Table 6.

The pharmacokinetics of recommended adjuvants for the treatment of neuropathic in patients with advanced CKD

Characteristic	Gabapentin (56,57)	Pregabalin (57,58)a	Carbamazepine (59)	Amitriptyline (60,61)	Ketamine (62,63)
Clinical description	Gabapentin is an analog of the neurotransmitter GABA with high-affinity binding to the α2δ protein. It reduces the release of excitatory neurotransmitters from the brain although does not have activity at GABA receptors. It has analgesic and anticonvulsant activity.	Pregabalin is also an analog of the neurotransmitter GABA with high-affinity binding to the α2δ protein. It reduces the release of excitatory neurotransmitters from the brain but has no activity at GABA receptors. It has analgesic, anxiolytic, and anticonvulsant activity.	Carbamazepine is an anticonvulsant used to treat seizure disorders and neuropathic pain. It is a tricyclic compound chemically related to TCAs and also functions as a mood stabilizer.	Amitriptyline is a TCA with sedative effects that is used to treat major depressive and anxiety disorders as well as migraines and neuropathic pain.	Ketamine is an anesthetic with analgesic, anti-inflammatory, and antidepressant properties when used in subanesthetic doses. It is a potent NMDA receptor channel antagonist. Its use is typically reserved for intractable neuropathic pain resistant to opioids and other adjuvants.
Oral bioavailability	High-to-moderate: approximately 80% at up to 300 mg daily but decreases with increasing dose, particularly with doses >900 mg daily.	High: >90% irrespective of dose	High: approximately 89%	Low-to-moderate due to extensive first-pass hepatic metabolism: approximately 33%–62%	Low due to extensive first-pass hepatic metabolism: 16%–29%
Peak plasma concentration	Approximately 3 h	Approximately 1 h	Approximately 6 h	Approximately 6 h	Oral: 20–120 min
					iv: <5 min
Route of clearance	Not appreciably metabolized and >95% is excreted unchanged by the kidneys. No inhibition of the enzyme systems responsible for the metabolism of other drugs.	Not appreciably metabolized and >95% is excreted unchanged by the kidneys. No inhibition of the enzyme systems responsible for the metabolism of other drugs.	Metabolized in the liver via phase 1 metabolism primarily by CYP3A4. The metabolites are excreted via the kidneys with approximately 20%–30% excreted via the feces. Only 3%–5% is excreted unchanged by the kidneys.	Extensively metabolized on first pass through the liver. It undergoes phase 1 metabolism primarily by CYP2D6 and CYP3A4.	Extensively metabolized on first pass through the liver. It undergoes phase 1 metabolism primarily by CYP3A4 and CYP2B6 to its two principal metabolites norketamine (has analgesic properties) and hydroxynorketamines (may have low potency antidepressant effects) before being further metabolized to mostly inactive dehydronorketamine. Metabolites are cleared by the kidneys with low levels cleared as ketamine (2%), norketamine (2%), and dehydronorketamine (16%). Most (80%) is cleared as hydroxynorketamines.
Plasma t1/2	Increases linearly with decreased kidney function.	Increases linearly with decreased kidney function.	Approximately 35 h; remains unchanged with ESKD.	Highly variable at 10–28 h; remains unchanged with ESKD.	2–4 h
		Cl Cr>60 ml/min=9 h
		Cl Cr 30–60 ml/min=17 h
		Cl Cr 15–29 ml/min=25 h
		Cl Cr<15 ml/min=49 h
		On hemodialysis 3/wk=55 h
Serum protein binding	Not bound to plasma proteins	Not bound to plasma proteins	70%–80%	Highly bound to plasma and tissue proteins	10%–50%
Water solubility	High	High	High	Low; highly lipophilic	High
Removal by HD	Well dialyzed. Approximately 50% of serum drug is removed during a 4-h session. Supplemental dosing postdialysis may be required. Gabapentin is also cleared by continuous ambulatory PD although this is a slow method to treat toxicity (31).	Well dialyzed. Approximately 50% of serum drug is removed during a 4-h session. The t1/2 during dialysis treatment is approximately 3 h. Supplemental dosing post HD may be required.	Dialyzed. Clearance in the era of low flux HD membranes is twice the endogenous plasma clearance. However, it appears that supplemental dosing post HD is not required because of the long elimination t1/2 of carbamazepine of 35 h compared with a 4-h session.	Not dialyzed with HD or PD	Not studied in dialysis
Dosing recommendations	Dose post HD. Below are maximum recommended doses. It may be reasonable, especially for older patients, or those with moderate rather than severe neuropathic pain, to start with doses as low as 100 mg postdialysis or 100 mg every second night in patients with stage 5 CKD managed conservatively.	Dose post HD. Below are maximum recommended doses. It may be reasonable, especially for older patients, or those with moderate rather than severe neuropathic pain, to start with doses as low as 25 mg post HD or 25 mg every second night in patients with stage 5 CKD managed conservatively.	Start at 100 mg daily or twice daily and increase by 100 mg daily to a maximum of 1200 mg daily.	Although no dose reduction is required, a low starting dose of approximately 25 mg nightly is recommended given the likelihood of anticholinergic adverse effects such as blurred vision, dry mouth, and constipation.	Given the pharmacokinetic, no dose reduction is required.
	eGFR 50–79 ml/min: 600 mg three times per d	eGFR>30–60 ml/min: 150 mg twice per d			By mouth: 0.5 mg/kg twice daily or 2 mg/kg daily
	eGFR 30–49 ml/min: 300 mg three times per d	eGFR 15–30 ml/min: 150 mg once per d			Subcutaneously: 0.05–0.15 mg/kg per h for up to 7 d
	eGFR<15 ml/min: 300 mg once per d	eGFR 15–29 ml/min: 300 mg twice per d			iv: 0.15–0.25 mg/kg
					To reduce the adverse effects of psychosis and tachycardia, the concurrent administration of haloperidol or midazolam is recommended.

GABA, γ-aminobutyric acid; α₂δ protein, α-2-δ protein; TCA, tricyclic antidepressant; NMDA, N-methyl-D-aspartate; CYP, cytochrome P450; Cl _Cr, creatinine clearance; HD, hemodialysis; PD, peritoneal dialysis.

^aOn the basis of a single dose of 50 mg of pregabalin in an open-label, parallel-group study.