3 years ago today: Subanesthetic Ketamine Infusion #2

originally published 3/22/2011 -- republished to honor fred


I'm pretty blue, pretty exhausted.  Can't think of a reason why yesterday's treatment should be behind either of those states, but heck... who knows?

They upped the dose to 90 mg and infused it in about 2.5 hours.  It was not pleasant but I apparently did a good job hiding that from Fred.  The nurse somehow knew I wasn't having the time of my life, and gave me a pep talk at discharge about how finding the right dose takes time and then several treatments at that dose, or higher.  Monique, her name was Monique.

Without saying much, she said a lot.  Like how this may be pissing into the wind because I am starting so long after onset.  Nine years.  Nine years.  Nine years of this.

She wouldn't use the port (that's right -- after all we went through to get it in before the second infusion -- the doctor having said he would refuse to treat me if I showed up without one...) because it was so new, the site very... raw.  It's swollen, bruised, and just not healed at the "edges."  I could see Fred eating his outrage before bending to his book.

Instead of sitting by my side, he sat in the wheelchair at the foot of the guerny, so as to stay out of the way of the nurse and tech, who do vital signs frequently -- like every 15 minutes.  He was beautiful to behold, at least in my tripping mind -- standing out against the bleak fluorescence of the hallway, a silhouette I've come to love, a faithfulness I surely do not merit.

I remember crying. My legs spasming, relentless.  The i.v. tubing, the blood pressure cuff, the oxygen monitor --each thing assumed terrible proportions just by tapping against my skin, each tap scathingly painful. I remember thinking that so long as I didn't open my eyes, I'd be fine.  That's probably why Fred thought all was well, thought I was sleeping through it.  Not so.  Not even close.

I asked for my purse there toward the end.  I had wanted to take a clip of the statue in front of the hospital.  Instead, while completely out of my mind on ketamine, I took a video of the ceiling in my cubicle, the curtains surrounding my cubicle, the empty hall near my cubicle, and...

...the most comforting of comforts, perched in the wheelchair there at the end of everything, my sentinel, my guard -- the best argument, the best reason I know for opening the eyes...

Next week, an even higher dose.  Then, the following Monday, an assessment and decisions.



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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.

Functional imaging (fMRI) of allodynia in CRPS

Brain cells are one thing an fMRI can't hone in on.         Purestock/Getty Images

This article dates from 2006 and yet I've not heard much mention of people with CRPS having access or using functional MRI to assess allodynia.  Most likely, it offers little real information that can be put to use within treatment, but may open doors and minds within the research community. Should it become part of the diagnostic protocol?  

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Functional imaging of allodynia in complex regional pain syndrome

1. Christian Maihöfner, MD, PhD, 
2. Hermann O. Handwerker, MD, PhD and 
3. Frank Birklein, MD, PhD

+SHOW AFFILIATIONS

1. Address correspondence and reprint requests to Dr. C. Maihöfner, Department of Neurology/Institute for Physiology and Experimental Pathophysiology, University of Erlangen–Nuremberg, Universitätsstrasse 17, D-91054 Erlangen, Germany; e-mail:maihoefner@physiologie1.uni-erlangen.de

1. doi: 10.1212/01.wnl.0000200961.49114.39Neurology March 14, 2006 vol. 66 no. 5 711-717

ABSTRACT 

Objective: To investigate cerebral activations underlying touch-evoked pain (dynamic–mechanical allodynia) in patients with neuropathic pain.

Methods: fMRI was used in 12 patients with complex regional pain syndromes (CRPSs). Allodynia was elicited by gently brushing the affected CRPS hand. Elicited pain ratings were recorded online to obtain pain-weighted predictors. Both activations and deactivations of blood oxygenation level–dependent signals were investigated.

