Codeine Analgesia Is Due to Codeine‐6‐glucuronide, Not Morphine

Abstract

SUMMARYEighty per cent of codeine is conjugated with glucuronic acid to codeine‐6‐glucuronide. Only 5% of the dose is O‐demethylated to morphine, which in turn is immediately glucuronidated at the 3‐ and 6‐ position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the μ‐receptor to result in analgesia, codeine‐6‐glucuronide in analogy to morphine‐6‐glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O‐demethylation to morphine, experience analgesia from codeine‐6‐glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype. (Int J Clin Pract 2000; 54(6): 395‐398)

Analgesic effect of oral paracetamol 1000 mg/ibuprofen 400 mg, paracetamol 1000 mg/codeine 60 mg, paracetamol 1000 mg/ibuprofen 400 mg/codeine 60 mg, or placebo on acute postoperative pain: a single-dose, randomized, and double-blind study

“…Metabolic conversion to morphine, and possibly the 6-glucuronide metabolite of morphine, is generally suggested to explain the analgesic efficacy of codeine, while others claim an analgesic contribution from codeine or its 6-glucuronide metabolite based on animal and human experiments [ 30 , 31 ]. The selectivity for mu-receptors is much greater for morphine and its 6-glucuronide metabolite than codeine and its 6-glucuroide metabolite, while they all have much lower affinity for kappa-receptors than mu-receptors in animal brain tissue experiments [ 32 ].…”

Atualização no manejo da dor musculoesquelética

“…Since codeine removal through dialysis is complicated, it is best to avoid it in dialysis patients. 34 …”

Current evidence for a modulation of low back pain by human genetic variants

“…The cytochrome P450 (CYP) isoenzyme 2D6 metabolizes some opioid analgesics, most importantly codeine and tramadol, but also amitriptyline that is often used as a co‐analgesic in patients with neuropathic pain and might have some limited usefulness in lumbar root pain [170, 171]. Codeine ineffectiveness is partly caused by the lack of formation of its active metabolite morphine, which has a 200‐times higher affinity and intrinsic activity at μ‐opioid receptors than codeine itself [172, 173] and is therefore considered the active principle of codeine despite some evidence that codeine or codeine‐6‐glucuronide contribute to the pharmacodynamic effects [174–178]. In approximately 7% of the Caucasian population, the CYP2D6 enzyme catabolizing codeine O‐demethylation to morphine [179] is known to be inactive for genetic reasons [180], with differences in other ethnicities [181], and in these individuals codeine fails to produce relevant clinical analgesia [182, 183].…”