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PubMed1991

Impact of environmental and genetic factors on codeine analgesia.

The polymorphic cytochrome P-450 DB1 (P-450 IID6) is responsible for the O-demethylation of codeine to morphine by human liver microsomes. The influence of P-450 DB1 variable activity on the bioactivation of codeine in vivo to morphine and on its analgesic effect was investigated in phenotyped healthy volunteers--7 extensive [EM] and 1 poor [PM] metabolizer of debrisoquine. After pretreatment with oral placebo or quinidine sulphate 50 mg, codeine phosphate 100 mg or placebo were administered orally according to a double-blind randomized crossover design. In EM subjects the plasma morphine Cmax was 17.9 nmol/l, whereas virtually no morphine was detectable after quinidine pretreatment (1.5 nmol/l), and in the PM subject (0.60 nmol/l). In EM codeine significantly increased subjective (VAS) and objective (R-III reflex) pain thresholds in response to selective transcutaneous nerve stimulation, whereas no significant analgesia was detected after placebo, or after codeine with quinidine pretreatment, or in the PM. In PM of genetic origin, or due to environmental alteration of the phenotypic expression (i.e. drug interaction), codeine is not activated into morphine and is an inefficient analgesic.

Administration, Oral↗
PubMed1991

Codeine O-demethylation: rat strain differences and the effects of inhibitors.

The oxidative metabolism of more than 20 drugs (e.g. sparteine, debrisoquine, dextromethorphan) is mediated by cytochrome P450IID6. Codeine O-demethylation to morphine was recently demonstrated to co-segregate with the polymorphic metabolism of debrisoquine and dextromethorphan. The female Dark-Agouti rat (DA) is an animal model for the poor metabolizer phenotype (PM) using debrisoquine or dextromethorphan as substrates. Studies were carried out to evaluate codeine metabolism in liver microsomes from female DA and Sprague-Dawley (SD) rats. The intrinsic clearance of codeine to morphine was 10-fold lower in DA rats due to a 5-fold higher Km (287 vs 49 microM) and a 2-fold lower Vmax (48 vs 94 nmol/mg/hr). Nineteen drugs were tested for inhibition of codeine O-demethylation. The four most potent competitive inhibitors were dextromethorphan (Ki = 2.53 microM), propafenone (Ki = 0.58 microM), racemic methadone (Ki = 0.3 microM) and quinine (Ki = 0.07 microM). The differences in morphine formation from codeine between SD and DA rats and the inhibition results show that this animal model appears to be a suitable model for the human EM and PM phenotypes, respectively. These strains could be used to study the pharmacodynamic consequences of the genetic polymorphism in codeine O-demethylation, and the effects of metabolic inhibitors. The outcome of these studies could impact on the therapy of pain control.

Animals↗
PubMed1978

Tolerance and evidence of physical dependence to daily codeine injections in the rat.

Core temperatures, measured by telemetry, and acquisition of food pellets on a continuous reinforcement schedule were recorded every 30 min in unrestrained male rats given saline for 5 days before and 5 days after 10 daily SC injections of codeine phosphate (200 mg/kg) at 08:00 hr. After the first codeine injection rats were immobile, slightly catatonic, breathed shallowly and had elevated core temperatures, loss of body weight and inhibition of feeding activity. As injections of codeine were repeated, the initial depressant signs decreased and the period of inhibited feeding was replaced by prolonged (greater than 8 hr) post-injection bouts of feeding activity (stimulated feeding) during daylight hours. Core temperatures remained elevated during this phase of drug-induced feeding activity. Mean body weight and 24-hr food intake remained below control levels over the 10-day codeine period as diurnal feeding patterns became reversed. On the first withdrawal day core temperatures declined and feeding patterns changed from those responses on the last codeine day as the rats lost body weight and were hyperirritable. As withdrawal continued core temperature and feeding patterns began to resemble those of the saline control period, body weights increased and hyperirritability subsided. In this study, tolerance and evidence of physical dependence to daily injections of codeine could be demonstrated in rats by continuous monitoring of their diurnal feeding and temperature responses.

Animals↗
PubMed1990

Codeine analgesic and morphine hyperalgesic effects on thermal nociception in domestic fowl.

The effects of codeine phosphate and morphine sulfate (2.5, 15.0, and 30 mg/ml/kg; IM) on latency of a jump response elicited by a noxious (61 degrees C) thermal stimulus were studied in White Leghorn cockerels at 15-16 days posthatch. Codeine induced a significant dose-dependent increase in jump response latency (analgesic effect), whereas morphine at each dose induced a significant decrease in jump response latency (hyperalgesic effect). Naloxone (5 mg/ml/kg) reversed the hyperalgesic effect of morphine (30 mg/ml/kg) and potentiated codeine analgesic effects. It is unlikely that codeine analgesic effects in domestic fowl reflect demethylation of codeine to morphine. These opposite codeine and morphine effects may reflect the interaction of these opiates at different populations of opioid receptors or at different substrates.

