1 Anaesthetic Department, The Royal London Hospital, Whitechapel, London E1 1BB, UK. 2 Portex Department of Anaesthesia, Institute of Child Health, Guilford Street, London WC1N 1EH, UK. 3 Anaesthetic Department, The Royal National Throat, Nose and Ear Hospital, Grays Inn Road, London WC1X 8DA, UK. 4 Department of Anaesthesia, Great Ormond Street Hospital for Children NHS Trust and Children Nationwide Pain Research Centre, Great Ormond Street, London WC1N 3JN, UK r.howard@ich.ucl.ac.uk
Accepted for publication: July 8, 2002
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Abstract |
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Methods. Ninety-six children received either codeine 1.5 mg kg1 or morphine 0.15 mg kg1 in a randomized, double-blind design. Genetic analysis was performed and plasma morphine concentrations at 1 h were determined. Postoperative analgesia and side-effects were recorded.
Results. Forty-seven per cent of children had genotypes associated with reduced enzyme activity. Mean (SD) morphine concentrations were significantly lower (P<0.001) after codeine [4.5 (0.3) ng ml1] than after morphine [24.7 (1.5) ng ml1], and morphine and its metabolites were not detected in 36% of children given codeine. There was a significant relationship between phenotype and plasma morphine (P=0.02). More children required rescue analgesia after codeine at both 2 (P<0.05) and 4 h after administration (P<0.01). Fifty-six per cent of children vomited after morphine and 29% after codeine (P<0.01). Neither phenotype nor morphine concentration was correlated with either pain score or the need for rescue analgesia (r=0.21, 95% confidence interval 0.4, 0.01).
Conclusions. Reduced ability for codeine metabolism may be more common than previously reported. Plasma morphine concentration 1 h after codeine is very low, and related to phenotype. Codeine analgesia is less reliable than morphine, but was not well correlated with either phenotype or plasma morphine in this study.
Br J Anaesth 2002; 89: 83945
Keywords: analgesia, genetic factors; analgesics opioid, codeine; enzymes, cytochrome P450 CYP2D6; surgery, adenotonsillectomy
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Introduction |
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The aims of the current studies were to investigate: (i) genotype, phenotype and morphine production from codeine in a UK urban population of children undergoing adenotonsillectomy; and (ii) the efficacy, reliability and side-effects of codeine as part of a postoperative analgesic regimen.
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Methods |
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Surgery was performed using electrocautery for tonsillar dissection and haemostasis. The anaesthetist and surgeon present varied depending on which day and on which operating list the procedure was performed. All staff involved in the procedure and the perioperative care of the child were blinded as to which opioid was administered.
No premedication was given. Topical local anaesthesia to facilitate i.v. cannulation was applied before anaesthesia, which was induced either by the i.v. route (propofol 25 mg kg1) or by inhalation (oxygen, nitrous oxide and sevoflurane). Once adequate anaesthesia had been established, a laryngeal mask of appropriate size was inserted into the airway. Anaesthesia was maintained with oxygen, nitrous oxide and sevoflurane with spontaneous ventilation. Analgesia (study drug plus diclofenac) was administered as soon as convenient after induction. Hartmans solution 10 ml kg1 was given during the procedure and continued into the postoperative period at a maintenance rate appropriate to each individual child. At the end of the procedure the patient was allowed to breathe 100% oxygen, and the laryngeal mask was removed once airway reflexes had returned. Patients were kept in the recovery area until they were awake and comfortable and able to return to the ward. Further analgesia was not given during the procedure unless indicated on the basis of clinical judgement. Ondansetron 0.10.2 mg kg1 was administered if required.
