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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.
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As noted above, two important features distinguishing naloxone from naltrexone are the very limited oral bioavailability of naloxone and the extended action of naltrexone. Both, naltrexone and naloxone may interact with all classes of opioid receptors12 but they do so most strongly at mu-opioid receptors.9 However, the typical naltrexone doses used for addiction therapy (50–100 mg/day orally) and naloxone dosing for reversing opioid overdose (0.4–1.0 mg/dose IV or IM) are, in most cases, different from the dosing protocols used in pain management applications (discussed below). In general, the literature refers to doses of antagonists, particularly naltrexone, in the 1 to 5mg range as “low dose”; whereas, those less than 1 mg, in microgram amounts, are usually designated as “ultralow dose.”

Special Qualities of Opioid Antagonists

In an excellent review of the role opioid antagonists may play in pain management, Sloan and Hamann13 note that interest in this topic dates back to the 1950s. It was observed that low doses of the antagonist nalorphine had pain-relieving properties in humans comparable to low-dose morphine in some cases. It was suspected that a combined opioid agonist-plus-antagonist agent might offer significant pain-relief without the undesirable side effects of opioids alone. However, this line of research was not pursued until quite recently.

It was later discovered that naloxone had an analgesic effect at very low doses but no such effect at higher doses. For example, experiments in opioid-naïve human subjects during the 1970s found that “low-dose” naloxone (up to 2mg) had analgesic effects that were lacking at higher naloxone doses (eg, 7.5mg and 10mg).13 The proposed neurobiological mechanisms behind this are complex and still being defined.

Studies in opioid-free animals have shown that, by causing a transient blockade of opioid receptors, low doses of antagonists stimulate increased production, or upregulation, of mu-opioid receptors in regions of the brain that control pain responses.14 Therefore, it seems plausible that after antagonist effects wear off — which may take minutes or hours depending on the agent and dose — greater numbers of opioid receptors are available to bind with pain-relieving opioids in the circulatory system, whether externally administered (eg, morphine) or endogenous peptides (eg, endorphins). At the same time, it has been noted that the body responds to the temporary opioid-receptor blockade by producing substantially increased amounts of beneficial natural endorphins.15,16 However, if the opioid-receptor blockade by antagonist is too extensive or continues too long, these pain relieving benefits are not realized, so the dose and half-life of the particular antagonist are critical factors.

Laboratory experiments further demonstrated that opioid antagonists may help to prevent the potential hyperalgesic (pain enhancing) and other negative effects of opioid pain relievers. At a cellular level, it is believed that exposure to opioid analgesics at certain doses and for prolonged periods of time may lead to aberrant signaling patterns by opioid receptors. These patterns can be reversed and restored to normal by the actions of opioid antagonists in very low concentrations.13,17

“...appropriately low doses of opioid antagonists have been postulated to ‘reset’ the opioid-receptor system for a period of time...”19

The ultimate effects of these mechanisms, demonstrated in animal studies and human trials, appears to be an enhancement by low- or ultralow-dose naloxone or naltrexone of opioid-agonist antinociceptive (pain relieving) efficacy. Along with this, tolerance to and physiologic dependency on opioid agonists, such as morphine and others, may be diminished.18 Essentially, appropriately low doses of opioid antagonists have been postulated to “reset” the opioid-receptor system for a period of time,19 which seems analogous to how rebooting a malfunctioning computer clears memory, refreshes the software, and often restores normal function. The best type of antagonist, the optimal dose of it for achieving these effects, and the duration of effects have been explored by various investigators, as described below. Note that in most of the literature, ultralow-dose applications of antagonists are usually expressed in microgram amounts. However, since the more well-known applications of naloxone and naltrexone are in milligram increments, doses in this paper are converted from micrograms to milligrams (1 mcg = .001mg).

Research on Naloxone in Pain Management

The traditional role of naloxone has been the complete reversal of opioid effects, particularly in cases of opioid overmedication or life-threatening overdose. However, the potentials of this agent in pain management have been described in a number of studies.

Loitman19 reported an interesting case series of three patients with intractable chronic pain—despite receiving large doses of strong opioids, other medications, and complementary procedures— who underwent a brief and temporary inpatient opioid-receptor reversal (that is, detoxification) procedure with intravenous naloxone (0.6–1.2mg). This induced rapid withdrawal as the opioids were displaced from their receptors by the antagonist. Distressing withdrawal symp-toms were ameliorated by sedation and, after a brief period of time (about 20 minutes), opioid pain relievers were readministered.

All patients responded very positively to the procedure, achieving much greater pain relief than before the brief detoxification and at significantly lower doses of opioid analgesics. Overall, Loitman noted that vastly improved pain relief was achieved in less than one hour on about one-third of the original opioid dose. Although exact mechanisms were unclear, the opioid receptors were thought to have been “reset” (as discussed above), overcoming prior opioid tolerance and/or hyperalgesia.

A number of clinical investigations have suggested potential benefits of ultralow-dose oral naloxone administration for postoperative pain:

Last updated on: December 20, 2011
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