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stYour 1 Step Matters
In Post OperativePain Management
PER
/016
/04-
09Fo
r H
ospi
tal U
se O
nly
1. Benhamou D, Berti M, Brodner G et al. Postoperative Analgesic Therapy Observational Survey (PATHOS) : A practice pattern study in 7 central/southern European countries. Pain 2008,
136:134-141. 2. Stephens J, Laskin B, Pashos C et al. The burden of acute postoperative pain and the potential role of the COX-2-specific inhibitors. Rheumatol 2003;42(suppl 3): iii40-
iii52. 3. Apfelbaum L.J et al., Postoperative Pain Experience: Results from a National Survey Suggest Postoperative Pain Continues to Be Undermanaged. Anesth Analg 2003; 97:534-40
4. Commission on the provision of surgical services. Report of the working party on pain after surgery. London: The royal college of surgeons of England, The college of Anaesthetists,
1990. 5.Lorenz M Fischer et al, Discontinuation of Nonsteroidal Anti-inflammatory Drug Therapy and Risk of Acute Myocardial Infarction. Anch Intern Med. 2004: 164:2472-2476 6. Andrew
Moore R et al, Nonsteroidal anti-inflammatory drugs ( NSAIDs), Cyclooxygenase-2 selective inhibitors(coxibs) and gastrointestinal harm: review of clinical trials and clinical practice. BMC
Musculoskeletal Disorders 2006, 7:79 7. Giannoudis P.V et al, Nonunion of the femoral diaphysis. J Bone Joint Surg 2000; 82-B: 655-8. 8. http ;//arthritis-symptom.com/arthritis
drugs/opioid.htm(1 to 8) 9. Timothy D Warner et al, Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum? PNAS October 15,2002. Vol 99, No.21: 13371-13373
10. Chandrashekaran .N.V et al, COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. PNAS. Oct
15,2002, Vol 99, No.21, 13926-13931 11. Olivier Malaise et al, Intravenous paracetamol: a review of efficacy and safety in therapeutic use. Future Neurol 2007. 2(6), 673-688. 12. I Power,
Recent advances in postoperative pain therapy. BJA 2005, 95 (1): 43-51 13. Duggan S.t et al, Intravenous Paracetamol, Drugs 2009, 69(1) :101-113. 14. V. Piguet et al, Lack of
acetaminophen ceiling effect on R-III nociceptive flexion reflex. Eur J Clin Pharmacol 1998, 53:321-324. 15. M Depre et al, Tolerence and pharmacokineticsof propacetamol, a paracetamol
formulation for intravenous use. Fundam Clin Pharmacol 1992, 6: 259 – 262. 16. Bannwarth .B.et al, Plasma and cerebrospinal fluid concentration of paracetamol after a single intravenous
dose of propacetamol. Eur J Clin Pharmacol 1992, 34: 79-81. 17. Perfalgan Product Monograph, India 2009. 18. India Product Insert, 2009. 19. Oscier C.D et al, Peri-operative use of
paracetamol. Anaesthesia, 2009, 64:65-72. 20. James C. Crews, Multimodal Pain Management Strategies for Office-Based and ambulatory procedures. JAMA, Aug 2002,Vol288. No.5
21. Acute Pain Management: Scientific Evidence, Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Second edition 2005. 22. Henrich W.L et al,
Anal;gesics and Kidney, AJKD, 1996, Vol 27, No.1, 162-165 23. Tian J Zhou et al, Propacetamol versus ketorolac for the treatment of acute postoperative pain after total hip or knee
replacement. Anaesth Analg 2001, 92 1569-75 24. Hynes D et al, Analgesic efficacy of parentral paracetamol(propacetamol) and diclofenac in post-operative orthopedic pain. Acta
Anaesthesiol Scand 2006: 50: 374-381. 25. Hugo Van Aken et al, Assessing Analgesia in single and repeated administrations of propacetamol for postoperative pain: Comparison with
Morphine after Dental Surgery. Anesth Analg 2004: 98:159-65. 26. Alhashemi J.A et al, Intravenous acetaminophen Vs oral ibuprofen in combination with morphine PCIA after Cesarean
delivery. Can J Anesth 2006, 53:12: 1200-1206. 27. Lolter Cattabriga et al, Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double bling
randomized controlled trial. Eur J of Cardio-thoracic surgery 2007, 32:527-531. 28. Kehlet H et al, Multimodal strategies to improve surgical outcome. The American Journal of Surgery
2002, 183:630-641. 29. Peduto V.A et al, Efficacy of propacetamol in the treatment of postoperative pain. Acta Anaesthesiol Scand 1998: 42: 293-298. 30. Sinatra R.s et al, Efficacy and
safety of single and repeated administration of 1 gram Intravenous Acewtaminophen Injection for pain management after Major Orthopedic Surgery.Anaesthesiology 2005: 102:822-31.
