Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN)

Pradeep Chopra, Mark S Cooper, Pradeep Chopra, Mark S Cooper

Abstract

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.

Figures

Fig. 1
Fig. 1
Advanced CRPS symptoms in Case 1. 4.5 years after onset of the disorder. a Allodynia and pronounced vasomotor dysfunction are present in the lower right extremity (photo taken 9/18/2008). b One week later, the leg has developed numerous ulcerations
Fig. 2
Fig. 2
Case 1. Certain symptoms are attenuated following treatment with low-dose naltrexone (LDN) in a long-standing case of CRPS (6 years after onset). a Allodynia is greatly reduced in both legs after LDN. However, bilateral trophic changes remain in the lower extremities. Slight swelling is present in the distal portion of the right foot. Within 2 months of treatment with LDN, the patient was able to bear full body weight, and walk without assistance. Before LDN, the patient utilized a cane for 6 years. b One year after LDN treatment, the patient still has persistent long-term trophic changes in the skin of both lower extremities (taken 1/16/2013)
Fig. 3
Fig. 3
(Case 2) Fixed dystonia, allodynia, and vasomotor abnormalities in the right lower extremity of a CRPS patient (panel a) remitted following treatment with a low-dose naltrexone. b No symptoms and signs of CRPS after LDN treatment. Two months after surgical reinforcement of the right ankle for Ehlers-Danlos Syndrome (EDS)

