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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↗

PubMed1983

The peripheral analgesic effect of morphine, codeine, pentazocine and d-propoxyphene.

The prostaglandin hyperalgesia and tail immersion tests were used to evaluate the analgesic action of morphine, codeine, d-propoxyphene and pentazocine following intraperitoneal, intraplantar and intracerebroventricular administration to rats. In the prostaglandin hyperalgesia test, all drugs produced a dose-dependent analgesia by the various routes. The rank order of potency after intraperitoneal administration was morphine (100) greater than d-propoxyphene (4) greater than pentazocine (2) greater than codeine (1). Although morphine (ID50 = 4 micrograms) was a very potent analgesic when given intracerebroventricularly, very shallow dose-response curves were obtained with the other substances which promoted less than 30% of inhibition at doses up to 250 micrograms. In the paw, morphine (ID50 = 5 micrograms) was only 5-8 times more potent than pentazocine, propoxyphene and codeine. Thus, in contrast with morphine, intraplantar administration of codeine, pentazocine and d-propoxyphene is much more effective than intracerebroventricular administration. In the tail immersion test the smallest intraperitoneal doses which affected the reaction time were 9 mg/kg morphine, 16.2 mg/kg codeine and pentazocine and 48.6 mg/kg d-propoxyphene. When injected intracerebroventricularly morphine (10 micrograms) was the only opiate that caused a detectable analgesic effect. In the prostaglandin hyperalgesia test, a small dose of naloxone (1 micrograms) given into the rat paw significantly antagonized the analgesic effect of d-propoxyphene, codeine and pentazocine administered either intraperitoneally or intraplantarly. These results clearly indicate that a method involving or mimicking inflammatory hyperalgesia is much more sensitive in detecting opiate analgesia than a method which uses heat as a nociceptive stimulus. Furthermore, our results support the proposition that part of the overall analgesia which follows the systemic administration of opiates is due to a peripheral antinociceptive action.

Analgesia↗

PubMed1981

[Codeine seeking behavior in rats using a weight-pulling method].

The purpose of this work was to examine the development of preference for codeine and codeine-seeking behavior by using an apparatus in which rats were compelled to pull against a weight to gain access to codeine-admixed food but not in the case of normal food. Rats developed a strong preference for codeine-admixed food by the repetition of choice and forced trails. The preference for codeine-admixed food was maintained at levels between 60 to 80% for 14 days without any forced trial. After rats developed this preference, they were tested as to whether they might pull against the weight in the apparatus. We observed that the rats did pull at most 40-120 g/100 g body weight in order to reach the drug-admixed food. This is defined as maximum pulling weight. As the weight load was increased, the rats showed more frequent weight pulling behavior for the codeine-admixed food while the duration of eating decreased. The maximum weight pulled was more than 70 g/100 g body weight in 4 out of 6 rats. These results suggest that the degree of drug-seeking behavior in rats can be detected by the use of the weight-pulling method.

Animals↗

PubMed1982

Liquid chromatography of codeine in plasma with fluorescence detection.

This analytical method for easier determination of codeine in human plasma is based on "high-performance" liquid chromatography for separation and the natural fluorescence of codeine for detection. Codeine is extracted from alkalinized plasma with a mixture of hexane and dichloromethane, and the extract is further purified and chromatographed. The method can be used for routine assay of codeine at the concentrations of 10 micrograms/L or greater in human plasma. As little as 4 micrograms/L can be detected. Coefficients of variation for the assay of codeine in the concentration range of 10 to 100 micrograms/L were 2.2-7.4% (n = 6). We used this method to establish a concentration/time profile for plasma from a human volunteer after a 60-mg oral dose of codeine sulfate.

Administration, Oral↗

PubMed1993

Conjunctival provocation tests with codeine phosphate. Effect of disodium cromoglycate.

