- Email: [email protected]
Low-Dose Naltrexone reduces symptoms in Stiff-Person Syndrome
Medical Hypotheses 137 (2020) 109546
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Low-Dose Naltrexone reduces symptoms in Stiff-Person Syndrome a,b,⁎
Mauro Zappaterra
d
c
, Elizabeth Shouse , Reed Loring Levine
T
a
Synovation Medical Group, Pasadena, CA 91105, USA Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA Synovation Medical Group, Pasadena Rehabilitation Institute, 1017 S. Fair Oaks Ave, Pasadena, CA 91105, USA d Harmonae Psychological Services, Inc., 130 S. Euclid Ave, Suite 8, Pasadena, CA 91101, USA b c
ARTICLE INFO
ABSTRACT
Keywords: Low Dose Naltrexone Stiff-Person Syndrome Chronic pain
Stiff-Person Syndrome (SPS) is a rare neurologic disorder characterized by severe and progressively worsening muscle stiffness and rigidity. SPS can be very painful due to unpredictable muscle spasms which can be triggered by various stimuli, such as noise, touch, or emotional experiences. There is thought to be an autoimmune component to the disorder. We present the case of a 59-year-old woman diagnosed with SPS who appears to have experienced a dramatic reduction in her symptoms after being treated with Low-Dose Naltrexone (LDN). Prior to this treatment regimen, she had tried many treatments with only limited derived benefit. She was started on LDN and after 6 weeks, reported reductions in pain, anxiety, depression, agoraphobia, and muscle tightness. Upon multiple follow-ups, leading up to 12 months, she continually displayed reduced symptoms and improved quality of life. We conclude that LDN may have some utility in treating and managing the symptoms of SPS. We hypothesize that this may be possible due to LDN operating via anti-inflammatory pathways as well as acting as an opioid antagonist. We assert that further research as it relates to LDN and SPS in addition to other chronic pain conditions is warranted.
Introduction Stiff-Person Syndrome (SPS) is a rare neurologic disorder believed to be autoimmune mediated [1], however the exact pathogenic mechanism is not fully known. It is characterized by severe and progressively worsening muscle stiffness and rigidity, primarily affecting trunk regions and lower extremities in which afflicted individuals may be too disabled to walk or move. SPS is often quite painful due to muscle spasms which can be triggered by various stimuli, such as unanticipated auditory, tactile, or emotional experiences [2]. As such, individuals suffering from SPS may display heightened sensitivity to such things as noise, touch, and emotional distress. SPS affects twice as many women as men [3]. Historically, treatment for SPS included administration of some combination of anxiolytics, anticonvulsants, muscle relaxants, or pain medication. There is research indicating the effectiveness of intravenous immunoglobulin (IVIG) treatment in reducing stiffness and lowering sensitivity to triggers in people with SPS [4]. We present a case of Stiff Person’s Syndrome that appears to have been successfully managed using Low Dose Naltrexone (LDN).
Naltrexone is a drug that was introduced in the mid 80′s and FDA approved to reduce opiate toxicity or to reduce opiate addiction. Naltrexone and its active metabolite 6-β-naltrexol block activity at muand delta-opioid receptors as well as, kappa-opioid receptors [5,6]. The blockade of opioid receptors is the basis behind its action in the management of opioid dependence given that it reversibly blocks the effects of opioids. The term “LDN” refers to the administration of naltrexone in low doses in the range of 2–5 mg. Hypothesis The benefit of LDN in SPS is likely due to multiple mechanisms. LDN may work as a glial cell modulator [7,8]. Microglia are immune cells that reside in the central nervous system and when activated, can produce inflammatory as well as excitatory factors that can lend to pain sensitivity, sleep and cognitive disruption, mood disorders, and fatigue [9]. Naltrexone has an antagonist effect on non-opioid receptors (Tolllike Receptor 4) that are found on microglia and through this pathway LDN may exert anti-inflammatory effects. Another proposed mechanism of LDN is the temporary inhibition of endorphins. This results in a re-
Corresponding author at: Synovation Medical Group, Pasadena, CA 91105, USA. E-mail addresses: [email protected] (M. Zappaterra), [email protected] (E. Shouse), [email protected] (R.L. Levine). ⁎
https://doi.org/10.1016/j.mehy.2019.109546 Received 7 November 2019; Accepted 31 December 2019 0306-9877/ Published by Elsevier Ltd.