The analysis was performed at the Department of Molecular Biology at University College London. Whole blood was stored at 70°C until analysis and all the samples were processed in one batch. DNA was extracted from the whole blood, which was then split using a two-stage polymerase chain reaction (PCR). The PCR products were labelled fluoroscopically to allow detection electronically using an ABI-377 analyser (Applied Biosystems, Foster City, CA, USA). Over 50 variants of the CYP2D6 gene have been identified and most are classified as rare, 87% of genotypes being accounted for by five variants.9 13 It is impractical to look for all these different variants in each sample of DNA; thus, the most common polymorphisms causing alteration in enzyme activity were targeted. These were CYP2D6*1, *2, *3, *4, *5, *9, *10 and *17. CYP2D6*1 is considered the normal or wild-type gene and has normal activity. Variants *3, *4, *5 and *9 have no activity and account for over 90% of PMs, whilst *2, *10 and *17 have reduced activity. Four possible phenotypes were identified. If a patient was homozygous for polymorphisms known to show no activity, he or she was classified as a PM, whilst a combination of a polymorphism of reduced activity with one of no activity classified the patient as an intermediate/poor metabolizer (IM/PM). An intermediate metabolizer (IM) was a patient with either a combination of two polymorphisms with reduced activity or a combination of one normal polymorphism with one of no activity, and an extensive metabolizer (EM) was a patient who was either homozygous for the normal gene or who had a combination of a normal polymorphism with one of reduced activity. Genotyping identified all the polymorphisms apart from *1 so, if none was found, the sample was considered to be from a patient with the normal gene. Thus, there was a chance that a PM patient with another polymorphism could have been considered an EM (false negative), though as these polymorphisms are rare the estimated risk of this occurrence was very small.
For measurement of plasma morphine and metabolites, the blood samples were centrifuged at 3000 r.p.m. for 10 min within 15 min of being taken. The plasma was stored before processing at 70°C. Plasma morphine and its glucuronide metabolites were measured by high-performance liquid chromatography at the Institute of Child Health, London. Analysis of the samples was in two batches, and limits of detection were 5 (SD 2) ng ml1 for morphine and 10 (2) ng ml1 for morphine-6-glucuronide (M6G) in both. The coefficient of variation for morphine was 4% at 20 ng ml1. The limit of detection for morphine-3-glucuronide (M3G) was 30 (8) ng ml1 in the first batch and 60 (8) ng ml1 in the second.
Time to first analgesia (time from the injection of the opioid to the first dose of supplementary analgesia) and pain scores (using self-report and behavioural pain assessment tools) both at rest and on swallowing were used to assess analgesia. The need for extra analgesia was assessed on clinical grounds by the anaesthetist and/or the nurse responsible for the patient. Further analgesia was given as an i.v. bolus of morphine 20 µg kg1, oral morphine solution 0.1 mg kg1 or oral acetaminophen 20 mg kg1 at their discretion and the patient was subsequently excluded from the analysis.
Two methods of pain scoring were used, both of which have been verified in this age group. A faces type self-reporting pain tool14 was used in the recovery ward at the time of blood sampling for measurement of plasma morphine concentrations and 1, 2, 3 and 4 h after the end of the procedure, and the Childrens Hospital of Eastern Ontario Pain Score (CHEOPS)15 in the recovery ward. The scores were taken at each time point, both at rest and on swallowing, to provide static and dynamic measures of analgesia. The children were introduced to the self-reporting pain scale at the preoperative visit and shown how to use it. All nursing staff involved in the care of the children enrolled in the study had been taught previously how to use both pain scores.
Respiratory rate and a five-point sedation score (1=awake, 5=hard to rouse) were also recorded at the same time points as above. Postoperative vomiting was assessed by counting the number of vomiting episodes for each patient in a number of set time periods (<1, 12, 24 and 48 h). Again, patients were removed from analysis once further analgesia had been administered. Other unexpected complications and adverse effects were also recorded. Patients were monitored closely until discharge from the hospital.
All data were handled electronically and calculations performed using either Microsoft Excel 2000 or Graphpad Prism 3.0. Comparisons between continuous variables were made using either analysis of variance with Bonferroni post-test corrections or t-tests as appropriate. Survival analysis was performed using KaplanMeier survival curves. Categorical data were analysed using the 2 test and correlation between independent variables was tested with Pearsons correlation coefficient. For all comparisons, P<0.05 was considered significant.
