paracetamol - widening the horizon in pain managment

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Dr Giridhar Panpalia

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Page 1: Paracetamol - widening the horizon in pain managment

Dr Giridhar Panpalia

Page 2: Paracetamol - widening the horizon in pain managment

Clinical definition of pain1

“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage...

1. IASP Pain Terminology. In Merskey H & Bogduk N eds. Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy. IASP Press, Seattle 1994:209-14.

Every one needPain Relief

Page 3: Paracetamol - widening the horizon in pain managment

Nociceptive pain Transient pain in response to noxious stimuli

Inflammatory pain Spontaneous pain and hypersensitivity to pain in response

to tissue damage and inflammation

Neuropathic pain Spontaneous pain and hypersensitivity to pain in

association with damage to or a lesion of the nervous system

Woolf. Ann Intern Med. 2004;140:441-451.

Page 4: Paracetamol - widening the horizon in pain managment

Ref:- Wall and Melzacks text book of pain. 2005

Reuben et al. J Bone Joint Surg. 2000;82:1754-1766.

Page 5: Paracetamol - widening the horizon in pain managment

Myocardialischemia

Increasedsympatheticactivity

Myocardial Myocardial OO2 2

consumptionconsumption

GI effectsSplinting,shallowbreathing

Increasedcatabolicdemands

Anxietyand fear

Peripheral/centralsensitization

GI motilityGI motilityAtelectasis,Atelectasis,hypoxemia,hypoxemia,hypercarbiahypercarbia

Poor woundPoor woundhealing/musclehealing/musclebreakdownbreakdown

Sleeplessness,Sleeplessness,helplessnesshelplessness

AvailableAvailabledrugsdrugs

Delayed recovery Pneumonia

Weaknessand impairedrehabilitation

Psycho-logical

Chronic pain

Acute Pain

Page 6: Paracetamol - widening the horizon in pain managment

20032003 19931993

No. 5:No. 5:Treatment by healthcare Treatment by healthcare professionalsprofessionals 30%30% 30%30%

No. 4: Pain during surgeryNo. 4: Pain during surgery 33%33% 34%34%

No. 3: Full recovery from surgeryNo. 3: Full recovery from surgery 46%46% 42%42%

No. 2: Will surgery improve No. 2: Will surgery improve conditioncondition 51%51% 51%51%

No. 1: Pain after surgeryNo. 1: Pain after surgery 59%59% 57%57%

Warfield et al. Anesthesiology. 1995;83:1090-1094.

Apfelbaum et al. Anesth Analg. 2003;97:534-540..

Page 7: Paracetamol - widening the horizon in pain managment

Patie

nts

(%)

Patie

nts

(%)

*Includes pain in immediate postop period and up to 2 weeks post discharge. *Includes pain in immediate postop period and up to 2 weeks post discharge. Warfield et al. Anesthesiology. 1995;83:1090-1094. Apfelbaum et al. Anesth Analg. 2003;97:534-540..

Page 8: Paracetamol - widening the horizon in pain managment

21%21%

8%8% 19%19%

52%52%

SlightSlight ModerateModerate SevereSevere ExtremeExtremePain IntensityPain Intensity

Apfelbaum et al. Anesth Analg. 2010;97:534-540.

Page 9: Paracetamol - widening the horizon in pain managment

Pain ControlPain Control41%41%

Setting and Route Setting and Route of Administrationof Administration

12%

Side-Effect SeveritySide-Effect Severity19%19%

Side-Effect Type28%

Patients prefer avoiding side effects over complete pain control

47%

Gan et al. Br J Anaesth. 2004;92:681-688.

Page 10: Paracetamol - widening the horizon in pain managment

Postoperative pain management is still sub-optimal

1. Kuhn S et al. BMJ 1990;300(6741):1687-90.2. Poisson-Salomon AS et al. La Presse Médicale 1996;25(22):1013-7.3. Vallano A et al. Br J Clin Pharmacol 1999;47:667-73.4. McHugh GA et al. Anaesthesia 2002;57(3):270-5.5. Rawal N et al. Eur J Anaesth 1998;15:354-63.6. Puig MM et al. Acta Anaesthesiol Scand 2001;45:465-70.

