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A controlled trial of naloxone infusions for the pruritus of chronic cholestasis
GASTROENTEROLOGY
1992:102:544-549
A Controlled Trial of Naloxone Infusions for the Pruritus of Chronic Cholestasis NORA V. BERGASA, THOMAS L. TALBOT, DAVID W. ALLING, JOSEPH M. SCHMITT, ELIJAH C. WALKER, BENNIE L. BAKER, JULIA C. KORENMAN, YOON PARK, JAY H. HOOFNAGLE, and E. ANTHONY JONES Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases; Applied Clinical Engineering Section, Biomedical Engineering and Instrumentation Program, National Center for Research Resources; and Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
To test the hypothesis that opioid agonist activity contributes to the pruritus of cholestasis, a placebo-controlled single-blinded trial of naloxone, an opioid antagonist, was conducted in eight patients with primary hiliary cirrhosis. After discontinuation of all conventional antipruritic medications, one or two continuous @&hour) IV infusions of naloxone (0.2 pg *kg-’ - min-‘) and placebo solution were administered consecutively in an order that was not predetermined. Pruritus was assessed suhjectively by means of four hourly recordings of a visual analogue score. In addition, objective measurements of scratching activity that were independent of gross body movements were continuously recorded using an apparatus specifically designed to measure the frequencies associated with this activity. No side effects associated with naloxone infusions were observed. Only scratching activity data obtained for the same periods of day and night during both naloxone and placebo infusions were compared. Naloxone infusions were consistently associated with a decrease in values of the scratching activity index. In addition, in 50% of the patients the infusions were associated with a decrease in visual analogue score. The mean decrease in scratching activity ranged from 29% to 96% (mean, 50%; P < 0.001).These findings imply that increased opioid agonist activity contributes to scratching activity in cholestatic patients. ruritus is a frequent complication of cholestasis.’ This symptom can be distressing and a major problem to manage. Unrelieved chronic pruritus can be an indication for liver transplantation. The etiology of the pruritus of cholestasis is unknown. It has been suggested that it arises as a consequence of the interaction between nerve endings in the skin and one or more substances (e.g., bile acids) that are re-
tained in plasma in cholestasis.2 However, trials of a variety of experimental therapies for the pruritus of cholestasis, including the bile acid sequestering resin, cholestyramine, have failed to definitively implicate any specific class of substance in the pathogenesis of the pruritus.’ A component of the pruritus of cholestasis may have a neurogenic central origin involving the opioid receptor system. The basis for this suggestion is as follows: (a) opiates, such as morphine, induce pruritus’; (b) patients with cirrhosis have increased sensitivity to morphine3; (c) an opioid antagonist has been reported to induce in patients with cirrhosis a syndrome that resembles the withdrawal reaction of opiate addiction4; (d) plasma levels of enkephalins (endogenous opioid agonist ligands) are elevated in patients with chronic liver disease4+; (e) pentapeptide enkephalins can cross the blood brain barrierg; and (f) as assessed by subjective criteria, opioid antagonists have been reported to ameliorate the pruritus of cholestasis.4,‘0*” To define further the role of the opioid system in this syndrome, we have conducted a pilot study of the effects of an opioid antagonist, naloxone, given by IV infusion, on the pruritus of chronic cholestasis. The design of the study controlled for the possible placebo effects of an IV infusion. In addition, scratching activity was quantitated using a newly devised apparatus that objectively and continuously measures scratching activity independent of gross body movements.
P
Materials and Methods The protocol of this study was approved by the Institute of Diabetes and Digestive and Kidney
NaDis-
This is a U.S. government work. There are no restrictions its use. 0016-5065/92/$0.00
on
tional
NALOXONE FOR PRURITUS OF CHOLESTASIS 545
February 1992
eases Clinical Research Subpanel. A written consent was signed by all participating patients.
informed
Patients Eight female patients with chronic pruritus secondary to primary biliary cirrhosis were studied (Table 1). In none of the patients was pruritus relieved satisfactorily by conventional medications prescribed for this symptom. Other causes of pruritus were excluded by conventional clinical and laboratory criteria.13 Each of these patients was observed to scratch with their fingernails at frequent intervals.
Design of Study All antipruritic medications were discontinued 5 days before the study (Table 1). None of the patients had received any opiates within the previous 3 months. Initially, a dose-finding study was conducted to assess the tolerability of continuous infusions of naloxone in patients with chronic cholestatic liver disease. Doses of up to 0.4 pg. kg-’ - min-’ for 4 hours were found to be well tolerated.
Table 1. Clinical
and Laboratory
Data on the Patients
During the trial each patient received consecutive 24 hour IV infusions of both 5% dextrose/O.&% NaCl (placebo infusion) and naloxone (0.2 pg. kg-’ - min-‘) in 5% dextrose/0.45% NaCl. The total volume infused per 24 hours was 0.5 L. Each naloxone infusion was preceded by an IV bolus injection of 0.4 mg naloxone in 1 mL saline, and each placebo infusion was preceded by an IV bolus injection of 1 mL saline. Patients 1 and 3 received one naloxone and one placebo infusion. Patients 2 and 4-8 received two naloxone and two placebo infusions. All infusions were consecutive. The order of naloxone and placebo infusions was not predetermined. Patients were blinded to the content of the infusions and the bolus injections. However, because naloxone was being continuously infused into cholestatic patients, the possibility existed that an opiate withdrawal-like syndrome might be precipitated. Therefore, the physicians involved in this study were not blinded. Vital signs were continuously recorded throughout the study using an automatic blood pressure monitor (Critikon Corp., Tampa, FL). Symptoms, including opiate withdrawal-like phenomenon,‘4-‘6 were assessed clinically and by a questionnaire,
Studied Alkaline
Dura-
tient no.
phos-
tion
phatase
bilirubin
AST
Scheuer
tion
histo-
of
pruri-
Age
logical
PBC
tus
distribution
Associated
W)
stage”
W
of pruritus
conditions
66
IV
Pa-
be
Anti-
Duraof
3
Description
Medications
and
“Biting”;
Hypothy-
generalized
roidism.
