Evidence suggests that the pruritus of cholestasis is,

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1 Gabapentin in Patients With the Pruritus of Cholestasis: A Double-Blind, Randomized, Placebo-Controlled Trial Nora V. Bergasa, 1 Monnie McGee, 2 Iona H. Ginsburg, 3 and Danielle Engler 3 Pruritus is defined as the second order of nociception, the first being pain; thus, there is a rationale to study gabapentin, a drug that increases the threshold to experience nociception. The aim of this double-blind, randomized, placebo-controlled trial was to study the effect of gabapentin on the perception of pruritus and its behavioral manifestation, scratching, in cholestasis. The participants were 16 women with chronic liver disease and chronic pruritus. Hourly scratching activity (HSA) was continuously recorded for up to 48 hours at baseline and on treatment for at least 4 weeks in an inpatient setting. The perception of pruritus was assessed by interviews and by a visual analog score (VAS) of pruritus recorded every hour while patients were awake. Patients were randomized to the study drug (gabapentin or placebo) at a starting dose of 300 mg orally per day in divided doses to a maximum of 2,400 mg or until relief from pruritus. Gabapentin was associated with an increase in mean HSA, in contrast to the placebo, which was associated with a decrease. The mean VAS decreased significantly among those taking the placebo and in some patients on gabapentin. In conclusion, gabapentin did not provide a significant therapeutic advantage over the placebo; in fact, it was associated with an increase in the perception of pruritus and in HSA in some patients. (HEPATOLOGY 2006;44: ) Evidence suggests that the pruritus of cholestasis is, in part, mediated by neurotransmitters/neuromodulators, including endogenous opioids. 1 The idea of altered neurotransmission in the mediation of the pruritus of cholestasis has led to the study of drugs with neuropsychiatric effects for the treatment of this type of pruritus. 2 As pruritus is a nociceptive stimulus, 3 there is a rationale to study gabapentin, a drug that increases the threshold of nociception. 4,5 Furthermore, gabapentin was reported to be effective in the treatment of brachioradial pruritus. 6 These reports were the basis for the present study of the effect of gabapentin on the pruritus of cholestasis. Patients and Methods The study was approved by the institutional review board of Columbia University College of Physicians and From the 1 State University of New York at Downstate, Brooklyn, NY; 2 Southern Methodist University, Dallas, TX; and 3 Columbia University, New York, NY Received March 26, 2006; accepted August 2, Supported by 1RO3DK A1 and GCRC grant RR This trial has been registered at and its registration number is Address reprint requests to: Nora V. Bergasa, M.D., Division of Hepatology, State University of New York at Downstate, 450 Clarkson Avenue, Box 50, Brooklyn, NY Nora.Bergasa@downstate.edu. Copyright 2006 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience ( DOI /hep Potential conflict of interest: Nothing to report. Surgeons and of the New York Presbyterian Hospital, where it was conducted. All patients signed a consent form prior to entry into the study. A physician with expertise in liver disease was the study monitor. The recruitment rate was less than anticipated; thus, after a 3-year period we stopped recruiting for the study. Participants. Fifty-six patients with chronic liver disease and chronic pruritus were evaluated as potential candidates for the study. Twenty-six patients were found to be eligible. Of these, 9 did not wish to participate after the index visit or follow-up visits, and one did not return for further evaluation. Thus, 16 patients were enrolled in the study (Fig. 1). The study group consisted of 16 women whose median age was 49 years (range years). Nine patients (patients 1, 2, 4, 6, 9, 10, 12, 15, and 16) had primary biliary cirrhosis (PBC), one patient (patient 3) had primary sclerosing cholangitis (PSC), and 6 patients (patients 5, 7, 8, 11, 13, and 14) had chronic liver disease secondary to infection with the hepatitis C virus. The duration of the pruritus was 1-12 years, except in patient 11, for whom it was 4 months. All the patients reported it interfered with their quality of life. All patients had a serum hepatic panel consistent with cholestasis, with a median serum alkaline phosphatase activity of 397 U/L (range U/L, normal U/L). The drugs used to treat the pruritus, including cholestyramine, antihistamines, naltrexone, rifampicin, ser- 1317

