A New Molecule for A New Molecule for Post Operative Pain Post Operative Pain

Management Management

Dr.P.Selvakumar M.D.,Dr.P.Selvakumar M.D.,Senior consultantSenior consultant

Apollo Specialty Hospitals Apollo Specialty Hospitals MaduraiMadurai

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.

ObjectivesObjectives

Types of painTypes of pain Pain physiologyPain physiology Multimodal analgesia Multimodal analgesia Intravenous agents used for Intravenous agents used for

postoperative painpostoperative pain ConclusionsConclusions

Pain: Clinical TypesPain: Clinical Types Nociceptive pain Nociceptive pain

Transient pain in response to noxious stimuliTransient pain in response to noxious stimuli

Inflammatory pain Inflammatory pain Spontaneous pain and hypersensitivity to pain Spontaneous pain and hypersensitivity to pain

in response to tissue damage and inflammationin response to tissue damage and inflammation

Neuropathic painNeuropathic pain Spontaneous pain and hypersensitivity to pain Spontaneous pain and hypersensitivity to pain

in association with damage to or a lesion of the in association with damage to or a lesion of the nervous systemnervous system

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

Nociceptive PainNociceptive Pain

Spinal CordSpinal Cord

BrainBrain

Pain-Pain-Autonomic ResponseAutonomic Response - Withdrawal Reflex- Withdrawal Reflex

Noxious Peripheral StimuliNoxious Peripheral Stimuli

Nociceptor Sensory Nociceptor Sensory NeuronNeuron

HeatHeat

ColdCold

IntenseIntenseMechanicalMechanical

ForceForce

ChemicalChemicalIrritantsIrritants

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

Is responsive to NSAID’s, coxibs, paracetamol and opiates

Inflammatory PainInflammatory Pain

Spinal CordSpinal Cord

BrainBrain

Spontaneous PainSpontaneous PainPain HypersensitivityPain Hypersensitivity -Allodynia -Allodynia -Hyperalgesia -Hyperalgesia

Nociceptor Sensory Nociceptor Sensory NeuronNeuron

MacrophageMacrophage

Tissue Tissue DamageDamage

InflammationInflammation

Mast CellMast Cell

NeutrophilNeutrophilGranulocyteGranulocyte

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

Is responsive to NSAID’s,coxibs, paracetamol, and opiates

Neuropathic PainNeuropathic Pain

Spinal Cord InjurySpinal Cord Injury

BrainBrainPeripheral NervePeripheral NerveDamageDamage

StrokeStroke

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

•May respond to• local anaesthetic• anticonvulsants• antidepressants

•Less responsive to opioids

•No response to NSAID’s, coxibs, or paracetamol

Spontaneous PainSpontaneous PainPain HypersensitivityPain Hypersensitivity

PerceptionPerception

ModulationModulation

TransductionTransduction

TransmissionTransmission

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

Postoperative pain is nociceptivePostoperative pain is nociceptive

Is responsive to NSAID’s,coxibs, paracetamol and opiates

Consequences of Unrelieved Consequences of Unrelieved PainPain

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

Courtesy of Sunil J Panchal, MD

21%21%

8%8% 19%19%

52%52%

Intensity of Pain After Intensity of Pain After Discharge:Discharge:

81% Report Moderate to Extreme Pain 81% Report Moderate to Extreme Pain

SlightSlight ModerateModerate SevereSevere ExtremeExtremePain IntensityPain Intensity

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

Guidelines for optimisingPOP 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.

Effective pain management may improve outcomes1,2,3

Effective analgesia included in a comprehensivepostoperative rehabilitation programme1,2

Improved patient comfort and satisfactionDecreased postoperative morbidity

Faster recoveryShorter hospital stay1,2,3

Very favourablecost/benefit ratio2

Low cost of analgesic techniquesand drugs2

1. Kehlet H. Br J Anaesth 1994;72(4):375-8.2. Jayr C. In Les Aspects Economiques de l’Anesthésie. JEPU 2000:131-8.3. D’Amours RH et al. JOSPT 1996;24(4):227-36.

Physiology & Physiology & pharmacological pharmacological management of management of

postoperative painpostoperative pain

Pain pathway and modulation1

Descending inhibitory controls /

Diffuse noxious inhibitory controlsInterpretation

incerebral cortex:

pain

Stimulation of nociceptors

(A and C fibers) / Release of

neurotransmitters and neuromodulators (i.e.

PG)

1. Adapted from: Bonica JJ. Postoperative pain. In Bonica JJ, ed. The management of pain. Philadelphia: Lea and Febiger;1990:461-80.

Release of serotonin, noradrenalin and

enkephalins at spinal level

Activation of serotoninergic and noradrenergic pathways

Injury

Ascending nociceptive pathways

Modes of action of analgesics1,2,3,4

1. D’Amours RH et al. JOSPT 1996;24(4):227-36. 2. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4.3. Pini LA et al. JPET 1997;280(2):934-40.4. Chandrasekharan NV et al. PNAS 2002;99(21):13926-31.

Opioids

Activation ofopioid receptors

Paracetamol

Inhibition of central Cox-3 (?)

