Table 1:

Overview of bothersome symptoms associated with dialysis and current treatment options.

Symptom	Treatment	Efficacy/safety	Approval/off-label for treatment of symptom?
Fatigue	Non-pharmacologic interventions: sleep hygiene, energy conservation, acupressure	Limited evidence of efficacy in small-scale studies [54]	NA
	Pharmacologic interventions: hematopoietics, antidepressants, anxiolytics, levocarnitine, human growth hormone, more frequent dialysis	Hematopoietics and antidepressants show some efficacy in patients with underlying anemia or depression	Treatments approved for underlying conditions such as anemia and depression [54]
		Levocarnitine and human growth hormone have limited evidence of efficacy in small-scale studies
		Increased dialysis frequency has demonstrated efficacy but also increases overall time on dialysis [54]
Depression	Psychotherapy	Some evidence of efficacy, although quality of evidence is low [55]	NA
	SSRIs	Limited evidence of efficacy in the dialysis population [55]	Approved in general population
Pain	Conservative management, e.g. exercise, massage, heat/cold therapy, cognitive behavioral therapy	Some evidence of efficacy, although quality of evidence is low [56]	NA
	Analgesics: opioid analgesics are indicated if pain control is not optimal with other methods	Evidence of efficacy in the general population, limited evidence in dialysis populations [56]	Approved in general population
	Gabapentin/pregabalin	Demonstrated efficacy in several small, short-term randomized trials conducted in patients on HD [57]	Recommended for the treatment of neuropathic pain in patients with kidney failure [58]
		Associated with increased risk of mental state changes and falls [57]
Anxiety	Psychotherapy	Some evidence of efficacy [59]	NA
	Pharmacologic agents, including SSRIs and benzodiazepines	Evidence of efficacy in the general population, limited evidence in dialysis populations	Approved in general population
		Treatment with benzodiazepines is not suitable for long-term treatment [59]
Cramps	Hypertonic solutions	Evidence of efficacy in patients on HD	NA
		Mild post-dialysis hyperglycemia and hypernatremia have been reported [60]
	Pharmacologic agents	Limited evidence of efficacy of quinine, vitamin E supplementation and L-carnitine [60, 61]	Off-label treatment
Restless legs syndrome	Non-pharmacologic: exercise, near-infrared light, vibration and massage	Limited evidence of efficacy in small-scale studies [62]	NA
	Pharmacologic: dopamine agonists, levodopa and iron supplements	Limited evidence of efficacy in small-scale studies [62]	Off-label treatment
	Parathyroidectomy	Limited evidence of efficacy in small-scale studies [62]	NA
Nausea	Ondansetron, metoclopramide and haloperidol	Evidence of efficacy for uremia-associated nausea [63]	Approved in general population
Sleep disturbance	Non-pharmacologic: exercise and sleep hygiene	Evidence of efficacy in the general population, limited evidence in dialysis populations [64]	NA
	Pharmacologic: treatment of underlying disorders, e.g. restless legs syndrome, pruritus or use of hypnotics	Evidence of efficacy in the general population, limited evidence in dialysis populations [64]	Several medications approved for insomnia in the general population—only eszopiclone is approved for longer-term use [64]
Pruritus	Difelikefalin	Robust clinical efficacy and safety data from large well-designed Phase 3 RCTs [13, 46, 48]	Only treatment that is FDA-approved by regulatory authorities for treatment of CKD-aP
	Gabapentinoids (pregabalin and gabapentin)	Effective for reduction of itch intensity	Not approved for CKD-aP, off-label treatment
		Risk of potentially serious adverse effects, particularly at higher doses, including altered mental status, falls and fractures [57]

FDA, Food and Drug Administration; NA, not applicable; RCT, randomized controlled trial; SSRI, selective serotonin reuptake inhibitor.