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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↗

PubMedDate not supplied

Excretion of codeine and morphine following ingestion of poppy seeds.

After the ingestion of three poppy-seed bagels, the following codeine and morphine concentrations were determined in the urine: 214 ng/mL codeine and 2797 ng/mL morphine at 3 h, and 16 ng/mL codeine and 676 ng/mL morphine at 22 h. This work indicates that a positive finding of codeine or morphine in the urine of an individual does not necessarily indicate heroin, morphine, or codeine use.

Codeine↗

PubMedDate not supplied

Determination of morphine and codeine in blood and bile by gas chromatography with a derivatization procedure.

Two gas chromatographic methods for the simultaneous quantitation of morphine and codeine in blood and bile from cases of opiate-related deaths are described. Both methods employ simple solvent extraction followed by hexane-ethanol partitioning clean-up and use nalorphine as the internal standard. The first method relies on the formation of trimethylsilyl derivatives and detection with a nitrogen-phosphorous detector. The second method involves the formation of heptafluorobutyryl derivatives and detection with an electron capture detector. Both methods are sensitive, able to detect down to 0.04 microgram/mL of morphine and 0.1 microgram/mL of codeine. Their wide linear dynamic ranges cover from low therapeutic to lethal levels for both morphine and codeine. The methods are amenable to batchwise operation and each analysis can be completed within three hours. The results of both methods correlate very well. The trimethylsilyl derivatives can be hydrolyzed and rederivatized for form heptafluorobutyryl derivatives for the second method, which then serves to confirm the results of the first method. Pholcodine, another common opiate, can likewise be determined. Average recovery was 80% for blood morphine and codeine and 60% for bile morphine and codeine.

Bile↗

PubMedDate not supplied

Forensic drug testing for opiates. V. Urine testing for heroin, morphine, and codeine with commercial opiate immunoassays.

Urine specimens collected after heroin, morphine, and codeine administration were tested by four commercial opiate immunoassays (TDx, CAC, ABUS, and EMIT) and GC/MS. Quantitative immunoassay results (morphine equivalents) were compared with results by GC/MS for total morphine, free morphine, or total codeine. Mean detection times for the broadly cross-reacting immunoassays (TDx, ABUS, and EMIT, 300 ng/mL cutoff) ranged from 15-44 hours following heroin and morphine administration and 33-54 hours following codeine administration. Detection times obtained with CAC (25 ng/mL cutoff) tended to be somewhat shorter as a result of the high selectivity of the antibody for free morphine. High correlations over a wide concentration range were obtained for TDx, CAC, and ABUS versus GC/MS, with specimens collected after heroin and morphine administration. EMIT showed a high correlation over a narrow concentration range (0-1000 ng/mL) with heroin and morphine specimens, but responses plateaued at higher concentrations. There was substantial variability in immunoassay responses with specimens collected after codeine administration. Generally, this study demonstrated that immunoassay responses for opiate urine testing can be used as a semi-quantitative guide for GC/MS confirmation; however, the presence of codeine increased variability and diminished the accuracy of the immunoassay response.

Codeine↗

PubMed1995

Analgesia after bilateral myringotomy and placement of pressure equalization tubes in children: acetaminophen versus acetaminophen with codeine.

Despite the brief nature of the procedure with limited tissue trauma, some form of analgesia is required in most children after bilateral myringotomy and placement of pressure equalization (PE) tubes. Previous studies have demonstrated the relative inefficacy of acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs), with 30%-55% of patients requiring supplemental postoperative analgesia. We undertook a prospective study evaluating the efficacy of the preoperative administration of oral acetaminophen (15 mg/kg) versus acetaminophen (10 mg/kg) and codeine (1 mg/kg). Fifty ASA grade I or II patients were randomized to receive oral midazolam premedication (0.7 mg/kg) mixed in either acetaminophen or acetaminophen with codeine elixir. Anesthesia was induced and maintained with halothane in nitrous oxide and oxygen. Postoperative pain was assessed at four times during the postoperative course using an objective pain scale. The two groups were similar with respect to age, weight, gender, duration of anesthesia, and duration of the surgical procedure. The patients who received acetaminophen with codeine had lower pain scores at all four points when compared with patients who received acetaminophen. None of the 25 patients who received acetaminophen with codeine required supplemental analgesics compared with 12 of 25 who received acetaminophen. No adverse effects were noted in either group. We conclude that the preoperative administration of acetaminophen with codeine provides superior analgesia after bilateral myringotomy and placement of PE tubes.

Acetaminophen↗

PubMed2002

Optimizing the hydrolysis of codeine and morphine glucuronides in urine.

Quality assurance data show that there is very significant inter-laboratory variation of the quantitation of codeine, especially in patient samples. The authors have examined hydrolysis procedures for codeine glucuronide (C6G) and morphine-3- and -6-glucuronides (M3G, M6G) because these are often present together in urine samples. Comparisons of hydrolysis using two different sources of beta-glucuronidases and various concentrations of hydrochloric acid were made. Samples were concentrated using solid phase extraction, derivatized and quantified by selective ion monitoring using gas chromatography-mass spectrometry (GC-MS). and beta-glucuronidase efficiently hydrolyzed M3G (90-95%), while hydrolysis of M6G was lower (60-85%) and that of C6G was very poor (45-58%). These findings were confirmed on examination of urine samples containing codeine and morphine from subjects who had taken codeine, morphine, or heroin. Erratic inter-laboratory quality assurance results for codeine are most probably a result of incomplete C6G hydrolysis. The authors' optimized hydrolysis method using 50% HCl for 1.5 hours at 120 degrees C gave reproducible results that approached the spiked concentration.

