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Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study
Journal of Hepatology 37 (2002) 717–722 www.elsevier.com/locate/jhep
Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study q Rube´n Terg 1,*, Emma Coronel 1, Juan Sorda´ 2, Alberto E. Mun˜oz 1, Jorge Findor 2 1
Unidad de Hepatologı´a, Hospital de Gastroenterologı´a Bonorino Udaondo, Escuela de Medicina, Universidad del Salvador, Avenida Caseros, 2061 (1264), Buenos Aires, Argentina 2 Hospital de Clı´nicas, Escuela de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
See Editorial, pages 863–865
Background/Aims: To assess the efficacy and safety of naltrexone for the short and long term treatment of pruritus of cholestasis. Methods: Twenty patients with pruritus and cholestasis were included. A baseline pruritus score was obtained over 1 week. Patients were then randomized to receive 50 mg/day of naltrexone or placebo for 2 weeks. Subsequently, a 1-week washout period ensued and patients were crossed over to the other therapy for 2 additional weeks. Pruritus was assessed daily with a visual analogue scale (VAS) from 0 to 10. Patients whose pruritus decreased .50% of basal with naltrexone received naltrexone 50 mg/day for 2 additional months. Results: Mean basal VAS was similar in both groups. VAS showed greater and more significant changes with naltrexone than with placebo (P , 0.0003). In nine out of 20 patients (45%) receiving naltrexone, pruritus decreased .50% compared to basal value, including five whose pruritus disappeared completely. No significant changes were observed in serum biochemistry. Most of the adverse events that occurred during the first 48 h of naltrexone therapy were consistent with opioid withdrawal-like phenomena and spontaneously disappeared 2 days after starting treatment. Conclusions: Naltrexone can be considered as an alternative option to treat pruritus of cholestasis. In the current study, side effects were transient and did not require specific medication. q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Cholestasis; Pruritus; Naltrexone
1. Introduction Pruritus is the most disabling symptom in chronic cholestatic liver disease. Many therapies have been used for the treatment of these patients with different outcomes [1–3]. Despite benefits from cholestyramine [4], ursodeoxycholic acid [5–7], or rifampin [8–12], there is an important number of patients who do not respond to medical treatment, in
Received 7 February 2002; received in revised form 15 July 2002; accepted 28 August 2002 q Presented in part at the 51st Annual Meeting of the American Association for the Study of Liver Diseases, Dallas, TX, USA, October 28–31, 2000, and published in abstract form in Hepatology 2000;32:167A. * Corresponding author. Tel.: 154-11-4304-0006; fax: 154-11-43062033. E-mail address: [email protected] (R. Terg).
whom unconventional methods, like plasmapheresis, [13] have been tried. Moreover, unrelieved chronic pruritus can be an indication for liver transplantation after therapeutic failure [14,15]. The mechanisms that explain this kind of itching are subject of controversy. Although it was classically thought to arise from retained bile acids [16,17], recent studies have suggested that pruritus due of cholestasis could be mediated by endogenous opioid substances in the central nervous system [18–20]. The evidence that supports this hypothesis is the following: (a) patients with chronic cholestatic liver disease have increased plasma levels of endogenous opioids substances, such as enkephalin [21]; (b) opiates produce itching that can be reversed by an opiate antagonist (naloxone) [22,23]; and (c) naloxone-reversible itching can be induced in monkeys by injecting plasma extracts from
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S 0168-827 8(02)00318-5
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cholestatic patients with pruritus into the medullary dorsal horn [24]. Recently, several published trials have confirmed that administration of opiate antagonists (naloxone and nalmefene) in patients with primary biliary cirrhosis leads to a significant improvement in pruritus measured by a reduction in scratching activity [18,25–27]. Unfortunately, the drugs investigated have important limitations. Naloxone has a short half-life and its oral bioavailability is low; so, it can only be administered parenterally [27,28]. On the other hand, opiate antagonist treatment has been associated with a severe opiate withdrawal-like syndrome [29,30]. Naltrexone, an oral opioid antagonist, has been recently released for use in the treatment of narcotic and alcohol dependence. It has bioavailability and half-life that lie between naloxone and nalmefene. This drug undergoes extensive (95%) first-pass metabolism and has high plasma levels in the first hour of ingestion. The clearance follows mainly the renal route [28,31,32]. It has also been proposed as a treatment for pruritus of cholestasis [33,34]. We have performed a double-blind, crossover, placebocontrolled trial to assess the efficacy and safety of oral naltrexone in the treatment of pruritus due to cholestasis, and to evaluate its effects in the short and long term. 2. Materials and methods
cal pills containing placebo (Group B) during 2 weeks. After this time the treatment was stopped. A 1-week washout period ensued, and the subjects were crossed over to the other therapy for 2 additional weeks. On the first day of each treatment, medication was administered at doses of 25 mg at 09:00 h and 25 mg at 14:00 h; subsequently, the patient received 50 mg naltrexone or placebo in a single daily dose. The severity of pruritus was assessed daily for daytime and night-time complaints using a visual analogue scale (VAS) for 1 week before starting treatment and during the 5 weeks of the study. Daytime pruritus was assessed before retiring to sleep while night-time pruritus was assessed at wake-up. A scale of 0–10 was used and noted in an individual log book [34]. Criteria for maximal score (i.e. 10) were pruritus that interfered with sleep, altered daily activities or resulted in self-inflicted skin breakdown; 0 was considered as absence of pruritus. Complete response was defined as disappearance of pruritus and partial response as . 50% reduction in the pruritus score. Pruritus score is expressed as the mean of each period. Compliance was assessed during the follow-up by counting the pills remaining in the bottles. Patients with partial or complete response were included in an open study to receive naltrexone 50 mg/day for 2 additional months and were followed as outpatients every 2 weeks. Severity of pruritus was evaluated using the same scoring system as the short-term treatment. Laboratory tests, including serum bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), prothrombin time, serum albumin, platelets, red and white cell count, serum urea, creatinine, sodium, potassium and g-glutamyltransferase (GGT), were assessed in basal conditions, every week during the short-term treatment and every 2 weeks during the long-term treatment. The study protocol conformed with the Helsinki Declaration and was approved by the Ethical Committees of the Hospital de Gastroenterologı´a Bonorino Udaondo and the Hospital de Clı´nicas. Written informed consent was obtained from all participants.