The reactivity of ocular mast cells is poorly characterized in man. Provocation tests with codeine phosphate, a molecule known to activate connective tissue mast cells, were performed in ten normal subjects. Ten-fold increasing concentrations of codeine phosphate (10(-5) to 10(-1) mg/mL) were tested in both eyes until a positive challenge was observed. Schirmer strips were placed under the eyelid and left for five minutes. A negative control was performed ten days later. All subjects had a strongly positive reaction for the same codeine phosphate concentration (10(-1) mg/mL). Histamine was released in 8/10 subjects (control: 7.06 +/- 4.19 nM/L, codeine phosphate: 18.2 +/- 15.7 nM/L, P < .018), PGD2 was released in 8/10 subjects (control: 0 codeine phosphate: 273.3 +/- 408.9 ng/L). Disodium cromoglycate blocked the release of histamine and PGD2. Codeine phosphate is potent at causing mast cell activation in the eye and this effect is blocked by disodium cromoglycate.

Adult↗

PubMed1993

Skin testing with food, codeine, and histamine in exercise-induced anaphylaxis.

A 33-year-old Chinese woman with exercise-induced anaphylaxis after ingesting Chinese seafood noodle soup, was studied for skin test reactivity to food, histamine, and codeine. Prick skin tests were negative for shrimp, wheat, and chicken soup base, but were positive at 5 to 6 mm (wheal diameter) to the whole broth after it had been combined with the other ingredients. No significant (> 3 mm) wheals were observed in eight controls who were simultaneously tested with the broth. To assess the role of exercise, three series of skin tests were performed with histamine, codeine, and whole broth before and after aerobic exercise on two occasions. Codeine elicited consistent increases in wheal size after exercise compared with pre-exercise skin tests. Histamine and whole broth wheal sizes did not increase significantly. Three control subjects also had codeine and histamine skin tests before and after exercise, No exercise-associated increases were noted for codeine. Potential insights into mast cell abnormalities in exercise-induced anaphylaxis may be gained by skin testing patterns with codeine and other mast cell degranulating agents.

Adult↗

PubMed1993

Codeine disposition in sickle cell patients compared with healthy volunteers.

The pharmacokinetics of codeine were determined after oral administration of codeine sulfate (60 mg) with sickle cell patients (SCPs) and healthy controls (HCs). Plasma concentrations of codeine were measured by reversed-phase high-pressure liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated using both compartmental and noncompartmental analysis. No significant differences were observed in time to reach maximum peak plasma concentration (tmax) (1.0 +/- 0.4 versus 1.4 +/- 1.0 hours), maximum peak plasma concentration (Cmax) (172 +/- 25 versus 225 +/- 97 ng/mL), area under the curve (AUC infinity) (590 +/- 96 versus 779 +/- 234 ng*h/mL), and Cl/F (104 +/- 17 versus 89 +/- 27 L/h) between SCPs and HCs. Conversely, significant differences were observed in mean residence time (MRT) (3.7 +/- 0.3 versus 4.7 +/- 0.3 hours) and half-life (t1/2) (1.7 +/- 0.2 versus 2.8 +/- 0.3 hours). In a separate study, significant differences were observed in the in vitro plasma protein binding of codeine in SCPs (66.0 +/- 8.6%) and HCs (30.5 +/- 2.7%) as well as in vivo binding (68.4 +/- 11.1% for SCPs versus 29.2 +/- 3.4% for HCs). Codeine is a relatively high-extraction drug that is primarily eliminated by metabolism in the liver. Generally, the clearance of such drugs is approximately equal to hepatic blood flow and is not affected by changes in protein binding. Therefore, the change in t1/2 observed in SCPs can be attributed to changes in volume of distribution rather than clearance.

Adult↗

PubMed1980

High-performance liquid chromatographic analysis of codeine in syrups using ion-pair formation.