I wantPain relief

Page 11: Paracetamol - widening the horizon in pain managment

Guidelines for optimising POP management1,2,3,4,5,6

Adequate and thorough patient information2,3,4,5,6

Use of written protocols1,3,4,5,6

Regular assessment of pain intensity1,2,3,4,5,6

Adequate medical and nursing staff training1,3,4,5,6

Use of balanced analgesia, PCA, and epidural drug administration1,2,3,4,5,6

1. The Royal College of Surgeons of England and the College of Anaesthetists. Commission on the provision of surgical services, report of the working party on pain after surgery. London, UK, HMSO.1990.2. Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services. Acute Pain Management in Adults: Operative Procedures. Quick Reference Guide for Clinicians. AHCPR Pub. No. 92-0019. Rockville, MD.1992.3. International Association for the Study of Pain, Management of acute pain: a practical guide. In: Ready LB, Edwards WT, eds. Seattle, 1992.4. Wulf H et al. Die Behandlung akuter perioperativer und posttraumatischer Schmerzen Empfehlungen einer interdisziplinaeren Expertenkommision. G. Thieme, Stuttgart, New York. 1997.5. EuroPain. European Minimum Standards for the Management of Postoperative Pain.1998.6. SFAR. Conférence de consensus. Prise en charge de la douleur postopératoire chez l’adulte et l’enfant. Ann Fr Anesth Réanim 1998;17:445-61.

Page 12: Paracetamol - widening the horizon in pain managment

Reduced doses

Improved pain relief

Reduce severityof side effects

Earlier discharge

Decreased costs

OpioidsOpioidsOpioidsOpioids

NSAIDs, coxibs,NSAIDs, coxibs,paracetamol,paracetamol,nerve blocksnerve blocks

NSAIDs, coxibs,NSAIDs, coxibs,paracetamol,paracetamol,nerve blocksnerve blocks

PotentiationPotentiation

Kehlet et al. Anesth Analg. 1993;77:1048-1056 (B).

Page 13: Paracetamol - widening the horizon in pain managment

“Is more effective & has a faster onset than oral paracetamol”

Page 14: Paracetamol - widening the horizon in pain managment

Paracetamol – how does it work?

Paracetamol is a centrally acting agent

It selectively inhibits nervous system PG synthesis2,3 probably via COX-3

Other central mechanisms of action depend on the bulbo-spinal serotoninergic pathway4,5

1. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4. 2. Carlsson KH et al. Pain 1988;32:313-26. 3. Flower RJ et al. Nature 1972;240:410-1. 4. Tjølsen A et al. Eur J Pharmacol 1991;193:193-201.5. Pélissier T et al. JPET 1996;278:8-14.

Tropisetron blocks the action; not ondansetron and granisetron

Page 15: Paracetamol - widening the horizon in pain managment

Does IV paracetamol have a fast onset and is it effective?1

Single-centre, randomised, double-blind, placebo and active-controlled, single-dose study Oral surgery Onset of analgesia measured by the double click- stopwatch method Pain intensity differences (PID) rated on VAS and VRS

N = 175

n=50 / i.v. paracetamol 1g / 2-min injection

n=50 / i.v. paracetamol 1g / 15-min infusion

n=50 / oral paracetamol 1g

n=25 / placebo

Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5): 642-8

Page 16: Paracetamol - widening the horizon in pain managment

Means of pain intensity differences (VAS)

Onset of action is fast and effective – within 5 minutes

Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5): 642-8

Page 17: Paracetamol - widening the horizon in pain managment

Jarde O et al. Clin Drug Invest 1997;14(6):474-81.

Time-effect curve

(n=109

IV paracetamol 1g is more effective than oral paracetamol 1g

Page 18: Paracetamol - widening the horizon in pain managment

Paracetamol PK/PD relationship in function of the dose

1. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.