2.1. Patients Twenty patients (36–70 years old) with pruritus associated with chronic intrahepatic cholestasis were included in this study. Fifteen patients had a diagnosis of primary biliary cirrhosis (PBC): three with negative antimitochondrial antibodies (AMA), two with chronic hepatitis C (one of them also had an hepatocellular carcinoma), one with primary sclerosing cholangitis (PSC), one with overlap syndrome (autoimmune hepatitis (AIH) and autoimmune cholangiopathy (AIC)) and one with cryptogenic cirrhosis. The duration of pruritus ranged from 6 to 11 months. Eleven patients received ursodeoxycholic acid, three of them a combination of ursodeoxycholic acid and cholestyramine, one a combination of ursodeoxycholic and corticosteroids; one patient received ursodeoxycholic acid, cholestyramine, phenobarbital, ondansentron and rifampicin. All of them had taken their medicine for longer than 3 months without significant response to treatment. Four patients did not receive any specific antipruritic treatment at all. Exclusion criteria encompassed the following: (1) use of opiates within the last 10 days; (2) changes in antipruritic medication within 1 month of entry; (3) serum creatinine . 1:5 mg/dl; (4) age , 18 years or pregnancy; (5) drug-induced cholestasis; (6) extrahepatic cholestasis. The study was performed from June to December 1999 at the Hospital de Gastroenterologı´a Bonorino Udaondo and at the Hospital de Clı´nicas, Buenos Aires. All patients were instructed to continue with their previous medication throughout the study.
2.2. Design of the study This study was double-blind, placebo-controlled. Randomization was generated by tables with two random numbers for each patient. These were the numbers of the bottles containing medication or placebo. The tables also included the order of their administration. Information about randomization was placed in sealed, opaque, and numbered envelopes. After a 1-week period in which baseline pruritus score was obtained, patients were randomized to receive pills containing 50 mg naltrexone (Revez; Soubeiran Chobet, Buenos Aires, Argentina) (Group A) or identi-
2.3. Statistical analyses The mean (SD) values of the VAS of the basal week and during the placebo–naltrexone treatment period were used for the evaluation of treatment response. t-Tests for two-group and matched-group (paired) analyses were performed. Qualitative data were tabulated and analyzed using twoway frequency tables by Yates’ corrected x 2 or Fisher’s exact test (one tail). A P value of less than 0.05 was considered significant.
3. Results 3.1. Effects of naltrexone on pruritus The baseline characteristics of the patients are presented in Table 1. The mean basal VAS was similar when the first test period was either naltrexone (Group A) or placebo (Group B). One patient (no. 16) changed by mistake the sequence of the bottles with the medication; for this reason, Group A included 11 patients and Group B included nine patients. At the end of naltrexone treatment, pruritus decreased significantly compared to basal (mean daytime pruritus VAS decreased from 6.29 ^ 2.28 to 3.55 ^ 2.39, P ¼ 0:0003; and night-time itching improved from 5.89 ^ 2.49 to 3.55 ^ 2.42, P ¼ 0:001). These outcomes with naltrexone were also seen in both Groups separately. For Group A, diurnal VAS went from 6.27 ^ 1.61 to 3.91 ^ 2.39, P ¼ 0:01 and night VAS was reduced from 6.52 ^ 2.42 to 3.89 ^ 2.17, P ¼ 0:02. For Group B diurnal itching went from 6.32 ^ 3.10 to
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Table 1 Characteristics of the studied patients a Group A (n ¼ 11) Sex (female/male) Age (years) Biochemistry Serum albumin (N: .3.5 g/dl) Serum bilirubin (N: ,1.2 mg/dl) Alkaline phosphatase (N: , 300 UI/ml) ALT (N: , 47 UI/ml) AST (N: , 47 UI/ml) GGT (N: , 36 UI/ml) Prothrombin time (N: .70%) Serum creatinine (N: ,1.6 mg/dl) Basal VAS (mean) Daytime pruritus Night-time pruritus Previous treatment Ursodeoxycholic acid Cholestyramine Rifampicin Phenobarbital Ondansentron Corticosteroids None Etiology PBC (n) PSC (n) Overlap syndrome (n) Cryptogenic cirrhosis (n) Chronic hepatitis C (n)
8/3 55 ^ 10 (36–70)
Group B (n ¼ 9) 9/0 55 ^ 9 (42–69)
3.75 ^ 0.35 2.05 ^ 2.08 1395 ^ 857 137 ^ 84 98 ^ 47 376 ^ 222 97 ^ 17 0.66 ^ 0.08
3.62 ^ 0.74 2.03 ^ 2.62 1072 ^ 543 182 ^ 206 174 ^ 175 236 ^ 191 94 ^ 8 0.78 ^ 0.17
6.26 ^ 1.61 6.52 ^ 2.42
5.93 ^ 3.12 5.32 ^ 2.48
9 4 1 1 1 2
7 0 0 0 0 1 2
8 1 1 0 1
7 0 0 1 1
a
Results are expressed as mean ^ SD. No significant changes were found between the two groups.
3.06 ^ 2.47, P ¼ 0:01 and night itching decreased from 5.03 ^ 2.48 to 3.05 ^ 2.77, P ¼ 0:02. On the other hand, changes during placebo intake were not significant compared to baseline values (daytime VAS: 6.12 ^ 2.34 to 5.20 ^ 2.43, P ¼ 0:07/night VAS: 5.98 ^ 2.46 to 5.25 ^ 2.49, P ¼ 0:06). These changes were independent of the sequence of treatment (placebo or naltrexone).
Fig. 1. Visual analogue scale (VAS) for daytime pruritus in patients starting with naltrexone (Group A). A significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.01). In contrast, a significant increase in VAS was observed after 2 weeks of placebo compared to the end of naltrexone treatment (**P , 0.02).
Fig. 2. VAS for night-time pruritus in patients starting with naltrexone (Group A). A significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.02). No significant changes in VAS were observed after 2 weeks of placebo compared to the end of naltrexone treatment.