2 1318 BERGASA ET AL. HEPATOLOGY, November 2006 Fig. 1. Potential candidates for participation in the study, reasons for exclusion from randomization, and subjects randomized. traline, and ondansetron, alone or in combination, had not provided satisfactory relief. Two patients who had chronic hepatitis C (patients 5 and 14) were taking ursodeoxycholic acid without any relief of pruritus. Study Design. The study was a double-blind, randomized, placebo-controlled trial with a treatment phase of 4 weeks duration. The trial was designed to study patients aged years with chronic pruritus secondary to liver disease. The exclusion criteria were history of hepatic encephalopathy, ascites, history of variceal bleeding, malignancy, inability to practice contraception, pregnancy, creatinine greater than 1.7 mg/dl, hemoglobin less than 10 g/dl, status of post liver transplantation, and infection with the human immunodeficiency virus. At baseline, the principal investigator took a complete history and performed a physical examination, and laboratory tests including a complete blood count, coagulation and comprehensive metabolic panels, and, when appropriate, a pregnancy test were obtained. To determine if depression existed at baseline, a psychiatrist (I.H.G.) evaluated the patients prior to their receiving the study drug, using the Hamilton Depression Rating Scale, a measure of the severity of current depression, 7 and the Structured Clinical Interview Questionnaire (SCID) for DSM IV, Axis I Disorders, an interview measure for the diagnosis of depression and anxiety syndromes. 8 A dermatologist (D.E.) examined the patients to exclude dermatological causes of the pruritus. Drugs prescribed for the treatment of pruritus were discontinued 5 days before the collection of baseline data and were not restarted during the study, as was done in previous studies Patients who took antihistamines to sleep were kept on those drugs. The data were collected in the inpatient and outpatient units of the General Clinical Research Center (GCRC) of New York Presbyterian Hospital. Each patient had 2 hospitalizations, at baseline and while on treatment. The patients were contacted by telephone by the principal investigator at weeks 1 and 3 after randomization to assess how they were tolerating the drug and to adjust the dose, and they were evaluated in person at week 2 with an exam and blood work. Evaluation of the Perception of Pruritus and Scratching Activity. The perception of pruritus was assessed every hour while the patients were awake with a 10-cm visual analog scale from which a visual analog score was derived, as previously described A scratching activity monitoring system specifically designed to record scratching behavior independent of gross body movement 13 and successfully utilized in several previous clinical trials was used Continuous recording of scratching activity was performed over one or two 24- hour periods (depending on the patient s availability), beginning on the morning of day 2 of admission and ending on the morning of day 4 during both the baseline and on-treatment hospitalizations. After the baseline HSA and VASs were collected, subjects were randomized to receive the placebo or the active drug according to a randomization code generated and kept at the research pharmacy. After at least 4 weeks on the study drug subjects were admitted to the GCRC for data collection, after which the code was broken. On completion of the treatment period, patients who had been randomized to the placebo were offered gabapentin for 4 weeks to provide them with possible relief; patients who had been randomized to gabapentin and who reported relief received a 1-week supply of the drug, to be continued by the referring physician, as per protocol. Each patient documented on a form the number of capsules taken and any effects associated with their intake. The forms were collected and reviewed on follow-up appointments. Study Drug. Gabapentin was obtained from the manufacturer (Parke Davis Pharmaceuticals, Ltd., Vega Baja, Puerto Rico) and packaged at the research pharmacy in 100- and 300-mg maroon capsules, like those of the placebo. Under code, the study drug was started at 100 mg by mouth 3 times a day for 3 days, to be increased, if necessary and in the absence of side effects, by 300 mg every 3 days to a maximum of 2,400 mg daily in divided doses. Patients 1-8 received a starting dose of the study medication of 300 mg once a day; however, because of reported vomiting by 2 patients, one of whom was a study