Total
mitoALT
chon-
IgM
(normal
(normal
(normal
(normal
drial
for pruritus
Other
range.
range.
range.
range,
anti-
range.
before
medica-
37-116
0.1-l
9-34
6-41
body
50-320
U/L1
mg/L)
entry Cholestyramine
(J/L)
ms/dLl
(“OrI”al
u/r,)
titers
Thyroxine
672
9.1
220
127
1:320
1550
Metho-
299
2.9
120
95
1:320
153
443
3.1
70
143
I:320
432
934
05
114
76
1:640
432
786
1.11
96
1%
1:320
876
520
1.6
98
52
Nega-
319
tions
Colestipol
Sjogren’s syndrome 46
111
1
Constant.
None
Cholestyramine
generalized; worse
trexate
right
before menstruation 48
Ill
6
Constant
Sjogren’s syndrome
Cholestyramine
Triazolam
Hydroxyzine
Metho-
HCI
trexate
Phenobarbital 58
111
Chest,
face,
and
scalp
Hypothyroidism,
Cholostyramine
Thyroxine Calcium
Sjogren’s
Vitamin
D
syndrome 48
II
Contagious-
NO”l?
ness
Cholestyramine
None
Hydroxyzine
concern; worse
HCI at
home; generalized 44
II
Constant: arms
Diabetes and
abdomen
mellitus, hypertension
40
II
Generalized
None
Cholestyramine Hydroxyzine HCI
NPH
and
regular
tive
insulin
Phenobarbital
Atenol
Cholestyramine
None
925
1.4
143
186
1:3211
Triazolam
402
1.6
87
149
1:32tl
458
Hydroxyzine HCI Colestipol 50
III
Generalized
None
Cholestyramine Cyproheptadine HCI
PBC, primary
biliary
“See reference
12.
bFrom
time
cirrhosis:
of diagnosis.
IgM. immunoglobulin
M.
1160
546
BERGASA
ET AL.
which the patients while awake.
Assessment Scratching
GASTROENTEROLOGY
were asked to fill out every 4 hours
of Pruritus Activity
Perception
and
Visual analogue scale. Every 4 hours while awake patients were asked to record the severity of their pruritus by making a mark with pen or pencil on a visual analogue scale. The scale consisted of a lo-cm horizontal line; 0 cm (beginning of scale on left side) was designated as representing no itching and 10 cm (end of scale on right side) worst itching ever.17 A visual analogue score (VAS) is the number of centimeters (to the nearest millimeter) between 0 cm and the point on the scale at which the patient made a mark. Scratching activity index. Scratching activity was continuously recorded throughout the infusions of naloxone and placebo solution in the form of a scratching activity index using a scratching activity monitoring system designed specifically for this purpose. This system consists of a vibration (scratch) transducer (Piezo Film Division, Atothem Corp., Philadelphia, PA), an FM transmitter and receiver [Radioshack (32-1221)], a custom-made signal processor, and a personal computer. The vibration transducer was taped to the middle fingernail of the dominant hand, which was not cut during the study. The transducer consists of a square piece of piezoelectric film, 28 pm thick, metallized on both sides with silver ink. It is connected by a wire to the transmitter box (2 X 7 X 6 cm), which is attached to the same arm by a Velcro cuff. The transducer converts the strain produced by vibrations of the fingernail as it traverses the skin in the act of scratching to an electrical voltage. The electrical signal is transmitted by the transmitter across the room where it is received, pro-
T”“~~$~~---+-~1
RE;;vER
ANALOG PERSONAL COMPUTER
SIGNAL PROCESSOR DIGITAL
SIGNAL
I
I
I
I
I
L__________
cessed, and logged by the personal computer as a scratching activity index in units of counts per unit time (Figure 1). Fourier analysis of the demodulated signals had indicated that frequencies associated with vibrations of the fingernail derived from scratching activity were between 50 and 1000 Hz (Figure 2). Two crucial aspects of signal processing by this system are that signals with an amplitude below a preset threshold and low-frequency signals associated with gross body movements are rejected. Consequently, only signals above the threshold and within the frequency band indicated above were used to generate the
scratching activity index (Figure Statistical
1).
Analyses
Data were analyzed by a statistician (D.W.A.) independent of the clinicians involved in the study. The periods of time during which scratching activity was recorded for each patient were divided into a series of intervals, each representing the duration of a naloxone or placebo infusion. These intervals were aligned so that corresponding hours of the day and night coincided. Only data obtained during the same periods of day and night were compared, thus minimizing differences between data during naloxone and placebo infusions attributable to possible effects of diurnal rhythms on scratching activity. The longest period of time common to the set of treatment intervals, in which continuous scratching activity data were available during both naloxone and placebo infusions, was determined by finding the latest initiation time and the earliest termination time in the set. The common period in question was defined as beginning at the latest initiation time and ending at the earliest termination time. Implicit in the design of this study was that each patient served as her own control. Scratching activity obtained for comparable periods during naloxone and placebo infusions was averaged and expressed per SO-second interval. The ratio of these averages (r) was compared to unity. The following one-sample t test was performed:
I
SIGNAL
-
-
Vol. 102, No. 2
____
in which ris the mean ratio for the eight patients and SE its standard error. Means were obtained for the VAS data obtained during each of the treatment intervals in which scratching activity was analyzed.
Results
READ COUNT
Figure 1. Block diagram of signal processor.
of monitoring
system with flow chart
No significant untoward clinical developments occurred during the infusions. In particular, they were not associated with any reduction in functional activity or mental alertness or with a constellation of findings consistent with an opiate withdrawal-like syndrome. Patients 1 and 8 associated naloxone infusions with relief of pruritus, and patient 5 associated the
NALOXONE
February 1992
FOR PRURITLJS OF CHOLESTASIS
547
Scratching
Body Movements 4alr
Figure 2. Results of Fourier analysis of demodulated signals indicating that frequencies generated by gross body movements are ~50 Hz and those generated by the scratching fingernail are between 50 and 1000 Hz.