The comparison between naltrexone and placebo treatments showed that mean diurnal pruritus VAS in naltrexone treatment was significantly lower compared to mean diurnal pruritus VAS in placebo treatment (3.55 ^ 2.39 vs. 5.34 ^ 2.41, P ¼ 0:006). In addition, mean night pruritus VAS also showed a significant decrease after 2 weeks of naltrexone treatment compared to placebo (5.19 ^ 2.55 vs. 3.55 ^ 2.42, P ¼ 0:01). Daytime and night-time pruritus VAS in Group A patients during short term administration are presented in Figs. 1 and 2, while daytime and night-time pruritus VAS in Group B patients are presented in Figs. 3 and 4. Two patients were withdrawn during short-term treatment (see side effects), so 18 out of 20 patients completed the study. In nine patients receiving naltrexone, pruritus decreased . 50% compared to basal value and they were recruited into an open trial where they received medication during 2 additional
Fig. 3. VAS for daytime pruritus in patients starting with placebo (Group B). No significant changes in VAS were observed after 2 weeks of placebo compared to basal. In contrast, a significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.01) and placebo treatment (**P , 0.01).
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R. Terg et al. / Journal of Hepatology 37 (2002) 717–722 Table 2 Biochemical and clinical data before and after 2 weeks of naltrexone treatment a After b
Before Serum bilirubin (N: ,1.2mg/dl) 2.09 ^ 2.32 Serum albumin (N: .3.5 g/dl) 3.73 ^ 0.41 Prothrombin time (N: .70%) 96 ^ 8 AST (N: ,47 UI/ml) 109 ^ 69 ALT (N: ,47 UI/ml) 130 ^ 88 Alkaline phosphatase(N: ,300 UI/ml) 1255 ^ 753 GGT (N: ,36 UI/ml) 308 ^ 221 Creatinine (,1.6 mg/dl) 0.70 ^ 0.14 Systolic blood pressure (mmHg) 130 ^ 17 Diastolic blood pressure (mmHg) 76 ^ 11 Pulse rate (beats/min) 73 ^ 11 Fig. 4. VAS for night-time pruritus in patients starting with placebo (Group B). No significant changes in VAS were observed after 2 weeks of placebo compared to basal. In contrast, a significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.02) and placebo treatment (**P , 0.05).
months. Two patients were withdrawn during long-term treatment (see side effects). Out of the seven remaining patients, two experienced exacerbation of their symptoms (patient nos. 2 and 12). One of these patients (no. 2) felt intense itching during washout time after a dramatic amelioration with naltrexone. She kept experiencing pruritus with placebo and did not respond to naltrexone when it was reinstituted. Although the dose was increased (to 100 mg/day) and treatment was interrupted for 2 days every week (drug holidays), no amelioration of her pruritus was achieved. She was subsequently treated with rifampicin and corticosteroids, which resulted in a decrease in pruritus. The other patient (no. 12) noted an increase of pruritus after 4 weeks of long-term treatment. She received double dose of medication without improvement of itching, although it remained below basal values. The other five patients kept a sustained response to naltrexone during the whole long-term treatment. The onset of the improvement in pruritus was, generally, during the first 2 days after starting with naltrexone administration. No significant changes were observed in the mean values of serum biochemistry, blood pressure or pulse rate in patients treated with naltrexone or placebo compared with basal values during short-term administration (Table 2). In addition, no significant biochemical changes were found during long-term treatment with naltrexone. Treatment compliance, assessed by pill counts, was 98%.
3.2. Side effects 3.2.1. Short -term administration Side effects observed during naltrexone or placebo shortterm administration are shown in Table 3. The most frequent side effects were dizziness (10 patients), nausea (eight patients), vomiting (six patients), headache and abdominal cramps (five patients). Most of them did not require addi-
2.29 ^ 2.86 3.70 ^ 0.59 94 ^ 12 88 ^ 53 108 ^ 82 1266 ^ 932 296 ^ 231 0.71 ^ 0.10 125 ^ 19 73 ^ 11 75 ^ 10
a Results are expressed as mean ^ SD. No significant changes were found. b Results are expressed as the mean of the 1st and the 2nd weeks of naltrexone treatment.
tional medication and side effects improved or disappeared 48 h after starting treatment. Two patients (nos. 17 and 19) abandoned the study on the third day during naltrexone treatment period due to the persistence of side effects. Patient no. 17 started with asthenia, dizziness, nausea and vomiting during naltrexone treatment and patient no. 19 began with mild epigastric pain and sporadic vomiting during the washout period, before naltrexone treatment, and continued this way during naltrexone treatment, stopping the treatment on the third day. Patient no. 3 reduced the dose of naltrexone to 25 mg. a day from the 3 rd to the 7 th day due to dizziness improving symptoms and following with naltrexone 50 mg until completion of the study. 3.2.2. Long -term administration The most frequent side effects during long-term adminTable 3 Side effects during short-term administration Symptoms
Dizziness Nausea Vomit Headache Abdominal cramps Asthenia Drowsiness Irritability Dry mouth Insomnia Tremor Tachycardia Anorexia Flushing Arterial hypertension
Naltrexone
Placebo
Patient no.
n
1, 2, 3, 4, 5, 7, 8, 9, 17 ,20 1, 2, 5, 6, 7, 9, 12, 17 2, 5, 12, 17, 19, 20 1, 2, 15, 16, 20 3, 4, 10, 15, 20 1, 9, 17 1, 8, 15 1, 3, 20 1, 3, 10 10, 20 4 7 7 10 20
10 8 6 5 5 3 3 3 3 2 1 1 1 1 1
Patient no.
6 19, 20 1, 6, 20 20 3, 11 3, 11
n 0 1 2 3 1 0 2 2 0 0 0 0 0 0 0
R. Terg et al. / Journal of Hepatology 37 (2002) 717–722
istration with naltrexone were nausea and vomiting (four patients), dizziness (three patients) and abdominal cramps (three patients). All of these symptoms occurred within the first 24 h and disappeared without additional medication. Two patients (nos. 4 and 5) were withdrawn from the study 48 h after starting long-term administration, patient no. 4 because of clinical impairment due to progression of prior hepatocarcinoma; patient no. 5 reported nausea and vomiting and refused to continue with the study.