Results: Nonpainful stimulation on the nonaffected hand activated contralateral primary somatosensory cortex (S1), bilateral insula, and secondary somatosensory cortices (S2). In contrast, allodynia led to widespread cerebral activations, including contralateral S1 and motor cortex (M1), parietal association cortices (PA), bilateral S2, insula, frontal cortices, and both anterior and posterior parts of the cingulate cortex (aACC and pACC). Deactivations were detected in the visual, vestibular, and temporal cortices. When rating-weighted predictors were implemented, only few activations remained (S1/PA cortex, bilateral S2/insular cortices, pACC).

Conclusions: Allodynic stimulation recruits a complex cortical network. Activations include not only nociceptive but also motor and cognitive processing. Using a covariance approach (i.e., implementation of rating-weighted predictors) facilitates the detection of a neuronal matrix involved in the encoding of allodynia. The pattern of cortical deactivation during allodynia may hint at a shift of activation from tonically active sensory systems, like visual and vestibular cortices, into somatosensory-related brain areas.

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There were, following publication, letters that pointed out both the study's strengths and one considerable weakness:

Functional imaging of allodynia in complex regional pain syndromeRon Kupers, PET Unit & Dept. Surgical Pathophysiology, Rigshospitalet
KF 3892, Blegdamsvej 9, 2100 Copenhagen, Denmark

Maihofner et al [1] describe fMRI data of allodynia in complex regional pain syndrome (CRPS). The authors are to be congratulated for a very carefully designed study. Of the 12 patients, 11 were suffering from pain and sensory abnormalities in the right hand. This homogeneity in the anatomical distribution of the pain complaints may explain why the authors obtained allodynia-induced activation of SI whereas other brain imaging studies failed/ [2]

Maihofner's study is also important because their pain-related activations are predominantly contralateral to the stimulated body area, conform with findings in acute, experimental pain studies. This contrasts with reports of bilateral responses in the pain matrix, often with a preponderence of responses in the hemisphere ipsilateral to stimulation. [2,3] Whereas these latter studies investigated neuropathic pain patients with minor [2] or major [3] lesions to the nervous system, Maihofner et al used CRPS-type I patients, a neuropathic pain condition characterized by an absence of lesion to the peripheral nervous system.

Taken together, this suggests that the ipsilateral activations are not driven by pain but may reflect central reorganization as a result of deafferentation. However, alternative interpretations cannot be excluded. For instance, the average duration of pain complaints in Maihofner's study is significantly shorter than in the two other reports (< 0.5 years compared to > 2 and > 5 years). [2,3]

Maihofner also reported a deactivation of the ipsilateral primary somatosensory cortex during non-painful brushing. They argue that this has never been reported in healthy subjects and and therefore they relate this finding to the chronic pain condition. We strongly disagree with this interpretation. Drevets et al [4] reported that anticipation of a painful stimulus causes a decrease in regional brain activity in parts of the somatosensory cortex ipsilateral to the location of the expected pain stimulus.

We showed that activity in ipsilateral SI in normal subjects decreases not only during the anticipation of a stimulus but also during actual somatosensory stimulation. [5] In another recent study in healthy volunteers, we found strong evidence for ipsilateral deactivations in SI (Figure 1). Taken together, the ipsilateral deactivation following allodynic brushing is unlikely to be linked to the chronic pain state. The most parsimonious explanation is that it reflects top-down anticipatory modulation elicited by attention to the expected stimulus.

References
1. Maihofner C, Handwerker HO, Birklein F. Functional imaging of allodynia in complex regional pain syndrome. Neurology 2006; 66: 711-7.
2. Witting N, Kupers RC, Svensson P, Jensen TS. A PET activation study of brush-evoked allodynia in patients with nerve injury pain. Pain 2006; 120: 145-54.
3. Peyron R, Schneider F, Faillenot I, Convers P, Barral FG, Garcia- Larrea L, Laurent B. An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain. Neurology 2004; 63: 1838-46.
4. Drevets WC, Burton H, Videen TO, Snyder AZ, Simpson JR Jr, Raichle ME. Blood flow changes in human somatosensory cortex during anticipated stimulation. Nature 1995; 373: 249-52.
5. Kupers R, Svensson S, Jensen TS. Central representation of muscle pain and mechanical hyperesthesia in the orofacial region: a positron emission tomography study. Pain 2004, 108: 284-93.
Disclosure: The author reports no conflicts of interest.

