Trials of opiate antagonists for the pruritus of cholestasis: primary efficacy endpoints and opioid withdrawal-like reactions
2002; Elsevier BV; Volume: 37; Issue: 6 Linguagem: Inglês
10.1016/s0168-8278(02)00347-1
ISSN1600-0641
Autores Tópico(s)Pharmacological Effects of Natural Compounds
ResumoOpiate agonists, such as morphine, induce increased opioidergic tone (neurotransmission mediated by the opioid neurotransmitter system) in the central nervous system (CNS) and generalized pruritus of central origin [1de Quincy T. Confessions of an English opium eater. London Magazine 1821. Penguin, London1971Google Scholar, 2Koenigstein H. Experimental study of itch stimuli in animals.Arch Dermatol Syph. 1948; 57: 828-849Crossref Scopus (79) Google Scholar, 3Ballantyne J.C. Loach A.B. Carr D.B. Itching after epidural and spinal opiates.Pain. 1988; 33: 149-160Abstract Full Text PDF PubMed Scopus (326) Google Scholar, 4Thomas D.A. Williams G.W. Iwata K. Kenshalo Jr, D.R. Dubner R. Effects of central administration of opioids on facial scratching in monkeys.Brain Res. 1992; 585: 315-317Crossref PubMed Scopus (77) Google Scholar, 5Bergasa N.V. Jones E.A. The pruritus of cholestasis. Potential pathogenic and therapeutic implications of opioids.Gastroenterology. 1995; 108: 1582-1588Abstract Full Text PDF PubMed Scopus (98) Google Scholar]. Opiate-induced generalized pruritus can be reversed by the opiate antagonist, naloxone, indicating that it is opioid receptor-mediated [3Ballantyne J.C. Loach A.B. Carr D.B. Itching after epidural and spinal opiates.Pain. 1988; 33: 149-160Abstract Full Text PDF PubMed Scopus (326) Google Scholar, 4Thomas D.A. Williams G.W. Iwata K. Kenshalo Jr, D.R. Dubner R. Effects of central administration of opioids on facial scratching in monkeys.Brain Res. 1992; 585: 315-317Crossref PubMed Scopus (77) Google Scholar, 5Bergasa N.V. Jones E.A. The pruritus of cholestasis. Potential pathogenic and therapeutic implications of opioids.Gastroenterology. 1995; 108: 1582-1588Abstract Full Text PDF PubMed Scopus (98) Google Scholar]. Thus, increased opioidergic tone in the CNS is a mechanism of generalized pruritus.During the past 15 years several studies have indicated that a component of the pathophysiology of the syndrome of cholestasis is increased CNS neurotransmission mediated by endogenous opioid agonists [5Bergasa N.V. Jones E.A. The pruritus of cholestasis. Potential pathogenic and therapeutic implications of opioids.Gastroenterology. 1995; 108: 1582-1588Abstract Full Text PDF PubMed Scopus (98) Google Scholar, 6Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar, 7Bergasa N.V. Rothman R.B. Vergalla J. Xu H. Swain M.G. Jones E.A. Central mu-opioid receptors are down-regulated in a rat model of acute cholestasis.J Hepatol. 1992; 15: 220-224Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 8Bergasa N.V. Alling D.W. Vergalla J. Jones E.A. Cholestasis in the male rat is associated with naloxone-reversible antinociception.J Hepatol. 1994; 20: 85-90Abstract Full Text PDF PubMed Scopus (104) Google Scholar, 9Jones E.A. Bergasa N.V. The pruritus of cholestasis.Hepatology. 1999; 29: 1003-1006Crossref PubMed Scopus (139) Google Scholar]. Increased central opioidergic tone in cholestasis would be expected to induce generalized pruritus. Indeed, generalized pruritus is a common complication of cholestasis. If increased central opioidergic tone contributes to pruritus in cholestatic patients, opiate antagonists should ameliorate the pruritus. This prediction has been confirmed. In controlled clinical trials intravenous infusions of the opiate antagonist, naloxone [10Bergasa N.V. Talbot T.L. Alling D.W. Schmitt J.M. Walker E.C. Baker B.L. et al.A controlled trial of naloxone infusions for the pruritus of cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 11Bergasa N.V. Alling D.W. Talbot T.L. Swain M.G. Yurdaydin C. Turner M.L. et al.Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomised controlled trial.Ann Intern Med. 1995; 123: 161-167Crossref PubMed Scopus (318) Google Scholar], and oral administration of the opiate antagonist, nalmefene [12Bergasa N.V. Schmitt J.M. Talbot T.L. Alling D.W. Swain M.G. Turner M.L. et al.Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.Hepatology. 1998; 27: 679-684Crossref PubMed Scopus (160) Google Scholar, 13Bergasa N.V. Alling D.W. Talbot T.L. Wells M.C. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar], have been shown to reduce scratching activity by cholestatic patients. These four controlled trials indicate that one of the general properties of opiate antagonists is their ability to ameliorate the pruritus of cholestasis. Consistent with this reasoning was the report, by Wolfhagen et al. [[14]Wolfhagen F.H.J. Sternieri E. Hop W.C.J. Vitale G. Bertolotti M. van Buuren H.R. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled trial.