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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Background : In patients with pruritus of cholestasis, response to conventional drug treatment may be unsatisfactory. Activation of 5-hydroxytryptamine receptors on dermal sensory nerve-endings plays a role in the perception of pruritus. The 5-hydroxytryptamine3 receptor antagonist, ondansetron, has been used in the treatment of pruritus of cholestasis, but there are few controlled data.

Aim : To determine whether ondansetron is effective in treating the pruritus of cholestasis.

Methods : A total of 19 patients with resistant pruritus were randomized, double blind, to receive either ondansetron 8 mg or placebo as a single intravenous bolus, followed by oral ondansetron 8 mg or placebo twice daily for 5 days. Patients’ perception of pruritus was recorded hourly using a visual analogue scale, and scratching activity measured by means of a piezo-electric crystal attached to the fingernail.

Results : Mean pruritus score using visual analogue scale and scratching activity were reduced on the first treatment day compared with baseline in both the ondansetron and placebo groups (P < 0.05), but there were no significant differences in mean pruritus perception or scratching activity between the two groups.

Conclusion : Ondansetron was of no benefit in this group of pruritic patients during short-term treatment.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Pruritus is a common and difficult to manage symptom of cholestatic liver disease, occurring in approximately a quarter of patients with jaundice.1 The rationale for treatment with drugs which have anticholestatic activity (such as ursodeoxycholic acid) is that pruritus may result from bile salt deposition and subsequent irritation of nerve endings in the skin. In support of this hypothesis, skin concentrations of bile salts are elevated in cholestasis2, 3 and itch can be produced by intradermal bile acid instillation4 or improved with agents which sequester bile acids [such as the anion-binding resins colestyramine (cholestyramine) and colestipol]. However, itch perception correlates poorly with serum bile acid concentrations,2 with some studies showing an improvement in pruritus despite rising serum bile acid levels.5

Opiate-related pruritus is mediated via central opioid receptors, but opioid receptors are also present on cutaneous sensory nerve fibres, and administration of opiates, such as morphine, can cause pruritus.6 In cholestasis there is also up-regulation of central opioid receptors.7 Treatment with the opiate antagonist naloxone8 or the oral opiate antagonist nalmefene has been reported to improve both objective and subjective measurement of pruritus,9 but the high incidence of adverse effects, similar to an opiate-withdrawal syndrome, limits their usefulness. Symptom response to other classes of antipruritic drugs, including enzyme-inducing drugs (such as rifampicin10–13 and phenobarbital14), or psychotropic agents such as sertraline,15 which alter the perception of the sensation of itch, has not been consistently reported.

Pruritus sensation may arise from the superficial layers of skin, which contain clustered nerve endings at ‘itch points’ close to the dermo-epidermal junction, and also the mucous membranes and conjunctiva.16–18 These receptors may be acted upon directly, by physical or chemical stimuli, or indirectly via histamine release. Itch impulses are transmitted through C fibres of polymodal nociceptors to the dorsal root ganglia and synapse there with secondary neurones. Efferents traverse to the contralateral spinothalamic tract and pass to the posterolateral spinothalamic tract, posterolateral ventral thalamic nucleus and then to the somatosensory cortex of the postcentral gyrus.19 5-Hydroxytryptamine (5-HT; serotonin) is an important neurotransmitter in these pathways.20, 21 A number of case reports22–24 and the results of one uncontrolled study25 and a crossover trial26 have suggested relief of cholestatic pruritus with the 5-HT3 receptor antagonist ondansetron. However, these studies were small and the measurement of pruritus based solely on the patients’ own assessments.

The aim of the present study was to define, in a double blind, placebo-controlled trial, the efficacy of ondansetron in the treatment of patients with pruritus of cholestasis in whom other medical antipruritic treatment had failed. Response was assessed by both a subjective evaluation of the severity of pruritus using a visual analogue scale (VAS) and an objective measurement of scratching activity, using a piezo-electric vibration transducer.27

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Nineteen patients (16 female; mean age 55 years, range: 27–80) with pruritus from cholestatic liver disease were enrolled into the study over an 8-month period. Seventeen patients had primary biliary cirrhosis (PBC), one had cirrhosis because of hepatitis C and one had chronic rejection 18 months after orthotopic liver transplantation for hepatitis C cirrhosis. The aetiology of the underlying liver disease had been established in all cases by needle biopsy before entry to the study. In all patients, conventional medical treatment had failed to control symptoms of pruritus, and none had clinical evidence of a primary dermatological or other systemic cause for pruritus.