References

    1. Bailey J, Nelson S, Lewis J, McCabe CS (2012) Imaging and clinical evidence of sensorimotor problems in CRPS: utilizing novel treatment approaches. J Neuroimmune Pharmacol (Epub ahead of print)
    1. Barbosa IG, Rocha NP, Huguet RB, Ferreira RA, Salgado JV, Carvalho LA, Pariante CM, Teixeira AL. Executive dysfunction in euthymic bipolar disorder patients and its association. J Affect Disord. 2012;137:151–155. doi: 10.1016/j.jad.2011.12.034.
    1. Besedovsky HO, del Rey A. Central and peripheral cytokines mediate immune-brain connectivity. Neurochem Res. 2011;36:1–6. doi: 10.1007/s11064-010-0252-x.
    1. Binkley K (2012) Improving the diagnosis and treatment of CRPS: insights from a clinical immunologist’s personal experience with an underrecognized neuroinflammatory disorder. J Neuroimmune Pharmacology (Epub ahead of print)
    1. Birklein F, Riedl B, Sieweke N, Weber M, Neundörfer B. Neurological findings in complex regional pain syndromes—analysis of 145 cases. Acta Neurol Scand. 2000;101:262–269. doi: 10.1034/j.1600-0404.2000.101004262x./.
    1. Church AJ, Dale RC, Giovannoni G. Anti-basal ganglia antibodies: a possible diagnostic utility in idopathic movement disorders? Arch Dis Child. 2004;89:611–614. doi: 10.1136/adc.2003.031880.
    1. Cohen HE, Hall J, Harris N, McCabe CS, Blake DR, Jänig W. Enhanced pain and autonomic responses to ambiguous visual stimuli in chronic Complex Regional Pain Syndrome (CRPS) type I. Eur J Pain. 2012;16:182–195. doi: 10.1016/j.ejpain.2011.06.016.
    1. Cooper MS. Nerve injuries and the fixed dystonias of CRPS. Pain Med. 2011;12:842–843. doi: 10.1111/j.1526-4637.2011.01082.x.
    1. Cooper MS, Clark VP (2012) Neuroinflammation, neuroautoimmunity, and the co-morbidities of CRPS. J Neuroimmune Pharm (Epub ahead of print)
    1. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, de Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;15:1017–1021. doi: 10.1038/nature04223.
    1. Del Valle L, Schwartzman RJ, Alexander G. Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav Immun. 2009;23:85–91. doi: 10.1016/j.bbi.2008.08.004.
    1. Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, Wenning GK, Stefanova N. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia. 2013;61:349–60. doi: 10.1002/glia.22437.
    1. Fong CY, de Sousa C. Childhood chorea-encephalopathy associated with human parvovirus B19 infection. Dev Med Child Neurol. 2006;48:526–528. doi: 10.1017/S0012162206001101.
    1. Grillo E, da Silva RJ. Childhood chorea-encephalopathy and unremarkable MRI: an association suggesting parvovirus B19 infection. Dev Med Child Neurol. 2009;51:759–761. doi: 10.1111/j.1469-8749.2009.03388.x.
    1. Hawley JS, Weiner WJ. Psychogenic dystonia and peripheral trauma. Neurology. 2011;77:496–502. doi: 10.1212/WNL.0b013e3182287aaf.
    1. Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, Patel SJ, Crysdale NY, Harrison JA, Maier SF, Rice KC, Watkins LR. Non-steroselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4) Eur J Neurosci. 2008;28:20–29. doi: 10.1111/j.1460-9568.2008.06321.x.
    1. Javed S, Sharples PM, Khan S, White E, Gill S. Recovery from fixed dystonia in complex regional pain syndrome type 1 (CRPS-1) following deep brain stimulation (DBS) surgery. Arch Dis Child. 2011;96(Suppl 1):A81. doi: 10.1136/adc.2011.212563.190.
    1. Kaindl AM, Degos V, Peineau S, Gouadon E, Chhor V, Loron G, Le Charpentier T, Josserand J, Ali C, Vivien D, Collingridge GL, Lombet A, Issa L, Rene F, Loeffler JP, Kavelaars A, Verney C, Mantz J, Gressens P. Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann Neurol. 2012;72:536–49. doi: 10.1002/ana.23626.
    1. Kharkar S, Ambady P, Venkatesh Y, Schwartzman RJ. Intramuscular botulinum toxin in complex regional pain syndrome: case series and literature review. Pain Phys. 2011;14:419–24.
    1. Kharkar S, Ambady P, Yedatore V, Schwartzman RJ. Intramuscular botulinum toxin A (BtxA) in complex regional pain syndrome. Pain Phys. 2011;14:311–316.
    1. Kohr D, Singh P, Tschernatsch M, Kaps M, Pouokam E, Diener M, Kummer W, Birklein F, Vincent A, Goebel A, Wallukat G, Blaes F. Autoimmunity against the b(2) adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain. 2011;152:2690–2700. doi: 10.1016/j.pain.2011.06.012.
    1. Kolb L, Lang C, Seifert F, Maihöfner C. Cognitive correlates of “neglect-like syndrome” in patients with complex regional pain syndrome. Pain. 2012;153:1063–1073. doi: 10.1016/j.pain.2012.02.014.
    1. Leow-Dyke S, Allen C, Denes A, Nilsson O, Maysami S, Bowie AG, Rothwell NJ, Pinteaux E. Neuronal toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro. J Neuroinflammation. 2012;9:230. doi: 10.1186/1742-2094-9-230.
    1. Linnman C, Becerra L, Borsook D (2012) Inflaming the brain: CRPS a model disease to understand neuroimmune interactions in chronic pain. J Neuroimmune Pharmacology (Epub ahead of print)
    1. Liu B, Du L, Hong JS. Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther. 2000;293:607–617.
    1. Maihöfner C, Peltz E. CRPS, the parietal cortex and neurocognitive dysfunction: an emerging triad. Pain. 2011;152:1453–1454. doi: 10.1016/j.pain.2011.03.018.
