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Efficacy of lidocaine in the treatment of pruritus in patients with chronic cholestatic liver diseases

      Pruritus is a disturbing clinical problem that often complicates chronic cholestatic liver disease.
      • Sherlock S.
      • Dooley J.
      Primary biliary cirrhosis.
      Pathogenesis remains undefined.
      • Jones E.A.
      • Bergasa N.V.
      Why do cholestatic patients itch?.
      For decades it has been associated with the effect of bile salts or other ill-defined pruritogenic substances over free unmyelinated type C nerve endings of dermic nociceptors. Yet, accumulating evidence supports the theory that different putative mediators involved in neurotransmission and neuromodulation over opioid and serotoninergic receptors (ie, enkephalins) may be potential mediators of cholestasis-induced itching in the central nervous system.
      • Jones E.A.
      • Bergasa N.V.
      The pruritus of cholestasis from bile acids to opiate agonists.
      • Schworer H.
      • Hartmann H.
      • Ramadori G.
      Relief of cholestatic pruritus by a novel class of drugs 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists; effectiveness of ondansetron.
      Thus, it is not surprising that treatment remains empirical and unsatisfactory in a significant proportion of patients. Lidocaine, a sodium channel blocker, may inhibit abnormal activity in peripheral nerve endings
      • Catterall W.
      • Mackie K.
      Local anesthetics.
      and could be useful in patients who are resistant to conventional antipruritic medications.
      The aim of our study was to determine the efficacy of lidocaine over treatment-resistant pruritus in patients with chronic cholestatic liver disease.

      Methods

      Eighteen patients with treatment-resistant pruritus associated with cholestatic liver disease were enrolled in the study between 1999 and 2002 at Hospital Italiano de Buenos Aires. Specific liver diseases were primary biliary cirrhosis (n = 13), primary sclerosing cholangitis (n = 4), and drug-induced chronic cholestasis (n = 1). All patients had persistent generalized pruritus during the preceeding 3 months. In none of the patients was the use of antipruritic medication associated with clinically accepted relief from pruritus. The profile of serum biochemical liver test results was consistent with chronic cholestatic liver disease. The mean serum alkaline phosphatase level was 704 ± 34 U/L (normal range 31-100 U/L). In all patients the following conditions were excluded: renal failure (creatinine >1.4 mg/dL), abnormal ECG, heart failure, presence of another condition known to be complicated by pruritus, changes in antipruritic medication (eg, cholestyramine, rifampicin, hydroxyzine, phenobarbital, naloxone, or ondasetron) within 1 month of entry, evidence of extrahepatic biliary obstruction, or a history of seizures. All patients were receiving ursodeoxycholic acid at entry, which was not discontinued.
      Patients were randomized (2:1) to receive: 100 mg lidocaine (5 cc saline) intravenously over 5 minutes or placebo (5 cc saline). Drug administration was done under strict double-blind conditions and the code was not opened until the final analysis of the results. Electrocardiographic monitoring was done during infusion and vital signs were recorded at baseline and every 15 minutes for the first hour postinfusion. The occurrence of adverse events during this period was carefully assessed.
      Patients were asked to record the severity of their pruritus on a visual analogue scale (VAS) at baseline and every 12 hours (before going to bed and after awakening) for the following 7 days. Scales were designed according to standard principles
      • McCormack H.M.
      • De L’Horne D.J.
      • Sheather S.
      Clinical applications of visual analogue scales a critical review.
      and consisted of 100-mm horizontal lines without intermediate marks. The left side (0 mm) represented the absence of pruritus and the right side (100 mm) represented an unbearable intensity. The mean of the values of the daily visual analogue scale scores for the 7 days of the study were analyzed. Similar visual analogue scales were used to record the severity of fatigue. Routine serum liver tests were done at the beginning of the study and at days 2 and 7 post lidocaine or placebo. Fifteen minutes postadministration of lidocaine or placebo blood samples were collected for determination of monoethylglycinexylidide (MEGX), a metabolite of lidocaine. MEGX concentrations were measured by a fluorescence polarization immunoassay with a TDx analyzer (Abbott Laboratories, Diagnostic Division, North Chicago, Ill).
      • Oellerich M.
      • Raude E.
      • Burdelski M.
      • et al.
      Monoethylglycinexylidide formation kinetics a novel approach to assessment of liver function.
      Sample size and statistics were calculated with the SPSS package of statistical programs (SPSS Inc, Chicago, Ill). Sample size was estimated to include 18 patients (alpha error 5%, beta error 10%, difference of 30%). A 2:1 randomization was used to increase the power of statistical test.
      All values are reported as mean ± 95% confidence interval. Analysis of variance for repeated measurements was used to evaluate the effect of the administration of lidocaine or placebo within the same group. Comparisons between groups were performed by analysis of variance (ANOVA) using the Bonferroni correction for multiple comparisons. Nonparametric test (Mann-Whitney) was used in appropriate cases (non-normal distribution). Statistical significance was established at a P value of <0.05.
      The study protocol was approved by the Institutional Review Board and Ethics Committee of the Hospital Italiano de Buenos Aires. All participating patients signed a written informed consent form.