Analgesics↗
PubMed1986

Discrimination between urticaria-prone and other allergic patients by intradermal skin testing with codeine.

To study the ability of cutaneous mast cells to degranulate in urticaria-prone patients, subjects were skin tested with the known mast cell degranulator, codeine sulfate. Sensitivity to codeine as determined by the concentrations of codeine necessary to cause a net wheal of 5 mm was compared between urticaria-prone subjects, allergic subjects, and normal control subjects. Urticaria-prone subjects were more sensitive to codeine at every concentration tested and exhibited a mean reactivity to codeine that was almost 100 times that of the other allergic individuals and normal control subjects. This difference could not be explained by an increased sensitivity to histamine in 71% of urticaria-prone patients nor by any dermatographic tendencies or increased relative allergic reactivity. These findings suggest that codeine skin testing can be used to identify a distinct population of patients with urticaria.

Adult↗
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↗
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↗
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↗
PubMed1989

Bioavailability study of fosfosal and codeine administered alone or in combination.

Fosfosal (2-phosphonoxybenzoic acid) is a new salicylic acid derivative which is used for treating inflammatory disease as well as in analgesic therapy. On the other hand, codeine together with acetylsalicylic acid is widely used in patients who require analgesic treatment for mild to moderate pain. The present study was carried out in ten healthy subjects to assess the pharmacokinetic profiles of single oral doses of fosfosal (1,200 mg) and codeine (30 mg) when administered alone or in combination. Blood samples were drawn on each study day and salicylic acid and codeine plasma concentrations were determined by HPLC and enzyme immunoassay methods, respectively. Individual pharmacokinetic parameters were calculated according to standard procedures and the magnitude and rate of bioavailability were tested using a 95% confidence internal approach. Results indicated no statistical differences in any of the kinetic parameters studied except for tmax values which were higher for fosfosal combined with codeine (2 +/- 0.39 h) when compared to fosfosal alone (1.55 +/- 0.35 h). Regarding codeine compared in combination with fosfosal, no significant differences were observed in Cmax and AUC values, while tmax showed a higher value for the combination (1.75 +/- 0.6 vs 0.85 +/- 0.32 h). Although statistical differences in the elimination constant rate and MRT were found between both codeine administrations, these cannot be considered significant in clinical terms. The changes in bioavailability rate observed for both drugs when administered together provide support for the use of this combination in a single formulation.

Adult↗
PubMed1986

Treatment of mild to moderate pain of acute soft tissue injury: diflunisal vs acetaminophen with codeine.

Acute soft tissue injuries create pain and limitation of function. Treatment requires analgesia and time for full recovery. Acetaminophen with codeine (650 mg plus 60 mg, respectively, every 4 to 6 hours) is used frequently as the analgesic of choice. Diflunisal (1,000 mg initially then 500 mg twice a day) vs acetaminophen with codeine was prospectively studied in the treatment of acute mild to moderate pain from soft tissue injuries. Thirty-five patients with acute strains, sprains, or low back pain were randomized to treatment (17 acetaminophen with codeine vs 18 diflunisal). Both groups were similar in the amount of pain and type of injury at initiation of therapy. Patient pain rating went from 3.3 +/- 0.6 to 1.6 +/- 1.5 for acetaminophen with codeine and from 3.3 +/- 0.6 to 1.3 +/- 1.1 for diflunisal. However, 65 percent of acetaminophen with codeine patients experienced side effects, with 35 percent of these patients stopping the medication because of intolerable side effects. In the diflunisal group, 28 percent of the patients experienced side effects and 5 percent had to stop the medication early. Diflunisal was found to be an effective analgesic in mild to moderate pain of acute soft tissue injuries, and caused fewer and more tolerable side effects than did acetaminophen with codeine.

Acetaminophen↗
PubMed1987

Fiorinal with Codeine in the management of tension headache: impact of placebo response.

The well-known difficulty in distinguishing the response to a combination headache medication and its individual components in the presence of a high placebo response was again demonstrated in a randomized, double-blind, placebo-controlled, multi-center trial comparing Fiorinal with Codeine and its Fiorinal and codeine phosphate components in relieving the pain, tension, and muscle contraction associated with tension headache. In the original analysis of the study data, no distinction was apparent between patient response to Fiorinal with Codeine and the response to the individual components, a finding that appeared to conflict with the results of a similar earlier study. This apparent discrepancy was attributable to a high placebo response in the later study. Separation of study subjects according to their baseline level of anxiety and pain identified a subset of less anxious patients with mild to moderate pain severity who were least likely to respond to placebo. Analysis of data from these patients showed that Fiorinal with Codeine was significantly better than placebo in improving patients' self-ratings of various symptoms of tension headache at 0.5, 1, 2, 3, and 4 hours after ingestion of the study medication. The combination drug was also consistently superior to Fiorinal alone and codeine alone in improving the patients' self-evaluation items, and differences between the combination and its components were generally of statistical or borderline significance during the last half of the study. The investigators' assessments of the effect of treatment on the three principal variables in tension headache (namely, headache pain, psychic tension, and muscle contraction of the head, neck, and shoulders) at the final patient visit also showed Fiorinal with Codeine to be not only significantly superior to placebo but also consistently superior to either component. The superiority of the combination over Fiorinal alone achieved borderline significance for headache pain and psychic tension.

