Signal Activity Data May Unlock Some Answers Behind Causes of Neuropathic Pain

Signal Activity Data May Unlock Some Answers Behind Causes of Neuropathic Pain

Clinicians seeking greater understanding of the neural activity behind pain can turn to the results of a University of Western Ontario study, which identified variations in neural activity associated with pain processing between control and neuropathic pain groups. These differences in signal activity—particularly in regions critical to endogenous analgesia—may represent a key step in elucidating the pathophysiology that underlies chronic neuropathic pain syndromes.Screen Shot 2015-10-19 at 3.46.52 PM

“Neuropathic pain affects approximately 5% of North Americans, and is considered to be caused by a lesion to the peripheral or central nervous system, trauma or disease,” said Jordan Leitch, MD, a resident at the London, Ontario, institution. “It’s characterized by either spontaneous episodic pain or pathological amplification of pain following a stimulus. In general, neuropathic pain is considered to be an expression of a maladaptive plasticity in the pain system that results in this constant state.”

During testing, functional MRI data were acquired while noxious stimuli were applied at the various pressures the patients had indicated the previous day. The researchers chose standardized pain ratings in lieu of standardized mechanical stimuli because pain response is subjective and varies widely between individuals.

As Dr. Leitch reported at the 2015 annual meeting of the Canadian Anesthesiologists’ Society (abstract 86017), both the volunteers and pain patients exhibited overall positive signal change at a pain rating of 2 and negative signal change at a pain rating of 6 in the midbrain and rostral medulla of the brainstem. However, consistent differences were observed between groups in the ipsilateral dorsal horn of the spinal cord, rostral ventromedial medulla and periaqueductal gray matter—three regions known to play an important role in nociceptive pain processing as well as the endogenous descending modulation of pain.

“In those regions, which we know are associated with ascending nociceptic transmission and the endogenous descending modulation of pain, we’re seeing positive signal change in the control group, but not much of anything in the carpal tunnel group,” she said.

“Another area we found interesting was around the dorsal horn of the cervical spinal cord, which is where the median nerve originates,” Dr. Leitch said. “And in the control group , we saw some variability from baseline, but not much deviation. But when we looked at the carpal tunnel patients, the times that correspond to pain levels 2, 4 and 6 show persistent positive signal changes that don’t follow what we would expect from controls.”

This study, the investigators concluded, is one of the first to identify variations in neural activity associated with pain processing. “I think seeing is believing in terms of pain,” she added. “This could be an important first step in the quantitative assessment of pain, in terms of both the diagnosis and treatment effect. In general, it’s a step towards a method to objectively visualize a sensation that has traditionally been completely limited to our patients’ subjective description.

“Obviously these signal changes are open to interpretation, but they could be the manifestation of the maladaptive plasticity that is postulated to be one of the causes of neuropathic pain,” Dr. Leitch explained. This research may contribute to future studies investigating endogenous analgesia and pain processing in patient groups, which may facilitate the optimization of pain management and improve quality of life for patients suffering from chronic neuropathic pain, he said.

Dr. Leitch was awarded second place at the meeting’s Residents’ Research Competition.

—Michael Vlessides

Weekly Breaking Research Updates

Weekly Breaking Research Updates

Scientific breakthroughs happen every day!  In an effort to help our patients stay up to speed on the most cutting edge treatment options available for them, our scientists monitor current research and publish weekly research updates.  The title of each article below is a link to the full study report.  If you’d like to make an appointment with Dr. Hanna to discuss your treatment options, please contact us.


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SR Totawar – Age, 2015

tchy action of the block, the block was converted to general anesthesia. If in case surg e effect

of the block wore off, rescue analgesia with intravenous ketamine given. In the circumstance

of nesthesia. If in case surgery was unduly us ketamine given.


Giuseppe D’Agostino1, 2*, Claudia Cristiano1, 2, 3, David J. Lyons2, Rita Citraro4, Emilio Russo4

C Avagliano, R Russo, GM Raso, R Meli, G De Sarro… – 2015

pharmacological PPAR-α agonist treatment in mice improves behavior in a pharmacological

model of ketamine-induced behavioral dysinhibition and repetitive behavior in BTBR T+ tf/J mice.

