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A patient presented with clinical features of drug overdose. Although heroin was suspected, codeine was identified by drug analysis. The clinical course was complicated by shock, respiratory arrest and laboratory evidence of acute hepatic insufficiency. An inital slow rate of codeine metaboism, possibly related to the hepatic damage, corresponded to prolonged respiratory depression.
A combination of 20 mg codeine base and ibuprofen 400 mg was compared with ibuprofen 400 mg in a randomised double-blind cross-over study of multiple doses in 25 patients after 2-stage bilateral third molar removal. The combination produced significantly greater pain relief and doubled the hours of minimum pain intensity and maximal relief on the day of surgery. The patients rated the combination significantly better than ibuprofen alone, and the combination was preferred by 16 of the 22 patients expressing a preference. There was no significant increase in side-effect incidence with the combination. The 30% increase in analgesic effect may be of clinical benefit, and this trial design, cross-over with multiple dosing in out-patients, may be a sensitive test for analgesics, potentially more predictive of side-effect problems than single-dose studies.
Morphine and codeine were isolated from blood with C18 Bond Elut columns and derivatised with pentafluoropropionic anhydride (PFPA). The PFPA-derivatives were examined by means of gas chromatography/mass spectrometry using electron impact and chemical ionisation (positive and negative mode). The negative chemical ionisation, as most sensitive, was applied for the quantitation of both examined substances in forensic blood samples.
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1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)
Plasma and urine concentrations of codeine and its measurable metabolites were determined by HPLC in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of 1 g paracetamol 8 hourly. After codeine alone, the t1/2 (h), AUC (mumol.l-1.h) and CLR (ml.min-1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively. For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml.min-1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6-glucuronide (820 codeine alone, 1022 codeine plus paracetamol). The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments.
A double-blind, randomised analgesic trial was carried out in 165 patients undergoing surgical removal of one impacted lower wisdom tooth. In a two-dose regimen, the analgesic efficacy of the combination ibuprofen-codeine 200 mg : 30 mg was compared with that of acetylsalicylic acid-codeine 500 mg : 30 mg and codeine 30 mg. Each dose was taken when the patient needed pain relief. The intensity of the pain was measured on a visual analogue scale during the 10-h period after the first dose. The mean pain reduction by Dose 1 in patients on ibuprofen-codeine, acetylsalicylic acid-codeine and codeine was 64%, 45% and 26%, respectively, and the mean duration of effect was 8.3, 6.3 and 5.6 h. According to the pain reduction, duration of effect and pain reduction index after Doses 1 and 1 + 2, there was a significant difference between ibuprofen-codeine and the other two drugs. The maximum pain reduction within 4 hours was 84% with ibuprofen-codeine. This was significantly different from the reduction achieved both with acetylsalicylic acid-codeine (64%) and codeine (35%). Seventeen patients reported adverse events: 5 on ibuprofen-codeine, 4 on acetylsalicylic acid-codeine and 8 on codeine. The most common events were tiredness and vertigo. It is concluded that the combination ibuprofen-codeine 200 mg : 30 mg had greater analgesic efficacy compared to the combination acetylsalicylic acid-codeine 500 mg : 30 or codeine 30 mg in patients with pain after removal of the lower third molars.
Recent research demonstrated that codeine produced hypoalgesia and morphine produced hyperalgesia against a noxious thermal stimulus in young domestic fowl. The bidirectional effects of these opiate agonists on nociception are inconsistent with the notion that codeine's algesic effects result through in vivo demethylation of codeine to yield morphine. In Experiment 1, the temporal pattern (15,30,60 and 120 min) of codeine (30 mg/kg) effects on thermal nociception and respiration were examined in 15-day-old cockerels. Codeine produced a time-dependent biphasic response: hypoalgesia at 15 min and hyperalgesia at 60 and 120 min. Respiration was depressed by codeine at all test intervals. To assess for opioid specificity, Experiment 2 examined the action of naloxone (5 mg/kg) on the temporal pattern (15 and 60 min) of codeine effects (30 mg/kg) on thermal nociception and respiration. Bidirectional codeine algesic effects were observed at the 15- and 60-min test intervals. Naloxone increased the codeine jump latency scores at the 15-min interval and decreased codeine jump latency scores at the 60-min interval. These results suggest that codeine engages opposed nonopioid-mediated hypoalgesic and opioid-mediated hyperalgesic nociceptive systems in this animal model. Codeine depressed respiration at both the 15- and 60-min test intervals and this respiratory depression was reversed by naloxone. These findings support the notion that codeine respiratory effects are mediated by opioid system activity.
