Codeine Phosphate

Abstract: Codeine is an old drug that still enjoys widespread clinical use although the logical basis for its popularity has been questioned. It is considered to be suitable for mild to moderate pain but not for more intense pain even in large doses. The World Health Organisation has devised a three-step analgesic ladder for the progressive treatment of increasing pain; on this codeine is considered a weak opioid and occupies a position on the second step (Fig. 1). A signi®cant degree of unpredictable, variable or poor response to treatment with codeine has been reported in many human and animal studies. Indeed, some single dose studies in adults, have shown no difference between codeine and placebo, 60 and a quantitative systemic review suggests that codeine 60 mg has a number needed to treat (NNT) of 18 which is very high when compared with 5.0 for paracetamol 600 mg and 3.1 for the combination. Codeine is frequently recommended for paediatric use. 37 100 A recent survey of paediatric anaesthetists in the UK showed that alongside morphine and fentanyl, codeine is the most widely prescribed opioid analgesic in paediatric anaesthetic practice. The reputedly lower incidence of opioid-related side effects has made codeine popular for the younger age groups including neonates and especially in situations where airway management and neurological assessment are critical. 69 102 106 These suggested bene®ts have been noted after single doses although they may not exist when repeated doses are used. In fact, few clinical studies of the analgesic ef®cacy or side effects of codeine in children have been undertaken, and although the incidence of side effects may be low, analgesia may be inadequate for post-operative pain in some circumstances. Pain assessment is dif®cult in paediatric populations especially neonates and preverbal children and this complicates both the study and use of analgesics particularly those with low ef®cacy or unpredictable effects. Signi®cant variability in both the pharmacokinetics and pharmacodynamics of codeine has been shown in animal and adult human laboratory experimental studies. 25 38 74 105 112 115 In this review we shall examine the reasons for this variability and unpredictability in the effects of codeine in both laboratory and clinical investigations and assess evidence for its suitability for use in preverbal infants and children.

Abstract: The thresholds of perception of sensations other than pain—touch, vibration, two-point discrimination, smell and hearing—were not raised by "therapeutic" amounts of morphine sulfate, codeine phosphate, ethyl alcohol (95%), a barbiturate ("Evipal") and acetylsalicylic acid.

Abstract: Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and beta-phase elimination half-lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 ng/ml (aspirin-codeine phosphate administration) and 7.4 ng/ml (acetaminophen-codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration-time curves for morphine and codeine was 0.095 for the aspirin-codeine phosphate study and 0.12 for the acetaminophen-codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.

Abstract: The influence of melanin on the binding of xenobiotics in hair will impact the interpretation of drug concentrations determined by hair testing. The purpose of this study was to determine if codeine, as a model compound of abused drugs, would be incorporated into black, brown, blond, or red hair as a function of melanin concentration. Such data would assist in the interpretation of codeine concentrations in hair and help elucidate the potential influence of hair color on incorporation of drugs. Male and female Caucasians with black (n = 6), brown (n = 12), blond (n = 8), or red hair (n = 6) and non-Caucasians with black hair (n = 12) aged 21-40 years were enrolled in the study. Each subject was administered oral codeine phosphate syrup in a dosage of 30 mg three times a day for five days. Twenty-four hours after the end of the treatment period, a 30-mg codeine dose was administered and the subject's plasma area under the concentration time curve (AUC) for codeine was determined. Codeine and melanin were measured in the first 3 cm of hair closest to the vertex region of the scalp prior to and 1, 4, 5, 6, and 7 weeks after dosing. The quantitative and qualitative melanin profiles were determined for each subject's hair to provide an objective measure of hair color. The plasma concentrations of codeine were measured to eliminate differences in the bioavailability and clearance of codeine as factors that might account for the differences in codeine hair concentrations. The subjects were asked not to cut their hair in the vertex region of the scalp or to use any form of chemical treatment on their hair, but otherwise normal hygienic measures were permitted. The mean (+/- SE) hair codeine concentrations 5 weeks after dosing were 1429 (+/- 249) pg/mg in black hair; 208 (+/- 17) pg/mg in brown hair; 99 (+/- 10) pg/mg in blond hair; and 69 (+/- 11) in red hair pg/mg. In black hair, codeine concentrations were 2564 (+/- 170) pg/mg for Asians and 865 (+/- 162) pg/mg for Caucasians. Similar concentration relationships were observed at weeks 4, 6, and 7. A strong relationship between the hair concentrations of codeine and melanin (R(2) = 0.73) was observed. Normalization of the codeine concentration with the melanin concentration reduced the hair color differences observed. These data demonstrate that the interpretation and reporting of hair test results for codeine are influenced by hair color. After this dosing protocol, the proposed federal guideline cutoff of 200 pg/mg of codeine would result in 100% of subjects with black hair and 50% of subjects with brown hair being reported as positive, and subjects with blond or red hair would be reported as negative. The incorporation of these drugs into hair should be studied carefully in humans to ensure the appropriate interpretation of drug concentrations.