      Results

      Baseline characteristics of the patients are presented in the Table. Two patients (lidocaine n = 1, placebo n = 1) were excluded from the analysis (liver transplantation n = 1, incomplete records n = 1). No significant changes in the severity of pruritus and fatigue were observed in patients receiving placebo (Figure 1, Figure 2). Lidocaine administration resulted in a significant reduction in pruritus severity when compared with placebo administration (P <0.05). This difference was evident at day 2 (mean VAS 39.1 ± 23.4 vs 70.8 ± 8.1, P <0.05 vs placebo) and day 3 (mean VAS 48.7 ± 23.3 vs 72.0 ± 11.7, P <0.05). Figure 3 shows the individual effect over the severity of pruritus evaluated at day 2 for patients treated with lidocaine or placebo. Significant differences with respect to baseline were found for the treatment group only (P <0.05). In the lidocaine group, 4 patients presented a temporary exacerbation of pruritus at day 1 whereas 3 patients experienced immediate relief (within 1 hour). Nine patients (responders) reported a significant amelioration of pruritus (P <0.05 vs baseline and P <0.05 vs placebo), which returned to baseline values by day 7 (Figure 1, Figure 2). These changes were associated with an improvement in the intensity of fatigue, which was more evident at days 4 and 5 (P <0.05 vs placebo, Figure 2).
      TablePatients characteristics at entry
      Lidocaine n = 12Placebo n = 6
      Age (years)45 ± 3 (33-54)48 ± 2 (31-67)
      Sex (men/women)2/102/4
      PBC/PSC/drug-induced9/2/14/2/0
      Total serum bilirrubin (mg/dL) (N, 0.30-1.0 mg/dL)2.2 ± 1.6 (0.6-4.8)2.9 ± 1.3 (0.8-5.2)
      Alkaline phosphatase (U/L) (N, 31-100 U/L)714 ± 52 (189-1790)702 ± 29 (243-1 498)
      Albumin (g/dL) (N, 3.3-4.5 g/dL)3.6 ± 0.8 (2.9-4.2)3.5 ± 1.0 (3.1-4.0)
      Baseline pruritus (VAS score)79.5 ± 12 (61-92)77.8 ± 10 (66-88)
      Baseline fatigue (VAS score)76.3 ± 21 (47-94)75.1 ± 16 (64-81)
      Previous antipruritic medications
       Cholestyramine104
       Hydroxycine116
       Rifampicin52
       Naloxone32
       Ondasetron61
      Note: Results are expressed in number of patients or mean ± SD (range).
      PBC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis; VAS = visual analogue scale.
      Figure thumbnail gr1
      Figure 1Severity of pruritus during the 7-day study period after placebo (white circles) or lidocaine (black circles) administration. Data are shown as mean values and error bars indicate 95% confidence interval. No significant differences versus baseline were observed in the placebo group. Significant differences with respect to placebo were found after lidocaine administration. *P <0.05 vs placebo. †P <0.05 vs baseline.
      Figure thumbnail gr2
      Figure 2Severity of fatigue during the 7-day study period after placebo (white circles) or lidocaine (black circles) administration. Data are shown as mean values and error bars indicate 95% confidence interval. No significant differences versus baseline were observed in the placebo group. Significant differences with respect to placebo were found after lidocaine administration. *P <0.05 vs placebo. †P <0.05 vs baseline.
      Figure thumbnail gr3
      Figure 3VAS* score of pruritus at baseline and at day 2 for each patient treated with (A) lidocaine or (B) placebo. Data are shown as absolute values. Only one patient in the lidocaine group showed no effect over severity of pruritus at day 2 (P <0.05 vs placebo). *VAS = visual analogue scale.
      No patient presented any severe adverse event related to lidocaine. Five patients in the lidocaine group experienced mild tinnitus associated with lingual paresthesias (2 patients) during infusion. These symptoms subsided 2 to 5 minutes post infusion. Two of these patients experienced no improvement in their pruritus in the following days. No changes were observed in liver function tests during the study period. Data on MEGX levels were obtained in 7 patients in the lidocaine group. No differences were observed in serum concentrations between responders to lidocaine (n = 5) and nonresponders (n = 2) (67 ± 5.1 vs 64 ± 3.0 ng/mL).

      Discussion

      Our study suggests that intravenous lidocaine ameliorates the severity of pruritus in patients with chronic cholestatic liver diseases resistant to conventional antipruritic medications. Reduction of pruritus is associated with an improvement in fatigue, probably related to quality of sleep.
      Although the pathogenesis of pruritus is still not fully understood, growing evidence suggests that the central nervous system takes part in the genesis and maintenance of itching.
      • Jones E.A.
      • Bergasa N.V.
      The pruritus of cholestasis from bile acids to opiate agonists.
      It has been observed that the reduction in the opioidergic tone in patients with cholestasis results in a decrease of scratching activity.
      • Bergasa N.V.
      • Talbot T.L.
      • Alling D.W.
      • Schmitt J.M.
      • et al.
      A controlled trial of naloxone infusions for the pruritus of cholestasis.
      • Bergasa N.V.
      • Schmitt J.M.
      • Talbot T.L.
      • et al.
      Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.
      Altered function of other neurotransmitter central systems (ie, the serotonin system
      • Schworer H.
      • Hartmann H.
      • Ramadori G.
      Relief of cholestatic pruritus by a novel class of drugs 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists; effectiveness of ondansetron.
      ) may also be involved. The beneficial effect of lidocaine observed in our study allows us to speculate that the activation of sodium channels in peripheral unmyelinated C-fiber polymodal afferents within superficial layers of skin and mucous membrane may also take part in the pathogenesis of pruritus induced by cholestasis. Successful treatment of pruritus with intravenous lidocaine has been previously reported by Fishman et al in a 37-year-old man with AIDS and cryptosporidium cholangiopathy.
      • Fishman S.M.
      • Caneris O.A.
      • Stojanovic M.P.
      • Borsook D.
      Intravenous lidocaine for treatment-resistant pruritus.
      It is not clear which mechanisms are involved in the latency observed in the antipruritic effect in the 8 patients that responded to lidocaine, with a maximun effect by day 2 postinfusion. Lidocaine is a short-life compound (half-life: average 100 minutes) that is rapidly dealkylated in the liver by mixed function oxidases to monoethylglycine xylidide (MEGX) and glycine xylidide.
      • Catterall W.
      • Mackie K.
      Local anesthetics.
      Both metabolites retain anesthetic activity, yet we have not observed in our study any difference in serum levels of MEGX between patients that responded or not to lidocaine administration, although the number of patients was scarce. In patients treated with intravenous lidocaine boluses for neuropathic pain, a prolongation of analgesic effect has been reported.
      • Edwars W.T.
      • Habib F.
      • Burney R.G.
      • Begin G.
      Intravenous lidocaine in the management of various chronic pain states a review of 211 cases.
      Whether this retarded effect is mediated by an active metabolite with a longer half-life and more significant antipruritic strength is still to be evaluated. At the same time, we do not have an explanation for the initial exacerbation of pruritus that was experienced by 4 of the patients after lidocaine administration, 3 of which responded during the following days. In none of our patients treated with intravenous lidocaine was pruritus completely abolished.
      Although several authors have suggested that visual analogue scores are subjective and represent an inadequate and unreliable method of assessing pruritus,
      • Jones E.A.
      • Bergasa N.V.
      The pruritus of cholestasis.
      more sophisticated and objective methods pose several practical difficulties. On the other hand, both pruritus and fatigue are subjective perceptions and, in accordance with Wolfhagen et al,
      • Wolfhagen F.H.J.
      • Sternieri E.
      • Hop W.C.J.
      • et al.
      Oral naltrexone treatment for cholestatic pruritus a double-blind, placebo-contolled study.
      we consider that, because the main goal of pruritus treatment is to improve the patients well-being and quality of life, this can only be measured subjectively.
      In conclusion, lidocaine may be a therapeutic alternative in patients with treatment-resistant pruritus related to cholestatic liver disease. The response of pruritus in these patients to repeated intermittent intravenous boluses of lidocaine or eventually to oral sodium channel blocker agents should be further evaluated.

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