The pruritus of cholestasis: From bile acids to opiate agonists: Relevant after all these years
Introduction
In 1990, we postulated that “a major factor contributing to the pruritus of cholestasis is increased availability of opiate agonist ligands at opioid receptors in the brain” [1] i.e. increased opioidergic neurotransmission or tone. A series of clinical and basic studies have provided evidence in support of this hypothesis, and in support of the use of opiate antagonists for the treatment of the pruritus of cholestasis [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The basis for this hypothesis was the reported opiate withdrawal-like syndrome precipitated by an opiate antagonist in association with the amelioration of the pruritus in patients with cholestasis secondary to primary biliary cirrhosis [2], a name that has been recently changed to primary biliary cholangitis (PBC) [12].
In this manuscript, the author provides an interpretation of data that have evolved over the past few years, and expands the hypothesis stating that the endogenous opioid system contributes to the pruritus of cholestasis.
Section snippets
Pruritus and the endogenous opioid system
There is strong evidence to support a role of the endogenous opioid system in the mediation of pruritus of central origin: (i) the administration of morphine intrathecally to human beings is associated with pruritus, which is ameliorated and which can be prevented by opiate antagonists [13], [14], (ii) in laboratory animals, the central administration of morphine and other agonists at the mu opioid receptor is associated with scratching behavior, which is decreased and also prevented by opiate
Lisophosphatidic acid and scratching behavior
Lisophosphatidic acid (LPA), and autotaxin, the enzyme that generates its production have received some attention in the past few years as potential mediators of the pruritus of cholestasis [30], [31]. Injections of LPA in the skin of C57BL/6J female mice were reported to cause scratching behavior, which was interpreted as evidence for a pruritogenic role of LPA in cholestasis [30]. It was also reported that skin injections of LPA and that of LPM, a pan-LPA receptor agonist, were associated
Hypothesis: the pruritus associated with the administration of obeticholic acid is mediated by the endogenous opioid system
Obeticholic acid is a synthetic derivative of chenodeoxycholic acid that is an agonist at the farnesoid nuclear receptor (FXR), a bile acid sensor associated with a decrease in bile acid production [40], and which has choleretic properties [41]. Obeticholic acid, in addition to FXR, activates TGR5 (also known as GPBAR1) [42] (see above). The administration of obeticholic acid to patients with PBC [43] and to patients with nonalcoholic steatohepatitis [44] was associated with pruritus in a
Studies to test the hypothesis that the pruritus associated with obeticholic acid is mediated by the endogenous opioid system
The hypothesis that obeticholic acid triggers pruritus via the endogenous opioid system can be tested in a clinical study of continuous naloxone infusions in patients on obeticholic acid who experience pruritus. The intravenous use of the opiate antagonist would be preferable to the oral route (e.g. naltrexone) as intravenous infusions can be controlled, as needed.
Opioid receptor specificity in the mediation of scratching behavior
Animal models on scratching behavior have revealed that stimulation of the mu opioid receptor by agonist ligands is associated with scratching and the stimulation of the kappa opioid receptor, with the prevention of opiate-induced scratching, i.e. anti-scratching [16], [17], [46], [47]. In this context, nalfurafine, an agonist at the kappa opioid receptor, was reported to decrease the sensation of pruritus, as measured subjectively, in patients with PBC, in controlled studies [48], [49]. These
Conflict of interest
None.
References (50)
- et al.
A controlled trial of naloxone infusions for the pruritus of chronic cholestasis
Gastroenterology
(1992) - et al.
Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study
Gastroenterology
(1997) - et al.
Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study
J Am Acad Dermatol
(1999) - et al.
Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study
J Hepatol
(2002) - et al.
Changing nomenclature for PBC: From 'cirrhosis' to 'cholangitis'
Clin Res Hepatol Gastroenterol
(2015) - et al.
Itching after epidural and spinal opiates
Pain
(1988) - et al.
Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial scratching
Brain Res
(1995) - et al.
Central mu-opioid receptors are down-regulated in a rat model of cholestasis
J Hepatol
(1992) - et al.
Endogenous opioids accumulate in plasma in a rat model of acute cholestasis
Gastroenterology
(1992) - et al.
Uptake and efflux of the peptidic delta-opioid receptor agonist
Neurosci Lett
(2001)
Potentials of the circulating pruritogenic mediator lysophosphatidic acid in development of allergic skin inflammation in mice: role of blood cell-associated lysophospholipase D activity of autotaxin
Am J Pathol
The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice
Gastroenterology
Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial
Lancet
Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats
Pharmacol Biochem Behav
The pruritus of cholestasis: from bile acids to opiate agonists
Hepatology
Opioid peptides and primary biliary cirrhosis
Br Med J
The pruritus of cholestasis
Semin Dermatol
Pilot study of the use of naltrexone to treat the severe pruritus of cholestatic liver disease
Am J Gastroenterol
Open-label trial of oral nalmefene therapy for the pruritus of cholestasis
Hepatology
Effect of oral naltrexone on pruritus in cholestatic patients
World J Gastroenterol
Use of oral naltrexone for severe pruritus due to cholestatic liver disease in children
J Pediatr Gastroenterol Nutr
The incidence of pruritus after epidural morphine
Anaesthesia
Activation of kappa-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys
J Pharmacol Exp Ther
The role of central mu opioid receptors in opioid-induced itch in primates
J Pharmacol Exp Ther
Cholestasis in the male rat is associated with naloxone-reversible antinociception
J Hepatol
Cited by (35)
Overview of Progressive Familial Intrahepatic Cholestasis
2022, Clinics in Liver DiseaseCitation Excerpt :Cholangiocarcinoma and pancreatic adenocarcinoma have also been reported.51,52 Supportive care for BSEP disease is similar to what is recommended for other PFIC disorders, with emphasis on pruritus management, nutrition optimization, fat-soluble vitamin supplementation, and expectant management of complications associated with cirrhosis and portal hypertension.5,53 Ursodiol is a mainstay of therapy and may have a particularly significant beneficial effect in those with less severe mutations.
Cholestatic pruritus: a knowledge update
2022, Anais Brasileiros de DermatologiaCitation Excerpt :Second, despite showing marked elevations in serum bile acid levels, not all patients with cholestasis report pruritus. Third, this symptom fluctuates regardless of serum bile acid levels.10 The pruritic effects of opioids, on the other hand, vary depending on the activity of their receptor subtypes.
Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis
2022, European Journal of Medicinal ChemistryThe effects of alcohol and illicit drug use on the skin
2021, Clinics in DermatologyDiscovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio
2021, Bioorganic and Medicinal ChemistryCitation Excerpt :Because the predicted benefits of OCA remained uncertain and they did not outweigh the potential risks sufficiently in the previous clinical trials, Intercept company needs to submit more additional evidence to prove the effectiveness and safety of OCA and the long-term clinical study of OCA is still needed. In the previous studies, it was reported that the activation of TGR5 by OCA may be responsible for the pruritus which was observed in clinical trials of OCA.9–12 Therefore, many researchers paid more attention to the discovery of novel selective non-steroidal FXR agonists (Fig. 1) which would not activate TGR5.