31. Flouvant B et al, Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects Int J Clin Pharmacol
Therapeutics. 2004;42(1):50-7
References:
Sep
tem
ber
2009
Evidence suggests that post-operative pain is sub-optimally 1 2managed and is not limited to the immediate recovery period
CONSEQUENCES OF INADEQUATE PAIN CONTROL FOLLOWING SURGERY ARE4
SIGNIFICANT AND CAN RESULT IN IMMEDIATE AND LONG-TERM COMPLICATIONS
• Hypoxaemia/atelectasis/pneumonitis
• Deep venous thrombosis/pulmonary embolus
• Delayed recovery of bowel function
• Myocardial Ischemia and infarction
• Urinary retention
• Residual psychological trauma
3Approximately 80% surgical patients have inadequate pain relief
*Post operative pain management
In POPM*
Yourst 1 Step
Matters
Limitations of Current Analgesics Agents in POPM*
Limitations of NSAID’s5
Inhibition of Platelet aggregation
Increased incidence of Gastrointestinal6ulcers
7Impairment of Bone healing
6Increased Cardiovascular risk
In POPM*
Yourst
1 StepMatters
*Post operative pain management
4,8Limitations of Opioids
Restlessness or Nervousness
Respiratory depression Hypotension
Constipation
Urinary retention
Severe weakness
Nausea and Vomiting
Stomach Pain or Cramps
1g IVUnleash the True Power & Potential of Unique I.V. Para Infusioncetamol
NSAIDs
Inhibition ofperipheral and
centralCox-1/Cox-2
(inhibition10,12
of PG synthesis)Interaction withserotoninergic
descending11inhibitory pathway
Inhibition of9central Cox-2 ,
10 Cox-3 (Inhibition of PG synthesis)
Opioids
Mode of Action of Analgesics
Activationof Opioid
12receptors
IV 13 ACTS AT BOTH, CENTRAL & PERIPHERAL COMPONENTS OF PAIN PATHWAY
1g IVUnleash the True Power & Potential of Unique I.V. Para Infusioncetamol
15IMPROVED PHARMACOKINETICS VS ORAL PROPACETAMOL
*p<0.0001
Bioavailability
T max
C max
AUC0-
IV propacetamol
100%
15 min*
12.72 µg/ml*
25.53 µg/ml.h*
Oral propacetamol
82.2%
1 h 28 min*
5.49 µg/ml*
21.04µg/ml.h*
Higher peak plasma paracetamol14concentrations
Higher paracetamol concentrations14cross the blood-brain barrier
14Heightened antinociceptive effects
Plasma and CSF paracetamol concentrations following a single IV dose of16paracetamol (2g) in patients with nerve root compression pain
CSF concentrations
Plasma concentrations
Para
ceta
mol
(µ
g/m
l)
0
2
4
6
8
10
12
14
16
0 2 4 6 8 10 12
Time (hrs)
3(adapted from Bannawarth B et al)
The Analgesic effect of Paracetamol is probablydependent on the Rate & Amount of active drug
14 reaching the CNS
lacks the Ceiling effect observed with oral propacetamol & exerts a Dose-
14dependent central Antinociceptive effect
IV
31Paracetamol 1g IV given as propacetamol 2g IV : bio-equivalent formulations therapeutically equivalent
1g IV
17Oxygen-Free Manufacturing Process
Preservative Free Solution pH Adjustment(5.5 for Max. Shelf-life)
Oxygen Free Manufacturing(Nitrogen & Argon gas + Cysteine
Hydrochloride Monohydrate)
Solubilization(Mannitol+Di sodium Phosphate)
(Terminal Sterilsation)
Characteristics of an Ideal Analgesic Agent in POPM*
1g IVUnleash the True Power & Potential of a Unique I.V. Para Infusioncetamol
Fast Onset of Action
Usage Flexibility
Support Balanced Analgesia
Usage in Wide Patient Type
Tolerability
Dosage Convenience
Characteristics18 5-10 Minutes19 Peri-operative
11Yes, Reducing Opioid Usage upto 46%
Yes
Yes
Ready to use Infusion
IV
IV 20,21is an effective analgesic for acute pain
*Post operative pain management
1g IVComparable postoperative analgesic efficacy
27undergoing cardiac surgery against placeboCardiac Surgery: provides significant pain reduction in patients1g IV
Diclofenac 75mg IM
24Total Hip Arthroplasty
1g IV
, 2 Dose 5 hours apart1g IV
26Cesarean Delivery
Perfalgan 1g IV is a reasonable alternative toIbuprofen 400mg Oral as an adjunct to morphine patient-
controlled analgesia after Cesarean delivery
Ibuprofen 400mg 6 hourly6 hourly1g IV
1g IV
25Dental Surgery
Morphine 10mg IMSingle Dose1g IV
Ketorolac 30mg IV
1g IV
23Total Hip or Knee Replacement
Single Dose1g IV
Balanced analgesia improves28postoperative pain relief through:
• synergisticAdditive or effects of multiple agents
• Reduction of side-effects (e.g. opioid sparing)
1g IVAn effective partner in balanced Analgesia
Sparing effect*29
43-46%
Morphine
1g Ø
: proven opioid-sparing effect
0
4
8
12
16
20 i.v. paracetamol (n=42)
placebo (n=47)
***p<0.001
PCAboluses
(no.)
