Paracetamol versus paracetamol-codeine in the treatment of post-operative dental pain: a randomized,double-blind,prospective trial

BACKGROUND: Codeine is frequently added to paracetamol to treat post-operative dento-alveolar pain; studies have shown effectiveness in relief of post-operative pain at high doses but at the expense of central nervous and gastrointestinal side effects. There has been no trial to compare the efficacy and safety of paracetamol 1000 mg with paracetamol 1000 mg combined with codeine 30 mg. METHOD: A randomized, single centre, double-blind prospective parallel group trial was performed to compare paracetamol 1000 mg with paracetamol 1000 mg with codeine 30 mg for the relief of pain following surgical removal of impacted third molars, and analysed on an intention-to-treat (ITT) basis. Eighty-two patients were assigned randomly to receive either drug for a maximum of three doses. Patients recorded their pain intensity one hour after surgery and hourly thereafter for 12 hours. RESULTS: The average increase in pain intensity over 12 hours was significantly less in patients receiving paracetamol plus codeine than in those receiving paracetamol alone (p=0.03) -1.81 cm/h compared with 0.45 cm/h - a difference of 1.13 cm/h (95 per cent CI: 0.18 to 2.08). Of the patients who received the paracetamol codeine combination, 62 per cent used escape medication compared with 75 per cent of those on paracetamol alone (p=0.20). There was no significant difference between the two groups in the proportion of patients experiencing adverse events (p=0.5). CONCLUSION: A combination of 1000 mg paracetamol and 30 mg codeine was significantly more effective in controlling pain for 12 hours following third molar removal, with no significant difference of side effects during the 12 hour period studied.     

Different effects of inhibitors on the O - and N -demethylation of codeine in human liver microsomes

Objective: The O- and N-demethylation of codeine is catalysed by CYP2D6 and CYP3A4 respectively. The formation rates of morphine by O-demethylation and norcodeine by N-demethylation were studied in two sets of human liver microsomes. Results: Relatively high K _m values were found for both O- and N-demethylations, suggesting a low affinity to the corresponding enzymes. The inhibitory effects of various drugs were found to be different for O- and N-demethylations. The substrates of CYP2D6 such as thioridazine, amitriptyline and metoprolol inhibited the O-demethylation of codeine preferentially, while the substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were all strong inhibitors of the N-demethylation of codeine. Quinidine and lignocaine, although they are substrates of CYP3A, showed preferential inhibition over the O-demethylation of codeine, suggesting a low affinity to the CYP3A. Methadone and dextropropoxyphene showed a preferential inhibition of CYP2D6 over CYP3A, while theophylline did not inhibit the O- or N-demethylation to a greater extent. Conclusion: It seems that there was a good correspondence between the capacity of drugs to inhibit the O- and N-demethylation of codeine in human liver microsomes and their apparent metabolism by CYP2D6 or CYP3A4, respectively in vivo in man, suggesting that this in vitro inhibition test may be a useful screen for drugs which interact with these two important drug-metabolising enzymes.     

人尿中氢可酮及其代谢物的检测研究

用气相色谱 质谱联用仪(GC/MSD)检测人尿中氢可酮及其代谢物双氢吗啡。尿样经酸解、乙醚/异丙醇提取后,用甲氧胺吡啶液将羰基保护生成肟,再用MSTFA-MBTFA及MSTFA-TMSI衍生化后,经GC/MS分析,形成各自的特征图谱。方法灵敏、准确,可快速鉴别氢可酮、可待因、双氢可待因等结构相似药物。     

Evaluation of a method for simultaneous quantification of codeine,dihydrocodeine, morphine,and 6-monoacetylmorphine in serum,blood, and postmortem blood

Summary A solid-phase extraction and gas chromatographic-mass spectrometric method for the simultaneous determination of codeine, dihydrocodeine, morphine, and 6-monoacetylmorphine in serum, blood or postmortem blood is described. The extraction technique allows the determination of free or total morphine (morphine plus morphine glucuronide). Experiments with spiked blood samples resulted in recoveries of 96.4% ± 4.2% for codeine, 95.8% ± 5.1% for dihydrocodeine, 90.3% ± 7.8% for 6-monoacetylmorphine and 92.5% ± 8.1% for morphine. Excellent linearity was obtained over the range 1–1500 ng/mL. The detection limit for all analytes is less than 1 ng/mL.     