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar], of a randomized, double-blind, placebo-controlled trial of the opiate antagonist, naltrexone, administered orally to patients with the pruritus of cholestasis. This report concluded that "oral naltrexone may be an effective and well-tolerated" treatment for the pruritus of cholestasis. The paper by Terg et al., which is published in this issue of the Journal [[15]Terg R. Coronel E. Sordá J. Muñoz A.E. Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.J Hepatol. 2002; 37: 717-722Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar], describes a randomized, double-blind, placebo-controlled, cross-over trial of oral naltrexone for the pruritus of cholestasis; their findings supplement those of Wolfhagen et al. [[14]Wolfhagen F.H.J. Sternieri E. Hop W.C.J. Vitale G. Bertolotti M. van Buuren H.R. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled trial.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar].There is a fundamental difference between the design of the two naloxone and two nalmefene trials and the design of the two naltrexone trials. The difference in design concerns the primary efficacy endpoint. In the naloxone/nalmefene trials this endpoint was measurements of scratching activity, independent of arm or hand movements, whereas in the naltrexone trials it was a visual analogue 'score' of pruritus generated by applying a visual analogue scale.Pruritus is defined as the need to scratch. It is an intrinsically subjective perception, which cannot be quantitated. Although application of visual analogue scales can be used to generate numbers, the question arises whether numerical 'scores' of pruritus obtained in this way represent an adequate or meaningful assessment of pruritus. The clinical application of visual analogue scales has been critically reviewed by McCormack et al. [[16]McCormack H.M. Horne D.J. Sheather S. Clinical applications of visual analogue scales: a critical review.Psychol Med. 1988; 18: 1007-1019Crossref PubMed Scopus (1402) Google Scholar]. Potential problems include: (i) trimodal distribution of data points with clusters at the midpoint and extremes of the visual analogue scale; (ii) interpatient variability in marking the scales; (iii) the requirement of the ability to transform a complex subjective experience into a visuospatial display (involving perceptual judgement and accuracy); (iv) the variety of factors that contribute to respondent error (e.g. age, ability to think abstractly, mental organization, perceptual skills); (v) the desire to look at how scales were marked on previous occasions; and (vi) early use of the maximum value which precludes subsequent accurate scoring of a greater perception. In other words, visual analogue scores are influenced by interindividual variations in the ability of patients to integrate the perception of itch over time and to translate this perception into a visuospatial score that is subject to individual differences in its conceptualization. Accordingly, visual analogue scores of the perception of pruritus in cholestatic patients represent subjective data of uncertain clinical significance [[16]McCormack H.M. Horne D.J. Sheather S. Clinical applications of visual analogue scales: a critical review.Psychol Med. 1988; 18: 1007-1019Crossref PubMed Scopus (1402) Google Scholar]; they are likely to be an unreliable index of the severity of the clinical problem. This reasoning is supported by practical experience with the use of such scores in clinical trials of new therapies for the pruritus of cholestasis [[17]Bergasa N.V. Alling D.W. Talbot T. Schmidt J. Jones E.A. Assessment of the pruritus of cholestasis: an appraisal of the visual analog score.Hepatology. 1990; 12: 887Google Scholar]. The fact that visual analogue scales have been extensively applied in clinical studies does not detract from the deficiencies inherent in their use.Scratching activity, in the context of the pruritus of cholestasis, can be defined as the behavioural consequence of this complication of cholestasis. In contrast to pruritus, scratching activity can be quantitated. Thus, the problems inherent in assessing the severity of the subjective perception of itch may be obviated by objectively quantifying the consequence of itch, scratching activity. While itching has been claimed to correlate strongly with scratching activity [[18]Shelly W.B. Arthur R.P. The neurohistology and neurophysiology of the itch sensation in man.Arch Dermatol. 1957; 76: 296-323Crossref Scopus (184) Google Scholar], the severity of the perception of the pruritus of cholestasis, as described subjectively by patients, does not necessarily correlate closely with scratching activity [10Bergasa N.V. Talbot T.L. Alling D.W. Schmitt J.M. Walker E.C. Baker B.L. et al.A controlled trial of naloxone infusions for the pruritus of cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 13Bergasa N.V. Alling D.W. Talbot T.L. Wells M.C. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 17Bergasa N.V. Alling D.W. Talbot T. Schmidt J. Jones E.A. Assessment of the pruritus of cholestasis: an appraisal of the visual analog score.Hepatology. 1990; 12: 887Google Scholar].Initial attempts to quantitate scratching activity involved the application of sophisticated arm and hand movement meters [19Felix R. Shuster S. A new method for the measurement of itch and the response to treatment.Br J Dermatol. 1975; 93: 303-312Crossref PubMed Scopus (85) Google Scholar, 20Summerfield J.A. Welch M.E. The measurement of itch with sensitive limb movement meters.Br J Dermatol. 1980; 102: 275-281Crossref Scopus (40) Google Scholar]. The development of these pioneering methods reflected the need to apply objective quantitative methods in clinical studies of pruritus. Unfortunately, measurements of arm and hand movements record activities in addition to scratching. The first monitoring system designed to quantitate scratching activity, independent of arm or hand movements, involved the application of piezofilm technology. The device comprised a vibration (scratch) transducer consisting of a piece of piezoelectric film, an FM transmitter and receiver, a custom-made signal processor, and a personal computer [[21]Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar]. Two components of the device were attached to an arm of the patient: the transducer was glued to a finger nail and was linked by wire to a battery-powered transmitter attached to the corresponding upper arm. The transducer acts as a contact microphone. When the finger nail vibrates, as it traverses the skin in the act of scratching, it induces bends (physical strain) in the piezofilm, which result in the generation of a weak electrical signal. This signal is telemetered to a receiver, located several meters away from the patient, for processing and storage in the computer in the form of counts. Fourier transformation of demodulated signals from the device revealed that the power of the signal associated with scratching was concentrated in a band of frequencies between 30 Hz and 1 kHz, whereas the frequencies of gross body movements were <30 Hz. Thus, the device could be programmed to exclude signals with frequencies of <30 Hz, enabling data on scratching activity to be obtained independent of arm or hand movements [[21]Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar].Verification that the measured quantitative index of scratching activity (counts per 30 s) is a valid representation of scratching activity was accomplished by both videotapes and independent visual observations. In particular, the stored counts were shown to be proportional to the duration and intensity of scratching. The main disadvantage of the prototypic device was that the patient had to be confined to a hospital room throughout the period of a recording (usually 24 h), and hence was not in his or her normal environment. This disadvantage may be important, because the pruritus of cholestasis may be influenced by a change of environment. The problem has been overcome by processing and storing the signals from a scratch transducer over a predetermined interval (e.g. 24 h) in a computer chip attached to the patient's body. At the end of the period of recording, the data in the chip are downloaded into a personal computer and stored [[22]Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar]. This modification of the monitoring system has the advantage of allowing scratching activity to be recorded while the patient is in a normal non-hospital environment. For more information on the design and application of these devices, the reader is referred to the relevant original reports in the bioengineering literature [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar].The discipline of clinical science, which has been largely responsible for the impressive advances in medicine since the second world war [[23]Le Fanu J. Clinical science – a new ideology for medicine.in: In: The Rise and Fall of Modern Medicine. Little Brown and Company, London1999: 196-205Google Scholar], requires that objective quantitative primary efficacy endpoints be used in controlled clinical trials. Clearly, attempts to quantitate the perception of pruritus, which is inherently unquantifiable, do not meet this requirement. While measurements of scratching activity have no place in routine clinical practice, at present, such measurements constitute the only scientifically acceptable primary efficacy endpoint available for trials of new therapies for the pruritus of cholestasis. Failure to apply a device for measuring scratching activity in a trial of a new therapy for the pruritus of cholestasis cannot reasonably be justified on the grounds of the complexity of the device, its impracticality or its expense. Any bioengineer, shown a block diagram of one of these devices [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar], would confirm the simplicity of its design. Both devices [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar] are easy to apply in practice and are well tolerated by patients. Finally, components of the devices [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar] are readily acquired and are inexpensive. For example, piezofilm is cheap and most clinical investigators already have access to a personal computer.In their trial of naltrexone for pruritus in cholestatic patients, Terg et al. noted, during the first 48 h of naltrexone therapy, several adverse events that were consistent with opioid withdrawal-like phenomena. The authors concluded that "most of the reported side effects are mild, transient and do not require specific medication" [[15]Terg R. Coronel E. Sordá J. Muñoz A.E. Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.J Hepatol. 2002; 37: 717-722Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. However, initiation of oral opiate antagonist therapy with nalmefene [[6]Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar] or naltrexone [24Jones E.A. Dekker L.R.C. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.Gastroenterology. 2000; 118: 431-432Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Neuberger J. Jones E.A. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.Eur J Gastroenterol Hepatol. 2001; 13: 1393-1394Crossref PubMed Scopus (45) Google Scholar, 26Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.Q J Med. 2002; 95: 547-552Crossref Scopus (90) Google Scholar] in cholestatic patients may be associated with florid opioid withdrawal-like reactions. Accordingly, it is prudent to take precautions to avoid precipitating such reactions. In this context, the administration of clonidine [[6]Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar] or starting treatment with subtherapeutic oral doses [[12]Bergasa N.V. Schmitt J.M. Talbot T.L. Alling D.W. Swain M.G. Turner M.L. et al.Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.Hepatology. 1998; 27: 679-684Crossref PubMed Scopus (160) Google Scholar] appears to be less satisfactory than initiating opiate antagonist therapy with a slow subtherapeutic intravenous infusion of naloxone, and then gradually increasing the infusion rate to one within the therapeutic range, before administering a small oral dose of an orally bioavailable opiate antagonist [24Jones E.A. Dekker L.R.C. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.Gastroenterology. 2000; 118: 431-432Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Neuberger J. Jones E.A. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.Eur J Gastroenterol Hepatol. 2001; 13: 1393-1394Crossref PubMed Scopus (45) Google Scholar, 26Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.Q J Med. 2002; 95: 547-552Crossref Scopus (90) Google Scholar].The observation that the oral administration of an opiate antagonist to cholestatic patients (who had not received an opiate) often precipitates a transient opioid withdrawal-like reaction [6Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar, 10Bergasa N.V. Talbot T.L. Alling D.W. Schmitt J.M. Walker E.C. Baker B.L. et al.A controlled trial of naloxone infusions for the pruritus of cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 11Bergasa N.V. Alling D.W. Talbot T.L. Swain M.G. Yurdaydin C. Turner M.L. et al.Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomised controlled trial.Ann Intern Med. 1995; 123: 161-167Crossref PubMed Scopus (318) Google Scholar, 12Bergasa N.V. Schmitt J.M. Talbot T.L. Alling D.W. Swain M.G. Turner M.L. et al.Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.Hepatology. 1998; 27: 679-684Crossref PubMed Scopus (160) Google Scholar, 13Bergasa N.V. Alling D.W. Talbot T.L. Wells M.C. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 14Wolfhagen F.H.J. Sternieri E. Hop W.C.J. Vitale G. Bertolotti M. van Buuren H.R. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled trial.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 15Terg R. Coronel E. Sordá J. Muñoz A.E. Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.J Hepatol. 2002; 37: 717-722Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 24Jones E.A. Dekker L.R.C. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.Gastroenterology. 2000; 118: 431-432Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Neuberger J. Jones E.A. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.Eur J Gastroenterol Hepatol. 