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PubMed2000

The prevalence of analgesics containing dextropropoxyphene or codeine in individuals suspected of driving under the influence of drugs.

To investigate the prevalence of analgesics containing dextropropoxyphene (DXP) or codeine in individuals suspected of driving under the influence of drugs, we analysed all blood samples in which drugs were screened for in cases of suspected drunken driving in Sweden during the years 1992-1997. DXP was found in 130 (2.7%) and codeine in 388 (7.9%) of the 4896 drug-screened cases. The ratio between the number of DXP and of codeine cases and prescription of defined daily dose/1000 inhabitants during a 12-month period (DDD) was determined. The quotient for DXP was trebled from 1992 (0.99) to 1997 (2.89), while the codeine quotient decreased by 9% (from 6 to 5.5). The blood samples showed polydrug use in all but 28 cases of the 486 cases where DXP and/or codeine was found. In 71% of the 486 cases benzodiazepines were also present and in 38% of the cases amphetamine and/or cannabis were present. It was concluded that analgesics containing DXP or codeine are not drugs of primary interest in this specific population. Nevertheless, because of the high toxicity of DXP, especially when combined with alcohol or other drugs, the increase in the DXP prevalence gives reason for concern, since the studied population represents a group of individuals who use large doses of therapeutic or illegal drugs.

Adolescent↗

PubMed1983

Codeine and aspirin analgesia in postpartum uterine cramps: qualitative aspects of quantitative assessments.

The analgesic response to codeine of patients with postpartum uterine-cramp pain has recently met with controversy. To readdress this question, we conducted a new study comparing codeine sulfate, 60 mg (N = 32) and 120 mg (N = 31), with aspirin, 650 mg (N = 34), and placebo (N = 32) in hospitalized women with moderate or severe postpartum uterine cramps treated with single oral doses in a parallel, stratified, randomized, double-blind trial. Subjective reports were used as indices of response, and patients rated pain intensity, pain relief, and side effects at periodic, uniformly conducted interviews for 6 hr. Most measures of analgesia exhibited important differences among the treatments. In patients with undifferentiated pain (N = 129) and in a subset of patients with pure uterine cramps (N = 56; i.e., no concomitant episiotomy), aspirin showed the greatest response, whereas codeine responses were equivocal with no evidence of a positive dose response. In contrast, in a subset of patients with mixed episiotomy-uterine pain (N = 73), 120 mg codeine showed good separation from placebo and compared favorably with aspirin. Codeine, 60 mg, showed a similar trend, and there was a strong suggestion of dose-dependent analgesia. Side effects were not remarkable except for dizziness and drowsiness after 120 mg codeine in all sets and subsets of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1.

We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). The O-demethylation of codeine was highly correlated with the O-demethylation of dextromethorphan (r = 0.90). The N-demethylation of codeine was catalyzed at a considerably higher rate than the O-demethylation. The N-demethylation to O-demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate of O-demethylation of codeine (r = 0.95) and of dextromethorphan (r = 0.88) in the extensive metabolizers. The comeasurement of the O-demethylation and N-demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P-450IID1.

Antibodies, Monoclonal↗

PubMedDate not supplied

Simultaneous determination of morphine and codeine in blood and bile using dual ultraviolet and fluorescence high-performance liquid chromatography.

The separation and identification of morphine and codeine from postmortem blood and bile was accomplished using a liquid-phase extraction method followed by reversed-phase high-performance liquid chromatography with combined UV and fluorescence detection. Identification of morphine and codeine was based on relative retention time matching with calibration standards, together with their fluorescence-to-UV response ratios. Linear calibration curves for morphine and codeine ranged from 0.10 to 3.0 mg/L for blood and 5.0 to 100 mg/L for bile. Morphine concentrations (in autopsy cases), where the intravenous use of heroin or morphine was suspected as the cause of death, were 0.10-0.89 mg/L (mean, 0.29 mg/L) for blood and 3.3-112 mg/L (mean, 38 mg/L) for bile. Codeine concentrations, where therapeutic use or overdosage of codeine occurred, were 0.06-6.4 mg/L (mean, 1.5 mg/L) in blood and 0.22-89 mg/L (mean, 24 mg/L) in bile. This method allowed simultaneous detection of morphine and codeine from blood and bile with little interference from extraneous peaks. The procedure described provides a selective, sensitive, accurate, and reliable method suitable for both clinical and forensic toxicology.

