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PubMed1997

Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype.

BACKGROUND: Codeine is widely used as an analgesic and antitussive drug. The analgesic effect of codeine is mediated by its metabolite morphine, which is formed by the polymorphically expressed enzyme CYP2D6; therefore poor metabolizers have no analgesia after administration of codeine. Like other opiates, codeine causes a delay of gastric emptying and spastic constipation. It is not yet known whether the effect on gastrointestinal motility is mediated by codeine or its metabolite morphine. METHODS: To test the hypothesis that the metabolite morphine is responsible for the effects of codeine on gastrointestinal motility, a randomized, double-blind, two-way crossover study was performed. The orocecal transit time was studied in five extensive and five poor metabolizers of sparteine with the sulfasalazine-sulfapyridine method, assuming that no effects are observed in poor metabolizers because negligible amounts of morphine are formed. RESULTS: No differences of orocecal transit times were observed between extensive metabolizers and poor metabolizers after oral placebo administration. However, after oral codeine administration orocecal transit time was significantly prolonged in extensive metabolizer but not poor metabolizer subjects. All pharmacokinetic parameters of codeine showed no differences between extensive metabolizers and poor metabolizers. The pharmacokinetic parameters (mean +/- SD) of the metabolite morphine were significantly different between extensive metabolizer and poor metabolizer subjects (peak serum concentration, 13.9 +/- 10.5 versus 0.68 +/- 0.15 pmol/ml; area under the serum concentration-time curve, 27.8 +/- 16.0 versus 1.9 +/- 0.7 hr.pmol/ml; total amount of morphine excreted in urine, 0.160 +/- 0.036 versus 0.015 +/- 0.007 mumol). CONCLUSIONS: Because the orocecal transit time prolongation after codeine administration was observed only in extensive metabolizers, the effect of codeine on gastrointestinal motility, like the analgesia, is mediated by its metabolite morphine.

Analgesics, Opioid↗
PubMedDate not supplied

Urine and plasma pharmacokinetics of codeine in healthy volunteers: implications for drugs-of-abuse testing.

Thirteen healthy volunteers participating in an open and randomized study received two single doses (25 and 50 mg) of codeine orally two weeks apart. Urine concentrations of opiates were studied for 96 h, and plasma concentrations of codeine and the metabolites codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were monitored for 24 h. Plasma was analyzed by high-performance liquid chromatography. Measurements of urine were made with the EMIT opiate-screening assay and with gas chromatography-mass spectrometry for total (conjugates liberated by acid hydrolysis) codeine, morphine, and norcodeine. In urine, the ratio between total recovered morphine and codeine as expressed in percent ranged from 2.3 to 23.3% with a mean value of 9.8%. This ratio increased with time, and, in all but three subjects, rose to greater than 1 after 22-36 h. In 58% of cases, this occurred within the detection time in the EMIT assay. The detection time in the EMIT screening assay was found to be 20-39 h after the 25-mg dose and 30-52 h after the 50-mg dose. Elimination rates calculated from urine data corrected for creatinine concentration showed that morphine was eliminated more slowly than codeine. In plasma, the highest concentrations and area-under-curve values were observed for C6G, followed by codeine and M3G. All compounds had peak plasma values 1-2 h after dosing. The elimination of M3G was slower than that of C6G. We concluded that the relative proportion of codeine and morphine varies both between individuals and as a function of time and that morphine may be present in concentrations above those of codeine even after moderate and single doses of codeine. This must be taken into consideration when interpreting the presence of opiates during drugs-of-abuse testing.

Administration, Oral↗
PubMed2000

Inhibition of cytochrome P450 2D6 modifies codeine abuse liability.

Oral codeine preparations, widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymatic O-demethylation of codeine is catalyzed by cytochrome P450 2D6 (CYP2D6), leading to the production of metabolites (morphine, morphine-6-glucuronide) that are pharmacologically more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine associated with abuse liability and to determine the importance of metabolic O-demethylation to codeine abuse liability. Twelve non-drug-dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose (FD) was determined for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly decreased the recovery of O-demethylated metabolites in plasma (p < 0.01) and resulted in a decrease in the positive (e.g., "high," p < 0.05) and negative (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation more than did single-dose quinidine pretreatment (p < 0.01), and it decreased positive codeine effects in the FD120 group (N = 7), but unexpectedly not in the FD180 group (N = 5). These results suggest that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.