4. Discussion The results of the current study suggest that the administration of an oral opiate antagonist, naltrexone, relieves the pruritus associated with chronic cholestatic liver disease. The decrease in values of VAS with naltrexone agrees with those found in two previously published reports [33,34]. In the first one, an open-label trial including five patients, pruritus decreased significantly after a week of naltrexone treatment [33]. The second, a placebo-controlled study showed a significant reduction in the perception of daytime itching (254 vs. 8%) and night-time itching (244 vs. 7%) within a 4-week course of naltrexone [34]. Some authors consider that the VAS is an inadequate and unreliable method of assessing the perception of pruritus and propose the use of an instrument that measures scratching activity attached to a fingernail [25]. We agree that such a measurement of could give a more objective evaluation of scratching activity, but the use of this device carries practical difficulties in outpatient assessment for long follow-up periods. In most of the studies, scratching activity was measured only during 24 h [25–27]. Furthermore, the efficacy of different agents currently recommended for the treatment of pruritus of cholestasis has been based on studies using subjective end-points such as VAS [4,8–12]. Although the scratching activity index appears to be more sensitive, some trials indicate good agreement with the VAS. Analysis of a double-blind trial comparing intravenous naloxone versus saline demonstrated that the scratching activity correlated significantly with the visual analogue score [25,26]. In a randomized controlled trial, the effect of ondansentron on scratching activity and on the perception of pruritus was reported to be similar in both groups [35] Finally, in clinical practice, VAS is widely used in the assessment of different symptoms, especially pain [36]. In the current study, two patients experienced a recurrence of pruritus after an initial decrease (breakthrough). The worsening of itching may have been due to adaptation in opioid receptors or to drug tolerance to (tachyphylaxis). These phenomena were reported with naltrexone [33,34,37] and with nalmefene [27]. Carson et al. suggested that interrupting treatment for 2 days every week (drug holidays) [33] could prevent recurrence of pruritus. However, in the present study these patients have not responded to drug holidays and to an increase in the dose of naltrexone.
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Adverse effects during short-term naltrexone treatment were mainly dizziness, nausea, vomits, headache and cramps. Two patients were withdrawn at this time: one due to the persistence of adverse effects. The other subject began with epigastric pain and vomiting during the washout period before naltrexone administration and continued during naltrexone treatment. It is quite likely that her symptoms did not have any relation with the drug. Similar adverse reactions were observed during long-term therapy and they generally disappeared on the second day of treatment. It is worth noticing that although many side effects reported in this study could be compatible with opioid withdrawal-like phenomena, they were generally mild and transient. It is possible that patients paid more attention to their symptoms taking into account that several adverse effects were also reported with placebo. Different adverse effects were associated with naltrexone [33,34,38] and nalmefene in previous studies [18,27], though those related to nalmefene treatment seemed to be more severe. Although some of the side effects observed in our study could be considered as part of a mild opiate withdrawal reaction, neurological or psychiatric symptoms found in other publications were not observed. To avoid such reaction, co-administering clonidine [18] or starting treatment with a subtherapeutic dose with subsequent dose escalation [27] was suggested. In accordance with previous studies with naltrexone [33,34], on the first day of the present study, naltrexone was given in two separate doses of 25 mg each in order to minimize adverse events. In another study of the pharmacokinetic behavior of naltrexone in 11 cirrhotic patients, a bolus of 100 mg of naltrexone was administered orally. Transient nausea and irritability in one patient and tremor in another was reported [32]. Recently, a woman developed severe opioid withdrawal-like reaction after oral administration of 12.5 mg and 2 mg naltrexone. Subsequent intravenous naloxone administration at subtherapeutic dose allowed reintroduction of oral naltrexone at a dose of 12.5 mg twice a day without any side effects [29]. So, it seems advisable to initiate naltrexone therapy with low doses with a gradual stepwise increase to a therapeutic dosage. Evidence of hepatotoxicity of naltrexone was shown in a placebo-controlled study in which obese subjects received naltrexone at a dose of 300 mg/day [39]. This was not reported in other studies for lower doses of naltrexone in patients with [33,34] and without [38] liver disease. In the present study, no significant changes in hepatic biochemistry were observed with naltrexone treatment. Thus, current data suggest that naltrexone can be safely administered to patients with chronic liver disease. The pathogenesis of cholestatic pruritus remains uncertain. The theory that increased opioidergic tone may be implicated is based on results of several studies [18,25,27,33,34,40,41]. However, treatment with opiate antagonists usually does not eliminate itching completely. It is also possible that non-opioid mechanisms contribute to pruritus from cholestasis. It is remarkable that different
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kinds of approaches such as cholestyramine, rifampicin, phenobarbital or ondansentron have been tried with varying efficacy, suggesting that pruritus of cholestasis is explained by a multifactorial mechanism. In summary, naltrexone must be considered as an alternative option for the treatment of pruritus due to cholestasis. Most of the reported side effects are mild, transient and do not require specific medication. Acknowledgements
[18] [19]
[20] [21] [22] [23]
E.C. was recipient of a grant by FUNDHIG (Fundacio´ n Argentina para el Estudio del Hı´gado). Laboratorios Souberian Chobet, Buenos Aires, provided naltrexone.