The authors replied:

Christian Maihöfner, Department of Neurology, University of Erlangen Frank Birklein; Department of Neurology; University of Mainz; Germany
Schwabachanlage 6, 91054 Erlangen, Germany

We thank Dr. Kupers for his comments on our article. [1] The patients investigated in our study had no skin nerve lesions and had a moderate time in pain. Furthermore, we agree that one potential advantage of our study is that our patient group was homogenous with allodynia in one body region – hands. Dr. Kupers et al [2] and Dr. Peyron et al [3] investigated patients who complained of allodynia in very different body regions. In Peyron´s study [3], a significant proportion of patients even had pain from central origin (stroke). For stroke, significant central reorganization is obvious, but whether peripheral nerve lesions indeed affect encoding of allodynia in a way so that it occurs primarily in the ipsilateral brain hemisphere is speculative.

We also found bilateral responses after allodynic brushing in the medial affective pain system, as has been recently reported. [6] It seems reasonable that the major afferent pathways of touching, regardless of pain project in the lateral somatosensory discriminative system on the contralateral side as has been found in a previous PET- study of Dr. Witting and Dr. Kupers in experimental allodynia. [7] This confirms recent fMRI studies of our group. [8]

Regarding Dr. Kupers second point, we did not observe ipsilateral S1 deactivation after allodynic brushing. We observed ipsilateral S1 deactivation only after pleasant and non-painful brushing the healthy limb. We observed no ipsilateral deactivation during painful allodynia brushing when anticipation of the pain should be more intense than during pleasant touch. We continue to assume that ipsilateral S1 deactivation could be related to tonic activation of this brain region in unilateral chronic pain. Possibly tonic pre- activation also underlies the inconstant activation of the contralateral brain region as discussed above.

The increase of regional cerebral blood flow during brain activation (underlying BOLD effect and PET activation) will not be endless; there must be some asymptotic approach to a ceiling. We do agree that during somatosensory stimulation other leading sensory systems like visual or vestibular systems might become deactivated. This was one result of our study (see figure (E) F2). The underlying mechanisms and significance of BOLD deactivations are controversial. It is unclear what deactivations of the BOLD signal really mean (e.g. neuronal deactivation and or shift of attention). Further studies are needed to investigate the causes of ipsilateral S1 deactivation.

References
6. Schweinhardt P, Glynn C, Brooks J, McQuay H, Jack T, Chessell I et al. An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 2006.
7. Witting N, Kupers RC, Svensson P, Arendt-Nielsen L, Gjedde A, Jensen TS. Experimental brush-evoked allodynia activates posterior parietal cortex. Neurology 2001;57:1817-1824.
8. Maihofner C, Schmelz M, Forster C, Neundorfer B, Handwerker HO. Neural activation during experimental allodynia: a functional magnetic resonance imaging study. Eur J Neurosci 2004;19:3211-3218.
Disclosure: The authors report no conflicts of interest.

© 2013 L. Ryan

Topical Treatments to Reduce Allodynia in Rat Models of CRPS

CREDIT: Rats have feelings too

The Journal of Pain
Volume 14, Issue 1, Pages 66-78, January 2013


Topical Combinations Aimed at Treating Microvascular Dysfunction Reduce Allodynia in Rat Models of CRPS-I and Neuropathic Pain


J. Vaigunda Ragavendran, André Laferrière, Wen Hua Xiao, Gary J. Bennett, Satyanarayana S.V. Padi, Ji Zhang, Terence J. Coderre*

*Contact for reprint requests


Abstract
Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α2A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α2A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain.

Perspective
This article presents the synergistic antiallodynic effects of combinations of α2A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.


NOTE:  It may seem odd to publish the references without providing access to the article text, but many is the time I have found helpful background reading among footnoted/referenced sources. It takes some digging, but can pay off in greater understanding and finding your own "leads" within your particular research interests.

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