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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↗

PubMed1995

Determination of codeine and metabolites in plasma and urine using ion-pair high-performance liquid chromatography.

A reversed-phase ion-pair high-performance liquid chromatographic method for the simultaneous determination of codeine and seven metabolites is described. The samples are purified by reversed-phase solid-phase extraction. Codeine, norcodeine, codeine-6-glucuronide, norcodeine-6-glucuronide and morphine-3-glucuronide are measured with UV detection. Detection limits are 3 nmol/l (morphine-3-glucuronide) to 20 nmol/l (codeine). Morphine, normorphine and morphine-6-glucuronide are measured with electrochemical detection. Detection limits are 0.4 nmol/1 (morphine-6-glucuronide) to 1.0 nmol/l (normorphine). Correlation coefficients better than 0.998 are normally obtained for all compounds. The method was applied to the determination of the kinetics of codeine and its metabolites in plasma and urine samples from healthy volunteers.

Calibration↗

PubMed2001

Precipitated withdrawal following codeine administration is dependent on CYP genotype.

The role of metabolic polymorphism in the development of physical dependence to codeine was assessed in cytochrome P450 2D2 (CYP2D2) deficient Dark Agouti and CYP2D2 intact Sprague-Dawley rats by assessment of the severity of naloxone precipitated withdrawal after codeine and morphine administration. Plasma morphine concentrations after codeine were significantly higher (P<0.01) in Sprague-Dawley than in Dark Agouti rats with metabolic ratios of 0.71 +/- 0.27 and 0.07 +/- 0.04, respectively. Withdrawal after codeine resulted in significantly greater hypothermia (3.5-4 degrees C, P<0.0001) in Sprague-Dawley animals compared to the other groups. Body weight loss was similar for all groups ranging from 6.2 +/- 0.4 to 8.2 +/- 0.6 g. When strain and treatment data were combined, a relationship between body temperature and plasma morphine concentration could be described by the inverse Hill equation (r(2)=0.76, EC(50)=556 +/- 121 ng/ml, n=2.9 +/- 1.5). These data indicate that dependence and withdrawal after codeine administration are dependent on its bioconversion to morphine.

Analgesics, Opioid↗

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↗

PubMed1997

A comparison of ibuprofen versus acetaminophen with codeine in the young tonsillectomy patient.

OBJECTIVE: To compare the use of ibuprofen with the use of acetaminophen with codeine for posttonsillectomy management. BACKGROUND: We were not satisfied with our traditional pain-management practice for tonsillectomy patients. We hoped to find a new approach for improved patient comfort and avoid scheduled, abusable drugs such as codeine. DESIGN: Intervention, prospective, randomized control trial. Follow-up was 1 month. SETTING: University referral center; institutional pediatric practice, ambulatory. PATIENTS: 110 children undergoing tonsillectomy with or without other procedures. Consecutive patients were offered participation. Enrollees were randomly assigned to one of two classes and analyzed with the initial assignment. No patients withdrew for adverse effects, although 12 in group 2 used codeine and 5 of those used acetaminophen, whereas 2 in group 1 received ibuprofen. INTERVENTIONS: Patients received either acetaminophen with codeine (group 1) or ibuprofen (group 2) for postoperative pain control. MAIN OUTCOME MEASURES: The main outcomes, determined before initiation of the study, were assessment of (1) postoperative bleeding, (2) pain, (3) efficacy of relief of pain by drug, (4) nausea, (5) emesis, (6) readmission to hospital, (7) average temperature, and (8) highest temperature after surgery. RESULTS: The only statistically significant difference is less nausea in patients receiving ibuprofen (p = 0.0049). Of note, no difference existed in postoperative bleeding, pain, or temperature control. CONCLUSIONS: Ibuprofen is at least as effective as acetaminophen with codeine for postoperative pain control in children after tonsillectomy.

Acetaminophen↗

PubMed2000

Single-dose vicoprofen compared with acetaminophen with codeine and placebo in patients with acute postoperative pain after third molar extractions.