+/
0 0
200
second placebo infusion with increased perception of pruritus. There was no consistent change between mean values for the VAS during naloxone infusions and corresponding values during placebo infusions (Table 2). Naloxone infusions were consistently associated with a decrease in values for the scratching activity index (Table 2; Figure 3). The decrease in scratching activity ranged from 29% to 96% (mean, 50%; P < 0.001). Of particular interest is the finding that there was no correlation between changes in scratching activity index and the VAS. For example, patient 3 had the largest reduction in scratching activity on naloxone (96%), but her mean VAS increased on naloxone. Furthermore, although patient 1 stated with confidence that infusions containing naloxone, but not placebo, were relieving her pruritus, her mean VAS also increased on naloxone. Discussion Pruritus or itching is a major complication of cholestasis. Itch is defined as the need to scratch and, hence, is intrinsically subjective. The perception of itch cannot be measured directly. Definitive inter-
Table
2. Effects of Naloxone Infusions Activity Index and VAS Change in mean scratching activity index
400
600
800
1(
Frequency(Hz)
on Scratching
Patient no.
(%I
Change in mean VAS (%I
1 2 3 4 5 6 7 8
-76 -44 -96 -32 -54 -36 -32 -29
+75 -30 +14 +150 -50 f50 -17 -37
pretation of studies of the effects of specific agents on the pruritus of cholestasis has been hampered by the subjectivity of this symptom and the difficulty in interpreting the results obtained using the subjective methods of evaluation that have been used to assess pruritus.‘8-21 In contrast to the pruritus of cholestasis, its consequence, increased scratching activity, can be quantitated. Indeed, when many patients perceive itching, they scratch. In 1975, Felix and Schuster reported the application of measurements of limb movements to study patients with pruritus caused by skin disorders22; subsequently, a more sophisticated apparatus was applied to measure limb movements of patients with pruritus caused by cholestatic liver disorders.23 The development of such an apparatus reflected the need to conduct objective quantitative studies in patients with pruritus caused by cholestasis. Unfortunately, measurements of limb movements record activities other than scratching activity. Accordingly, we have developed a device for quantitating scratching activity independent of limb movements. The validity of the device has been verified by demonstrating a close concordance between its output (numerical values for scratching activity index or intensity of an audio signal) and independent direct observations and video tapes of scratching activity. In particular, it was consistently observed that counts were not recorded by the device during gross movements of the hand that were not associated with the interaction between fingernails and the skin and that counts were recorded during the act of scratching by the hand to which the transducer was taped. The device is well tolerated by patients and enables scratching activity to be detected and quantitated. Scratching activity measured in this study varied appreciably within an hour and from hour to hour and tended to be reduced substantially during sleep. Furthermore, there was a striking lack of correlation between scratching activity and assessments of itch-
548
BERGASA
‘““J
ET AL.
GASTROENTEROLOGY
NALOXONE
p
PLACEBO
Vol. 102, No. 2
*
Time (hrs)
Figure 3. Representative data on scratching activity index in patient 5 during- placebo _ and naloxone infusions.
ing using the VASz4 This lack of correlation is not surprising, because a VAS requires the patient not only to integrate the perception of itch over the time interval covered by the VAS but also to translate this perception, which is inherently subjective, into a visuospatial score that is subject to individual differences in its conceptualization. Patients tend not to treat the visual analogue scale as a continuum, with the result that clustering of marks at the extremes or center of the scale may occur.17 As shown in this short-term study, the patient’s perception of itch, as assessed by the VAS, may persist undiminished, although scratching activity has diminished substantially. In particular, suppression of scratching activity by an effective treatment for pruritus may have to be both profound and sustained for a long period for the perception of itch in a patient with chronic pruritus to be appreciably diminished, as assessed by the VAS.25 Thus, a patient’s perception of itch, as assessed by the VAS, appears to be an unreliable indicator of scratching activity in a short-term study. It is proposed that quantitative data on scratching activity is a desirable component of clinical trials of therapies for the pruritus of cholestasis. In the present study we evaluated the role of the opioid system in the pruritus of cholestasis by assessing the effects of naloxone on scratching activity in patients with primary biliary cirrhosis. Naloxone is a well-characterized opioid antagonist. The major limitation of naloxone is that it must be given by frequent injections or continuous infusion.26 This requirement necessitated quantitating its effects on scratching activity over short (i.e., &hour) treatment periods. Initially, the infusion rate of naloxone was 0.026 pg. kg-’ - min-‘, which is approximately half the dose that has been used to reverse morphine anesthesia.z7 Once it was determined that no significant side effects occurred at this initial infusion rate, the infusion rate was increased to 0.052 pg. kg-l - mine1 and subsequently to 0.1, 0.2, and 0.4 p,g *kg-’ - min-' . No deleterious or unpleasant side effects were observed. The infusion rate chosen for the study is equivalent to 16-20 mg/24 hours.
In contrast to a previous study in which the opioid antagonist, nalmefene, was given to patients with chronic liver disease,4 administration of naloxone in this study did not precipitate a clinically overt opioid withdrawal-like syndrome. Possible reasons for this negative finding are that the dose of naloxone was not sufficient to precipitate such a syndrome or that naloxone and nalmefene differ in their affinities for different opiate receptorsz8 The results indicate that, in each of the eight patients studied, the infusion of naloxone was associated with a substantial reduction in scratching activity. We believe that this phenomenon constitutes a beneficial effect of naloxone in these patients. Naloxone would compete with any endogenous opioid agonist ligands for occupancy of opioid receptors in the nervous system and would consequently block the biological effects of endogenous opioid agonists.” Because opioid agonists are known to induce pruritus,’ a naloxone-mediated amelioration of scratching activity in cholestatic patients suggests that the pruritus of cholestasis is mediated, at least in part, by opioid agonist ligands. The mechanism of an opioid agonist-mediated component of the pruritus of cholestasis is currently unknown. Possibilities include increased availability of opioid agonist ligands,4-8 upregulation of opioid receptors, or an increased affinity of opioid ligands for their receptors.” Thus, previous subjective observations, which suggested that opioid antagonists can induce an amelioration of the pruritus of cholestasis,4*‘o’” are extended and made firmer by our results. However, the findings in this study need to be confirmed by conducting a double-blind controlled study. Possible reasons for naloxone not completely abolishing scratching activity in this study are that the dose of naloxone was insufficient, that a carryover of the chronic scratching habit into the treatment period may have occurredz5 and that a component of the syndrome may not be mediated by central opioid receptors. Such a component could still be opioid agonist mediated but by a peripheral mechanism in the skin that is not naloxone reversible.30
February
1992
The results of the present study suggest that naloxone infusions may be beneficial for the emergency treatment of intractable pruritus of cholestasis. However, they are clearly impractical for the long-term management of pruritus. Nevertheless, the beneficial effects of naloxone demonstrated in this study provide a rationale for the long-term treatment of the pruritus of chronic cholestasis with an opioid antagonist, such as nalmefene, which is effective when given orally.
NALOXONE
FOR PRURITUS OF CHOLESTASIS
549
ment of abrupt withdrawal from methadone. Am J Psychiatry 1986;143:831-837. 17. McCormack HM, de L’Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical review. Psycho1 Med 1988;18:1007-1019. effects in cholestatic 18. Bloomer JR, Boyer JL. Phenobarbital liver disease. Ann Intern Med 1975;82:310-317. 19. Ghent CN, Caruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin: results of a double-blind crossover randomized trial. Gastroenterology 1988;94:488-493. 20. Lauterburg BT, Pineda AA, Burgstadler EA, Taswell HF, Dickson ER, Carlson GL. Treatment of pruritus of cholestasis by plasma perfusion through USP-charcoal-coated glass References beads. Lancet 1980;2:53-55. 21. Woolf GM, Reynolds TB. Failure of rifampicin to relieve pruri1. Sherlock S. Cholestasis. In: Sherlock S. Diseases of the liver tus in chronic liver disease. J Clin Gastroenterol1990;12:174and biliary system. 8th ed. Oxford, England: Blackwell Scien177. tific, 1989:248-272. 22. Felix R, Shuster S. A new method for the measurement of itch 2 Jones EA, Bergasa NV. The pruritus of cholestasis. From bile and the response to treatment. Br J Dermatol1975;93:303-312, acids to opiate agonists. Hepatology 1990;11:884-887. 23. Summerfield JA, Welch ME. The measurement of itch with 3 Laidlaw J, Read AE, Sherlock S. Morphine tolerance in hesensitive limb movement meters. Br J Dermatol1980;102:275patic cirrhosis. Gastroenterology 1961;40:389-396. 281. 4 Thornton JR, Losowsky MS. Opioid peptides and primary bili24. Bergasa NV, Alling D, Talbot T, Schmitt J, Jones EA. Assessary cirrhosis. Br Med J 1988;297:1501-1504. ment of the pruritus of cholestasis: an appraisal of the visual 5. Thornton JR, Dean H, Losowsky MS. Is ascites caused by imanalogue scale (abstr). Hepatology 1990;12:887. paired hepatic inactivation of blood borne endogenous opioid 25. Edwards AE, Shellow VR, Wright ET, Dignam TF. Pruritic peptides? Gut 1988;29:1167-1172, skin disease, psychological stress and the itch sensation. Arch 6. Thornton JR, Losowsky MS. Plasma methionine enkephalin Dermatol 1976;112:339-343. concentration and prognosis in primary biliary cirrhosis. Br 26. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: MedJ 1988;297:1241-1242, Gilman AG, Goodman LS, Rall TW, Marad F, eds. The pharma7. Thornton JR, Dean HG, Losowsky MS. Do increased catecholcologic basis of therapeutics. 7th ed. New York: Macmillan, amines and plasma methionine enkephalins in cirrhosis pro1985:491-531. mote bleeding oesophageal varices? Q J Med 1988;68:541-551, 27. Johnstone RE, Jobes DR, Kennel1 EM, Behar MG, Smith TC. 8. Thornton JR, Losowsky MS. Plasma leucine enkephalin is inReversal of morphine anesthesia with naloxone. Anesthesiolcreased in liver disease. Gut 1989;3:1392-1395. ogy 1974;41:361-367. 9. Banks WA, Kastin AJ. Peptide transport across the blood28. Mitchel ME, Bolger G, Weissman BA. Binding of a new opiate brain barrier. Am J Physiol 1990;259:El-ElO. antagonist nalmefene to rat membranes. Methods Find Exp 10. Bernstein JE, Swift R. Relief of intractable pruritus with naloxClin Pharmacol 1985;7:175-177. one. Arch Dermatol 1979;115:1366-1367. 29. Blanchard SG, Chang K-T. Regulation of opioid receptors, In: 11. Summerfield JA. Naloxone modulates the perception of itch Pasternak GW, ed. The opiate receptors. Clifton, NJ: Humana, in man. Br J Clin Pharmacol 1980;10:180-182. 1988:425-439. 12. Scheuer PJ. Biliary disease. In: Scheuer PJ. Liver biopsy inter30. Fjellner B, Hagemark 0. Influence of the opiate antagonist pretation. 4th ed. London: Bailliere Tindall, 1988:40-65. naloxone on experimental pruritus. Acta Derm Venereol 13. Parker F. Skin diseases. In: Wyngaarden JB, Smith LH, eds. 1984;64:73-75. Cecil textbook of medicine. 18th ed. Philadelphia: Saunders, 1988:2300-2353. 14. Gold MS, Redmond DE, Kleber HD. Clonidine blocks acute Received January 10, 1991. Accepted May 21,1991. opiate-withdrawal symptoms. Lancet 1978;2:595-602. Address requests for reprints to: Nora V. Bergasa, M.D., Liver 15. Washton AM, Resnick RB. Clonidine for opiate detoxification: Unit, Building 10, Room 4D52,National Institutes of Health, Beoutpatient clinical trials. Am J Psychiatry 1980;137:1121- thesda, Maryland 20892. 1122. The authors wish to acknowledge the vigilance of Head Nurse 16. Charrey DS, Heninger GR, Kleber HD. The combined use of Joyce Harris and the nursing staff of Nursing Unit 9D, Clinical clonidine and naltrexone as a rapid, safe and effective treatCenter, National Institues of Health.
1992:102:544-549
A Controlled Trial of Naloxone Infusions for the Pruritus of Chronic Cholestasis NORA V. BERGASA, THOMAS L. TALBOT, DAVID W. ALLING, JOSEPH M. SCHMITT, ELIJAH C. WALKER, BENNIE L. BAKER, JULIA C. KORENMAN, YOON PARK, JAY H. HOOFNAGLE, and E. ANTHONY JONES Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases; Applied Clinical Engineering Section, Biomedical Engineering and Instrumentation Program, National Center for Research Resources; and Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
To test the hypothesis that opioid agonist activity contributes to the pruritus of cholestasis, a placebo-controlled single-blinded trial of naloxone, an opioid antagonist, was conducted in eight patients with primary hiliary cirrhosis. After discontinuation of all conventional antipruritic medications, one or two continuous @&hour) IV infusions of naloxone (0.2 pg *kg-’ - min-‘) and placebo solution were administered consecutively in an order that was not predetermined. Pruritus was assessed suhjectively by means of four hourly recordings of a visual analogue score. In addition, objective measurements of scratching activity that were independent of gross body movements were continuously recorded using an apparatus specifically designed to measure the frequencies associated with this activity. No side effects associated with naloxone infusions were observed. Only scratching activity data obtained for the same periods of day and night during both naloxone and placebo infusions were compared. Naloxone infusions were consistently associated with a decrease in values of the scratching activity index. In addition, in 50% of the patients the infusions were associated with a decrease in visual analogue score. The mean decrease in scratching activity ranged from 29% to 96% (mean, 50%; P < 0.001).These findings imply that increased opioid agonist activity contributes to scratching activity in cholestatic patients. ruritus is a frequent complication of cholestasis.’ This symptom can be distressing and a major problem to manage. Unrelieved chronic pruritus can be an indication for liver transplantation. The etiology of the pruritus of cholestasis is unknown. It has been suggested that it arises as a consequence of the interaction between nerve endings in the skin and one or more substances (e.g., bile acids) that are re-
tained in plasma in cholestasis.2 However, trials of a variety of experimental therapies for the pruritus of cholestasis, including the bile acid sequestering resin, cholestyramine, have failed to definitively implicate any specific class of substance in the pathogenesis of the pruritus.’ A component of the pruritus of cholestasis may have a neurogenic central origin involving the opioid receptor system. The basis for this suggestion is as follows: (a) opiates, such as morphine, induce pruritus’; (b) patients with cirrhosis have increased sensitivity to morphine3; (c) an opioid antagonist has been reported to induce in patients with cirrhosis a syndrome that resembles the withdrawal reaction of opiate addiction4; (d) plasma levels of enkephalins (endogenous opioid agonist ligands) are elevated in patients with chronic liver disease4+; (e) pentapeptide enkephalins can cross the blood brain barrierg; and (f) as assessed by subjective criteria, opioid antagonists have been reported to ameliorate the pruritus of cholestasis.4,‘0*” To define further the role of the opioid system in this syndrome, we have conducted a pilot study of the effects of an opioid antagonist, naloxone, given by IV infusion, on the pruritus of chronic cholestasis. The design of the study controlled for the possible placebo effects of an IV infusion. In addition, scratching activity was quantitated using a newly devised apparatus that objectively and continuously measures scratching activity independent of gross body movements.
P
Materials and Methods The protocol of this study was approved by the Institute of Diabetes and Digestive and Kidney
NaDis-
This is a U.S. government work. There are no restrictions its use. 0016-5065/92/$0.00
on
tional
NALOXONE FOR PRURITUS OF CHOLESTASIS 545
February 1992
eases Clinical Research Subpanel. A written consent was signed by all participating patients.
informed
Patients Eight female patients with chronic pruritus secondary to primary biliary cirrhosis were studied (Table 1). In none of the patients was pruritus relieved satisfactorily by conventional medications prescribed for this symptom. Other causes of pruritus were excluded by conventional clinical and laboratory criteria.13 Each of these patients was observed to scratch with their fingernails at frequent intervals.
Design of Study All antipruritic medications were discontinued 5 days before the study (Table 1). None of the patients had received any opiates within the previous 3 months. Initially, a dose-finding study was conducted to assess the tolerability of continuous infusions of naloxone in patients with chronic cholestatic liver disease. Doses of up to 0.4 pg. kg-’ - min-’ for 4 hours were found to be well tolerated.
Table 1. Clinical
and Laboratory
Data on the Patients
During the trial each patient received consecutive 24 hour IV infusions of both 5% dextrose/O.&% NaCl (placebo infusion) and naloxone (0.2 pg. kg-’ - min-‘) in 5% dextrose/0.45% NaCl. The total volume infused per 24 hours was 0.5 L. Each naloxone infusion was preceded by an IV bolus injection of 0.4 mg naloxone in 1 mL saline, and each placebo infusion was preceded by an IV bolus injection of 1 mL saline. Patients 1 and 3 received one naloxone and one placebo infusion. Patients 2 and 4-8 received two naloxone and two placebo infusions. All infusions were consecutive. The order of naloxone and placebo infusions was not predetermined. Patients were blinded to the content of the infusions and the bolus injections. However, because naloxone was being continuously infused into cholestatic patients, the possibility existed that an opiate withdrawal-like syndrome might be precipitated. Therefore, the physicians involved in this study were not blinded. Vital signs were continuously recorded throughout the study using an automatic blood pressure monitor (Critikon Corp., Tampa, FL). Symptoms, including opiate withdrawal-like phenomenon,‘4-‘6 were assessed clinically and by a questionnaire,
Studied Alkaline
Dura-
tient no.
phos-
tion
phatase
bilirubin
AST
Scheuer
tion
histo-
of
pruri-
Age
logical
PBC
tus
distribution
Associated
W)
stage”
W
of pruritus
conditions
66
IV
Pa-
be
Anti-
Duraof
3
Description
Medications
and
“Biting”;
Hypothy-
generalized
roidism.
Total
mitoALT
chon-
IgM
(normal
(normal
(normal
(normal
drial
for pruritus
Other
range.
range.
range.
range,
anti-
range.
before
medica-
37-116
0.1-l
9-34
6-41
body
50-320
U/L1
mg/L)
entry Cholestyramine
(J/L)
ms/dLl
(“OrI”al
u/r,)
titers
Thyroxine
672
9.1
220
127
1:320
1550
Metho-
299
2.9
120
95
1:320
153
443
3.1
70
143
I:320
432
934
05
114
76
1:640
432
786
1.11
96
1%
1:320
876
520
1.6
98
52
Nega-
319
tions
Colestipol
Sjogren’s syndrome 46
111
1
Constant.
None
Cholestyramine
generalized; worse
trexate
right
before menstruation 48
Ill
6
Constant
Sjogren’s syndrome
Cholestyramine
Triazolam
Hydroxyzine
Metho-
HCI
trexate
Phenobarbital 58
111
Chest,
face,
and
scalp
Hypothyroidism,
Cholostyramine
Thyroxine Calcium
Sjogren’s
Vitamin
D
syndrome 48
II
Contagious-
NO”l?
ness
Cholestyramine
None
Hydroxyzine
concern; worse
HCI at
home; generalized 44
II
Constant: arms
Diabetes and
abdomen
mellitus, hypertension
40
II
Generalized
None
Cholestyramine Hydroxyzine HCI
NPH
and
regular
tive
insulin
Phenobarbital
Atenol
Cholestyramine
None
925
1.4
143
186
1:3211
Triazolam
402
1.6
87
149
1:32tl
458
Hydroxyzine HCI Colestipol 50
III
Generalized
None
Cholestyramine Cyproheptadine HCI
PBC, primary
biliary
“See reference
12.
bFrom
time
cirrhosis:
of diagnosis.
IgM. immunoglobulin
M.
1160
546
BERGASA
ET AL.
which the patients while awake.
Assessment Scratching
GASTROENTEROLOGY
were asked to fill out every 4 hours
of Pruritus Activity
Perception
and
Visual analogue scale. Every 4 hours while awake patients were asked to record the severity of their pruritus by making a mark with pen or pencil on a visual analogue scale. The scale consisted of a lo-cm horizontal line; 0 cm (beginning of scale on left side) was designated as representing no itching and 10 cm (end of scale on right side) worst itching ever.17 A visual analogue score (VAS) is the number of centimeters (to the nearest millimeter) between 0 cm and the point on the scale at which the patient made a mark. Scratching activity index. Scratching activity was continuously recorded throughout the infusions of naloxone and placebo solution in the form of a scratching activity index using a scratching activity monitoring system designed specifically for this purpose. This system consists of a vibration (scratch) transducer (Piezo Film Division, Atothem Corp., Philadelphia, PA), an FM transmitter and receiver [Radioshack (32-1221)], a custom-made signal processor, and a personal computer. The vibration transducer was taped to the middle fingernail of the dominant hand, which was not cut during the study. The transducer consists of a square piece of piezoelectric film, 28 pm thick, metallized on both sides with silver ink. It is connected by a wire to the transmitter box (2 X 7 X 6 cm), which is attached to the same arm by a Velcro cuff. The transducer converts the strain produced by vibrations of the fingernail as it traverses the skin in the act of scratching to an electrical voltage. The electrical signal is transmitted by the transmitter across the room where it is received, pro-
T”“~~$~~---+-~1
RE;;vER
ANALOG PERSONAL COMPUTER
SIGNAL PROCESSOR DIGITAL
SIGNAL
I
I
I
I
I
L__________
cessed, and logged by the personal computer as a scratching activity index in units of counts per unit time (Figure 1). Fourier analysis of the demodulated signals had indicated that frequencies associated with vibrations of the fingernail derived from scratching activity were between 50 and 1000 Hz (Figure 2). Two crucial aspects of signal processing by this system are that signals with an amplitude below a preset threshold and low-frequency signals associated with gross body movements are rejected. Consequently, only signals above the threshold and within the frequency band indicated above were used to generate the
scratching activity index (Figure Statistical
1).
Analyses
Data were analyzed by a statistician (D.W.A.) independent of the clinicians involved in the study. The periods of time during which scratching activity was recorded for each patient were divided into a series of intervals, each representing the duration of a naloxone or placebo infusion. These intervals were aligned so that corresponding hours of the day and night coincided. Only data obtained during the same periods of day and night were compared, thus minimizing differences between data during naloxone and placebo infusions attributable to possible effects of diurnal rhythms on scratching activity. The longest period of time common to the set of treatment intervals, in which continuous scratching activity data were available during both naloxone and placebo infusions, was determined by finding the latest initiation time and the earliest termination time in the set. The common period in question was defined as beginning at the latest initiation time and ending at the earliest termination time. Implicit in the design of this study was that each patient served as her own control. Scratching activity obtained for comparable periods during naloxone and placebo infusions was averaged and expressed per SO-second interval. The ratio of these averages (r) was compared to unity. The following one-sample t test was performed:
I
SIGNAL
-
-
Vol. 102, No. 2
____
in which ris the mean ratio for the eight patients and SE its standard error. Means were obtained for the VAS data obtained during each of the treatment intervals in which scratching activity was analyzed.
Results
READ COUNT
Figure 1. Block diagram of signal processor.
of monitoring
system with flow chart
No significant untoward clinical developments occurred during the infusions. In particular, they were not associated with any reduction in functional activity or mental alertness or with a constellation of findings consistent with an opiate withdrawal-like syndrome. Patients 1 and 8 associated naloxone infusions with relief of pruritus, and patient 5 associated the
NALOXONE
February 1992
FOR PRURITLJS OF CHOLESTASIS
547
Scratching
Body Movements 4alr
Figure 2. Results of Fourier analysis of demodulated signals indicating that frequencies generated by gross body movements are ~50 Hz and those generated by the scratching fingernail are between 50 and 1000 Hz.
