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A nonsolvolytic (solid-state) acetylation of codeine phosphate in the presence of aspirin to yield acetylcodeine phosphate is reported. GLC assays for the simultaneous determination of aspirin and salicylic acid and codeine and acetylcodeine are described. The apparent heat of activation for codeine phosphate is estimated, and the possible reaction mechanisms are discussed.
Scheduled infusions of naloxone (1-100 micrograms/kg/inf.) and of buprenorphine (250 micrograms/kg/inf.) generated drug avoidance behavior in the non-dependent rhesus monkey under a continuous avoidance-escape paradigm. Pentazocine (1-100 micrograms/kg/inf.) codeine, (1-100 micrograms/kg/inf. and tilidine (1-250 micrograms/kg/inf.) were ineffective. Addition of varying doses of naloxone to scheduled infusions of codeine, tilidine, and pentazocine generated avoidance behavior not present with scheduled infusions of these opioids alone. The naloxone doses necessary for generation of avoidance behavior were low with the agonists codeine and tilidine, higher with the weak antagonist pentazocine, and highest with the strong antagonist buprenorphine. When monkeys were presented with the fixed tilidine-naloxone combination (100 + 8 parts) and pentazocine-naloxone combination (100 + 1 part) and the buprenorphine-naloxone combination (100 + 66 parts) presently in clinical use only the tilidine-naloxone combination generated drug avoidance behavior to an appreciable extent.
The aim of the present double-blind, placebo controlled, three-way cross over study was to evaluate the analgesic efficacy of single oral doses of paracetamol 1.0 g and paracetamol 1.0 g plus codeine 60 mg. Pain threshold and brain evoked potentials to laser stimulation were determined hourly for 6 h in 12 healthy volunteers. Pain threshold was significantly elevated compared to placebo 1 and 2 h after paracetamol ingestion. Paracetamol 1.0 g plus codeine 60 mg was superior to placebo 1 to 6 h after medication. Only at 1 and 2 h after ingestion the combined drug was better than paracetamol. The evoked potentials were significantly depressed compared to placebo 2 and 4 h after paracetamol. The combination of paracetamol and codeine was superior to placebo 1 to 6 h after ingestion. The potentials showed no difference between the two active drugs. The total analgesic effect (approximation of area under the time-efficacy curve), showed that the combined drug was superior to plain paracetamol. A higher incidence of adverse effects in 10 of the 12 subjects was observed after ingestion of the combined drug compared to plain paracetamol (1 of 12). Paracetamol appears to exert part of its action by a central effect. There was at least 1 h between the peak plasma concentration of paracetamol and the peak hypoalgesia.
In nine healthy volunteers, the clearance and metabolism of acetaminophen 1000 mg i.v. was evaluated with and without two concomitant oral doses of codeine in order to investigate a possible interaction. Plasma acetaminophen was followed for 720 min and urine was collected for 24 h after each dose for determination of metabolites. When codeine was coadministered, the average total clearance of acetaminophen and its clearance by glucuronidation, sulphation and mercapturate formation were 0.58 to 1.12-times the control values. It is concluded that therapeutic doses of codeine do not influence the clearance or metabolism of acetaminophen.
Capillary gas chromatography coupled to mass spectrometry was employed to quantify codeine in biological fluids and tissues in a death attributed to oral codeine ingestion. The blood concentration of codeine was 22.1 mg/l. Results are discussed in the light of the existing literature.
The O-demethylation of codeine (methylmorphine) into morphine is mediated by the polymorphic cytochrome P450 DB1 (P450 IID6). By means of in vitro screening in human liver microsomes we have studied the effect on codeine bioactivation of several drugs used as analgesics or as adjuvants for pain control. In microsomes from an extensive metabolizer subject, paracetamol (acetaminophen) and NSAIDs (acetylsalicylic acid, diclofenac, indomethacin, piroxicam, and pirprofen), benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flunitrazepam, and midazolam), and anticonvulsants (carbamazepine and phenytoin) did not alter the reaction. There was marked inhibition of in vitro morphine production by neuroleptics (chlorpromazine, haloperidol, levomepromazine, and thioridazine), metoclopramide, and tricyclic antidepressants (amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline). Enzyme kinetics showed competitive inhibition by neuroleptics (chlorpromazine Ki = 0.5 microM) and antidepressants (clomipramine Ki = 6.8 microM), which are substrates of the polymorphic monooxygenase. Due to the low affinity of codeine for P450 DB1 (Km = 100-200 microM), its bioactivation in extensive metabolizers, and thus its analgesic efficacy, is liable to vary greatly when it is combined with any drug that has a high affinity for the polymorphic isozyme.