Adult↗
PubMed1984

Metabolism of 14C-codeine in the isolated, perfused rat liver.

The metabolism of 14C-codeine in the isolated rat liver was studied in single-pass and recirculation perfusion experiments. The perfusate, a semi-synthetic medium with bovine erythrocytes, was delivered at a constant rate (12 ml/min.) and contained codeine in the range of 3-57 nmol/ml. Samples of perfusate were collected and analyzed for codeine and its metabolites after extraction and thin-layer chromatographic separation. In single-pass perfusion, steady state was reached within 20 min. The codeine concentration in the effluent perfusate varied from 17 to 48% of that in the affluent corresponding to extraction ratios of 0.83 to 0.52. There was a significant negative correlation between codeine dose and extraction ratio (r = 0.86, P less than 0.05, N = 6). The steady state concentration of free and conjugated morphine made a total of 21 to 49% of the molar concentration of codeine at the inflow side. The recovery of radioactivity at the end of the perfusions was on an average 89%. In recirculation perfusion experiments the codeine extraction ratios varied from 0.65 to 0.35. The amount of free morphine in the reservoir increased to a maximum within 25-45 min. Our results suggest a relatively high hepatic first-pass metabolism of codeine in the rat which is apparently dose-dependent. The quantitatively most significant metabolites of codeine are morphine and conjugated morphine. The rate and extent of morphine formation is compatible with the hypothesis that metabolically produced morphine may be responsible for the analgesic effect of codeine.

Animals↗
PubMed2006

Opioid disposition in human sweat after controlled oral codeine administration.

BACKGROUND: Characterization of opioid excretion in sweat is important for accurate interpretation of sweat tests in drug treatment, criminal justice, and workplace drug testing programs. METHODS: Participants (n=20) received placebo, 3 low (60 mg/70 kg) or 3 high (120 mg/70 kg) codeine sulfate doses (used as a model for opioid excretion) within 1 week. Codeine and metabolites in sweat were collected with PharmChek Sweat Patches; hourly patches were applied for 1 to 15 h (n=775) and weekly patches for 7 days (n=118). Patches were analyzed by solid-phase extraction and gas chromatography-mass spectrometry for codeine, norcodeine, morphine, normorphine, and 6-acetylmorphine. Limits of quantification were 2.5 ng/patch (codeine and morphine) and 5 ng/patch (other analytes). RESULTS: Codeine was the only analyte identified in 12.6% of hourly patches and 83.3% of weekly sweat patches worn during dosing. Weekly patch concentrations (SD) were 38.6 (59.9) ng/patch [median (range), 15.9 (0-225.1) ng/patch] for low and 34.1 (32.7) ng/patch [24.0 (0-96.2) ng/patch] for high codeine doses. Codeine detected 1 week after dosing was 4.6 (5.3) ng/patch [median (range), 4.0 (0-17.1) ng/patch; n=11] after low and 7.7 (7.1) ng/patch [6.9 (0-20.5) ng/patch; n=10] after high doses. In total, 2.6% of hourly, 38.5% of low-dose, and 45.5% of high-dose weekly patches contained codeine at the proposed Substance Abuse and Mental Health Services Administration cutoff. CONCLUSIONS: Codeine was the only analyte detected, at highly variable concentrations, up to 2 weeks after dosing. These results are consistent, considering the complex processes of codeine deposition in sweat. Sweat testing is a useful alternative technique for qualitative monitoring of opioid use.

Administration, Oral↗
PubMed1977

Actions and metabolism of codeine (methylmorphine) administration by continuous intravenous infusion to humans.

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.

Adult↗
PubMed1999

A practical approach to determine cutoff concentrations for opiate testing with simultaneous detection of codeine, morphine, and 6-acetylmorphine in urine.

