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The analgesic and anti-inflammatory efficacy of diflunisal and codeine after removal of impacted third molars.

A double-blind, randomized trial was carried out in 90 patients to compare the analgesic and anti-inflammatory efficacy of 500 mg diflunisal twice daily with that of 25 mg codeine phosphate 4-times daily and placebo in relieving pain and swelling after surgical removal of impacted third molars. Diflunisal was found to be superior to codeine and placebo on the first post-operative day, but the difference in efficacy of the drugs had diminished by the third post-operative day. In the diflunisal group of 30 patients, 10 (33%) developed 'dry socket' or alveolitis sicca dolorosa. Only 2 patients in the codeine group and 1 patient in the placebo group developed this very painful condition. The possible explanation of 'dry socket' is discussed.

Adolescent

Effects of zolpidem, codeine phosphate and placebo on respiration. A double-blind, crossover study in volunteers.

The effects of zolpidem, codeine phosphate and placebo on respiration were evaluated in a double-blind, randomised, crossover study involving 12 healthy men. Single oral doses of zolpidem 10 or 20 mg, codeine phosphate 60 mg or placebo were administered in the morning. Each treatment was separated by a washout period of at least 72 h. Ventilatory responses to carbon dioxide and mouth occlusion pressure, measured 1 h before and at 1 and 3 h after doses, were not significantly affected by either zolpidem dose; however, codeine phosphate produced a small but significant respiratory suppressant effect at 3 h. Mean inspiratory flow was noninvasively assessed using respiratory inductive plethysmography 1 h predose and at 1 to 5 h postdose. No significant change in mean inspiratory flow was noted after zolpidem 10 mg. Two hours after administration of zolpidem 20 mg, mean inspiratory flow was significantly lower than after placebo, possibly related to some individuals falling asleep during data collection. All volunteers reported adverse events; the most common were slurred speech (in 1 after 10 mg and in 5 after 20 mg of zolpidem), dizziness (in 4 after both 10 mg and 20 mg of zolpidem) and diplopia/blurred vision (in 4 after 20 mg of zolpidem). Zolpidem appears to be well tolerated, with no respiratory suppression up to doses of 10 mg and minimal suppression of mean inspiratory drive at doses of 20 mg.

Adult

Gas chromatographic/thin-layer chromatographic analysis of acetylated codeine and morphine in urine.

This procedure positively identifies codeine and morphine in urine. Urine samples are hydrolyzed and extracted with organic solvent, and the extracts are evaporated and acetylated. The presence of codeine and morphine is ascertained by gas chromatography (3% OV-25 and 3% Poly-A 103 columns) and confirmed by thin-layer chromatography (system: ethyl acetate/acetone/concd ammonium hydroxide, 100/10/4.5 by vol; reagent: iodoplatinate). As little as 0.5 mg each of codeine and morphine per liter, in free and conjugated forms, is detectable by this method.

Acetylation

Robotic method for the analysis of morphine and codeine in urine.

A totally automated procedure has been developed for the detection and quantitation of morphine and codeine in urine case samples. The samples were initially screened for these drugs by a Syva EMIT Toxicology System (ETS). A Zymate laboratory robotic system confirms positive samples from Syva ETS by performing the hydrolysis, extraction, and derivatization of morphine and codeine. The derivatized morphine and codeine were detected using gas chromatography/mass spectrometry (GC/MS). Enzymatic hydrolysis conditions were experimentally optimized during method development. The automation of these procedures has proven to be reliable and efficient.

Codeine

In vivo formation of codeinone and morphinone from codeine. Isolation and identification from guinea pig bile.

Codeinone (CO) and morphinone (MO) were isolated and identified in the bile of guinea pigs given sc injections of codeine. Authentic CO was synthesized and characterized by the NMR and mass spectra of its 2-mercaptoethanol (ME) adduct. This material was then used as the standard to identify the CO-ME adduct in the bile of codeine-treated animals. The MO-ME adduct was also identified in the bile with authentic materials prepared earlier. The results of our investigations indicated that 10.5 and 2.7% dose of CO and MO, respectively, were produced for 6 hr after the codeine was given. The metabolites were separated by preparative HPLC on a reverse phase column packed with C18 gel using a 10 mM sodium phosphate buffer, pH 6.8/CH3CN, 1:1 (v/v) as an eluate. For the further purification of metabolites, we used another reverse phase column with the same mobile phase. A structural elucidation of the ME adduct of metabolites was then performed by fast atom bombardment mass spectroscopy and 400 MHz fourier transform-NMR spectrometric analysis, and identified as (8S)-(2-hydroxyethylthio)dihydrocodeinone and (8S)-(2-hydroxyethylthio)dihydromorphinone, respectively.

Animals

Evaluation of ketorolac, ibuprofen, acetaminophen, and an acetaminophen-codeine combination in postoperative oral surgery pain.