The intravenous administration of codeine to diazepam-narcotized rabbits resulted in a shortened duration of loss of righting reflex. Coadministration of naltrexone plus codeine enhanced this analeptic effect and was also effective in shortening the duration of pentobarbital narcosis. The analeptic effect was blocked by atropine, but not by methylatropine, indicating involvement of a central cholinergic mechanism. In rats the analeptic activity correlated with the reversal of the diazepam-induced fall in sodium dependent high affinity choline uptake in hippocampal and cortical synaptosomes. These findings may represent the pharmacological basis of the recently reported antinarcoleptic action of codeine in man.
The analgesic efficacy and toxicity of oral diclofenac sodium 50 mg (q.i.d.) vs. nefopam 60 mg (q.i.d.) and a combination of 640 mg ASA and 40 mg codeine (q.i.d.) in cancer patients with moderate to severe chronic pain has been evaluated in a randomized double-blind study. Planned duration of treatment was 10 days. Pain intensity was evaluated by a visual analog scale. The length of patient participation in the trial, the patient's final global evaluation and the incidence of side effects were also evaluated. Ninety-nine patients were enrolled in the study. All treatments produced a statistically significant pain relief (P less than 0.01) without differences among groups but only 26 of 99 patients (26.3%) completed the planned treatment period. Mean time in the study was 4.65 days. Inefficacy and side effects were the main reasons for premature treatment interruption. Patients treated with nefopam had a significantly shorter period in the study than patients treated with the other 2 treatments. Adverse effects were slightly more frequent with the nefopam and ASA + codeine regimens. The 3 therapeutic regimens appear to be similar as to analgesic efficacy, but diclofenac presents the advantage of a slightly better safety profile than nefopam and the ASA + codeine combination.
A rapid and sensitive HPLC method has been developed for the determination of codeine, norcodeine and morphine in small volumes of a biological matrix, using a cyanopropyl column and a combination of coulometric and UV detection. The compounds were isolated using C18 solid-phase extraction cartridges prior to quantitative analysis. The limit of detection was 250 pg/ml for morphine and 5 ng/ml for both norcodeine and codeine. Recovery of each compound was greater than 90% and intra- and inter-assay precision was better than 10%. The method has been used to study the metabolism of codeine in microsomal incubations.
Codeine, ethylmorphine and morphine are the most commonly detected opiates in forensic blood samples in Norway. A method for the simultaneous quantification of these opiates utilizing solid phase extraction and gas chromatography-mass spectrometry has been evaluated. The detection limits were 0.026 mumol/l for codeine, 0.025 mumol/l for ethylmorphine and 0.032 mumol/l for morphine (corresponding to 7.8, 7.8 and 9.1 micrograms/l, respectively). The analytical variations at concentrations of 1.0 mumol/l codeine, 1.0 mumol/l ethylmorphine and 0.5 mumol/l morphine were less than 5%.
GC-MS is one of the recommended analytical techniques for the identification and confirmation of opiates in urine. A method for the qualitative detection and quantitation of codeine and morphine in urine samples by this technique has been developed. This method is also suitable for the detection of their main metabolites in urine: norcodeine and normorphine. It also allows the identification of 6-monoacetylmorphine in urine, which can be used as a confirmatory marker of heroine abuse. The derivatized compounds are separated by capillary gas chromatography (GC) and identified by mass spectrometry (MS) in the selective ion monitoring acquisition mode (SIM). The recoveries from urine at concentrations of 1000 ng ml-1 are 72% for codeine and 80% for morphine. The method is linear in the range studied (0-1000 ng ml-1) for codeine and morphine.
