Effect of oral naltrexone on pruritus in cholestatic patients

Mansour-Ghanaei, Fariborz; Taheri, Amir; Froutan, Hossein; Ghofrani, H; Nasiri-Toosi, Mohsen; Bagherzadeh, Amir-Hossein; Farahvash, M J; Mirmomen, Shahram; Ebrahimi-Dariani, Naser; Farhangi, Elham; Pourrasouli, Z

doi:10.3748/wjg.v12.i7.1125

Cited by 85 publications

(48 citation statements)

References 46 publications

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“…Considering that opioid (Rosenfeld, 1994) and cannabinoid (Lichtman et al, 1996) receptor activation in the PAG plays a prominent role in antinociception, their respective roles in modulation of pruritus are similarly anticipated. Opioid drugs such as the -receptor antagonist naltrexone and the -receptor agonist nalfurafine are being tested clinically as modulators of pruritus (Wikström et al, 2005;Mansour-Ghanaei et al, 2006;Bigliardi et al, 2007). Unlike the -opioid receptor, CB 1 receptor activation seems to have the benefit of inhibiting both nociceptive and pruriceptive signals.…”

Section: Discussionmentioning

confidence: 99%

Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: A New Prospective Neural Therapeutic Target for Pruritus

Schlosburg

Boger²,

Cravatt³

et al. 2009

J Pharmacol Exp Ther

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Pruritus (itch) is a common cause of discomfort by dermatological disorders. Several peripherally and centrally mediated pathologies that induce pruritus do not generally respond to typical allergenic and anti-inflammatory treatments. In accordance, we employed an acute allergenic murine model to determine whether the endogenous cannabinoid system could be targeted to treat pruritus. Subcutaneous administration of the mast cell degranulator compound 48/80 evoked an intense, concentration-dependent scratching response. Systemic ⌬ 9 -tetrahydrocannabinol reduced the scratching response, although this effect was accompanied with hypomotility. Complementary genetic and pharmacological approaches to target fatty acid amide hydrolase (FAAH), the primary enzyme responsible for the degradation of the endocannabinoid anandamide, were evaluated in the compound 48/80 model. FAAH(Ϫ/Ϫ) mice and mice treated with the respective irreversible and reversible FAAH inhibitors, URB597 (cyclohexylcarbamic acid 3Ј-carbamoylbiphenyl-3-yl ester) and OL-135 [1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane], displayed comparable reductions in scratching to mice treated with common nonsedative allergenic treatments (loratadine and dexamethasone) but without affecting locomotor behavior. The antiscratching phenotype of FAAH-compromised mice was completely blocked by either genetic deletion or pharmacological antagonism of the CB 1 receptor. Neural-specific conditional FAAH knockout (FAAH-NS) mice, which have FAAH exclusively restricted to neural tissues, showed a similar magnitude of scratching as wild-type mice. It is important that URB597 reduced compound 48/80-induced scratching in FAAH-NS mice, but it did not produce any further reduction in FAAH(Ϫ/Ϫ) mice. These findings indicate that neuronal FAAH suppression reduces the scratching response through activation of CB 1 receptors. More generally, these are the first preclinical data suggesting that FAAH represents a novel target to treat pruritus without eliciting overt side effects.Pruritus is the general clinical term for itch, characterized by a generally unpleasant sensation attributed to an area at or just below the skin. The sensation is closely related to the reflex desire and action to scratch the afflicted area. Pruritus can greatly reduce the quality of life of those inflicted and is a common symptom attributed to discomfort from dermatological conditions (Stante et al., 2005). Although there are no collective data on the prevalence of patients seeking treatment for pruritus, the numbers on skin diseases alone estimates an incidence of one in three Americans afflicted at any given moment, costing a yearly $28.3 billion in medical treatment (Bickers et al., 2006). Because of the great variety of pathophysiological conditions (e.g., anemia, parasites, liver/ kidney disease, thyroid disorders, HIV) underlying pruritus symptomology, common treatments are not always effective. Recent studies show that pruritus shares much of its neural substrates and signaling characteristics ...