Keywords: lipids; nuclear receptor; ketamine; memory; neurodevelopmental disorders;


[PDF] Efficacy conventional intersc approach Vs novel transscal of brachial plexus block

SR Totawar – 2015

In the circumstance of inad anaesthesia. If in case surgery was undu intravenous

ketamine given. If in case surgery was unduly prolonged and the effect of the block

wore off, rescue analgesia with intravenous ketamine given.


Radiofrequency Ablation of the Pancreas: Protective Effect of Local Cooling Techniques

A Geranios, E Pikoulis, A Papalois, M Kontos… – The American Surgeon, 2015

1). Surgical Procedure The animals were anesthetized with ketamine (15–20 mg/kg) and

midazolam (0.5 mg/kg) in- tramuscularly and then intubated. The maintenance of anesthesia

was achieved by thiopental (3.5 mg/kg/hr) and fentanyl (15 mg/kg/hr).


[HTML] Original Study Enhancement of Acute Tendon Repair Using Chitosan Matrix

E Melamed, BG Beutel, D Robinson – Am J Orthop, 2015

Tikva, Israel. The rats were anesthetized with ketamine 90 mg/kg and xylazine 10

mg/kg, both administered intramuscularly, and anesthesia was prolonged as needed

with 2% isoflurane, administered by nose cone. The skin


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HCS Abeysinghe, L Bokhari, GJ Dusting, C Roulston – J Neurol Neurophysiol, 2015

food and water. Rats were anaesthetized using a mixture of Ketamine/Xylazine

(75 mg/kg: 10 mg/kg respectively ip) and maintained throughout surgery by inhalation

of isoflurane (95% oxygen and 5% isoflurane). A 23-gauge


Antiseizure medications

S Sanders – Seizures in Dogs and Cats

felbamate (FBM); ketamine (KET); lacosamide (LCM). Summary. The uncommon drugs include

felbamate (FBM), ketamine (KET), lacosamide (LCM), and propofol (PRO). Some of the rarely

used drugs are carbamazepine, ethosuximide, and valproic acid. Get PDF (344K).


Chronic neurokinin-1 receptor antagonism fails to ameliorate clinical signs, airway hyper-responsiveness or airway eosinophilia in an experimental model of feline …

M Grobman, A Graham, H Outi, JR Dodam, CR Reinero – Journal of Feline Medicine …, 2015

23 Briefly, ketamine (30 mg IV) was used as a premedicant, propofol was used for induction

(6 mg/kg) and maintenance (0.3 mg/kg/min), and cisatracurium (0.1 mg/kg IV of with additional

doses of 0.01–0.02mg/kg titrated to effect) was administered for neuromuscular blockade.


[PDF] Evaluation of Anti-inflammatory and Analgesic Activities of Cymbopogon citratus in vivo-Polyphenols Contribution

R Garcia, JP Ferreira, G Costa, T Santos, F Branco… – Research Journal of …, 2015

Ketamine (Ketalar, 7.7 mg kgG )1 was purchased from Parke-Davis, Pfizer (Seixal,

Portugal) Chlorpromazine (Largatil, 2.3 mg kgG )1 was purchased from

Rhône-Poulenc Rores, Laboratório Vitória SA (Amadora, Portugal).


Acute neurokinin-1 receptor antagonism fails to dampen airflow limitation or airway eosinophilia in an experimental model of feline asthma

M Grobman, S Krumme, H Outi, JR Dodam… – Journal of Feline Medicine …, 2015

19 Briefly, ketamine (30 mg IV) was used as a premedicant, propofol was used for induction

(6 mg/kg) and maintenance (0.3 mg/kg/min), and cisatracurium (0.1mg/kg IV, with additional doses

of 0.01–0.02 mg/kg titrated to effect) was administered for neuromuscular blockade.