BACKGROUND: Both the Department of Defense (DoD) and the Department of Health and Human Services (DHHS) currently require two confirmation tests to verify use of heroin, one test for total morphine and a separate test for 6-acetylmorphine (6-AM). Our aim was to determine appropriate free-codeine, free-morphine, and 6-AM cutoff concentrations that could be substituted for total-morphine, total-codeine, and 6-AM cutoff concentrations and to develop a less labor-intensive method for measuring codeine, morphine, and 6-AM. METHODS: Urine samples containing opiates were extracted, derivatized, and analyzed using gas chromatography-mass spectrometry with selective ion monitoring. RESULTS: The limits of detection for codeine, morphine, and 6-AM were 6, 5, and 0.5 microg/L, respectively. Recoveries were >90%. Quantification was linear over the concentration range of 6-1000 microg/L for codeine, 5-5000 microg/L for morphine, and 0.5-800 microg/L for 6-AM. Cutoff concentrations for confirmation of opiates were 100, 100, and 10 microg/L for free codeine, free morphine, and 6-AM. CONCLUSION: The proposed cutoff concentrations for free morphine and 6-AM provide better detection windows for morphine and heroin use than the cutoff concentrations for total morphine and 6-AM used at present. Detection of free codeine, instead of total codeine, simplifies interpretation of codeine use. The single-extraction method enables simultaneous, less labor-intensive analysis of morphine, codeine, and 6-AM.

Codeine↗
PubMed2002

Plasma and oral fluid pharmacokinetics and pharmacodynamics after oral codeine administration.

BACKGROUND: The ease, noninvasiveness, and safety of oral fluid collection have increased the use of this alternative matrix for drugs-of-abuse testing; however, few controlled drug administration data are available to aid in the interpretation of oral fluid results. METHODS: Single oral codeine doses (60 and 120 mg/70 kg) were administered to 19 volunteers. Oral fluid and plasma were analyzed for free codeine, norcodeine, morphine, and normorphine by solid-phase extraction combined with gas chromatography-mass spectrometry (SPE/GC-MS). Physiologic and subjective effects were examined. RESULTS: Mean (SE) peak codeine concentrations were 214.2 +/- 27.6 and 474.3 +/- 77.0 micro g/L in plasma and 638.4 +/- 64.4 and 1599.3 +/- 241.0 micro g/L in oral fluid. The oral fluid-to-plasma ratio for codeine was relatively constant ( approximately 4) from 1 to 12 h. The mean half-life (t(1/2)) of codeine was 2.2 +/- 0.10 h in plasma and 2.2 +/- 0.16 h in oral fluid. Significant dose-related miosis and increases in sedation, psychotomimetic effect, and "high" occurred after the high dose. Mean codeine oral fluid detection time was 21 h with a 2.5 microg/L cutoff, longer than that of plasma (12-16 h). Detection times with the proposed Substance Abuse and Mental Health Services Administration cutoff (40 microg/L) were only 7 h. Norcodeine, but not morphine or normorphine, was quantified in both plasma and oral fluid. CONCLUSIONS: The disposition of codeine over time was similar in plasma and oral fluid, but because of high variability, oral fluid codeine concentrations did not reliably predict concurrent plasma concentrations. Oral fluid testing is a useful alternative matrix for monitoring codeine exposure with a detection window of 7-21 h for single doses, depending on cutoff concentrations. These controlled drug administration data should aid in the interpretation of oral fluid codeine results.

Administration, Oral↗
PubMed1994

Pharmacokinetic evaluation of two ibuprofen-codeine combinations.

The pharmacokinetics of ibuprofen and codeine were compared when given alone or in combination. Six treatments (ibuprofen 400 mg, codeine 60 mg, ibuprofen 400 mg and codeine 30 mg in two separate tablets, ibuprofen 400 mg and codeine 30 mg in one combination tablet, ibuprofen 400 mg and codeine 60 mg in two separate tablets, and ibuprofen 400 mg and codeine 60 mg in one combination tablet) were evaluated. Twenty-four healthy subjects were enrolled in the randomized block design study. Ibuprofen and codeine plasma concentrations were measured by reversed-phase liquid chromatography with UV and fluorescence detection. Pharmacokinetic parameters were estimated by non-compartmental data analysis techniques. Ibuprofen and codeine pharmacokinetic parameters obtained in this study were in agreement with previously published values. In addition, no pharmacokinetic interaction could be detected between codeine and ibuprofen when given alone or in combination. Furthermore, the similar half-life of both drugs (2-2.5 h) is advantageous for a fixed drug combination. The results suggest that ibuprofen and codeine can be given safely in a single oral dosage form.