PCAdose(mg)
24-hour morphine consumption in terms of total PCAin mg and total number of boluses
Hip Arthroplasty
-46%of morphineconsumption
9
17 ***
9.4
17.6 ***
4g paracetamol saved 8mg of morphine over 24 hours, which is equal to a sparing effect of 43-46%31
Ø Paracetamol 1g IV given as propacetamol 2g IV : bio-equivalent formulations therapeutically equivalent*
1g IVUnleash the True Power & Potential of a Unique I.V. Para Infusioncetamol
HAS THE RECOGNIZED SAFETY PROFILE OF PARACETAMOL
• Not associated with increased Incidence of nausea, vomiting and respiratory depression30 observed with opioids
• Not associated with deleterious gastrointestinal, haematological and renal effects associated30
with NSAID’s and COX-2 inhibitors30• Few drug interactions and contra-indications
• Recommended by the National Kidney Foundation (US) as the non-narcotic analgesic of choice22 in patients with underlying renal disease
29Renal and Hepatic tolerance at therapeutic doses similar to placebo
30Historically low incidence of adverse events and drug interactions
1g IVUnleash the True Power & Potential of a Unique I.V. Para Infusioncetamol
Safety and Tolerability18
The overall of adverse events in Perfalgan patients to placebo within the clinical trial set1can be observed in the tables bellow.
Adverse events in adults-greater than 100% (observed in the clinical trial set)
Perfalgan %n=99
Placebo%n=102
Neurological Dizziness Headache Dystonia
Gastrointestinal Vomiting Dry mouth Diarrhea Constipation Nausea Dyspepsia Enlarged abdomen Gastrointestinal disorder Haematological Anemia Post operative hemorrhage
Hepatobiliary Gamma GT - Increase SGPT - increase
2.71.3-
4.0-
1.36.710.01.32.02.0
2.72.0
1.31.3
2.94.9-
2.9--
11.88.8---
6.9-
--
Psychiatric Insomnia
Skin and Appendage Injection site pain Injection site reaction Post-Operative site reation Pruritus
- 1.96
Respiratory Alveolitis Coughing
Endocrine/Metabolic Hyperglycemia Hypokalaemia
General Fatigue Fever Oedema-peripheral Chest pain
Perfalgan %n=99
Placebo %n=102
2.02.672.673.3
---
4.9
1.32.0
2.94-
1.31.3
--
1.59--
1.33
-5.9--
_Severe renal impairment (creatinine clearance<30ml/min) : 6 hourly dosing schedule
1g IVUnleash the True Power & Potential of a Unique I.V. Para Infusioncetamol
• Administrated as a 15-minute IV infusion• Available in 100ml clear glass vials in packs of 12 vials• No need to reconstitute
• Store at room temperature, below 30° C• Shelf life of 2 years
is convenient and ready-to-use in patients with IV line1g
It is important to consider the contribution of all paracetamol containing medications, includingnon-prescription, oral or PR forms of drug to this total daily paracetamol dose prior to administering
18Dosage Profile
Dosing Interval
Adults (›50kg)
O Hrs
1g 1g
4-6 Hrs
1g
12 Hrs
1g
18 Hrs Maximum Daily dose
4g