PURPOSE: The purpose of this double-blind, randomized study was to compare the efficacy and safety of a single dose of the following medications: 2 tablets of Vicoprofen (ibuprofen 200 mg/hydrocodone 7.5 mg; Knoll Pharmaceutical Co, Mount Olive, NJ), 2 tablets ofp6 acetaminophen with codeine phosphate (acetaminophen 300 mg/codeine 30 mg), and 2 tablets of placebo in the management of moderate to severe postoperative dental pain after surgical extraction of at least one impacted mandibular third molar. PATIENTS AND METHODS: One hundred twenty-five patients (75 women, 50 men) participated in the study. The time of first perceptible pain relief and meaningful pain relief were measured using a stopwatch technique. Pain intensity and pain relief scores were recorded using standard verbal descriptors at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours after dosing. At the conclusion of the study, patients completed a global evaluation for the effectiveness of the study medication. RESULTS: Both active treatments were superior to placebo for all analgesic measures. Pain relief scores were significantly better for Vicoprofen than placebo throughout the study and significantly better than for acetaminophen with codeine from 2 through 8 hours after dosing. The duration of analgesia (time to remedication) was significantly longer for Vicoprofen (median, 5.50 hours) compared with acetaminophen with codeine (median, 3.03 hours) and placebo (median, 1.00 hours). Mean global evaluation for Vicoprofen was significantly better than for placebo and acetaminophen with codeine. Overall, there were no significant differences in the adverse event profile among the 3 treatment groups. CONCLUSIONS: Vicoprofen was found to be an effective postoperative analgesic medication in the management of acute postoperative dental pain. Its total analgesic effect, duration of analgesia, and global evaluation were superior to acetaminophen with codeine and placebo in this study model.

Acetaminophen↗

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↗

PubMed2000

LC and LC-MS-MS analyses of undeclared codeine in antiasthmatic Chinese proprietary medicine.

This paper describes an accurate and sensitive reversed phase high-performance liquid chromatographic (RP-HPLC) method for the detection and quantification of undeclared codeine in a Chinese Proprietary Medicine (CPM) for asthma. A rapid and specific liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) method was applied to confirm the presence of codeine by selected reaction monitoring (SRM). Codeine was extracted from the capsules by dissolving in sodium dihydrogen phosphate buffer (10 mM, pH = 2.2) and ethanol, then made alkaline (pH = 9) and extracted using chloroform. The amount of codeine in AsthmaWan was found to be 61.8 microg/capsule (R.S.D. = 7.9%, n = 9). Excellent resolution was obtained despite the complexity of the product which claimed to contain at least nine herbal ingredients, none of which will give rise to codeine. As a further confirmation method, LC-MS-MS is accurate and specific. The LC method has been validated for linearity, limit of detection, limit of quantification, accuracy and specificity. Greater awareness of and control over undeclared drugs in complementary medicine are necessary to ensure patients' safety.

Anti-Asthmatic Agents↗

PubMed1999

Stool water content and colonic drug absorption: contrasting effects of lactulose and codeine.

PURPOSE: By varying stool water content using lactulose and codeine, we investigated the influence of luminal water content on the absorption of quinine, a transcellular probe, and 51Cr-EDTA, a paracellular probe, from the distal gut. METHODS: Sixteen volunteers entered a three-way cross-over trial in which absorption of probe markers from a timed-release delivery system was determined following treatment with lactulose 20 mls tds (increasing water content), or codeine 30 gms qds (decreasing water content), and compared with control untreated values. Stool water content was assessed by freeze drying stool samples. Site of release was determined by gamma scintigraphy, and absorption was measured by plasma levels and urinary recovery of the marker probes. RESULTS: Lactulose accelerated ascending colon transit (3.7 +/- 0.8 vs 4.5 +/- 1.4 hrs, p < 0.05), increased stool water content (75 +/- 2 vs 71 +/- 2%, p < 0.01), caused greater dispersion of released material (dispersion score 3.4 +/- 0.3 vs 1.8 +/- 0.2, p < 0.01), and enhanced absorption of the transcellular probe quinine (4.66 +/- 0.78 vs 3.02 +/- 0.63%, p < 0.05) compared to control. Conversely codeine slowed ascending colon transit (8.9 +/- 1.8 hrs), reduced stool water content (61 +/- 2 vs 71.2%, p < 0.05), and tended to diminish absorption (2.60 +/- 0.77 vs 3.02 +/- 0.63%, p = 0.20). Within the ascending colon specifically, there was a significant trend for treatments increasing luminal water content to enhance quinine absorption (medians: codeine = 1.2%, [n = 81 < control = 2.3%, [n = 5] < lactulose = 3.2%, [n = 71, p < 0.01). Delivery site also had an important influence on absorption, with more distal release resulting in less absorption in the control arm (medians: small intestine = 4.4% [n = 5] > ascending colon = 2.3% [n = 5] > transverse colon = 1.5% [n = 6], p < 0.005). CONCLUSIONS: Lactulose accelerates transit, increases stool water content, and enhances drug absorption from the distal gut whilst codeine slows transit, decreases stool water content, and tends to diminish absorption, compared to controls. We conclude that water content may be an important determinant in colonic drug absorption.