Administration, Oral↗
PubMedDate not supplied

Codeine toxicokinetics in rats during a two-year dosed feed study.

Codeine toxicokinetics in F344 rats of both sexes were determined during a 2-year chronic toxicology study using dosed feed as the exposure route with a 12-hr light/dark cycle starting at 7:00 a.m. Rats were allowed to access to dosed feed formulations ad libitum with codeine concentrations at 0, 400, 800, and 1600 ppm. Blood samples were collected from individual rat on days 7, 21, and 90 at 7:00 p.m., 11:00 p.m., 3:00 a.m., and 7:00 a.m. Additional samples were collected at 16 and 24 months between 6:00-8:00 a.m. Plasma concentrations of codeine and morphine were determined directly by radioimmunoassay. Concentrations of their conjugates were determined indirectly by measuring the total amount of free codeine and morphine released after samples were treated with beta-glucuronidase. Results indicated that plasma concentrations of both codeine and morphine steadily decreased from day 7 to 16 months and then rebounded at 24 months. Results also indicated that plasma concentrations of both codeine and morphine correlated well with the amounts of codeine added to the feed. Bioavailability of codeine using the dosed feed route increased with dose, varying from 10% to 25%, which was somewhat higher than the previously reported approximately 8% bioavailability using the gavage route. Concentrations of conjugated codeine were very low, whereas concentrations of conjugated morphine were very high. These results suggested that demethylation of codeine to morphine in rats is the main metabolic pathway and was maintained over the course of the study.

Animals↗
PubMed2000

Single dose paracetamol (acetaminophen), with and without codeine, for postoperative pain.

BACKGROUND: Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Paracetamol (acetaminophen) is an important non-opiate analgesic, commonly prescribed, as well as being available for retail sale. This review seeks to examine the efficacy of paracetamol alone and in combination with codeine, and also considers adverse effects. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single dose of oral paracetamol (acetaminophen) alone and in combination with codeine for moderate to severe postoperative pain. SEARCH STRATEGY: Published trials were identified from: Medline (1966 to May 1996), Embase (1980 to 1996), Cochrane Library (Issue 2 1996) and the Oxford Pain Relief Database (1950 to 1994). Additional trials were identified from reference lists of retrieved studies. Date of most recent searches: July 1998. SELECTION CRITERIA: Inclusion criteria were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared paracetamol with placebo or a combination of paracetamol and codeine with either placebo or the same dose of paracetamol alone. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief over 4 to 6 hours compared with placebo. Adverse effects were used to calculate relative risk and number-needed-to-harm (NNH). MAIN RESULTS: We found 40 trials of paracetamol against placebo (4171 patients), 22 trials of paracetamol plus codeine against placebo (1407 patients) and 12 trials of paracetamol plus codeine against the same dose of paracetamol (794 patients). In postoperative pain paracetamol 1000 mg had an NNT of 4.6 (3.8-5.4) for at least 50% pain relief when compared with placebo, and paracetamol 600/650 mg had an NNT of 5.3 (4.1-7.2). Paracetamol 600/650 mg plus codeine 60 mg had an NNT of 3. 6 (2.9-4.5). Comparing paracetamol plus codeine 60 mg with the same dose of paracetamol alone gave an NNT of 7.7 (5.1-17) for at least 50% pain relief. Adverse effects: Relative risk estimates for paracetamol 600/650 mg plus codeine 60 mg versus placebo showed a significant difference for 'drowsiness'/somnolence (NNH 11 (7.5- 0)) and dizziness (NNH 27 (15-164)) but no significant difference for nausea/vomiting. REVIEWER'S CONCLUSIONS: Paracetamol is an effective analgesic with a low incidence of adverse effects. The addition of codeine 60 mg to paracetamol produces additional pain relief even in single oral doses, but may be accompanied by an increase in drowsiness and dizziness.

Acetaminophen↗
PubMed1977

Codeine kinetics as determined by radioimmunoassay.

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%).

Administration, Oral↗
PubMedDate not supplied

Analgesic efficacy of an ibuprofen-codeine combination.