    1. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F. Patterns of cortical reorganization in complex regional pain syndrome. Neurology. 2003;61:1707–1715. doi: 10.1212/01.WNL.0000098939.02752.8E.
    1. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F. Cortical reorganization during recovery from complex regional pain syndrome. Neurology. 2004;63:693–701. doi: 10.1212/01.WNL.0000134661.46658.B0.
    1. Mao-Ying QL, Wang XW, Yang CJ, Li X, Mi WL, Wu GC, Wang YQ. Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats. Mol Brain. 2012;5:16. doi: 10.1186/1756-6606-5-16.
    1. Marinus J, Moseley GL, Birklein F, Baron R, Maihöfner C, Kingery WS, van Hilten JJ. Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol. 2011;10:637–648. doi: 10.1016/S1474-4422(11)70106-5.
    1. Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci. 2009;10:23–36. doi: 10.1038/nrn2533.
    1. Mitchell SW (1872) Injuries of nerves and their consequences. J.B. Lippincott & Company
    1. Mitchell MC, Memisoglu A, Silverman BL. Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. J Stud Alcohol Drugs. 2012;73:991–997.
    1. Moriwaki K, Yuge O, Tanaka H, Sasaki H, Izumi H, Kaneko K. Neuropathic pain and prolonged regional inflammation as two distinct symptomatological components in complex regional pain syndrome with patchy osteoporosis—a pilot study. Pain. 1997;72:277–282. doi: 10.1016/S0304-3959(97)00029-8.
    1. Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol. 2009;65:629–638. doi: 10.1002/ana.21692.
    1. Ochoa JL, Verdugo RJ. Reflex sympathetic dystrophy. A common clinical avenue for somatoform expression. Neurol Clin. 1995;13:351–363.
    1. Raja SN. Motor dysfunction in CRPS and its treatment. Pain. 2009;143:3–4. doi: 10.1016/j.pain.2009.01.024.
    1. Rea F, Bell JR, Young MR, Mattick RP. A randomized, controlled trial of low dose naltrexone for the treatment of opioid dependence. Drug Alcohol Depend. 2004;75:79–88. doi: 10.1016/j.drugalcdep.2004.02.003.
    1. Rolan P, Hutchinson M, Johnson K. Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease. Expert Opin Pharmacother. 2009;10:2897–2904. doi: 10.1517/14656560903426189.
    1. Sansing LH, Tüzün E, Ko MW, Baccon J, Lynch DR, Dalmau J. A patient with encephalitis associated with NMDA receptor antibodies. Nat Clin Pract Neurol. 2007;3:291–296. doi: 10.1038/ncpneuro0493.
    1. Schouten AC, van de Beek WJ, van Hilten JJ, van der Helm FC. Proprioceptive reflexes in patiens with reflex sympathetic dystrophy. Exp Brain Res. 2003;151:1–8. doi: 10.1007/s00221-003-1420-x.
    1. Schwartzman RJ, Erwin KL, Alexander GM. The natural history of complex regional pain syndrome. Clin J Pain. 2009;25:273–280. doi: 10.1097/AJP.0b013e31818ecea5.
    1. Schwenkreis P, Janssen F, Rommel O, Pleger B, Völker B, Hosbach I, Dertwinkel R, Maier C, Tegenthoff M. Bilateral motor cortex disinhibition in complex regional pain syndrome (CRPS) type I of the hand. Neurology. 2003;61:515–519. doi: 10.1212/WNL.61.4.515.
    1. Sibanc B, Lesnicar G. Complex regional pain syndrome and lyme borreliosis: two different diseases? Infection. 2002;30:396–399. doi: 10.1007/s15010-002-2006-4.
    1. Sudeck PHM. Uber die akute (reflektorische) Knochenatrophie nach Entzundungen und Verletzungen an den Extremitaten und ihre klinischen Erscheinungen. Fortschr Geb Rontgenstr. 1901;5:277.
    1. Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci U S A. 2005;102:5856–5861. doi: 10.1073/pnas.0501634102.
    1. van de Warrenburg BPC, Cordivari C, Brown P, Bhatia KP. Persisting hyperekplexia after idiopathic, self-limiting brainstem encephalopathy. Mov Disord. 2007;22:1017–1020. doi: 10.1002/mds.21411.
    1. van Hilten JJ. Movement disorders in complex regional pain syndrome. Pain Med. 2010;11:1274–1277. doi: 10.1111/j.1526-4637.2010.00916.x.
    1. van Hilten BJ, van de Beek WJ, Hoff JI, Voormolen JH, Delhass EM. Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med. 2000;343:625–630. doi: 10.1056/NEJM200008313430905.
    1. van Hilten JJ, van de Beek WJ, Vein AA, van Dijk JG, Middlekoop HA. Clinical aspects of multifocal or generalized tonic dystonia in reflex sympathetic dystrophy. Neurology. 2001;56:1762–176. doi: 10.1212/WNL.56.12.1762.
    1. van Hilten JJ, Rooijen DE, Geraedts EJ, Marinus J, Jankovic J. Peripheral trauma and movement disorders: a systematic review of reported cases. J Neurol Neurosurg Psychiatry. 2011;82:892–898. doi: 10.1136/jnnp.2010.232504.
    1. van Rijn MA, Marinus J, Putter H, Bosselar SR, Moseley GL, van Hilten JJ. Spreading of complex regional pain syndrome: not a random process. J Neural Transm. 2011;118:1301–1309. doi: 10.1007/s00702-011-0601-1.
    1. Verdugo RJ, Ochoa JL. Abnormal movements in complex regional pain syndrome. Muscle Nerve. 2000;23:198–205. doi: 10.1002/(SICI)1097-4598(200002)23:2<198::AID-MUS9>;2-4.
    1. von Hehn C, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Cell. 2012;73:638–651.
    1. Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci. 2009;30:581–591. doi: 10.1016/j.tips.2009.08.002.
    1. Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10:663–672. doi: 10.1111/j.1526-4637.2009.00613.x.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe