Wednesday, January 18, 2012
By guest author, Dmitry M. Arbuck, MD
The use of opioid antagonists in chronic pain management is gaining more recognition and increasing acceptance . Application of these agents, such as naltrexone, is based on the notion that there are fundamental differences between mechanisms of chronic versus acute pain generation and perception. While pain is defined as “an experience” by the International Association for the Study of Pain, this experience can be driven by different underlying physiological and psychological mechanisms, depending on whether the patient is experiencing acute protective pain or a chronic diseased pain state.
Whereas opioid antagonists have no place in the treatment of acute pain, they can be useful for the management of pathologic pain mechanisms evident in chronic pain. Specifically regarding the opioid antagonist naltrexone, there are four general categories of doses that may apply: Pico-Dose, Ultra-Low-Dose, Low-Dose, and High-Dose.
[Readers are advised that the following discussion includes descriptions of off-label applications of oral naltrexone that have not been U.S. FDA approved, and these are neither endorsed nor specifically recommended by Pain Treatment Topics. — Editor.]
Miniscule, picogram levels (1-trillionth of a gram) of naltrexone may occur in the blood when certain abuse-deterrent medications containing the opioid antagonist are properly ingested; that is, even when it is not tampered with. Naltrexone in this case is inert and such tiny concentrations of an opioid antagonist have no bearing on the therapeutic function of the medication. Conversely, if such a combination medication is crushed and injected intravenously, the blood level of the opioid antagonist increases exponentially and reaches levels high enough to block euphoric effects of the opioid or to even cause withdrawal symptoms. At present, this specifically applies only to Embeda® (extended-release morphine + naltrexone, which is temporarily off-market due to manufacturing issues) .
The use of very small doses of naltrexone  has gained some traction in the pain-treatment community. Orally or transdermally administered naltrexone in a 1 to 8 microgram (mcg) dose in the presence of ongoing opioid analgesia is too small to cause withdrawal in the majority of patients, but is high enough to bind to excitatory opioid receptors and prevent unwanted adverse effects, such as opioid tolerance, sweating, lower leg edema, itching, etc. [4,5,6]. Also, opioid antagonists in microgram doses seem to decrease “liking” by patients of pure mu-opioid agonists they are combined with , which reduces the prospects of opioid abuse in individuals taking such a combination. The use of oral naltrexone is more practical than naloxone for this purpose, since it is better absorbed in the GI tract.
Presently micro doses of naltrexone are not commercially available and physicians have to use compounding pharmacies for making such preparations. Preparing the compound is uncomplicated and 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 adheres to the highest standards because a mistake in 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.
We prescribe an oral dose of 1 mL (1 mcg) twice daily (b.i.d.) for a week with titration up to 8 mL (8 mcg) total per day in divided dose (4 mL, 4 mcg b.i.d.), depending on the patient’s response. The price varies from one compounding pharmacy to another but, on average, 120 mL of compounded micro-dose naltrexone costs about $30.00 to $60.00 for the patient per month, which is an out-of-pocket expense.
Positive clinical effects are usually obvious to patients with chronic pain who use such doses of naltrexone in combination with their usual maintenance opioids. The majority of patients invest in this medication and comply with the prescribed regimen either because of the sharp decreases in opioid side effects mentioned above or a desire to prophylactically avoid increases in opioid doses over time due to tolerance development.
Some combination products use naloxone instead of naltrexone. Our clinical observation is that the presently available preparation Suboxone® — combining buprenorphine + naloxone — produces a sizable clinical effect, which is reflected in the greater pain control and lower abuse rate of Suboxone® versus Subutex® (which is a pure buprenorphine preparation).We have observed in our practice that buprenorphine monotherapy (Subutex® or the Butrans® patch) provides less robust pain control than the buprenorphine-naloxone combination, and this is sufficiently noticeable clinically that we usually combine micro-doses of oral naltrexone (1 to 8 mcg) with buprenorphine patch therapy [see further discussion of this in an earlier UPDATE here].
There are reports of small doses of naltrexone at 1 to 6 mg per day having beneficial effect in treating Crohn’s disease, interstitial cystitis, and other painful conditions [1,2,3]. However, this dose of naltrexone must be effective on its own and cannot be combined with opioids due to precipitation of opioid withdrawal. In this case, the effects of naltrexone on pain, if any, are probably secondary to an improvement in underlying disease processes and are unpredictable.
Our clinical experience has not shown positive effects of low-dose naltrexone (2 to 6 mg/day) on pain in Crohn’s disease, multiple sclerosis, fibromyalgia, or interstitial cystitis in even a single patient. We have stopped using those doses in our clinical practice; although, it is possible that there is a certain sub-group of patients who respond to this treatment and are not present in our pain clinic population.