[24]
[25]
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bile acids in human cholestasis; relation to serum levels and to pruritus. Gastroenterology 1992;102:544–549. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. Br Med J 1988;297:1501–1504. Jones EA, Bergasa NV. The pruritus of cholestasis and the opioid system in Grand Rounds at the clinical center of the National Institutes of Health. J Am Med Assoc 1992;23:3359–3362. Jones EA, Bergasa NV. The pruritus of cholestasis. Hepatology 1999;29:1003–1006. Thornton JR, Losowsky MS. Plasma leucine enkephalin is increased in liver disease. Gut 1989;3:1392–1395. Jones EA, Bergasa NV. The pruritus of cholestasis. From bile acids to opiate antagonists. Hepatology 1990;11:884–887. Bergasa NV, Jones EA. Management of the pruritus of cholestasis: potential role of opiate antagonists. Am J Gastroenterol 1991;86:1404–1412. Bergasa NV, Thomas DA, Vergalla J, Turner ML, Jones EA. Plasma from patients with the pruritus of cholestasis induces opioid receptormediated scratching in monkeys. Life Sci 1993;53:1253–1257. Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, Korenman JC. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992;102:544–549. Bergasa NV, Alling DW, Talbot TL, Swaln MG, Yurdaydin C, Turner ML, Schmitt JM. Effects of naloxone infusions in patients with the pruritus of cholestasis. Ann Intern Med 1995;123:161–167. Bergasa NV, Schmitt JM, Talbot TL, Alling DW, Swain MG, Turner ML, et al. Open label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998;27:679–684. Jaffe H, Martin D. Opioid analgesics and antagonists. In: Gilman A, Goodman L, Rall T, Marad F, editors. The pharmacologic basis of therapeutics, 7th ed. New York: MacMillan, 1985. pp. 491–531. Jones EA, Dekker LR. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis. Gastroenterology 2000;118:431–432. Shawcross D, Jalan R. Delayed opioid withdrawal-like reaction in primary biliary cirrhosis following naloxone therapy. Gastroenterology 2001;121:743–744. Gonzalez JP, Brodgen RN. Naltrexone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 1988;35:192–213. Bertolotti M, Ferrari A, Vitale G, Stefani M, Trenti T, Loria P, et al. Effect of liver cirrhosis on the systemic availability of naltrexone in humans. J Hepatol 1997;27:505–511. Carson KL, Tran TT, Cotton P, Sharara AI, Hunt CM. Pilot study of the use of Naltrexone to treat the severe pruritus of cholestatic liver disease. Am J Gastroenterol 1996;91:1022–1023. Wolfhagen FHJ, Sternieri E, Hop WCJ, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double blind placebo-controlled study. Gastroenterology 1997:1264–1269. O’Donohue JW, Haigh C, Williams R. Ondasentron in the treatment of the pruritus of cholestasis: a randomised controlled trial. Gastroenterology 1997;112:A1349. McCormack H, Horne D, Sheather S. Clinical applications of visual analogue scales: a critical review. Psychol Med 1988;18:1007–1019. Pauli-Magnus C, Mikus G, Alscher DM, Kirschner T, Nagel W, Gugeler N, et al. Naltrexone does not relieve uremic pruritus: results of a randomized, double blind, placebo-controlled crossover study. J Am Soc Nephrol 2000;11:514–519. Sax DS, Kornetsky C, Kim A. Lack of hepatotoxicity with naltrexone treatment. J Clin Pharmacol 1994;34:898–901. Mitchell JE. Naltrexone and hepatotoxicity. Lancet 1986;i:1215. Jones EA, Bergasa NV. The pathogenesis and treatment of pruritus and fatigue in patients with PBC. Eur J Gastroenterol Hepatol 1999;11:623–631. Terra SG, Tsunoda SM. Opioid antagonists in the treatment of pruritus from cholestatic liver disease. Ann Pharmacother 1998;32:1228– 1230.
Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study q Rube´n Terg 1,*, Emma Coronel 1, Juan Sorda´ 2, Alberto E. Mun˜oz 1, Jorge Findor 2 1
Unidad de Hepatologı´a, Hospital de Gastroenterologı´a Bonorino Udaondo, Escuela de Medicina, Universidad del Salvador, Avenida Caseros, 2061 (1264), Buenos Aires, Argentina 2 Hospital de Clı´nicas, Escuela de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
See Editorial, pages 863–865
Background/Aims: To assess the efficacy and safety of naltrexone for the short and long term treatment of pruritus of cholestasis. Methods: Twenty patients with pruritus and cholestasis were included. A baseline pruritus score was obtained over 1 week. Patients were then randomized to receive 50 mg/day of naltrexone or placebo for 2 weeks. Subsequently, a 1-week washout period ensued and patients were crossed over to the other therapy for 2 additional weeks. Pruritus was assessed daily with a visual analogue scale (VAS) from 0 to 10. Patients whose pruritus decreased .50% of basal with naltrexone received naltrexone 50 mg/day for 2 additional months. Results: Mean basal VAS was similar in both groups. VAS showed greater and more significant changes with naltrexone than with placebo (P , 0.0003). In nine out of 20 patients (45%) receiving naltrexone, pruritus decreased .50% compared to basal value, including five whose pruritus disappeared completely. No significant changes were observed in serum biochemistry. Most of the adverse events that occurred during the first 48 h of naltrexone therapy were consistent with opioid withdrawal-like phenomena and spontaneously disappeared 2 days after starting treatment. Conclusions: Naltrexone can be considered as an alternative option to treat pruritus of cholestasis. In the current study, side effects were transient and did not require specific medication. q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Cholestasis; Pruritus; Naltrexone
1. Introduction Pruritus is the most disabling symptom in chronic cholestatic liver disease. Many therapies have been used for the treatment of these patients with different outcomes [1–3]. Despite benefits from cholestyramine [4], ursodeoxycholic acid [5–7], or rifampin [8–12], there is an important number of patients who do not respond to medical treatment, in
Received 7 February 2002; received in revised form 15 July 2002; accepted 28 August 2002 q Presented in part at the 51st Annual Meeting of the American Association for the Study of Liver Diseases, Dallas, TX, USA, October 28–31, 2000, and published in abstract form in Hepatology 2000;32:167A. * Corresponding author. Tel.: 154-11-4304-0006; fax: 154-11-43062033. E-mail address: [email protected] (R. Terg).
whom unconventional methods, like plasmapheresis, [13] have been tried. Moreover, unrelieved chronic pruritus can be an indication for liver transplantation after therapeutic failure [14,15]. The mechanisms that explain this kind of itching are subject of controversy. Although it was classically thought to arise from retained bile acids [16,17], recent studies have suggested that pruritus due of cholestasis could be mediated by endogenous opioid substances in the central nervous system [18–20]. The evidence that supports this hypothesis is the following: (a) patients with chronic cholestatic liver disease have increased plasma levels of endogenous opioids substances, such as enkephalin [21]; (b) opiates produce itching that can be reversed by an opiate antagonist (naloxone) [22,23]; and (c) naloxone-reversible itching can be induced in monkeys by injecting plasma extracts from
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S 0168-827 8(02)00318-5
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cholestatic patients with pruritus into the medullary dorsal horn [24]. Recently, several published trials have confirmed that administration of opiate antagonists (naloxone and nalmefene) in patients with primary biliary cirrhosis leads to a significant improvement in pruritus measured by a reduction in scratching activity [18,25–27]. Unfortunately, the drugs investigated have important limitations. Naloxone has a short half-life and its oral bioavailability is low; so, it can only be administered parenterally [27,28]. On the other hand, opiate antagonist treatment has been associated with a severe opiate withdrawal-like syndrome [29,30]. Naltrexone, an oral opioid antagonist, has been recently released for use in the treatment of narcotic and alcohol dependence. It has bioavailability and half-life that lie between naloxone and nalmefene. This drug undergoes extensive (95%) first-pass metabolism and has high plasma levels in the first hour of ingestion. The clearance follows mainly the renal route [28,31,32]. It has also been proposed as a treatment for pruritus of cholestasis [33,34]. We have performed a double-blind, crossover, placebocontrolled trial to assess the efficacy and safety of oral naltrexone in the treatment of pruritus due to cholestasis, and to evaluate its effects in the short and long term. 2. Materials and methods
cal pills containing placebo (Group B) during 2 weeks. After this time the treatment was stopped. A 1-week washout period ensued, and the subjects were crossed over to the other therapy for 2 additional weeks. On the first day of each treatment, medication was administered at doses of 25 mg at 09:00 h and 25 mg at 14:00 h; subsequently, the patient received 50 mg naltrexone or placebo in a single daily dose. The severity of pruritus was assessed daily for daytime and night-time complaints using a visual analogue scale (VAS) for 1 week before starting treatment and during the 5 weeks of the study. Daytime pruritus was assessed before retiring to sleep while night-time pruritus was assessed at wake-up. A scale of 0–10 was used and noted in an individual log book [34]. Criteria for maximal score (i.e. 10) were pruritus that interfered with sleep, altered daily activities or resulted in self-inflicted skin breakdown; 0 was considered as absence of pruritus. Complete response was defined as disappearance of pruritus and partial response as . 50% reduction in the pruritus score. Pruritus score is expressed as the mean of each period. Compliance was assessed during the follow-up by counting the pills remaining in the bottles. Patients with partial or complete response were included in an open study to receive naltrexone 50 mg/day for 2 additional months and were followed as outpatients every 2 weeks. Severity of pruritus was evaluated using the same scoring system as the short-term treatment. Laboratory tests, including serum bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), prothrombin time, serum albumin, platelets, red and white cell count, serum urea, creatinine, sodium, potassium and g-glutamyltransferase (GGT), were assessed in basal conditions, every week during the short-term treatment and every 2 weeks during the long-term treatment. The study protocol conformed with the Helsinki Declaration and was approved by the Ethical Committees of the Hospital de Gastroenterologı´a Bonorino Udaondo and the Hospital de Clı´nicas. Written informed consent was obtained from all participants.
