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Current dosing recommendations for naloxone in treating pruritus associated with cholestasis
David F. McAuley, Pharm.D.
GlobalRPh Inc.

Introduction:
     Generalized pruritus is a common, and often distressing, complication of cholestasis and certain non-cholestatic chronic liver diseases.1,2,3  The pruritus associated with cholestasis varies from mild to severe and may limit normal activities, cause sleep deprivation and when unmanageable may lead to suicidal ideation.1,4  The pathogenesis of the pruritus is unknown, but several hypotheses have been proposed including bile acid accumulation, and an increase in the concentration or activity of endogenous opioids.4  Evidence continues to build regarding the important role endogenous opioids seem to play in the pathogenesis of cholestatic pruritus.5  Exogenously administered opioids can produce pruritus in normal individuals, most likely through a central action. Further, endogenous opioid levels have been found to be elevated (via an uncertain mechanism) in patients with chronic liver disease, and many reports have shown a reduction in pruritus associated with cholestasis in patients treated with an opioid antagonist such as naloxone.1,3,4,6,7,8

     The treatment of choice for pruritus associated with cholestasis is the correction of the underlying disease if possible.1 If definitive therapy is not possible, several measures can be attempted to relieve the pruritus. In mild cases of pruritus, nonspecific measures can be used to control the symptoms such as emollients and warm baths.1,9 However, these measures often fail in moderate to severe cases of pruritis. One option for moderate to severe cases are the opioid antagonists such as intravenous naloxone (0.2 µg/kg per min for 24 hours) or oral naltrexone (50 mg daily). The use of an opiate antagonist is often associated with substantial relief of cholestatic pruritus.1,7 In one controlled, crossover trial of 29 patients, for example, naloxone led to a 27 percent reduction in scratching activity and to a significant reduction in the perception of pruritus.1


Evidence:

Generally speaking, It is difficult for controlled studies to evaluate therapy for pruritis because of the subjective nature of this complaint. Investigators must carefully define and categorize various degrees of pruritis in order to effectively judge the results.



     N. Bergasa and associates in 1995 performed a double-blinded, placebo-controlled, crossover trial to determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of naloxone on pruritus and scratching activity in 29 pruritic patients with liver diseases of various causes. Treatments: Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours. (Placebo: 5% dextrose/0.45% NaCl. Treatment: Naloxone infusion: 0.2 micrograms/kg/minute – diluted in 5% dextrose/0.45% NaCl ) Measurements: visual analog scores of pruritus were recorded q4h while patients were awake, while scratching activity independent of limb movements was recorded continuously. Results: The mean of a visual analog score of the perception of pruritus (maximum 10.0) was 0.582 lower with the naloxone infusions compared to the placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Conclusion: naloxone administration was associated with an improvement of the perception of pruritus and reduction of scratching activity in cholestatic patients. 

     E. Jones and associates reported in 2002 that initiating therapy with an oral opiate antagonist such as nalmefene may precipitate an opioid-withdrawal like reaction in patients with pruritus due to cholestasis. The withdrawal response is due to the elevated opioidergic tone found in this condition. These withdrawal reactions can be minimized, or avoided completely, by infusing low doses of naloxone before giving small oral doses of an orally bioavailable opiate antagonist. After carefully titrating the dose of naloxone based on the patient’s response, the infusion can then be stopped and therapy may be continued with an orally bioavailable opiate antagonist such as naltrexone.4

     Relevant comments/quotes from the DRUGDEX® database: A single-blinded study evaluated the impact of a naloxone infusion on pruritus in female patients (n=8) with chronic pruritus secondary to primary biliary cirrhosis. Patients received a 24-hour infusion of a placebo solution and the same solution containing naloxone 0.2 mcg/kg/min (preceded by a 0.4 mg bolus). Six of the patients received 2 placebo and 2 naloxone infusions. A visual analog scale was used to assess pruritis. Conclusion: Naloxone solutions consistently showed a decrease in scratching activity ranging from 29% to 96%.6


Conclusion:
     Several studies have shown a connection between the increased opiate tone that is seen with cholestasis and the resulting pruritis. Although opioid antagonists have been found to have a significant effect on cholestasis-induced itching, the itching usually is not completely abolished. Also, It is possible that additional non-opioid mechanisms may be contributing to the pruritus associated with cholestasis.10  Many references do not recommend opiate antagonists as first line therapy of pruritis associated with cholestasis because of the potential for an opiate withdrawal reaction. Features of this reaction have included anorexia, nausea, colicky abdominal pains, tremor, insomnia, perspiration, increased blood pressure, decreased pulse, mood changes and hallucinations.4  The risk of a withdrawal reaction can be minimized by initiating therapy with a low dose intravenous infusion of naloxone ~(0.2 µg/kg per min). Treatments should always be based upon the severity of the pruritus. In mild cholestatic pruritus, nonspecific measures such as warm baths, emollients and antihistamines should be considered as first-line therapy.1,9  According to M. Kaplan, therapy for moderate to severe pruritus may require a diverse array of agents such as: cholestyramine, phenobarbital, rifampin, and opioid antagonists.1 Other options include plasmapheresis or phototherapy. In any case, non-specific measures like frequent use of emollients should never be forgotten.9

     Further long-term clinical trials are needed to compare opioid antagonists with other therapies to clearly establish the role of these agents.10  Combination therapy may also be required, since monotherapy with either opioid antagonists or other therapies have failed to completely relieve the pruritus caused by cholestasis. Given the potential for severe withdrawal reactions, opioid antagonists should be reserved for patients refractory to other treatments.

Even though naloxone may be effective in reducing pruritis, there are three major limitations for long-term use: 1) Naloxone has a short half-life and therefore requires frequent dosing. 2) Naloxone also has a significant first-pass metabolism and must be given parenterally (not orally bioavailable). 3) Potential tachyphylaxis with long-term treatment.10


References: 

1) Kaplan MM, Chopra S. Pruritus associated with cholestasis. UpToDate®. 2005;13(2). http://www.uptodate.com/. Accessed: 7/20/2005.

2) Jones EA, Bergasa, N. The pruritus of cholestasis: From bile acids to opiate agonists. Hepatology 1990; 11:884. 

3) Bergasa NV. Treatment of the Pruritus of Cholestasis. Curr Treat Options Gastroenterol. 2004 Dec;7(6):501-508. 

4) Jones EA, Neuberger J, Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions. QJM. 2002 Aug;95(8):547-52.

5) Jones EA, Bergasa NV. The pruritus of cholestasis and the opioid system. JAMA 1992; 268:3359. 

6) Klasco RK (Ed): DRUGDEX® System. Thomson Micromedex, Greenwood Village, Colorado (Edition expires [ 11/2005]).

7) Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, Korenman JC, Park Y, Hoofnagle JH, Jones EA. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology. 1992 Feb;102(2):544-9. 

8. Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, Schmitt JM, Walker EC, Jones EA. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med. 1995 Aug 1;123(3):161-7. 


9) Zylicz Z; Stork N; Krajnik M. Severe pruritis of cholestasis in disseminated cancer: developing a rational treatment strategy. J PAIN SYMPTOM MANAGE. 2005 Jan;29(1):p 100-103.

10) Terra SG, Tsunoda SM. Opioid antagonists in the treatment of pruritus from cholestatic liver disease. Ann Pharmacother. 1998 Nov;32(11):1228-30.

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