A New Molecule for
Post Operative Pain
Management
Dr.P.Selvakumar M.D.,
Senior consultant
Apollo Specialty Hospitals
Madurai
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.
Objectives





Types of pain
Pain physiology
Multimodal analgesia
Intravenous agents used for postoperative
pain
Conclusions
Pain: Clinical Types

Nociceptive pain


Inflammatory pain


Transient pain in response to noxious stimuli
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
Is responsive to NSAID’s, coxibs,
paracetamol
and opiates
Noxious Peripheral
Stimuli
Pain-Autonomic Response
Heat
- Withdrawal Reflex
Cold
Intense
Mechanical
Force
Nociceptor Sensory
Neuron
Brain
Chemical
Irritants
Spinal Cord
Woolf. Ann Intern Med. 2004;140:441-451.
Inflammatory Pain
Is responsive to NSAID’s,coxibs,
paracetamol, and
opiates Pain
Inflammation
Spontaneous
Macrophage
Mast Cell
Neutrophil
Granulocyte
Pain Hypersensitivity
-Allodynia
-Hyperalgesia
Nociceptor Sensory
Neuron
Brain
Tissue
Damage
Spinal Cord
Woolf. Ann Intern Med. 2004;140:441-451.
Neuropathic Pain
Spontaneous Pain
Pain Hypersensitivity
•May respond to
• local anaesthetic
• anticonvulsants
• antidepressants
Peripheral Nerve
Damage
•Less responsive to opioids
Brain
Stroke
Spinal Cord Injury
•No response to NSAID’s, coxibs, or
paracetamol
.
Woolf. Ann Intern Med. 2004;140:441-451
Postoperative pain is nociceptive
Perception
Modulation
Is responsive to NSAID’s,coxibs,
paracetamol and
opiates
Transmission
Transduction
Reuben et al. J Bone Joint Surg. 2000;82:1754-1766.
Consequences of Unrelieved Pain
Acute Pain
Increased
sympathetic
activity
GI effects
Splinting,
shallow
breathing
Increased
catabolic
demands
Anxiety
and fear
Peripheral/
central
sensitization
Myocardial
O2
consumption
GI motility
Atelectasis,
hypoxemia,
hypercarbia
Poor wound
healing/muscle
breakdown
Sleeplessness,
helplessness
Available
drugs
Myocardial
ischemia
Delayed
recovery
Pneumonia
Weakness
and impaired
rehabilitation
Psychological
Chronic
pain
Courtesy of Sunil J Panchal, MD
Intensity of Pain After Discharge:
81% Report Moderate to Extreme Pain
8%
19%
21%
52%
Pain Intensity
Slight
Moderate
Apfelbaum et al. Anesth Analg. 2003;97:534-540.
Severe
Extreme
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.
Physiology &
pharmacological
management of
postoperative pain
Pain pathway and modulation1
Ascending nociceptive pathways
Interpretation in
cerebral cortex:
pain
Stimulation of nociceptors
(A and C fibers) /
Release of
neurotransmitters and
neuromodulators (i.e. PG)
Descending inhibitory controls /
Diffuse noxious inhibitory controls
Activation of serotoninergic
and noradrenergic pathways
Release of serotonin,
noradrenalin and enkephalins
at spinal level
Injury
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
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. 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.
Multimodal and Preemptive
Approaches to Managing
Postoperative 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
Acute Pain Treatment
Patients prefer avoiding side effects
over complete pain control
Side-Effect Severity
19%
Pain Control
41%
47%
Setting and Route
of Administration
12%
Gan et al. Br J Anaesth. 2004;92:681-688.
Side-Effect Type
28%
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. 2004;92:1-8.
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
Opioids
Potentiation
NSAIDs, coxibs,
paracetamol,
nerve blocks
Kehlet et al. Anesth Analg. 1993;77:1048-1056 (B).

Reduced doses

Improved pain relief

Reduce severity
of AEs

Earlier discharge

Decreased costs
Intravenous agents for
multimodal analgesia
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
“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:
clinical pharmacology
Paracetamol: a well known analgesic
agent

First proper account of clinical use in 1894

Analgesic effect formally demonstrated in 1948 (Flinn and Brodie)

Recommended first-line analgesic therapy:
(Hinsberg and Treupel)1
- for the treatment of osteoarthritis since 2000
- for musculoskeletal pain in elderly since 2002
- for patients with renal disease since 1996
4
5
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.
2,3
1
Paracetamol – how does it work?

Paracetamol is a centrally acting agent
It selectively inhibits nervous system PG
synthesis probably via COX-3

2,3
Other central mechanisms of action depend on
the bulbo-spinal serotoninergic pathway

4,5
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
Indications
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



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 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
3
 No gastrointestinal side effects


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.
How to use Perfalgan
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 ?


How?
•

First administration in the OR
15-minute infusion every 4 to 6 hours
Dosing schedule:
- Adolescents and adults weighing more than 50kg:
1 g / 4 times a day
Storage

Shelf life is 2 years

Do not store above 30°C

Do not refrigerate or freeze
Conclusions

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.