2.1. Patients Twenty patients (36–70 years old) with pruritus associated with chronic intrahepatic cholestasis were included in this study. Fifteen patients had a diagnosis of primary biliary cirrhosis (PBC): three with negative antimitochondrial antibodies (AMA), two with chronic hepatitis C (one of them also had an hepatocellular carcinoma), one with primary sclerosing cholangitis (PSC), one with overlap syndrome (autoimmune hepatitis (AIH) and autoimmune cholangiopathy (AIC)) and one with cryptogenic cirrhosis. The duration of pruritus ranged from 6 to 11 months. Eleven patients received ursodeoxycholic acid, three of them a combination of ursodeoxycholic acid and cholestyramine, one a combination of ursodeoxycholic and corticosteroids; one patient received ursodeoxycholic acid, cholestyramine, phenobarbital, ondansentron and rifampicin. All of them had taken their medicine for longer than 3 months without significant response to treatment. Four patients did not receive any specific antipruritic treatment at all. Exclusion criteria encompassed the following: (1) use of opiates within the last 10 days; (2) changes in antipruritic medication within 1 month of entry; (3) serum creatinine . 1:5 mg/dl; (4) age , 18 years or pregnancy; (5) drug-induced cholestasis; (6) extrahepatic cholestasis. The study was performed from June to December 1999 at the Hospital de Gastroenterologı´a Bonorino Udaondo and at the Hospital de Clı´nicas, Buenos Aires. All patients were instructed to continue with their previous medication throughout the study.
2.2. Design of the study This study was double-blind, placebo-controlled. Randomization was generated by tables with two random numbers for each patient. These were the numbers of the bottles containing medication or placebo. The tables also included the order of their administration. Information about randomization was placed in sealed, opaque, and numbered envelopes. After a 1-week period in which baseline pruritus score was obtained, patients were randomized to receive pills containing 50 mg naltrexone (Revez; Soubeiran Chobet, Buenos Aires, Argentina) (Group A) or identi-
2.3. Statistical analyses The mean (SD) values of the VAS of the basal week and during the placebo–naltrexone treatment period were used for the evaluation of treatment response. t-Tests for two-group and matched-group (paired) analyses were performed. Qualitative data were tabulated and analyzed using twoway frequency tables by Yates’ corrected x 2 or Fisher’s exact test (one tail). A P value of less than 0.05 was considered significant.
3. Results 3.1. Effects of naltrexone on pruritus The baseline characteristics of the patients are presented in Table 1. The mean basal VAS was similar when the first test period was either naltrexone (Group A) or placebo (Group B). One patient (no. 16) changed by mistake the sequence of the bottles with the medication; for this reason, Group A included 11 patients and Group B included nine patients. At the end of naltrexone treatment, pruritus decreased significantly compared to basal (mean daytime pruritus VAS decreased from 6.29 ^ 2.28 to 3.55 ^ 2.39, P ¼ 0:0003; and night-time itching improved from 5.89 ^ 2.49 to 3.55 ^ 2.42, P ¼ 0:001). These outcomes with naltrexone were also seen in both Groups separately. For Group A, diurnal VAS went from 6.27 ^ 1.61 to 3.91 ^ 2.39, P ¼ 0:01 and night VAS was reduced from 6.52 ^ 2.42 to 3.89 ^ 2.17, P ¼ 0:02. For Group B diurnal itching went from 6.32 ^ 3.10 to
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Table 1 Characteristics of the studied patients a Group A (n ¼ 11) Sex (female/male) Age (years) Biochemistry Serum albumin (N: .3.5 g/dl) Serum bilirubin (N: ,1.2 mg/dl) Alkaline phosphatase (N: , 300 UI/ml) ALT (N: , 47 UI/ml) AST (N: , 47 UI/ml) GGT (N: , 36 UI/ml) Prothrombin time (N: .70%) Serum creatinine (N: ,1.6 mg/dl) Basal VAS (mean) Daytime pruritus Night-time pruritus Previous treatment Ursodeoxycholic acid Cholestyramine Rifampicin Phenobarbital Ondansentron Corticosteroids None Etiology PBC (n) PSC (n) Overlap syndrome (n) Cryptogenic cirrhosis (n) Chronic hepatitis C (n)
8/3 55 ^ 10 (36–70)
Group B (n ¼ 9) 9/0 55 ^ 9 (42–69)
3.75 ^ 0.35 2.05 ^ 2.08 1395 ^ 857 137 ^ 84 98 ^ 47 376 ^ 222 97 ^ 17 0.66 ^ 0.08
3.62 ^ 0.74 2.03 ^ 2.62 1072 ^ 543 182 ^ 206 174 ^ 175 236 ^ 191 94 ^ 8 0.78 ^ 0.17
6.26 ^ 1.61 6.52 ^ 2.42
5.93 ^ 3.12 5.32 ^ 2.48
9 4 1 1 1 2
7 0 0 0 0 1 2
8 1 1 0 1
7 0 0 1 1
a
Results are expressed as mean ^ SD. No significant changes were found between the two groups.