Bile↗

PubMed1999

Drug testing with alternative matrices II. Mechanisms of cocaine and codeine deposition in hair.

A 10-week inpatient study was performed to evaluate cocaine, codeine, and metabolite disposition in biological matrices collected from volunteers. An initial report described drug disposition in plasma, sebum, and stratum corneum collected from five African-American males. This report focuses on drug disposition in hair and sweat collected from the same five subjects. Following a three-week washout period, three doses of cocaine HCl (75 mg/70 kg, subcutaneous) and three doses of codeine SO4 (60 mg/70 kg, oral) were administered on alternating days in week 4 (low-dose week). The same dosing sequence was repeated in week 8 with doubled doses (high-dose week). Hair was collected by shaving the entire scalp once each week. Hair from the anterior vertex was divided into two portions. One portion was washed with isopropanol and phosphate buffer; the other portion was not washed. Hair was enzymatically digested, samples were centrifuged, and the supernatant was collected. Sweat was collected periodically by placing PharmChek sweat patches on the torso. Drugs were extracted from sweat patches with methanol/0.2 M sodium acetate buffer (75:25, v/v). Supernatants from hair digests, hair washes, and sweat patch extracts were processed by solid-phase extraction followed by gas chromatography-mass spectrometry analysis for cocaine, codeine, 6-acetylmorphine, and metabolites. Cocaine and codeine were the primary analytes identified in sweat patches and hair. Drugs were detected in sweat within 8 h after dosing, and drug secretion primarily occurred within 24 h after dosing. No clear relationship was observed between dose and drug concentrations in sweat. Drug incorporation into hair appeared to be dose-dependent. Drugs were detected in hair within 1-3 days after the last drug administration; peak drug concentrations generally occurred in the following 1-2 weeks; thereafter, drug concentrations decreased. Solvent washes removed 50-55% of cocaine and codeine from hair collected 1-3 days after the last drug dose. These data may reflect removal of drug that was deposited by sweat shortly after dosing. Drug removed by washing hair collected 1-3 weeks after the last dose was minimal for cocaine but variable for codeine. Drug in these specimens was likely transferred from blood to germinative hair cells followed by emergence of drug in growing hair. These findings suggest that drug deposition in hair occurs by multiple mechanisms.

Cocaine↗

PubMed1997

Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators.

The O-demethylation of codeine is polymorphic and catalyzed by CYP2D6. The metabolites of codeine formed through O- and N-demethylation as well as glucuronidation were quantified in the ultrarapid metabolizers of debrisoquine and compared with the normal extensive (EM) and poor metabolizers (PM). The urinary codeine and its seven metabolites were detected after 25 mg codeine in 24 healthy Caucasian subjects with low debrisoquine metabolic ratios (MR, < or = 0.11) and a group of 132 subjects tested earlier with codeine and debrisoquine including 114 EMs (MR < 12.6) and 18 PMs (MR > 12.6). Whereas the O-demethylated metabolites accounted for < 0.4% of the total recovery on average in the PMs and 1.7% to 8.7% in the EMs, they accounted for 15.3% in the 24 subjects with ultrarapid metabolism of debrisoquine. This study suggests that the ultrarapid debrisoquine hydroxylators may develop increased O-demethylated metabolite-dependent effects or side-effects of codeine.

Adolescent↗

PubMed1996

A double-blind comparison of codeine and morphine for postoperative analgesia following intracranial surgery.

Codeine and morphine were compared in a double-blind study of postoperative analgesia in 40 patients after intracranial neurosurgery. Eighteen patients received codeine phosphate 60 mg and 18 morphine sulphate 10 mg, both by intramuscular injection; 4 patients (10%) required no analgesia. Both drugs provided analgesia within 20 min of injection but morphine was more effective than codeine beyond 60 min (p = 0.01). Fewer doses of morphine than codeine were required (p = 0.003). Nine patients requested one dose of morphine and 9 two doses. Seven patients required three doses of codeine and 1 patient required four doses. Neither drug caused respiratory depression, sedation, pupillary constriction or unwanted cardiovascular effects. We conclude that, in the doses used, morphine is a safe alternative to codeine for analgesia after neurosurgery and has a more persistent action.

Adult↗

PubMed1980

A sex difference in the effects of oral codeine and promethazine on the ventilatory response to carbon dioxide in human volunteers.

