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PubMed1977

Self-administration of codeine plus acetylsalicylic acid in rhesus monkeys with unlimited access to the drugs.

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.

Animals↗

PubMed1987

Analgesic efficacy of two ibuprofen-codeine combinations for the treatment of postepisiotomy and postoperative pain.

Our purpose was to compare the analgesic efficacy and safety of single oral doses of the combination of ibuprofen 400 mg plus codeine 60 mg and the combination of ibuprofen 200 mg plus codeine 30 mg with ibuprofen 400 mg alone, codeine sulfate 60 mg alone, and placebo. One hundred ninety-five patients with severe pain resulting from episiotomy, cesarean section, or gynecologic surgery completed a randomized, double-blind, stratified, parallel-group study. Patients were observed during a 4-hour period after medication. Based on the sum of the pain intensity differences (SPID), total pain relief (TOTPAR), and most of the hourly direct measures of pain and relief, both doses of the combination and ibuprofen 400 mg alone were statistically superior to placebo. Codeine 60 mg was statistically superior to placebo based on TOTPAR, the global ratings, and a few hourly measures. The mean effect of the combination of ibuprofen 400 mg plus codeine 60 mg was significantly superior to the mean effect of ibuprofen 400 mg alone 1/2, 1, and 2 hours after medication and to the mean effect of ibuprofen 400 mg alone and codeine 60 mg alone for SPID, TOTPAR, and other measures as well. The low-dose combination was significantly more effective than codeine 60 mg for a few hourly measures but was not significantly superior to ibuprofen 400 mg. Based on these findings it appears that the combination of ibuprofen 400 mg plus codeine 60 mg, particularly in the first few hours after medication, is more efficacious than its constituents.

Adult↗

PubMed1986

Treatment of narcolepsy with codeine.

The effectiveness of codeine as a treatment for the excessive daytime sleepiness of narcolepsy was studied in two experimental trials. In an open trial of codeine in five narcoleptic subjects, dramatic clinical improvement was reported. However, all-night polysomnography and maintenance of wakefulness tests before and after codeine showed no significant differences. A double-blind placebo-codeine trial was conducted in which eight narcoleptic subjects received codeine for 1 week and placebo for 1 week in a random order. During the week they kept a diary, and on the sixth evening and for 10 h following awakening on the seventh day they were monitored by radiotelemetry in the sleep laboratory for electroencephalogram, electro-oculogram, and electromyogram. The results were analyzed for sleep stages as well as four levels of wakefulness. The results showed no significant differences in any of the objective sleep or wakefulness parameters. However, the diaries showed significantly fewer naps during the week on codeine as compared with the placebo week. Eighteen of 27 narcoleptic patients treated with codeine report clinical improvement. Codeine consistently results in subjective clinical improvement. However, this is not reflected in the objective measures generally used to assess daytime sleepiness.

Adult↗

PubMed1986

Comparative disposition of codeine and pholcodine in man after single oral doses.

Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/- 0.4 h (mean +/- s.d.)]. While codeine kinetics were adequately described by a one-compartment open model with first-order absorption, a two-compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/- 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration.

Administration, Oral↗

PubMed1989

Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation.

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.

Adolescent↗

PubMed1991

A comparison of the pharmacokinetics of codeine and its metabolites in healthy Chinese and Caucasian extensive hydroxylators 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.

Administration, Oral↗

PubMed1975

Further studies on self-administration of antipyretic analgesics and combination of antipyretic analgesics with codeine in rhesus monkeys.

The possible reinforcing effect of acetylsalicylic acid (ASA) was studied in a group of rhesus monkeys that had no history of self-administration of drugs. Rates of lever pressing were compared under conditions in which each lever-pressing response resulted in an infusion of saline, an infusion of saline plus delivery of a food pellet or an infusion of ASA (0.4, 1.0, 2.5 OR 5.0 MG/KG /infusion). Responding was engendered and maintained by the delivery of food pellets but not by infusions of saline alone nor by ASA; however, responding was subsequently engendered and maintained in these monkeys by codeine (0.05 mg/kg/infusion). In another group of monkeys that had been trained to respond under a 10-response fixed-ratio schedule of i.v. infusions of codeine, the possible reinforcing effects of aminophenazone, phenylbutazone and of combinations of each of these drugs with codeine were studied. Aminophenazone and phenylbutazone (0.4-5.0 mg/kg/infusion) did not maintain responding previously engendered by codeine. Mixtures of aminophenazone and phenylbutazone with codeine decreased the number of codeine self-administrations. Thus, codeine intake was reduced when aminophenazone and phenylbutazone were added to codeine in the solution to be self-administered. These experiments suggest that antipyretic analgesics are not effective in reinforcing behavior in the rhesus monkey.

