Codeine Administration Research Articles

Midazolam Reduces Vomiting After Tonsillectomy in Children

Comment This investigation, which concluded that intravenous midazolam, 75 μg/kg, reduced vomiting after tonsillectomy in children, had a number of strong design features, including large (more than 100 patients) sample sizes, a power level of 0.80, and precise application of the nonparametric Fisher's exact test to assess differences between the placebo-and midazolam-treated groups in unscheduled hospital admissions for vomiting. This investigation also had a number of design weaknesses, including investigator bias, confounding by the administration of anesthetics and analgesics with emetic effects, and underrepresentation of males in both study samples. Investigator bias was introduced in the topic sentence that “hypothesized that midazolam would decrease vomiting after tonsillectomy in children.” Investigators should have remained neutral, unbiased observers, prepared to test the null hypothesis of no effect (midazolam equals placebo) with appropriate test statistics. Fentanyl, nitrous oxide, and neostigmine were administered intraoperatively to all patients and have been associated with postoperative vomiting (POV). Although both placebo and midazolam-treated groups received the same anesthetics, confounding between anesthetic adjuvants and POV could have been eliminated by avoiding known emetics and by administering air/oxygen, nonnarcotics, and short-acting muscle relaxants that do not require reversal. The postoperative administration of codeine, another emetic, may have also confounded assessment of POV in the treatment groups. The authors correctly emphasized that POV is age-related and that their study groups were similar for age, eliminating confounding by age. Unfortunately, POV is also sex-related, more common in adolescent females than males, especially at menarche and during menses. There were more females than males in both groups (placebo, 52% female; midazolam, 53% female) again confounding proper assessment of pure treatment effects, not sex-related effects, on POV. Finally, the study groups were separate and distinct (unpaired) and were assessed for effects and outcome differences appropriately with the unpaired t-test. Where was the paired t-test (to assess differences in the same group) applied? A possible application would have been to evaluate hospital admission rates for vomiting in each group separately, with each group serving as its own control, but this was not reported.

Effects of codeine, naproxen and dexamethasone on formalin-induced pain in the naked mole-rat.

A dilute solution of formalin (20 microliters of 10% formalin) was injected subcutaneously in the dorsal right hind paw of the naked mole-rat. The injection of the dilute formalin produced two periods of pain behaviour, the early (0-5 minutes) and the late phase (25-60 minutes). These were quantified as the total time spent licking the injected paw. Codeine phosphate (10, 25 or 50 mg kg-1) significantly reduced pain behaviour in both the early and late phase. Codeine administration also induced aggressive, hyperactive behaviour and motor impairment that was naloxone (2 mg kg-1) reversible. Naproxen (200 mg kg-1) and dexamethasone phosphate (30 mg kg-1) significantly reduced licking activity in the late phase only.

Differences between jejunal myoelectric activity after a meal and during phase 2 of migrating motor complexes in healthy humans.

Using an intraluminal probe with six pairs of annular electrodes, the myoelectric activity of the proximal jejunum was recorded during 48-hr sessions in 16 healthy volunteers receiving evening and noon meals (1000 kcal) and breakfast (400 kcal). In 10 subjects receiving no drug, the characteristics of the migrating motor complexes (period, duration of each phase, velocity of propagation of phase 3, duration of the postprandial disruption) varied markedly between subjects but were relatively constant from the first to the second day of recording. Single spike bursts propagated at a rate of 2-5 cm/sec, clusters of 3-10 spike bursts propagated at a rate of 0.5-1 cm/sec, and similar clusters recurring repetitively each 1.5-2 min were observed after the meals and very rarely in the fasted state during phase 2 of nocturnal migrating motor complexes. In six subjects, oral administration of codeine (50 mg) 1 hr before a meal induced migrating motor complexes in the postprandial state, with characteristics similar to that observed in the fasted state except a longer duration of phase 2. Single spike bursts and isolated and repetitive clusters of spike bursts were observed during phase 2 of the codeine-induced migrating motor complexes and after meals preceded by placebo, but very rarely during the phase 2 of nocturnal (fasted state) migrating motor complexes. It is concluded that the patterns of jejunal contractions consisting of propagated single spike bursts and isolated or repetitive spike bursts characterize the postprandial state in healthy humans and are dependent upon digesta flow.

