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 644-653

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Nsaids bibliography:levels of excellence

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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):446-54.

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.

Mechanism of action:2� 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 thrombosis

Mechanism of action:3� 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; 12:269-280

� 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

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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

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

Utilization and enzyme inhibit.of PGE

since GSH is a cofactor..

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. Acetaminophen-induced 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

ADULTS

Pharmacokinetics/Pharmacodynamics of Acetaminophen Analgesia inJapanese 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

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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.

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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 (20 mg/kg

Acetaminophen+diclofenac

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

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10 healthy adult volunteers increasing doses of rectal paracetamol (15, 25, 35, and 45 mg kg-1).

Children

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

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orally, 0.5-1.0 h preop (n = 20), at induction of anesthesia

(n = 100).

Children undergoing outpatient tonsillectomy

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 20-

mg/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.

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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. 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 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 24-

Hour 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

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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

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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

� Arachidonic acid --- COX- prostaglandin G2

� prostaglandin G2 peroxidase prostaglandin H2

� prostaglandin H2 thromboxane synthase-- Tx2� G protein—coupled receptors on� the surface of the platelet.� :aggregation

Para NSAIDs

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, appendicetomy

no =

Sinatra,2005 morphine Major orthop -30% = propacetamol

Peduto,1998 morphine Major orthop -46% - placebo

Del Bos,1995 morphine Knee ligamentoplasty

-27% = placebo

Remy,metanalysis ,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,metamizol

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 indicatesless morphine consumption with active compared with control. When the 95% confidence interval (CI) does not include0, 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 morphine-related 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 notinclude 1, the difference is considered statistically significant. * Sedation ordrowsiness or somnolence. ** Ileus orconstipation or intestinal obstruction.Meta-analyses were performed when datafrom at least three trials or 100 patientscould be combined.

key publications,examples....

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

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Para 1 gr

Propacet 2 gr

placebo

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

Mean pain intensity differenc esSinatra 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

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placebo

Time to Ist rescue medication

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placebo

total morphine doses received over 24 h: 38.3 ± 35.1 mg for i.v.acetaminophen40.8 ± 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

-2

0

2

4

6

8

10

12

totpar spid sprid

para

propara

placebo

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

acetaminophen

propacetamol

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

Mean scores of PIDMoller 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 paracetamol Selective COX 2 Inhib

Pain active active

fever active active

inflammation inactive active

platelets active,but rapidly reversible

inactive

Rheumatoid arthritis (inactive)? active

Intestinal damage inactive inactive

Decreased Na renal excretion

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 “

Duodecim. 2009;125(5):563-4.[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 Management. Anesthesiology 2004 Jun;100(6):1573-81

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 non-steroidal 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

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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

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Drugs with littleVariability between concentrationAnd effect have steepCurves 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

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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

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15 20 30analgesia

4

0

fent

para(da dati di Anderson)

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 .

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

Calculating NNT

»Active controlTotal Ta Ca

improved IA Ic

1

NNt= ----------------

(Ia/Ta)-(Ic/Tc)

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

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

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

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: evidence-based,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, placebo-controlled study in patients with post-operative dental pain. Eur J Clin Pharmacol. 2009 Apr;65(4):343-53.

Comparison studies

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 nonsteroidalantiinflammatory 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

Ketor 30

Ketor 15

Paracet 1 gr

patients undergoing total hip or knee replacement first morning after major joint replacement surgery164 patients experiencing moderate-to-severe pain

A little

moderate

A lot

complete

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

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

propacet

Ketor 15

Ketor 30

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 JPostoperative 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.

�

Rawal N, Allvin R,Amilon A,Ohlsson T,Hallén JPostoperative Analgesia at Home After Ambulatory Hand Surgery: A

Controlled Comparison of Tramadol, Metamizol, and Paracetamol Anesthesia and Analgesia 2001; 92:347-351.

Rawal N, Allvin R,Amilon A,Ohlsson T,Hallén JPostoperative Analgesia at Home After Ambulatory Hand Surgery: A

Controlled Comparison of Tramadol, Metamizol, and Paracetamol Anesthesia and Analgesia 2001; 92:347-351

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

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

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

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 the overall 'result' [3].

Paracetamol alone

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).

Paracetamol+codeine

� 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

Paracetamol+oxycodone

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.

P L A I N L A N G U A G E S U M M A R YSingle 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 dose-response 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 surgeryR. Troglio,M. Berti,G. Danelli,C. Consigli

Paracetamol+ tramadol

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.

� 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 association: the easy solution for mild-moderate pain

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 placebo-controlled 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), adverse events were similar for active treatments.

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 placebo-controlled 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 (pinprick-hyperalgesia). 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.

Paracetamol 650

Paracetamol+tramadol(325+37.5)

Tramadol 75

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 ratingsAreas 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.

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

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

Pain model/dosage Paracetamol plus tramadol

Placebo NNT (95% CI)

Dental pain: Paracetamol 650 mg + tramadol 75 mg

145/340 (43) 14/339 (4) 2.6 (2.3 to 3.0)

Postsurgical pain: Paracetamol 975 mg + tramadol 112.5 mg

61/101 (60) 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.

PARA + NSAIDs

Comparison of Para vs PARA+NSAIDfrom Romsing BJA 2002)

Author() Nsaid surgery Effect on pain score

Consumption of analgesics

Time to 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 childrenP.-A. Lo¨nnqvist,N. S. Morton.Br J Anaesth 2005; 95: 59–68

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

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

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

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 meta-

analyses.� 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 Patient-

controlled 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

FINE

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.

Br. J. clin. Pharmac. (1991), 31, 131-138Effect 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.

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Relationship between the percentage inhibition ofTXB2 generation and log plasma concentration of unbound Sibuprofen,for subject number 2. The symbols are actual datapoints, and the line represents the predicted relationship,according to a sigmoidal Emax model, from the computergeneratedanalysis

Paracetamol

0123456789

10

NNT

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

paracetamol 650+Tramadeol 75

paracetamol 975+tramadol112