1 Interactions between codeine and promethazine have been studied in male and female volunteers, measuring ventilation, end tidal PCO2, ventilatory response to CO2, pulse and blood pressure. 2 The effects of codeine on the above measurements have been compared in subjects who habitually smoke cigarettes and non smoking subjects. 3 Codeine displaced the ventilatory response to CO2 to the right and increased end tidal PCO2 in female subjects but not in males. 4 Promethazine plus codeine displaced the ventilatory response to CO2 to the right in male subjects but tended to reduce the response to codeine in females. 5 The slope of the ventilatory response to CO2 was significantly steeper in smokers and codeine caused significant reductions in slope in these subjects.

Adult↗

PubMed1986

Effects of a mu-opioid receptor agonist (codeine phosphate) on visuo-motor coordination and dynamic visual acuity in man.

Effects of codeine (30, 60 and 90 mg) on visuo-motor coordination and dynamic visual acuity, together with critical flicker fusion, digit symbol substitution, complex reaction time and subjective assessments of mood, were studied from 0.75-2.0 h after ingestion by six healthy female adults. The study was double-blind and placebo controlled, and triprolidine (10 mg) was used as the active control. The effect on visuo-motor coordination was limited and was dose related and linear, and performance was altered on visuo-motor coordination with 60 and 90 mg codeine, and on dynamic visual acuity with 90 mg codeine (P less than 0.05). No other effect of codeine was detected. Modulated neuromuscular function is likely to be the common denominator of the changes in performance with codeine, though nausea, but not sedation, may be a contributory factor. It is possible that altered performance with codeine may involve interactions with different receptors than those which lead to sedation.

Adult↗

PubMed1991

Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.

1. The kinetics of codeine and seven of its metabolites codeine-6-glucuronide (C6G), norcodeine (NC), NC-glucuronide (NCG), morphine (M), M-3 (M3G) and 6-glucuronides (M6G), and normorphine (NM) were investigated after a single oral dose of 50 mg codeine phosphate in 14 healthy Caucasian subjects including eight extensive (EM) and six poor (PM) hydroxylators of debrisoquine. The plasma and urine concentrations of codeine and the metabolites were measured by h.p.l.c. 2. The mean area under the curve (AUC), half-life and total plasma clearance of codeine were 1020 +/- 340 nmol l-1 h, 2.58 +/- 0.57 h and 2.02 +/- 0.73 l h-1 kg-1, respectively. There were no significant differences between EM and PM in these aspects. 3. PM had significantly lower AUC of M3G, the active metabolites M6G, NM and M (P less than 0.0001), and lower partial metabolic clearance by O-demethylation (P less than 0.0001). In contrast, the PM had higher AUC of NC (P less than 0.05) than the EM. There was no difference between PM and EM in the AUC of C6G and NCG, nor in the partial clearances by N-demethylation and glucuronidation. 4. Among EM, the AUC of C6G was 15 times higher than that of codeine, which in turn was 50 times higher than that of M. The AUCs of M6G and NM were about 6 and 10 times higher than that of M, respectively. The partial clearance by glucuronidation was about 8 and 12 times higher than those by N- and O-demethylations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1995

A randomized cross-over study of the efficacy of codeine phosphate versus Ispaghulahusk in patients with gynaecological cancer experiencing diarrhoea during pelvic radiotherapy.

Diarrhoea is the commonest acute complication during radiotherapy treatment to the pelvis. Codeine phosphate and a low residue diet is the standard therapy for radiation-induced diarrhoea at The Royal Marsden NHS Trust. The hypothesis put forward was that Ispaghulahusk and codeine phosphate were equally effective in the treatment of diarrhoea during radiotherapy. Participants in the study were female patients who had experienced change of bowel habit whilst receiving radiotherapy for their gynaecological cancer. Quantitative data was collected from patient diaries and treatment flow-sheets. Ten patients were randomized into the trial, five to codeine phosphate, and five to Ispaghulahusk. Continuing the trial was questioned after 10 patients had been treated. All five patients in the codeine phosphate arm received adequate control, while the five patients allocated to the Ispaghulahusk arm were all crossed-over to codeine phosphate with resolution of their diarrhoea. The results show that Ispaghulahusk, whilst not totally ineffective at controlling diarrhoea, was significantly less effective than codeine phosphate. Our conclusion is that there is insufficient reason to change to a less effective and less palatable preparation for the control of radiation-induced diarrhoea.

