 103:1296–1304

4 main results emerge from these metaanalyses.

1) all these nonopioid analgesics are morphine
sparing.
2)pain intensity, when measured with a standard
VAS scale, is significantly decreased at 24 h with
NSAIDs only.
3) there is evidence of a reduction in the incidence of
some morphine-related adverse effects with NSAIDs.

Elia et al..Does Multimodal Analgesia with Acetaminophen, Nonsteroidal
Antiinflammatory Drugs, or Selective Cyclooxygenase-2 Inhibitors and Patientcontrolled Analgesia Morphine Offer Advantages over Morphine Alone? Meta-analyses of
Randomized TrialsAnesthesiology 2005;

103:1296–1304

“Finally,

with both NSAIDs and COX-2
inhibitors, there were reports of rare
but clinically important adverse effects”

but none with acetaminophen!
» C.Melloni,reviewer

Insomma:

paracetamolo

per chi: per tutti
Con che cosa:con tutti

Robert C, Saenz-Feijoo R, Gaudy JF, Arreto CD. Quantitative analysis of
the scientific literature on acetaminophen in medicine and biology: a
2003-2005 studydagger .Fundam Clin Pharmacol. 2009 Mar 9.
Fundam Clin Pharmacol. 2009 Mar 9. [Epub ahead of print]

A total of 1626 documents involving acetaminophen
published by 74 countries during 2003-2005 in the
Thompson-Scientific Life sciences and Clinical
Medicine collections were identified and analyzed. The
USA leads in the number of publications followed by the UK, and
industrialized countries, including France, Japan and Germany; the
presence of countries such as China, India and Turkey among the top
15 countries deserves to be noticed.

Effect of racemic ibuprofen dose on the magnitude and duration of platelet
cyclo-oxygenase inhibition: relationship between inhibition of
thromboxane production and the plasma unbound concentration of S(+)ibuprofen.A. M. EVANS, R. L. NATION', L. N. SANSOM', F.
BOCHNER,A. A. SOMOGYI.
Relationship between the
percentage inhibition of
TXB2 generation and log
plasma concentration of
unbound Sibuprofen,
for subject number 2. The
symbols are actual data
points, and the line
represents the predicted
relationship,
according to a sigmoidal
Emax model, from the
computergenerated
analysis


Paracetamol
10
9
8
7
6
5
4
3
2
1
0

paracetamol 325
paracetamol 500
paracetamol600/650
paracetamol 1000
paracetamol 1500
parac300+codeina30
paracetamol 500+ Codeina 30
paracetamol600+codeina60
paracetamol 800+ codeina 60
paracetamol 1000+codeina 60

NNT

paracetamol 650+Tramadeol 75
paracetamol 975+tramadol112

Paracetamol per napoli sia 2009

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Paracetamol per napoli sia 2009