+/
0 0
200
second placebo infusion with increased perception of pruritus. There was no consistent change between mean values for the VAS during naloxone infusions and corresponding values during placebo infusions (Table 2). Naloxone infusions were consistently associated with a decrease in values for the scratching activity index (Table 2; Figure 3). The decrease in scratching activity ranged from 29% to 96% (mean, 50%; P < 0.001). Of particular interest is the finding that there was no correlation between changes in scratching activity index and the VAS. For example, patient 3 had the largest reduction in scratching activity on naloxone (96%), but her mean VAS increased on naloxone. Furthermore, although patient 1 stated with confidence that infusions containing naloxone, but not placebo, were relieving her pruritus, her mean VAS also increased on naloxone. Discussion Pruritus or itching is a major complication of cholestasis. Itch is defined as the need to scratch and, hence, is intrinsically subjective. The perception of itch cannot be measured directly. Definitive inter-
Table
2. Effects of Naloxone Infusions Activity Index and VAS Change in mean scratching activity index
400
600
800
1(
Frequency(Hz)
on Scratching
Patient no.
(%I
Change in mean VAS (%I
1 2 3 4 5 6 7 8
-76 -44 -96 -32 -54 -36 -32 -29
+75 -30 +14 +150 -50 f50 -17 -37
pretation of studies of the effects of specific agents on the pruritus of cholestasis has been hampered by the subjectivity of this symptom and the difficulty in interpreting the results obtained using the subjective methods of evaluation that have been used to assess pruritus.‘8-21 In contrast to the pruritus of cholestasis, its consequence, increased scratching activity, can be quantitated. Indeed, when many patients perceive itching, they scratch. In 1975, Felix and Schuster reported the application of measurements of limb movements to study patients with pruritus caused by skin disorders22; subsequently, a more sophisticated apparatus was applied to measure limb movements of patients with pruritus caused by cholestatic liver disorders.23 The development of such an apparatus reflected the need to conduct objective quantitative studies in patients with pruritus caused by cholestasis. Unfortunately, measurements of limb movements record activities other than scratching activity. Accordingly, we have developed a device for quantitating scratching activity independent of limb movements. The validity of the device has been verified by demonstrating a close concordance between its output (numerical values for scratching activity index or intensity of an audio signal) and independent direct observations and video tapes of scratching activity. In particular, it was consistently observed that counts were not recorded by the device during gross movements of the hand that were not associated with the interaction between fingernails and the skin and that counts were recorded during the act of scratching by the hand to which the transducer was taped. The device is well tolerated by patients and enables scratching activity to be detected and quantitated. Scratching activity measured in this study varied appreciably within an hour and from hour to hour and tended to be reduced substantially during sleep. Furthermore, there was a striking lack of correlation between scratching activity and assessments of itch-
548
BERGASA
‘““J
ET AL.
GASTROENTEROLOGY
NALOXONE
p
PLACEBO
Vol. 102, No. 2
*
Time (hrs)
Figure 3. Representative data on scratching activity index in patient 5 during- placebo _ and naloxone infusions.
ing using the VASz4 This lack of correlation is not surprising, because a VAS requires the patient not only to integrate the perception of itch over the time interval covered by the VAS but also to translate this perception, which is inherently subjective, into a visuospatial score that is subject to individual differences in its conceptualization. Patients tend not to treat the visual analogue scale as a continuum, with the result that clustering of marks at the extremes or center of the scale may occur.17 As shown in this short-term study, the patient’s perception of itch, as assessed by the VAS, may persist undiminished, although scratching activity has diminished substantially. In particular, suppression of scratching activity by an effective treatment for pruritus may have to be both profound and sustained for a long period for the perception of itch in a patient with chronic pruritus to be appreciably diminished, as assessed by the VAS.25 Thus, a patient’s perception of itch, as assessed by the VAS, appears to be an unreliable indicator of scratching activity in a short-term study. It is proposed that quantitative data on scratching activity is a desirable component of clinical trials of therapies for the pruritus of cholestasis. In the present study we evaluated the role of the opioid system in the pruritus of cholestasis by assessing the effects of naloxone on scratching activity in patients with primary biliary cirrhosis. Naloxone is a well-characterized opioid antagonist. The major limitation of naloxone is that it must be given by frequent injections or continuous infusion.26 This requirement necessitated quantitating its effects on scratching activity over short (i.e., &hour) treatment periods. Initially, the infusion rate of naloxone was 0.026 pg. kg-’ - min-‘, which is approximately half the dose that has been used to reverse morphine anesthesia.z7 Once it was determined that no significant side effects occurred at this initial infusion rate, the infusion rate was increased to 0.052 pg. kg-l - mine1 and subsequently to 0.1, 0.2, and 0.4 p,g *kg-’ - min-' . No deleterious or unpleasant side effects were observed. The infusion rate chosen for the study is equivalent to 16-20 mg/24 hours.
In contrast to a previous study in which the opioid antagonist, nalmefene, was given to patients with chronic liver disease,4 administration of naloxone in this study did not precipitate a clinically overt opioid withdrawal-like syndrome. Possible reasons for this negative finding are that the dose of naloxone was not sufficient to precipitate such a syndrome or that naloxone and nalmefene differ in their affinities for different opiate receptorsz8 The results indicate that, in each of the eight patients studied, the infusion of naloxone was associated with a substantial reduction in scratching activity. We believe that this phenomenon constitutes a beneficial effect of naloxone in these patients. Naloxone would compete with any endogenous opioid agonist ligands for occupancy of opioid receptors in the nervous system and would consequently block the biological effects of endogenous opioid agonists.” Because opioid agonists are known to induce pruritus,’ a naloxone-mediated amelioration of scratching activity in cholestatic patients suggests that the pruritus of cholestasis is mediated, at least in part, by opioid agonist ligands. The mechanism of an opioid agonist-mediated component of the pruritus of cholestasis is currently unknown. Possibilities include increased availability of opioid agonist ligands,4-8 upregulation of opioid receptors, or an increased affinity of opioid ligands for their receptors.” Thus, previous subjective observations, which suggested that opioid antagonists can induce an amelioration of the pruritus of cholestasis,4*‘o’” are extended and made firmer by our results. However, the findings in this study need to be confirmed by conducting a double-blind controlled study. Possible reasons for naloxone not completely abolishing scratching activity in this study are that the dose of naloxone was insufficient, that a carryover of the chronic scratching habit into the treatment period may have occurredz5 and that a component of the syndrome may not be mediated by central opioid receptors. Such a component could still be opioid agonist mediated but by a peripheral mechanism in the skin that is not naloxone reversible.30
February
1992
The results of the present study suggest that naloxone infusions may be beneficial for the emergency treatment of intractable pruritus of cholestasis. However, they are clearly impractical for the long-term management of pruritus. Nevertheless, the beneficial effects of naloxone demonstrated in this study provide a rationale for the long-term treatment of the pruritus of chronic cholestasis with an opioid antagonist, such as nalmefene, which is effective when given orally.