(Inhibition of PG synthesis)

Paracetamol

Interaction withserotoninergic descending

inhibitory pathway

NSAIDs / Coxibs

Inhibition of peripheral and central Cox-1 / Cox-2

(Inhibition of PG synthesis)

Multimodal and Multimodal and Preemptive Preemptive

Approaches to Approaches to Managing Managing

Postoperative PainPostoperative Pain

The concept and benefits of balanced analgesia

“The rationale for multimodal analgesia is achievement of sufficient analgesia due to

additive or synergistic effects between different analgesics, with concomitant

reduction of side effects, due to resulting lower doses of analgesics and differences in

side -effect profiles”

1. Kehlet H et al. Anesth Analg 1993;77:1048-56.

Patients’ Preferences for Patients’ Preferences for Acute Pain TreatmentAcute Pain Treatment

Pain ControlPain Control41%41%

Setting and Route Setting and Route

of Administrationof Administration12%12%

Side-Effect SeveritySide-Effect Severity19%19%

Side-Effect TypeSide-Effect Type28%28%

Patients prefer avoiding side effects over complete pain control

47%47%

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

Proportion of Patients Proportion of Patients Experiencing Adverse EventsExperiencing Adverse Events

Proportion of Patients Proportion of Patients Experiencing Adverse EventsExperiencing Adverse Events

Gan et al. Br J Anaesth. 2004;92:1-8.

Adverse Event (AE)Adverse Event (AE) Total %Total %

ConstipationConstipation 5050

Mental cloudiness/dizzinessMental cloudiness/dizziness 8282

ItchingItching 5454

Nightmares/hallucinationsNightmares/hallucinations 3232

Mood changes/alterationsMood changes/alterations 3434

NauseaNausea 7070

Sleep disordersSleep disorders 4848

VomitingVomiting 3232

Preventive Multimodal Preventive Multimodal AnalgesiaAnalgesia

Significant improvement inSignificant improvement in Pain reductionPain reduction Opioid useOpioid use Opioid-related AEsOpioid-related AEs Recovery or day ward length of stayRecovery or day ward length of stay Unplanned admission to the hospitalUnplanned admission to the hospital

Reuben et al. Acute Pain. 2004;6:87-93.Reuben et al. Acute Pain. 2004;6:87-93.

““Real World”: Multimodal Real World”: Multimodal AnalgesiaAnalgesia

Reduced doses Reduced doses

Improved pain reliefImproved pain relief

Reduce severityReduce severityof AEs of AEs

Earlier dischargeEarlier discharge

Decreased costsDecreased 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).

Intravenous agents Intravenous agents for multimodal for multimodal

analgesiaanalgesia

IV morphineIV morphine

Intermittent IV bolus dosesIntermittent IV bolus doses Is best method for acute painIs best method for acute pain Optimal doses and dose intervals not Optimal doses and dose intervals not

establishedestablished 2-3 mg doses at 5 minute intervals appears 2-3 mg doses at 5 minute intervals appears

effectiveeffective

Continuous infusionContinuous infusion Compared with PCA there is a 5-fold increase Compared with PCA there is a 5-fold increase

in respiratory depressionin respiratory depression

IV paracetamol - premiseIV paracetamol - premise

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

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

Paracetamol:Paracetamol:clinical clinical

pharmacologypharmacology

Paracetamol: a well known analgesic agent

First proper account of clinical use in 1894 (Hinsberg and Treupel)1

Analgesic effect formally demonstrated in 1948 (Flinn and Brodie)1

Recommended first-line analgesic therapy:

- for the treatment of osteoarthritis since 20002,3

- for musculoskeletal pain in elderly since 20024

- for patients with renal disease since 19965

1. Prescott LF. Am J Therapeut 2000;7(2):143-7.2. EULAR recommendations. Pendleton A et al. Ann Rheum Dis 2000;59(12):936-44.3. American College of Rheumatology Subcommittee on osteoarthritis guidelines. Arthritis Rheum 2000;43(9):1905-15.4. AGS Panel on Persistent Pain in Older Persons. JAGS 2002;50:S205-24.5. Henrich WL et al. Am J Kidney Dis 1996;27(1):162-5.

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.

1. Piletta P et al. Clin Pharmacol Ther 1991;49(4):350-4.

Objective R-III reflex threshold changes expressed as a percentage of difference from baseline

Paracetamol clinically demonstrates central activity1

What were the challenges?

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

IndicationsIndications

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

No difference in adverse events vs placebo

Oral surgery

Lange-Møller P. Anesth Analg 2005;101:90 –6.

%

No difference in adverse events vs placeboOrthopaedic surgery

Sinatra RS. Anesthesiology 2005; 102:822–3

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

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

Renal safetyRenal safety

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 side 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.

.

How to use How to use PerfalganPerfalgan

• No reconstitution

Saves nurses time1

Reduces use of ancillary products1

Reduces risk of dosage error1

Reduces risk of contamination1

Perfalgan is ready-to-use

1. Schmitt E et al. Pharm Hosp 2001;36(147):9-18.

1. Take the cap off

2. Link the bottle to a drip with an air intake

3. Hook the bottle with the built-in calliper

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

Perfalgan infusion

Shelf life is 2 years

Do not store above 30°C

Do not refrigerate or freeze

Storage

ConclusionsConclusions

Perfalgan is a fast-acting analgesic, as effective as morphine 10mg1

Perfalgan is a proven opioid-sparing agent2

Perfalgan is well tolerated in all types of patients

Perfalgan is ready-to-use and cost-effective3

1. Van Aken H. 1991. Anesth Analg 2004; 98: 159-65 2. Peduto VA et al. Acta Anaesthesiol Scand 1998;42:293-8.3. Schmitt E et al. Pharm Hosp 2001;36(147):9-18.