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A Fresh Look at Opioid Antagonists in Chronic Pain Management

A wide array of pharmacological tools and approaches may help patients overcome opioid deficiencies.
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As clinicians reduce their reliance on opioids for the treatment of pain, they are turning to a wider array of pharmacological tools and approaches to help overcome deficiencies of opioids, such as treatment-limiting side effects, and as aids in relieving difficult-to-treat pain conditions.1

One such approach is the use of opioid antagonists. The use of opioid antagonists—in particular, naltrexone and naloxone—in chronic pain management is not new, but it deserves more recognition and acceptance than it enjoys presently.

An array of pharmacological tools, including opioids, can help relieve pain.An array of pharmacological tools can help relieve pain.

The application of opioid antagonists, such as low- to high-dose naltrexone, is based on the notion that there are fundamental differences between the mechanisms that cause chronic and acute pain. Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”.2

This experience, however, can be driven by different underlying physiologic and psychologic mechanisms—depending on whether the patient is experiencing acute, protective pain or a chronic, disease-state pain. Any approaches that may interrupt mechanisms underlying metamorphosis of acute pain into a chronic condition is of value. Opioid antagonists may be one such tool.

Opioid Antagonists in Chronic Pain

Opioid antagonists have been available and studied for decades as agents that displace opioid molecules from their central nervous system (CNS) receptors and block opioids from attaching to and activating those receptors. These qualities can be of important benefit, including in the treatment of opioid use disorder (ie, naloxone) as well as in reversing the toxic effects of opioid overmedication or overdose (ie, naltrexone).3

Opioid antagonists appear to work in pain management by attenuating the pro-inflammatory response initiated by microglia cell activation in the CNS.4 Endorphins are produced in the CNS in response to any painful or stressful stimuli—acute or chronic—in a natural attempt to suppress those noxious signals. If painful or stressful stimuli are either prolonged (and cumulative) or acute (and overwhelming), endorphin levels must be either sustained for a prolonged period of time, which overwhelms normal mechanisms of endorphin regulation, or produced in such high quantities that they destabilize the normal regulatory system of pain defense.

The pathological result of those two scenarios is the need for the CNS to maintain high levels of endorphins “just in case,” or prophylactically, to prevent pain or diminish stress that is expected to return.

Physiologically, endorphins are not produced without sufficient cause. To produce endorphins, when normally such production is not needed, requires lowering the pain threshold. This results in experiencing stimuli that are not normally painful as being pain (allodynia) and then maintaining endorphins at a higher level due to this misperception. Therefore, the very production of endorphins becomes a paradoxical pathologic process of allodynia for the purpose of then numbing the pain with endorphins.

This results in a disease state of a pathologic pain continuum (central sensitization). Rather than responding favorably to an increase in the CNS opioid level (such as by administration of opioid analgesics), patients require a decrease of the endogenous opioid level that can be facilitated by opioid antagonists.

In tandem with endorphins, dopamine plays an equally important role in the defense against stress, and, specifically, the suffering portion of pain. Similar to the endorphin mechanism, dopamine levels are kept abnormally high in response to noxious stress stimuli.

Eventually, the stress tolerance diminishes with prolonged stress or overwhelming psychologic trauma. This explains why there may be utility in a combination of opioid antagonists and dopamine-blocking agents in the management of chronic pain.

Opioid antagonists, therefore, are most beneficial in neurobiologically or physiologically based chronic pain (eg, fibromyalgia, central sensitization, chronic migraine and headache, PTSD-related pain). Consequently, this approach is not applicable to pain caused by tissue damage (eg, acute pain, degenerative disc disease, arthritis, severe peripheral neuropathy, endometriosis, interstitial adhesions, and others).

As an analogy, the use of naltrexone is like fixing the software of a malfunctioning computer and rebooting the system, which addresses processing-based issues. When there is hardware damage—akin to painful tissue-damage disorders—a different sort of repair is needed. Opioid antagonists address “software” failures at the core of brain function.

Dose Categories

Depending on the clinical scenario, there are four general categories of opioid antagonist doses that may apply: pico-dose, ultra-low-dose, low-dose, and high-dose (Table 1). 

The proposed relationship between the intensity of pain and doses of opioids and opioid antagonists is schematically presented in Figure 1.Pico-Dose

Miniscule, picogram levels (1-trillionth of a gram) of naltrexone or naloxone may occur in the blood when abuse-deterrent medications containing an opioid antagonist are properly ingested. In this case, both naltrexone and naloxone are inert, and such tiny concentrations of an opioid antagonist theoretically have no bearing on the therapeutic function of the medication.

Conversely, if such a combination medication is crushed and injected intravenously or snorted, the blood level of the opioid antagonist increases exponentially and reaches levels high enough to block the euphoric effects of the opioid or to even cause withdrawal symptoms. In our experience, even a minuscule dose of an opioid antagonist absorbed from combination medications may present additional benefit and aid in overall pain control. At present, this applies to any of the recently reformulated opioid medications approved by the US Food and Drug Administration: Embeda (extended-release morphine + naltrexone), Targiniq ER (oxycodone + naloxone), and Troxyca ER (oxycodone + naltrexone).5-7

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