Codeine↗

PubMed1992

Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection.

Codeine is often used as a standard antitussive against which new antitussives are compared. However there is little information available about the effects of codeine on cough associated with upper respiratory tract infection. The present study investigated the effects of codeine syrup B.P. (30 mg/10 ml, q.d.s.) or syrup vehicle on cough frequency and the subjective severity of cough during a 3-h laboratory phase and a 4-day home phase of treatment. Cough frequency and subjective scores of cough severity were significantly decreased during the 3-h laboratory phase but at no time point was there a significant difference between the codeine- and placebo-treated groups. The results of the 4-day home phase diary were similar to those of the laboratory phase as at no time point was there a significant difference between the mean scores for the codeine- and placebo-treated groups. The results indicate that codeine, either as a single 30-mg dose or in a total daily dose of 120 mg, is no more effective than the syrup vehicle in controlling cough associated with acute upper respiratory tract infection.

Acute Disease↗

PubMed1990

Glucuronidation of codeine and morphine in human liver and kidney microsomes: effect of inhibitors.

Glucuronidation of codeine was detected and compared with that of morphine in microsomes from human livers and kidneys. Vmax values for codeine-6-glucuronide (C6G) were 0.54 +/- 0.24 and 0.74 +/- 0.35 nmol/mg/min. in the livers and 0.10 and 0.13 nmol/mg/min. in the kidney, respectively, when codeine and UDP-glucuronic acid (UDPGA) were incubated with microsomal preparation. The corresponding Km values were 2.21 +/- 0.68 and 1.41 +/- 0.36 mM in the livers and 6.69 and 4.12 mM in the kidney. The average codeine glucuronyltransferase (GT) activity was 14-fold lower in the six kidneys than in the 11 livers. Higher GT activities were observed in liver microsomes from patients who had been exposed to enzyme inducers. Rates of glucuronide formation from morphine correlated significantly with those from codeine in both human liver and kidney microsomes. Morphine, amitriptyline, diazepam, probenecid and chloramphenicol inhibited codeine glucuronidation with Ki values of 3.6, 0.13, 0.18, 1.7 and 0.27 mM, respectively.

Adult↗

PubMed1990

Codeine in analgesic doses does not depress respiration in patients with severe chronic obstructive lung disease.

Nineteen normocapnic patients with chronic obstructive lung disease participated in an open single dose safety study (part one) followed by a randomized double-blind cross-over study comparing two seven-days treatment periods of 1 g of paracetamol t.i.d. with 60 mg of codeine plus 1 g of paracetamol t.i.d., respectively (part two). In part one, continuous monitoring after a single dose of 2 g of paracetamol and 120 mg of codeine revealed no deterioration in the respiration and gas tensions. In part two, respiratory parameters and arterial gas tensions were recorded one hour after the last morning dose. PaCO2 increased insignificantly (0.05 less than P less than 0.10) by a median of 0.38 kPa during treatment with codeine and paracetamol compared to treatment with paracetamol alone. PaO2 decreased by 0.12 kPa (P greater than 0.10). There was no correlation between changes in PaCO2 and changes in PaO2. FVC, FEV1 and dyspnoea at rest were unchanged. Gastrointestinal side effects were reported significantly (P less than 0.02) more often during treatment with codeine plus paracetamol. There was no correlation between the plasma concentration of codeine or morphine and changes in respiratory parameters or adverse effects. The limitation for the short time clinical use of codeine as an analgesic to normocapnic patients with severe chronic obstructive lung disease in stable phase seem to be gastrointestinal side effects.

Acetaminophen↗

PubMed1990

Effect of codeine on the sensations elicited by loaded breathing.

The present study examined the effect of codeine, a centrally acting opiate, on the respiratory sensations elicited in normal subjects by breathing to exhaustion against externally applied inspiratory threshold loads. Subjects were tested on two separate days following the double-blind, randomized administration of either placebo or codeine (90 mg). The intensity of the sensations of effort and discomfort experienced during two loaded breathing trials (a "high" load that was 73% of the maximum inspiratory pressure (MIP) and a "low" load that was 63% of the MIP) was evaluated using category (Borg) scores on each day of study. To verify that the dosage of codeine administered was sufficient to produce analgesia, we also determined the effect of this dosage on the time that subjects could tolerate immersion of one hand in ice water. Codeine altered neither the perceived effort nor the sense of discomfort associated with breathing against external loads and had no appreciable effect on the time to exhaustion during loaded breathing trials. This dose of codeine did, however, increase the time that ice water immersion could be tolerated and reduced the rate at which the sense of discomfort increased over time during ice water trials. These results indicate that, provided the pressure-time index of respiratory muscle contraction remains constant, analgesic doses of codeine alter neither the sensations elicited by loaded breathing nor the total time that breathing against a fatiguing inspiratory load can be tolerated.

