Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes

Mignat, Christian; Wille, Uta; Ziegler, Albrecht

doi:10.1016/0024-3205(95)00010-4

Cited by 155 publications

(100 citation statements)

References 16 publications

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“…While glucuronidation at C-6 or N-demethylation did not change affinity or were related to a small decrease in affinity only, O-demethylation brought about a pronounced increase in affinity. 7,8-Dihydro derivatives had slightly higher affinities when compared to their unsaturated counterparts (Chen et al 1991;Mignat et al 1995;Lö ser et al 1996). 3-O-Glucuronides had essentially no relevant affinity to opioid receptors, and the apparent displacement of the radioactive ligands observed may well result from contamination with the more active parent substances (Bartlett & Smith 1995;Löser et al 1996).…”

Section: Discussionmentioning

confidence: 96%

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Schmidt¹,

Vormfelde

Klinder³

et al. 2002

Pharmacology & Toxicology

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Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine-6-O-, dihydromorphine-3-O-and dihydromorphine-6-O-glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to m-, d-and k-opioid receptors. Codeine, morphine, d,l-methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [ 3 H]DAMGO (m-opioid receptor), [ 3 H]DPDPE (d-opioid receptor) and [ 3 H]U69,593 (k-opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively. All substances had their greatest affinity to the m-opioid receptor. The affinities of dihydromorphine and dihydromorphine-6-O-glucuronide were at least 70 times greater compared with dihydrocodeine (K i 0.3 mmol/ l), whereas the other metabolites yielded lower affinities. For the d-opioid receptor, the order of affinities was similar with the exception that dihydrocodeine-6-O-glucuronide revealed a doubled affinity in relation to dihydrocodeine (K i 5.9 mmol/ l). In contrast, for the k-opioid receptor, dihydrocodeine-6-O-and dihydromorphine-6-O-glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (K i 14 mmol/l), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6-O-glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O-demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P-450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.The semisynthetic opioid dihydrocodeine is an analgesic and antitussive drug. It exerts its actions by interaction with opioid receptors of different types (m-, d-and k-opioid receptors). Since the beginning of the 1960s dihydrocodeine and dihydrocodeine-containing drugs were used by opioid addicts as a substitute drug to heroin. Recently this use increased by prescribing dihydrocodeine in maintenance treatment of addicts. Individual doses prescribed vary from 60 to 3000 mg dihydrocodeine daily (Frießem & Täschner 1991).Dihydrocodeine, the 7,8-dihydro analogue of codeine, has similar metabolic pathways as codeine (Fromm et al. 1995;Hufschmid et al. 1995). These include O-demethylation to dihydromorphine, formation of the corresponding 6-and/ or 3-O-glucuronides dihydrocodeine-6-O-, dihydromorPart of these results have been presented at

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Section: Discussionmentioning

confidence: 96%

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Schmidt¹,

Vormfelde

Klinder³

et al. 2002

Pharmacology & Toxicology

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“…33 Alternatively, C6G has been proposed to exert analgesic effects because of its high amounts. 34 However, the K i value of C6G for the m-opiate receptor is about twice that of codeine, 35 and glucuronides are less likely to enter the brain owing to their hydrophilic properties. In addition, as no randomized placebo-controlled design was used in this study, minor placebo effects on adverse event monitoring or pupil size measurements cannot entirely be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication

et al. 2006

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Codeine is an analgesic drug acting on m-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5-17) mg h l À1 in EMs and 16 (10-24) mg h l À1 in UM (P ¼ 0.02). In urine collected over 12 h, the metabolic ratios of the codeine þ codeine-6-glucuronide divided by the sum of morphine þ its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P ¼ 0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P ¼ 0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.

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“…Increased synaptic excitatory amino acids, such as glutamate, would potentiate the NMDA receptor. Further, it has been suggested that large doses of systemic morphine may potentiate excitotoxic cell death through a kappa-opiate mediated cascade [47,48,49,50,51] potentiating NMDA receptor function and enhancing neurotransmitter release in the spinal cord [46,52,53]. Interactions between opioid exposure and sensitization of primary afferent nociceptive neurons (i.e., by tissue injury or inflammation) have been previously reported [for review see 54,55].…”

Section: Discussionmentioning

confidence: 99%

The impact of morphine after a spinal cord injury

Hook

Liu

Washburn

et al. 2007

Behavioural Brain Research

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Nociceptive stimulation, at an intensity that elicits pain-related behavior, attenuates recovery of locomotor and bladder functions, and increases tissue loss after a contusion injury. These data imply that nociceptive input (e.g., from tissue damage) can enhance the loss of function after injury, and that potential clinical treatments, such pretreatment with an analgesic, may protect the damaged system from further secondary injury. The current study examined this hypothesis and showed that a potential treatment (morphine) did not have a protective effect. In fact, morphine appeared to exacerbate the effects of nociceptive stimulation. Experiment 1 showed that after spinal cord injury 20 mg/kg of systemic morphine was necessary to induce strong antinociception and block behavioral reactivity to shock treatment, a dose that was much higher than that needed for sham controls. In Experiment 2, contused rats were given one of three doses of morphine (Vehicle, 10, 20 mg/kg) prior to exposure to uncontrollable electrical stimulation or restraint alone. Despite decreasing nociceptive reactivity, morphine did not attenuate the long-term consequences of shock. Rats treated with morphine and shock had higher mortality rates, and displayed allodynic responses to innocuous sensory stimuli three weeks later. Independent of shock, morphine per se undermined recovery of sensory function. Rats treated with morphine alone also had significantly larger lesions than those treated with saline. These results suggest that nociceptive stimulation affects recovery despite a blockade of pain-elicited behavior. The results are clinically important because they suggest that opiate treatment may adversely affect the recovery of function after injury.

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Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes

Cited by 155 publications

References 16 publications

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication

The impact of morphine after a spinal cord injury

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