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Section: Discussionmentioning

confidence: 99%

Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: A New Prospective Neural Therapeutic Target for Pruritus

Schlosburg

Boger²,

Cravatt³

et al. 2009

J Pharmacol Exp Ther

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“…If rifampicin is ineffective within 2 weeks, the μ-opioid antagonist naltrexone is recommended as third-line treatment. Naltrexone moderately improved pruritus at doses of 25-50 mg/day in four small placebo-controlled trials [90,91,92,93]. Adverse effects may include withdrawal-like reactions, particularly during the first days of therapy.…”

Section: Managementmentioning

confidence: 99%

Advances in Pathogenesis and Management of Pruritus in Cholestasis

Kremer

Bolier

Dijk

et al. 2014

Dig Dis

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Chronic pruritus is a burdensome feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy. Bile salts, μ-opioids, serotonin, histamine and steroids have been controversially discussed in the pathogenesis of cholestatic pruritus. However, for these substances neither a correlation with itch severity nor a causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may play a key element in the pathogenesis of cholestatic pruritus. Serum activity of autotaxin correlated with itch intensity and response to antipruritic treatment in patients with cholestatic pruritus, but not other forms of pruritus. Autotaxin activity thereby represents the first biomarker for pruritus and had a positive predictive value of 70% in differentiating cholestatic pruritus from other forms of pruritus. Treatment options for patients with cholestatic pruritus include the anion exchange resin colestyramine, the PXR agonist rifampicin, the μ-opioid antagonist naltrexone, and the serotonin reuptake inhibitor sertraline. These drugs are recommended by evidence-based guidelines as a stepwise therapeutic approach. Patients unresponsive to these drugs should be referred to specialized centers to receive experimental approaches such as UVB phototherapy, albumin dialysis, plasmapheresis or nasobiliary drainage. This review discusses pruritogen candidates in cholestasis, gives novel insights into the neuronal signaling pathway of pruritus and summarizes evidence-based treatment options for patients suffering from pruritus in cholestasis.

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“…Naltrexone moderately alleviated pruritus at doses of 25-50 mg/day in 4 small placebo-controlled trials [121][122][123][124] . Adverse effects may include withdrawallike reactions, particularly during the first days of therapy.…”

Section: Management Of Cholestatic Pruritusmentioning

confidence: 99%

Pathogenesis and Management of Pruritus in PBC and PSC

Kremer¹,

Namer

Bolier

et al. 2015

Dig Dis

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Pruritus is a preeminent symptom in patients with chronic cholestatic liver disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. More than two-thirds of these patients experience itching during the course of their disease. This symptom is also frequently observed in patients with other causes of cholestasis such as cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy, but may accompany almost any other liver disease. The pathogenesis of pruritus of cholestasis remains largely elusive. Increased concentrations of bile salts, histamine, serotonin, progesterone metabolites and endogenous opioids have been controversially discussed as potential pruritogens. However, for these molecules, neither a correlation with itch intensity nor a causative link could be established. The G protein-coupled receptor for bile salts, TGR5, has been shown to be expressed in dorsal root ganglia and give rise to itch in rodents, albeit upon stimuli with suprapathological concentrations of bile salts. The potent neuronal activator lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX), could be identified in the serum of patients with cholestatic pruritus. ATX activity correlated with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients. Thus, the ATX-LPA-axis may represent a key element in the pathogenesis of this agonizing symptom. Treatment options for pruritus of cholestasis remain limited to a few evidence-based and several experimental medical and interventional therapies. The current guideline-based recommendations include the anion exchange resins colestyramine, the pregnane X receptor-agonist and enzyme inducer rifampicin, the μ-opioid antagonist naltrexone, and the selective serotonin reuptake inhibitors sertraline. Still, a considerable part of patients is unresponsive to these drugs and requires experimental approaches including phototherapy, plasmapheresis, albumin dialysis or nasobiliary drainage. This review outlines the current knowledge on pathogenesis of cholestatic pruritus and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients with itch.

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Effect of oral naltrexone on pruritus in cholestatic patients

Abstract: Naltrexone can be used in the treatment of pruritus in cholestatic patients and is a safe drug showing few, mild and self-limited complications.

Cited by 85 publications

References 46 publications

Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: A New Prospective Neural Therapeutic Target for Pruritus

Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: A New Prospective Neural Therapeutic Target for Pruritus

Advances in Pathogenesis and Management of Pruritus in Cholestasis

Pathogenesis and Management of Pruritus in PBC and PSC

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