Table 5.

The pharmacokinetics of opioids recommended for use in patients with advanced CKD

Clinical descriptionA potent µ receptor agonist that is approximately 5–7 times more potent than morphine after oral administration and approximately three times more potent after intravenous administration. It may cause less pruritus, sedation, and nausea than morphine.A potent synthetic opioid that is 50–100 times more potent than morphine. It causes less histamine release, has a lower incidence of constipation, and affords greater cardiovascular stability than morphine.A potent synthetic opioid with activity mainly at the µ receptor. It also appears to function as an NMDA receptor antagonist and therefore may be more effective for neuropathic pain than other strong opioids, although evidence to support this remains limited.A potent semisynthetic opioid. It is a partial µ receptor agonist and a κ receptor antagonist.
Oral bioavailabilityLow-to-moderate: 5%–35%Low: usually administered intravenously or transdermallyHigh: >80%Low: administered effectively sublingually or transdermally.
Route of clearanceExtensive first-pass hepatic metabolism with little unchanged drug found in the urine. It is metabolized principally to H3G, which has no analgesic activity but possibly causes neuro-excitation, agitation, confusion, and hallucinations. Unlike morphine, which has an active analgesic 6-glucuronide metabolite, H6G is present in trace amounts only. The pharmacokinetics of the active parent compound are not substantially altered by CKD, due to the rapid conversion to H3G (46).Hepatic metabolism with 10%–20% excreted by the kidneys. Metabolites are inactive.Hepatic metabolism into inactive metabolites with approximately 20% excreted unchanged in the urine. In patients who are anuric, methadone is exclusively excreted in feces with no significant accumulation in plasma (47).Extensive first-pass hepatic metabolism with little unchanged drug found in the urine (48). The two major metabolites, B3G and norbuprenorphine, are mostly excreted fecally with only 10%–30% excreted in the urine (49). B3G is inactive with no analgesic properties. Norbuprenorphine is a less potent analgesic at the µ receptor than buprenorphine; its clinical relevance is thought to be limited because it does not cross the blood-brain barrier readily. A study with ten patients on HD showed no elevated buprenorphine or norbuprenorphine plasma levels after receiving transdermal buprenorphine (median dose 52.5 μg/h) for at least 1 wk (50).
Plasma t1/2Hydromorphone: unchanged with CKD.Unchanged with CKD.Unchanged with CKD. However, prolonged pharmacologic action due to slow release from tissue reservoirs of up to 60 h (51).Unchanged with CKD.
H3G: prolonged—33 h
Volume of distributionLow: 1.22 L/kgHigh: 2–5 L/kgHigh: 4.1–6.7 L/kgVery high, greater than physiologic volumes. Estimated to be 188–430 L after iv administration (transdermal unknown).
Serum protein bindingLow: 19%High: 79%High: 60%–90%High: 96%
Water solubilityHighLow (lipophilic): suitable for a transdermal deliveryLow (lipophilic): suitable for a transdermal deliveryHigh
mol wtLow: 285.3 g/molLow: 336.5 g/molLow: 309.5 g/molLow: 467.6 g/mol
Removal by HDH3G accumulates between dialysis treatments but appears to be effectively removed during HD with no significant change in pain scores post HD or a need for supplemental dosing (46,52).Not removed to any significant degree but there is the possibility of adsorption to CT190 dialysis membranes (53).aParent drug and metabolites do not seem to be removed by HD: approximately 6.0%–14.9% reductions in plasma methadone (52,54,55). No significant difference in pain scores post HD and supplemental methadone is not required post HD (52). Q-T interval increased significantly: maximum 152 min after methadone intake. Remained <500 ms and was not linearly associated with serum methadone concentration—but may be exacerbated by HD reductions in serum potassium and/or magnesium (54).HD does not appear to affect buprenorphine plasma levels, and analgesic effect is stable during HD (50).
Dosing recommendationsStart at 0.5 mg by mouth (or 0.2 mg subcutaneously) every 4–6 h.Not recommended in opioid-naïve patients. When converting from hydromorphone, 6–8 mg oral hydromorphone daily can be converted to 12 μg/h transdermally every 72 h.Start 1–2 mg every 12–24 h by mouth. Obtain a pretreatment ECG and a follow-up ECG 2–4 wk after initiation to monitor for prolonged Q-T interval.Start at 5 μg/h transdermally every 7 d.
  • NMDA, N-methyl-D-aspartate; H3G, hydromorphone-3-glucuronide; H6G, hydromorphone-6-glucuronide; B3G, buprenorphine-3-glucuronide; HD, hemodialysis; ECG, electrocardiogram.

  • a On the basis of data from a single patient receiving maintenance hemodialysis.