Medical Hypotheses 137 (2020) 109546
M. Zappaterra, et al.
active increase in the production of endorphins, which yields a “paradoxical” analgesic effect, thus resulting in a reduction of painful symptoms and an increased sense of wellbeing [10].
Discussion This report describes the successful use of LDN on symptom management for at least twelve months in a case of SPS. To date there does not appear to be any other case reports or research on the use of LDN on SPS. We hypothesize that LDN may have proven effective for this case perhaps due to multiple mechanisms. The patient derived significant pain reduction, a reduction in muscle tightness as well as a reduction in anxiety. It is possible that LDN was helpful via multiple anti-inflammatory pathways, and/or by acting as an opioid antagonist. There are a few studies exploring the efficacy of LDN as a treatment for chronic pain conditions. Thus far, the condition which appears to have the most empirical support for the efficacy of LDN treatment is Crohn’s Disease. The first published LDN trial in humans was in 2007, with a sample size of 17 patients who evinced significantly lower scores on the Crohn’s Disease Activity Index (CDAI) after 12 weeks of daily LDN administration [11]. Further, 89% of patients exhibited a response to treatment and 67% experienced a remission. Subsequent studies have again shown declines in CDAI scores, as well as declines in Crohn’s Disease endoscopy severity index scores (CDEIS) with the daily administration of 4.5 mg of Naltrexone [12]. In a pediatric population, scores on the Pediatric Crohn’s Disease Activity Index (PCDAI) were significantly reduced from pretreatment measures and 25% of those in the treatment group experienced remission [13]. It is hypothesized that LDN acts on the opioid receptors as an antagonist and this reverses inflammation in the afflicted areas, as there is some evidence that endogenous opioid peptides play a role in the development of inflammation [14–16]. Support for this theory is found in the prior reports of pain reduction, in addition to the objective measurements of inflammation and disease severity improvement. Findings are somewhat more controversial when it comes to LDN use with multiple sclerosis. There are large amounts of unpublished anecdotal reports circulating the internet from MS patients that the drug not only prevents relapses in MS, but also slows the progression of the disease. However, to date, there is little scientific research on the use of LDN in this area. There have been some reports of significant improvements in spasticity and mental health [17,18]. It has been proposed that MS results from microglial activation, as well as apoptosis of oligodendrocytes caused by oxidative stress and/or excitatory amino acid toxicity. The mechanism of LDN in MS is thought to be by preventing the excitatory neurotoxicity of glutamate on cells [19] by the reduction of nitric oxide synthase activity. This inhibits the microglial cells and prevents the apoptosis of oligodendrocytes, and thus the myelin is preserved. There is some evidence that LDN may have utility in treating Fibromylagia (FM). It is thought that LDN may decrease the activity of microglia activity in the central nervous system and reverse central and peripheral inflammation. In one single-blind crossover trial, the drug was found to reduce FM symptoms [particularly pain, stress, and fatigue] by 30% over placebo in 6 participants out of a 10-person cohort [20]. Interestingly, patient response to LDN was directly correlated with erythrocyte sedimentation rates, again suggesting that LDN may reduce inflammation which may contribute to the painful aspect of FM. In a larger, double-blind study, the LDN group was found to have significantly lower pain levels [28.8% reduction vs. 18% reduction in the placebo group.] LDN was also associated with improved mood and improved life satisfaction. In one case study [21] LDN was used to treat Fibromyalgia based on the theory that FM indicates low endorphin secretion. Rationale for use was based on findings that a 4.5 mg dose of Naltrexone increases specific opioid receptors [22] by creating a temporary blockade followed by a rebound of increased endorphin activity. The patient in the aforementioned case study reported a reduction of pain in specific areas [back and neck] along with reduction in gait unsteadiness and improvements in fatigue, sleep, work capacity, mood