3 HEPATOLOGY, Vol. 44, No. 5, 2006 BERGASA ET AL participant (patient 8), after a dose of 300 mg of gabapentin, the protocol was amended to a starting dose of 100 mg, as described previously. Statistical Methods. Exploratory descriptive statistics and graphics were analyzed according to whether patients were randomized to gabapentin (i.e., the gabapentin group) or to placebo (i.e., the placebo group), with those in each group further assessed both pre- and on-treatment, making 4 categories. Mean differences in measurements were determined by subtracting each on-treatment value from each pretreatment value for each subject and calculating the mean of all the differences. A positive mean difference indicates that, on average, the pretreatment mean HSA and the pretreatment mean VAS were greater than the corresponding on-treatment values. Paired t tests were computed for each subject. One-sided P values were calculated because we hypothesized a decrease in HSA, particularly for subjects taking gabapentin. For the HSA the significance level of each test was Bonferroni-adjusted at 0.05/ Correlations between pre- and on-treatment HSA and VAS scores for the same patient were examined using a standard correlation test; a correlation coefficient of zero indicated changes in the values of one variable did not affect the values of the other variable. The data contained imputed values as replacements for missing observations; a nearest-neighbor hot deck imputation method was used to estimate these values. 14,15 In hot deck imputation, missing data are replaced by values taken from complete records of subjects with characteristics similar to the subject for whom data are missing. 14,15 Two mixed-effects models, one with HSA as the dependent variable and one with VAS as the dependent variable, were run on the imputed data using the PROC MIXED procedure of SAS V8.2 (SAS Institute, Cary, NC). These results were calculated using data collected in the first 24 hours, as these were available from most subjects. The fixed effects were time of measurement, treatment group (i.e., patients randomized to gabapentin or to placebo), treatment phase (i.e., pretreatment or on-treatment), and an interaction term of treatment group and treatment phase. Subjects were included as nested random effects because they represented a random sample from a population of patients with chronic pruritus secondary to liver disease, and the effects due to the subjects per se were dependent on the effect due to the treatment group. The data were log-transformed to stabilize the variance among groups and to make the distribution of the HSA measurement normal. In the mixedeffects model differences were considered significant at P less than.05. Results Dermatological Evaluation. None of the patients had a dermatological disease associated with pruritus. Psychiatric Evaluation. Data on the full psychiatric evaluation were available for 13 of the 16 patients. One patient (patient 11) did not have an evaluation performed because she was moving to another state, and the admission could not be coordinated with the psychiatric exam, 1 patient (patient 5) dropped out of the study prior to the exam, and the exam of another patient (patient 4) was incomplete and not helpful, as only data from the SCID were available. The results of the full 17-item Hamilton scale, which includes items intrinsic to medical conditions (i.e. fatigue, sleep, and concern about health), showed that 8 patients (patients 2, 3, 7, 10, 12, 13, 15, and 16 [62%]) scored in the range of mild depression, 3 (patients 1, 9, and 14 [23%]) in the range of moderate depression, and 2 (patients 6 and 8 [15%]) in the range of no to minimal depression (0-7); however, the scores of the latter group were 6-7, which might be considered minimal rather than absent depression. When the items relating to medical conditions were omitted, 7 patients (patient 1, 2, 7, 9, 12, 13, and 14 [54%]) scored in the range of mild depression, none in the range of moderate depression, and 6 (patients 3, 6, 8, 10, 15, and 16 [46%]) in the range of no to minimal depression. Four subjects remained in the mildly depressed range despite receiving antidepressant treatment (patient 9 received doxepin; patient 12, Lexapro; patient 13, Lamictal, Seroquel, and Ambien; and patient 