2001; 13: 1393-1394Crossref PubMed Scopus (45) Google Scholar, 26Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.Q J Med. 2002; 95: 547-552Crossref Scopus (90) Google Scholar] supports the hypothesis that opioidergic tone in the CNS is increased in cholestasis, and strengthens the rationale for treating the pruritus of cholestasis with an opiate antagonist. Opiate agonists, such as morphine, induce increased opioidergic tone (neurotransmission mediated by the opioid neurotransmitter system) in the central nervous system (CNS) and generalized pruritus of central origin [1de Quincy T. Confessions of an English opium eater. London Magazine 1821. Penguin, London1971Google Scholar, 2Koenigstein H. Experimental study of itch stimuli in animals.Arch Dermatol Syph. 1948; 57: 828-849Crossref Scopus (79) Google Scholar, 3Ballantyne J.C. Loach A.B. Carr D.B. Itching after epidural and spinal opiates.Pain. 1988; 33: 149-160Abstract Full Text PDF PubMed Scopus (326) Google Scholar, 4Thomas D.A. Williams G.W. Iwata K. Kenshalo Jr, D.R. Dubner R. Effects of central administration of opioids on facial scratching in monkeys.Brain Res. 1992; 585: 315-317Crossref PubMed Scopus (77) Google Scholar, 5Bergasa N.V. Jones E.A. The pruritus of cholestasis. Potential pathogenic and therapeutic implications of opioids.Gastroenterology. 1995; 108: 1582-1588Abstract Full Text PDF PubMed Scopus (98) Google Scholar]. Opiate-induced generalized pruritus can be reversed by the opiate antagonist, naloxone, indicating that it is opioid receptor-mediated [3Ballantyne J.C. Loach A.B. Carr D.B. Itching after epidural and spinal opiates.Pain. 1988; 33: 149-160Abstract Full Text PDF PubMed Scopus (326) Google Scholar, 4Thomas D.A. Williams G.W. Iwata K. Kenshalo Jr, D.R. Dubner R. Effects of central administration of opioids on facial scratching in monkeys.Brain Res. 1992; 585: 315-317Crossref PubMed Scopus (77) Google Scholar, 5Bergasa N.V. Jones E.A. The pruritus of cholestasis. Potential pathogenic and therapeutic implications of opioids.Gastroenterology. 1995; 108: 1582-1588Abstract Full Text PDF PubMed Scopus (98) Google Scholar]. Thus, increased opioidergic tone in the CNS is a mechanism of generalized pruritus. During the past 15 years several studies have indicated that a component of the pathophysiology of the syndrome of cholestasis is increased CNS neurotransmission mediated by endogenous opioid agonists [5Bergasa N.V. Jones E.A. The pruritus of cholestasis. Potential pathogenic and therapeutic implications of opioids.Gastroenterology. 1995; 108: 1582-1588Abstract Full Text PDF PubMed Scopus (98) Google Scholar, 6Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar, 7Bergasa N.V. Rothman R.B. Vergalla J. Xu H. Swain M.G. Jones E.A. Central mu-opioid receptors are down-regulated in a rat model of acute cholestasis.J Hepatol. 1992; 15: 220-224Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 8Bergasa N.V. Alling D.W. Vergalla J. Jones E.A. Cholestasis in the male rat is associated with naloxone-reversible antinociception.J Hepatol. 1994; 20: 85-90Abstract Full Text PDF PubMed Scopus (104) Google Scholar, 9Jones E.A. Bergasa N.V. The pruritus of cholestasis.Hepatology. 1999; 29: 1003-1006Crossref PubMed Scopus (139) Google Scholar]. Increased central opioidergic tone in cholestasis would be expected to induce generalized pruritus. Indeed, generalized pruritus is a common complication of cholestasis. If increased central opioidergic tone contributes to pruritus in cholestatic patients, opiate antagonists should ameliorate the pruritus. This prediction has been confirmed. In controlled clinical trials intravenous infusions of the opiate antagonist, naloxone [10Bergasa N.V. Talbot T.L. Alling D.W. Schmitt J.M. Walker E.C. Baker B.L. et al.A controlled trial of naloxone infusions for the pruritus of cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 11Bergasa N.V. Alling D.W. Talbot T.L. Swain M.G. Yurdaydin C. Turner M.L. et al.Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomised controlled trial.Ann Intern Med. 1995; 123: 161-167Crossref PubMed Scopus (318) Google Scholar], and oral administration of the opiate antagonist, nalmefene [12Bergasa N.V. Schmitt J.M. Talbot T.L. Alling D.W. Swain M.G. Turner M.L. et al.Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.Hepatology. 1998; 27: 679-684Crossref PubMed Scopus (160) Google Scholar, 13Bergasa N.V. Alling D.W. Talbot T.L. Wells M.C. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar], have been shown to reduce scratching activity by cholestatic patients. These four controlled trials indicate that one of the general properties of opiate antagonists is their ability to ameliorate the pruritus of cholestasis. Consistent with this reasoning was the report, by Wolfhagen et al. [[14]Wolfhagen F.H.J. Sternieri E. Hop W.C.J. Vitale G. Bertolotti M. van Buuren H.R. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled trial.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar], of a randomized, double-blind, placebo-controlled trial of the opiate antagonist, naltrexone, administered orally to patients with the pruritus of cholestasis. This report concluded that "oral naltrexone may be an effective and well-tolerated" treatment for the pruritus of cholestasis. The paper by Terg et al., which is published in this issue of the Journal [[15]Terg R. Coronel E. Sordá J. Muñoz A.E. Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.J Hepatol. 