Radiofrequency Ablation (RFA)


Radiofrequency Ablation of the Pancreas: Protective Effect of Local Cooling Techniques

A Geranios, E Pikoulis, A Papalois, M Kontos… – The American Surgeon, 2015

Pancreatic carcinoma is one of the commonest malignant diseases today and the majority of

patients are suitable for palliative treatment only. Radiofrequency ablation (RFA) has been

used extensively for the treatment of solid organ tumors but little is known on the efficacy


Effects of renal denervation from the intima and the adventitia of renal arteries on renal sympathetic nerve activity in dogs: a comparative study

M Bai, C Yang, C Gao, X Wang, H Liu, Y Zhang, J Liu… – Cardiology, 2015

A cardiac radiofrequency ablation catheter was then applied to ablate the adventitia from the

outside, also of 8 W or less and lasting up to 2 min each to obtain up to six ablations separated

both longitudinally and rotationally, which was the same as the ablation of renal


[PDF] Laryngopharyngeal Reflux: a Syndrome that Mimics Asthma

M Merchant – Proceedings of UCLA Healthcare, 2015

Surgical options include minimally invasive procedures such as radiofrequency ablation of the

lower esophageal sphincter as well as endoscopic Nissen Fundoplication, a procedure where

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Helical DeNervation Ablation Catheter Apparatus

J Mogul – US Patent 20,150,126,992, 2015

sympathetic nerves which run through the adventitia of the renal arteries using radiofrequency

(RF) energy The catheter’s RF-ablation electrode(s) will then be deployed by movement of the

slider the endoluminal, or inner arterial, surface of the artery in order to ablate the renal


Method and Apparatus for Tissue Ablation

VK Sharma, H Jabs – US Patent 20,150,126,990, 2015

can use one or more sources of infrared, electromagnetic, acoustic or radiofrequency energy

to anal canal; engaging the targeted hemorrhoid by suctioning the hemorrhoid into the ablation

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[PDF] N. Ayez1, EP van der Stok1, DJ Grünhagen1, J. Rothbarth1, E. van Meerten2, AM Eggermont3, C. 5 Verhoef1 6 7

DJ Grünhagen – 2015

Local treatment was performed in 122 170 patients (47%) (surgery, radiofrequency ablation,

stereotactic radiotherapy), 112 patients (43%) had 171 palliative chemotherapy and 29 patients

(11%) received neither chemotherapy nor local treatment. 172



M Jurna, JA Palero, MR Horton – US Patent 20,150,126,913, 2015

The modifier is configured to decrease the electrical impedance for the radiofrequency energy,

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Apparatus and Methods Related to Constrained Deployment of Cryogenic Balloons for Limited Cryogenic Abiation of Vessel Walls

B Kelly, J Kelly, G Kelly, B Mullins – US Patent 20,150,126,986, 2015

As compared to ablation lesions formed via radiofrequency energy, cryotherapy typically utilizes

much less power vessel wall and thus results in a smaller nominal treatment area/ablation pattern

than In another embodiment (not shown), if it is desired to ablate more than half of


[PDF] Long-term efficacy of radiofrequency ablation compared to surgical resection for the treatment of small hepatocellular carcinoma

X Bu, Z Ge, J Ma, S Guo, Y Wang, J Liu

Xiangyang Bu1,2*, Zhong Ge3*, Jian Ma4, Shanyuan Guo5, Yi Wang3, Jun Liu6 1Department

of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan 250021, China; 2Department

of Hepatobiliary Surgery, Qingdao Municipal Hospital, Qingdao 266011, China;


Complex Regional Pain Syndrome (CRPS/RSD)


Evolving Chinese Restaurant Processes for Modeling Evolutionary Traces in Temporal Data

P Wang, C Zhou, P Zhang, W Feng, L Guo, B Fang – Advances in Knowledge …, 2015

To model cluster branching over time, ECRP lets each cluster in current epoch form a Chinese

Restaurant Process (CRP) and uses the combination of cluster-specific CRPs as the prior for

clusters in the next epoch. where ωt−1,k and ωt,O are the weights of CRPs.