Adult↗

PubMed1981

Fenoprofen and codeine analgesia.

Studies were conducted on postpartum and postoperative patients to estimate the dose-response line of fenoprofen and to contrast it with codeine and placebo. The postpartum patients included women with episiotomy pain and with uterine cramping. This mix allowed contrast of ability of the various pain models to distinguish codeine from placebo. The methodology for the studies was single-dose parallel groups design with interviews conducted by trained nurse observers to obtain subjective responses. More than 850 patients participated in the trial. The results indicate that fenoprofen at doses as low as 12.5 mg has analgesic properties. In each of the five studies, the mean value of 100- and/or 200-mg doses of fenoprofen for the variable sum of the pain intensity difference (SPID) was higher than that of 65 mg codeine. The pooled relative potency calculation based on SPID suggests that 100 mg fenoprofen is approximately equivalent to 60 mg codeine. In their ability to distinguish codeine from placebo, patients with uterine cramp, episiotomy, or surgical pain did not appear to differ.

Analgesics↗

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↗

PubMed2002

Growth hormone replacement therapy induces codeine clearance.

BACKGROUND: The increasing clinical use of growth hormone (GH) has raised questions about other than growth-related metabolic effects of this treatment. GH regulates the expression of several hepatic drug metabolising enzymes in the rat, but it is not known whether GH treatment alters the expression of such liver enzymes in man. We have investigated the effects of GH on codeine clearance and two enzymes of the cytochrome P450 (CYP) family, CYP3A and CYP2D6, and UDP-glucuronosyl transferase (UDPGT). These enzymes have a superior importance in hepatic biotransformation of numerous drugs. In addition, CYP3A and UDPGT are catalysts of many reactions with endobiotics such as steroid hormones. METHODS: We used codeine as a probe drug for assessment of the enzyme activities. Codeine was administered as a single-dose prior to, and after 3 months of GH substitution in GH-deficient patients. Total clearance, and clearance along each of the three primary metabolic pathways of codeine, was assessed. RESULTS: Three months of GH substitution increased the total clearance of codeine (21%, P < 0.01) and clearance catalysed by UDPGT significantly (31%, P < 0.05). The treatment tended to increase the clearance via the CYP3A pathway (83%, P = 0.05). CONCLUSIONS: The effects of GH replacement therapy on drug metabolism may have clinical implications when combined with drugs that are substrates of UDPGT and CYP3A. Effects on steroid hormone metabolism with endocrine consequences can not be ruled out.

Adult↗

PubMed2000

No effect of preoperative paracetamol and codeine suppositories for pain after termination of pregnancies in general anaesthesia.

