LDN as novel anti-inflammatory for chronic pain

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RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

LDN as novel anti-inflammatory for chronic pain

Post by RitaA » Fri 24 Oct 2014 10:04

http://www.ncbi.nlm.nih.gov/pubmed/24526250
Clin Rheumatol. 2014 Apr;33(4):451-9. doi: 10.1007/s10067-014-2517-2. Epub 2014 Feb 15.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain.

Younger J1, Parkitny L, McLain D.

Author information

1 Stanford University, Stanford, CA, USA

Abstract

Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

PMID:
24526250
[PubMed - in process]
PMCID:
PMC3962576
Free PMC Article

The full article is here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/

I found the section “Beyond LDN” (near the end of the full article) especially interesting. As the authors of the article point out, it will take funding to pursue the various possibilities that they raise. Why isn't this type of research being generously funded by the NIH in the U.S. and the Canadian Institutes of Health Research (as just two examples)?

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: LDN as novel anti-inflammatory for chronic pain

Post by RitaA » Wed 27 May 2015 19:53

It’s encouraging for me to see that at least some research has already been conducted into the use of low-dose (in this case ultra-low dose) naltrexone in the management of pain syndromes. Chronic pain -- regardless of the cause -- is a growing concern in North America and no doubt other parts of the world.

http://www.molecularpain.com/content/6/1/22
Research

Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats

Theresa-Alexandra M Mattioli1, Brian Milne13 and Catherine M Cahill123*

1 Department of Pharmacology & Toxicology, Queen's University, Kingston, Ontario, K7L 3N6, Canada

2 Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, K7L 3N6, Canada

3 Department of Anaesthesiology, Kingston General Hospital, Queen's University, Kingston, Ontario, K7L 2V7, Canada

Molecular Pain 2010, 6:22 doi:10.1186/1744-8069-6-22

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance.

Results

Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration.

Conclusion

Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone. This research provides further validation for using ultra-low dose opioid receptor antagonists in the treatment of various pain syndromes.

[snip]

Conclusions

The results of this study may have a significant impact on the clinical management of moderate to severe pain. Patients currently treated with chronic opioid therapy may benefit not only from increased efficacy of combined opioid treatment [23,39], but may also experience fewer and less severe adverse effects [24,40], as sufficient analgesia can be achieved and maintained at lower opioid doses. Additionally, an understanding of the mechanism of action of opioid drugs will provide insight toward the development of more selective and efficacious pharmacological treatments for pain management. Not the least of which could be for improving treatment of chronic pain conditions such as neuropathic pain where glial activation is also evident, with reactive gliosis being a key contributor to the painful neuropathy [41-44]. Additionally, reduced opioid analgesic efficacy has also been reported in patients with neuropathic pain [45,46], however, co-administration of ultra-low dose antagonists with opioid agonists increased analgesic efficacy in animal models of neuropathic pain [47] and in clinical trials [23,24]. Future research will be required to determine if ultra-low dose naltrexone is able to alleviate established chronic pain.
Here's hoping that the "future" research mentioned in the last sentence is already underway in Canada and other countries.

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: LDN as novel anti-inflammatory for chronic pain

Post by RitaA » Wed 27 May 2015 20:22

Although this has already been posted in another thread, I think it's worthwhile repeating here:

http://link.springer.com/article/10.100 ... ltext.html
Journal of Neuroimmune Pharmacology

© The Author(s) 2013

10.1007/s11481-013-9451-y

PERSPECTIVE

Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)

Pradeep Chopra1 and Mark S. Cooper2

(1) Department of Medicine, Alpert Medical School of Brown University, 102 Smithfield Ave, Pawtucket, RI 02860, USA

(2) Department of Biology, Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA 98195-1800, USA


Received: 7 November 2012

Accepted: 4 March 2013

Published online: 2 April 2013

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.

Keywords:

Chronic pain – Complex regional pain syndrome – CRPS – Reflex sympathetic dystrophy – RSD – Neuropathic pain – Naltrexone – Fixed dystonia – Allodynia – Vasomotor – Ulceration – Dystonic spasms – Conversion disorder – Functional movement disorder – LDN

[snip]

Conclusion

Our use of LDN treatment for CRPS patients was motivated by a presumed neuroinflammatory etiology for long-standing CRPS symptoms. The remission of pain and dystonic spasms in Case 1, as well a remission of all CRPS symptoms (including fixed dystonia) in Case 2, provide evidence that a multi-modal interventional approach, which includes low-dose naltrexone (a known glial attenuator), should be considered as a treatment option for the treatment of CRPS patients, particularly those patients with dystonic movement disorders.

[snip]

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: LDN as novel anti-inflammatory for chronic pain

Post by RitaA » Wed 27 May 2015 21:02

Despite being a staunch critic when it comes to the use of naltrexone in certain doses and clinical situations, Dr. Dmitry M. Arbuck, MD did mention the need for further research into the use of low-dose naltrexone in a 2012 guest blog entry. Also, in fairness to Dr. Arbuck, it's important to acknowledge that some of his views may have changed since then and/or will change in the future as a result of scientific research and/or published case studies.

http://updates.pain-topics.org/2012/01/ ... ronic.html
Wednesday, January 18, 2012

Unique Uses of Naltrexone in Chronic Pain

The use of opioid antagonists in chronic pain management is gaining more recognition and increasing acceptance [7]. 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.]

[snip]

Low-Dose Naltrexone

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.

[snip]

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.

[snip]

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.

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