Ignite Creation Date:
2024-05-05 @ 4:39 PM
Last Modification Date:
2024-10-26 @ 9:22 AM
Study NCT ID:
NCT00286650
Status:
COMPLETED
Last Update Posted:
2006-02-03
First Post:
2006-02-01
Brief Title:
Comparison of Two Different Doses of Paracetamol for Post-Operative Pain Relief
Sponsor:
University of Otago
Organization:
University of Otago
Study Overview
Official Title:
Comparison of Two Different Doses of Paracetamol for Post-Operative Pain Relief
Status:
COMPLETED
Status Verified Date:
2004-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Paracetamol is commonly used to reduce pain after operations Recently anaesthetists have been using bigger doses of paracetamol because it has been suggested that bigger doses will work better However these bigger doses have never been assessed scientifically in adult patients to see if they work better and it has not been determined at which dose the maximum effect in reducing pain occurs We We will investigate whether a 90 mg per kg body weight dose works better than a 60 mg per kilogram dose in reducing pain after wisdom tooth extraction We will also examine the pharmacokinetics the way the body removes the drug of paracetamol and whether paracetamol changes the way blood clots at these doses We will also examine whether these doses are safe by monitoring liver enzymes and making sure the blood level of paracetamol is not greater than that previously recognised to cause liver disease The patients will be healthy volunteers scheduled to have wisdom tooth extraction They will have blood taken at intervals for four hours after having the paracetamol They will fill in pain scores at the same times they have blood taken
Detailed Description:
A randomised crossover dose-effect trial of paracetamol 60 and 90 mgkg in third molar surgery
Background Paracetamol is the most widely used analgesic in New Zealand but relatively little is known about its dose effect and concentration effect relationships It appears that there is greater effect above the currently recommended dose but the maximal effect has not as yet been described
Paracetamol is toxic in overdose but the dose at which toxicity becomes apparent is disputed In the past the dose at which toxicity may become apparent has been 125 mgkgday but more recently this has been revised upwards to 150 mgkgday in children 1 In children it has been proposed that toxicity does not develop following single ingestions of up to 200 mgkgday 2
Paracetamol is metabolised by multiple pathways urinary excretion of an oral dose is 55 as glucuronide conjugates 30 as cysteine conjugates 4 as mercapturic acid and cysteine conjugates 3 The mercapturic and cysteine conjugates are derived from a toxic intermediary metabolite produced by oxidative metabolism by CYP2E1 and to a lesser degree CYP3A4 and CYP1A2 4 At doses of up to 1500 mg the metabolism appears to be unchanged but there is no data for doses at or above 90 mgkg 5 It has been proposed that paracetamol metabolism becomes saturated at higher doses and saturation of sulfation has been observed in rats 6 However saturation of either sulfation or glucuronidation has not been observed in cultured human hepatocytes 6
In overdose paracetamol has been observed to inhibit the activity of vitamin-K dependent clotting factors in particular functional factor VII 7 This may explain the interaction between paracetamol and warfarin
Aims
To describe the dose and effect relationship for paracetamol
To describe the concentration and effect relationship for paracetamol
To examine the changes in metabolism of paracetamol with escalating doses
To examine the effect of paracetamol on functional factor VII effect on coagulation mechanism with increasing dose
Methods
Subjects
Eighteen healthy adults male or female aged 18 to 50 years scheduled for removal of bilateral impacted lower wisdom teeth will be recruited for the trial in the dental school
Exclusion criteria
Intolerance to oral medication
Taking paracetamol and unable to abstain prior to the study
Hypersensitivity to paracetamol
Liver or renal failure
Pregnancy
Breast feeding
Poor nutritional status eating disorder or Body Mass Index BMI less than 16
Weight greater than 87 kg
Anticonvulsant medication
Chronic ethanol abuse
Ho bleeding disorders
Participants will be instructed to avoid all non-essential medications paracetamol alcohol herbal medicines and recreational drugs for 72 hours prior to the study and are required to fast for three hours prior to the study
Demographic data Demographic data including height weight and age will be recorded for each patient Medications pre- peri- and post-operatively will be recorded Regular use of alcohol caffeinated beverages and smoking will be recorded
Treatment