The chromatographic behavior of morphine, codeine, and ethylmorphine was examined using reversed-phase high-performance liquid chromatography and ion-pair formation. Alkyl sulfonates and sulfates significantly increased the retention times for these compounds. The carbon chain length of the pairing ions was linearly related to the log of the capacity factors of these amine drugs. A mechanism for the increased retention based on ion-pair formation in the mobile phase is proposed. The use of dioctyl sodium sulfosuccinate as a pairing ion for codeine is described, and a method utilizing this pairing ion was developed for the quantitation of codeine in syrups. This method was applied successfully to various syrups containing codeine or codeine phosphate.

Chromatography, High Pressure Liquid↗

PubMed1984

Determination of codeine in human plasma by reverse-phase high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for the determination of codeine in human plasma is described. The specific, precise, and sensitive method can be used to determine plasma codeine levels after administration of therapeutic doses of codeine. After purification on a C18 extraction column, codeine in the form of hydrochloride is eluted. After addition of the internal standard, the codeine is separated on a reverse-phase C18 column using a slightly alkaline mobile phase and is then determined by UV detection. The analysis takes 3.5 min per run; the limit of detection is approximately 3 micrograms/L for a 50-microL loop and 800 microL of plasma. The absolute recovery is 98.4 +/- 6.7% (n = 14) in the 10-300-micrograms/L range. Within the range, the calibration curve is linear.

Adult↗

PubMed1994

Use of codeine analgesics in a general population. A Norwegian study of moderately strong analgesics.

The prescribing of controlled analgesics (codeine, buprenorphine and pentazocine preparations) was studied, using prescriptions from the three pharmacies in the municipality of Tromsø, Norway. All prescriptions dispensed during one year were analysed. The study sample comprised 3083 women (58%) and 2223 men (42%) between 10 and 99 years of age. About 8% of the population had obtained one or more prescriptions of controlled analgesics. Combined codeine preparations were by far the most frequently prescribed subgroups, and the average amount purchased during 1 year was 30 defined daily doses (DDD). The sporadic users were in the majority. A few users had purchased high amounts of controlled analgesics. The prevalence of use, the mean number of defined daily doses of analgesics, and the proportion of 'weekly' drug users was higher in women than men. The prevalence increased significantly with age, from 0.7 to 22.3% in women and from 0.5 to 14.1% in men. The mean number of DDD during one year also increased with age, from 12.6 to 50.6 DDD in women, and from 6.6 to 40.6 DDD in men. The users of buprenorphine and pentazocine differed in several aspects from the codeine users. The highest use of combined codeine preparations was seen in elderly people especially in women. Use of lower codeine doses or intermittent treatment with other drugs e.g. plain paracetamol in adequate doses, may be appropriate alternatives reducing the risk of adverse drug reactions such as nausea and constipation. Monitoring of prescribing and use of controlled analgesics according to certain criteria may uncover possible misuse.

Adolescent↗

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↗

PubMed1985

In vitro formation of codeinone from codeine by rat or guinea pig liver homogenate and its acute toxicity in mice.

In vitro metabolism of codeine was investigated by using a 9000 g supernatant fraction of rat or guinea pig liver homogenate. When a mixture of [N-14CH3] and [C-6-3H]codeine was incubated with the rat liver 9000 g supernatant fraction in the presence of NAD, formation of codeinone, morphine and norcodeine was detected. Replacement of NAD with NADP abolished only the formation of codeinone. On the other hand, when the guinea pig liver homogenate was used in the presence of NAD, codeinone was the main metabolite of codeine. NADP was also ineffective in forming codeinone with the guinea pig liver homogenate. The acute toxicity of codeinone was thirty times higher than that of codeine. The roles of codeinone as a metabolic intermediate and in the acute toxicity of codeine are discussed.

Animals↗

PubMed1987

Effects of chronic administration of codeine and promethazine on breathlessness and exercise tolerance in patients with chronic airflow obstruction.