The standard full dose of naltrexone is in the range of 25 to 100 mg per day and, compared with the other dose ranges, is considered here as high-dose. Use of this full dose of opioid antagonist in the treatment of chronic pain is least reported, least investigated, and most neglected [8,9]. The rationale for use of full doses of 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.
Role of Endorphins & Dopamine
Endorphins are produced in response to any painful or stressful stimuli — which may be either acute or chronic — in a natural attempt to suppress those noxious signals. If painful or stressful stimuli are either prolonged and accumulative, or acute and overwhelming, endorphin levels must be either (a) sustained for a prolonged period of time, which overwhelms normal mechanisms of endorphin regulation, or (b) produced in such high quantities that it destabilizes the normal regulatory system of pain defense. The pathological result of those two scenarios is the need for the brain to maintain high levels of endorphins “just in case,” or prophylactically, to prevent pain or diminish stress that are 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 and, then, maintaining endorphins at a higher level due to this misperception.
Therefore, the very production of endorphins becomes a paradoxical pathological process of producing pain for the purpose of then numbing it with endorphins. This results in a disease state. or pathological pain continuum, which, rather than responding favorably to an increase in the CNS opioid level, such as by administration of opioid analgesics, requires 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 endorphin mechanisms, in response to noxious stress stimuli dopamine levels are kept abnormally high and, eventually, stress tolerance diminishes with prolonged stress or overwhelming psychological trauma.
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:
- Posttraumatic Stress Disorder (PTSD) — when one experiences psychological trauma, it is suppressed by increased levels of dopamine and endorphins. Flashbacks, nightmares, autonomic hyper-arousal, and pathological pain perception in this situation are motivated by a need to keep high levels of dopamine and endorphins by any means. This sets up a vicious cycle of stress and pain which increase dopamine and endorphins production, which then pathologically perpetuate the stress and pain .
- Borderline Personality Disorder — activity of both dopamine and endorphin is pathologically heightened in this disorder, which may manifest as self-mutilation, stress provoking behavior, anger, dissociation, or multiple other symptoms of the disorder [11,12,13,14].
- Battered Woman and Child Syndrome — may occur when the victim repeatedly approaches the perpetrator of harm, thereby pathologically seeking pain and stress in order to maintain endorphins and dopamine at higher levels, which re-enforces self-destructive behaviors.
- Central Neuropathic Pain Syndromes — including fibromyalgia, present pain management challenges due to deep psychiatric roots that may influence pathologic endorphin/dopamine production.
Sensations of physical or emotional numbness during a traumatic experience (both physical and mental) 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. Both of those symptom categories may represent markers of the most severe illness and the worst prognosis in the above mentioned conditions of PTSD, Borderline Personality Disorder, Battered Woman and Child Syndrome, and Central Neuropathic Pain Syndromes, including some types of fibromyalgia [16,17].
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 leading causes of pathological stress and pain perception, then the treatment would be dopamine and endorphin blockade using appropriate antagonists. We have used this blockade approach successfully for many years in all four mentioned conditions.
To explain this complicated mechanism to patients, I use the example of PTSD:
Wouldn’t it be logical for the brain to defend itself and to forget the trauma? However, if the patient continues to re-experience flashbacks, has autonomic hyper-arousal, nightmares and, frequently, chronic pain, what is the physiological benefit in that? Well, the symptoms occur due to a pathological need to increase dopamine and endorphins by decreasing the stress and pain threshold, and this creates a vicious cycle that maintains the pathologic pain and other symptoms.
The same may occur with fibromyalgia. Pain becomes a way of maintaining heightened levels of endorphins, and a cycle of pathologic neurobiological, subconscious gratification is established. Interrupting this pathway with high doses of an opioid antagonist becomes a gateway to pain control; that is, pain becomes just pain, no gratification is attached. Stress becomes just stress. This extinguishes the pathological state of pain and stress maintenance.
However, fibromyalgia is not a homogenous disease. The primary manifestation of fibromyalgia is generalized muscular pain, which may be caused by completely different pathological mechanisms. The type of fibromyalgia that responds to high-dose naltrexone treatment has to be a truly central production of pain, in the brain, with minimal peripheral triggers. In this regard, naltrexone also is effective in a number of other centrally produced pain syndromes, such as Parkinsonism, multiple sclerosis, and thalamic pain.
Guidance on High-Dose Naltrexone
Proper selection of patients for treatment with high doses of naltrexone is crucial. The following are criteria that we use in selecting eligible patients:
- Lack of significant peripheral triggers for pain; such as obvious cervical pathology, endometriosis, active osteoarthritis, etc.
- Significant psychopathology, especially the presence of “oddness and peculiarity” in the patient.
- “Difficult” patient in whom either nothing ever works or causes intolerable side effects.
- Little exposure to treatment with opioids.
- Multiple unexplained symptoms.
- History of childhood sexual abuse.
- History of substance abuse.