Forensic Drug Testing for Opiates, III. Urinary Excretion Rates of Morphine and Codeine Following Codeine Administration

The urinary excretion profile of free and conjugated codeine and morphine was determined by GC/MS for four healthy male subjects after intramuscular administration of 60- and 120-mg doses of codeine. Codeine and metabolites were rapidly excreted with the majority of drug appearing in the first 24 h. No dose-related differences in metabolism were observed. The initial ratio of total codeine to total morphine was substantially greater than 1.0 but declined over time. For two of the four subjects, the codeine-morphine ratio declined below 1.0 late in the elimination phase. With a 300-ng/mL cutoff, one subject tested positive on more than one occasion for total morphine and negative for codeine during the terminal elimination phase. The data indicate that urine codeine-morphine ratios are not reliable indices of the type of opiate exposure.

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Forensic Drug Testing for Opiates: I. Detection of 6-Acetylmorphine in Urine as an Indicator of Recent Heroin Exposure; Drug and Assay Considerations and Detection Times

The urinary excretion patterns of 6-acetylmorphine (6-AM), free morphine, and total morphine were determined by GC/MS assay for six human subjects who received single doses of 3.0 and 6.0 mg of heroin hydrochloride. Clinical specimens were collected and combined with standardized drug urines into a 400 specimen/standard set. The urines were coded, randomized, and analyzed under blind conditions. The GC/MS assay had a limit of sensitivity of 0.81 ng/mL for 6-AM and displayed a linear response across a concentration range of 1-100 ng/mL. Following heroin administration, 6-AM was excreted rapidly with an average half-life of 0.6 h. This resulted in a very short detection time for 6-AM with a range of 2-8 h at the most sensitive cutoff limit. This short detection time limits the usefulness of 6-AM as a marker for identification of heroin abusers to a period immediately after drug use. In contrast, free morphine and total morphine were detectable up to approximately 24 h after heroin administration. The average half-life for free morphine was 3.6 h and for total morphine was 7.9 h. After morphine and codeine administration, no 6-AM was detected by GC/MS above the 0.81-ng/mL detection limit of the assay. It is concluded that the presence of 6-AM in urine can be interpreted with confidence to mean that heroin, or 6-AM, was administered within 24 h of specimen collection and that the presence of 6-AM in urine is not caused by morphine or codeine administration.

Effect of Codeine on the Sensations Elicited by Loaded Breathing

The present study examined the effect of codeine, a centrally acting opiate, on the respiratory sensations elicited in normal subjects by breathing to exhaustion against externally applied inspiratory threshold loads. Subjects were tested on two separate days following the double-blind, randomized administration of either placebo or codeine (90 mg). The intensity of the sensations of effort and discomfort experienced during two loaded breathing trials (a "high" load that was 73% of the maximum inspiratory pressure (MIP) and a "low" load that was 63% of the MIP) was evaluated using category (Borg) scores on each day of study. To verify that the dosage of codeine administered was sufficient to produce analgesia, we also determined the effect of this dosage on the time that subjects could tolerate immersion of one hand in ice water. Codeine altered neither the perceived effort nor the sense of discomfort associated with breathing against external loads and had no appreciable effect on the time to exhaustion during loaded breathing trials. This dose of codeine did, however, increase the time that ice water immersion could be tolerated and reduced the rate at which the sense of discomfort increased over time during ice water trials. These results indicate that, provided the pressure-time index of respiratory muscle contraction remains constant, analgesic doses of codeine alter neither the sensations elicited by loaded breathing nor the total time that breathing against a fatiguing inspiratory load can be tolerated.

Morphine formation from codeine in rat brain: A possible mechanism of codeine analgesia

The O-demethylation of codeine to morphine was demonstrated in rat brain homogenate. Maximal formation occurred at 10 minutes, with a Vmax of 5.93 +/- 0.16 nmol/g brain/h and Km of 37.82 +/- 4.99 microM. The formation was significantly (P less than 0.05) greater in the microvessel-rich brain fraction. Intraperitoneal injection of codeine in the rat resulted in brain concentrations of morphine which could not be solely attributed to transfer of morphine from the blood stream across the blood-brain barrier. Morphine formed in the brain after codeine administration may be an important mechanism for codeine-induced analgesia.

CHANGES IN PUPIL DIAMETER AFTER ORAL ADMINISTRATION OF CODEINE

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).

Excessive grooming induced by the administration of codeine and morphine

Previous studies have shown that peripheral injections of the codeinone RX 336-M can induce excessive grooming in rats in an age-dependent fashion. The present experiment demonstrates that codeine, itself, also induces excessive grooming but with apparent equal effectiveness at all ages tested. Because of the structural similarity between codeine and morphine, the effects of intraperitoneally administered morphine were examined as well. Morphine was found to produce a temporal course of excessive grooming quite different from that produced by codeine. Morphine did not affect grooming in the first half (30 min) of the observation period, but accentuated it, briefly, for the next 30-45 min. Intraventricular administration of codeine at doses of 0.3 or 1.0 microgram/3 microliter had no effect on grooming in animals previously shown to demonstrate excessive grooming in response to either dose.

