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10 Articles in Volume 17, Issue #8
A Fresh Look at Opioid Antagonists in Chronic Pain Management
Addressing Chronic Pain in the United States Armed Forces
Are biosimilars as effective as their biologic counterparts?
Integrative Pain Care: When and How to Prescribe?
Lady Gaga, Fame, and Fibromyalgia
Letters to the Editor: An opportunity to learn what is on the minds of your colleagues and patients.
Must-Have Devices for Your Pain Practice
Obsessive-Compulsive Disorder & Chronic Pain
Theory of Motivated Information Management and Coping With Death
United Nations Says Untreated Pain Is “Inhumane and Cruel”

A Fresh Look at Opioid Antagonists in Chronic Pain Management

A wide array of pharmacological tools and approaches may help patients overcome opioid deficiencies.

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

Ultra-Low-Dose

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.”1

Administered either orally or transdermally, naltrexone in a 1 to 8 microgram (mcg) dose in the presence of ongoing opioid analgesia is too low to cause withdrawal in the majority of patients, but is high enough to bind to the excitatory opioid receptors and prevent unwanted adverse effects, such as opioid-induced hyperalgesia, sweating, lower leg edema, and itching (Table 2).9-11

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.12

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.12 This may reduce the prospect of opioid abuse in individuals taking such combinations. 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.

Preparing the compound is not complicated; it involves 1 mg of naltrexone powder dissolved in 1,000 mL of sterile water, which makes a concentration of 1 mcg/mL. It is imperative that the compounding pharmacy maintains the highest standards because a mistake in the concentration of naltrexone may exceed the recommended micro-doses and initiate opioid withdrawal.

Unfortunately, we have encountered this error on a number of occasions over the years. In my clinic, we prescribe an oral dose of 1 mL (1 mcg) twice daily (bid) for a week, with titration up to 4 mL (4 mcg) total per day in a divided dose.

Positive clinical effects are usually obvious to patients with chronic pain. Since the FDA has not approved micro-doses, compounded medications, as a rule, are not covered by insurance. Most patients invest in this medication (typically $50 to $75 per month) and comply with the prescribed regimen because of the sharp decreases in the opioid side effects mentioned in Table 2.

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 effect, which is reflected in greater pain control and a lower abuse rate compared with the use of pure buprenorphine preparations alone.

This is sufficiently noticeable clinically and makes it reasonable to combine micro-doses of oral naltrexone (1 to 8 mcg) with the buprenorphine patch (Butrans), buprenorphine buccal film (Belbuca), or generic sublingual buprenorphine.  

Low-Dose Naltrexone

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.13-16 This amount of naltrexone, however, can cause withdrawal symptoms if combined with an opioid.

Therefore, it must be given alone. Low-dose naltrexone (LDN) has been associated with reduced plasma concentrations of various interleukins (IL): IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF).17

In a study by Younger et al, women with fibromyalgia who had no known inflammatory or autoimmune disorder were given a regimen of LDN (4.5 mg/d) for 8 weeks.15 Participants’ blood was tested twice a week for cytokine concentrations, following a 2-week washout period. After the 10-week study was completed, the investigators found that 5 of 8 participants had an overall reduction in pain (range: 12.2% to 52.3%).

After correcting for multiple comparisons, 11 of the analytes showed a significant decrease over time in: IL-1Ra (P = 0.002), IL-2 (P = 0.002), IL-5 (P = 0.009), IL-6 (P<0.001), IL-12p70 (P = 0.003), G-CSF (P=0.010), TNF-α (P = 0.005), TGF-β (P=0.006), MCP-3 (P = 0.003), ENA-78 (P = 0.001), and resistin (P = 0.003).16

Only a limited number of studies on the use of LDN exist to date, and even the best studies need to be replicated. This makes it impossible to conclude whether the use of naltrexone in low doses is effective or safe.18

High-Dose Naltrexone

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.

The standard full dose of naltrexone is in the range of 25 to 200 mg per day, and compared with the other dose ranges, is considered here as a high-dose. Use of this full dose of an opioid antagonist in the treatment of chronic pain is least reported, least investigated, and most neglected.

In one small study of patients with Parkinson’s disease, there was a small reduction in levodopa-induced dyskinesias (LIDs) with naltrexone (5 mg/kg/d) compared with placebo (20.5% vs -4.1%, P < 0.05).19 This study suggests that short-term therapy with high-dose naltrexone (250-350 mg/d) has no or minimal effect on reducing LIDs in Parkinson’s disease.

Future studies will be needed to further elucidate the role of high-dose naloxone in the treatment of pain.