The patients will be fasted for three hours prior to the procedure An intravenous line will be inserted and intravenous midazolam administered with the dose titrated to sedative effect use of sedation oral or intravenous for third molar extractions is a common practice in dentistry Local anaesthetic 2 Lignocaine with adrenaline 180000 will be administered at the commencement of the procedure The paracetamol will be administered as capsules made by the Pharmacy Dept of the University of Otago 30 minutes prior to the procedure Dosing will be observed
Rndomised double blind cross over design will be used for each side for the surgery Both the side of extraction and the treatment will be randomised
During the procedure the patients will be observed by using pulse oximetry and blood pressure The patients will be requested to stay at the dental school for 4 hours after the paracetamol dosing
If the patient should require additional pain relief they will be given codeine 30 mg or diclofenac 50 mg The patients will be instructed to avoid additional doses of paracetamol for 48 hours Further analgesia on subsequent days will be provided with NSAIDs diclofenac and or codeine phosphate In appropriate doses Prophylactic antibiotics will be used where necessary according to usual treatment practice-
Samples
Blood will be collected at times 0 15 30 60 90 120 180 240 480 minutes through the cannula already in place in the standard manner Note time 0 is the time of paracetamol dosing 3-6 mL of blood is collected on each occasion and then transferred into a 6 mL heparinised saline vacutainer These will be spun in an Eppendorf Centrifuge 5810R at 4000 g for 5 minutes Plasma will be removed and transferred into a 2 mL microtube Eppendorf safe lock prior to freezing at -20C The catheter line and extension will be kept patent using heparinised saline 10 IU mL flushes
Urine collected from pass urine at time 0 and discard 0 to 120 120 to 240 and 240 to 480 minutes Urine volume will be measured and recorded An aliquot of urine from each time interval will be stored at -200C prior to assay
Blood will also be collected at 0 and 24 hours for ALT AST PT and clotting factors
An additional sample of blood will be collected at four hours after administration of paracetamol forserum paracetamol level estimation If this level is greater than the treatment threshold on the New Zealand Poisons Centre Substance Database the patient will be treated with n-acetylcysteine by the standard treatment protocol as soon as possible
Pain score
Visual analogue pain score 0-100 mm scale will be recorded at 0 30 60 90 120 150 180 210 240 480 minutes and at 24 hours after the end of surgery Mouth opening trismus will be assessed at 0 and 24 hours
Analytical methods
Urine
All samples were analysed using high performance liquid chromatography HPLC to determine the concentrations of paracetamol and its metabolites paracetamol glucuronide paracetamol cysteine paracetamol sulphate and paracetamol mercapturate Urine samples were prepared for HPLC by centrifuging at 2000rpm and then diluting the supernatent 1 in 10 with mobile phase This was injected directly onto an Aqua C18 reversed phase column 250mm x 46mm id with a 5 micron pore size Phenomenex via a C18 5 micron guard column The mobile phase used was 7 acetonitrile - 93 orthophosphoric acid 20mM pH 67 at a flow rate of 1mlmin using a Shimadzu LC10-AT pump and a Shimadzu SPD-10AV ultraviolet absorbance detector operating at 254nm Calibration curves were constructed for each of the metabolites and paracetamol in blank urine using the peak area and were linear over the range 005 - 5mM The method was found to be reproducible with a coefficient of variation of 26 The metabolites of paracetamol glucuronide cysteine sulphate mercapturate and paracetamol itself eluted in 39 8 102 122 and 134 minutes respectively Reference samples of paracetamol cysteine sulphate and mercapturate were kindly supplied by Dr Anthony R Temple MD McNeil Consumer Healthcare Camp Hill Road Fort Washington Pennsylvania USA
Sample size calculation
Previous studies of dental pain have indicated a maximum intensity of pain at around 8 hours following third molar extractions On a 100 mm visual analogue scale the mean SD pain score was 409 244 At a pain score of 273 the SD was 172 We estimate that 17 patients are required for a power of 80 and a 50 decrease in pain
Ethical issues The fee for surgery will be waived for the participants There will be no other financial inducement Paracetamol is known to cause hepatotoxicity and fatality in overdosage These effects have not been reported with single ingestions of less than 150 mgkg
The patient will be undergoing a dental procedure and there will be the normal risks associated with such procedures
1 National Poisons Centre New Zealand toxinz In 2001
