current concepts and management of the pruritus of...
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Current Concepts and Management of the Pruritus of Cholestasis
Nora V. Bergasa, M.D. Chief, Department of Medicine Metropolitan Hospital Center
New York, New York Professor of Medicine
Valhalla, New York
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Cholestasis
• Definition
– Impaired secretion of bile
• Consequence of most liver diseases
• Accumulation in tissues of substances
excreted in bile
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Causes of Cholestasis • Intrahepatic
• Benign recurrent intrahepatic cholestasis (BRIC)
• Alagille’s syndrone • Drug toxicity • Primary biliary cirrhosis • Primary sclerosing
cholangitis • Pregnancy • α−1 antitrypsin deficiency • Granulomatous disease • Lymphoma • Chronic hepatitis C infection
• Extrahepatic – Obstruction
Stones Strictures (e.g. post-
cholescystectomy) Malignancy
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Pruritus in Cholestasis
• Complication of cholestasis • Etiology unknown • Treatments not universally
satisfactory • Indication for liver transplantation
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Pruritus of cholestasis
• May be intermittent
• Generalized or localized
• Worse in the premenstrual
period in 25% of subjects
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Pruritus in PSC • Due to :
– Cholestasis
– Cholangitis
• Infection must be excluded and
treated with antibiotics
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On the Pruritogen(s) of Cholestasis
• Made in the liver
• Excreted in bile
• Accumulate in tissues due to cholestasis
• Direct correlation between serum markers of cholestasis and pruritus not documented
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Substances and Neurotransmission Systems of Interest In Pathogenesis of Pruritus
• Bile Acids • Histamine • Serotonin • Substance P • Autotaxin • Endogenous Opioids
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Bile Acids
• Intradermal injection associated with pruritus – Not a model of pruritus of cholestasis
• Pruritus is intermittent and independent from concentrations of serum bile acids – Specific profile may be relevant
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Bile acids (II) • Study of obeticholic acid for treatment
of primary biliary cirrhosis – Side effect: pruritus
• Recent study in animals revealed that some bile acids can stimulate neurons that can fruther stimulate opioid pathways
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Histamine • Serum histamine concentration increases
in cholestasis and pruritus However, • Skin of patients with cholestasis and
pruritus devoid of histamine-related signs • Antihistamines are associated with
sedation and may result in some relief of pruritus by that mechanism
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Serotonin Neurotransmission
• Involved in mediation of nociception
– Ondansetron, type 3 serotonin receptor antagonist
– Serotonin re uptake inhibitors reported to relief
pruritus
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Substance P Neurotransmission
• Substance P is:
– Excitatory substance that realtes to inflammation, pain, and possibly pruritus
• Substance P concentrations in serum are high in patients with liver disease and pruritus
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CLD w P, N: 13 CLD w/o P, N: 17
Control: N:12 Trivedi and Bergasa J Hepatol 2010
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Autotaxin • Autotaxin is the enzyme that activates
lipophosphatidic acid (LPA)
• It was reported to be high in patients with cholestasis and pruritus and not in patients with pruritus from other conditions
• It decreases in association with pruritus relief by partial diversion of bile, and to increase when pruritus returns
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Increased Opioidergic Tone in Cholestasis: Symptoms And Signs Associated With Nalmefene In Patients With Cholestasis
• abdominal pain • diaphoresis • insomnia • lack of
concentration • palpitations • changes in vital
signs
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Meaning of the opiate withdrawal like reaction
• Withdrawal reaction occurs when brain used to high concentrations of opiate drugs, i.e. heroin, morphine
• In the absence of drugs, a withdrawal like reaction suggests that the subjects have increase in natural opioids in the brain
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Relationship between opioids and pruritus
• Endogenous (natural) opioids exert their
effects by binding to opioid receptors and
stimulating cellular signals: endogenous
analgesia or pain relief