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Results |
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Patient characteristics are shown in Table 1. There was no significant difference between the two groups for age, sex or duration of surgery, or in the make-up of the ethnic groups of the patients randomized to the two arms of the study.
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The percentage of patients who vomited in the first 4 h after operation was 56.3 for group M and 29.2 for group C (P<0.01). Figure 4 shows a comparison between groups M and C for the number of patients who vomited in each time period. There was no difference between the two groups in the proportion of patients who vomited at <1, 12 and 48 h but the difference was significant at 24 h (P<0.01), with more vomiting in group M. In group C, neither of the PM patients vomited but otherwise postoperative nausea and vomiting was evenly distributed between the phenotypes (P>0.05). There was no difference between the two groups in the time to oral intake, which was measured from the end of surgery. Intravenous fluids were continued because of vomiting in two patients in group M and one in group C, but discharge from hospital was not delayed.
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Discussion |
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Plasma morphine concentration has not been directly related to analgesia, but pharmacokinetic studies have suggested that a range of 565 ng ml1 may be therapeutic in children.1921 One hour after administration of codeine in this study, mean plasma morphine was below this range in all phenotypes after codeine, including normal and extensive metabolizers. The half-life of both codeine and morphine after i.m. injection is 23 h, and the usual recommended dosing regimen for both is 4- to 6-hourly.1 22 23 However, such low concentrations at 1 h imply that analgesia from codeine-derived morphine after that time would be unlikely.
In the second part of the present study, the analgesia and side-effects of codeine and morphine combined with diclofenac were compared. Diclofenac was included for ethical reasons because the concurrent use of opioid and NSAID (non-steroidal anti-inflammatory drug) analgesia is standard practice after adenotonsillectomy. Significantly more children needed rescue analgesia at 2 and 4 h in the group given codeine (group C) than in the group given morphine (group M). However, behavioural and self-report pain assessments did not differentiate between the groups at any stage of the study. All the mean scores were within the satisfactory range. However, the codeine subgroup who needed supplementary analgesia had significantly higher scores in recovery than the rest of that group. Although within group C plasma morphine was related to phenotype, no relationship could be found between phenotype and analgesia; as morphine concentrations were very low and differences in morphine production between phenotypes were small, this may not be surprising. The concurrent use of diclofenac may also have masked any differences between the groups, as such analgesic combinations are known to increase efficacy substantially in comparison with monotherapy (see below).
In the first 4 h after operation, 29.2% of the patients vomited in group C compared with 56.3% of patients in group M. Vomiting is common after adenotonsillectomy in children, with a reported incidence of between 30 and 75%.24 25 The causes are multiple and may include stimulation of laryngeal and pharyngeal reflexes, gastric irritation as a result of swallowed blood, anaesthetic agents and analgesic administration.26 27 Broadly, there was little difference between the two drug groups in terms of sedation and respiratory rate. Previous studies in both adults and children have suggested that, although the incidence of side-effects may be low, the overall efficacy of codeine is also low and analgesia may be inadequate for postoperative pain in some circumstances.3 28 29 Indeed, in the adult some single-dose studies have shown no difference between codeine and placebo, and a quantitative systemic review suggests that codeine 60 mg has a number needed to treat (NNT) of 18, which is very high when compared with 5.0 for acetaminophen 600 mg and 3.1 for the combination.3032
In conclusion, we have found that reduced ability to metabolize codeine to morphine was common in this population of children, and that plasma concentrations of morphine are generally very low 1 h after i.m. codeine for patients of all phenotypes, even those who have normal metabolic capability. Codeine analgesia with diclofenac was less reliable than morphine, but a clear relationship between plasma morphine or phenotype and analgesia could not be established. Uncertainties regarding the efficacy and any possible advantages of codeine over morphine or other opioids mean that its use cannot be recommended without reservation. Situations in which pain is known to be significant and pain assessment problematic present particular difficulties, which will only be heightened by the use of codeine.
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Acknowledgements |
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