Codeine often causes gastrointestinal cramping and pain. Treatment for such symptoms is usually symptomatic and supportive. Although naloxone is commonly used to treat other medical problems due to opiates, its use in treating such cramping has not been previously reported. The authors present four cases in which naloxone (Narcan) was used with success in relieving gastrointestinal side effects that were apparently due to codeine. It is suggested that patients with gastrointestinal symptoms and a history that strongly implicates codeine as the etiology be treated with naloxone.
Codeine O-demethylation to its active moiety morphine was investigated in human liver microsomes from 1 poor and 5 extensive metabolizer subjects (debrisoquine-type of oxidation polymorphism). Apparent Km of the reaction in one extensive metabolizer's microsomes was 149 microM and Vmax 17.6 nmol X mg P-1 X hour-1 versus greater than 1 mM and 1.6 nmol X mg P-1 X hour-1 respectively in one poor metabolizer. In vitro morphine production was competitively inhibited by quinidine (Ki 15 nM), the selective inhibitor of cytochrome P-450 dbl/bufI. There was also an excellent correlation between dextromethorphan O-demethylation, a prototype reaction for cytochrome P-450 dbl/bufI activity, and codeine O-demethylation. These data allow to conclude that codeine bioactivation to morphine is dependent on the polymorphic monooxygenase known as cytochrome db1/bufI.
A stability-indicating high-performance liquid chromatographic method has been developed for the simultaneous determination of acetaminophen, codeine phosphate and sodium benzoate in an elixir formulation. The reversed-phase paired-ion method utilizes UV detection at 214 nm, a C18 column at 50 degrees C and requires ca. 10 min per analysis. The method has been validated for use with elixirs containing 120 mg of acetaminophen, 12 mg of codeine phosphate and 7.5 mg sodium benzoate preservative per 5 ml. The known potential degradation products p-aminophenol, codeine N-oxide and codeinone are separated for quantitation simultaneous with the parent compounds. The method has been shown to be linear, reproducible, specific, sensitive and rugged.
A high-performance liquid chromatographic method has been developed for the simultaneous determination of acetaminophen and codeine phosphate for product stability studies, and release and dissolution testing of tablets and capsules. The reversed-phase method utilizes UV detection at 214 nm, a C18 column and requires a maximum of 10 min per analysis. The method has been validated for use with products containing as much as 500 mg of acetaminophen and as little as 7.5 mg of codeine phosphate. The known potential degradation products, p-aminophenol, codeine N-oxide, and codeinone are separated for quantitation simultaneous with the parent compounds. The method has been shown to be linear, reproducible, specific, sensitive and rugged.
A specific and highly sensitive capillary column gas chromatographic method was developed for the simultaneous determination of codeine and chlorpheniramine in human plasma. The method involves a solvent extraction and analysis by capillary column gas chromatography on a cross-linked 50% phenylmethyl silicone fused-silica capillary column with flame thermionic detection. A 10% solution of n-butanol in toluene was used as extraction medium and pyrilamine was used as internal standard. Reproducibility, linearity of calibration curves and specificity were all satisfactory with both drugs. The plasma concentration of codeine and chlorpheniramine could be measured at levels down to 0.9 ng/ml as codeine phosphate and 0.4 ng/ml as chlorpheniramine maleate, respectively. The method was applied to plasma samples from normal volunteers, and was confirmed to be adequate for biopharmaceutical and pharmacokinetic studies.
Endogenous codeine and morphine were identified in rat brain by immunological determination following HPLC. To demonstrate occurrence of a biosynthetic pathway to morphine in mammals similar to that used by the poppy plant, (+)-salutaridine, (-)-thebaine, and (-)-codeine were administered to rats intravenously. These compounds, which are intermediates in the synthesis of morphine in Papaver somniferum, caused a marked increase in the codeine and morphine levels in rat tissues. This provides evidence for a biosynthetic pathway to morphine in mammalians.
Pupillary constriction occurs following administration of opioids and may be used as a marker of opioid activity. We have measured plasma concentrations and pupil diameters in 16 healthy volunteers after the oral administration of placebo or codeine. Pupil size decreased significantly after codeine compared with placebo. Pupil size was related to the plasma concentrations of codeine (P less than 0.05).