Practical Problems With Clinical Guidelines for Breast Cancer Prevention Based on Remaining Lifetime Risk

AS Quante, AS Whittemore, T Shriver, JL Hopper… – Journal of the National …, 2015

To evaluate discrimination, we computed the overall AUC and we plotted case risk

percentiles (CRPs, also called standardized placement values) (21) for the subjects who

developed breast cancer within 10 years of recruitment (case patients).



S Arimori – US Patent 20,150,126,516, 2015

A01N43/58. Related US Applications: 20040209906, Composition comprising


October, 2004, Cavazza et al. 20070249732, USE OF CERTAIN


[PDF] News from the Patient Liaison Committee: The brave new world ‘How are pain services evolving–the impact on patients?’

A Chuter – Reltebon® Oxycodone Prolonged-release Tablets, 2015

Page 16. March 2015 Vol 13 No 1 l Pain News 13 Pain News 2015, Vol 13 (1)

13–14 © The British Pain Society 2015 News After months of planning by Geraldine

Granath, Colin Preece, Liz Killick, Austin Leach and Antony Chuter



KD Benson, VR Lucente, JR Miklos – US Patent 20,150,126,894, 2015

Neuromodulation has also been used safely and effectively to help relieve chronic back pain,

pain from cancer and other nerve injuries, and pain from Complex Regional Pain Syndrome

(CRPS) and Reflex Sympathetic Dystrophy (RSD), greatly improving the quality of life for



EV Smith-Forbes – 2015

Multi-joint Fracture Multiple 0.0% 0.0% 0.0% 2.0% CRPS 0.0% 0.0% 0.0% 1.6% Nerve Injury

0.0% 0.0% 0.0% 1.2% MCID= minimal clinical important difference, DRUJ= distal radio-ulnar

joint, CRPS = complex regional pain syndrome, ROC = receiver operator characteristics


[PDF] Temperature Dependent Dielectric Model at 1.4 GHz for an Agricultural Soil Thawed and Frozen

VL Mironov, AY Karavaysky

0.513 The results of validation measurements for the soil CRPs are displayed in

Fig. range. To obtain the error of the developed model, we correlated the predicted

CRPs with the ones especially measured for validation. In Fig.


[PDF] A Bayesian A Bayesian Beta Markov Random Beta Markov Random Field Calibration of the Term structure of implied risk neutral densities densities

R Casarin, FR Casarin, F Leisen, GMGMG Molina…

Page 1. A Bayesian A Bayesian Beta Markov Random Beta Markov Random Field Calibration

of the Term structure of implied risk neutral densities densities Roberto Casarin, Fabrizio Roberto

Casarin, Fabrizio Leisen, German Molina German Molina German Molina,





[PDF] Heart rate turbulence analysis in female patients with fibromyalgia

O Solak, H ToktasIV – 2015

OBJECTIVE: Fibromyalgia is characterized by diffuse musculoskeletal pain and discomfort.

There are several reports regarding autonomic nervous system dysfunction in patients with

fibromyalgia. Heart rate turbulence is expressed as ventriculophasic sinus arrhythmia and



ME Platt – Alternative Medicine, 2015

Abstract From a survival standpoint, the body always wants to make sure the brain has

enough fuel.[…] any time the body detects a low amount of fuel in the brain, it releases

adrenaline to raise sugar levels.[…] use of these methods often leads to a cure for


[PDF] Association of Impaired Sleep Quality in Patients With Burning Mouth Syndrome: A Case-Control Study

F Arbabi-Kalati, NM Bakhshani, B Tahmtan… – 2015

deprivation. Sleep deprivation can also lead to mood changes, insomnia and fatigue,

affecting pain sensation (2). Patients with known fibromyalgia have a lower noc- turnal

sleep quality compared to controls and have more insomnia


Dizziness, Lightheadedness, and Syncope in a Patient with Type 2 Diabetes

S Paturi, JL Gilden, F FCP – Diabetes Case Studies: Real Problems, Practical …, 2015


Vagally mediated heart rate variability in headache patients—a systematic review and meta-analysis

