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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.
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.
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.
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.
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.
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.
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.
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.
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.
A 64-year-old man with narcolepsy could not take stimulant drugs due to coronary heart disease. In the past he noted improvement in alertness when taking codeine for pain, but this was eventually discontinued. After he developed end-stage renal disease, and because the use of stimulants in this setting may be difficult, treatment with codeine was again initiated. This resulted in dramatic improvement in alertness and substantial reduction of cataplexy. Because it is simple to use and familiar to most physicians, codeine may be the drug of choice for narcoleptic patients who are undergoing hemodialysis.
In a single dose cross-over study with 12 healthy male volunteers the plasma concentrations of diclofenac (CAS 15307-86-5) and codeine (CAS 76-57-3) were determined after oral and rectal application of formulations containing 50 mg of each drug. For kinetic analysis of the concentration-time profiles non-compartmental as well as compartmental procedures were used. The compartment model included two disposition compartments supplemented by a dissolution and drug absorption step. For both compounds, the AUC0-infinity values of the two treatments were similar with only a slightly higher AUC for the suppositories, which was not found to be significantly different under the employed conditions (p > 0.05). Referring to the pharmacokinetic parameters Cmax and tmax typical differences between oral and rectal formulations were observed. For the suppositories, diclofenac and codeine average peak plasma concentrations were only half as high as for the tablets, whereas the respective tmax values were doubled. The results obtained show a similar extent of diclofenac and codeine bioavailability for both administration routes, but the rate of drug input was lower for the suppositories. The total mean input time (MITtot) was found to be significantly longer for the suppositories. This seems to be caused by a slow release from the dosage form or dissolution of the drugs, which is confirmed by a longer MITtot compared to the MRTsys in most of the volunteers.
Poppy seeds from seven different origins (Dutch, Australian, Hungarian, Spanish, Czech, and two Turkish) were analyzed for the amount of opiates present. Four grams of each kind of seeds, equivalent to the amount of seeds on two bagels, were ingested by volunteers. One volunteer also ingested four times the same amount of poppy seeds from the same origin (Spanish). During 24 hours urine samples were obtained and screened for the presence of morphine and codeine using the FPIA technique (cut-off = 200 ng/mL) and a GC/MS confirmation with a limit of detection (LOD) of 25 ng/mL for codeine and morphine. Poppy seeds from different origins contain a wide variation of morphine (2-251 micro g/g) and codeine (0.4-57.1 micro g/g) content. No other opiate could be detected. After ingestion a large interindividual variation of excretion of opiates exists. The testing results from the same kind of seeds ingested four times with a one week interval by the same volunteer also show a poor reproduceability. Several kinds of poppy seeds can give positive testing results (Australian, Hungarian, Spanish and one kind of Turkish seeds). Within 24 hours all testing results became negative.
Following enzymatic hydrolysis of urine, a gas chromatography-mass spectrometry method for the simultaneous determination of codeine, morphine, hydrocodone, and hydromorphone uses hydroxylamine to form oxime derivatives of the keto-opiates (i.e., hydrocodone, hydromorphone, oxycodone, and oxymorphone). These trimethylsilyl-derivatized forms no longer interfere with the detection and quantitation of codeine and morphine. Samples are extracted on solid-phase columns and quantitated by deuterated internal calibrations of each analyte with selected ion monitoring. Codeine, morphine, hydrocodone, and hydromorphone are completely separated, allowing simultaneous quantitation without interference and a chromatographic analysis time < 9 min.
There has been much debate in urine drug testing over what criteria should be applied to total codeine and total morphine concentration data to determine the likelihood that a urine donor has used heroin and whether such use can be demonstrated by the presence of 6-acetylmorphine. After determining that the stability of 6-acetylmorphine in frozen urine is adequate for a period of at least two years, a database of over 100 codeine and/or morphine positive urine specimens was subjected to relative operating characteristic analysis to identify a criterion that would indicate a high probability of detecting 6-acetylmorphine in a specimen and thus confirming heroin use. A two-fold criterion was identified. By using a criterion that requires the total morphine concentration to be greater than 5.000 mg/L and the total codeine to total morphine ratio to be less than 0.125, one can predict the presence of 6-acetylmorphine with a sensitivity of 92%, a specificity of 79%, and an overall accuracy of 73%. Although this criterion is statistically the most accurate in terms of both sensitivity and specificity for the data analyzed by the author, the results of other, criteria are presented to aid toxicologists and medical review officers in determining if analysis for 6-acetylmorphine is likely to produce useful results.
Tortoise shell guinea pigs (n = 7) were administered codeine (1 mg/mL codeine-base) in their drinking water for 3 weeks. Black, reddish-brown and white hair was collected separately from each animal before and after treatment. The hair samples were analyzed by GC/MS. The experiment showed positive results for all hair fibers with large individual variability of drug incorporation. Low drug intake resulted in small differences of the drug content in hair fibers different in color, whereas in cases of high drug intake a strong influence of hair pigmentation on the analytical results was observed. The highest drug content was always found in black hair samples, non-pigmented hair showed the lowest drug concentrations and the drug content in reddish-brown fibers was less than in black hair samples from the same animal. From the results it was concluded, that eumelanins rather than phenomelanins are the decisive factor for codeine-melanin binding in hair and the amount of drug intake was suggested to determine the relevance of hair pigmentation on the analytical results.
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.
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.
The analgesic effect of preoperatively administered ibuprofen was evaluated in 107 dental outpatients undergoing the removal of impacted third molars. Subjects were given 800 mg ibuprofen prior to the procedure and 400 mg ibuprofen 4 and 8 hours later. Comparison was made to groups receiving either placebo at all three doses, 600 mg acetaminophen administered on the same schedule, or preoperatively administered placebo followed by two doses of postoperatively administered 600 mg acetaminophen plus 60 mg codeine. Ibuprofen pretreatment resulted in significantly less pain than placebo or acetaminophen pretreatment as the local anesthetic wore off. Ibuprofen also resulted in less postoperative pain than acetaminophen plus codeine following the second dose. Side effects were similar across drug treatments and placebo with the exception of greater reports of drowsiness following the opiate-analgesic combination. These findings indicate that pretreatment with a nonsteroidal antiinflammatory drug, such as ibuprofen, results in a suppression of postoperative pain when compared to standard therapy without an increase in side effects.