Study design

All antipruritic medications (including ursodeoxycholic acid) were withdrawn at least 3 days before hospital admission and entry into the study. The pre-treatment 24 h observation phase was commenced at 09:00 hours on day 0. Patients were then randomized, double blind, to receive either ondansetron or placebo throughout the treatment phase (days 1–5). Each patient was consecutively allocated an individual sequential treatment number that corresponded to one of two, identical in appearance, medication regimens. The study pharmacist held sealed envelopes containing the codes to the treatment regimens, so that the patient and all investigators were unaware which of the regimens was being administered. The treatment phase began on day 1, when a single dose of either ondansetron 8 mg in 10 mL 0.9% saline or 10 mL saline alone, in identical-appearing vials, was administered by intravenous injection over 5 min. Eight hours after the intravenous injection, patients were prescribed oral tablets containing either ondansetron 8 mg or placebo. These were continued twice daily for a further 4 days (days 2–5). Patients were discharged on day 2 and instructed to record their pruritus rating in the diary card at 3-h intervals between 09:00 and 24:00 hours. Patients returned to the hospital for a post-treatment follow-up interview within 2 weeks of the last dose of study medication, at which time any adverse events were documented and a blood sample was taken for routine hepatic and renal biochemical markers.

Assessment of pruritus perception

Patients recorded their perception of pruritus on a diary card with the aid of a VAS, where zero represented no pruritus and 10 the worst imaginable pruritus. On day 0, recordings were made every 15 min during the first hour, and hourly thereafter during waking hours. The same intervals were used on day 1 after trial treatments were initiated with either intravenous injection of ondansetron or placebo. On days 2–5 recordings were made at 3 h intervals from 09:00 to 24:00 hours. Patients also recorded whether they were awoken with pruritus and rated the worst itch experienced during the night on a VAS.

Scratching activity

Objective measurements of scratching activity were made using a device which measured scratching independent of limb movements (a ‘scratchometer’), which has been previously validated by correlating measurements with videotaped evidence of patients scratching throughout a 24-h time period.27 The device consisted of a vibration transducer, an frequency modulation (FM) transmitter and receiver, a signal processor and a personal computer. The transducer used was a square piece of piezo-electric film attached to the middle fingernail of the dominant hand, which in turn was connected by a wire to a small portable FM transmitter attached to the patient's belt or clothing. The vibration transducer produced an electrical current as the nail scratched the skin. The amplified current was transmitted to a remote receiving unit (up to 30 m away) connected to a signal processor and personal computer, which logged the scratching activity index in counts per 30-s interval. The system was programmed to record only high-frequency signals in the range produced by scratching. Lower frequency signals below a preset threshold, such as those produced by coarse finger or hand movements unrelated to scratching, were filtered out.

Scratching activity was recorded continuously between 09:00 and 24:00 hours on day 0 (pre-treatment) and day 1 (post-treatment).

Statistical analysis

The primary end-point of the study was a >50% reduction (arbitrarily defined as meaningful relief) in the severity of pruritus as recorded on the diary card on day 1 relative to baseline (day 0). A >50% decrease in itch burden (the weighted mean area under the itch score profile), and the time to onset of meaningful relief during the 5-day follow-up period, were used as secondary end-points. Missing values accounted for <5% of data points and were linearly interpolated if occurring during a sequence and ignored if occurring at either end of a sequence. Treatment failure was defined as the need for additional antipruritic medication to be given or the patient requesting withdrawal from the study because of intractable pruritus.

Written informed consent was obtained from all patients before entry into the study, and the study protocol was approved by the ethics committee of King's College Hospital.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Nine patients were randomized to receive treatment with ondansetron and 10 to placebo. The ondansetron and placebo groups were well matched in terms of age, height and body mass index. Apart from one patient with hepatitis C recurrence postliver transplant and a serum bilirubin of 731 μm who was randomized to ondansetron, liver biochemical abnormalities were relatively mild, with median serum bilirubin levels of 28 and 45 μm, respectively (Table 1). The use of antipruritic medications before entry into the study was also comparable in the two groups. In the 3 months prior to study entry, a total of 17 patients had been prescribed colestyramine, 12 ursodeoxycholic acid, nine antihistamines, two tamoxifen, one ciclosporin and one rifampicin.

Table 1.  Demographic and biochemical characteristics at entry (there were no significant differences between the two groups)
 OndansetronPlacebo
Number of patients910
Sex (F/M)7/29/1
Age (years), mean (s.d.)55.3 (15.9)54.8 (15.3)
Body mass index (kg/m2), mean (s.d.)25.5 (7.7)27.2 (6.2)
Liver biochemistry, median (range)
 Serum albumin (g/dL)38 (28–42)33 (26–44)
 Alkaline phosphatase (IU/L)432 (92–812)430 (139–833)
 Serum bilirubin (μg/L)28 (6–731)45 (26–73)
 Prothrombin time (s)0.9 (0.8–1)1 (0.8–1.2)

Perception of pruritus

During the pre-treatment period, the mean pruritus burdens (as assessed by VAS) in the ondansetron (mean 4.1, range: 0.4–7.1) and placebo (4.7, 2.7–9.3) groups were similar (Figure 1). At 24 h, two of the nine patients (22%) in the ondansetron group and one given placebo (10%) had a meaningful (>50%) reduction in perceived pruritus (N.S.), with a non-significant mean reduction in VAS of 17% in both the ondansetron and placebo groups. At completion of the study, only one patient in the ondansetron group and two of those given placebo had had a meaningful reduction in mean pruritus burden over the 5 treatment days compared with baseline. Furthermore, there was no significant difference in reduction in the mean pruritus burden over the 5-day treatment period compared with baseline – 21% in the ondansetron group and 22% in the placebo group.

image

Figure 1. Mean pruritus scores (±S.E.M.) by visual analogue scale before (day 0) and after (days 1–5) treatment with ondansetron or placebo.

