Clinical research in the pruritus of cholestasis was stimulated by the landmark publication by Thornton and Losowsky [12] in which it was reported that patients with PBC and pruritus experienced an opiate withdrawal-like reaction and a marked decrease in the pruritus after the intake of an opiate antagonist (i.e., nalmefene) [12]. The reaction, which included high blood pressure, insomnia, and abdominal pain, was in sharp contrast to the absence of any reaction in normal volunteers who, in other studies, had taken 60 times the dose of the drug administered to the patients with cholestasis [12]. The relief of the pruritus by nalmefene was proposed to be from the inhibition of release of pruritogens by the opiate antagonist [12]. The results of this study stimulated a reassessment of the mechanism by which nalmefene had relieved pruritus in the patients reported [12]. An alternative interpretation was submitted as a hypothesis: “increased availability of endogenous opiate [opioid] agonist ligands at central opiate [opioid] receptors may contribute to the pruritus of cholestasis” [13]. The basis for this hypothesis was: (i) the opiate withdrawal-like reaction precipitated by the opiate antagonist nalmefene in patients with cholestasis [12], hence suggesting that central opioid neurotransmission was increased, and (ii) the pruritus associated with the pharmacologic increase in opioidergic neurotransmission (tone) by the central administration of drugs (i.e., morphine) with agonist activity at the opioid receptors (i.e., mu opioid receptor according to current knowledge) that can be prevented and ameliorated by opiate antagonists [14].

If cholestasis is associated with increased opioidergic tone [13], and the pruritus of cholestasis is mediated, at least in part, by this type of neurotransmission, opiate antagonists should decrease the sensation and its behavioral manifestation, scratching activity. Indeed, evidence in support of this hypothesis has been provided by controlled clinical trials that have documented a significant relief in the perception of pruritus [15–21] and a significant decrease in hourly scratching activity, measured by a scratching activity monitoring system that records scratching activity independent from gross body movements [15,16,19,20]. The results of a meta-analysis that included five trials of opiate antagonists, three that tested the effect of opiate antagonists administered orally (i.e., naltrexone and nalmefene) and two that tested the effect of intravenous naloxone, with a total of 84 participants, also support an ameliorating effect of this type of drug on the pruritus of cholestasis [22]. Accordingly, the use of opiate antagonists to treat patients with this type of pruritus is specific, and supported by scientific evidence from controlled clinical trials, based on a clear rationale [15–21]. Studies exploring the role of single types of opioid receptors have identified an antiscratching effect of kappa agonists [8]. In this regard, nalfurafine, an agonist at the kappa opioid receptor, has been reported to decrease the sensation of pruritus in patients with uremia in controlled studies [23]. Thus, there is a rationale to study this type of drug in patients with the pruritus of cholestasis.

One question that arises is whether an increase in serum concentration of some endogenous opioids in patients with cholestasis, and the potential liver origin of these peptides, as suggested by the enhanced hepatic expression of Met-enkephalin immunoreactivity in liver disease [24,25], are related to the high central opioidergic tone of cholestasis. In this context, however, some transporters that can transport opiates in vitro are common to the basolateral domain of the hepatocyte, to the choroid plexus, and to the blood–brain barrier [11]. Accordingly, it is plausible that they can also transport periphery-derived opioids into the CNS, which would increase central opioidergic tone. In this regard, the results of brain scans by single photon emission computed tomography and functional magnetic resonance methodology in patients with cholestasis during periods of itch and no itch have suggested that the limbic system is the primary CNS pathway involved in the perception of itch, and that the findings support a central origin for this type of pruritus [26]. In addition, a central component of the pruritus may also arise from central sensitization for itch, which has been suggested to result from the constant stimuli of C-pruriceptors in conditions associated with chronic itch, which allow for nociceptive stimuli to facilitate itch instead of inhibiting it, leading to nonpruritogenic stimuli to be perceived as pruritus.

In regards to opioid receptors, the SNP A118G in the gene that codes for the mu opioid receptor 1 (OPRM1), to which morphine and opiate drugs bind, was found in heterozygosity 1.5 times more frequently in DNA samples from a group of patients from the United States with PBC who had not experienced pruritus than in the rest of the samples, which were from patients from Italy [27]. These results may suggest that patients with the A118G SNP in the OPRM1 may be protected from the itch in cholestasis [27]. Indeed, the presence of the G or A allele in A118G SNP has been associated with a difference in the degree of pruritus secondary to epidural morphine [28]. In addition, ethnicity may inform the experience of side effects, including pruritus, from the administration of intravenous morphine in children [29]. Thus, SNP in the gene that codes OPRM1 may also explain, in part, why not all patients with cholestasis report pruritus (see above) [8,11]. Accordingly, genetic analyses that apply techniques including genome-wide association studies may be useful in identifying specific features in the group of genes that code for transport proteins in the hepatobiliary system, in the CNS, and those involved in the activation of sensory neurons including the phospholipase C B3 pathway [30].

Bile acids accumulate in the tissues of patients with cholestasis [9]. They were reported to trigger local “itch” when injected intracutaneously in normal volunteers [31]; however, this is not a model of the pruritus of cholestasis. Intake of synthetic bile acids, including cholylsarcosine and ursodeoxycholic acid, has been associated with pruritus in patients with liver disease (i.e., PBC). These reports alone cannot be interpreted as evidence to support a role of bile acids as the pruritogens in liver disease, as pruritus is intermittent and triggered by a variety of factors including foodstuffs [32]. Furthermore, (i) in liver failure, when bile acids are maximally elevated, pruritus tends to cease [9], (ii) some patients with cholestasis and marked elevations of serum bile acids do not experience pruritus throughout the course of their disease, and (iii) pruritus can fluctuate and even remit spontaneously without concomitant changes in serum bile acid concentrations. A certain profile of serum bile acids may contribute to the pruritus but, based on current data, a role of bile acids in the mediation of the pruritus of cholestasis has not been demonstrated. In this context, a study published in abstract form revealed that the administration of obeticholic acid to patients with PBC was associated with itch, severe enough to require discontinuation of the drug, in contrast to the placebo intervention [33]. Obeticholic acid is a synthetic derivative of chenodeoxycholic acid, which is an agonist at the farsenoid nuclear receptor (FXR), and which has choleretic properties [33]. FXR is a bile acid sensor associated with a decrease in bile acid production [8]. The relevance of this observation to the pruritus from liver disease is unknown.

Substance P is an excitatory neurotransmitter that acts through the NK-1 receptor synthesized by primary afferent nociceptors and released into the spinal cord after noxious stimuli. In animal studies, increased opioidergic tone activates mechanisms that promote pain (e.g., nociception) in association with stimulation of the NK-1 receptor and substance P expression in the dorsal root ganglia [34]. Increased opioidergic tone in cholestasis may also contribute to a state of enhanced nociception and perceived as pruritus mediated, in part, by substance P. In this regard, the mean serum concentration of substance P in patients with liver disease and pruritus was significantly higher than in patients with liver disease without pruritus, and that of a control group of subjects [34]. These data suggest that substance P may mediate some of the manifestations of liver disease, including pruritus. In this context, the substance P antagonist aprepitant was reported to relieve pruritus in an uncontrolled study that used subjective methodology and that was comprised of a heterogeneous group of patients [35]. These findings seem to support a rationale to study aprepitant to treat pruritus in patients with liver disease in controlled clinical trials.

Serum histamine concentrations were reported to be increased in patients with liver disease and pruritus [36]. However, antihistamines do not ameliorate the pruritus of cholestasis, suggesting that histamine does not have a major role in the pathogenesis of this type of pruritus. However, this type of medication is associated with drowsiness, which may facilitate sleep in some patients, a definite aim in the management of patients with pruritus.

In animal studies, it has been reported that lipophosphatidic acid (LPA) induces nociception through substance P release from peripheral nerve endings [37], and it has been implicated as a mediator in animal and in in vitro