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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↗
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↗
PubMed1990

Skin reactivity to codeine and histamine during prolonged corticosteroid therapy.

Corticosteroids, used in low to moderate doses for short time intervals, do not suppress immediate percutaneous skin test responses to allergens, compound 48/80, or histamine. During routine skin testing, in our clinic, intradermal injection of codeine (1 mg/ml) and histamine (0.02 mg/ml) are used as positive controls. We had noted that responses to codeine but not histamine are decreased in some patients with asthma who had been receiving prolonged corticosteroid therapy. Therefore, we retrospectively compared skin test responses to codeine and histamine between 25 adult subjects with asthma receiving steroids (group I) and 25 age-matched control subjects (group II). In group I, the mean wheal diameters, induced by codeine but not histamine, were significantly less than diameters in group II. This decreased skin test reactivity to codeine was not due to effects of theophylline also taken by group I subjects, since the skin test reactions of other subjects with asthma, treated with theophylline but not steroids (group III), were not significantly different from reactions in group II. We conclude that prolonged courses of corticosteroids do not appear to alter histamine-induced vascular reactivity in skin but may affect cutaneous mast cell responses by an undefined mechanism.

Adrenal Cortex Hormones↗
PubMed1989

Direct determination of codeine-6-glucuronide in plasma and urine using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

A sensitive and selective method was developed for the direct determination of codeine-6-glucuronide in plasma and urine using high-performance liquid chromatography (HPLC) with fluorescence detection. Codeine-6-glucuronide was synthesised and its purity estimated using acid and enzyme hydrolysis. The hydrolysis of codeine-6-glucuronide by beta-glucuronidase was incomplete and urine reduced the extent of hydrolysis. Codeine-6-glucuronide was recovered from plasma using a solid-phase extraction column and separated on a reversed-phase C18 HPLC column. The assay showed good reproducibility and accuracy (within 10%), and standard curves were linear between 32 and 1600 ng/ml in plasma and between 0.32 and 160 micrograms/ml in urine. The assay has been applied to the study of the pharmacokinetics and metabolism of codeine in patients.

Chromatography, High Pressure Liquid↗
PubMed1990

Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine.

The analgesic efficacy and kinetics of a single oral dose of 75 mg codeine was investigated in 12 extensive metabolizers and 12 poor metabolizers of sparteine in a double-blind, placebo-controlled crossover study. The cosegregation of the O-demethylation of codeine to morphine with the sparteine oxidation polymorphism was confirmed. Hence morphine could not be detected in the plasma of any of the poor metabolizers, whereas detectable morphine plasma levels were found in 10 of 12 extensive metabolizers. Pain thresholds to laser stimuli were determined before drug intake and 90, 150, and 210 minutes after drug intake. Codeine significantly increased the pricking pain thresholds in the extensive metabolizers (p less than 0.05), whereas there were no significant changes in the poor metabolizers. No change in pain thresholds occurred with placebo in any of the two phenotypes. In the extensive metabolizers there was a significant positive correlation between the increase in pain threshold and plasma concentration of codeine. The study supports the hypothesis that morphine formation is essential for achievement of analgesia during codeine treatment.

Administration, Oral↗
PubMed1988

Transformation of thebaine to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes.

Thebaine, an intermediate of morphine biosynthesis in the poppy plant, Papaver somniferum, was transformed to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes in the presence of an NADPH-generating system. The formation of morphine, codeine, and oripavine was identified by a specific RIA, HPLC, and GCMS. Thebaine also gave rise to four other compounds, which for the moment are unidentified. NADH dramatically increased the formation of both codeine and morphine when used together with an NADPH-generating system, especially in liver microsomes. NADPH is essential in the formation of oripavine from thebaine and morphine from codeine, while NADH is critical in the conversion of thebaine to codeine and from oripavine to morphine. Carbon monoxide or SKF 525A inhibited the conversion, indicating a role of cytochrome P-450. These results provide evidence for the enzymatic in vitro conversion by mammalian tissues of thebaine to morphine. The pathway is similar to that which exists in plants.

Animals↗
PubMedDate not supplied

Excretion of codeine and morphine following ingestion of poppy seeds.

After the ingestion of three poppy-seed bagels, the following codeine and morphine concentrations were determined in the urine: 214 ng/mL codeine and 2797 ng/mL morphine at 3 h, and 16 ng/mL codeine and 676 ng/mL morphine at 22 h. This work indicates that a positive finding of codeine or morphine in the urine of an individual does not necessarily indicate heroin, morphine, or codeine use.

Codeine↗
PubMedDate not supplied

Determination of morphine and codeine in blood and bile by gas chromatography with a derivatization procedure.

Two gas chromatographic methods for the simultaneous quantitation of morphine and codeine in blood and bile from cases of opiate-related deaths are described. Both methods employ simple solvent extraction followed by hexane-ethanol partitioning clean-up and use nalorphine as the internal standard. The first method relies on the formation of trimethylsilyl derivatives and detection with a nitrogen-phosphorous detector. The second method involves the formation of heptafluorobutyryl derivatives and detection with an electron capture detector. Both methods are sensitive, able to detect down to 0.04 microgram/mL of morphine and 0.1 microgram/mL of codeine. Their wide linear dynamic ranges cover from low therapeutic to lethal levels for both morphine and codeine. The methods are amenable to batchwise operation and each analysis can be completed within three hours. The results of both methods correlate very well. The trimethylsilyl derivatives can be hydrolyzed and rederivatized for form heptafluorobutyryl derivatives for the second method, which then serves to confirm the results of the first method. Pholcodine, another common opiate, can likewise be determined. Average recovery was 80% for blood morphine and codeine and 60% for bile morphine and codeine.

Bile↗
PubMed1978

Appraisal of codeine as an analgesic in older patients.

In an investigation of a new oral analgesic agent, codeine was chosen as the reference drug because of its established reputation as an effective agent for the relief of pain. Thirty-five patients with cancer pain were studied. Their average age was 58 years, During a 5-day hospital stay they received, on each of three days, either codeine (120 mg or 60 mg) or placebo. At hourly intervals after ingestion the nurse observer collected data on pain intensity and the degree of pain relief, and the patients independently charted the hourly intensity. Statistical analysis failed to show any significant superiority of either dose of codeine over placebo. Moreover, codeine is known to have a constipating effect. Re-appraisal of the value of codeine as an analgesic agent in elderly patients seems justified.

Adult↗
PubMed1985

Identification of transformation products arising from bacterial oxidation of codeine by Streptomyces griseus.

14-Hydroxycodeine and norcodeine were rigorously identified as products arising from codeine oxidation by Streptomyces griseus ATCC 10137. Both products were routinely detected in extracted culture filtrates after growth of cells in the presence of codeine for 1 week. Under these conditions, about 4 mol% of the codeine starting material was consumed, with norcodeine and 14-hydroxycodeine representing the only identifiable transformation products (molar ratio, 4:1, respectively). Extraction of a series of culture filtrates and purification of the pooled metabolites by thin-layer and high-pressure liquid chromatography led to the isolation of both biological products, the structures of which were verified by high-resolution mass spectrometry and proton nuclear magnetic resonance spectroscopy. The identities of both biological products were further confirmed by comparison of their spectral properties with those of authentic standards. This is the first report providing structural evidence for the biological formation of 14-hydroxycodeine from codeine and of codeine oxidation by S. griseus.

Biotransformation↗