Two-hundred six outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned on a double-blind basis to receive oral doses of ketorolac tromethamine 10 and 20 mg, ibuprofen 400 mg, acetaminophen 600 mg, a combination of acetaminophen 600 mg plus codeine 60 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 6 hours after medicating. All active medications were significantly superior to placebo. Analgesia was similar for ketorolac 10 and 20 mg and ibuprofen 400 mg; however, these treatments were superior to acetaminophen alone and the acetaminophen-codeine combination. The analgesic effect of each active medication was significant by hour 1 and persisted for 5-6 hours. The data suggest a plateau in ketorolac's analgesic efficacy at the 10-mg level. Repeat-dose data indicated that on the day of surgery ketorolac 10 and 20 mg and ibuprofen 400 mg were superior to acetaminophen 600 mg; ketorolac 20 mg was also superior to acetaminophen-codeine. Differences among active medications were not significant when data for the entire postoperative period (days 0-6) were evaluated. The frequency of adverse effects was similar for the active medications.

Acetaminophen

Comparison of diflunisal and acetaminophen with codeine in the management of grade 2 ankle sprain.

The emergency physician treats many patients with mild to moderate pain due to musculoskeletal injury. The physician must consider the extent of injury, the patient's medication history, and the potential for abuse when prescribing an oral analgesic. A study was designed to compare the efficacy of two oral analgesics, one containing a narcotic and one nonnarcotic, in relieving mild to moderate pain associated with grade 2 ankle sprain. Forty patients were enrolled--all with moderate pain--and were randomly allocated to treatment with either diflunisal or acetaminophen with codeine. Both analgesic agents were equally effective in relieving the pain. Side effects were experienced by six patients, all of whom were receiving acetaminophen with codeine; none of the patients given diflunisal noted side effects. Global assessments of the efficacy and tolerability of the study drugs showed that 89% of 19 patients given diflunisal and 43% of 21 patients given acetaminophen with codeine considered their respective analgesics excellent or very good.

Acetaminophen

Scarlatiniform rash and urticaria due to codeine.

Scarlatiniform rash and urticaria were observed twice in the same patient following codeine intake. This rare drug-induced eruption may lead to mis-diagnosis in patients taking mild analgesics containing codeine. The side effects of codeine, hypersensitivity mechanisms, and the use of analgesic combination products are discussed.

Adult

Double-blind comparison of meclofenamate sodium with codeine and placebo for the pain of episiotomy.

Meclofenamate sodium, a nonsteroidal anti-inflammatory agent, was compared at two dose levels (100 mg and 200 mg) with codeine (60 mg) and placebo in a double-blind, randomized study of 218 women after normal vaginal delivery. The purpose was to determine the analgesic efficacy and safety of meclofenamate sodium for the short-term treatment of acute episiotomy pain. Meclofenamate sodium was significantly better than placebo in most measures of pain relief and reduction of pain intensity. The 100-mg dose of meclofenamate sodium was significantly better than codeine in relieving pain. Adverse experiences with the study medications were minimal (6.4%). Patients receiving codeine reported more side effects than did those receiving either dose of meclofenamate sodium. Meclofenamate sodium is a safe, effective analgesic for acute episiotomy pain.

Adolescent

Comparison of meclofenamate sodium with codeine and placebo for the treatment of episiotomy pain.

Meclofenamate sodium, a nonsteroidal anti-inflammatory drug with proven analgesic effects, was compared at two dose levels (200 mg and 100 mg) with codeine (60 mg) and placebo in a double-blind, randomized study of 327 women experiencing episiotomy pain after normal delivery. Meclofenamate sodium at either dose was significantly better than codeine or placebo in reducing pain intensity and increasing pain relief, and it had a longer duration of action. Adverse effects were minimal, and their frequency did not differ significantly among treatment groups. Meclofenamate sodium appears to be as safe as and more effective than codeine for the management of episiotomy pain.

Adolescent

Acetylsalicylic acid compared with acetylsalicylic acid plus codeine as postoperative analgesics after removal of impacted mandibular third molars.

In a multicenter, double blind clinical trial a combination of acetylsalicylic acid 500 mg + codeine phosphate 30 mg has been compared with acetylsalicylic acid 500 mg as postoperative analgesics in patients with pain after surgical removal of impacted mandibular third molars. Evaluation of the results from 129 patients showed that the combination of acetylsalicylic acid and codeine provided better pain relief and also the number of tablets used was smaller and the time intervals between repeated doses were longer than with acetylsalicylic acid only. Adverse effects were few and similar for both drugs. It may be concluded that the combination of 500 mg acetylsalicylic acid and 30 mg codeine phosphate provides a useful analgesic for more severe pain conditions in oral surgery.

Adolescent

[The bioavailability of combination preparations of acetylsalicylic acid and codeine phosphate].

Plasma levels time curves of acetylsalicylic acid, salicylic acid, salicyluric acid and codeine were monitored after intravenous, oral and rectal application (single dose) of preparations containing acetylsalicylic acid and codeine. The mean absolute bioavailability of acetylsalicylic acid was 68% after oral application and 60% after rectal application. The corresponding bioavailability data of codeine were 59% and 63%, respectively.

Administration, Oral

Acute toxicity and analgesic action of a combination of buclizine, codeine and paracetamol ('Migraleve') in tablet and suppository form in rats.

