Intravenous pro-pacetamol and paracetamol versus old formulations?

Tarjei Rygnestad, MD, PhD.

Consultant, Department of Anaesthesia and Intensive Care, The University Hospital in Trondheim and Professor in Clinical Pharmacology, The Norwegian University of Science and Technology, Trondheim, Norway

Paracetamol is frequently used for postoperative analgesia, alone or in combination with an opioid. Paracetamol is a safe drug (high therapeutic index), and can be used in analgesic doses by most patients, allergy to the drug or active hepatitis being the most important contraindications. Clinical studies have shown that both paracetamol and other non-opioid drugs are potent analgesics and reduce opioid consumption (1, 2). The opioid-sparing effect reduces the risk for opioid related side effects (3, 4). There are, however, studies unable to confirm this (5), which illustrates that both pharmacokinetic and pharmacodynamic properties must be considered when doses, dose intervals and ways of administration are chosen.

Most studies on intravenous paracetamol in postoperative pain have used a dose equivalent to 1 gr paracetamol every 6 hours. Time to reach steady state usually takes 5 times the half-life of the drug. For paracetamol (t½ » 2-3 hours) this takes 10-15 hours or more. It is reason to believe that the analgesic and antipyretic effects of paracetamol are concentration dependent and that the lower concentration threshold is 10 mg/l (65 mmol/l) with increasing effect up to 20 mg/l (130 mmol/l) (5).

To achieve an effective serum concentration fast a sufficient loading dose must be given followed by maintenance doses to replace the amount of drug eliminated from the effect site (by distribution, metabolism and excretion). As illustrated by the figure the peak concentration is highest after intravenous administration but falls rapidly thereafter. After intramuscular, oral and rectal administration the time to maximum concentration is longer, the peak is lower but the concentration s above the effective concentration for a longer time with comparable doses. With a standard bolus dose the effect is short lasting. Increasing the bolus dose can compensate this.

Sufficient time must also be allowed for the drug to reach an effective concentration (6). The lag time after oral administration is 20-30 min and the absorption t½ approximately 10-30 min. The lag time after rectal administration often exceeds 1 hour with an absorption t½ of 10-30 min.

The maintenance dose must be sufficient to compensate for the elimination.

In adults paracetamol can be dosed as shown in the table

	First Dose		Maintenance dose
	< 70 kg	³ 70 kg	< 70 kg	³ 70 kg
Intravenous	1,0 gr	1,5 gr	1,0 gr	1,5 gr
Oral	1,5 gr	2,0 gr	1,0 gr	1,5 gr
Rectal*	2,0 gr	3,0 gr	2,0 gr	3,0 gr

*Due to variable absorption suppositories should be used as short as possible (<3 days)

To optimise the effect the bolus dose must be adjusted to the patient’s weight (don’t give the standard 500 – 1000 mg oral or rectal dose) and also compensate for the initial rapid distribution. Rectal absorption is poor (bioavailability oral/rectal approximately 0,67) and slow. Thus the dose must be increased by 50% in adults and must be given early enough. The maintenance dose must also be adjusted to the individual patient and must be big enough. Absorption can be slow and irregular if opioids are being used. And if the rectal route is used many suppositories must be administered.

Intravenous paracetamol is an attractive route of administration because of predictable concentrations. It can easily be administered shortly before or during surgery and is a practical administration form when the oral route cannot be used both before and after surgery. Most studies have not use an increased bolus dose, which might increase efficacy and decrease the used of opioids. The major drawback of the intravenous form is the price, being 50 – 100 times more expensive than the oral formulation.

Prices (Norway)

	First Dose		Maintenance dose
	< 70 kg	³ 70 kg	< 70 kg	³ 70 kg
Intravenous
Propacetamol	9,7 €	14,5 €	9,7 €	14,5 €
Paracetamol	4,7 €	7,1 €	4,7 €	7,1 €
Oral	0,2 €	0,2 €	0,1 €	0,2 €
Rectal	1,1 €	1,7 €	1,1 €	1,7 €

References

1. http://www.jr2.ox.ac.uk/bandolier/Extraforbando/APain.pdf (03.03.2004)
2. Anesthetic Pharmacology 2001; 92: 1473-6
3. J of Pain and Symptom Management 1995; 10: 279-86
4. Acta Anaesthesiologica Scandinavica 1998; 42: 293-8.
5. Br J Anaesthesia 2003; 90: 314-9.
6. Aesthesiology 1999; 90: 411-21
7. Br J Clinical Pharmacology 1998; 46: 237-43.