Aminopyrine↗

PubMed1991

Effect of codeine on rat and guinea pig tracheal ciliary beat frequency.

Codeine, the basic antitussive drug, has generally been thought to impair mucociliary function. Using the photodetection method the effect of codeine on mucociliary function was studied in rat after local and systemic administration and in guinea pig after systemic administration. In vitro rat tracheal ciliary beat frequency (CBF) was measured up to 40 min. There was 24.6 +/- 2.5% and 26.6 +/- 1.6% decrease in CBF after 1 mg/ml and after 10 mg/ml codeine solutions, respectively. In vivo codeine was administered in single i.v. doses of 10 and 15 mg/kg. No statistically significant differences were found in CBF responses, although there was a CBF decreasing tendency after the 15 mg/kg dose. The total follow-up time was 120 min. In guinea pig, 10 days s.c. codeine administration in daily doses of 3, 10 and 30 mg/kg had no effect on CBF. Although codeine was used in much higher concentrations than tissues concentrations after therapeutic doses of codeine, the effects on CBF were minimal. So it can be concluded that the generally accepted ciliostatic effect of codeine is overestimated.

Animals↗

PubMed1987

Comparison of diflunisal and an aspirin-codeine combination in the management of patients having one-visit endodontic therapy.

One hundred seventy-nine patients with asymptomatic or mildly symptomatic endodontic disease had single-visit therapy and were given either diflunisal (n = 94) or aspirin with codeine (n = 85) to control posttreatment pain. In this open-label, randomized study, diflunisal was judged superior to the aspirin-codeine combination in all major categories evaluated. Of patients receiving diflunisal, 93.6% needed the medication for only one day. In contrast, 77.7% of patients receiving aspirin with codeine needed the medication for only one day. Almost 64% of patients receiving diflunisal needed only one dose, while 32.9% of patients using aspirin with codeine needed only one dose. Four or more doses were required by 5.3% of patients receiving diflunisal and by 23.5% of patients receiving the aspirin-codeine combination. In patients receiving diflunisal, 20.2% experienced side effects. In contrast, 29.4% of patients receiving aspirin with codeine reported side effects. Thirty-five percent of patients receiving diflunisal rated the analgesic as excellent; 5.3% rated it as fair or poor. In contrast, 12.9% of patients receiving aspirin with codeine rated the analgesic combination as excellent; another 12.9% rated it as fair or poor. Diflunisal was found to be generally effective and well-tolerated, and superior to aspirin with codeine in the management of pain from endodontic treatment.

Adolescent↗

PubMed1992

The postoperative pharmacokinetics of codeine.

The metabolism and systemic availability of codeine have been studied in 12 patients after cholecystectomy. They were given 20 mg codeine as an IV bolus dose on the first day after surgery and 50 mg codeine as a single oral on the fourth day after surgery. Codeine had a medium to high extraction ratio and a total plasma clearance of 10.8 (4.3) ml.min-1.kg-1. The clearance varied four-fold between subjects. All the patients were extensive metabolizers with regard to the debrisoquine/sparteine polymorphism, as tested using dextromethorphan as the probe drug. Nevertheless, the formation of morphine from codeine was very small and plasma morphine concentrations were below the detection limit of 3.3 nmol.l-1 (1 ng.ml-1). As a corollary, the morphine/codeine ratio in the the concentration-time curves was less than 3% in all the patients. The systemic availability of codeine varied extensively between subjects (range 12-84%). This might partly explain differences in the dose of codeine required as an analgesic.

Adult↗

PubMedDate not supplied

Interaction of ethanol with codeine metabolism in rat hepatocytes: a multicompartmental model.

