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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.

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a new molecule for post operative pain management

A New Molecule for Post Operative Pain Management

Dr.P.Selvakumar M.D.,

Senior consultant

Apollo Specialty Hospitals



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.


Types of pain

Pain physiology

Multimodal analgesia

Intravenous agents used for postoperative pain


pain clinical types
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. 2004;140:441-451.

nociceptive pain
Nociceptive Pain

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

Noxious Peripheral Stimuli

Pain-Autonomic Response

- Withdrawal Reflex





Nociceptor Sensory Neuron



Spinal Cord

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

inflammatory pain
Inflammatory Pain

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


Spontaneous PainPain Hypersensitivity -Allodynia -Hyperalgesia


Mast Cell


Nociceptor Sensory Neuron


Tissue Damage

Spinal Cord

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

neuropathic pain
Neuropathic Pain

Peripheral NerveDamage



Spinal Cord Injury

Spontaneous PainPain Hypersensitivity

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

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

postoperative pain is nociceptive
Postoperative pain is nociceptive


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




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

consequences of unrelieved pain
Consequences of Unrelieved Pain

Weaknessand impairedrehabilitation



Delayed recovery


Acute Pain








Anxietyand fear

GI effects

Myocardial O2 consumption




Poor woundhealing/musclebreakdown



GI motility

Chronic pain

Courtesy of Sunil J Panchal, MD

intensity of pain after discharge 81 report moderate to extreme pain
Intensity of Pain After Discharge:81% Report Moderate to Extreme Pain








Pain Intensity


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


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.


Effective pain management may improve outcomes1,2,3

Effective analgesia included in a comprehensive

postoperative rehabilitation programme1,2

Improved patient comfort and satisfaction

Decreased 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 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.


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)


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


Modes of action of analgesics1,2,3,4


Inhibition of central Cox-3 (?)

(Inhibition of PG synthesis)


Activation of

opioid receptors


Interaction with


NSAIDs / Coxibs

Inhibition of peripheral and central Cox-1 / Cox-2(Inhibition of PG synthesis)

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.


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. AnesthAnalg 1993;77:1048-56.

patients preferences for acute pain treatment
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. 2004;92:681-688.

proportion of patients experiencing adverse events
Proportion of Patients Experiencing Adverse Events

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

preventive multimodal analgesia
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. 2004;6:87-93.

real world multimodal analgesia
“Real World”: Multimodal Analgesia

Reduced doses

Improved pain relief

Reduce severityof AEs

Earlier discharge

Decreased costs



NSAIDs, coxibs,


nerve blocks

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

iv morphine
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

iv paracetamol premise
IV paracetamol - premise

“Is more effective & has a faster onset 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: 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.


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

Paracetamol clinically demonstrates central activity1

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


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


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 2005;101:90 –6

2. Sinatra RS. Anesthesiology 2005; 102:822–3

India 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 placebo

Orthopaedic surgery


Sinatra RS. Anesthesiology 2005; 102:822–3


Hepatic safety at therapeutic doses1

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

(>4g / day)1

Good hepatic safety

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

renal safety
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 disease3

Good renal tolerance

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.


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 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.



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 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


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



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

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.