Department of Anaesthesia, South Devon Healthcare Trust, Torquay, Devon TQ2 7AA, UK 1Present address: Department of Anaesthesia, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK
Accepted for publication: May 18, 2001
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Abstract |
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Br J Anaesth 2001; 87: 63840
Keywords: analgesics non-opioid, paracetamol; anaesthetic techniques, rectal; adults
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Introduction |
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The analgesic therapeutic concentration for paracetamol is not well defined. Plasma concentrations of 1020 µg ml1 are associated with antipyretic activity.1 No formal work has been completed to define paracetamol concentrations needed for analgesia. However, previous work has assumed that analgesic and antipyretic concentrations will be similar.25
Oral paracetamol doses of 1020 mg kg1 are used in adults and children and provide plasma concentrations within the accepted therapeutic range. However, when given rectally, these doses may be insufficient. Work in children has shown that doses of up to 40 mg kg1 are needed to achieve these target plasma concentrations.24 Similar doses may be needed in adults.
The aim of our study was to ascertain what dose of rectal paracetamol is needed, in adult volunteers, to achieve plasma paracetamol concentrations of 1020 µg ml1.
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Methods and results |
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Each volunteer took part in the study on four occasions separated by at least 48 h. No paracetamol containing medication was taken for 24 h prior to any of the study days. Volunteers received increasing doses of rectal paracetamol starting with 15 mg kg1, rising by 10 mg kg1 to a maximum of 45mg kg1.
Paracetamol is not evenly distributed within standard suppositories. Hence, it was not possible to provide exact paracetamol doses by shaving portions off these suppositories. Each volunteer was weighed and suppositories were specifically manufactured to achieve exact doses. Witepsol was used as the base for these suppositories. Multiple numbers of suppositories were used to avoid any single suppository of greater than 1 g of paracetamol. This is consistent with clinical practice where multiple suppositories are used in order to achieve the most appropriate patient dose. This is important, as it is known that rectal absorption of paracetamol varies with suppository size.
On each day of the study, an i.v. cannula was inserted and a baseline blood sample taken. The suppository was then self administered and serial blood samples taken every 30 min for 4 h and then hourly for a further 4 h. Samples were refrigerated and dispatched to the laboratory as a batch at the end of each day. If any plasma paracetamol concentration had been recorded as greater than 30 µg ml1 that volunteer would not have received further doses.
The assay used to measure plasma paracetamol concentrations was a Cambridge Life Sciences enzymatic assay using a Roches Hitachi multichannel analyser (inter-assay CV 1.11.4%, concentration range 0300 µg ml1, intra-assay CV 0.51%, concentration range 0130 µg ml1, dynamic range of the assay 0378 g ml1, sample size per assay is 20). The lower limit of detection in our laboratory was 10 µg ml1.
Concentration vs time curves were plotted for all 10 volunteers for each dose of paracetamol received. The median values for each time period at each dose are shown in Figure 1.
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Comment |
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Concern that these higher doses of paracetamol may cause toxicity appears unfounded, the highest serum concentration we measured was 25 µg ml1, this is well below the accepted toxic concentration of 120 µg ml1.
The limitation of our assay (lower limit of detection 10 g ml1) has restricted our ability to perform pharmacokinetic analysis. However, the aim of the study was to ascertain what dose of paracetamol was needed to achieve plasma concentrations of 1020 g ml1 and our assay was adequate for the purpose of answering this question.
We conclude that doses of 3545 mg kg1 of paracetamol are needed in adult volunteers to achieve serum concentrations of 1020 µg ml1. This is in agreement with data from paediatric studies. However, more work is needed to establish whether this is in fact the target serum plasma for analgesia.
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Acknowledgements |
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References |
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2 Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four hour pharmacokinetics of rectal acetaminophen in children. Anesthesiology 1997; 87: 24452[ISI][Medline]
3 Montgomery CJ, McCormack JP, Reichert CC, Marsland CP. Plasma concentrations after high-dose (45 mg kg1) rectal acetaminophen in children. Can J Anaesth 1995; 42: 9826[Abstract]
4 Anderson BJ, Woolard GA, Holford NHG. Pharmacokinetics of rectal paracetamol after major surgery in children. Paediatr Anaesth 1995; 5: 23742[ISI][Medline]
5 Beck DH, Schenk MR, Hagemann K, Doepfmer UR, Kox WJ. The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomized study. Anesth Analg 2000; 90: 4316
6 Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR. Morphine consumption in patients receiving rectal paracetamol and diclofenac alone and in combination. Br J Anaesth 1996; 77: 4457