Low Dose Naltrexone (LDN) in Recalcitrant CRPS

If you've heard of the drug Naltrexone, it's likely to have been according to its most known context, as explained by the good Wikipedia:

Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade. In some countries including the United States, a once-monthly extended-release injectable formulation is marketed under the trade name Vivitrol.

Yet, there is a movement calling for low dose Naltrexone clinical trials, as anecdotal evidence accrues that it is improving the quality of life for people with Parkinson's Disease, Crohn's, Multiple Sclerosis, and several cases of pancreatic cancer.

I tend toward skepticism but try to remember that Ketamine, which has proven useful to many CRPS patients, and others with unrelenting pain from things as diverse as advanced cancers to phantom limb pain, also came on the scene as the result of a single case study.

If you -- like me -- would like to read up on LDN therapies, a sort of clearinghouse of information is available through the efforts of doctors and researchers calling themselves "The LDNscience™ Team" HERE.

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This is the first article I've seen dealing specifically with CRPS and low dose Naltrexone.
Full text available online courtesy of SpringerLink

Journal of Neuroimmune Pharmacology
© The Author(s) 2013
Received: 7 November 2012
Accepted: 4 March 2013

Published online: 2 April 2013
10.1007/s11481-013-9451-y


Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)
Pradeep Chopra (1)  and Mark S. Cooper (2)
(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

Pradeep Chopra (Corresponding author)
Email: painri@yahoo.com

Mark S. Cooper
Email: mscooper@u.washington.edu

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

Introduction
Complex Regional Pain Syndrome (CRPS), formerly known as Reflex Sympathetic Dystrophy (RSD) is a neuroinflammatory condition that is characterized by a combination of sensory, autonomic, vasomotor, and motors dysfunctions. One of the characteristic symptoms of this condition is that the pain is out of proportion to the initial injury. Diagnoses of CRPS are often delayed because it is under recognized (Binkley 2012). If effective treatments are given early enough in progression of the disease, there is reduced chance for the spread of regional pain, autonomic dysfunction, motor changes, and negative sensory symptoms, such as hypoalgesia (Marinus et al. 2011). As CRPS progresses, it becomes refractory to sympathetic nerve blocks, conventional analgesics, anticonvulsants and antidepressants.

During neuroimmune activation, TLR4 (Toll-Like Receptor 4) is upregulated in microglia, resident immune cells of the central nervous system (Watkins et al. 2009). After transection of the L5 spinal nerve in the rat, TLR4 expression is increased in spinal microglia. This correlates with the rodent developing neuropathic pain (Tanga et al. 2005). From a post-mortem analysis of a CRPS patient, activated microglia and astroglia in the central nervous system (CNS) have been implicated in the generation of CRPS symptoms (Del Valle et al. 2009).

Activation of TLR4 in both microglia and CNS neurons augments the production of pro-inflammatory cytokines via the NF-κB pathway (Milligan and Watkins 2009; Leow-Dyke et al. 2012). NF-kB is a multi-functional transcription factor that is activated by c-Jun-N-terminal kinase (JNK), extracellular signal-related kinase (ERK), or p38 (Milligan and Watkins 2009). In activated glia and neurons, NF-κB activity promotes the production of pro-inflammatory cytokines and neurotoxic superoxides (Milligan and Watkins 2009; Leow-Dyke et al. 2012; Fellner et al. 2013), which act as mediators for neuropathic pain, as well as other neurological dysfunctions (Liu et al. 2000; Barbosa et al. 2012; Besedovsky and del Rey 2011). Pro-inflammatory cytokines, as well as the neurotrophin BNDF (brain-derived neurotrophic factor), induce enhanced excitatory tone and diminished inhibitory tone in nociceptive neural networks, leading to hyperalgesia or allodynia (von Hehn et al. 2012). Sustained TLR4 stimulation in microglial populations can also lead to neuronal injury and death (Fellner et al. 2013).

In rodents, the TLR4 antagonist, naltrexone, is able to suppress allodynia arising from bone cancer (Mao-Ying et al. 2012). In rodents, naltrexone is able to cross the blood–brain barrier, suppress glial cell activation, and reverse neuropathic pain arising from chronic constriction nerve injury (Hutchinson et al. 2008).

A recent study reports that low-dose oral naltrexone reduces pain in fibromyalgia patients (Younger and Mackey 2009). Low-dose naltrexone (LDN) refers to doses approximately 50-fold lower than doses of naltrexone typically given to patients addicted to opioids (Rea et al. 2004; Younger and Mackey 2009).
Opiate antagonists differ from opioids through a replacement of the characteristic N-methyl group with a N-cyclopropyl, N-allyl group. At low concentrations, naltrexone is able to antagonize TLR4 on activated glial cells, without inhibiting other opioid receptors in the CNS (Hutchinson et al. 2008). This allows endogenous anti-nociceptive pathways involving μ-receptors to continue operating.

A recent paper has reported positive benefit of ibudilast, an oral glial attenuator, for the treatment of neuropathic pain in several CRPS patients (Rolan et al. 2009). Below, we describe positive outcomes of two CRPS patients treated with low-dose naltrexone, in combination with other CRPS therapies. Low-dose naltrexone was utilized in these patients after more conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms. Each patient met IASP criteria for the diagnosis of CRPS.

Here are two sets of photos from the article of the first case study, before and after treatment with LDN:

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

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)

DISCUSSION

Causalgia, which is often a salient feature of CRPS, has long been viewed as having a neuroinflammatory etiology (Mitchell 1872; Sudeck 1901). Although centralized neuropathic pain has been connected to activated glia in rodents (Milligan and Watkins 2009), it is an open question whether the symptoms in CRPS in humans are linked to activated glia in the CNS. The positive responses of the two patients discussed above to LDN are among the first reported benefits of glial attenuators for CRPS symptoms. A prior study described moderate pain benefit to several CRPS patients enrolled in a clinical trial of ibudilast, another glial attenuator that is unrelated to LDN in its molecular action (Rolan et al. 2009).

The second case study addressed in this work is based on a teen who suffered from several other disorders, including  Ehlers-Danlos Syndrome. It's unfortunate (and, on a personal note, infuriating) but her instance, in particular, the evidence of "fixed dystonia" was glossed over as a probable conversion disorder.  That seems to be the state of things in areas of study that are a bit removed from clinical experience.

It's also important to recognize the limitations of all case study reports, and in these cases, there not being, for example, the exclusions and protocols of a clinical trial, both patients received a variety of concomitant treatments, and the methods of evaluation were diverse, and sometimes, lacking.

That said, it's something else for those of us with advanced CRPS non-responsive to treatment to check out. There is a large amount of anecdotal evidence/support among MS patients for use of Low Dose Naltrexone, but no sufficiently rigorous clinical trials to date.  It has also gained much support in the treatment of Crohn's disease, but again, more in popular media than scientific.

There have been accusations that LDN may fall into the frustrating category of "an unprofitable cure."

To read about both case studies and further discussion, click HERE.