Case presentation LF is a 59-year old woman referred for evaluation and treatment of long-standing diffuse muscle pain associated with SPS. She had already had her diagnosis confirmed by multiple physicians including a neurologist at a major university medical center. Her pain symptoms began in the late 1990′s and through the course of the day were quite variable, ranging from 0 to 7 out of 10, with occasional “flare-ups” in the 9–10/10 range. She reported a poor tolerance for many activities of daily living, as exacerbations could be triggered by physical exertion, grocery shopping, housework and dayto-day chores. She also expressed a concern that her ribcage on one side was gradually drawing closer to her pelvis over time and was uncomfortable. Her past workup included many studies such as “blood tests”, EMG/ NCS, MRIs, CT scans as well as X-Rays. She explained that the studies revealed no etiology for her symptoms aside from SPS. The treatments she had received only helped her “a bit” and what she found most helpful was “massage therapy…but it only helps for a day or so”. She said at times she felt sad, hopeless and frustrated with her situation but never suicidal. Her medication management at the time of consultation included gabapentin 2100 mg/day, diazepam 35 mg/day, baclofen 30 mg/day, bupropion 200 mg/day, sertraline, regular IVIG infusions and oxycodone/acetaminophen typically 10 mg/day. She expressed frustration with opiate therapy she had received in the past and did not find her current or past treatments to be adequate. She had been offered a trial of intrathecal baclofen for possible intrathecal pump implantation but declined in the past and again declined at her pain management consultation. She was interested “mainly in natural therapies… not to take more pills…especially not narcotics…”. She was sent for an evaluation with a physical medicine and rehabilitation specialist and physical therapy, to pulmonology for baseline pulmonary function testing and offered a trial of a topical compounded medication including baclofen + cyclobenzaprine + ketoprofen + lidocaine. Initially she felt the topical gel was helpful, although after a few weeks its benefits waned. A discussion was had about the possibility that off-label use of LDN might help her, although she would need to come off all opiates first. She decided it was something she wished to try. After stopping her opiates for approximately two weeks, she was started on compounded oral naltrexone at 1.5 mg in the evening for a week, then 3 mg for a week, then increased to 4.5 mg. Six weeks after starting LDN she reported that her pain levels had decreased by approximately 50%, her anxiety had decreased, her agoraphobia had decreased and she reported a subjective recollection of fewer episodes of significant muscle tightness and discomfort. She reported no side effects aside from “sometimes weird or vivid dreams”. Fifteen weeks after starting LDN she reported continued benefit without additional side effects. Approximately six months after starting LDN she reported that her back pain had nearly completely resolved. She was participating in ongoing physical therapy and by nine months after starting LDN she reported that she was “doing even better” and reported that this was the most successful symptomatic treatment she had yet received for her condition. At a twelve month follow up, she continued to endorse dramatic reductions in pain (almost 100% reduction in her back pain), in addition to the maintenance of reductions in her other symptoms.
2
Medical Hypotheses 137 (2020) 109546
M. Zappaterra, et al.
and quality of life. There was also a decrease in objective pain measurements when Cold Pressor Test times were compared. In the treatment of osteoarthritis, one study looked at the effectiveness of Oxytrex, which is ultralow-dose naltrexone combined with oxycodone [23]. The authors cite earlier studies demonstrating the capacity of ultralow-dose opioid antagonists to enhance and prolong opiate analgesia and alleviate opioid tolerance and withdrawal in rats and mice. In this study involving 360 human participants, subjects with moderate to severe pain from osteoarthritis were administered placebo, oxycodone four times a day [qid], Oxytrex qid, or Oxytrex twice a day (bid). The Oxytrex bid administration produced a 39% reduction in pain intensity which proved to be significantly greater than that of placebo, oxycodone qid, and Oxytrex qid. Further, the Oxytrex administration was found to be superior to placebo in terms of quality of pain reduction, duration of pain control, global assessments by patients, and osteoarthritis index scores. Following the theory that LDN acts as a glial cell attenuator [specifically, an antagonist effect on Toll-Like Receptor-4 found on microglia], two case studies derived positive outcomes when LDN was used to treat Complex Regional Pain Syndrome, which involves central sensitization and glial activation in the central nervous system [24]. When LDN was added to already-established treatment regimens for CRPS, these patients reported a decrease of CRPS symptoms including pain levels, dystonic spasms and fixed dystonia.
References: [1] Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes. Muscle Nerve 2012 May;45(5):623–34. [2] Ameli R, Snow J, Rakocevic G, Dalakas MC. A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 2005;65:1961–3. [3] What is Stiff Person Syndrome? National Institute of Neurological Disorders and Stroke Web site. http://www.ninds.nih.gov/disorders/stiffperson/stiffperson.htm Published November 15, 2010. Accessed February 8, 2014. [4] Dalakas MC. The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. J Neurol 2005;252(1):19–25. [5] Wang D, Sun X, Sadee W. Different effects of opioid antagonists on mu-, delta-, and kappa-opioid receptors with and without agonist treatment. J Pharmacol Exp Ther 2007;321(2):544–52. [6] Shader RI. Antagonists, Inverse Agonists, and Protagonists. J Clin Pharmacol 2003;23(4):321–2. [7] Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF. Norman cousins lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun 2007;21(2):131–46. [8] Younger J, Parkitny L, McLain D. The use of low-dose naltrexone as a novel antiinflammatory treatment for chronic pain. Clin Rheumatol 2014;33(4):451–9. [9] Dantzer R. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 2007;21(2):153–60. [10] Greeley JD, Le AD, Poulos CX, Cappell H. “Paradoxical” analgesia induced by naloxone and naltrexone. Psychopharm [Berlin] 1988;96(1):36–9. [11] Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-Dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol 2007;102:1–9. [12] Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Dig Dis Sci 2011;56:2088–97. [13] Smith JP, Field D, Bingaman SI, Evans R, Mauger DT. Safety and tolerability of lowdose naltrexone therapy in children with moderate to severe Crohn’s disease: a pilot study. J Clin Gastroenterol 2013;47(4):339–45. [14] Pol O, Puig MM. Expression of opioid receptors during peripheral inflammation. Curr Top Med Chem 2004;4:51–61. [15] Rogers TJ, Peterson PK. Opioid G Protein-coupled receptors: signals at the crossroads of inflammation. Trends Immunol 2003;24–116-121.. [16] Kamphuis S, Eriksson F, Kavelaars,, et al. Role of endogenous pro-enkephalin Aderived peptides in human T cell proliferation and monocyte IL-6 production. J Neuroimmunol 1998;84:53–60. [17] Gironi M, Martinelli-Boneschi F, Sacerdote P, et al. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler 2008;14:1076–83. [18] Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol 2010;68:145–50. [19] Agrawal YP. Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses 2005;64:721–4. [20] Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med 2009;10(4):663–72. [21] Ramanathan S, Panksepp J, Johnson B. Is Fibromylagia an endocrine/endorphin deficit disorder? Is low dose naltrexone a new treatment option? Psychosomatics 2012;53(6):591–4. [22] Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses 2009;72:333–7. [23] Chindalore VL, Craven RA, Butera PG, Yu KP, Burns LH, Friedmann N. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia. J Pain 2005;6:392–9. [24] Chopra P, Cooper MS. Treatment of complex regional pain syndrome [CRPS] using low dose naltrexone [LDN]. J Neuroimmune Pharm 2013;8(3):470–6.
Conclusion: LDN may have utility in treating SPS symptoms. It is important to note that the use of LDN for these various conditions is extremely preliminary. Much of the available research comes in the form of case reports, or pilot studies having several limitations (e.g. open-label, small sample size, etc.). There certainly needs to be more replication of research in order to draw any solid conclusions. Here we present one case wherein LDN proved to be effective for SPS symptom management. We by no means are asserting that this translates over perfectly to other cases of SPS, only that these findings indicate a promising area of research involving the use of LDN with not only SPS, but also other chronic pain conditions. Conflict of Interest: The authors disclose no conflicts of interest. Acknowledgements: The authors disclose no financial conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.mehy.2019.109546.