It has been reported that short-term treatment with relatively high doses of opiates or promethazine causes improvements in dyspnoea and exercise tolerance in patients with chronic airflow obstruction (CAO). This study was designed to determine whether initial benefits were sustained during chronic administration of codeine or promethazine and to compare the two drugs in terms of their efficacy and possible mechanisms of action. Eleven patients with stable CAO were entered into a double-blind, randomized cross-over trial in which codeine (30 mg four times daily) or promethazine (25 mg four times daily) were orally administered for 1-month periods. Treatment effects were assessed by spirometry, arterial blood gases, 12-minute walk distance and subjective dyspnoea ratings. A statistically significant increase from the baseline in mean arterial PCO2 at at 24 hours (P less than 0.01) and at 1 month (P less than 0.05) occurred with codeine administration. There was no significant change from baseline for any other measurement with either drug, and no differences were detected between the two treatment arms. Four of the eleven patients did not complete the study; three of the four experienced worsening of their CAO requiring hospitalization (two while receiving codeine, one while receiving promethazine). We conclude that chronic treatment with either codeine or promethazine provides uncertain benefits to patients with CAO which may not outweigh potential risks.

Aged↗

PubMed1979

Effects of response-contingent clock stimuli on behavior maintained by intravenous codeine in the rhesus monkey.

Response-contingent brief presentations of clock stimuli differentially correlated with food availability altered rates of codeine-maintained lever pressing. Rhesus monkeys performed under a two lever multiple schedule: Multiple fixed interval clock 5 min variable interval 2 min. Different colored lights were presented during successive 75 sec period of the fixed-interval clock component. Lever pressing under the FI Clock schedule was maintained by presentation of 1 g Noyes pellets, and lever pressing under the VI schedule by 0.05 mg/kg infusions of codeine PO4. Characteristic schedule-controlled performance developed in both schedule components. When the clock stimulus from the first or the final period of the FI Clock schedule was presented contingent upon completion of a short fixed ratio of responses during the variable-interval schedule component, the first clock stimulus decreased and the final clock stimulus increased rates of codeine-maintained lever pressing. Neither the first nor the final clock stimulus altered the frequency of codeine injection. The effect of each clock stimulus was accentuated by increasing the duration of stimulus presentation and by decreasing the response requirement for stimulus illumination. These rate-altering effects of the clock stimuli were most pronounced when different reinforcers were presented in the two components of the multiple schedule when either food or intravenous codeine injection was available under both components of the multiple schedule, response-contingent clock stimulus presentation did not alter response rates under the VI schedule.

Animals↗

PubMed1989

Effect of codeine and oxazepam on afternoon cortisol secretion in men.

The objective of this study was to investigate the effects of oral codeine and oxazepam on afternoon cortisol secretion. Nine subjects received either oxazepam (30 mg) or codeine (30 mg) or placebo at 1700h on separate days in a counterbalanced design; the subjects were not aware of the sequence. Blood samples were collected with an indwelling intravenous catheter at 30-min intervals from 1500h to 1630h. Codeine, but not oxazepam, suppressed cortisol secretion. The trend of the declining cortisol values following codeine was significantly linear. These results are consistent with other evidence indicating the presence of an inhibitory opioid mechanism in the human hypothalamo-pituitary-adrenal (HPA) axis. The cortisol response to codeine may be a reliable and potentially useful paradigm for the study of the role of opioidergic mechanisms in HPA axis dysfunction.

Adult↗

PubMed1991

Direct determination of codeine, norcodeine, morphine and normorphine with their corresponding O-glucuronide conjugates by high-performance liquid chromatography with electrochemical detection.

A high-performance liquid chromatographic method has been developed for the detection, separation and measurement of codeine and its metabolites norcodeine, morphine and normorphine, with their glucuronide conjugates. The glucuronidase Escherichia coli type VIIA hydrolyses codeine-6-glucuronide completely and is used for the construction of the calibration curves of codeine-6-glucuronide. Enzymic hydrolysis of codeine-6-glucuronide depends on the specific activity of the glucuronidase applied. Examples are shown of a volunteer who is able to form morphine from codeine and one who is unable to do so.

Chromatography, High Pressure Liquid↗