Abstract
Off-Label Drug Uses
This Hospital Pharmacy feature is extracted from Off-Label DrugFacts, a quarterly publication available from Wolters Kluwer Health. Off-Label DrugFacts is a practitioner-oriented resource for information about specific FDA-unapproved drug uses. This new guide to the literature will enable the health care professional/clinician to quickly identify published studies on off-label uses and to determine if a specific use is rational in a patient care scenario. The most relevant data are provided in tabular form, so the reader can easily identify the scope of information available. A summary of the data—including background, study design, patient population, dosage information, therapy duration, results, safety, and therapeutic considerations—precedes each table of published studies. References direct the reader to the full literature for more comprehensive information prior to patient care decisions. Direct questions or comments regarding “Off-Label Drug Uses” to
Background
Pruritus, a relatively common manifestation of skin disease, may also be a symptom of systemic disease (eg, obstructive biliary disease, endocrine disorders, malignancies, autoimmune syndromes). Pruritus associated with chronic uremia, or uremic pruritus, occurs in almost half of patients on dialysis and significantly interferes with sleep and quality of life. The exact mechanism for the cause of uremic pruritus has not been established but likely involves multiple pathways, including the peripheral and central nervous systems, as well as local chemical and inflammatory mediators. Thus, the selection of effective treatment based on possible mechanisms has been difficult. Traditionally, treatment has focused on the use of antihistamines, but in many cases when these agents have been ineffective, opioid antagonists, serotonin receptor blockers, and antipruritic lotions have also been used with varying success rates.1,2
Gabapentin, which has been useful in several neuropathic syndromes, has shown beneficial antipruritic results in a patient with diabetes as well as uremic pruritus undergoing chronic hemodialysis. 3
Study Design
Controlled Trials
One randomized, doubleblind, placebo-controlled, crossover trial: 25 patients.
Case Reports/Series
One case series: six patients.
Patient Population
Adult hemodialysis patients with chronic, severe, refractory uremic pruritus of more than 8 weeks' duration.
Dosage and Duration
The most commonly used dosage has ranged from 100 to 300 mg three times weekly, administered at the end of the hemodialysis session for 1 month.3,4 In one study, some patients continued therapy for a median of 8 months (range, 7 to 10 months). 3
Because gabapentin is eliminated primarily through the kidneys and is removed by hemodialysis, it has a significantly longer half-life in patients on hemodialysis than in those with normal renal function. Thus, these patients may need lower doses at less frequent intervals.
Results
The use of gabapentin in the treatment of uremic pruritus has been limited to one small controlled trial and a case series report enrolling a total of 31 patients. In all cases, the pruritus was of greater than 8 weeks' duration and unresponsive to conventional therapies, including antihistamines, ultraviolet light therapy, or topical agents.
Controlled Trials
In a double-blind, placebo-controlled, crossover trial, 25 adult hemodialysis patients with uremic pruritus were randomized to receive either gabapentin 300 mg or placebo three times weekly for a total of 4 weeks. Treatment was administered at the end of the hemodialysis session. The severity of itching was subjectively measured daily by the patients and reported via a 10-cm visual analog scale (VAS; 0 = no itch; 10 = severe itch). The primary end point was at least a 50% reduction in VAS score. The mean VAS score at baseline was 8.4. After the placebo phase of the study, there was not a significant reduction (VAS score: 7.6); however, four patients had VAS score reductions of more than 50%. After the 1-week washout period, the mean pruritus score returned to baseline levels (7.9). At the end of the gabapentin phase, there was a significant decrease in the mean score to 1.2 (P = 0.0001). Although the specific number of patients achieving at least 50% reduction in VAS score after gabapentin therapy was not provided, it was noted that only one patient's symptoms did not improve significantly. 4
Summary of Clinical Literature on the Use of Gabapentin for the Treatment of Uremic Pruritus
ABBREVIATIONS
BSL = baseline
BSL2 = second baseline period
GAB = gabapentin
PO = oral
VAS = visual analog scale
SCALES
Visual Analog Scale: A 10-cm horizontal line scale used to assess the severity of itching: 0 = no itch and 10 = maximum itch.
Case Series
In a case series report, six adult hemodialysis patients with uremic pruritus received gabapentin therapy after each hemodialysis session. The first patient was considered the index case and received 100 mg after each session. After the first dose, the patient reported a subjective improvement in diabetic neuropathy and a spontaneous resolution of pruritus. The dosage was reduced to 50 mg, and then 20 mg after each session in an effort to reverse persistent drowsiness. After 1 week, scratching lesions disappeared. Based on these data, the remaining five patients received 100 mg three times weekly at the end of each dialysis session for 30 days. After the first dose, there was a rapid subjective improvement of pruritus reflected by a reduction in mean VAS scores from 8.4 to 1.6. Two patients experienced a complete resolution with VAS scores reduced from 9 to 0. Three patients experienced partial resolution. After the second week of treatment, the response diminished in three patients, requiring a dosage increase to 100 mg four times a week, which resulted in better itch control without adverse reactions. On day 35 (5 days after the drug was initially stopped), four patients developed high VAS scores, requiring reintroduction of the drug for up to a median follow-up of 8 months (range, 7 to 10 mo). Although some patients experienced only partial improvement in itching, a great improvement in sleep and general quality of life was noted. 3
Safety
Drowsiness, dizziness, and fatigue were the most commonly reported adverse effects observed in the controlled trial, but they were mild to moderate in nature. Typically, the effects appeared after the first dose of the drug, with gradual resolution within 7 days. No patients withdrew from the study because of side effects. 4 In the case series, only the first patient, who received much higher doses initially (100 mg daily), experienced drowsiness, which resolved with reduced dosing (20 mg at the end of each dialysis session). No adverse reactions were observed in the remaining 5 patients. 3
Therapeutic Considerations
Initial data from isolated case reports suggest that gabapentin may be beneficial in hemodialysis patients with uremic pruritus unresponsive to previous therapy. However, these data are limited by a small population, and further study is required in larger controlled settings to identify optimal dosage recommendations.