Evaluation of a solid-phase extraction procedure for the simultaneous determination of morphine, 6-monoacetylmorphine,codeine and dihydrocodeine in plasma and whole blood by GC/MS

Different procedures of solid-phase extraction were re-examined and a new solid-phase extraction procedure was developed using gas chromatography-mass spectrometry for the simultaneous detection and quantitation of morphine, 6-monoacetylmorphine, codeine and dihydrocodeine in plasma and whole blood. The effects of different types of sorbent and buffer solutions on the recoveries and purity of the extracts were also studied. Some preparation techniques on whole blood samples were also investigated. The method developed using Chromabond C18 (100) with spiked plasma samples had good recoveries for all opiates of interest: morphine 93.1% ± 7.4%, 6-monoacetylmorphine 68.0% ± 6.7%, codeine 77.0% ±8.3% and dihydrocodeine 67.9% ± 8.4%. The detection limit of all compounds was less than 5 g/L. The blank plasma showed no interfering peaks in the GC/MS-analysis.     

Acute gingivostomatitis in children: Epidemiology in the emergency department,pain, and use of codeine before its restriction

Acute gingivostomatitis is relatively frequent in children; of viral origin, its diagnosis is usually straightforward. Acute gingivostomatitis is very painful and for many years, codeine, whose use was restricted in 2013, was widely employed in this context. The aim of this study was to ascertain the prevalence of acute stomatitis in pediatric emergency care, to evaluate the pain caused by stomatitis, and to determine the analgesic resources deployed both in the emergency department and at discharge, over the 5-year period preceding restriction of the use of codeine.

The occurrence of acetaminophen/codeine as an adulterant in herbal analgesic supplements in Hamadan,Iran: A pilot study

Analgesics, such as acetaminophen (APAP) and codeine (COD), are used to adulterate medicinal herbs and/or herbal supplements. This study evaluated the APAP and COD levels in 60 herbal supplement and/or herb-based medicine samples collected from apothecaries in Hamadan, Iran. The samples were analysed using a high-performance liquid chromatography (HPLC) system. The results showed that 15% of the samples contained 38900–165200 ng/g and 31.1–603.3 ng/g of APAP and COD, respectively. Due to the side-effects of analgesic drugs in human, control of these drugs is recommended in herbal supplements.     

Simultaneous Determination of codeine and noscapine by flow-injection chemiluminescence method using N-PLS regression

A flow injection chemiluminescent (FI-CL) method has been developed for the simultaneous determination of codeine and noscapine using N-PLS regression. The method is based on the fact that kinetic characteristics of codeine and noscapine are different in the Ru(phen)₃²⁺–Ce(IV) CL system. In flow injection mode, codeine gives broad peak with the highest CL intensity at 4.4 s, whereas the maximum CL intensity of the noscapine appears at about 2.6 s. Moreover, the effect of increasing H₂SO₄ concentration was different on the CL intensity of the compounds. An experimental design, central composite design (CCD), was used to realize the optimized variables such as Ru(II) and Ce(IV) concentrations for the both compounds. At the optimized condition, a three-way data structure (samples, H₂SO₄ concentration, time) was constructed and followed by N-PLS regression. The number of factors for the N-PLS regression was selected based on the minimum values for the root mean squared error of cross validation (RMSECV). The proposed method is applied to the simultaneous quantification of codeine and noscapine in the pharmaceutical preparations.     

O-demethylation of codeine to morphine inhibited by low-dose levomepromazine

Purpose  Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6. Methods  Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay and gas chromatography–mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine. Results  Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly higher (P = 0.016, Mann–Whitney test) after the C/P treatment (0.092, range 0.041–0.096) than after the L+C/P treatment (0.031, range 0.009–0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011–0.042) vs. 0.026 (range 0.009–0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011–0.096) vs. 0.030 (range 0.009–0.042), respectively; P = 0.122]. Conclusions  Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination, the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine.