Metabolism: The liver is the major site of biotransformation from parent opioid compounds to active or inactive metabolites. Unfortunately, neither of these tools nor other endogenous markers are able to provide any assessment of hepatic clearance; therefore, an alternative approach in determining drug dosing is needed in the hepatic impairment patient population.
Nonetheless, one possible way utilized in dosage guidance is classifying drugs by the extent to which the liver metabolizes them, a process known as the hepatic extraction ratio. This ratio ranges from 0 to 1, with 0 reflecting the inability of the liver to metabolize the drug and a ratio of 1 reflecting the ability to metabolize the entire drug via first pass.
Development of portal-systemic shunts occurs in patients with cirrhosis, leading to decreased blood flow and subsequently halting drug metabolism by the liver. These highly hepatically metabolized agents are bypassing first-pass metabolism as a result of the shunts.
Excretion: Mild-to-moderate liver disease may lead to renal impairment. Three mechanisms influencing renal excretion of opioids exist: glomerular filtration, tubular secretion, and tubular reabsorption. Estimations of the glomerular filtration rate GFR are used to predict renal excretion of medications, due to the lack of feasibility in estimating tubular secretion and reabsorption. Renal adjustment for medications may also be based on creatinine clearance CrCl. This is due to the variability in muscle mass and the decreased conversion of creatine to creatinine.
The following section will review clinical considerations when selecting an opioid in the renal impairment and dialysis patient population. Morphine: Morphine, which was invented in , is among the oldest and most studied drugs compared to other opioid analgesics.
Conversely, M6G, a mu receptor agonist, possesses analgesic properties. Drugs with a low volume of distribution Vd and low protein binding are hydrophilic, and possess low-molecular-weight properties that are recognized as dialyzable agents.
Morphine is known to have a low Vd and is water-soluble; however, a form of its M6G metabolite is lipophilic. Practitioners should still exercise caution when prescribing hydromorphone due to its risk of accumulation. In an open, parallel-group, single-dose study involving 23 patients, 4-mg of immediate-release hydromorphone Dilaudid IR was administered. The results of the study evidenced an increase in the AUC corresponding with worsening of renal function.
More data are needed in the setting of dialysis with hydromorphone. Hydromorphone is water-soluble and has low-molecular-weight properties. Codeine: Codeine undergoes biotransformation into many metabolites.
In a single-dose study by Guay et al, 60 mg of codeine phosphate was administered to 6 hemodialysis patients and 6 healthy volunteers, resulting in a significantly increased half-life of codeine in the dialysis group when compared to results in the volunteers. A case report presented by Talbott et al discussed a pediatric patient with renal failure, who developed respiratory depression from codeine conversion to M6G.
Meperidine: Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by partial conjugation with glucuronic acid. Normeperidine has an elimination half-life five to 10 times longer than the parent compound. A case report by Hassan et al describes a patient who received meperidine on continuous cycles of peritoneal dialysis and developed myoclonic contractions and a tonic-clonic seizure.
This reduction in clearance may lead to respiratory depression. Methadone: Methadone is metabolized to pyrrolidine, followed by its conversion to pyrroline. This information is not medical advice. Fast Facts are not continually updated, and new safety information may emerge after a Fast Fact is published. Health care providers should always exercise their own independent clinical judgment and consult other relevant and up-to-date experts and resources. Some Fast Facts cite the use of a product in a dosage, for an indication, or in a manner other than that recommended in the product labeling.
Accordingly, the official prescribing information should be consulted before any such product is used. In addition, many diseases such as hypertension and diabetes mellitus are associated with an accelerated decline in renal function. Renal dysfunction affects the metabolism of compounds and thus has important therapeutic consequences for drug safety. For pain patients who have reduced renal function such as those in palliative care, most opioids used for chronic pain treatment should be administered at reduced dosages, with increased dosage intervals, or not at all because of the risk of accumulation of the parent compound or its metabolites.
Renal impairment is likely to cause the accumulation of the inactive metabolites but not the parent compound, so dose reduction is not necessary with the use of this agent in renal insufficiency or dialysis. Mefenamic acid Ponstel is metabolized in the liver. Mefenamic acid can further deteriorate renal function in patients with underlying renal disease.
Dose reduction is recommended in renal insufficiency and dialysis, as it not dialyzable. Ketorolac accumulates in renal insufficiency; therefore, it is contraindicated in these patients and in patients at risk for renal failure, including those with volume depletion.
Naproxen is metabolized in the liver to inactive compounds. Use of naproxen is not recommended in patients with moderate to severe renal impairment. Celecoxib is the only cyclooxygenase-2 COX-2 inhibitor available in the U. It is metabolized extensively by the liver and is unlikely to be removed by dialysis.
Therefore, use of COX-2 inhibitors should be avoided in severe renal impairment and in those on dialysis. Opioid options. The use of opioids in the renally impaired population is challenging, as one must balance opioid-related adverse events with adequate pain control. As such, it is recommended to start with lower-than-recommended doses and slowly titrate up the dose while extending the dosing interval.
This will help limit adverse effects, such as respiratory depression and hypotension. Hydrocodone is metabolized to hydromorphone Dilaudid , which is then metabolized to its major metabolite hydromorphineglucuronide H3G and minor metabolite hydromorphinehydroxy, all of which are excreted renally along with the parent compound.
H3G has no analgesic properties, but it can potentially cause neuroexcitation, agitation, confusion, and hallucination. Hydromorphone has been used safely in patients with renal insufficiency and dialysis, as it is expected to be dialyzable. Tramadol is metabolized in the liver, producing one active compound. It is recommended to reduce the dose and increase the dosing interval in patients with renal insufficiency, but tramadol is generally well-tolerated in patients with renal insufficiency and dialysis.
It is significantly removed by hemodialysis; therefore, redosing after a session may be necessary. Oxycodone can be used in patients with mild to moderate renal insufficiency but should be used at reduced dosing; it has been associated with significant sedation with usual doses in renal failure patients.
Methadone and its metabolites are excreted in the urine and feces. Methadone has been used safely in patients with renal insufficiency, but it is poorly removed by dialysis and no specific recommendations are available regarding its dosing in dialysis.
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