Escitalopram Is a Weak Inhibitor of the CYP2D6-Catalyzed O-Demethylation of (+)-Tramadol but Does Not Reduce the Hypoalgesic Effect in Experimental Pain

Noehr-Jensen, Lene; Zwisler, Stine Thorhauge; Larsen, Frank; Sindrup, Søren Hein; Damkier, Per; Brøsen, Kim

doi:10.1038/clpt.2009.154

Cited by 23 publications

(16 citation statements)

References 29 publications

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“…However, available clinical data provide controversial results regarding the analgesic effi cacy of tramadol in subjects with different CYP2D6 phenotype/genotype. Some clinical studies revealed decreased analgesic effi cacy in CYP2D6 poor metabolizers (11) in line with experimental model of pain (12), while inhibition of CYP2D6 by escitalopram did not impair the analgesic effect of tramadol in another study although there was a shift in drug pharmacokinetics confi rming decreased CYP2D6 (13). This is in line with different observations in pain model in healthy volunteers, in which PM subjects reported analgesia during electrical stimulation test (14).…”

supporting

confidence: 77%

Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms

Slanař¹,

Dupal²,

Matousková³

et al. 2012

BLL

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Abstract:Objectives: The aim of our study was to evaluate impact of CYP2D6 and MDR1 polymorphisms on the analgesic effi cacy of tramadol in patients after a knee arthroscopy. Background : Pharmacokinetics of tramadol and its metabolites is stereoselective and displays high interindividual variability correlating with polymorphic CYP2D6 in the population. Available data provide controversial results regarding the analgesic effi cacy of tramadol in subjects with different CYP2D6 genotypes. Methods: Pain intensity was assessed using visual analogue scale at 2 and 24 hours after the knee arthroscopy in 156 patients. Polymorphisms CYP2D6*3,*4,*5,*6, and gene duplication and C3435T in MDR1 gene were analyzed by PCR -RFLP. Results: Mean VAS 2h value in the whole study group was 44.0 ± 16.5 mm. Mean pain difference, was lowest in the UM group and highest in the PM group. The pain difference varied signifi cantly among the CYP2D6 subgroups (F = 4.29; p = 0.006) with signifi cant differences between homEM vs hetEM, homEM vs PM, and UM vs PM subgroups. There were no signifi cant differences among MDR1 subgroups with regards of pain difference. Mean tramadol consumption was 2.47 ± 1.17 mg/kg during the 24 h period. There were no signifi cant differences in the drug consumption, reporting of adverse reactions, need for rescue analgesic medication or verbal description of pain among the CYP2D6 or MDR1 genotype subgroups. Conclusion: CYP2D6 plays a signifi cant role in tramadol analgesic effi cacy. The non-opioid analgesia in PMs was associated with better subjective pain relief in patients after a knee arthroscopy (Tab. 3, Ref. 18). Full Text in PDF www.elis.sk.

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supporting

confidence: 77%

Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms

Slanař¹,

Dupal²,

Matousková³

et al. 2012

BLL

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“…In vivo studies [12,13,14] have shown that citalopram and escitalopram are weak inhibitors of CYP2D6 [15]. Demethylcitalopram is a more potent inhibitor of CYP2D6 than citalopram and may mediate some mild interaction with other drugs metabolized by CYP2D6 [16].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Abrudan

Popa²,

Gheldiu³

et al. 2017

Pharmacology

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Background/Aims: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Methods: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC®. Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. Results: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Conclusion: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

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“…Escitalopram could significantly decrease the median AUC (0–infinity) of (+)-M1 by 29%, but it did not impair the analgesic effect of tramadol assessed by the cold pressor test 61. The underlying mechanism may be that escitalopram is a weak inhibitor of CYP2D6 whereas paroxetine is a strong CYP2D6 inhibitor.…”

Section: Resultsmentioning

confidence: 91%

Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management

Feng¹,

Zhu²,

Zhou³

2017

JPR

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BackgroundMultimorbidity results in complex polypharmacy which may bear a risk of drug interactions. A better understanding of opioid analgesics combination therapy used for pain management could help warrant medication safety, efficacy, and economic relevance. Until now there has been no review summarizing the opioid analgesics-related pharmacokinetic drug interactions from the perspective of evidence based on randomized controlled trials (RCTs).MethodA literature search was performed using PubMed, MEDLINE, and the Cochrane Library, using a PRISMA flowchart.ResultsFifty-two RCTs were included for data interpretation. Forty-two RCTs (80.8%) were conducted in healthy volunteers, whereas 10 RCTs (19.2%) enrolled true patients. None of the opioid–drug/herb pairs was listed as contraindications of opioids involved in this review. Circumstances in which opioid is comedicated as a precipitant drug include morphine–P2Y12 inhibitors, morphine–gabapentin, and methadone–zidovudine. Circumstances in which opioid is comedicated as an object drug include rifampin–opioids (morphine, tramadol, oxycodone, methadone), quinidine–opioids (morphine, fentanyl, oxycodone, codeine, dihydrocodeine, methadone), antimycotics–opioids (buprenorphine, fentanyl, morphine, oxycodone, methadone, tilidine, tramadol), protease inhibitors–opioids (ritonavir, ritonavir/lopinavir–oxycodone, ritonavir–fentanyl, ritonavir–tilidine), grapefruit juice–opioids (oxycodone, fentanyl, methadone), antidepressants–opioids (paroxetine–tramadol, paroxetine–hydrocodone, paroxetine–oxycodone, escitalopram–tramadol), metoclopramide–morphine, amantadine–morphine, sumatriptan–butorphanol nasal sprays, ticlopidine–tramadol, St John’s wort–oxycodone, macrolides/ketolides–oxycodone, and levomepromazine–codeine. RCTs investigating the same combination, almost unanimously, drew consistent conclusions, except two RCTs on amantadine–intravenous morphine combination where a different amantadine dose was used and two RCTs on morphine–ticagrelor combination where healthy volunteers and true patients were enrolled, respectively. RCTs investigating in true patients may reflect a realistic clinical scenario and overcome the limitation of RCTs performed in healthy volunteers under standardized conditions. Further research opportunities are also presented in this review.ConclusionEffective and safe combination therapy of opioids can be achieved by promoting the awareness of potential changes in therapeutic efficacy and toxicities, prescribing alternatives or changing administration strategy, tailoring dose, reviewing the appropriateness of orders, and paying attention to medication monitoring.

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Escitalopram Is a Weak Inhibitor of the CYP2D6-Catalyzed O-Demethylation of (+)-Tramadol but Does Not Reduce the Hypoalgesic Effect in Experimental Pain

Cited by 23 publications

References 29 publications

Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms

Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Opioid analgesics-related pharmacokinetic drug interactions: from the perspectives of evidence based on randomized controlled trials and clinical risk management

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