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Sub-therapeutic plasma paracetamol concentrations following rectal administration
- Nik K Husain, Daryl Hampson-Evans (19 July 2007)
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Don't dismiss a small but useful effect from acetaminophen
- J Robert Sneyd (30 March 2007)
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Nik K Husain, Specialist Registrar St. George's Hospital, London, Daryl Hampson-Evans
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Editor- The study by van der Marel CD(1)and colleagues concluded a lack of an opioid-sparing effect of rectal paracetamol (acetaminophen) in newborns and infants following major thoracic (non-cardiac) or abdominal surgery. What is striking from this study is the large inter-individual variability in paracetamol plasma concentration (range 0.8- 59.9 mg/l) which represents an astonishing 75 fold difference. In the light of this huge range and analysis of the mean paracetamol plasma concentration aginst time graph, we would suggest that comparison between the Rectal Paracetamol and Placebo group is misleading when a significant proportion of patients had sub-therapeutic plasma concentrations of paracetamol throughout the duration of the study. There is increasing evidence that sub-therapeutic levels occur frequently in the paediatric population following standard dosing regimens. Hansen TG et al(2)showed that following rectal administration of paracetamol, no infants in their study achieved therapeutic plasma concentrations. Anderson BJ et al(3)established that an anti-pyretic efficacy is achieved with a plasma paracetamol concentration of 10-20 mg/l; whilst > 20mg/l has been proposed for analgesic efficacy. A computer simulation of rectal dosing regimens(3)supports a 70mg/kg rectal loading dose and 50mg/kg 8 hourly to achieve a plasma concentration of 25mg/l. Thus, it is clear that the usual practice of 15-40 mg/kg loading dose and 15-20 mg/kg 6 hourly rectally is wholly inadequate. In our hospital, the use of rectal paracetamol is being substituted in favour of the intravenous formulation which avoids the unpredictability of rectal dosing and guarantees 100% bioavailability. The British National Formulary for children recommends 15 mg/kg every 4-6 hours (max. 60 mg/kg) for children weighing 10-50 kg and 1 g every 4-6 hours (max. 4g daily) for children weighing more than 50 kg. We understand that intravenous paracetamol is not licensed for use in children weighing less than 10kg and so would not have been applicable to the population group studied. However, we feel that that the conclusion that paracetamol has no opioid- sparing effect can only be made after ensuring that therapeutic plasma concentrations have been achieved. This study adds further evidence that rectal paracetamol administration is unreliable. In addition, we would suggest that there is very little cost benefit, if any, in using paracetamol suppositories (Paracetamol suppositories 60mg = £1.00; 125mg = £1.15; 250mg = £2.30; 500mg = £0.99)(4) instead of the intravenous formulation (1g vial = £1.50)(4) when considering the superior pharmacokinetics and efficacy(5) of the latter. N.K.A. Husain* D. Hampson- Evans St. George’s Hospital, London, UK *E-mail: nkahusain@doctors.net.uk (1) van der Marel CD, Peters JWB, Bouwmeester NJ, et al. Rectal acetaminophen does not reduce morphine consumption after major surgery in young infants. Br J Anaesth 2007; 98: 372-9 (2) Hansen TG, O’Brien K, Morton NS, et al. Plasma paracetamol concentratons and pharmacokinetics following rectal administration in neonates and young children. Acta Anaesthes Scand 1999; 43: 855-9 (3) Anderson BJ, Holford NH. Rectal paracetamol dosing regimens: determination by computer simulation. Ped Anesth 1997; 7: 451-5 (4) British National Formulary for children 2006 (5) Moller PL, Sindet-Pedersen S, Petersen PT, et al. Onset of acetaminophen analgesia: comparison of oral and intravenous routes after third molar surgery. Br J Anaesth 2005; 94: 642-8 Conflict of Interest:None declared |
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J Robert Sneyd, Professor of Anaesthesia Peninsula Medical School, Plymouth, UK
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Improving analgesia in children is a timely and important topic for investigation and van der Marel and colleagues have described a well conducted study. I am however concerned by the conclusions drawn from the data. We are told 'Acetaminophen, as an adjuvant to morphine infusion, does not have an additional analgesic effect.....'. Well, it depends what you mean... Figure 2 of the paper clearly shows that the baseline (placebo) arm of the study provided good analgesia - mean VAS of 10mm during the first six hours - although there was considerable interpatient variability (show as long, undefined error bars which are presumably either SD or SEM). The addition of acetaminophen reduced the VAS to almost zero for the first several hours after surgery. Simple inspection of the graphs provide almost indisputable evidence of the analgesic effect - the only issues for discussion are whether the degree of additional analgesia is of clinical importance and whether the study is adequately powered (i.e. large enough). The power calculation described indicates a study powered to detect a very large reduction in supplementary morphine use (from 80% to 40%). In fact, the control therapy was so good that the median number of additional morphine boluses and morphine infusion rate increases were both zero. Thus the baseline condition was actually very different from that anticipated at the time of the power calculation. What can we conclude? Certainly, morphine infusion, as described here, is very effective in these patients. Supplementary acetaminophen probably provides a small additional analgesic benefit and possibly improved COMFORT scores hovever the effect is small and may not be important. Given the large degree of interpatient variability and limited number of patients it is probably appropriate to adopt more modest conclusions. Finally, the description of mean peroperative fentanyl doses of 12 mg kg-1 is presumably a mistake? Conflict of Interest:None declared |
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