A New Molecule for Post Operative Pain Management

1
A New Molecule for Post Operative Pain
Management
Dr.P.Selvakumar M.D., Senior consultant Apollo
Specialty Hospitals Madurai
2
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 1994209-14.
3
Objectives

• Types of pain
• Pain physiology
• Multimodal analgesia
• Intravenous agents used for postoperative pain
• Conclusions

4
Pain Clinical Types

• 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. 2004140441-451.
5
Nociceptive Pain
Is responsive to NSAIDs, coxibs, paracetamol and
opiates
Noxious Peripheral Stimuli
Pain-Autonomic Response - Withdrawal Reflex
Heat
Cold
Intense MechanicalForce
Nociceptor Sensory Neuron
Brain
ChemicalIrritants
Spinal Cord
Woolf. Ann Intern Med. 2004140441-451.
6
Inflammatory Pain
Is responsive to NSAIDs,coxibs, paracetamol, and
opiates
Inflammation
Spontaneous PainPain Hypersensitivity
-Allodynia -Hyperalgesia
Macrophage
Mast Cell
NeutrophilGranulocyte
Nociceptor Sensory Neuron
Brain
Tissue Damage
Spinal Cord
Woolf. Ann Intern Med. 2004140441-451.
7
Neuropathic Pain
Spontaneous PainPain Hypersensitivity

• May respond to
• local anaesthetic
• anticonvulsants
• antidepressants
• Less responsive to opioids
• No response to NSAIDs, coxibs, or paracetamol

Woolf. Ann Intern Med. 2004140441-451.
8
Postoperative pain is nociceptive
Perception
Is responsive to NSAIDs,coxibs, paracetamol and
opiates
Modulation
Transmission
Transduction
Reuben et al. J Bone Joint Surg.
2000821754-1766.
9
Consequences of Unrelieved Pain
Acute Pain
Increased sympathetic activity
Splinting,shallowbreathing
Increasedcatabolic demands
Peripheral/centralsensitization
Anxietyand fear
GI effects
Myocardial O2 consumption?
Atelectasis, hypoxemia, hypercarbia
Poor woundhealing/musclebreakdown
Availabledrugs
Sleeplessness,helplessness
GI motility?
Chronic pain
Courtesy of Sunil J Panchal, MD
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Intensity of Pain After Discharge81 Report
Moderate to Extreme Pain
8
19
21
52
Moderate
Severe
Extreme
Slight
Pain Intensity
Apfelbaum et al. Anesth Analg. 200397534-540.
11
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
ladulte et lenfant. Ann Fr Anesth Réanim
199817445-61.
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Effective pain management may improve
outcomes1,2,3
Effective analgesia included in a
comprehensive postoperative rehabilitation
programme1,2
Improved patient comfort and satisfaction Decrease
d postoperative morbidity Faster recovery Shorter
hospital stay1,2,3
Very favourable cost/benefit ratio2
Low cost of analgesic techniques and drugs2
1. Kehlet H. Br J Anaesth 199472(4)375-8. 2.
Jayr C. In Les Aspects Economiques de
lAnesthésie. JEPU 2000131-8. 3. DAmours RH et
al. JOSPT 199624(4)227-36.
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Physiology pharmacological management of
postoperative pain
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Pain pathway and modulation1
Descending inhibitory controls / Diffuse noxious
inhibitory controls
Ascending nociceptive pathways
Interpretation in cerebral cortex pain
Activation of serotoninergic and noradrenergic
pathways
Release of serotonin, noradrenalin and
enkephalins at spinal level
Stimulation of nociceptors (A? and C fibers) /
Release of neurotransmitters and neuromodulators
(i.e. PG)
Injury
1. Adapted from Bonica JJ. Postoperative pain.
In Bonica JJ, ed. The management of pain.
Philadelphia Lea and Febiger1990461-80.
15
Modes of action of analgesics1,2,3,4
Paracetamol ? Inhibition of central Cox-3
(?) (Inhibition of PG synthesis)
Opioids ? Activation of opioid receptors
Paracetamol ? Interaction with serotoninergic
descending inhibitory pathway
NSAIDs / Coxibs ? Inhibition of peripheral and
central Cox-1 / Cox-2(Inhibition of PG synthesis)
1. DAmours RH et al. JOSPT 199624(4)227-36.
2. Piguet V et al. Eur J Clin Pharmacol
199853321-4. 3. Pini LA et al. JPET
1997280(2)934-40. 4. Chandrasekharan NV et al.
PNAS 200299(21)13926-31.
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Multimodal and Preemptive Approaches to Managing
Postoperative Pain
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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 1993771048-56.
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Patients Preferences for Acute Pain Treatment
Patients prefer avoiding side effects over
complete pain control
Side-Effect Severity19
Pain Control41
Side-Effect Type28
Setting and Route of Administration12
Gan et al. Br J Anaesth. 200492681-688.
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Proportion of Patients Experiencing Adverse
Events
Adverse Event (AE) Total
Constipation 50
Mental cloudiness/dizziness 82
Itching 54
Nightmares/hallucinations 32
Mood changes/alterations 34
Nausea 70
Sleep disorders 48
Vomiting 32
Gan et al. Br J Anaesth. 2004921-8.
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(No Transcript)
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Preventive Multimodal Analgesia