(n = 11)

No ceiling effect with i.v. paracetamol1

Page 19: Paracetamol - widening the horizon in pain managment

Single-centre, randomised, double-blind, placebo and active-controlled, repeated-dose study Oral surgery Summed pain intensity differences (SPID) and total pain relief (TOTPAR) after 5 and 10 hours

N = 95

n=31 / i.v. paracetamol 1g + i.v. paracetamol 0.5g after 5 hours

n=30 / i.m. morphine 10 mg + i.m. morphine 5 mg after 5 hours

n=34 / placebo

Does Paracetamol 1g compare with Morphine 10mg in terms of analgesic efficacy1

1. Van Aken H. Anesth Analg 2004; 98: 159-65

Page 20: Paracetamol - widening the horizon in pain managment

Time course of pain relief versus initial pain

Comparable analgesic efficacy

Oral surgery

1. Van Aken H. Anesth Analg 2004; 98: 159-65

Page 21: Paracetamol - widening the horizon in pain managment

Multi-centre, randomised, double-blind, placebo- controlled, single-dose study

Total hip or knee replacement surgery

Pain intensity differences (PID) measured on a VAS and a VRS

Pain relief (PR)

1. Zhou TJ et al. Anesth Analg 2001;92:1569-75.

N = 164

n=57 / i.v. paracetamol 1g

n=27 / i.v. ketorolac 30mg

n=28 / i.v. ketorolac 15mg

n=52 / placebo

…and Ketorolac 30mg1

Page 22: Paracetamol - widening the horizon in pain managment

1. Zhou TJ et al. Anesth Analg 2001;92:1569-75.

(n=57)

(n=28)

Total hip or knee replacementPain relief scores at rest

Not dissimilar for the first 5 hours in terms of analgesic efficacy

Page 23: Paracetamol - widening the horizon in pain managment

Single-centre, randomised, double-blind, placebo and active-controlled, double-placebo, repeated-dose study Total hip arthroplasty Total pain relief (TOTPAR) and Pain relief (PR) measured on a VRS

N = 120

n=40 / i.v. paracetamol 1g / 2 times at 5-hour interval

n=40 / i.m. diclofenac 75mg

n=40 / placebo

...and Diclofenac 75mg?

1. Hynes D et al. Acta Anaesthesiol Scand 2006; 50: 374—381

Page 24: Paracetamol - widening the horizon in pain managment

Time course of pain relief versus initial pain

Total hip arthroplasty

The analgesic effect provided by i.v. paracetamol is similar to that provided by a single i.m. injection of diclofenac 75mg.1

1. Hynes D et al. Acta Anaesthesiol Scand 2006; 50: 374—381

Page 25: Paracetamol - widening the horizon in pain managment
Page 26: Paracetamol - widening the horizon in pain managment

Multi-centre, randomised, double-blind, placebo-controlled, repeated-dose study Hip arthroplasty Total doses of PCA morphine over 24 hours, and number of self-administered boluses

Pain intensity assessed on a VRS and VAS

Global efficacy assessed on a VRS

1. Peduto VA et al. Acta Anaesthesiol Scand 1998;42:293-8.

N = 89n=42 / i.v. paracetamol 1g + morphine (PCA)

n=47 / i.v. placebo + morphine (PCA)

Does paracetamol have an opioid-sparing effect1

Page 27: Paracetamol - widening the horizon in pain managment

1. Peduto VA et al. Acta Anaesthesiol Scand 1998;42:293-8.

24-hour morphine consumption in terms of total PCA amountin mg and total number of boluses

Hip arthroplasty

46% less opioid consumed

Page 28: Paracetamol - widening the horizon in pain managment

Paracetamol - Safety

Page 29: Paracetamol - widening the horizon in pain managment

Similar overall incidence of adverse events

Similar incidence of local adverse events

No clinically significant changes in vital signs or laboratory tests

Phase III clinical trials1,2 VS. placebo

IV paracetamol as safe as placebo

1. Lange-Møller P. Anesth Analg 2005;101:90 –6 2. Sinatra RS. Anesthesiology 2005; 102:822–3India Prescribing Information

Page 30: Paracetamol - widening the horizon in pain managment

Paracetamol hepatotoxicity was found to be very rare (<1 / 2,500)1

It was always related to misuse and overdose (>4g / day)1

Hepatic safety at therapeutic doses1

1. Whitcomb DC et al. JAMA 1994;272(23):1845-50.

Good hepatic safety

Page 31: Paracetamol - widening the horizon in pain managment

Can Paracetamol be given in alcoholics?