2 Mohler C Nordt SP Williams SR Manoguerra AS Clark RF Prospective evaluation of mild to moderate pediatric acetaminophen exposures Ann Emerg Med 2000371114-116
3 Prescott LF Kinetics and metabolism of paracetamol and phenacetin Br J Clin Pharmacol 198010Suppl 2291S-298S
4 Dai Y Cederbaum AI Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells J Pharmacol Exp Ther 199527331497-1505
5 Steventon GB Mitchell SC Waring RH Human metabolism of paracetamol acetaminophen at different dose levels Drug Metabol Drug Interact 1996132111-117
6 Kane RE Li AP Kaminski DR Sulfation and glucuronidation of acetaminophen by human hepatocytes cultured on Matrigel and type 1 collagen reproduces conjugation in vivo Drug Metab Dispos 1995233303-307
7 Whyte IM Buckley NA Reith DM Goodhew I Seldon M Dawson AH Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII Ther Drug Monit 2000226742-748
Background Paracetamol is the most widely used analgesic in New Zealand but relatively little is known about its dose effect and concentration effect relationships It appears that there is greater effect above the currently recommended dose but the maximal effect has not as yet been described
Paracetamol is toxic in overdose but the dose at which toxicity becomes apparent is disputed In the past the dose at which toxicity may become apparent has been 125 mgkgday but more recently this has been revised upwards to 150 mgkgday in children 1 In children it has been proposed that toxicity does not develop following single ingestions of up to 200 mgkgday 2
Paracetamol is metabolised by multiple pathways urinary excretion of an oral dose is 55 as glucuronide conjugates 30 as cysteine conjugates 4 as mercapturic acid and cysteine conjugates 3 The mercapturic and cysteine conjugates are derived from a toxic intermediary metabolite produced by oxidative metabolism by CYP2E1 and to a lesser degree CYP3A4 and CYP1A2 4 At doses of up to 1500 mg the metabolism appears to be unchanged but there is no data for doses at or above 90 mgkg 5 It has been proposed that paracetamol metabolism becomes saturated at higher doses and saturation of sulfation has been observed in rats 6 However saturation of either sulfation or glucuronidation has not been observed in cultured human hepatocytes 6
In overdose paracetamol has been observed to inhibit the activity of vitamin-K dependent clotting factors in particular functional factor VII 7 This may explain the interaction between paracetamol and warfarin
Aims
To describe the dose and effect relationship for paracetamol
To describe the concentration and effect relationship for paracetamol
To examine the changes in metabolism of paracetamol with escalating doses
To examine the effect of paracetamol on functional factor VII effect on coagulation mechanism with increasing dose
Methods
Subjects
Eighteen healthy adults male or female aged 18 to 50 years scheduled for removal of bilateral impacted lower wisdom teeth will be recruited for the trial in the dental school
Exclusion criteria
Intolerance to oral medication
Taking paracetamol and unable to abstain prior to the study
Hypersensitivity to paracetamol
Liver or renal failure
Pregnancy
Breast feeding
Poor nutritional status eating disorder or Body Mass Index BMI less than 16
Weight greater than 87 kg
Anticonvulsant medication
Chronic ethanol abuse
Ho bleeding disorders
Participants will be instructed to avoid all non-essential medications paracetamol alcohol herbal medicines and recreational drugs for 72 hours prior to the study and are required to fast for three hours prior to the study
Demographic data Demographic data including height weight and age will be recorded for each patient Medications pre- peri- and post-operatively will be recorded Regular use of alcohol caffeinated beverages and smoking will be recorded
Treatment
The patients will be fasted for three hours prior to the procedure An intravenous line will be inserted and intravenous midazolam administered with the dose titrated to sedative effect use of sedation oral or intravenous for third molar extractions is a common practice in dentistry Local anaesthetic 2 Lignocaine with adrenaline 180000 will be administered at the commencement of the procedure The paracetamol will be administered as capsules made by the Pharmacy Dept of the University of Otago 30 minutes prior to the procedure Dosing will be observed
Rndomised double blind cross over design will be used for each side for the surgery Both the side of extraction and the treatment will be randomised
During the procedure the patients will be observed by using pulse oximetry and blood pressure The patients will be requested to stay at the dental school for 4 hours after the paracetamol dosing