Outcomes of treatment with high-dose of naltrexone are most favorable if 3 or fewer of the above criteria are present. If 5 or more criteria are present the outcome is less optimistic.
Although in many cases the use of high-dose naltrexone is enough to control pain, a combination with dopamine blockers — eg, novel antipsychotic/mood stabilizing medications, such as risperidone, ziprasidone, quetiapine, and others — may produce better results. Unlike with usual opioid therapy, the use of opioid antagonists is often curative; that is, after a period of time of taking either opioid antagonists 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 endorphin-producing areas of the brain. This is why it can be important to initiate treatment with opioid antagonists BEFORE opioids are tried in patients who fit the profile described above.
Titration of naltrexone doses is based on the patient’s clinical response. We usually start with a 6.25 mg or 12.5 mg dose once a day and increase it in weekly intervals to a full dose (50 mg to 100 mg per day) either in single- or split-dose administration. For patients’ convenience and to increase compliance, a once-monthly 380 mg injection of depot naltrexone — Vivitrol®, clinically comparable to roughly 50 mg/day of oral naltrexone — may replace daily doses of oral naltrexone .
Nausea and lower leg edema are the two most common observed side effects of naltrexone therapy. The patient must be warned about not combining regular opioids with naltrexone. The drug has been reported to be hepatotoxic in doses above 400 mg and we avoid using naltrexone in patients experiencing liver failure. Periodic checking of liver function tests in all patients taking high-dose naltrexone is recommended.
Conclusions: Software vs Hardware Fixes
As discussed above, various doses of the opioid antagonist naltrexone may be beneficial in specific groups of patients with chronic pain. Here is a recap:
- Pico-Dose — no clinical use in pain management (currently applies only to abuse-deterrent formulation).
- Ultra-Low-Dose (1 to 8 mcg/day) — used in preventing development of opioid tolerance and other excitatory adverse effects. This dose is combined with ongoing, maintenance opioid therapy.
- Low-Dose (1 to 6 mg/day) — used in Crohn’s disease, fibromyalgia, abdominal pain, interstitial cystitis, multiple sclerosis, although more research is needed to support this. May precipitate opioid withdrawal if the two are used concurrently.
- High-Dose (25 to 100 mg/day) — used without concurrent opioids in PTSD, Borderline Personality Disorder (eg, self-mutilation), Battered Woman and Child Syndrome, and Central Neuropathic Pain Syndromes (eg, fibromyalgia).
In sum, miniscule, pico doses of naltrexone are not of any clinical benefit in patients with pain. Ultra-low doses, in microgram amounts, may be used in combination with opioid analgesics to prevent tolerance development, providing an opioid-sparing effect, and assisting in the amelioration of excitatory opioid side effects. Low doses need further investigation, specifically for painful gastrointestinal conditions and other conditions.
High doses of naltrexone are most beneficial in neurobiologic or physiologic, process-based chronic pain (eg, in fibromyalgia, central sensitization, psychogenic, PTSD-related, and others) when no specific tissue damage can be found. Consequently, this approach is not applicable to tissue-damage-based chronic pain (degenerative disc disease, arthritis, peripheral neuropathy, endometriosis, interstitial adhesions, and others).
As an analogy, the use of high-dose naltrexone is like fixing the software of a malfunctioning computer and rebooting the system, which addresses processing-based issues. Whereas, if there is hardware damage instead — akin to painful tissue-damage disorders — a different sort of fix is needed. Opioid analgesics and other interventions may be helpful in ameliorating “hardware” issues to an extent, but naltrexone addresses “software” failures at the core of computer functioning.
While further research evidence is needed regarding all of the above-mentioned applications of naltrexone, our clinical experience already supports the selective use of this agent in the treatment of many chronic pain conditions.
About the Author: Dmitry M. Arbuck, MD, is a psychiatrist specializing in pain management. In 2000 he started Meridian Health Group, a pain management practice that grew into a multidisciplinary pain management facility treating all types of chronic pain. He also has an appointment as a volunteer Assistant Professor of Psychiatry and Medicine at Indiana University School of Medicine and is the former president of the Russian American Medical Association. Dr. Arbuck has served on the speakers’ bureaus of AstraZeneca, Cephalon, Forest Laboratories, King Pharmaceuticals, Metagenics, Pfizer, Reckitt Benckiser, Sanofi, and many other companies. For more information, you can e-mail Dr. Arbuck at [email protected], phone him at 317-814-1000, or visit his clinic website at: http://www.meridianhealthgroup.com.
Proviso: Facts, advice, and opinions expressed above are those of the guest author. Pain Treatment Topics — including our associates, affiliates, and supporters — do not endorse, recommend, or promote the use of any specific medications or the off-label prescribing of any medications. Any drugs mentioned by name are strictly for informational purposes and brands are registered trade marks of their respective manufacturers.
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