Outpatient surgery demands rapid recovery and satisfied patients. The purpose of the study was to investigate whether rectal premedication with paracetamol and codeine would reduce the need of rescue analgesics, reduce the postoperative pain experience and result in faster eligibility for discharge. Ninety pregnant patients scheduled for day-case surgery with evacuation of the uterine cavity were randomly assigned into two groups. The paracetamol and codeine group was given a suppository with 60 mg of codeine and 800 mg of paracetamol together with standard premedication of intramuscular midazolam 0.08 mg/kg. The placebo group was given a placebo suppository and midazolam. All patients underwent the surgical procedure under general anaesthesia with alfentanil 15 microg/kg and propofol 1.5-2 mg/kg. There were no statistically significant differences between the groups in the postoperative pain experience as judged by Visual Analogue Scale (VAS-scale), verbal scale or the need for rescue analgesic medication with ketobemidone. Most of the patients experienced little postoperative pain with more than 70% scoring less than 20 mm on a VAS-scale from 0-100 mm at any time during the postoperative period. The paracetamol and codeine patients were significantly more sleepy at 30 min postoperatively. There were no differences between the groups in postoperative nausea or vomiting and no difference in discharge eligibility. The use of pre-operative suppository with paracetamol 800 mg and codeine 60 mg is unnecessary in this group of patients.

Abortion, Induced↗

PubMed1999

The role of codeine phosphate premedication in fibre-optic bronchoscopy under insufficient local anaesthesia and midazolam sedation.

Midazolam is widely used as a sedative agent to produce amnesia in patients undergoing fibre-optic bronchoscopy. However, if a patient does not receive sufficient local anaesthesia, continuous severe cough and physical movement may interrupt the procedure and reduce its safety. We therefore examined whether codeine phosphate is a useful premedication for bronchoscopy. The study design was a randomized comparison between codeine phosphate and a placebo in patients undergoing light local anaesthesia and midazolam sedation. We used low dose local anaesthesia (5 ml of nebulized 2% xylocaine) on the assumption of insufficient local anaesthesia. Patients were allocated to receive codeine phosphate 0.4 mg kg-1 or a saline placebo 60 min before they were sedated with i.v. midazolam. If the patients exhibited severe cough during bronchoscopy, intrabronchial supplemental local anaesthesia (2% xylocaine solution in 1 ml increments) was instilled via a bronchoscope to the trachea and segmental bronchi to suppress the cough. The dose of supplemental xylocaine was assessed and the requirements were significantly lower in the codeine group compared to the placebo group: 36.4 +/- 10.2 mg vs. 95.1 +/- 24.6 mg, respectively. After bronchoscopy, patients were interviewed by a doctor to assess their willingness to undergo a repeat procedure if one was clinically indicated, but no significant difference was observed between the two groups. If local anaesthesia is insufficient, midazolam together with codeine phosphate premedication is useful for both the patient and the bronchoscopist.

Aged↗

PubMed2002

Evaluation of ketorolac (Toradol) with varying amounts of codeine for postoperative extraction pain control.

This study analyzes the combination of oral ketorolac 10 mg with varying amounts of codeine phosphate, and the postoperative pain relief that developed from these combinations. Five groups of patients were administered the codeine/ketorolac combinations. Variations of the combinations were analyzed to ascertain if an optimal analgesic ratio existed. All controllable variables involved with the surgical procedure were held constant to allow for better evaluation of postoperative pain. Results obtained from 67 patients indicated that the best pain relief was achieved with a combination of 10 mg ketorolac and 15 mg codeine phosphate. Codeine alone provided adequate analgesia, but the addition of ketorolac reduced the patients' perceived side effects. The presence of codeine in the analgesic combination was also shown to reduce the number of days that the patient required the medication postoperatively. Reducing the duration of medication use postoperatively may also minimize the possible side effects of ketorolac and codeine, which could develop with extended periods of use.

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↗

PubMed1999

Analgesia after intracranial surgery: a double-blind, prospective comparison of codeine and tramadol.

We have compared codeine and tramadol in a prospective, double-blind study of postoperative analgesia in 75 patients after elective intracranial surgery. Twenty-five patients received codeine 60 mg, tramadol 50 mg or tramadol 75 mg i.m. Patients receiving codeine had significantly lower pain scores over the first 48 h after operation (P < 0.0001). Although there was no difference in visual analogue scale (VAS) scores between the three groups at 24 h, the codeine group had significantly lower scores at 48 h (P < 0.0001). The tramadol 75 mg group had significantly higher scores for both sedation and nausea and vomiting (P < 0.0001 for both scores). We conclude that codeine 60 mg i.m. provided better postoperative analgesia than tramadol after craniotomy and that tramadol 75 mg should be avoided because of its side effects of increased sedation and nausea and vomiting.

Adolescent↗