Codeine (30 mg phosphate) was metabolized by eight human volunteers to the following six metabolites: codeine-6-glucuronide 81.0 +/- 9.3 per cent, norcodeine 2.16 +/- 1.44 per cent, morphine 0.56 +/- 0.39 per cent, morphine-3-glucuronide 2.10 +/- 1.24 per cent, morphine-6-glucuronide 0.80 +/- 0.63 per cent, and normorphine 2.44 +/- 2.42 per cent. Two out of eight volunteers were unable to O-dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme. The half-life of codeine was 1.47 +/- 0.32 h, that of codeine-6-glucuronide 2.75 +/- 0.79 h, and that of morphine-3-glucuronide 1.71 +/- 0.51 h. The systemic clearance of codeine was 2280 +/- 840 ml min-1, the renal clearance of codeine was 93.8 +/- 29.8 ml min-1, and that of codeine-6-glucuronide was 122 +/- 39.2 ml min-1. The plasma AUC of codeine-6-glucuronide is approximately 10 times higher than that of codeine. Protein binding of codeine and codeine-6-glucuronide in vivo was 56.1 +/- 2.5 per cent and 34.0 +/- 3.6 per cent, respectively. The in vitro protein binding of norcodeine was 23.5 +/- 2.9 per cent; of morphine, 46.5 +/- 2.4 per cent; of normorphine, 23.5 +/- 3.5 per cent; of morphine-3-glucuronide, 27.0 +/- 0.8 per cent; and of morphine-6-glucuronide, 36.7 +/- 3.8 per cent.
Rhesus monkeys were trained to respond under a variable interval 2 min schedule for codeine or ethanol injections. Both codeine and ethanol were effective in the initiation of variable-interval responding; responding was maintained over a range of codeine (0.003-1.0 mg/kg/injection) and ethanol doses (32.0-560 mg/kg/injection). Maximum rates of responding were obtained at the 0.01 mg/kg/injection codeine dose (0.14 responses/sec) and at the 180 mg/kg/injection codeine dose (0.19 responses/sec). Rates of responsing were bitonic functions of the reinforcer dose for both codeine and ethanol; maximum rates were obtained at intermediate doses and lower rates occurred at the extremes of the dose range. Both codeine and ethanol showed within-session decreases in responding across the range of reinforcer doses. Codeine-reinforced responding declined in rate within the one-hour session without a similar change in the frequency of drug injection; in contrast, both ethanol-reinforced responding and the frequency of ethanol injections declined within each session across a range of doses. Increasing or decreasing the codeine dose half-way through the one-hour session resulted in increases or decreases in codeine responding compared to controls. These data indicate that the progressive decline in codeine-reinforced responding is not the result of a generalized disruption of responding.
The pharmacokinetics of codeine was examined in six male Sprague-Dawley rats following iv bolus (3 mg/kg) and oral (5 mg/kg) codeine in a randomized crossover design. Whole blood concentrations of codeine and its O-demethylated metabolite, morphine, were determined by HPLC with electrochemical detection. Following iv codeine administration, the distribution and elimination are best described by an open two-compartment model. The weight normalized volume of distribution of (Vdarea) and total body clearance (CL) were 5.1 +/- 1.7 liters/kg and 6.2 +/- 1.5 liters/kg/hr, respectively. Mean residence time of codeine averaged 34.1 +/- 6.9 minutes. The ratio of AUCmorphine/AUCcodeine was 0.05 +/- 0.02. The absolute bioavailability of codeine calculated was 8.3 +/- 3.2%, indicating extensive first pass metabolism of codeine. An equivalent amount of codeine and morphine were present in the rat following oral codeine. Thus, the amount of morphine formed following codeine administration depends on the route of codeine administration.
