1 Pharmacy Department Dunkerque Hospital 2 Biopharmacy and Clinical Pharmacy Department Faculty of Pharmaceutical and Biological Sciences Lille 3 Nephrology and Dialysis Department, Dunkerque Hospital, 4 Pharmacology, Pharmacokinetic and Clinical Pharmacy Department Faculty of Pharmaceutical and Biological Sciences Lille, France.
Sir,
Pruritus is a frequent feature found in uraemic patients, and several causes have been implicated in its pathogenis. In addition, endogenous opioids have been implicated in cholestatic pruritus. This condition is associated with increased blood levels of these substances in humans [1], and treatment with opioid antagonists has been shown to improve pruritus [2]. Thus, the same mechanism may be at the origin of uraemic pruritus. Peer et al. [3] showed that naltrexone, an opioid antagonist, reduced pruritus. However, the plasma levels of ß-endorphin were not correlated with the pruritus intensity. Three different precursor proteins give rise to endogenous opioid peptides: pre-pro-opiomelanocortin, pre-enkephalin, and pre-dynorphin. The expression of each precursor is controlled separately. Given the findings of Peer et al. [3], we speculate that intractable dialysis itches result from increases in dynorphin and/or enkephalin plasma levels.
We conducted a preliminary study to measure plasma levels of all opioid peptides by radio receptor assay (RRA), and compared plasma levels in haemodialysis (HD) patients with pruritus, HD patients without pruritus, and in control patients not on HD. We further evaluated the effect of naltrexone on pruritus while comparing plasma endogenous opioid levels before naltrexone administration.
Eight chronic HD patients (four with severe pruritus and four without pruritus), aged 63±18 years, with a mean duration of HD of 45±7 months and a kt/V=1.47±0.12, were compared with four control patients (not haemodialysed). None of the patients was taking medications that could interfere with the assay of endogenous opioid peptides. All major causes of dialysis-related pruritus were ruled out, and all antipruritic treatment was stopped a week before the study. During the first 2 weeks of the study, plasma endogenous opioid levels were measured by RRA. Thereafter, patients with intractable pruritus received a daily tablet of 50 mg naltrexone hydrochloride (Nalorex®, Du Pont Pharmaceutical). Patients were asked to record the severity of their pruritus on a visual analogue 10 cm scale, before and 7 days after the first naltrexone administration. Blood samples were collected before each 5-h HD session. Results presented are the mean of two measures that were taken in triplicate. The assay was completed using the RRA method. This assay is based on the principle that opioid peptides in the serum compete for the binding of [D-Ala2, N-methyl-phe4,-glycol5][tyrosyl-3-5-3H] ([3H]DAMGO) to the µ opiate receptor. The assays were carried out according to the protocol by Swain et al. [1] with minor modifications. A methionineenkephalin standard curve was plotted logarithmically against the percentage inhibition of DAMGO binding. Serum opioid activity, expressed in nanograms of methionineenkephalin equivalents per millilitre of serum, was obtained by linear regression from the percentage inhibition of DAMGO binding.
Before naltrexone administration, four of the patients presented HD intractable itch scores of 10 out of 10. After treatment, pruritus decreased significantly (mean score=1.25±1.5, P=0.013). In fact, pruritus disappeared completely in two patients (responders) and was present, but weaker, in the other two (30% of initial pruritus, partial responders). This result appears to confirm the effect of this opioid antagonist in the treatment of intractable pruritus. At 50 mg/day naltrexone, there were no side-effects in the four patients treated. Plasma endogenous opioid levels in HD patients without pruritus and in control subjects were not significantly different (0.51±0.10 vs 0.63±0.29 ng met-enkephalin equivalents/ml serum; P=0.61); however, the difference was significant between HD patients without and with pruritus (0.63±0.29 vs 6.57±5.70 met-enkephalin equivalents/ml serum; P=0.016). In the pruritus group, great inter patient variation was observed: plasma levels varied between 0.57 and 13.43 ng met-enkephalin equivalents/ml serum. This variation disappeared when HD patients with pruritus were subdivided according to naltrexone response: partial responders had higher opioid plasma levels than total responders (12.27±1.17 vs 1.21±0.74 ng met-enkephalin equivalents/ml serum). Moreover, there was a strong correlation between pruritus intensity scores obtained 2 weeks after naltrexone administration and pre-therapeutic plasma endogenous opioid levels (r=0.957, P=0.043, Figure 1).
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Conflicting results concerning ß-endorphin plasma concentrations in HD patients have been reported [5] and our findings may provide the first explanation for these discrepancies. One explanation may involve the sensitivity of the laboratory assay. All previous published studies used a radioimmunoassay (RIA) with an extraction technique. Differences in the specificity of antibodies used for these assays may also explain the differences between studies. Selective antibodies for ß-endorphin measure parts of other endogenous opioid peptides including enkephalin and dynorphins. Moreover, the extraction step may be responsible for the variation in results. In our study, these problems were resolved because RRA produced a measure of all active opioids present in plasma, and sensitivity without extraction was achieved. The second advantage of the RRA method was the measurement of global plasma opioid activity on the µ opioid receptor. As reported by Mansour et al. [4], most opioid peptides bind to the µ opiate receptor with a high affinity. Naltrexone is a selective antagonist of the µ opioid receptor and its effect on pruritus may be related to blockade of the µ opioid receptor.
Recently, Mamianetti et al. [6] showed that HD patients have increases in the plasma total concentration of bile acid. By analogy with cholestatic pruritus [1,2], and in the context of our study, we speculate that increases in serum bile acid lead to an increase in enkephalins by the down-regulation of opiate brain receptors [6]. Enkephalins, like any other opioid agonist, induce basophile histamine release that produces pruritus. Naltrexone, acting as an opioid antagonist, blocks basophile histamine release and thus decreases pruritus.
We also demonstrated that the intensity of intractable pruritus is correlated with total opioid serum levels, and probably with enkephalin plasma levels. From other apparently contradictory results [7,8], it is possible but unlikely that intractable pruritus is provoked by increases in plasma enkephalin levels rather than ß-endorphin levels. In weak and/or moderate pruritus, other pathological mechanisms may be involved. Our study apparently confirmed a favourable effect of naltrexone on haemodialysed patients with severe pruritus, and indicates that it should be used for patients with severe and persistent pruritus, notably after failure of other therapies. However, additional studies in larger populations are needed to confirm the role of opioid antagonists in the treatment of uraemic pruritus.
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