• Opiate drugs and morphine also bind to the
opioid receptors: analgesia
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Relationship between opioids and pruritus
• Opiate drugs and morphine cause pruritus when given intrathecally (i.e. spinal canal such as epidural treatment of pain)
• This type of pruritus can be relieved and prevented by opiate antagonists, which prevent or counteract the effects of the drugs (e.g. naloxone)
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Hypothesis
• Increased central opioidergic tone contributes to the pruritus of cholestasis
» Jones and Bergasa, Hepatology 1990
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• If so, opiate antagonists, which prevent the effect of natural opioids and opiate drugs should relieve this type of pruritus and scratching
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Methods to study pruritus
• Questionnaires and visual analogue scales
• Measures of scratching, the behavior that results from itching
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Effect of Naloxone Infusions on Hourly Scratching Activity
Bergasa et al Ann Int Med 1995
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Opiate Antagonists for Treatment of the Pruritus of Cholestasis
• Documented in controlled, randomized, double blind studies that applied behavioral methodology
• Numerous reports on their effectiveness
• A therapeutic alternative in the guideline of pruritus in cholestasis (i.e. PBC)
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Opiate Antagonists for Pruritus: Safety
• Opioid withdrawal reaction Low doses of opiate antagonists (e.g. IV naloxone (e.g. 0.002 ⇑ microg/kg/min 0.2-0.8 microg/kg/min ⇒ oral naltrexone 12.5- 50 to 100 mg /day (Jones, Neuberger and Bergasa QJM2002)
• Potential hepatotoxicity at high doses
• Altered metabolism in decompensated disease
• Monitoring of liver tests • No hepatotoxicity at short term
(Krystal et al NEJM 2001)
• Decreased conversion to metabolite but safe (Bertolotti et al JHepatol 1997)
• Usually not relevant: pruritus ceases in hepatocellular dysfunction
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Liver Met-enkephalin Immunoreactivity Expression in Primary Biliary Cirrhosis
• Data from scratching behavior in animals
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Management of Pruritus: Removal of Pruritogen(s) from the Circulation
• Nonabsorbable resins (presumed mechanism)
• Extracorporeal albumin dialysis (MARS)
• Plasmapheresis
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Cholestyramine
• Rationale: pruritogens that accumulate in gallbladder during overnight fast pour on small bowel after fast in broker
• 4 g before and after breakfast • 4 g with lunch and breakfast if
needed, not to exceed 16 g per day
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• Metronidazole – 250 mg p.o.BID
• Rifampicin • Agonist at the PXR receptor (e.g.
detoxification) • May have opiate-antagonist activity in
vivo • Doses:
– 10 mg/kg P.O. (Bachs et al 1991) –Hepatotoxicity
Management of Pruritus: Antibiotics
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Management of Pruritus: Neuromodulators
• Serotonin reuptake inhibitor
– Sertraline 75 mg per day, subjective
methodology (Mayo et al Hepatology 2007)
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Management of the Pruritus: Increased Threshold to Nociception
• Pruritus is a nociceptive stimulus; thus, increasing threshold to nociception may decrease pruritus – Cannabinoidergic neurotransmission
• Dronabinol 5- 10 mg p.o. daily
– Gabaergic neurotransmission • Gabapentin in some subjecdts
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Other treatments
• Anesthetics – Lidocaine
– Propofol
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Anticipated therapies
• Specific opioid receptor acting agents
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Challenges With The Use Of Opiate Antagonists
• Some patients do not respond to opiate antagonists
• “Tolerance” • Not desirable to be in an antiopiate
state
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Kappa agonists
• Nalfurafine approved in Japan for pruritus
from kidney disease
• Being studied for pruritus of cholestasis
scratching
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Available drugs with antipruritic effects
• Drugs for neuropathy: Lyrica
• Substance P antagonists: aprepitant
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Scientific interest in pruritus • International Forum for the Study of
Itch • Identification of receptors and
substances that mediate nerve cell signals interpreted as itch
• Use of imaging studies to study the brain in the state of itch and scratching
• Optimism