Studies in rats were carried out to determine the acute toxicity and analgesic effect of a combination preparation ('Migraleve') containing codeine and paracetamol and the individual analgesics when given orally or by rectal administration. The results showed that the combination was no more toxic than paracetamol alone and, on the basis of the LD50:ED50 ratio, was less toxic by the oral than by the rectal route. In the rat-tail test, the combination induced a well-defined dose-dependent analgesic response which was greater after rectal administration. Codeine and paracetamol tested individually were effective only at relatively high dosage and, like the combination, their analgesic effects were greater after rectal administration and more clearly dose-dependent than after oral administration. Comparison of the area under the time-effect curves for the combination and the individual components confirmed the synergism between codeine and paracetamol.

Acetaminophen

[Bioavailability of codeine and paracetamol in a combination preparation following oral and rectal administration].

The plasma concentrations of acetaminophen (paracetamol) and codeine were determined in a cross-over study in twelve healthy volunteers after oral and rectal application of a compound preparation. The relative bioavailability from the two forms of application was also computed. The two active substances showed almost parallel plasma concentration paths, and thus were systemically available at the same time. The maximum levels in plasma were already reached after one to two hours. In both active substances the suppositories displayed a classical retardation effect. In contrast to acetaminophen the rectal absorption of codeine was almost as effective as the oral absorption. Thus this application form shows almost bioequivalency vis-à-vis the capsule form. Based on these results the rectal form of administration of codeine as well as the combination of this substance with acetaminophen can be regarded, from the pharmacokinetic point of view, as a rational enhancement of the treatment of various forms of pain.

Acetaminophen

Zomepirac sodium vs APC with codeine for oral surgery pain.

In this double-blind, repeat-dose study, 323 outpatients with moderate to severe pain after oral surgery assessed zomepirac sodium, a new oral, single-entity, nonnarcotic analgesic, and APC with codeine, 30 mg, a reference standard. Pain relief obtained with 100 mg of zomepirac sodium was significantly superior to that of APC with codeine, 30 mg; 50 mg of zomepirac sodium was as effective as the reference drug. The analgesic acceptability was highest for 100 mg of zomepirac sodium. Both doses of this new drug produced significantly fewer adverse reactions than APC with codeine, 30 mg.

Aspirin

Four cases of recurrent pseudo-scarlet fever caused by phenathrene alkaloids with a 6-hydroxy group (codeine and morphine).

Four patients with a clinical picture resembling that of scarlatina are described. This clinical picture was found to be based on a delayed-type allergy for codeine and morphine. Investigation showed that the codeine or morphine allergy is essentially dependent on the hydroxyl group at the 6 position of the basic phenanthrene structure but only when this group is bound equatorially, as is the case for codeine and morphine.

Adult

Simultaneous detection and quantitation of O6-monoacetylmorphine, morphine and codeine in urine by gas chromatography with nitrogen specific and/or flame ionization detection.

It is of importance to differentiate heroin intake from the absorption of opiate-containing pharmaceuticals or opiates from other sources. A method for the routine determination of O6-monoacetylmorphine (6-MAM), the specific metabolite of heroin in human urine, by gas chromatography and classical detectors without having recourse to gas chromatography/mass spectrometry-selected ion mode (GC/MS-SIM) is described. With dual detection by nitrogen selective and flame ionization detectors, the limits of detection for 6-MAM were determined to be 2 ng/mL and 4 ng/mL urine for a 10 mL sample. When applied to urines preliminarily screened for opiates, the results appeared consistent in comparison with those obtained by GC/MS-SIM. The method was also developed for the simultaneous quantitative analysis of morphine and codeine. The linearity was tested up to 600 ng/mL for the three compounds of interest 6-MAM, morphine and codeine and their absolute recoveries were 76%, 78%, 75% respectively.

Chromatography, Gas

Naproxen, aspirin, and codeine in postpartum uterine pain.

The analgesic efficacy of oral naproxen and its sodium salt was compared with that of aspirin and codeine in two separate trials involving 140 and 90 patients, respectively, with postpartum uterine pain in a single-dose, parallel, stratified, randomized, placebo-controlled, double-blind design. With 300 or 600 mg naproxen and with 275 mg naproxen sodium, significant analgesia, measured subjectively by pain intensity differences (PID), was prolonged at least 7 or 8 hr; onset tended to be delayed 2 hr or more. With 650 mg aspirin analgesia began within 1 hr and continued until the fifth hour, while with 60 mg codeine responses were indistinguishable from placebo responses throughout the 8-hr time course. Although time-effect patterns with naproxen sodium and aspirin were different, summed analgesic effects (SPID) showed equal efficacy and superiority over placebo (p less than 0.005). With each of the 2 doses of naproxen, SPID separation from placebo was comparable to that above (p less than 0.02 and 0.005, respectively), but analgesic dose response, though measurable, was not significant. Side effects were not significant with any of the treatments. It appears that naproxen and naproxen sodium are analgesics with efficacy equal to aspirin and may prove to be rational substitutes for currently available analgesics in some painful states in which longer pain relief would be desireable.

Adolescent