2002; 37: 717-722Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar], describes a randomized, double-blind, placebo-controlled, cross-over trial of oral naltrexone for the pruritus of cholestasis; their findings supplement those of Wolfhagen et al. [[14]Wolfhagen F.H.J. Sternieri E. Hop W.C.J. Vitale G. Bertolotti M. van Buuren H.R. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled trial.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar]. There is a fundamental difference between the design of the two naloxone and two nalmefene trials and the design of the two naltrexone trials. The difference in design concerns the primary efficacy endpoint. In the naloxone/nalmefene trials this endpoint was measurements of scratching activity, independent of arm or hand movements, whereas in the naltrexone trials it was a visual analogue 'score' of pruritus generated by applying a visual analogue scale. Pruritus is defined as the need to scratch. It is an intrinsically subjective perception, which cannot be quantitated. Although application of visual analogue scales can be used to generate numbers, the question arises whether numerical 'scores' of pruritus obtained in this way represent an adequate or meaningful assessment of pruritus. The clinical application of visual analogue scales has been critically reviewed by McCormack et al. [[16]McCormack H.M. Horne D.J. Sheather S. Clinical applications of visual analogue scales: a critical review.Psychol Med. 1988; 18: 1007-1019Crossref PubMed Scopus (1402) Google Scholar]. Potential problems include: (i) trimodal distribution of data points with clusters at the midpoint and extremes of the visual analogue scale; (ii) interpatient variability in marking the scales; (iii) the requirement of the ability to transform a complex subjective experience into a visuospatial display (involving perceptual judgement and accuracy); (iv) the variety of factors that contribute to respondent error (e.g. age, ability to think abstractly, mental organization, perceptual skills); (v) the desire to look at how scales were marked on previous occasions; and (vi) early use of the maximum value which precludes subsequent accurate scoring of a greater perception. In other words, visual analogue scores are influenced by interindividual variations in the ability of patients to integrate the perception of itch over time and to translate this perception into a visuospatial score that is subject to individual differences in its conceptualization. Accordingly, visual analogue scores of the perception of pruritus in cholestatic patients represent subjective data of uncertain clinical significance [[16]McCormack H.M. Horne D.J. Sheather S. Clinical applications of visual analogue scales: a critical review.Psychol Med. 1988; 18: 1007-1019Crossref PubMed Scopus (1402) Google Scholar]; they are likely to be an unreliable index of the severity of the clinical problem. This reasoning is supported by practical experience with the use of such scores in clinical trials of new therapies for the pruritus of cholestasis [[17]Bergasa N.V. Alling D.W. Talbot T. Schmidt J. Jones E.A. Assessment of the pruritus of cholestasis: an appraisal of the visual analog score.Hepatology. 1990; 12: 887Google Scholar]. The fact that visual analogue scales have been extensively applied in clinical studies does not detract from the deficiencies inherent in their use. Scratching activity, in the context of the pruritus of cholestasis, can be defined as the behavioural consequence of this complication of cholestasis. In contrast to pruritus, scratching activity can be quantitated. Thus, the problems inherent in assessing the severity of the subjective perception of itch may be obviated by objectively quantifying the consequence of itch, scratching activity. While itching has been claimed to correlate strongly with scratching activity [[18]Shelly W.B. Arthur R.P. The neurohistology and neurophysiology of the itch sensation in man.Arch Dermatol. 1957; 76: 296-323Crossref Scopus (184) Google Scholar], the severity of the perception of the pruritus of cholestasis, as described subjectively by patients, does not necessarily correlate closely with scratching activity [10Bergasa N.V. Talbot T.L. Alling D.W. Schmitt J.M. Walker E.C. Baker B.L. et al.A controlled trial of naloxone infusions for the pruritus of cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 13Bergasa N.V. Alling D.W. Talbot T.L. Wells M.C. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 17Bergasa N.V. Alling D.W. Talbot T. Schmidt J. Jones E.A. Assessment of the pruritus of cholestasis: an appraisal of the visual analog score.Hepatology. 1990; 12: 887Google Scholar]. Initial attempts to quantitate scratching activity involved the application of sophisticated arm and hand movement meters [19Felix R. Shuster S. A new method for the measurement of itch and the response to treatment.Br J Dermatol. 1975; 93: 303-312Crossref PubMed Scopus (85) Google Scholar, 20Summerfield J.A. Welch M.E. The measurement of itch with sensitive limb movement meters.Br J Dermatol. 1980; 102: 275-281Crossref Scopus (40) Google Scholar]. The development of these pioneering methods reflected the need to apply objective quantitative methods in clinical studies of pruritus. Unfortunately, measurements of arm and hand movements record activities in addition to scratching. The first monitoring system designed to quantitate scratching activity, independent of arm or hand movements, involved the application of piezofilm technology. The device comprised a vibration (scratch) transducer consisting of a piece of piezoelectric film, an FM transmitter and receiver, a custom-made signal processor, and a personal computer [[21]Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar]. Two components of the device were attached to an arm of the patient: the transducer was glued to a finger nail and was linked by wire to a battery-powered transmitter attached to the corresponding upper arm. The transducer acts as a contact microphone. When the finger nail vibrates, as it traverses the skin in the act of scratching, it induces bends (physical strain) in the piezofilm, which result in the generation of a weak electrical signal. This signal is telemetered to a receiver, located several meters away from the patient, for processing and storage in the computer in the form of counts. Fourier transformation of demodulated signals from the device revealed that the power of the signal associated with scratching was concentrated in a band of frequencies between 30 Hz and 1 kHz, whereas the frequencies of gross body movements were <30 Hz. Thus, the device could be programmed to exclude signals with frequencies of <30 Hz, enabling data on scratching activity to be obtained independent of arm or hand movements [[21]Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar]. Verification that the measured quantitative index of scratching activity (counts per 30 s) is a valid representation of scratching activity was accomplished by both videotapes and independent visual observations. In particular, the stored counts were shown to be proportional to the duration and intensity of scratching. The main disadvantage of the prototypic device was that the patient had to be confined to a hospital room throughout the period of a recording (usually 24 h), and hence was not in his or her normal environment. This disadvantage may be important, because the pruritus of cholestasis may be influenced by a change of environment. The problem has been overcome by processing and storing the signals from a scratch transducer over a predetermined interval (e.g. 24 h) in a computer chip attached to the patient's body. At the end of the period of recording, the data in the chip are downloaded into a personal computer and stored [[22]Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar]. This modification of the monitoring system has the advantage of allowing scratching activity to be recorded while the patient is in a normal non-hospital environment. For more information on the design and application of these devices, the reader is referred to the relevant original reports in the bioengineering literature [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar]. The discipline of clinical science, which has been largely responsible for the impressive advances in medicine since the second world war [[23]Le Fanu J. Clinical science – a new ideology for medicine.in: In: The Rise and Fall of Modern Medicine. Little Brown and Company, London1999: 196-205Google Scholar], requires that objective quantitative primary efficacy endpoints be used in controlled clinical trials. Clearly, attempts to quantitate the perception of pruritus, which is inherently unquantifiable, do not meet this requirement. While measurements of scratching activity have no place in routine clinical practice, at present, such measurements constitute the only scientifically acceptable primary efficacy endpoint available for trials of new therapies for the pruritus of cholestasis. Failure to apply a device for measuring scratching activity in a trial of a new therapy for the pruritus of cholestasis cannot reasonably be justified on the grounds of the complexity of the device, its impracticality or its expense. Any bioengineer, shown a block diagram of one of these devices [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar], would confirm the simplicity of its design. Both devices [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar] are easy to apply in practice and are well tolerated by patients. Finally, components of the devices [21Talbot T.L. Schmitt J.M. Bergasa N.V. Jones E.A. Walker E.C. Application of piezofilm technology for the quantitative assessment of pruritus.Biomed Instrum Technol. 1991; 25: 400-403PubMed Google Scholar, 22Molenaar H.A.J. Oosting J. Jones E.A. Improved device for measuring scratching activity in patients with pruritus.Med Biol Eng Comput. 