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Scratching activity

In three patients, there was technical failure of the piezo electrode to measure itch, so that evaluable scratchometer data were available in 16 patients (eight ondansetron and eight placebo). In both groups, there was a clear diurnal variation, with remission of scratching activity during sleep. On day 1 post-treatment, two patients in the ondansetron group and one given placebo had a meaningful reduction in scratching activity. Scratching activity was reduced on the first treatment day in both groups, but did not suggest a meaningful decrease in itchiness; the mean reduction in scratching activity was 6% in the ondansetron group and 16% in the placebo group (N.S.). There was no correlation between individual scratchometer and VAS readings during day 1 post-treatment or the observation period, for either the ondansetron or placebo groups.

Adverse events

All but one patient completed the study. This patient had cholestasis because of chronic rejection postorthotopic liver transplantation and was randomized to ondansetron, but required rescue antipruritic treatment (oral antihistamine) on day 2 because of increasing pruritus, and was defined as a treatment failure.

One patient in the ondansetron group had moderate increases from baseline in serum alkaline phosphatase (from 306 to 812 IU/L) and bilirubin levels (628–731 μg/L) at the post-treatment visit (day 7). Constipation occurred in four patients in the ondansetron group (44%) but in none of those given placebo (Fisher's exact test: P = 0.03). Conversely, nausea (in three patients) and headache (in two patients) were reported only in the placebo group.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Serotonin activation of 5-HT3 receptors on unmyelinated dermal sensory nerve-endings,21 the dorsal horn of the spinal cord and in the medulla,20 may be involved in the perception and generation of pruritus, and these observations which led to the use of the 5-HT3 receptor antagonists such as ondansetron.19 Initial small case series from two groups suggested symptomatic improvement in patients with cholestasis-related pruritus of different aetiologies. In a German report,22, 23 four patients with pruritus resistant to conventional drug therapy were treated with intravenous ondansetron. This resulted in an 80–100% reduction in the patients’ assessment of their pruritus within 30 min of administration, and symptom relief was sustained for up to 24 h. Three of these patients were studied in a controlled fashion, with saline infusion producing minimal benefit. Similarly, in an uncontrolled Austrian trial of five patients, rapid relief of pruritus was reported after intravenous ondansetron.24 In three of these patients, oral treatment was continued successfully for some weeks. In 1995, Schworer et al. conducted a single blinded, placebo-controlled trial of intravenous ondansetron 8 mg in 10 patients, and reported that it was effective for a period of up to 6 h in 50%, whereas a lower dose of 4 mg was maximally effective for up to 4 h.25

Limitations of the above studies were that none was double blinded, and only one measurement of outcome was used, namely the patients’ own perception of their itch. In the one double-blinded study carried out to date,26 patients were randomized to receive either oral ondansetron 8 mg three times daily or identical-appearing placebo tablets for 1 week, followed by crossing over to the other arm after a 1-week washout period. VAS scores were determined four times daily, and showed a mean 5 day peak VAS score decrease of 1.3-points with ondansetron over that produced by placebo.

Our study of ondansetron is novel in that it utilized both an objective tool (scratchometer) and a subjective scoring system for pruritus. We did not find any correlation in variation of scratchometer data with the VAS assessment; which is an easy-to-use but subjective means of accurately assessing pruritus.28 This lack of correlation may also have been related to the relatively small numbers in each group. Our use of a scratchometer was limited by failure of the piezo electrode (as a result of perspiration or sensor failure) to measure itch in two patients who received placebo, and one who received ondansetron. We chose a twice daily rather than thrice daily dose as ondansetron is hepatically metabolized and in severe liver disease its metabolism may be only 20% of normal.29 Finally, our study group was composed mainly of patients with PBC, and it may not be appropriate to extrapolate these findings to other cholestatic liver diseases.

In conclusion, although 5-HT3 receptors have been shown to be involved in the pathway of pruritus sensation, in contrast to previous studies we did not demonstrate a significant early benefit utilizing intravenous ondansetron and no improvement in pruritus during a 5-day course of the oral preparation.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

This study was funded by a grant from GlaxoWellcome, Uxbridge, Middlesex, UK.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
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