3
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Low-Dose Naltrexone reduces symptoms in Stiff-Person Syndrome a,b,⁎
Mauro Zappaterra
d
c
, Elizabeth Shouse , Reed Loring Levine
T
a
Synovation Medical Group, Pasadena, CA 91105, USA Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA Synovation Medical Group, Pasadena Rehabilitation Institute, 1017 S. Fair Oaks Ave, Pasadena, CA 91105, USA d Harmonae Psychological Services, Inc., 130 S. Euclid Ave, Suite 8, Pasadena, CA 91101, USA b c
ARTICLE INFO
ABSTRACT
Keywords: Low Dose Naltrexone Stiff-Person Syndrome Chronic pain
Stiff-Person Syndrome (SPS) is a rare neurologic disorder characterized by severe and progressively worsening muscle stiffness and rigidity. SPS can be very painful due to unpredictable muscle spasms which can be triggered by various stimuli, such as noise, touch, or emotional experiences. There is thought to be an autoimmune component to the disorder. We present the case of a 59-year-old woman diagnosed with SPS who appears to have experienced a dramatic reduction in her symptoms after being treated with Low-Dose Naltrexone (LDN). Prior to this treatment regimen, she had tried many treatments with only limited derived benefit. She was started on LDN and after 6 weeks, reported reductions in pain, anxiety, depression, agoraphobia, and muscle tightness. Upon multiple follow-ups, leading up to 12 months, she continually displayed reduced symptoms and improved quality of life. We conclude that LDN may have some utility in treating and managing the symptoms of SPS. We hypothesize that this may be possible due to LDN operating via anti-inflammatory pathways as well as acting as an opioid antagonist. We assert that further research as it relates to LDN and SPS in addition to other chronic pain conditions is warranted.
Introduction Stiff-Person Syndrome (SPS) is a rare neurologic disorder believed to be autoimmune mediated [1], however the exact pathogenic mechanism is not fully known. It is characterized by severe and progressively worsening muscle stiffness and rigidity, primarily affecting trunk regions and lower extremities in which afflicted individuals may be too disabled to walk or move. SPS is often quite painful due to muscle spasms which can be triggered by various stimuli, such as unanticipated auditory, tactile, or emotional experiences [2]. As such, individuals suffering from SPS may display heightened sensitivity to such things as noise, touch, and emotional distress. SPS affects twice as many women as men [3]. Historically, treatment for SPS included administration of some combination of anxiolytics, anticonvulsants, muscle relaxants, or pain medication. There is research indicating the effectiveness of intravenous immunoglobulin (IVIG) treatment in reducing stiffness and lowering sensitivity to triggers in people with SPS [4]. We present a case of Stiff Person’s Syndrome that appears to have been successfully managed using Low Dose Naltrexone (LDN).
Naltrexone is a drug that was introduced in the mid 80′s and FDA approved to reduce opiate toxicity or to reduce opiate addiction. Naltrexone and its active metabolite 6-β-naltrexol block activity at muand delta-opioid receptors as well as, kappa-opioid receptors [5,6]. The blockade of opioid receptors is the basis behind its action in the management of opioid dependence given that it reversibly blocks the effects of opioids. The term “LDN” refers to the administration of naltrexone in low doses in the range of 2–5 mg. Hypothesis The benefit of LDN in SPS is likely due to multiple mechanisms. LDN may work as a glial cell modulator [7,8]. Microglia are immune cells that reside in the central nervous system and when activated, can produce inflammatory as well as excitatory factors that can lend to pain sensitivity, sleep and cognitive disruption, mood disorders, and fatigue [9]. Naltrexone has an antagonist effect on non-opioid receptors (Tolllike Receptor 4) that are found on microglia and through this pathway LDN may exert anti-inflammatory effects. Another proposed mechanism of LDN is the temporary inhibition of endorphins. This results in a re-
Corresponding author at: Synovation Medical Group, Pasadena, CA 91105, USA. E-mail addresses: [email protected] (M. Zappaterra), [email protected] (E. Shouse), [email protected] (R.L. Levine). ⁎
https://doi.org/10.1016/j.mehy.2019.109546 Received 7 November 2019; Accepted 31 December 2019 0306-9877/ Published by Elsevier Ltd.