14, Celexa), whereas one subject (patient 16) who went from moderate depression to none was on one antidepressant (Zoloft) and previously had been on another one (Celexa), suggesting she was considered to be depressed at one point. On the SCID, one patient (patient 14) had major depressive disorder with atypical features. The remainder of the patients were diagnosed with a mood disorder because of a general medical condition, 8 with depressive features (patients 2, 3, 6, 8, 10, 12, 15, and 16), and 4 with major depression-like episodes (patients 1, 7, 9, and 13). The results of the psychiatric evaluations suggested that liver disease and pruritus might have contributed to the depressive symptomatology of the subjects. Side Effects Associated with Gabapentin and Placebo. On gabapentin, patient 1 experienced a rise in her serum bilirubin at the end of the study period, interpreted as resulting from progression of her disease (PBC), which was confirmed by histology after she had a liver transplantation several months later. On gabapentin, patient 2 experienced fatigue, patient 4 dizziness, patient 7 worsening

4 1320 BERGASA ET AL. HEPATOLOGY, November 2006 Table 1. Effect of Gabapentin or Placebo on the Perception of Pruritus as Reported Orally and on HSA and VAS Patient No. Oral Report HSA Mean Difference VAS Mean Difference Patients randomized to gabapentin 1 No relief (0.361) (0.002) 14 No relief (0.002) (0.033) 16 Initial relief/no relief in the last days of treatment 8.2 (0.382)* (0.005) 2 Relief at times (0.027) (0.077) 6 Some relief (0.019) (0.000) 10 Relief (0.011) (0.098) 12 Relief Technical failure (pre) (0.012) Patients randomized to placebo 3 Relief most of the time (0.000) (0.000) 4 Relief (0.025) (0.000) 7 No relief initially/relief in the last days of treatment (0.000) (0.001) 11 Relief (0.085) (0.717) 15 Relief (0.183) (0.034) 13 No relief Technical failure (pre) (0.013) Abbreviations: HAS, hourly scratching activity; VAS, visual analog score. *Based on 10 measurements. All others based on measurements. P values in parentheses; statistical significance defined as P.004; a negative number indicates that the treatment measurement was higher (i.e., worse) than that at baseline. symptoms of carpal tunnel syndrome, patient 8 vomiting, and patient 16 dizziness on increasing dose and a fluctuating rise in serum creatinine. Gabapentin was discontinued in these patients. On placebo, patient 3 developed fatigue and leukopenia, and patient 7 developed symptoms of carpal tunnel syndrome. Effect of Study Drug on Pruritus of Cholestasis. The results and the subjects oral reports of their perception of pruritus after 4 weeks of treatment are given in Table 1. Patients 4 and 7, who took gabapentin after completing treatment with placebo, did not continue on gabapentin, and patients 3, 11, 10, and 15 remained on gabapentin; patient 3 underwent liver transplantation several months later because of progression of her disease (PSC). Patient 12, who had stage IV PBC, underwent liver transplantation, as hepatocellular carcinoma was suspected from screening. Three of the 16 patients dropped out of the study one (patient 5) prior to randomization because she did not wish to remain hospitalized for baseline evaluation, one (patient 8) on day 2 because of side effects, and one (patient 9), who had been randomized to placebo, because of persistent severe pruritus within 2 weeks of randomization. All the patients who completed the 4-week study under code went up to the dose of 2,400 mg per day except patients 15 and 16, who took 1,200 and 1,500 mg daily, respectively. Results of Statistical Analysis. The graphs for baseline HSA (Fig. 2A,B) show that scratching activity of the patients randomized to gabapentin (Fig. 2A) was higher than that of the patients randomized to placebo (Fig. 2B). The scratching activity of the patients on gabapentin did not decrease (Fig. 3A); in contrast, the scratching activity of the patients on placebo was near zero (Fig. 3B). The group randomized to gabapentin, however, seemed to have higher HSA at baseline than the group randomized to placebo, which might have given the placebo treatment some advantage. These observations are supported by the results of the statistical tests reported in Table 1. Correlations between HSA and VAS scores at baseline and on treatment varied from 0.23 to 0.97, suggesting the VAS correlated poorly with HSA. In addition, there was no relationship between baseline and on-treatment