Paracetamol - Alcohol syndrome

Overdose of Paracetamol in alcoholics results in severe hepatotoxicity

Alcohol induces CYP2E1 but inhibits NAPQI

Page 32: Paracetamol - widening the horizon in pain managment

1. Making paracetamol soluble Use of hydrophilic ingredients (mannitol and disodium phosphate)

2. Ensuring its stability in solution- By controlling hydrolysis Use of a pH buffer (disodium phosphate and sodium hydroxide)

- By preventing oxidation Addition of cysteine hydrochloride

Oxygen-free manufacturing process

What were the challenges?

Page 33: Paracetamol - widening the horizon in pain managment

Up to 4g / day, paracetamol has an excellent renal safety profile1

No evidence exists for the development of chronic nephropathy with paracetamol2

Recommended by the National Kidney Foundation as the non-narcotic analgesic of choice in patients with underlying renal disease 3

1. Whelton A. Am J Therapeut 2000;7(2):63-74.2. Blantz RC. Am J Kidney Dis 1996;28(1):S3-6.3. Henrich WL et al. Am J Kidney Dis 1996;27(1):162-5.

Good renal tolerance

Page 34: Paracetamol - widening the horizon in pain managment

No centrally mediated side-effects1

(e.g. sedation, constipation, nausea, vomiting, respiratory depression) No effect on platelet aggregation, bleeding, or uric acid excretion2

No gastrointestinal Sidé effects3

Good renal4 and hepatic5 safety Few contra-indications and drug interactions

Paracetamol safety benefits in POP

1. Lechat P et al. Thérapie 1989;44:337-54.2. Insel PA. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Goodman & Gilman eds. The pharmacological basis of therapeutics. McGraw Hill, 9th edition, 1996:617-57.3. Singh G. Am J Therapeut 2000;7(2):115-21.4. Whelton A. Am J Therapeut 2000;7(2):63-74.5. Whitcomb DC et al. JAMA 1994;272(23):1845-50.

.

Page 35: Paracetamol - widening the horizon in pain managment

Where ? First administration in the OR

How?• 15-minute infusion every 4 to 6 hours

Dosing schedule:- Adolescents and adults weighing more than 50kg: 1 g / 4 times a day

Paracetamol infusion

Page 36: Paracetamol - widening the horizon in pain managment

DoseDose Minimum Minimum dosing dosing intervalinterval

Maximum daily Maximum daily dosedose

Adults Adults >50 kg>50 kg 1g qds1g qds 4 hrs4 hrs 4 g4 g

Adults/Adults/Children 33-50 Children 33-50 kgkg

15 mg/kg qds15 mg/kg qds 4 hrs4 hrs 60mg/kg60mg/kg

Not to exceed 3gNot to exceed 3g

Children 10-33 Children 10-33 kgkg

15 mg/kg qds15 mg/kg qds 4 hrs4 hrs 60mg/kg60mg/kg

Not to exceed 2gNot to exceed 2g

Newborn & Newborn & infants infants <10 kg<10 kg

7.5 mg/kg qds7.5 mg/kg qds 4 hrs4 hrs 30mg/kg30mg/kg

Paracetamol - Doses

Page 37: Paracetamol - widening the horizon in pain managment

An opioid An NSAID or a Coxib A local anaesthetic block

Local infiltration Local nerve block Plexus nerve block Neuraxial block

And now……… IV paracetamol

Page 38: Paracetamol - widening the horizon in pain managment