• Significant improvement in
• Pain reduction
• Opioid use
• Opioid-related AEs
• Recovery or day ward length of stay
• Unplanned admission to the hospital

Reuben et al. Acute Pain. 2004687-93.
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Real World Multimodal Analgesia

• Reduced doses
• Improved pain relief
• Reduce severityof AEs
• Earlier discharge
• Decreased costs

Opioids
Potentiation
NSAIDs, coxibs, paracetamol, nerve blocks
Kehlet et al. Anesth Analg. 1993771048-1056 (B).
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Intravenous agents for multimodal analgesia
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IV morphine

• Intermittent IV bolus doses
• Is best method for acute pain
• Optimal doses and dose intervals not established
• 2-3 mg doses at 5 minute intervals appears
  effective
• Continuous infusion
• Compared with PCA there is a 5-fold increase in
  respiratory depression

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IV paracetamol - premise

• Is more effective has a faster onset than oral
  paracetamol

27
Onset of action is fast and effective within 5
minutes
Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5)
642-8
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Paracetamolclinical pharmacology
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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 20007(2)143-7. 2.
EULAR recommendations. Pendleton A et al. Ann
Rheum Dis 200059(12)936-44. 3. American College
of Rheumatology Subcommittee on osteoarthritis
guidelines. Arthritis Rheum
200043(9)1905-15. 4. AGS Panel on Persistent
Pain in Older Persons. JAGS 200250S205-24. 5.
Henrich WL et al. Am J Kidney Dis
199627(1)162-5.
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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
199853321-4. 2. Carlsson KH et al. Pain
198832313-26. 3. Flower RJ et al. Nature
1972240410-1. 4. Tjølsen A et al. Eur J
Pharmacol 1991193193-201. 5. Pélissier T et al.
JPET 19962788-14.
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Paracetamol clinically demonstrates central
activity1
1. Piletta P et al. Clin Pharmacol Ther
199149(4)350-4.
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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

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Indications
34
Phase III clinical trials1,2 VS. placebo

• Similar overall incidence of adverse events
• Similar incidence of local adverse events
• No clinically significant changes in vital signs
  or laboratory tests

IV paracetamol as safe as placebo
1. Lange-Møller P. Anesth Analg 200510190 6
2. Sinatra RS. Anesthesiology 2005
1028223 India Prescribing Information
35
No difference in adverse events vs placebo
Oral surgery
Lange-Møller P. Anesth Analg 200510190 6.
36
No difference in adverse events vs placebo
Orthopaedic surgery

Sinatra RS. Anesthesiology 2005 1028223
37
Hepatic safety at therapeutic doses1

• Paracetamol hepatotoxicity was found to be very
  rare (lt1 / 2,500)1
• It was always related to misuse and overdose
• (gt4g / day)1

Good hepatic safety
1. Whitcomb DC et al. JAMA 1994272(23)1845-50.

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Renal 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

Good renal tolerance
1. Whelton A. Am J Therapeut 20007(2)63-74. 2.
Blantz RC. Am J Kidney Dis 199628(1)S3-6. 3.
Henrich WL et al. Am J Kidney Dis
199627(1)162-5.
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Paracetamol safety benefits in POP

• 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

1. Lechat P et al. Thérapie 198944337-54. 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, 1996617-57. 3. Singh G. Am J
Therapeut 20007(2)115-21. 4. Whelton A. Am J
Therapeut 20007(2)63-74. 5. Whitcomb DC et al.
JAMA 1994272(23)1845-50. .
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How to use Perfalgan
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Perfalgan is ready-to-use

• No reconstitution
• Saves nurses time1
• Reduces use of ancillary products1
• Reduces risk of dosage error1
• Reduces risk of contamination1

1. Schmitt E et al. Pharm Hosp 200136(147)9-18.

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• 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

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Perfalgan infusion

• 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

44
Storage

• Shelf life is 2 years
• Do not store above 30C
• Do not refrigerate or freeze

45
Conclusions
46

• 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 199842293-8. 3. Schmitt E et al. Pharm
Hosp 200136(147)9-18.