HSA or between baseline and on-treatment VAS, as correlations ranged from 0.3 to 0.7 for both variables. Analysis of the imputed log-transformed HSA data showed the treatment group and the interaction of the treatment group with the treatment phase were significant (P.013 and.026, respectively); however, the effects of the subjects and of the treatment phase per se were not significant (P.2 and.16). This implies a detectable difference in HSA measurements between those subjects on gabapentin and those on placebo without consideration of the phase (i.e., baseline or on treatment) at which the measurement was taken. This result may reflect the difference between the treatment groups in the baseline measurements of the subjects (Fig. 2A-B); however, the difference was also affected by the treatment phase (i.e., pre- or on-treatment) during which the measurement was taken. Table 2 gives the means with standard deviations of the non-transformed HSA for the 4 groups: baseline prior

5 HEPATOLOGY, Vol. 44, No. 5, 2006 BERGASA ET AL Fig. 2. Mean baseline hourly scratching activity (HSA) in patients subsequently randomized to gabapentin (A) and to placebo (B). Fig. 3. Mean hourly scratching activity (HSA) in patients randomized to gabapentin (A) and to placebo (B) after at least 4 weeks on treatment. to randomization to gabapentin and on gabapentin, and baseline prior to randomization to placebo and on placebo; these data helped to determine the direction of the effect. It can be appreciated that the significance of the interaction effect came from 2 sources: a large increase in the mean HSA associated with treatment with gabapentin and a large decrease in the mean HSA associated with treatment with placebo. Discussion Our findings indicate that gabapentin does not have a therapeutic advantage over placebo for patients with the pruritus of cholestasis, some of whom were refractory to drugs used to treat this symptom; in fact, this drug appears to worsen pruritus. In contrast, treatment with placebo was associated with relief from pruritus for most patients by all measures used to assess this symptom. The correlations between baseline HSA and VAS were low, suggesting that the VAS of the pruritus of cholestasis is an unreliable predictor of HSA, in general, as was found in a previous study. 9 We also found that the time at which HSA and VAS was recorded influenced the results; accordingly, a VAS of pruritus obtained at random may not be interpretable. The most stunning results of this study can be visually appreciated from Figs. 2 and 3. It is clear that patients on placebo (Fig. 3B) scratched less than those on gabapentin (Fig. 3A), indicating that the placebo effect resulted not only in subjective improvement, but also in a change in Table 2. Nontransformed Mean Hourly Scratching Activity* by Treatment Phase Group Hourly Scratching Activity [mean (SD)] Pre gabapentin (89.35) On gabapentin (125.09) Pre placebo (99.52) On placebo (41.23) *Hourly scratching activity is expressed in arbitrary units.

6 1322 BERGASA ET AL. HEPATOLOGY, November 2006 behavior. In contrast, some patients on gabapentin reported no relief of pruritus and scratched more and had a higher mean VAS, some significantly so, than at baseline. A question arises: did gabapentin interfere with the placebo effect? In trying to address this question, current ideas on the placebo response should be discussed. The placebo effect results from at least 2 types of changes, subjective and physiological (i.e., changes in neurotransmission). 16 In this context, studies that used positron emission tomography demonstrated that the mechanism mediating the placebo response in Parkinson s disease is associated with a release of dopamine in response to the activation of the nigostriatal dopamine system by the placebo intervention. 17 The association of a placebo intervention with dopamine release raises another question: can dopamine exert an antipruritic effect? The answer is yes. Evidence suggests that the pruritus of cholestasis is mediated, at least in part, by increased central opioidergic tone, which is the reason this type of pruritus is treated with opiate antagonists. 9-12,18-21 It has been shown that the pruritus resulting from the central administration of morphine (i.e., pruritus secondary to increased opioidergic tone), which may be analogous to the pruritus of cholestasis, can be relieved effectively by droperidol, 22,23 a short-acting neuroleptic agent with affinity for the D2 dopamine receptor. 