Medical Hypotheses 137 (2020) 109546
M. Zappaterra, et al.
active increase in the production of endorphins, which yields a “paradoxical” analgesic effect, thus resulting in a reduction of painful symptoms and an increased sense of wellbeing [10].
Discussion This report describes the successful use of LDN on symptom management for at least twelve months in a case of SPS. To date there does not appear to be any other case reports or research on the use of LDN on SPS. We hypothesize that LDN may have proven effective for this case perhaps due to multiple mechanisms. The patient derived significant pain reduction, a reduction in muscle tightness as well as a reduction in anxiety. It is possible that LDN was helpful via multiple anti-inflammatory pathways, and/or by acting as an opioid antagonist. There are a few studies exploring the efficacy of LDN as a treatment for chronic pain conditions. Thus far, the condition which appears to have the most empirical support for the efficacy of LDN treatment is Crohn’s Disease. The first published LDN trial in humans was in 2007, with a sample size of 17 patients who evinced significantly lower scores on the Crohn’s Disease Activity Index (CDAI) after 12 weeks of daily LDN administration [11]. Further, 89% of patients exhibited a response to treatment and 67% experienced a remission. Subsequent studies have again shown declines in CDAI scores, as well as declines in Crohn’s Disease endoscopy severity index scores (CDEIS) with the daily administration of 4.5 mg of Naltrexone [12]. In a pediatric population, scores on the Pediatric Crohn’s Disease Activity Index (PCDAI) were significantly reduced from pretreatment measures and 25% of those in the treatment group experienced remission [13]. It is hypothesized that LDN acts on the opioid receptors as an antagonist and this reverses inflammation in the afflicted areas, as there is some evidence that endogenous opioid peptides play a role in the development of inflammation [14–16]. Support for this theory is found in the prior reports of pain reduction, in addition to the objective measurements of inflammation and disease severity improvement. Findings are somewhat more controversial when it comes to LDN use with multiple sclerosis. There are large amounts of unpublished anecdotal reports circulating the internet from MS patients that the drug not only prevents relapses in MS, but also slows the progression of the disease. However, to date, there is little scientific research on the use of LDN in this area. There have been some reports of significant improvements in spasticity and mental health [17,18]. It has been proposed that MS results from microglial activation, as well as apoptosis of oligodendrocytes caused by oxidative stress and/or excitatory amino acid toxicity. The mechanism of LDN in MS is thought to be by preventing the excitatory neurotoxicity of glutamate on cells [19] by the reduction of nitric oxide synthase activity. This inhibits the microglial cells and prevents the apoptosis of oligodendrocytes, and thus the myelin is preserved. There is some evidence that LDN may have utility in treating Fibromylagia (FM). It is thought that LDN may decrease the activity of microglia activity in the central nervous system and reverse central and peripheral inflammation. In one single-blind crossover trial, the drug was found to reduce FM symptoms [particularly pain, stress, and fatigue] by 30% over placebo in 6 participants out of a 10-person cohort [20]. Interestingly, patient response to LDN was directly correlated with erythrocyte sedimentation rates, again suggesting that LDN may reduce inflammation which may contribute to the painful aspect of FM. In a larger, double-blind study, the LDN group was found to have significantly lower pain levels [28.8% reduction vs. 18% reduction in the placebo group.] LDN was also associated with improved mood and improved life satisfaction. In one case study [21] LDN was used to treat Fibromyalgia based on the theory that FM indicates low endorphin secretion. Rationale for use was based on findings that a 4.5 mg dose of Naltrexone increases specific opioid receptors [22] by creating a temporary blockade followed by a rebound of increased endorphin activity. The patient in the aforementioned case study reported a reduction of pain in specific areas [back and neck] along with reduction in gait unsteadiness and improvements in fatigue, sleep, work capacity, mood