If the patient should require additional pain relief they will be given codeine 30 mg or diclofenac 50 mg The patients will be instructed to avoid additional doses of paracetamol for 48 hours Further analgesia on subsequent days will be provided with NSAIDs diclofenac and or codeine phosphate In appropriate doses Prophylactic antibiotics will be used where necessary according to usual treatment practice-
Samples
Blood will be collected at times 0 15 30 60 90 120 180 240 480 minutes through the cannula already in place in the standard manner Note time 0 is the time of paracetamol dosing 3-6 mL of blood is collected on each occasion and then transferred into a 6 mL heparinised saline vacutainer These will be spun in an Eppendorf Centrifuge 5810R at 4000 g for 5 minutes Plasma will be removed and transferred into a 2 mL microtube Eppendorf safe lock prior to freezing at -20C The catheter line and extension will be kept patent using heparinised saline 10 IU mL flushes
Urine collected from pass urine at time 0 and discard 0 to 120 120 to 240 and 240 to 480 minutes Urine volume will be measured and recorded An aliquot of urine from each time interval will be stored at -200C prior to assay
Blood will also be collected at 0 and 24 hours for ALT AST PT and clotting factors
An additional sample of blood will be collected at four hours after administration of paracetamol forserum paracetamol level estimation If this level is greater than the treatment threshold on the New Zealand Poisons Centre Substance Database the patient will be treated with n-acetylcysteine by the standard treatment protocol as soon as possible
Pain score
Visual analogue pain score 0-100 mm scale will be recorded at 0 30 60 90 120 150 180 210 240 480 minutes and at 24 hours after the end of surgery Mouth opening trismus will be assessed at 0 and 24 hours
Analytical methods
Urine
All samples were analysed using high performance liquid chromatography HPLC to determine the concentrations of paracetamol and its metabolites paracetamol glucuronide paracetamol cysteine paracetamol sulphate and paracetamol mercapturate Urine samples were prepared for HPLC by centrifuging at 2000rpm and then diluting the supernatent 1 in 10 with mobile phase This was injected directly onto an Aqua C18 reversed phase column 250mm x 46mm id with a 5 micron pore size Phenomenex via a C18 5 micron guard column The mobile phase used was 7 acetonitrile - 93 orthophosphoric acid 20mM pH 67 at a flow rate of 1mlmin using a Shimadzu LC10-AT pump and a Shimadzu SPD-10AV ultraviolet absorbance detector operating at 254nm Calibration curves were constructed for each of the metabolites and paracetamol in blank urine using the peak area and were linear over the range 005 - 5mM The method was found to be reproducible with a coefficient of variation of 26 The metabolites of paracetamol glucuronide cysteine sulphate mercapturate and paracetamol itself eluted in 39 8 102 122 and 134 minutes respectively Reference samples of paracetamol cysteine sulphate and mercapturate were kindly supplied by Dr Anthony R Temple MD McNeil Consumer Healthcare Camp Hill Road Fort Washington Pennsylvania USA
Sample size calculation
Previous studies of dental pain have indicated a maximum intensity of pain at around 8 hours following third molar extractions On a 100 mm visual analogue scale the mean SD pain score was 409 244 At a pain score of 273 the SD was 172 We estimate that 17 patients are required for a power of 80 and a 50 decrease in pain
Ethical issues The fee for surgery will be waived for the participants There will be no other financial inducement Paracetamol is known to cause hepatotoxicity and fatality in overdosage These effects have not been reported with single ingestions of less than 150 mgkg
The patient will be undergoing a dental procedure and there will be the normal risks associated with such procedures
1 National Poisons Centre New Zealand toxinz In 2001
2 Mohler C Nordt SP Williams SR Manoguerra AS Clark RF Prospective evaluation of mild to moderate pediatric acetaminophen exposures Ann Emerg Med 2000371114-116
3 Prescott LF Kinetics and metabolism of paracetamol and phenacetin Br J Clin Pharmacol 198010Suppl 2291S-298S
4 Dai Y Cederbaum AI Cytotoxicity of acetaminophen in human cytochrome P4502E1-transfected HepG2 cells J Pharmacol Exp Ther 199527331497-1505
5 Steventon GB Mitchell SC Waring RH Human metabolism of paracetamol acetaminophen at different dose levels Drug Metabol Drug Interact 1996132111-117
6 Kane RE Li AP Kaminski DR Sulfation and glucuronidation of acetaminophen by human hepatocytes cultured on Matrigel and type 1 collagen reproduces conjugation in vivo Drug Metab Dispos 1995233303-307
7 Whyte IM Buckley NA Reith DM Goodhew I Seldon M Dawson AH Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII Ther Drug Monit 2000226742-748
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None