Codeine produces a cholinergically mediated analeptic effect in rats and rabbits.

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.

Oral administration of codeine in the presence of ethanol: a pharmacokinetic study in man.

Three healthy male volunteers were given a codeine (1 mg/kg) solution in the absence and presence of ethanol in a cross-over designed study. The blood ethanol concentration was kept at approximately 16 mM for 8 hrs. Blood samples were taken at several occasions during the first day after the codeine administration. Urine was sampled during three days. There were no significant differences in the area under serum concentration versus time curve in the absence and presence of ethanol with respect to free codeine, total codeine and total morphine. The fraction of codeine glucuronized in serum (approximately 94%), the maximum serum concentration of free (0.34 microM) and total codeine (6.3 microM), the time to reach the maximum serum concentration values (approximately 65 min.) were also similar in the absence and presence of ethanol. The accumulated percentage of the codeine dose given which was found as codeine and morphine and their conjugates in the urine ranged from 50 to 91 percent in the different subjects. The accumulated percentage of the administered codeine dose found as free morphine in the urine, was significantly lower in the ethanol exposed individuals (0.18 +/- 0.03%) compared to the controls (0.39 +/- 0.09%). The percentage of the codeine dose found in the urine in the control situation as free codeine (5.2 +/- 2.2%) was not statistically different from the amount found in the urine after ethanol treatment (4.3 +/- 2.0%). The percentage glucuronized morphine (95.3 +/- 0.4%) and codeine (91.9 +/- 2.2%) in the urine in the absence of ethanol was similar to glucuronized morphine (95.3 +/- 2%) and codeine (93.1 +/- 3%) after ethanol exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Codeine-mediated hepatotoxicity in isolated rat hepatocytes

Administration of codeine to freshly isolated rat hepatocytes resulted in cytotoxicity characterized by a dose- and time-dependent leakage of lactate dehydrogenase (LDH) out of the cells. Codeine also caused a decrease in hepatic reduced sulfhydryl content. Cytochrome P-450 content and NADPH levels were not changed. Induction and inhibition studies of several potential pathways of codeine biotransformation were carried out in order to determine if codeine must be metabolized to a reactive intermediate to elicit these hepatotoxic effects. Codeine hepatotoxicity as measured by LDH release was not changed after induction of cytochrome P-450 by phenobarbital and was decreased after cytochrome P-448 induction by β-naphthoflavone. However, codeine hepatotoxicity was inhibited when an inhibitor of cytochrome P-450 metabolism, metyrapone, was added. Inhibition of the other major hepatic oxidative enzyme system, flavin adenine dinucleotide (FAD)-containing monooxygenase, increased the cytotoxicity of codeine. Inhibition of alcohol dehydrogenase had no effect on codeine hepatotoxicity. These results indicate that codeine hepatotoxicity is caused by a cytochrome P-450-generated intermediate of codeine, whereas FAD-containing monooxygenase may metabolize codeine to a nontoxic intermediate.

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 crossover 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 Pco 2 at 24 hours ( P<0.01) and at 1 month ( P<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.

Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration.

Plasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2-3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.

359 NEONATAL APNEA AND MATERNAL CODEINE USE

The occurrence of apnea in term and near term neonates is usually associated with a definitive organic etiology. We have recently studied 4 infants (x GA=37 wks, range 35-40 wks; x BW= 2660g, range 1980-3140g) with significant apnea and increased periodic breathing. All infants had been born by cesarean section (apgars 8/9) following uncomplicated perinatal courses and were well until 4-6 days of age when apnea developed. Complete bacteriologic, hematologic, metabolic, and cardiac evaluations were normal. Cardiorespirograms were abnormal showing multiple episodes of short apnea (5–10 sec x=25.5, range 15–39; 10-15 secs x=23, range 10-35) and increased periodic breathing (x=16.3%, range 1-35%). One episode of prolonged apnea (>20 secs) and multiple bradycardias were seen in one patient.All mothers had been breast feeding and receiving codeine 60 mg every 4–6 hours for analgesia. Breast feeding was held for 24 hours and the codeine discontinued. Codeine was not detected in the serum of one infant. Apnea resolved within 24–48 hours and the infants were discharged. Repeat cardiorespirograms within 7-10 days were normal. Experience in these 4 infants suggest: 1)Although only trace amounts of codeine are reported to enter breast milk, it may be sufficient to affect newborn respiratory control. 2)The metabolism of codeine in the newborn is uncertain. It may take 4–5 days for sufficient drug to accumulate and influence respiratory control. 3)Caution should be used with codeine administration in breast feeding mothers.