Case presentation LF is a 59-year old woman referred for evaluation and treatment of long-standing diffuse muscle pain associated with SPS. She had already had her diagnosis confirmed by multiple physicians including a neurologist at a major university medical center. Her pain symptoms began in the late 1990′s and through the course of the day were quite variable, ranging from 0 to 7 out of 10, with occasional “flare-ups” in the 9–10/10 range. She reported a poor tolerance for many activities of daily living, as exacerbations could be triggered by physical exertion, grocery shopping, housework and dayto-day chores. She also expressed a concern that her ribcage on one side was gradually drawing closer to her pelvis over time and was uncomfortable. Her past workup included many studies such as “blood tests”, EMG/ NCS, MRIs, CT scans as well as X-Rays. She explained that the studies revealed no etiology for her symptoms aside from SPS. The treatments she had received only helped her “a bit” and what she found most helpful was “massage therapy…but it only helps for a day or so”. She said at times she felt sad, hopeless and frustrated with her situation but never suicidal. Her medication management at the time of consultation included gabapentin 2100 mg/day, diazepam 35 mg/day, baclofen 30 mg/day, bupropion 200 mg/day, sertraline, regular IVIG infusions and oxycodone/acetaminophen typically 10 mg/day. She expressed frustration with opiate therapy she had received in the past and did not find her current or past treatments to be adequate. She had been offered a trial of intrathecal baclofen for possible intrathecal pump implantation but declined in the past and again declined at her pain management consultation. She was interested “mainly in natural therapies… not to take more pills…especially not narcotics…”. She was sent for an evaluation with a physical medicine and rehabilitation specialist and physical therapy, to pulmonology for baseline pulmonary function testing and offered a trial of a topical compounded medication including baclofen + cyclobenzaprine + ketoprofen + lidocaine. Initially she felt the topical gel was helpful, although after a few weeks its benefits waned. A discussion was had about the possibility that off-label use of LDN might help her, although she would need to come off all opiates first. She decided it was something she wished to try. After stopping her opiates for approximately two weeks, she was started on compounded oral naltrexone at 1.5 mg in the evening for a week, then 3 mg for a week, then increased to 4.5 mg. Six weeks after starting LDN she reported that her pain levels had decreased by approximately 50%, her anxiety had decreased, her agoraphobia had decreased and she reported a subjective recollection of fewer episodes of significant muscle tightness and discomfort. She reported no side effects aside from “sometimes weird or vivid dreams”. Fifteen weeks after starting LDN she reported continued benefit without additional side effects. Approximately six months after starting LDN she reported that her back pain had nearly completely resolved. She was participating in ongoing physical therapy and by nine months after starting LDN she reported that she was “doing even better” and reported that this was the most successful symptomatic treatment she had yet received for her condition. At a twelve month follow up, she continued to endorse dramatic reductions in pain (almost 100% reduction in her back pain), in addition to the maintenance of reductions in her other symptoms.
2
Medical Hypotheses 137 (2020) 109546
M. Zappaterra, et al.
and quality of life. There was also a decrease in objective pain measurements when Cold Pressor Test times were compared. In the treatment of osteoarthritis, one study looked at the effectiveness of Oxytrex, which is ultralow-dose naltrexone combined with oxycodone [23]. The authors cite earlier studies demonstrating the capacity of ultralow-dose opioid antagonists to enhance and prolong opiate analgesia and alleviate opioid tolerance and withdrawal in rats and mice. In this study involving 360 human participants, subjects with moderate to severe pain from osteoarthritis were administered placebo, oxycodone four times a day [qid], Oxytrex qid, or Oxytrex twice a day (bid). The Oxytrex bid administration produced a 39% reduction in pain intensity which proved to be significantly greater than that of placebo, oxycodone qid, and Oxytrex qid. Further, the Oxytrex administration was found to be superior to placebo in terms of quality of pain reduction, duration of pain control, global assessments by patients, and osteoarthritis index scores. Following the theory that LDN acts as a glial cell attenuator [specifically, an antagonist effect on Toll-Like Receptor-4 found on microglia], two case studies derived positive outcomes when LDN was used to treat Complex Regional Pain Syndrome, which involves central sensitization and glial activation in the central nervous system [24]. When LDN was added to already-established treatment regimens for CRPS, these patients reported a decrease of CRPS symptoms including pain levels, dystonic spasms and fixed dystonia.