A multicompartmental pharmacokinetic model is presented, which based upon data from a previous study, describes the effects of ethanol (60 mM) on the metabolism of codeine (10 microM) in isolated rat hepatocytes. According to this model, about one third of codeine metabolized was transformed to morphine (13%) and norcodeine (18%), and two-thirds to unknown metabolites in the absence of ethanol. In the presence of ethanol, the apparent first order fractional rate of total codeine metabolism was reduced by 66% (0.0783 vs 0.0271 min-1). There was no alteration in the portion of codeine metabolized to norcodeine, but there was a 44% decrease in the fraction transformed to unknown metabolites and a tripling in the portion transformed to morphine. The fractional rate of codeine O-demethylation to morphine was apparently not sensitive to ethanol. In the absence of ethanol, about two-thirds of morphine was metabolized to morphine-3-glucuronide and the other third to unidentified metabolites. Only the glucuronidation process seemed to be inhibited by ethanol. The fractional rate of further metabolism of norcodeine to normorphine was similar in the absence or presence of ethanol. In conclusion ethanol co-incubation with codeine resulted in an inhibition of codeine conversion to unknown metabolites and norcodeine, and with morphine to morphine-3-glucuronide, but no inhibition in morphine production.

Animals↗

PubMed1976

Radioimmunoassay for the simultaneous determination of morphine and codeine.

Antiserum against morphine was produced in rabbits immunized with morphine hapten conjugated to bovine serum albumin. The carrier protein was conjugated to the nitrogen atom of the opiate alkaloid in order to make the phenolic hydroxy group on C3 and the alcoholic group on C6 as determinant groups. The antibody does not recognize codeine or the major metabolite of morphine, 3-O-monoglucuronide. This antibody was used in conjunction with an antibody prepared against 3-O-carboxymethylmorphine to develop a radioimmunoassay which can measure codeine in the presence of morphine. The assay was used to follow both the plasma and brain levels of codeine and its biotransformation to morphine. Codeine when administered at a dose of 5 mg/kg i.v. showed a biphasic plasma decay curve the first phase of which had a +1/2 of 26 min. Peak concentrations of morphine were detected in the plasma following that dose of codeine at 0.5 h. 30 min after the injection of 20 mg/kg i.p. codeine, the brain levels of morphine were only 2% that of codeine. Thereafter, the brain levels of morphine slowly declined.

Animals↗

PubMed1988

Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease.

The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half-life and mean residence time were increased significantly in the hemodialysis group (18.69 +/- 9.03 hours and 12.77 +/- 7.09 hours, mean +/- SD, respectively) compared with the healthy volunteer group (4.04 +/- 0.60 hours and 3.90 +/- 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple-dose codeine therapy.

Adult↗

PubMed1992

Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.

1. Codeine was administered rectally to thirteen infants and young children undergoing elective surgery. Nine infants (6-10 months old) received a 4 mg suppository and four children (3-4 years old) an 8 mg suppository. Codeine and its metabolite morphine were measured in plasma by GC/MS. 2. The mean concentrations of codeine at 3, 4 and 5 h after administration were 240, 163 and 123 nmol l-1 in the younger and 309, 251 and 169 nmol l-1 in the older patients. The corresponding concentrations of morphine were 8.3, 7.4 and 4.5 nmol l-1 and 6.8, 5.5 and 2.8 nmol l-1 respectively. One patient in each age group had no detectable amounts of morphine. 3. In the four children, the rectal dose was repeated 6-hourly for four doses. The plasma concentrations of codeine and morphine following the fifth dose were similar to those after the first dose. The mean AUC(0,5 h) of morphine was 1.6% that of codeine. 4. In the infants the mean plasma half-lives of codeine and morphine were 2.6 and 2.5 h. The two infants with the lowest body weights had the longest half-lives. 5. The mean morphine/codeine concentration ratio was 4.3% in the infants and 1.6% in the children, suggesting impaired glucuronidation of morphine in the former group. The hourly concentration ratios were almost identical following the first and fifth dose in the children. 6. We conclude that at the age of 6 months infants are capable of O-demethylating codeine to morphine.

Biotransformation↗

PubMed1978

Effect of codeine phosphate, Lomotil, and Isogel on iileostomy function.