3.06 ^ 2.47, P ¼ 0:01 and night itching decreased from 5.03 ^ 2.48 to 3.05 ^ 2.77, P ¼ 0:02. On the other hand, changes during placebo intake were not significant compared to baseline values (daytime VAS: 6.12 ^ 2.34 to 5.20 ^ 2.43, P ¼ 0:07/night VAS: 5.98 ^ 2.46 to 5.25 ^ 2.49, P ¼ 0:06). These changes were independent of the sequence of treatment (placebo or naltrexone).
Fig. 1. Visual analogue scale (VAS) for daytime pruritus in patients starting with naltrexone (Group A). A significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.01). In contrast, a significant increase in VAS was observed after 2 weeks of placebo compared to the end of naltrexone treatment (**P , 0.02).
Fig. 2. VAS for night-time pruritus in patients starting with naltrexone (Group A). A significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.02). No significant changes in VAS were observed after 2 weeks of placebo compared to the end of naltrexone treatment.
The comparison between naltrexone and placebo treatments showed that mean diurnal pruritus VAS in naltrexone treatment was significantly lower compared to mean diurnal pruritus VAS in placebo treatment (3.55 ^ 2.39 vs. 5.34 ^ 2.41, P ¼ 0:006). In addition, mean night pruritus VAS also showed a significant decrease after 2 weeks of naltrexone treatment compared to placebo (5.19 ^ 2.55 vs. 3.55 ^ 2.42, P ¼ 0:01). Daytime and night-time pruritus VAS in Group A patients during short term administration are presented in Figs. 1 and 2, while daytime and night-time pruritus VAS in Group B patients are presented in Figs. 3 and 4. Two patients were withdrawn during short-term treatment (see side effects), so 18 out of 20 patients completed the study. In nine patients receiving naltrexone, pruritus decreased . 50% compared to basal value and they were recruited into an open trial where they received medication during 2 additional
Fig. 3. VAS for daytime pruritus in patients starting with placebo (Group B). No significant changes in VAS were observed after 2 weeks of placebo compared to basal. In contrast, a significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.01) and placebo treatment (**P , 0.01).
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R. Terg et al. / Journal of Hepatology 37 (2002) 717–722 Table 2 Biochemical and clinical data before and after 2 weeks of naltrexone treatment a After b
Before Serum bilirubin (N: ,1.2mg/dl) 2.09 ^ 2.32 Serum albumin (N: .3.5 g/dl) 3.73 ^ 0.41 Prothrombin time (N: .70%) 96 ^ 8 AST (N: ,47 UI/ml) 109 ^ 69 ALT (N: ,47 UI/ml) 130 ^ 88 Alkaline phosphatase(N: ,300 UI/ml) 1255 ^ 753 GGT (N: ,36 UI/ml) 308 ^ 221 Creatinine (,1.6 mg/dl) 0.70 ^ 0.14 Systolic blood pressure (mmHg) 130 ^ 17 Diastolic blood pressure (mmHg) 76 ^ 11 Pulse rate (beats/min) 73 ^ 11 Fig. 4. VAS for night-time pruritus in patients starting with placebo (Group B). No significant changes in VAS were observed after 2 weeks of placebo compared to basal. In contrast, a significant reduction in VAS was observed after 2 weeks of naltrexone treatment compared to basal (*P , 0.02) and placebo treatment (**P , 0.05).
months. Two patients were withdrawn during long-term treatment (see side effects). Out of the seven remaining patients, two experienced exacerbation of their symptoms (patient nos. 2 and 12). One of these patients (no. 2) felt intense itching during washout time after a dramatic amelioration with naltrexone. She kept experiencing pruritus with placebo and did not respond to naltrexone when it was reinstituted. Although the dose was increased (to 100 mg/day) and treatment was interrupted for 2 days every week (drug holidays), no amelioration of her pruritus was achieved. She was subsequently treated with rifampicin and corticosteroids, which resulted in a decrease in pruritus. The other patient (no. 12) noted an increase of pruritus after 4 weeks of long-term treatment. She received double dose of medication without improvement of itching, although it remained below basal values. The other five patients kept a sustained response to naltrexone during the whole long-term treatment. The onset of the improvement in pruritus was, generally, during the first 2 days after starting with naltrexone administration. No significant changes were observed in the mean values of serum biochemistry, blood pressure or pulse rate in patients treated with naltrexone or placebo compared with basal values during short-term administration (Table 2). In addition, no significant biochemical changes were found during long-term treatment with naltrexone. Treatment compliance, assessed by pill counts, was 98%.
3.2. Side effects 3.2.1. Short -term administration Side effects observed during naltrexone or placebo shortterm administration are shown in Table 3. The most frequent side effects were dizziness (10 patients), nausea (eight patients), vomiting (six patients), headache and abdominal cramps (five patients). Most of them did not require addi-
2.29 ^ 2.86 3.70 ^ 0.59 94 ^ 12 88 ^ 53 108 ^ 82 1266 ^ 932 296 ^ 231 0.71 ^ 0.10 125 ^ 19 73 ^ 11 75 ^ 10
a Results are expressed as mean ^ SD. No significant changes were found. b Results are expressed as the mean of the 1st and the 2nd weeks of naltrexone treatment.
tional medication and side effects improved or disappeared 48 h after starting treatment. Two patients (nos. 17 and 19) abandoned the study on the third day during naltrexone treatment period due to the persistence of side effects. Patient no. 17 started with asthenia, dizziness, nausea and vomiting during naltrexone treatment and patient no. 19 began with mild epigastric pain and sporadic vomiting during the washout period, before naltrexone treatment, and continued this way during naltrexone treatment, stopping the treatment on the third day. Patient no. 3 reduced the dose of naltrexone to 25 mg. a day from the 3 rd to the 7 th day due to dizziness improving symptoms and following with naltrexone 50 mg until completion of the study. 3.2.2. Long -term administration The most frequent side effects during long-term adminTable 3 Side effects during short-term administration Symptoms
Dizziness Nausea Vomit Headache Abdominal cramps Asthenia Drowsiness Irritability Dry mouth Insomnia Tremor Tachycardia Anorexia Flushing Arterial hypertension
Naltrexone
Placebo
Patient no.
n
1, 2, 3, 4, 5, 7, 8, 9, 17 ,20 1, 2, 5, 6, 7, 9, 12, 17 2, 5, 12, 17, 19, 20 1, 2, 15, 16, 20 3, 4, 10, 15, 20 1, 9, 17 1, 8, 15 1, 3, 20 1, 3, 10 10, 20 4 7 7 10 20
10 8 6 5 5 3 3 3 3 2 1 1 1 1 1
Patient no.