24 Initial treatment with neuroleptics, which may be analogous to the acute effect of droperidol administration, is associated with activation of dopamine neurons and enhanced dopamine release. 24 Accordingly, if droperidol decreases central, morphine-induced pruritus, endogenous dopamine release may decrease central, opioid-mediated pruritus (i.e., as it is hypothesized to occur in cholestasis). Thus, activation of the nigrostriatal system (i.e., dopamine release) by a placebo intervention may mediate a decrease in pruritus by signals transmitted via the neural networks that connect the basal ganglia, which release dopamine, with the cerebral cortex, 25,26 where itch stimuli and the urge to scratch are represented Having considered the role of dopamine in the placebo effect, it does appear that gabapentin could have interfered with the placebo effect. Animal studies 30,31 have documented that gabapentin blocks dopamine release from the basal ganglia (i.e., the striatum) and from the nucleus accumbens, preventing dopamine-mediated behavior. 31 Accordingly, it seems plausible that gabapentin, by virtue of its ability to block dopamine release, may have interfered with dopamine-mediated relief of pruritus triggered by a placebo intervention. It is evident that in this study gabapentin was not a placebo intervention; however, it is the expectation of relief and, likely, the degree of that expectation that appear to mediate, at least in part, the release of dopamine that occurs with a placebo intervention. 17,32 Thus, patients with pruritus expected relief, but this expectation, which mediates the placebo effect and would have resulted in dopamine release and hence an antipruritic effect, was blocked by gabapentin. This is our hypothesis. The dichotomous effect of gabapentin in this study can be explained by the differences among the patients in the threshold for activation of neurotransmission and in the degree of expectation. 17,32 A high expectation of relief may have resulted in a strong stimulus for dopamine release, which may not have been completely blocked by gabapentin at the doses used in this study, allowing enough dopamine to mediate neurotransmission with the result of some relief from the pruritus. In contrast, a low expectation of relief may have resulted in a weak stimulus for dopamine release, which could have been blocked by the gabapentin at the doses used, preventing dopamine-mediated relief of pruritus. This interpretation suggests that patients expectation is an important question to address in studies of pruritus; unfortunately, information on the expectations of relief by the patients in our study was not sought a priori. The small number of patients was a limitation of this study; however, the strong placebo effect observed has focused our attention on the antipruritic effects of placebo in the pruritus of cholestasis and emphasizes that any intervention on pruritus may be difficult to interpret without some objective measure of change. As documented by the psychiatric evaluation, the pruritus of cholestasis has a negative impact on the emotional life of patients, and it can be an indication for liver transplantation even in the absence of liver failure. 33,34 These facts stress the importance of exploring why this symptom continues to escape understanding, contributing to the lack of consistently effective and specific treatments. In summary, in this study gabapentin was not associated with a significant amelioration of the pruritus secondary to liver disease; in fact, on average, it worsened the pruritus and the scratching behavior. Several scientific questions have emerged from this experience, including the role of dopamine neurotransmission in the treatment of pruritus and on the neurophysiologic basis for the placebo effect on the pruritus of cholestasis. Acknowledgment: The authors thank Glen Gillen, MPA, OTR, Sabrina Salvant, MS, MPH, Jane Bear- Lehman, PhD, OTR, FAOTA, Jacqueline Brown, MS, OTR/L, CHT, and Batsheva Meisels, OTR/L, CHT, from Occupational Therapy for making the orthotic devices, the staff of the Research Pharmacy and the GCRC for facilitating the conduct of the study, Erica Torres for her administrative work, and Howard J. Worman, MD, for