Codeine-induced memory changes: nature and relationship to opiate system.

Learning and recall processes were studied in three experiments with 33 subjects, 1 and 3 h after oral administration of codeine phosphate 25 mg, 50 mg and 100 mg. Recall was measured 3 and 24 h after drug administration. Nine subjects received naloxone i.m. with the 50 mg dose of codeine. Learning and memory were assessed by using associative, serial and concept learning tasks. Flicker fusion frequency was measured to assess the general vigilance level of the subjects. Learning performance in the serial learning task was improved 3 h after administration of codeine 100 mg. Recall in the serial learning task was also improved after codeine 25 mg, but only when the material was learnt after 1 hour and was recalled 24 h after drug intake. To demonstrate the enhanced recall both learning and recall had to take place under the same drug condition. The same test showed a tendency to enhanced recall after codeine 50 mg of material learnt 1 hour after drug intake and recalled 24 h later. This effect was counteracted by naloxone. The data are consistent with the hypothesis that codeine may exert its action via opiate receptors and that this system participates in memory functions.

Pharmacokinetics of Nicocodine in Rats

Abstract The antitussive Nicocodine (Codeine-6-nicotinic acid ester) exhibits at least twice the potency of codeine in clinical experiments. The study of the pharmacokinetic behaviour of nicocodine by means of blood and brain level curves of rats after i, v. application showed that the penetration of the blood brain barrier seems to be favoured for nicocodine. The detected peak concentration of nicocodine in brain after i. v. application is 4, 4 times higher than the blood level values at the same time – codeine the main metabolite is detected in almost equal amounts in brain and blood. A comparative assay of codeine and nicocodine after p. o. application of equimolar doses per kg body weight revealed that predominantly codeine Is found in brain and its peak value after nicocodine administration is 3-fold higher than after codeine administration. Free morphine as further metabolite can also be traced, but in relatively low concentrations. It seems that in the case of nicocodine the bioavailability for the...

Regional cerebral hemodynamics during migraine and cluster headaches measured by the 133Xe inhalation method.

SYNOPSISMeasurements of noninvasive regional cerebral blood flow (rCBF) were made by the 133Xe inhalation method in 71 patients with different types of headache and 32 age matched normal controls. Flow gray (Fg) was calculated by two compartmental analysis from the x‐ray subtracted gamma curves, and extracerebral flow indices (EFI) were calculated as an estimate of the percentage contribution by extracerebral tissues.During the headache phase, mean Fg in a group (N = 13) with classic and common migraine was significantly higher compared to a comparable group (N = 12) measured in the headache‐free interval. Serial measurement made during progression in the severity of the migraine headaches showed accompanying increases in the mean Fg as the headache worsened. In 24 patients with severe migraine studied 2‐48 hours after the headache subsided, the mean Fg values remained significantly increased during this immediate post‐headache interval compared with patients who were headache‐free for six days or longer. Serial measurements made during and after the headache showed progressive reduction of mean Fg values to normal within six days after the headache subsided. Marked cerebral dysauto‐regulation was present during the migraine headache and showed progressive recovery as the headache subsided. Reduction of the head pain by administration of codeine decreased hemispheric Fg values but did not change the high flows in the basilar artery territory. Conversely, administration of ergotamine did not change hemispheric Fg values but reduced rCBF in brain stem‐cerebellar regions. Significant regional reductions of Fg correlating with the neurological deficit was measured during the prodrome of classic migraine and during the headache and post‐headache intervals of complicated migraine. During cluster headaches, mean Fg values were also significantly increased and the extracerebral flow indices showed marked increases with highest values recorded at the site of the headache. It was concluded that cerebral hyperperfusion during migraine headaches is mainly due to post‐ischemic reactive hyperemia but may be compounded by functional hyperemia due to the head pain itself.

Simultaneous determination of codeine and morphine in biological samples by gas chromatography with electron capture detection.

A sensitive gas chromatographic method for the simultaneous determination of codeine and morphine in plasma and brain samples is described. The method involves solvent extraction of the compounds from plasma, derivatization with pentafluoropropionic anhydride and subsequent separation on a 3% OV-17 column. The quantification is performed with electron capture detection. The sensitivity of the method (0.75 ng of morphine and 7.5 ng of codeine in a sample) makes it especially useful for pharmacokinetic investigations. The method was successfully applied to determine the time course of codeine and its metabolite morphine after intravenous administration of codeine to the rat.