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A New Molecule for Post Operative Pain Management. Dr.P.Selvakumar M.D., Senior consultant Apollo Specialty Hospitals Madurai. Clinical definition of pain 1. - PowerPoint PPT Presentation
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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.
Recommended