Pure Opioid Antagonists for Management of Opioid-induced Pruritus

Medscape |

Abstract and Introduction

Abstract

Purpose. Published reports on placebo-controlled clinical trials and other studies investigating the use of pure opioid antagonists for the prevention and treatment of opioid-induced pruritus (OIP) were evaluated.
Summary. OIP is a common adverse effect of therapeutic use of opioid medications that can have a major impact on patients’ comfort, quality of life, and willingness to continue opioid therapy. A literature search identified more than a dozen published reports on the use of pure opioid antagonists (naloxone, naltrexone, methylnaltrexone) for the management of OIP in pediatric and adult patients. Of the studies included in this review, most investigated the effects of naloxone administered by various parenteral routes for the prevention of OIP. Some of those studies indicated a significant reduction in the frequency or severity of pruritus with use of naloxone (a low-dose, continuous i.v. infusion of naloxone appeared to be the most effective treatment). A significant diminution of analgesia requiring increased cumulative doses of morphine was also observed in some studies. A number of studies evaluating the use of orally administered naltrexone for the management of OIP yielded generally less favorable results. Evidence from one small study suggested a potential role for orally administered methylnaltrexone in the prevention of OIP.
Conclusion. Based on the existing data, a low-dose, continuous i.v. infusion of naloxone has the largest body of evidence supporting its use for prevention of OIP in adult and pediatric patients.

Introduction

Opioid analgesics are the cornerstone of the treatment of moderate-to-severe pain, but their use is often limited by opioid-related adverse effects, such as sedation, pruritus, nausea, respiratory depression, hypotension, and constipation. Opioid-induced pruritus (OIP) affects 10–50% of patients receiving i.v. opioids and 20–100% of those receiving epidural or intrathecal opioid therapy.[1] The frequency of OIP rises with increasing opioid dosages.[2] A variety of medications with differing mechanisms of action have been used for the prevention and treatment of OIP, with mixed results; these medications include pure opioid-receptor antagonists, mixed opioid-receptor agonist–antagonists, serotonin 5-HT3 antagonists, dopamine D2-receptor agonists, and antihistamines.[1]

The mechanism of OIP has not been fully elucidated; several mechanisms have been proposed. Traditionally, because it was believed that OIP occurs secondary to histamine release from mast cells, antihistamines (e.g., diphenhydramine) were used as first-line agents. However, research has shown that central μ-opioid receptors play a significant role in the pathophysiology of OIP.[3] Moreover, itching may be mediated by the peripheral effects of opioid peptides.[4] In light of those findings, pure opioid antagonists (e.g., naloxone, naltrexone) have been evaluated for the management of OIP. Published studies have evaluated the use of opioid antagonists for OIP prevention; however, there are limited data on the use of opioid antagonists for the treatment of active pruritus. Due to the mechanism of action of pure opioid antagonists, it is prudent to balance the potential benefits of their use as adjunct agents for management of OIP against the potential for reversal of analgesic activity. This article evaluates the current body of literature for evidence on the most effective pure opioid antagonist, route of administration, and dosage for the management of OIP.

A search was conducted using MEDLINE (1950–May 2010), EMBASE (1988–May 2010), International Pharmaceutical Abstracts (1970–May 2010), and the Cochrane Library (1996–May 2010) with the keywords naloxone, naltrexone, pruritus, and opioid antagonist. The search was limited to English-language human studies. Reference citations from relevant articles were also reviewed.