J Koenig, DWP Williams, AH Kemp, JF Thayer – Cephalalgia, 2015

capabilities (21). Lower vmHRV is reported in a variety of chronic painful conditions,

such as chronic neck pain (22), chronic pelvic pain (23), complex regional pain (24),

fibromyalgia (25,26) and irritable bowel syndrome (27). In


Novel Therapeutic Uses of Mu-Opiate Receptor Peptides

TE Maione – US Patent 20,150,126,455, 2015

pain. 16. The method, according to claim 1, used to reduce chronic noncancer pain

selected from pain associated with arthritis, neuropathy, low back pain, osteoarthritis,

fibromyalgia, headache, and diabetic neuropathy. 17.


Brain-gut axis: gastroenterology-IBS

J Wright – The Specialist Forum, 2015

to controls. Interestingly, this hypoalgesia was even greater in patients with concomitant

fibromyalgia, suggesting a commonality between these two symptom-driven diagnoses.

Anticipatory factors may also play a part. In experiments


[PDF] A Pilot Study Measuring Outcomes of Managing Fascial Health for Individuals With Fibromyalgia

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diagnosed with fibromyalgia based on the protocol developed by the author, Dr. Kirstie

Bender Segarra, and implemented in a pilot study of five clients. The protocol was


[PDF] The Somatosensory Amplification in Vitiligo and Chronic Urticaria Patients: A Controlled Study

M Sukan, F Maner – J Neurol Disord, 2015

Amplification may be a pathogenic mechanism in certain specific amplification

disorders such as fibromyalgia and irritable bowel syndrome [9]. Some individuals

are generally more sensitive to bodily sensation than others.


Psychotherapy and mental health as a psychological science discipline

HU Wittchen, S Härtling, J Hoyer – Verhaltenstherapie, 2015

which behavioural factors play a significant role in the initiation, maintenance and rehabilitation,

such as cancer (eg [Fors et al., 2011]), cardiovascular disease (eg [Gulliksson et al., 2011]),

metabolic disease and obesity (eg [Grilo et al., 2012]), and fibromyalgia [Kashikar-Zuck et

Cannabinoids for neuropathic pain conditions

Cannabinoids for neuropathic pain conditions

Neuropathic pain is often very difficult to treat with current Food and Drug Administration (FDA)-approved analgesics.  The most commonly prescribed medication to treat these chronic pain conditions is opioids.  Opioids have very limited efficacy in patients with chronic neuropathic pain conditions.  This has sparked research into new targets for the treatment of these patients.  Promising research by investigators at the Cleveland Clinic demonstrated that microglial inflammation is a common pathway for neuropathic pain and other treatment-resistant neuroinflammatory conditions, such as Alzheimer’s disease (AD).

“Microglial inflammation is a mechanism of many CNS disorder – neuropathic pain, Alzheimer’s disease, multiple sclerosis, parkinsonism, you name it,” said lead researcher Mohamad Naguid, MD, of Cleveland Clinic’s Anesthesiology Institute, Department of Pain Management.

Subsequently, this team of researchers has synthesized a molecule called MDA7, which is a cannabinoid type 2 (CB2) receptor-selective agonist.  Preliminary studies with this new drug candidate have shown that it can inhibit microglial activation and recruitment, which is fundamental to microglial inflammation and neuropathic pain.

Thus far, their research is in the preclinical phase.  They have shown efficacy in a rodent model of Chemotherapy-induced neuropathic pain1, CRPS (not yet published), and some promising results in an animal model of Alzheimer’s disease2.  They hope to test MDA7 in humans as a next step.  The team is very hopeful that their preclinical results translate well to the clinic.  Only time will tell.


1. Naguib, M., Xu, J.J., Diaz, P., Brown, D.L., Cogdell, D., Bie, B., Hu, J., Craig, S., Hittelman, W.N., 2012. Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system. Anesthesia and analgesia 114, 1104-1120.

2. Bie, B., Wu, J., Yang, H., Xu, J.J., Brown, D.L., Naguib, M., 2014. Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency. Nature neuroscience 17, 223-231.