7 HEPATOLOGY, Vol. 44, No. 5, 2006 BERGASA ET AL monitoring the study. Dr. Bergasa is grateful to Thomas Talbot, Engineer, for his continued support and advice on the use of the scratching activity monitoring system. References 1. Jones EA, Bergasa NV. The pruritus of cholestasis. HEPATOLOGY 1999;29: Bergasa NV. The pruritus of cholestasis. J Hepatol 2005;43: Magerl W. Neural mechanisms of itch sensation. IASP Newsletter 1996; Sept-Oct. 4. Gustafsson H, Flood K, Berge OG, Brodin E, Olgart L, Stiller CO. Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice. Exp Neurol 2003;182: Rodrigues-Filho R, Campos MM, Ferreira J, Santos AR, Bertelli JA, Calixto JB. Pharmacological characterisation of the rat brachial plexus avulsion model of neuropathic pain. Brain Res 2004;1018(2): Bueller HA, Bernhard JD, Dubroff LM. Gabapentin treatment for brachioradial pruritus. J Eur Acad Dermatol Venereol 1999;13: Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatr 1960;23: Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, et al. The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite test-retest reliability. Arch Gen Psychiatry 1992;49: Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992;102: Bergasa NV, Talbot TL, Schmitt JP, Alling DW, Swain MG, Turner M, et al. Open label trial of oral nalmefene therapy for the pruritus of cholestasis. HEPATOLOGY 1998;27: Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Schmitt JM, et al. Naloxone ameliorates the pruritus of cholestasis: results of a double-blind randomized placebo-controlled trial. Ann Intern Med 1995; 123: Bergasa NV, Alling DW, Talbot TL, Wells M, Jones EA. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol 1999;41: Talbot TL, Schmitt JM, Bergasa NV, Jones EA, Walker EC. Application of piezo film technology for the quantitative assessment of pruritus. Biomed Instrum Technol 1991;25: Little R, Rubin D. Statistical Analysis with Missing Data. 2nd ed. New York: Wiley Interscience, McGee M, Bergasa NV. Imputing Missing Data in Clinical Pilot Studies. Technical Report. Dallas, TX: Southern Methodist University, Kradin RL. The placebo response: its putative role as a functional salutogenic mechanism of the central nervous system. Perspect Biol Med 2004; 47: de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson s disease. Science 2001;293: 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: Wolfhagen FHJ, Sternieri E, Hop WCJ, Vitale G, Bertolotti M, van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a doubleblind, placebo-controlled study. Gastroenterology 1997;113: Neuberger J, Jones EA. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy. Eur J Gastroenterol Hepatol 2001;13: Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol 2002;37: Horta ML, Ramos L, Goncalves ZR. The inhibition of epidural morphineinduced pruritus by epidural droperidol. Anesth Analg 2000;90: Horta ML, Ramos L, Goncalves Zda R, de Oliveira MA, Tonellotto D, Teixeira JP, et al. Inhibition of epidural morphine-induced pruritus by intravenous droperidol. The effect of increasing the doses of morphine and of droperidol. Reg Anesth 1996;21: Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Molinoff PB, Ruddon RW, eds. The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 1996: Coté L, Crutcher M. The basal ganglia. In: Kandel ER, Scwartz JH, Jessell TM, eds. Principles of Neural Science. Norwalk: Appleton and Lange, 1991: McFarland NR, Haber SN. Thalamic relay nuclei of the basal ganglia form both reciprocal and nonreciprocal cortical connections, linking multiple frontal cortical areas. J Neurosci 2002;22: Hsieh JC, Hagermark O, Stahle-Backdahl M, Ericson K, Eriksson L, Stone-Elander S, et al. Urge to scratch represented in the human cerebral cortex during itch. J Neurophysiol 1994;72: Drzezga A, Darsow U, Treede RD, Siebner H, Frisch M, Munz F, et al. Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies. Pain 2001;92(1-2): Mochizuki H, Tashiro M, Kano M, Sakurada Y, Itoh M, Yanai K. Imaging of central itch modulation in the human brain using positron emission tomography. Pain 2003;105(1-2): Reimann W. Inhibition by GABA, baclofen and gabapentin of dopamine release from rabbit caudate nucleus: are there common or different sites of action? Eur J Pharmacol 1983;94: Andrews N, Loomis S, Blake R, Ferrigan L, Singh L, McKnight AT. Effect of gabapentin-like compounds on development and maintenance of morphine-induced conditioned place preference. Psychopharmacology (Berl) 2001;157: Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303: Elias E. Liver Transplantation. J Roy Coll Phys London 1993;27: Jones EA, Neuberger J, Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions. QJM 2002;95: