Subscription is FREE for qualified healthcare professionals in the US.

Opioid Antagonists in Pain Management

Available evidence suggests that the opioid antagonists naloxone and naltrexone offer potential benefits for enhancing opioid analgesia as well as monotherapy for managing certain challenging pain conditions.
Page 1 of 7

Editor’s note: This article is reprinted with permission and minor edits from the author’s peer-reviewed research report, “Opioid Antagonists, Naloxone & Naltrexone—Aids for Pain Management: An Overview of Clinical Evidence,” from Pain Treatment Topics;

Robert Foery, PhD, DABCC/TC

Achieving effective, durable, and safe pain relief, especially in patients with chronic and/or severe pain conditions, can be a clinical challenge. For many types of pain, prescription opioids are among the most effective analgesics.1 However, there could be concerns about the development of opioid tolerance or adverse effects, and in some cases opioids seem to worsen pain (eg, hyperalgesia).2-4 For certain difficult conditions, such as fibromyalgia or neuropathies, opioids alone are sometimes considered of limited effectiveness.5

Healthcare providers interested in pain management must be alert to new or novel approaches that help to overcome deficiencies of opioids, such as treatment-limiting side effects, and as aids in relieving difficult-to-treat pain conditions. In this regard, there is a growing body of evidence suggesting potential benefits of opioid antagonists.

Opioid antagonists—in particular, naloxone and naltrexone—have been available and studied for decades as agents that displace opioid molecules from their neuroreceptors, and block opioids from attaching to and activating those receptors. Such qualities can be of important benefit, as short-acting antagonists like naloxone are used effectively to quickly reverse toxic effects of opioid overmedication or overdose.

Laboratory research and clinical trials have demonstrated the unexpected, paradoxical effects of opioid antagonists as adjuvants for enhancing rather than attenuating analgesic effects of opioids like morphine, oxycodone, and others. Further benefits of opioid antagonists, as monotherapy, for better managing certain chronic pain conditions also have been discovered.

This paper provides an overview of naloxone and naltrexone pharmacology, and briefly examines some of the theoretical foundations of opioid antagonists for pain management. Available evidence from the literature describing opioid-antagonist therapy in adult humans, as portrayed in case examples or clinical trials, is reviewed and summarized. It must be understood, however, that opioid antagonists are not yet FDA-approved as adjuvant analgesics or for other pain management purposes, so their uses described in this report are off-label. Further investigations to assess the safety and efficacy of these applications would be appropriate.

Opioid Antagonist Pharmacology

Opioid antagonists have been available for many decades and are well known for their applications in addiction treatment (naltrexone) and as an antidote for opioid overdose (naloxone). The first report of agents having opioid antagonist-like properties was in 1915, when N-allylnorcodeine was observed to block the respiratory-depressant effects of morphine and heroin. The opioid antagonist nalorphine was synthesized in the 1940s; however, it also had partial agonist activity and its unsettling effects on mood (causing dysphoria) discouraged widespread use for treating opioid intoxication or overdose.6,7

In 1960, naloxone was synthesized as a more potent and less toxic antagonist than nalorphine. Naloxone produces no dysphoria but it has a short duration of action and poor oral bioavailability due to high first-pass hepatic metabolism; it is 15 times more potent by injection than by mouth. The need for a long-acting opioid antagonist as a treatment for addiction, by blocking the euphoric effects of illicit opioids for an extended period of time, motivated the development of naltrexone in 1963. This antagonist has reasonably good oral bioavailability, a long duration of action, and twice the potency of naloxone (see Table 1).6,8,9

Table 1. Pharmacokinetic Data
  Naltrexone Naloxone
Chemical Formula C20H23NO4 C19H21NO4
Oral Bioavailability Up to 40% 2% (high absorption but extensive first-pass metabolism)
Metabolism Hepatic Hepatic
Peak Concentration 1–2 hours 10 minutes
Half-life Up to 14 hrs (oral) 30–81 min. (IV, IM)
Duration of Action Up to 24+ hrs 1–4 hrs
Excretion Renal Renal, Biliary
Sources: Crabtree 19848; Gonzales and Brogden 19886;Reisine and Pasternak 19969

The development of these agents was facilitated by the interesting fact that relatively minor structural changes could convert an opioid agonist drug into one with antagonist actions; that is, blocking various opioid receptors and preventing their activation. Thus, morphine was transformed into nalorphine, and oxymorphone into either naloxone or naltrexone. A more recent development, nalmefene, is a pure mu-receptor antagonist that is at least equipotent with naloxone but longer acting, with a duration of action between naloxone and naltrexone. Additional antagonists that are selectively active at other opioid receptors have been developed largely for experimental purposes.7,9,10

Naloxone and naltrexone are the two opioid antagonists that have been most extensively studied and are commercially available today. They are FDA-approved for the treatment of alcoholism or opioid addiction (naltrexone; eg, Trexan®, Revia®, Depade®) or opioid overdose (naloxone; eg, Narcan®). A long-acting, high-dose depot form of naltrexone (Vivitrol®) for intramuscular injection also is approved for addiction therapy. In the interest of abuse deterrence rather than therapeutic enhancement, these antagonists also are being used or tested as ingredients in specially formulated opioid analgesics to deter their misuse or abuse. These agonist-antagonist combinations contain a sustained-release opioid with a sequestered antagonist, usually naltrexone. The concept is that the antagonist remains latent and is only released in the event of tampering, such as by crushing or dissolving the product, in an attempt to extract the abusable opioid ingredient. The activated antagonist would then impede desired opioid effects making the product less prone to abuse.11

Last updated on: December 20, 2011
First published on: April 1, 2009