NALOXONE
FOR PRURITUS OF CHOLESTASIS
549
ment of abrupt withdrawal from methadone. Am J Psychiatry 1986;143:831-837. 17. McCormack HM, de L’Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical review. Psycho1 Med 1988;18:1007-1019. effects in cholestatic 18. Bloomer JR, Boyer JL. Phenobarbital liver disease. Ann Intern Med 1975;82:310-317. 19. Ghent CN, Caruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin: results of a double-blind crossover randomized trial. Gastroenterology 1988;94:488-493. 20. Lauterburg BT, Pineda AA, Burgstadler EA, Taswell HF, Dickson ER, Carlson GL. Treatment of pruritus of cholestasis by plasma perfusion through USP-charcoal-coated glass References beads. Lancet 1980;2:53-55. 21. Woolf GM, Reynolds TB. Failure of rifampicin to relieve pruri1. Sherlock S. Cholestasis. In: Sherlock S. Diseases of the liver tus in chronic liver disease. J Clin Gastroenterol1990;12:174and biliary system. 8th ed. Oxford, England: Blackwell Scien177. tific, 1989:248-272. 22. Felix R, Shuster S. A new method for the measurement of itch 2 Jones EA, Bergasa NV. The pruritus of cholestasis. From bile and the response to treatment. Br J Dermatol1975;93:303-312, acids to opiate agonists. Hepatology 1990;11:884-887. 23. Summerfield JA, Welch ME. The measurement of itch with 3 Laidlaw J, Read AE, Sherlock S. Morphine tolerance in hesensitive limb movement meters. Br J Dermatol1980;102:275patic cirrhosis. Gastroenterology 1961;40:389-396. 281. 4 Thornton JR, Losowsky MS. Opioid peptides and primary bili24. Bergasa NV, Alling D, Talbot T, Schmitt J, Jones EA. Assessary cirrhosis. Br Med J 1988;297:1501-1504. ment of the pruritus of cholestasis: an appraisal of the visual 5. Thornton JR, Dean H, Losowsky MS. Is ascites caused by imanalogue scale (abstr). Hepatology 1990;12:887. paired hepatic inactivation of blood borne endogenous opioid 25. Edwards AE, Shellow VR, Wright ET, Dignam TF. Pruritic peptides? Gut 1988;29:1167-1172, skin disease, psychological stress and the itch sensation. Arch 6. Thornton JR, Losowsky MS. Plasma methionine enkephalin Dermatol 1976;112:339-343. concentration and prognosis in primary biliary cirrhosis. Br 26. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: MedJ 1988;297:1241-1242, Gilman AG, Goodman LS, Rall TW, Marad F, eds. The pharma7. Thornton JR, Dean HG, Losowsky MS. Do increased catecholcologic basis of therapeutics. 7th ed. New York: Macmillan, amines and plasma methionine enkephalins in cirrhosis pro1985:491-531. mote bleeding oesophageal varices? Q J Med 1988;68:541-551, 27. Johnstone RE, Jobes DR, Kennel1 EM, Behar MG, Smith TC. 8. Thornton JR, Losowsky MS. Plasma leucine enkephalin is inReversal of morphine anesthesia with naloxone. Anesthesiolcreased in liver disease. Gut 1989;3:1392-1395. ogy 1974;41:361-367. 9. Banks WA, Kastin AJ. Peptide transport across the blood28. Mitchel ME, Bolger G, Weissman BA. Binding of a new opiate brain barrier. Am J Physiol 1990;259:El-ElO. antagonist nalmefene to rat membranes. Methods Find Exp 10. Bernstein JE, Swift R. Relief of intractable pruritus with naloxClin Pharmacol 1985;7:175-177. one. Arch Dermatol 1979;115:1366-1367. 29. Blanchard SG, Chang K-T. Regulation of opioid receptors, In: 11. Summerfield JA. Naloxone modulates the perception of itch Pasternak GW, ed. The opiate receptors. Clifton, NJ: Humana, in man. Br J Clin Pharmacol 1980;10:180-182. 1988:425-439. 12. Scheuer PJ. Biliary disease. In: Scheuer PJ. Liver biopsy inter30. Fjellner B, Hagemark 0. Influence of the opiate antagonist pretation. 4th ed. London: Bailliere Tindall, 1988:40-65. naloxone on experimental pruritus. Acta Derm Venereol 13. Parker F. Skin diseases. In: Wyngaarden JB, Smith LH, eds. 1984;64:73-75. Cecil textbook of medicine. 18th ed. Philadelphia: Saunders, 1988:2300-2353. 14. Gold MS, Redmond DE, Kleber HD. Clonidine blocks acute Received January 10, 1991. Accepted May 21,1991. opiate-withdrawal symptoms. Lancet 1978;2:595-602. Address requests for reprints to: Nora V. Bergasa, M.D., Liver 15. Washton AM, Resnick RB. Clonidine for opiate detoxification: Unit, Building 10, Room 4D52,National Institutes of Health, Beoutpatient clinical trials. Am J Psychiatry 1980;137:1121- thesda, Maryland 20892. 1122. The authors wish to acknowledge the vigilance of Head Nurse 16. Charrey DS, Heninger GR, Kleber HD. The combined use of Joyce Harris and the nursing staff of Nursing Unit 9D, Clinical clonidine and naltrexone as a rapid, safe and effective treatCenter, National Institues of Health.