Adult↗

PubMed1982

Studies of the mechanism of the antidiarrheal effect of codeine.

To determine whether the antidiarrheal action of opiate drugs in humans is due to enhanced intestinal absorption rates, as suggested by recent experiments in animals, or is due to altered intestinal motility, as traditionally thought, we studied the effect of therapeutic doses of codeine on experimental diarrhea and on the rate of intestinal absorption of water and electrolytes in normal human subjects. Our results show that codeine (30-60 mg i.m.) markedly reduced stool volume during experimental diarrhea induced by rapid intragastric infusion of a balanced electrolyte solution. There was, however, no evidence that codeine stimulated the rate of intestinal absorption in the gut as a whole or in any segment of the gastrointestinal tract, either in the basal state or when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. We also measured segmental transit times to determine whether and where codeine delayed the passage of fluid through the intestine. Codeine caused a marked slowing of fluid movement through the jejunum, but had no effect on the movement of fluid through the ileum or colon. In other studies, we found that the opiate antagonist naloxone did not significantly affect water or electrolyte absorption rates in the jejunum or ileum. We conclude (a) that therapeutic doses of codeine increase net intestinal absorption (and thereby reduce stool volume) by increasing the contact time of luminal fluid with mucosal cells, not by increasing the rate of absorption by the mucosal cells; and (b) that endogenous opiates do not regulate intestinal absorption in humans.

Adult↗

PubMed1993

Codeine and the breastfed neonate.

Codeine is an analgesic commonly used to relieve pain in the early post partum. Its metabolite, morphine, is probably responsible for its effectiveness in this use. However, morphine may also cause neonatal apnea. We studied free codeine and morphine levels in breastmilk of 17 samples from seven mothers and neonatal plasma of 24 samples from 11 healthy, term neonates. Levels were determined by radioimmunoassay. Milk codeine levels ranged from 33.8 to 314 ng/ml 20 to 240 minutes after codeine; morphine levels ranged from 1.9 to 20.5 ng/ml. Infant plasma samples one to four hours after feeding had codeine levels ranging from < 0.8 to 4.5 ng/ml; morphine ranged from < 0.5 to 2.2 ng/ml. Low infant plasma levels are secondary to low excretion into milk and the small amounts of milk available in the first few days. Moderate codeine use during this time (< or = four 60 mg doses) is probably safe.

Breast Feeding↗

PubMed1999

Codeine concentration in hair after oral administration is dependent on melanin content.

BACKGROUND: Analysis of drugs in hair has been used on a qualitative basis to estimate earlier exposure to drugs. Clinical applications are rare because of the lack of dose-response relationships in the studies performed to date, and questions remain regarding the mechanisms of drug incorporation into hair. Several human studies have shown differences in drug accumulation between pigmented and nonpigmented hair. However, the melanin concentration in hair was not determined and correlated to the amount of drug incorporated. METHODS: Nine human subjects were given codeine as a single oral dose, and plasma codeine concentrations were determined for 24 h, using gas chromatography-mass spectrometry. Hair samples were obtained weekly for a month. Total melanin, eumelanin, and codeine were measured quantitatively in hair samples by spectrophotometry, HPLC, and gas chromatography-mass spectrometry, respectively. RESULTS: There was an exponential relationship between codeine and melanin concentrations in hair, (r(2) = 0.95 with total melanin and r(2) = 0.83 with eumelanin). After normalizing the results by the area under the curve for codeine in plasma, we obtained r(2) = 0.86 for codeine vs total melanin and r(2) = 0.90 vs eumelanin. CONCLUSIONS: Our results stress the importance of melanin determination when measuring drugs in hair. We postulate that analysis of drug concentration in hair may be worthwhile in the monitoring of drug compliance if the results are normalized for melanin content.

Chromatography, High Pressure Liquid↗