Subjects who had undergone dental impaction surgery and who had moderate to severe postoperative pain were given, under double-blind, randomized conditions, a single dose of either codeine 60 mg, aspirin 650 mg, ibuprofen 400 mg, aspirin 650 mg + codeine 60 mg, ibuprofen 400 mg + codeine 60 mg, or placebo. A total of 249 subjects were included in the statistical analysis. On a report form, subjects recorded pain intensity, pain relief, and side effects hourly for four hours. They also gave an overall impression at the end of the observation period. Analysis of variance and pairwise contrasts were used to analyze the data. For the sum of pain intensity differences, the total of the hourly pain relief scores, and overall impression, there was a significant analgesic effect for codeine, aspirin, and ibuprofen and no significant interaction when they were used in combination. Ibuprofen alone was statistically superior to aspirin and also achieved higher mean scores than the aspirin-codeine combination. The ibuprofen-codeine combination was the most effective treatment for every analgesic parameter, but it was not statistically superior to ibuprofen alone. The possibility exists that the ibuprofen-codeine combination peaked out the sensitivity of the model. There was no notable difference in the frequency or intensity of side effects among the treatment groups, and no subject had to withdraw due to an adverse effect. This study again confirms the superiority of ibuprofen to aspirin and suggests that ibuprofen is at least as effective as an aspirin-codeine combination. Codeine added a small amount of additional analgesia when used in combination with ibuprofen.

Adolescent↗
PubMed1993

Increased erythrocyte and protein binding of codeine in patients with sickle cell disease.

Erythrocyte binding and plasma protein binding of codeine in sickle cell patients and healthy controls were determined. A reversed-phase HPLC procedure was used for codeine analysis. Codeine was extracted from alkalinized plasma, separated on a CN column, and assayed by fluorescence detection. The erythrocyte-buffer partition coefficient was significantly higher in sickle cell patients (1.72 +/- 0.21) than in healthy controls (1.25 +/- 0.14). No time dependence of partitioning was observed. The fraction of codeine bound to plasma proteins, determined by ultrafiltration, was significantly higher in sickle cell patients (66.0% +/- 8.6%) than in healthy controls (30.5% +/- 2.7%). No concentration dependence of erythrocyte or protein binding was observed. Further studies were performed to elucidate the binding mechanisms. From a ghost cell binding study it was concluded that the major binding sites for codeine are in the cell membrane. A decrease in codeine binding was observed in the presence of bilirubin. Codeine binding to alpha 1-acid glycoprotein was found to be minimal. The levels of alpha 1-acid glycoprotein and other glycoproteins in sickle cell patients and healthy controls were measured by glycoprotein electrophoresis. The results showed no significant difference between the two groups. Plasma protein electrophoresis was performed for the two groups. The results showed a significant difference in gamma-globulin levels between sickle cell patients and healthy controls. Codeine is known to bind to gamma-globulin, a fact that may explain in part the observed increase in the plasma protein binding of codeine in sickle cell patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Sickle Cell↗
PubMedDate not supplied

Codeine, cough and upper respiratory infection.

Codeine is generally accepted as a standard or reference antitussive against which new antitussive medications can be compared. However there are very few studies which have investigated the antitussive efficacy of codeine using cough associated with upper respiratory tract infection (URTI) and there is little if any evidence to support the antitussive efficacy of codeine in this model. This paper discusses the mechanism of cough in man and describes some clinical investigations on the effects of codeine on cough associated with URTI. The recent clinical investigations do not provide any evidence to support an antitussive action of codeine in the treatment of cough associated with URTI yet there is evidence in the literature which indicates that codeine inhibits fictive cough in animal models and also has antitussive activity against both induced and chronic cough models in man. In order to explain these different effects of codeine on the different models of cough, a hypothesis is put forward that there are two cough pathways in man. A voluntary pathway associated with cough related to URTI which is not affected by codeine, and a reflex pathway associated with induced and chronic cough which is inhibited by codeine.

Acute Disease↗
PubMed1980

Behavior maintained by intravenous injection of codeine, cocaine, and etorphine in the rhesus macaque and the pigtail macaque.

