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Low dose naltrexone for neuropathic pain

Low dose naltrexone is popular in the alternative treatment world. It is a bit strange, as this molecule is quite non-alternative. But low dose naltrexone (LDN) is recommended on lay internetsites for a multitude of diseases, from MS to cancer. That always provokes anti-bodies by doctors, but naltrexone indeed has anti-inflammatory properties. It might be an interesting treatment option for  treatment refractory neuropathic pain patients.

Low dose naltrexone, inflammatory response and neuropathic pain

Glia, asterocytes and modulation of inflammatory responses are hot in the search for new treatments for neuropathic pain. [1] [2][3] And not only the cannabinoids might work via this mechanism, [4] low dose naltrexone, popular at the time in patients suffering from MS [5], might play a role in this pathogenesis. [6][7]

The later is quite interesting, it provokes us to rethink the putative role of low dose naltrexone in the treatment of neuropathic pain… [8][9][10]

Let us review the only trial I know assessing the effects of low dose naltrexone in a sort of neuropathic pain: fibromyalgia.

Naltrexone low dose (LDN): a pilot trial

Recently a pilot trial was reported on the efficacy and safety of low dose naltrexone (4.5 mg) in fibromyalgia. Especially patients with a high ESR were found to be responders to the naltrexone theraoy. That is quite fitting with the above hypothesis. Especially since we know patients suffering from fibromyalgia pain also respond positive tp pregabeline. [11]  The authors of the report, Younger and Mackey, conducted a placebo-controlled, single-blind, crossover design study in 10 patients with moderately-severe fibromyalgia, and the dose was 4.5 mg/day.

Naltrexone treatment resulted in 32.5% decrease of overall fibromyalgia symptom severity on the visual analog scale compared with baseline, whereas the reduction was only 2.3% during the placebo phase (P<0.0005 versus baseline and P=0.003 versus placebo). [12] More details on the site of Stanford.

And the same dose seemed to inhibit the symptoms of Crohn’s disease.[13]

Thus, LDN, 3-4.5 mg/day a.n. might be an interesting therapeutic option for patients refractory to other pharmacological interventions.

LDN in our clinic

Meanwhile we gained positive experience prescribing 1-2.5 mg LDN, sometimes in combination with a gift of tramadol 12 hours later. That might boost the analgesic effects even more. Especially in overweight, obese individuals suffering from neuropathic pain, this regime worked quite impressive in our hands. But mostly in combination with the supplement palitoylethanolamide (PeaPure).

August 2010, Jan M. Keppel Hesselink, MD, PhD , revision feb 2014

Referentie

[1] Suter MR, Wen YR, Decosterd I, Ji RR. | Do glial cells control pain? | Neuron Glia Biol. | 2007 Aug;3(3):255-268.

[2] Ji RR, Xu ZZ, Wang X, Lo EH. | Matrix metalloprotease regulation of neuropathic pain. | Trends Pharmacol Sci. | 2009 Jul;30(7):336-40. Epub 2009 Jun 10.

[3] Byrnes KR, Stoica B, Loane DJ, Riccio A, Davis MI, Faden AI. | Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity. | Glia. | 2009 Apr 1;57(5):550-60.

[4] Rivers JR, Ashton JC. | The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies. | Cent Nerv Syst Agents Med Chem. | 2010 Mar;10(1):47-64.

[5] Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G. | A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. | Mult Scler. | 2008 Sep;14(8):1076-83.

[6] Lin SL, Tsai RY, Tai YH, Cherng CH, Wu CT, Yeh CC, Wong CS. | Ultra-low dose naloxone upregulates interleukin-10 expression and suppresses neuroinflammation in morphine-tolerant rat spinal cords. | Behav Brain Res. | 2010 Feb 11;207(1):30-6. Epub 2009 Sep 30.

[7] 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-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). | Eur J Neurosci. | 2008 Jul;28(1):20-9.

[8] Tsai RY, Jang FL, Tai YH, Lin SL, Shen CH, Wong CS. | Ultra-low-dose naloxone restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in PTX-treated rats. | Neuropsychopharmacology. | 2008 Oct;33(11):2772-82. Epub 2008 Jan 23.

[9] Tsai RY, Tai YH, Tzeng JI, Lin SL, Shen CH, Yang CP, Hsin ST, Wang CB, Wong CS. | Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats and prevents glutamate transporter downregulation by suppressing the p38 mitogen-activated protein kinase signaling pathway. | Neuroscience. | 2009 Apr 10;159(4):1244-56. Epub 2009 Feb 3.

[10] Largent-Milnes TM, Guo W, Wang HY, Burns LH, Vanderah TW. | Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling. | J Pain. | 2008 Aug;9(8):700-13. Epub 2008 May 12.

[11] Straube S, Derry S, Moore RA, McQuay HJ. | Pregabalin in fibromyalgia: meta-analysis of efficacy and safety from company clinical trial reports. | Rheumatology (Oxford). | 2010 Apr;49(4):706-15. Epub 2010 Jan 7.

[12] Younger J, Mackey S. | Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. | Pain Med. | 2009 May-Jun;10(4):663-72. Epub 2009 Apr 22.

[13] 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 Apr;102(4):820-8. Epub 2007 Jan 11.

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