. Author manuscript; available in PMC: 2022 Mar 1.

Published in final edited form as: Nat Rev Nephrol. 2021 Oct 7;18(2):113–128. doi: 10.1038/s41581-021-00484-6

Table 2 |.

Clinical considerations for the use of specific opioids in patients with kidney failure

Medication	Advantages	Disadvantages	Other considerations
Fentanyl	Generally favourable pharmacokinetic properties in patients with kidney failure^53,105,180 Available in multiple formulations, including transdermal	50–100 times more potent than morphine¹⁸⁹, thus increases the risk of overdose Variable transdermal absorption; wide range of morphine equivalents listed for each patch strength Multiple potential drug interactions	Transdermal formulation might have metal foil backing that is not compatible with MRI Because of the potentially dangerous disadvantages, should only be used by appropriately trained prescribers
Hydrocodone	Limited data do not suggest substantial accumulation or toxicity	Metabolized in the liver via CYP to hydromorphone Drug concentration might be significantly altered in patients with CYP2D6 polymorphism and patients may be at increased risk of drug interactions with CYP2D6 inducers or inhibitors^104,183 187	Semisynthetic opioid derived from codeine Should be used cautiously until more data on drug safety in kidney failure are available^53 105 180
Hydromorphone	Potent semisynthetic opioid; well-studied in patients with kidney failure Fewer side effects than morphine Parent drug does not accumulate in patients with kidney failure¹⁷⁴	Primary metabolite H3G accumulates in patients with kidney failure and can lead to neuroexcitation (for example, tremor or myoclonus) and cognitive impairment¹⁹⁰ Easily dialysed, which might result in opioid withdrawal symptoms, although supplemental dosing is generally not recommended	Short half-life and the need for frequent dosing complicate its use for effective management of chronic pain
Methadone	Generally favourable pharmacokinetic properties in patients with kidney failure^53,105,180 No substantial parent drug or metabolite accumulation owing to elimination via faecal route NMDA receptor antagonist and i-opioid receptor agonist; might improve efficacy for neuropathic pain and reduce analgesic tolerance¹⁹¹	Long, variable, unpredictable half-life (serum half-life 15–60 h; up to 120 h in some studies) with an analgesic effect of only 6–8 h; risk of drug accumulation and delayed respiratory depression Risk of dangerous QTc prolongation¹⁹² and numerous drug interactions	Inexpensive; no active metabolites; available in small dosage units; tablets may be broken without altering formulation Because of the potentially dangerous disadvantages, should only be used by appropriately trained prescribers
Tramadol	Might enhance central suppression of ascending pain signalling in addition to analgesia from opioid agonism; helpful for both nociceptive and neuropathic pain¹⁹³ Weak (μ-opioid receptor agonist and SNRI, theoretical benefit for comorbid mood disorder	Tramadol and its metabolite accumulate in kidney failure and increase risk of respiratory depression and seizures¹³⁹ Increased risk of serotonin syndrome^a, especially when used concurrently with other serotonergic agents, or CYP2D6 and CYP3A4 inhibitors^104,187 Concentrations might be significantly altered in patients with CYP2D6 polymorphism	Limited data in patients with kidney failure but metabolites are predominantly excreted in the kidney and caution is therefore advised^53,105,180

CYP, cytochrome P450; H3G, hydromorphone-3- glucuronide, NMDA, N- methyl- d- aspartate; QTc, corrected QT interval; SNRI, serotonin–norepinephrine reuptake inhibitor.

Serotonin syndrome consists of a combination of mental status changes, neuromuscular hyperactivity and autonomic hyperactivity caused by overactivation of the serotonin receptor.