Codeine↗

PubMed1995

Patient-controlled analgesia (PCA) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan.

Postoperative pain relief with codeine was evaluated in 11 women undergoing hysterectomy. Patient-controlled analgesia (PCA) was used to administer codeine. After the study the patients were phenotyped with respect to the O-demethylation of dextromethorphan (cytochrome P4502D6 polymorphism). Ten were extensive metabolisers and one a poor metaboliser. There was a nine-fold variation in the minimum plasma concentration of codeine consistent with pain relief (40-350 ng ml-1). Two patients did not experience any effect of codeine, one of whom was a poor metaboliser of dextromethorphan, confirmed by genotyping. In the other nine patients the effective dose of codeine varied from 4.8-25.3 mg h-1.

Adult↗

PubMed1996

Analgesic efficacy of paracetamol and its combination with codeine and caffeine in surgical pain--a meta-analysis.

The objective of this study was to quantify the analgesic efficacy of paracetamol and its combination with codeine or caffeine through a systematic overview and meta-analysis of relevant randomized controlled trials (RCTs). Systematic retrieval of relevant clinical trials was carried out using computerized searches, historical searches and communication with manufacturers. The results of RCTs were pooled to estimate (i) the difference in percentage improvement of total pain relief (TOTPAR%) and the sum of pain intensity difference (SPID%); (ii) the proportions of patients obtaining moderate to excellent pain relief relative to placebo (ResRR) and (iii) the ratio of patients requiring analgesic re-medication (RemRR). Head-to-head comparisons were also undertaken for paracetamol versus its combination with codeine or caffeine. A total of 80 RCT reports describing 103 placebo comparisons and 26 head-to-head comparisons were identified. The total pain relief score in the single dose studies increased by 38 percentage points for paracetamol and by 24 points for placebo. The difference (d) in TOTPAR% between the two was highly significant (d = 14, 95% CI: 12, 16). For the difference in SPID%, d = 12, 95% CI: 11, 13. Patients were more than twice as likely to obtain moderate to excellent pain relief on paracetamol than on placebo (ResRR = 2.39, 95% CI: 1.89, 3.02), and less likely to require re-medication (RemRR = 0.78, 95% CI: 0.69, 0.88). There was no significant (P > 0.05) dose-response relationship. The analgesic efficacy of paracetamol 600 mg was enhanced with the addition of codeine 60 mg (using TOTPAR% as outcome) in both indirect and head-to-head comparisons. SPID%, but not ResRR and RemRR, data supported this conclusion. Much weaker effects were observed with the caffeine combination. Adverse effects were mild. Surprisingly, drowsiness was seen more often with paracetamol and paracetamol-codeine combinations than with placebo. The relative risks (95% CI) were 1.83 (1.29, 2.59) and 2.39 (1.58, 3.57), respectively. In conclusion paracetamol is an effective analgesic for post-surgical pain. Caffeine adds little to the analgesic effect of paracetamol. However, there is some evidence that codeine 60 mg adds to the analgesic effects of paracetamol 600 mg, using pain relief or pain intensity scores as outcomes, but this is not necessarily translated into an increase in number of patients who obtain moderate to excellent pain relief.

Acetaminophen↗

PubMed1978

Appraisal of codeine as an analgesic in older patients.

In an investigation of a new oral analgesic agent, codeine was chosen as the reference drug because of its established reputation as an effective agent for the relief of pain. Thirty-five patients with cancer pain were studied. Their average age was 58 years, During a 5-day hospital stay they received, on each of three days, either codeine (120 mg or 60 mg) or placebo. At hourly intervals after ingestion the nurse observer collected data on pain intensity and the degree of pain relief, and the patients independently charted the hourly intensity. Statistical analysis failed to show any significant superiority of either dose of codeine over placebo. Moreover, codeine is known to have a constipating effect. Re-appraisal of the value of codeine as an analgesic agent in elderly patients seems justified.

Adult↗

PubMed2000

A new source of drug-induced acute pancreatitis: codeine.

A variety of drugs have been reported to cause acute pancreatitis during the past 40 years. We report the first series of four cases of acute pancreatitis related to codeine ingestion. Four patients (three female, mean age 50.2 yr) presented with clinical, biochemical, and radiological evidence of acute pancreatitis. All four had ingested a therapeutic dose of codeine 1-3 h before the onset of abdominal symptoms. Unintentional rechallenge occurred in three cases and was followed by recurrence of acute pancreatitis in all three. All patients made a full recovery. All four patients had had a previous cholecystectomy. The likely underlying pathophysiological mechanism is codeine-induced spasm of the sphincter of Oddi combined with sphincter of Oddi dysfunction related to a previous cholecystectomy. Codeine ingestion leads to acute pancreatitis in some individuals. Previous cholecystectomy seems to predispose to codeine-induced pancreatitis.

Acute Disease↗

PubMed1982

The effect of codeine on involutional and senile depression.

The authors studied the effect of codeine on 12 severely depressed patients who failed to respond to tricyclic antidepressants. They all were in involution. Eight patients received codeine in combination with other tricyclic antidepressants and only one of them showed improvement. Four depressed patients received codeine alone and none of them improved. The patients were kept on codeine up to three weeks. The dose was gradually increased from 90 mg/day to 180 mg/day. All patients suffered from severe constipation--more than what they had on tricyclic antidepressant medication. All of the patients experienced a sedative effect. None of them had euphoria and none of them developed dependence. After the failure of codeine, the patients finally accepted electroconvulsive therapy or monoamine oxidase inhibitors, and with one exception, all improved.

Aged↗