Adult↗
PubMed1986

Pentazocine and codeine: effects on human performance and mood and interactions with diazepam.

Effects of two opioid analgesics on performance and their interactions with diazepam were studied double-blind and cross over in ten healthy students. At two-week intervals the subjects received first a single oral dose of placebo, codeine (100 mg) or pentazocine (75 mg). Then, 1 h 30 min later they were all given diazepam (0.25 mg/kg) orally. Lastly, naloxone (0.4 mg) was injected intravenously at 4 h. In addition to this, the subjects on pentazocine received a second 75 mg dose at 3 h. Codeine and pentazocine alone failed to affect performance in objective tests (body sway, digit symbol substitution, flicker fusion, Maddox wing, nystagmus) recorded at 1 h 30 min. Visual analogue scales showed subjective drug effects: pentazocine made the volunteers talkative, contented, interested and energetic, whilst codeine rendered them mentally slow. 75 mg of pentazocine and 100 mg of codeine produced comparable plasma opiate activity (determined in morphine equivalents) according to radioreceptor bioassay with [3H]-dihydromorphine as a ligand. Impaired performance was clear at the tests done 1.5 and 2.5 h after diazepam. No major interactions were found between opiates and diazepam in objective tests with the exception that nystagmus was stronger after the combined treatment than after diazepam alone. Codeine reduced the absorption of diazepam. Subjectively codeine and pentazocine counteracted the effects of diazepam. The subjects overestimated their performance after opiate + diazepam when compared to diazepam alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The effect of quinidine on the analgesic effect of codeine.

We have studied the hypoalgesic effect of codeine (100 mg) after blocking the hepatic O-demethylation of codeine to morphine via the sparteine oxygenase (CYP2D6) by quinidine (200 mg). The study was performed in 16 extensive metabolizers of sparteine, using a double-blind, randomized, four-way, cross-over design. The treatments given at 3 h intervals during the four sessions were placebo/placebo, quinidine/placebo, placebo/codeine, and quinidine/codeine. We measured pinprick pain and pain tolerance thresholds to high energy argon laser stimuli before and 1, 2, and 3 h after codeine or placebo. After codeine and placebo, the peak plasma concentration of morphine was 6-62 (median 18) nmol.l-1. When quinidine pre-treatment was given, no morphine could be detected (less than 4 nmol.l-1) after codeine. The pin-prick pain thresholds were significantly increased after placebo/codeine, but not after quinidine/codeine compared with placebo/placebo. Both placebo/codeine and quinidine/codeine increased pain tolerance thresholds significantly. Quinidine/codeine and quinidine/placebo did not differ significantly for either pin-prick or tolerance pain thresholds. These results are compatible with local CYP2D6 mediated formation of morphine in the brain, not being blocked by quinidine. Alternatively, a hypoalgesic effect of quinidine might have confounded the results.

Adult↗
PubMed1986

Comparative study of flurbiprofen, zomepirac sodium, acetaminophen plus codeine, and acetaminophen for the relief of postsurgical dental pain.

The relative analgesic efficacy and safety of single oral doses of 50 and 100 mg of flurbiprofen (Ansaid, Upjohn) were compared with 100 mg of zomepirac sodium, 650 mg of acetaminophen plus 60 mg of codeine, 650 mg of acetaminophen alone, and placebo in a randomized, double-blind, parallel-group study. A total of 182 patients entered the study with moderate pain from a third molar extraction and were evaluated for six hours. For many efficacy variables, all active treatments were significantly (p less than or equal to 0.05) more effective than placebo. The two doses of flurbiprofen gave approximately similar results, suggesting a plateau effect above 50 mg. With the exception of relief at one hour, there were no significant differences between zomepirac and either dose of flurbiprofen. However, the mean response with zomepirac was greater than with either 50 or 100 mg of flurbiprofen during the first four hours and lower during the last two hours. The analgesic effects of acetaminophen alone were not significantly different from acetaminophen in combination with codeine. At the first hour, acetaminophen plus codeine led to significantly better pain relief than did 100 mg of flurbiprofen. After the first hour, flurbiprofen resulted in greater mean scores than acetaminophen alone or acetaminophen plus codeine, and these differences were significant at the fifth and sixth hours. Five patients had adverse reactions while receiving acetaminophen, acetaminophen plus codeine, or placebo. There were no adverse effects with flurbiprofen or zomepirac.

Acetaminophen↗