CASE REPORT

Juan Pablo Aristizábal Linares*, Lester Andrade Almario**

* Médico anestesiólogo, Clínica Saludcoop Armenia, Colombia. Correspondencia: Carrera 23 norte No.15-21. Armenia, Colombia. Correo electrónico: juanpablo.aristizabal@gmail.com.

** Médico anestesiólogo, Clínica Saludcoop Armenia, Colombia. Correo electrónico: andradelester28@gmail.com.

Recibido: agosto 24 de 2010. Enviado para modificaciones: septiembre 12 de 2010. Aceptado: enero 13 de 2011.

Introduction. Pruritus is a frequent complication in liver disease and may be difficult to manage. Increased cerebral opiod tone has been proposed as the physiological mechanism that causes pruritus. Opiod antagonism, therefore, leads to an improvement and resolution of symptoms in these patients.

Objective. Describe the management of severe pruritus using opiod antagonists in a patient who does not respond to conventional medical management, and conduct a review of the literature.

Methodology and results. This is the case of a 50 year-old female patient with a history of autoimmune hepatitis with a five-year history of severe pruritus secondary to cholestasis which does not improve after management with antihistamines, steroids, ursodeoxycholic acid and cholestyramine. It is decided to initiate management with opiod antagonists, starting with an infusion of naloxone for 24 hours with dose escalation from 0.002 μg/kg/min up to 0.2 μg/kg/min, followed by naltrexone up to a dose of 50 mg/day. The therapeutic response was assessed using the visual analog scale (VAS). Within 24 hours of initiating the infusion, there is a reduction in the VAS score down to 0/10, with clinical and symptomatic improvement.

Conclusions. The approach to patients with refractory pruritus should include the use of opioid antagonists as a therapeutic option

Fifty year-old female patient with a five-year history of autoimmune hepatitis and secondary cholestasis managed by gastroenterology and dermatology. Associated with the existing disease, the patient has presented severe pruritus managed with antihistamines, steroids, cholestyramine and ursdeoxycholic acid during that time, with no improvement. It is decided to use opioid antagonists as rescue therapy for the management of the pruritus, and the patient is admitted in order to start treatment with naloxone, followed later on by naltrexone.

There are no other significant findings.

Laboratory test results before the start of treatment were as follows: hemoglobin 10.5 gr/dl, hematocrit 33 %, leukocytes 6,300/mm³, platelets 340.000/mm³. Total bilirubin 1.33 mg/dl, indirect bilirubin 0.44 mg/dl, direct bilirubin 0.89 mg/dl, TGO 106 u/lt (5-34 u/lt), TGP 149u/ lt (0-55 u/lt). Serum creatinine 0.73 mg/dl.

The patient is hospitalized and a naloxone infusion was started on the first day, at a dose of 0.002 μg/kg/min gradually increased every hour over a 24-hour period up to 0.2 μg/kg/min, at which point the infusion is interrupted and the oral treatment is started. Naltrexone is started on the second day at 25 mg every 12 hours, with dose escalation to 50 mg/day in order to continue with four weeks of outpatient management thereafter. Non-invasive arterial pressure monitoring, visoscopy and pulse oxymetry were used for monitoring throughout treatment, with no significant changes in vital signs during that period. Pruritus was assessed every six hours using the visual analog scale for the first 24 hours after initiating the intravenous management, where 0 = no pruritus and 10 = severe pruritus. The first VAS score was 10/10; at 6 hours, 5/10; at 12 hours, 4/10; at 18 hours, 0/10, and at 24 hours, 0/10. After that, the patient scored 0/10 on the VAS every day until discharge. Adverse effects were documented on the second day, including abdominal pain and general discomfort, but they were transient and resolved without the need to modify the treatment.

During follow-up, the patient again presented symtoms of nausea, general discomfort and anxiety, and on day seven she decided to reduce, of her own accord, the dose of naltrexone to 25 mg/day. In view of the persistence of symptoms, the patient abandoned the treatment definitively on day nine. The symptoms of pruritus reappeared and the VAS score rose steadily to 10/10.

We present the case of a female patient with severe pruritus managed over a five-year period with multiple pharmacological options, and no improvement. Management with opioid antagonists with dose escalation, followed by four weeks of therapy, is proposed. During this treatment, the patient showed complete clinical improvement, with VAS scores of 0/10. After the first week of treatment, the patient decided to interrupt treatment voluntarily of her own accord, because of adverse side effects. Symptoms reappeared and the VAS score for pruritus rose again to 10/10.

Pruritus is a frequent complication of liver disorders that may or may not be associated with cholestasis. It usually affects the palms of the hands and the soles of the feet. It may even limit normal daily activities and cause sleep deprivation, to the point of suicidal ideation (1). On microscopic examination, the skin is usually normal or, in some cases, may reveal chronic changes secondary to intense itching such as nodular excoriations or prurigo. Usually, traditional therapies for pruritus are empirical, based mainly on symptomatic management, with no clear understanding of the pathophysiological mechanisms, leading to partially effective results (2).

During the past decade, increased cerebral opioid tone has been proposed as part of the pathophysiology of pruritus secondary to liver disorders, associated or not with cholestasis. This hypothesis has been demonstrated on the grounds of three fundamental reasons: 1) pruritogenic effect secondary to increased opioid tone; 2) increased cerebral opioid agonism as a cause of pruritus in patients with liver disorders; and 3) reduced pruritus as a result of opioid antagonism (2,3).

Due to increased cerebral opioid tone as the underlying mechanism for pruritus, opioid antagonism should reduce secondary symptoms. The first report on opioid antagonism for the management of the pruritus of cholestasis was published in 1979. Severe pruritus diminished following subcutaneous injections of naloxone in patients with primary biliary cirrhosis (4). Subsequent double-blind randomized trials with intravenous naloxone showed modulation of secondary symptoms of pruritus in patients with liver cirrhosis.

Later, in 1988, Thornton and Losowsky introduced the use of oral opioid antagonists with nalmefene for treatments lasting up to six months, showing symptomatic remission of pruritus in eight out of nine patients treated. In their study, they reported the presence of adverse reactions following the administration of nalmefene 5 mg, including anorexia, nausea, abdominal pain, insomnia, blood hypertension and hallucinations. These reactions were transient and usually disappeared after 24-48 hours, despite continuation of the medication. The characteristics of these side effects mimic the presence of a “withdrawal syndrome” following opioid supression, strongly suggesting an associated increase in cerebral endogenous opioid tone in patients with liver disorders and associated cholestasis (5).

It was Thornton himself who described three approaches to reduce the occurrence of these “withdrawal-type” reactions upon starting opioid antagonism. The first is the concomitant administration of clonidine with nalmefene. Clonidine reduces the presence of these symptoms in patients who are addicted to medications. The initial dose of clonidine was 100 μg three times a day, for three consecutive days, followed by tapering over a seven-day period. Co-administration of clonidine apparently reduces the severity of these reactions, but does not prevent their onset (5).

The second approach is to start a low-dose oral opioid antagonist and increase the dose slowly until the desired therapeutic dose is reached. When the treatment is initiated in this way, the intensity and incidence of the “withdrawal syndrome” diminish. It is recommended to administer increasing doses of naltrexone, starting at 12.5 mg until a dose of 50 mg/day is reached. There are reports in the literature of adverse effects in up to 46 % of cases when naltrexone is started at a high dose of 50 mg/ day. These adverse effects may be mild-tomoderate and resolve spontaneously within 24-48 hours after the initiation of oral therapy (6,7).

The third strategy is to initiate treatment in combination with low-dose intravenous naloxone, starting at 0.002 μg/kg/min, followed by an increase to 0.2 μg/kg/min over 24 hours before starting naltrexone at a dose of 12.5 mg twice a day, with escalation up to 50 mg/day. When this approach is utilized, the naloxone infusion may be doubled if there are no symptoms; otherwise, the infusion is stopped until symptoms subside. This strategy may help reduce hospital stay and initiate naltrexone as early as possible.

In a double-blind randomized trial in 1995, Bergasa et al. compared two groups, the first receiveing naloxone at a dose of 0.2 μg/kg/minfor 24 hours, and the second receiving placebo. They assessed the pruritus response every four hours using the visual analog scale, and the “itching” activity using a vibration-sensitive transducer connected to the fingers. The results showed a significant reduction in pruritus and “itching” during the infusion, supporting the hypothesis of an increased cerebral opioid tone in patients with liver disorders, and supporting the use of an opioid antagonist (naloxone) in infusion as a therapeutic option (2,8).

Opioid antagonists have also been used in burned patients with chronic pruritus that does not respond to antihistamines and anticonvulsants such as gabapentin. The use of naltrexone starting at a dose of 25 mg/day, increased to 50 mg, led to a reduction in pruritus in 44 % of patients with burns covering 40 % of their total body surface. This antagonism was considered a useful therapeutic option following conventional treatment (9).

In conclusion, the literature supports the hypothesis that increased cerebral opioid tone is one of the pathophysiological mechanisms of pruritus associated with liver disorders and cholestasis and, therefore, the use of opioid antagonists as a form of optimal treatment. In controlled studies, opioid antagonism, either with intravenous naloxone or oral naltrexone o nalmefene, has shown a reduction in the symptoms of “itching” secondary to pruritus.

This treatment has gained importance because liver transplant -a new option for patients with intractable pruritus that does not respond to conventional treatment- is contraindicated until a test treatment with opioid antagonists is performed (10). However, this treatment may trigger responses that mimic a “withdrawal syndrome”, but these may be avoided by starting at low doses with slow escalation, or with intravenous naloxone. This infusion must be increased gradually until opioid antagonism is achieved before starting oral treatment with the goal of obtaining therapeutic effects (2).

We present the case of a patient with a five-year history of intractable pruritus, in whom we decided to use the third approach proposed by Thornton, consisting of a combination of naloxone and naltrexone. We were able to demonstrate an absolute reduction in the symptoms of pruritus within the first 24 hours, and support the hypothesis of increased cerebral opioid tone in patients with liver disorders.

1. Jones EA, Bergasa NV. The pruritus of cholestasis. J. Hepatol. 1999;29:1003-6.

2. Jones EA, Neuberger J. Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis: The Avoidance of opioide withdrawal-like reactions. Q J Med. 2002;95:547-52.

3. Jones EA, Bergasa NV. The pruritus of cholestasis: potencial pathogenic and therapeutic implications of opioids. Gastroenterol. 1995;108:1582-8.

4. Bernstein JE, Swift R. Relief of intractable pruritus with naloxone. Arch Dermatol. 1979;115:1366-7.

5. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrosis. Br Med J. 1988;297:1501-4.

6. Terg R, Coronel E, Sorda J. Oral naltrexone treatment for cholestatic pruritus: A randomized, double blind, crossover study. Hepatology. 2000;32:167.

7. Fariborz MG, Amir T, Hossein F et al. Effect of oral naltrexone on pruritus in cholestatic patients. World J Gastroenterol. 2006;12:1125-8.

8. Bergasa NV, Alling DW, Talbot TL et al. Effects of naloxone infusions in patients with the pruritus of cholestasis: A double-blind, randomized, controlled trial. Ann Intern Med. 1995;123:161-7.

9. Jung SI, Cheong HS, Kiun J, et al. Efficacy of naltrexone in the treatment of chronic refractory itching in burn patients: preliminary report of an open trial. J Burn Care Resp. 2009;30:257-60.

10. Neuberger J, Jones EA. Liver transplantation for intractable pruritus is contraindicated before an adecuate trial of opiate antagonist therapy. Eur J Gastroenterol Hepatol. 2001;13:1393-94.