Lever-pressing behavior of two species of macaque, the rhesus macaque (M. mulatta) and the pigtail macaque (M. nemestrina) was maintained by intravenous injection of codeine, etorphine, or cocaine. Monkeys responded under a fixed-ratio 30 timeout 600 s schedule of drug injection during two daily experimental sessions. Drug-maintained behavior was studied under two access conditions. Under the first condition, selected doses of codeine or cocaine were available for ten consecutive sessions. Under the second condition, responding was maintained by 0.32 mg/kg codeine or 0.32 mg/kg cocaine, and saline and selected doses of codeine, etorphine, and cocaine were substituted during single experimental sessions. Performance varied with drug and injection dose, access condition, and macaque species. For all three drugs, response rate increased and then decreased as injection dose increased. Maximal rates were maintained by 0.10-0.32 mg/kg codeine, 0.0003-0.001 mg/kg etorphine, and 0.10-0.32 mg/kg cocaine. A cocaine dose of 0.32 mg/kg maintained higher rates than any dose of codeine or etorphine, and maintained higher rates when available during consecutive sessions than when substituted for codeine for a single session. Codeine maintained similar rates under all access conditions. The pigtail macaques had short catheter lives, did not readily acquire codeine-maintained responding, and displayed lower rates of drug-maintained lever pressing than the rhesus macaques.

Animals↗
PubMed1998

Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers.

The subjective, psychomotor, and physiological effects of analgesic doses of oral codeine and morphine were examined in 12 healthy volunteers. Subjects ingested placebo, morphine 20 or 40 mg, or codeine 60 or 120 mg in a randomized, double-blind, crossover design. The smaller and larger doses of each drug were putatively equianalgesic, and the cold-pressor test was included to test this assumption. Codeine and morphine increased ratings of "feel drug effect" but had little effect on other subjective measures, including the Addiction Research Center Inventory, visual analog scales, and adjective checklists. The few subjective effects that were observed were modest and were dose-related for morphine but not for codeine. The drugs did not affect performance on Maddox-Wing, digit-symbol substitution, coordination, auditory reaction, reasoning, and memory tests. Dose-related decreases in pupil size (miosis) were observed following codeine and morphine. Ratings of pain intensity decreased in a dose-related manner for morphine but not for codeine. Plasma codeine and morphine levels varied as an orderly function of dose. These results suggest that oral codeine and morphine are appropriate drugs for outpatient pain relief because they are effective analgesics at doses that have only modest effects on mood, produce few side effects, and do not impair performance. The results also suggest a possible ceiling effect of codeine on analgesia and subjective effects.

Adult↗
PubMed1999

Utilisation of codeine and propoxyphene: geographic and demographic variations in prescribing, prescriber and recipient categories.

OBJECTIVES: To assess (1) whether the utilisation of codeine or propoxyphene differs among the three major Swedish cities (Stockholm, Göteborg and Malmö) and between urban and semirural areas; (2) if so, whether it co-varies with the utilisation of other potentially dependence-promoting drugs, benzodiazepines; (3) what influence age, gender and socioeconomic factors have on the prescribing of the two narcotic analgesics; and (4) whether different codeine-prescriber categories have different prescribing habits. METHODS: In Sweden, all pharmacies are owned by one corporation, Apoteket AB. This corporation collects, stores and compiles statistics on all drug sales in Sweden, and data are available both on national, regional, county and municipal levels. The employed unit is defined daily dose (DDD) per 1,000 inhabitants per day. Using the pharmacy computer system while dispensing a drug, prescription patterns can be elucidated. This system describes the number of drug items dispensed, drug amounts and age and gender of patients. Furthermore, data from another, ecological study were used to relate codeine and propoxyphene utilisation to that of benzodiazepines and to various socioeconomic data available from records of the city of Malmö. RESULTS: The utilisation of analgesics in Sweden has increased during a 10-year period. The withdrawal of over-the-counter combinations containing aspirin and low-dose codeine in 1990 resulted only in a transient decrease of codeine use. The utilisation of codeine in Malmö and Göteborg was considerably higher than that in Stockholm and in the rest of Sweden, including the surroundings of Malmö. In Malmö and Göteborg, codeine was most often prescribed by private physicians to middle-aged persons, particularly women. Districts in Malmö with a high utilisation of codeine were associated with unfavourable socioeconomic conditions and a high utilisation of benzodiazepines. The utilisation pattern of propoxyphene showed less or no such deviations. CONCLUSION: The results suggest an inappropriate use of codeine in two major cities in Sweden.

Adolescent↗