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): When one experiences psychological trauma, the stress of trauma is suppressed by increased levels of dopamine and endorphins. Flashbacks, nightmares, autonomic hyperarousal, and pathological pain perception are motivated by a need to maintain high levels of dopamine and endorphins, by any (in this case pathological) means. A need to maintain these higher levels of dopamine and endorphins may become more important than stress itself. This sets up a vicious cycle of stress and pain, which increases dopamine and endorphin production, which then pathologically perpetuate the stress and pain.20
  • Borderline personality disorder: Activity of both dopamine and endorphins is pathologically heightened in this disorder, which may manifest as self-mutilation (which paradoxically makes a person feel better), stress-provoking behavior, anger, dissociation and multiple other symptoms of the disorder.21-24
  • Battered woman/child syndrome: This may occur when the victim repeatedly approaches the perpetrator of harm, thereby pathologically seeking pain and stress to maintain endorphins and dopamine at higher levels, which reinforces self-destructive behaviors.
  • Central neuropathic pain syndromes: These syndromes present pain management challenges due to deep psychiatric roots that may influence pathologic endorphin/dopamine production. Sensations of physical or emotional numbness during the traumatic experience (both physical and mental), for example, are based on the production of excessive amounts of endorphins. Whereas feelings of detachment or dissociation, observing events from the outside “as in a movie,” signify pathologically high levels of dopamine at the time of trauma.

High levels of dopamine and endorphins may represent markers of the most severe illness and the worst prognosis in PTSD, borderline personality disorder, battered woman/child syndrome, and central neuropathic pain syndromes, including some types of fibromyalgia.25,26

For example, prolonged stress, as in repeated abuse during childhood, can predispose patients to develop one or a combination of the four conditions mentioned above. If increased levels of dopamine and endorphins are the leading causes of pathological stress and pain perception, then interrupting this pathway with an opioid antagonist may become a gateway to pain control—that is, pain becomes just pain; no gratification is attached. Stress becomes just stress. We have used this blockade approach successfully for many years in all the mentioned conditions.

However, fibromyalgia is not a homogenous disease.The primary manifestations of fibromyalgia are widespread muscular pain, increased sensitivity to normal physical stimuli (allodynia), and fatigue. The type of fibromyalgia that responds to high-dose treatment has to be based on a truly central production of pain with minimal peripheral triggers.

In this regard, naltrexone also may be effective in other centrally produced pain syndromes, such as Parkinson’s disease, multiple sclerosis, and, theoretically, thalamic pain. Patients who have chronic headaches and certain risk factors also respond favorably to opioid antagonist treatment (Table 3).27

Outcomes of treatment with high-dose naltrexone are most favorable if four or fewer of the criteria listed in Table 3 are present. If five or more criteria are present, the outcome is less optimistic. Although in many cases the use of low- to high-dose naltrexone is enough to control pain, a combination with dopamine blockers—for example, novel antipsychotic/mood stabilizing medications, such as risperidone, ziprasidone, quetiapine, and others—may produce better results.

Therapy Can Be Curative

Unlike with normal opioid therapy, treatment with opioid antagonists often can be curative—that is, after a period of taking either an opioid antagonist or a combination of opioid and dopamine antagonists, patients may be able to discontinue those medications with no recurrence of pain or other symptoms. However, patients are often afraid to stop opioid antagonists due to fear of symptom recurrence.

Extensive use of opioids in the patient’s history frequently presents a barrier to successful treatment with opioid antagonists, probably due to pharmacologically induced changes in the endorphin-producing areas of the brain. This is why it can be important to initiate treatment with opioid antagonists before trying opioids in patients who fit the profile described above. Titration of naltrexone doses is based on the patient’s clinical response.

Patients are usually started at a 6.25 mg or 12.5 mg dose once a day; they increase the dose at weekly intervals to a full dose (50 mg to 200 mg per day) given either in single- or split-dose administration. For patients’ convenience and to increase compliance, a once-monthly 380 mg injection of depot naltrexone, clinically comparable to roughly 50 mg/day of oral naltrexone, may replace daily doses of oral naltrexone.28

Nausea and lower leg edema are the two most commonly observed side effects of high-dose naltrexone therapy. In addition, patients must be warned about not combining regular opioids with naltrexone. The drug has been reported to be hepatotoxic in doses above 400 mg; using naltrexone in patients experiencing liver failure should be avoided. Periodic liver function tests in all patients taking high-dose naltrexone are recommended.

Conclusions

While further research evidence is needed regarding the applications of naltrexone and naloxone discussed herein, the author’s clinical experience supports the selective use of naltrexone in the treatment of many chronic pain conditions.

A more widely known and accepted clinical application of opioid antagonists is in the management of postoperative pain, but discussion of this topic was beyond the scope of this article.

Last updated on: October 16, 2017
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