References: [1] Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes. Muscle Nerve 2012 May;45(5):623–34. [2] Ameli R, Snow J, Rakocevic G, Dalakas MC. A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 2005;65:1961–3. [3] What is Stiff Person Syndrome? National Institute of Neurological Disorders and Stroke Web site. http://www.ninds.nih.gov/disorders/stiffperson/stiffperson.htm Published November 15, 2010. Accessed February 8, 2014. [4] Dalakas MC. The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. J Neurol 2005;252(1):19–25. [5] Wang D, Sun X, Sadee W. Different effects of opioid antagonists on mu-, delta-, and kappa-opioid receptors with and without agonist treatment. J Pharmacol Exp Ther 2007;321(2):544–52. [6] Shader RI. Antagonists, Inverse Agonists, and Protagonists. J Clin Pharmacol 2003;23(4):321–2. [7] Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF. Norman cousins lecture. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun 2007;21(2):131–46. [8] Younger J, Parkitny L, McLain D. The use of low-dose naltrexone as a novel antiinflammatory treatment for chronic pain. Clin Rheumatol 2014;33(4):451–9. [9] Dantzer R. Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 2007;21(2):153–60. [10] Greeley JD, Le AD, Poulos CX, Cappell H. “Paradoxical” analgesia induced by naloxone and naltrexone. Psychopharm [Berlin] 1988;96(1):36–9. [11] Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-Dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol 2007;102:1–9. [12] Smith JP, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, et al. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Dig Dis Sci 2011;56:2088–97. [13] Smith JP, Field D, Bingaman SI, Evans R, Mauger DT. Safety and tolerability of lowdose naltrexone therapy in children with moderate to severe Crohn’s disease: a pilot study. J Clin Gastroenterol 2013;47(4):339–45. [14] Pol O, Puig MM. Expression of opioid receptors during peripheral inflammation. Curr Top Med Chem 2004;4:51–61. [15] Rogers TJ, Peterson PK. Opioid G Protein-coupled receptors: signals at the crossroads of inflammation. Trends Immunol 2003;24–116-121.. [16] Kamphuis S, Eriksson F, Kavelaars,, et al. Role of endogenous pro-enkephalin Aderived peptides in human T cell proliferation and monocyte IL-6 production. J Neuroimmunol 1998;84:53–60. [17] Gironi M, Martinelli-Boneschi F, Sacerdote P, et al. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler 2008;14:1076–83. [18] Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol 2010;68:145–50. [19] Agrawal YP. Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses 2005;64:721–4. [20] Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med 2009;10(4):663–72. [21] Ramanathan S, Panksepp J, Johnson B. Is Fibromylagia an endocrine/endorphin deficit disorder? Is low dose naltrexone a new treatment option? Psychosomatics 2012;53(6):591–4. [22] Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses 2009;72:333–7. [23] Chindalore VL, Craven RA, Butera PG, Yu KP, Burns LH, Friedmann N. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia. J Pain 2005;6:392–9. [24] Chopra P, Cooper MS. Treatment of complex regional pain syndrome [CRPS] using low dose naltrexone [LDN]. J Neuroimmune Pharm 2013;8(3):470–6.
Conclusion: LDN may have utility in treating SPS symptoms. It is important to note that the use of LDN for these various conditions is extremely preliminary. Much of the available research comes in the form of case reports, or pilot studies having several limitations (e.g. open-label, small sample size, etc.). There certainly needs to be more replication of research in order to draw any solid conclusions. Here we present one case wherein LDN proved to be effective for SPS symptom management. We by no means are asserting that this translates over perfectly to other cases of SPS, only that these findings indicate a promising area of research involving the use of LDN with not only SPS, but also other chronic pain conditions. Conflict of Interest: The authors disclose no conflicts of interest. Acknowledgements: The authors disclose no financial conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.mehy.2019.109546.
3