The effect on ileostomy function of codeine phosphate, Lomotil, or Isogel was tested in 20 subjects at home living a normal life, studied over two three-day periods on and off treatment. Codeine phosphate 60 mg three times daily was associated with a reduction in the mean total weight of ileostomy output and the ileostomy outputs of water, sodium, and potassium (p < 0.05). The proportion of faecal solids increased on codeine and the effluent appeared thicker but the output of faecal solids remained unchanged. Mean faecal fat increased on codeine. The transit rate from mouth to stoma was slower in four of the five subjects on codeine and a further two subjects withdrew from the trial with temporary intestinal obstruction while on the drug. Lomotil two tablets three times daily was associated with a small and statistically not quite significant fall in the mean total weight of ileostomy output and the ileostomy output of water. Sodium and potassium outputs in the effluent fell on Lomotil (p < 0.05) but the other parameters remained unchanged. Isogel 15 ml three times daily was associated with an increase in the mean total weight of ileostomy output and the ileostomy outputs of water, sodium, potassium, and faecal solids (p < 0.01). Although the effluent looked more viscid on Isogel, the proportion of faecal solids was unchanged. These results suggest that codeine phosphate has a beneficial effect on ileostomy function, reducing the loss of water and electrolytes, while Lomotil has a similar but less effective action in the dosage tested. By contrast, Isogel increases the ileostomy loss of water and electrolytes and will aggravate their depletion in patients with excessive fluid effluents. The increase in faecal fat associated with taking codeine phosphate suggests that it should be stopped before collecting specimens for faecal fat estimations.

Adolescent↗

PubMedDate not supplied

Comparison of the effects of acupuncture and codeine on postoperative dental pain.

The analgesic effects of acupuncture were compared with those of codeine in the treatment of postoperative dental pain in 40 healthy male volunteers 18 to 30 years old. Upon the patient's recovery from local anesthesia (lidocaine), he was asked by a trained observer to classify the intensity of his pain as none, mild, moderate, or severe. He then received one of the following treatments: 1. Placebo: lactose, plus acupuncture placebo 2. Codeine: codeine, plus acupuncture placebo 3. Acupuncture (Ho-Ku): lactose, plus 2 Ho-Ku points 4. Codeine-acupuncture: codeine, plus 2 Ho-Ku points. The pain intensity score was recorded by the observer at half-hour intervals for 3 hours. Patients in treatment groups 2, 3 and 4 showed significantly greater pain relief than those in treatment group 1. For the 1st half hour, there was more pain relief with Ho-Ku alone than with codeine plus Ho-Ko (p less than 0.01). However, for the 2, 2 1/2, and 3-hour periods, codeine plus Ho-Ku produced more pain relief than any of the other treatments.

Acupuncture Therapy↗

PubMed1990

Skin prick test responses to codeine, histamine, and ragweed utilizing the Multitest device.

Epicutaneous skin testing is a useful diagnostic tool in evaluating allergic disorders. Utilizing the Multitest device, skin prick test responses to codeine phosphate, histamine phosphate, and ragweed were examined in 56 human subjects. Relationships between the two positive controls, codeine and histamine, and their use as a reference denominator for ragweed reactions were assessed. Ragweed elicited detectable wheals in 15/56. Histamine phosphate (2.75 mg/mL) elicited a positive wheal response in 52/56 subjects, while codeine phosphate elicited a positive wheal in 39/56 and 30/56 subjects at 30 and 3 mg/mL, respectively. Wheal sizes for codeine phosphate at both 30 and 3 mg/mL showed significantly concordant relationships with histamine phosphate-induced wheal sizes (Spearman rho, P = .0084 and .0155, respectively); however the intersubject coefficient of variation was lower for histamine-induced wheal sizes (44%) than for codeine-induced wheal sizes (64% and 65%, respectively for 30 and 3 mg/mL). When a ratio of allergen to positive control reaction size was used to grade ragweed reactions, different patterns were observed using codeine compared with histamine. These results have implications in utilizing codeine phosphate as a positive skin prick test control for allergy testing.

Adolescent↗

PubMedDate not supplied

Determination of codeine and morphine in human plasma by high performance liquid chromatography with serial electrochemical detection.

A method is described for the determination of codeine and its metabolite, morphine, at low nanogram concentrations in plasma. Analysis is accomplished by high-performance liquid chromatography utilizing a cyanopropyl normal bonded phase (NBP) column in reversed-phase mode and two electrochemical detectors in series configuration. Two internal standards are utilized, ethyl morphine for codeine and nalorphine for morphine. Codeine and morphine concentration data are presented for several patients receiving codeine-containing medications. The lower limit of detectability was 2.00 +/- 0.39 ng per mL for codeine and 1.20 +/- 0.83 ng per mL for morphine. The patient sample mean within-run coefficients of variation for codeine and morphine (at 10 ng per mL) were less than 10 percent, n = 30. The between-run coefficient of variation for codeine was also less than 10 percent (over a range of two to 190 ng per mL, n = 61), and was approximately 15 percent for morphine (over a range of two to 40 ng per mL, n = 31).

Chromatography, High Pressure Liquid↗