A Fresh Look at Opioid Antagonists in Chronic Pain Management – October 16, 2017 – By Dmitry M. Arbuck, MD
The article explains how these drugs are *not* effective for the pain from physical damage but are able to reduce the pain from neurological “central pain sensitization”.
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.
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.
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.
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).
Opioid antagonists appear to work in pain management by attenuating the pro-inflammatory response initiated by microglia cell activation in the CNS.
In other words, these are different from our usual opioid medications which dampen nociceptive signaling.
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.
This is a critical factor in how opioid medications are used by the body during serious or prolonged pain.
As our own internal opioids (endorphins) are depleted, our bodies can use additional external opioids (medications) to supplement this innate pain-regulation process.
When opioids are used only to re-stabilize our “normal regulatory system of pain defense”, there is no excess to confer the “euphoria” experienced by those that ingest excessive opioid medication (opioid abuse).
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).
Because much of the pain from EDS is a result of physical damage, this approach would not be effective.
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.
EDS, with its weak and defective connective tissue, definitely results in “hardware problems” with damage to the physical tissues.
Opioid antagonists address “software” failures at the core of brain function.
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)
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).
Use of very small doses of naltrexone has gained some traction in the pain treatment community.8 According to Levitt, “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.”
In higher doses, opioid antagonists block both excitatory and inhibitory functions of the mu receptors. In micro-doses, excitatory function is diminished or blocked and inhibitory function remains intact. This allows for improved pain control with a decrease in unwanted excitatory adverse effects of opioid medications.
In addition, opioid antagonists given in microgram doses seem to decrease “liking” by patients of pure mu-opioid agonists (morphine) when they are given together.
Arbuck D, Gharibo C, Labhsetwar S, et al. Management of opioid tolerability and related adverse effects. J Med. 2010;3(1):1-10.
The use of oral naltrexone is more practical than naloxone for this purpose since it is better absorbed in the gastrointestinal (GI) tract. Micro-doses of naltrexone are not commercially available, so physicians would have to rely on compounding pharmacies to prepare the medication.
Positive clinical effects are usually obvious to patients with chronic pain.
Some combination products use naloxone instead of naltrexone. In our clinical experience, combining buprenorphine and naloxone—although not-FDA approved, but very effective for chronic pain—produce a sizable clinical effec
There are reports that small doses of naltrexone (1 to 6 mg/d) can have a beneficial effect in treating Crohn’s disease, multiple sclerosis, fibromyalgia, and other painful conditions
The rationale for the use of full doses of an opioid antagonist for the treatment of chronic pain conditions is based on a theoretical model of chronic pain development, largely involving endorphin and dopamine regulation in the brain.
Use of this full dose of an opioid antagonist in the treatment of chronic pain is least reported, least investigated, and most neglected.
Painful Manifestations of Pathologic Processes
Pathological mechanisms producing a need to maintain high levels of endorphins and dopamine are observed in four conditions that are interrelated and have overlapping clinical manifestations, including pain.
Patients with the following conditions may be candidates for treatment with an opioid antagonist.
- Post-traumatic stress disorder (PTSD):
- Borderline personality disorder:
- Battered woman/child syndrome:
- Central neuropathic pain syndromes
High levels of dopamine and endorphins may represent markers of the most severe illness and the worst prognosis