Miosis produced by codeine is not antagonized by nalorphine until large oral doses are administered for several days. The present experiment was conducted in order to further study this characteristic of the codeine effect. Eight healthy male volunteers, who were former drug users, were divided into two groups. Subjects in the first group were given a continuous infusion of codeine, 30 mg/hr for 11-16 hr. No subjective effects were reported by the volunteers. In three of the individuals definite miosis antagonized by nalorphine was observed at 9.5 hr. The dose of codeine for the second group was 60 mg/hr for 11 hr. Mild but definite subjective effects were experienced by each of the participants in this group. Miosis appeared between 2 and 6 hr. Challenges at 4 and 6 hr were positive in two subjects and negative or equivocal in the other two. Codeine was excreted in the urine as free and conjugated codeine, morphine, and norcodeine. Maximum rates of excretion were similar for both groups, suggesting that the maximum amount of codeine that can be metabolized is equal or less than 30 mg/hr. Also codeine clearance, being greater than creatinine clearance, suggests that codeine might be excreted by glomerular filtration and tubular secretion. Blood levels of codeine in the 60 mg/hr group were about 10 times those reported as therapeutic. However, morphine or norcodeine were not detectable by the methods used.
Radioimmunoassay (RIA) was used to determine several pharmacokinetic parameters of codeine in man, including the relative bioavailability after oral and intramuscular administration. The study followed a crossover design in 6 healthy, young (18 to 21 yr), male volunteers. Three subjects received 65 mg codeine phosphate orally in an analgesic mixture which also contained aspirin, phenacetin, and caffeine. At the same time a similar group received an equivalent dose of codeine phosphate in a single intramuscular injection. Two weeks later the study was repeated so that each group received the alternate treatment. Plasma samples were collected at various times after drug administration, and codeine concentrations were determined by a specific RIA procedure. The procedure can detect less than 50 pg of codeine. Following intramuscular administration, peak plasma concentrations (194 to 340 ng/ml) were observed between 0.25 to 1 hr; after oral dosing, peak codeine plasma concentrations (102 to 140 ng/ml) appeared within 0.75 to 1 hr. The mean plasma t1/2 and volume of distribution of codeine following intramuscular injection were 3.32 hr and 5.1 L/kg, respectively. Oral, relative to intramuscular, bioavailability of codeine, based on areas under the codeine plasma curves, was 42% to 71% (mean, 53%).
This randomized, double-blind, multi-centre study was undertaken to evaluate the efficacy and safety of treatment for 4 weeks with codeine plus paracetamol versus paracetamol in relieving chronic pain due to osteoarthritis of the hip. A total of 158 outclinic patients entered the study. Eighty-three patients (mean age 66 years) were treated with codeine 60 mg plus paracetamol 1 g 3 times daily, and 75 patients (mean age 67 years) with paracetamol 1 g 3 times daily. Ibuprofen 400 mg was prescribed as rescue medication. Due to an unexpected high rate of adverse drug reactions, the study was closed before the planned 400 patients had entered. Over weeks 1-4, 87%, 64%, 61% and 52% of patients in the codeine plus paracetamol group, and 38%, 31%, 22% and 29% of patients in the paracetamol group had one or more adverse drug reactions. Significantly more patients in the codeine plus paracetamol group had adverse drug reactions in each of the 4 weeks. Nausea, dizziness, vomiting and constipation were predominant adverse reactions in the codeine plus paracetamol group. During the first week of treatment, 30 patients (36%) in the codeine plus paracetamol group and 9 (12%) in the paracetamol group dropped out. As evaluated from patients completing the first week of treatment, the pain intensity during that week compared to their baseline pain was significantly lower in the codeine plus paracetamol group than in the paracetamol group. Moreover, during the first week the paracetamol group received rescue medicine significantly more frequently. In conclusion, when evaluated after 7 days of treatment, the daily addition of codeine 180 mg to paracetamol 3 g significantly reduced the intensity of chronic pain due to osteoarthritis of the hip joint. However, several adverse drug reactions, mainly of the gastrointestinal tract, and the larger number of patients withdrawing from treatment means that the addition of such doses of codeine cannot be recommended for longer-term treatment of chronic pain in elderly patients.