6 19, 20 1, 6, 20 20 3, 11 3, 11
n 0 1 2 3 1 0 2 2 0 0 0 0 0 0 0
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istration with naltrexone were nausea and vomiting (four patients), dizziness (three patients) and abdominal cramps (three patients). All of these symptoms occurred within the first 24 h and disappeared without additional medication. Two patients (nos. 4 and 5) were withdrawn from the study 48 h after starting long-term administration, patient no. 4 because of clinical impairment due to progression of prior hepatocarcinoma; patient no. 5 reported nausea and vomiting and refused to continue with the study.
4. Discussion The results of the current study suggest that the administration of an oral opiate antagonist, naltrexone, relieves the pruritus associated with chronic cholestatic liver disease. The decrease in values of VAS with naltrexone agrees with those found in two previously published reports [33,34]. In the first one, an open-label trial including five patients, pruritus decreased significantly after a week of naltrexone treatment [33]. The second, a placebo-controlled study showed a significant reduction in the perception of daytime itching (254 vs. 8%) and night-time itching (244 vs. 7%) within a 4-week course of naltrexone [34]. Some authors consider that the VAS is an inadequate and unreliable method of assessing the perception of pruritus and propose the use of an instrument that measures scratching activity attached to a fingernail [25]. We agree that such a measurement of could give a more objective evaluation of scratching activity, but the use of this device carries practical difficulties in outpatient assessment for long follow-up periods. In most of the studies, scratching activity was measured only during 24 h [25–27]. Furthermore, the efficacy of different agents currently recommended for the treatment of pruritus of cholestasis has been based on studies using subjective end-points such as VAS [4,8–12]. Although the scratching activity index appears to be more sensitive, some trials indicate good agreement with the VAS. Analysis of a double-blind trial comparing intravenous naloxone versus saline demonstrated that the scratching activity correlated significantly with the visual analogue score [25,26]. In a randomized controlled trial, the effect of ondansentron on scratching activity and on the perception of pruritus was reported to be similar in both groups [35] Finally, in clinical practice, VAS is widely used in the assessment of different symptoms, especially pain [36]. In the current study, two patients experienced a recurrence of pruritus after an initial decrease (breakthrough). The worsening of itching may have been due to adaptation in opioid receptors or to drug tolerance to (tachyphylaxis). These phenomena were reported with naltrexone [33,34,37] and with nalmefene [27]. Carson et al. suggested that interrupting treatment for 2 days every week (drug holidays) [33] could prevent recurrence of pruritus. However, in the present study these patients have not responded to drug holidays and to an increase in the dose of naltrexone.
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Adverse effects during short-term naltrexone treatment were mainly dizziness, nausea, vomits, headache and cramps. Two patients were withdrawn at this time: one due to the persistence of adverse effects. The other subject began with epigastric pain and vomiting during the washout period before naltrexone administration and continued during naltrexone treatment. It is quite likely that her symptoms did not have any relation with the drug. Similar adverse reactions were observed during long-term therapy and they generally disappeared on the second day of treatment. It is worth noticing that although many side effects reported in this study could be compatible with opioid withdrawal-like phenomena, they were generally mild and transient. It is possible that patients paid more attention to their symptoms taking into account that several adverse effects were also reported with placebo. Different adverse effects were associated with naltrexone [33,34,38] and nalmefene in previous studies [18,27], though those related to nalmefene treatment seemed to be more severe. Although some of the side effects observed in our study could be considered as part of a mild opiate withdrawal reaction, neurological or psychiatric symptoms found in other publications were not observed. To avoid such reaction, co-administering clonidine [18] or starting treatment with a subtherapeutic dose with subsequent dose escalation [27] was suggested. In accordance with previous studies with naltrexone [33,34], on the first day of the present study, naltrexone was given in two separate doses of 25 mg each in order to minimize adverse events. In another study of the pharmacokinetic behavior of naltrexone in 11 cirrhotic patients, a bolus of 100 mg of naltrexone was administered orally. Transient nausea and irritability in one patient and tremor in another was reported [32]. Recently, a woman developed severe opioid withdrawal-like reaction after oral administration of 12.5 mg and 2 mg naltrexone. Subsequent intravenous naloxone administration at subtherapeutic dose allowed reintroduction of oral naltrexone at a dose of 12.5 mg twice a day without any side effects [29]. So, it seems advisable to initiate naltrexone therapy with low doses with a gradual stepwise increase to a therapeutic dosage. Evidence of hepatotoxicity of naltrexone was shown in a placebo-controlled study in which obese subjects received naltrexone at a dose of 300 mg/day [39]. This was not reported in other studies for lower doses of naltrexone in patients with [33,34] and without [38] liver disease. In the present study, no significant changes in hepatic biochemistry were observed with naltrexone treatment. Thus, current data suggest that naltrexone can be safely administered to patients with chronic liver disease. The pathogenesis of cholestatic pruritus remains uncertain. The theory that increased opioidergic tone may be implicated is based on results of several studies [18,25,27,33,34,40,41]. However, treatment with opiate antagonists usually does not eliminate itching completely. It is also possible that non-opioid mechanisms contribute to pruritus from cholestasis. It is remarkable that different
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kinds of approaches such as cholestyramine, rifampicin, phenobarbital or ondansentron have been tried with varying efficacy, suggesting that pruritus of cholestasis is explained by a multifactorial mechanism. In summary, naltrexone must be considered as an alternative option for the treatment of pruritus due to cholestasis. Most of the reported side effects are mild, transient and do not require specific medication. Acknowledgements
[18] [19]
[20] [21] [22] [23]
E.C. was recipient of a grant by FUNDHIG (Fundacio´ n Argentina para el Estudio del Hı´gado). Laboratorios Souberian Chobet, Buenos Aires, provided naltrexone.
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