Pharmacokinetics of Opioids in Renal Dysfunction

Abstract

Patients with renal insufficiency commonly require the administration of an opioid analgesic to provide adequate pain relief. The handling of morphine, pethidine (meperidine) and dextropropoxyphene in patients with renal insufficiency is complicated by the potential accumulation of metabolites. While morphine itself remains largely unaffected by renal failure, accumulation, as denoted by an increase in both mean peak concentrations and the area under the concentration-time curve, of both the active metabolite (morphine-6-glucuronide) and the principal metabolite (morphine-3-glucuronide, thought to possess opiate antagonist properties) have been reported. The increased elimination half-lives of the toxic metabolites norpethidine and norpropoxyphene in patients with poor renal function administered pethidine and dextropropoxyphene, respectively, makes their routine use ill advised. Case reports of prolonged narcosis associated with the use of both codeine and dihydrocodeine in patients with renal insufficiency call for care to be used when prescribing these agents under such conditions. Although the pharmacokinetics of buprenorphine, alfentanil, sufentanil and remifentanil change little in patients with renal failure, the continuous administration of fentanyl can lead to prolonged sedation.

Analgesic prescription patterns among hemodialysis patients in the DOPPS: Potential for underprescription

“…Aspirin has beneficial effects as an anti-platelet agent [1] and is relatively safe in renal failure. However, alterations in pharmacokinetic and pharmacodynamic properties of narcotic and nonnarcotic analgesics in patients with CKD and ESRD may result in increased potential for adverse effects [2][3][4][5][6][7][8][9][10]. Clearance may be reduced for those agents and their metabolites that are primarily excreted by the kidney.…”

The Metabolism of Opioid Agents and the Clinical Impact of Their Active Metabolites

“…139 The predominant product (>99%) of its metabolism by the liver is norfentanyl, with minor production of despropionylfentanyl and hydroxyfentanyl, hydroxynotfentanyl and N-phenylproprion amide; norfentanyl is produced by duodenal metabolism as well. 140 Potential pathways included piperidine N-dealkylation to norfentanyl [4-n-(N-propionylanilino) piperdine], amide hydrolysis to despropionylfentanyl, terminal methyl hydroxylation to hydroxyfentanyl or hydroxynorfentanyl, and amide-N-dealkylation to N-phenylpropionamide.…”

Principles of Drug Therapy, Dosing, and Prescribing in Chronic Kidney Disease and Renal Replacement Therapy

“…22,23 Metabolite accumulation in renal impairment prolongs drug action and predisposes to central nervous system (CNS) toxicity (sedation, respiratory depression, confusion, hallucinations, and seizures), which is often difficult to distinguish from the symptoms of uremia. Regular opioid use in fluid-restricted patients can exacerbate constipation, particularly in peritoneal dialysis.…”