The reinforcing effects of codeine (5.0 mcg/kg/infusion), acetylsalicylic acid (ASA) (2500 mcg/kg/infusion) and those of combinations of codeine (50 mcg/kg/infusion) plus (2500 or 10,000 mcg/kg/infusion) were studied in four groups of drug naive rhesus monkeys. Responding was engendered and maintained by infusions of 50 mcg/kg of codeine; maximal number of daily infusions being 500 to 1000. Infusions of 2500 mcg/kg of ASA plus 50 mcg/kg of codeine per infusion initiated responding from the 9th to the 10th day of the drug period on. The number of self-administered infusions did not exceed 200 daily. Monkeys self administered codeine without signs of intoxication. All three monkeys self-administering the combination of 50 mcg/kg of codeine plus 2500 mcg/kg of ASA died during the experiment. They exhibited signs of severe intoxication. A combination of 50 mcg/kg of codeine and 10,000 mcg/kg of ASA was not self-administered until the 12th day of the drug period. Two out of three monkeys initiated responding for the combination during the drug period. The number of self-administered infusions did not exceed 50 per day. A third monkey did not initiate self-administration during the 14 day drug period. Both monkeys which engendered self-administration died on the 14th day of the experiment as a result of general intoxication. These experiments suggest that even toxic doses of ASA will not prevent monkeys from self-administration when offered together with a positive reinforcing drug such as codeine under a schedule of continuous self-administration.
1. A single oral dose of codeine (25 mg) was given to 132 healthy Swedish Caucasians who had previously been phenotyped with respect to debrisoquine hydroxylation. The 'metabolic ratios' (MR) in urine of codeine O-demethylation (codeine/(morphine (M) + morphine-3- and 6-glucuronides (M3G and M6G) + normorphine], N-demethylation (codeine/(norcodeine (NC) + norcodeine glucuronide + normorphine (NM]) and glucuronidation (codeine/codeine-6-glucuronide (C6G] were calculated following h.p.l.c. analysis of urine samples collected over 8 h. 2. There was a significant correlation between the log MR for debrisoquine hydroxylation and the log MR for codeine O-demethylation (rs = 0.77, P less than 0.001). The poor debrisoquine hydroxylators had MRs of codeine O-demethylation between 8.3 and 55.1, while the values for extensive hydroxylators were between 0.4 and 5.5. 3. The poor debrisoquine hydroxylators excreted significantly less M, M3G, M6G and NM, while the urinary recovery of C6G and NC was significantly higher in these subjects compared to the extensive hydroxylators. 4. The MRs for glucuronidation and N-demethylation did not exhibit a bimodal distribution, and were not related to the MR of debrisoquine hydroxylation. 5. No associations were found between sex, body-weight, smoking habits, age, urine volume or urine pH and the O-demethylation of codeine. 6. The O-demethylation of codeine to form M appears to be under the same polymorphic genetic control as the 4-hydroxylation of debrisoquine.
1. The kinetics of codeine and metabolites were studied in eight unrelated healthy Chinese subjects following a single oral dose of 50 mg codeine phosphate. The data were compared with those from eight Caucasian subjects who were matched with the Chinese group according to their metabolic ratio (MR) of debrisoquine. 2. Mean values of Cmax (445 nmol l-1) and AUC (1660 nmol l-1 h) of codeine in the Chinese were significantly higher than those in the Caucasians (292 nmol l-1 and 1010 nmol l-1 h). Thus plasma clearance was significantly lower (P less than 0.02) and the plasma half-life was longer (P less than 0.05) in the Chinese. 3. Partial clearance by glucuronidation was significantly lower (0.79 +/- 0.14 s.d. vs 1.42 +/- 0.48 s.d. 1 h-1 kg-1) in Chinese than in Caucasians. 4. The total urinary recovery of drug-related material in 48 h urine was similar in Chinese (82.2%) and Caucasians (84.4%). The recovery of unchanged codeine was significantly higher in Chinese (5.7%) than in Caucasians (3.3%). 5. The AUC ratios of codeine relative to its 6-glucuronide, morphine and norcodeine were 1:9, 35:1 and 4:1, respectively in Chinese. The corresponding ratios in Caucasians were 1:15, 50:1 and 6:1. 6. There was no significant difference between Chinese and Caucasians in the renal clearances of codeine and its primary metabolites. 7. Large interethnic differences in the kinetics of codeine have been shown. The Chinese are less able to metabolise codeine mainly because of a lower efficiency in glucuronidation.