1998; 36: 220-224Crossref PubMed Scopus (36) Google Scholar] are readily acquired and are inexpensive. For example, piezofilm is cheap and most clinical investigators already have access to a personal computer. In their trial of naltrexone for pruritus in cholestatic patients, Terg et al. noted, during the first 48 h of naltrexone therapy, several adverse events that were consistent with opioid withdrawal-like phenomena. The authors concluded that "most of the reported side effects are mild, transient and do not require specific medication" [[15]Terg R. Coronel E. Sordá J. Muñoz A.E. Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.J Hepatol. 2002; 37: 717-722Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. However, initiation of oral opiate antagonist therapy with nalmefene [[6]Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar] or naltrexone [24Jones E.A. Dekker L.R.C. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.Gastroenterology. 2000; 118: 431-432Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Neuberger J. Jones E.A. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.Eur J Gastroenterol Hepatol. 2001; 13: 1393-1394Crossref PubMed Scopus (45) Google Scholar, 26Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.Q J Med. 2002; 95: 547-552Crossref Scopus (90) Google Scholar] in cholestatic patients may be associated with florid opioid withdrawal-like reactions. Accordingly, it is prudent to take precautions to avoid precipitating such reactions. In this context, the administration of clonidine [[6]Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar] or starting treatment with subtherapeutic oral doses [[12]Bergasa N.V. Schmitt J.M. Talbot T.L. Alling D.W. Swain M.G. Turner M.L. et al.Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.Hepatology. 1998; 27: 679-684Crossref PubMed Scopus (160) Google Scholar] appears to be less satisfactory than initiating opiate antagonist therapy with a slow subtherapeutic intravenous infusion of naloxone, and then gradually increasing the infusion rate to one within the therapeutic range, before administering a small oral dose of an orally bioavailable opiate antagonist [24Jones E.A. Dekker L.R.C. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.Gastroenterology. 2000; 118: 431-432Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Neuberger J. Jones E.A. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.Eur J Gastroenterol Hepatol. 2001; 13: 1393-1394Crossref PubMed Scopus (45) Google Scholar, 26Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.Q J Med. 2002; 95: 547-552Crossref Scopus (90) Google Scholar]. The observation that the oral administration of an opiate antagonist to cholestatic patients (who had not received an opiate) often precipitates a transient opioid withdrawal-like reaction [6Thornton J.R. Losowsky M.S. Opioid peptides and primary biliary cirrhosis.Br Med J. 1988; 297: 1501-1504Crossref PubMed Scopus (260) Google Scholar, 10Bergasa N.V. Talbot T.L. Alling D.W. Schmitt J.M. Walker E.C. Baker B.L. et al.A controlled trial of naloxone infusions for the pruritus of cholestasis.Gastroenterology. 1992; 102: 544-549PubMed Google Scholar, 11Bergasa N.V. Alling D.W. Talbot T.L. Swain M.G. Yurdaydin C. Turner M.L. et al.Effects of naloxone infusions in patients with the pruritus of cholestasis: a double-blind, randomised controlled trial.Ann Intern Med. 1995; 123: 161-167Crossref PubMed Scopus (318) Google Scholar, 12Bergasa N.V. Schmitt J.M. Talbot T.L. Alling D.W. Swain M.G. Turner M.L. et al.Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.Hepatology. 1998; 27: 679-684Crossref PubMed Scopus (160) Google Scholar, 13Bergasa N.V. Alling D.W. Talbot T.L. Wells M.C. Jones E.A. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.J Am Acad Dermatol. 1999; 41: 431-434Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 14Wolfhagen F.H.J. Sternieri E. Hop W.C.J. Vitale G. Bertolotti M. van Buuren H.R. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled trial.Gastroenterology. 1997; 113: 1264-1269Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 15Terg R. Coronel E. Sordá J. Muñoz A.E. Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study.J Hepatol. 2002; 37: 717-722Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 24Jones E.A. Dekker L.R.C. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis.Gastroenterology. 2000; 118: 431-432Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 25Neuberger J. Jones E.A. Liver transplantation for intractable pruritus is contraindicated before an adequate trial of opiate antagonist therapy.Eur J Gastroenterol Hepatol. 2001; 13: 1393-1394Crossref PubMed Scopus (45) Google Scholar, 26Jones E.A. Neuberger J. Bergasa N.V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions.Q J Med. 2002; 95: 547-552Crossref Scopus (90) Google Scholar] supports the hypothesis that opioidergic tone in the CNS is increased in cholestasis, and strengthens the rationale for treating the pruritus of cholestasis with an opiate antagonist.
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