Small Molecule Angiotensin II Type 2 Receptor (AT2R) Antagonists as Novel Analgesics for Neuropathic Pain: Comparative Pharmacokinetics, Radioligand Binding, and Efficacy in Rats

Pain Medicine

1. Maree T. Smith PhD^1,2,*, 
2. Bruce D. Wyse PhD^1,2, 
3. Stephen R. Edwards PhD^1,2

Article first published online: 14 MAR 2013

DOI: 10.1111/pme.12063

Abstract

Objective

Neuropathic pain is an area of unmet clinical need. The objective of this study was to define the pharmacokinetics, oral bioavailability, and efficacy in rats of small molecule antagonists of the angiotensin II type 2 receptor (AT₂R) for the relief of neuropathic pain.

Design and Methods.

Adult male Sprague-Dawley (SD) rats received single intravenous (1–10 mg/kg) or oral (5–10 mg/kg) bolus doses of EMA200, EMA300, EMA400 or EMA401 (S-enantiomer of EMA400). Blood samples were collected immediately pre-dose and at specified times over a 12- to 24-hour post-dosing period. Liquid chromatography tandem mass spectrometry was used to measure plasma drug concentrations. Efficacy was assessed in adult male SD rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve.

Results.

After intravenous administration in rats, mean (±standard error of the mean) plasma clearance for EMA200, EMA300, EMA400, and EMA401 was 9.3, 6.1, 0.7, and 1.1 L/hour/kg, respectively. After oral dosing, the dose-normalized systemic exposures of EMA400 and EMA401 were 20- to 30-fold and 50- to 60-fold higher than that for EMA300 and EMA200, respectively. The oral bioavailability of EMA400 and EMA401 was similar at ∼30%, whereas it was only 5.9% and 7.1% for EMA200 and EMA300, respectively. In CCI rats, single intraperitoneal bolus doses of EMA200, EMA300, and EMA400 evoked dose-dependent pain relief. The pain relief potency rank order in CCI rats was EMA400 > EMA300 > EMA200 in agreement with the dose-normalized systemic exposure rank order in SD rats.

Conclusion.

The small molecule AT₂R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain.

Management of Neuropathic Pain with Methylprednisolone at the Site of Nerve Injury

1. Pain Medicine
2. H. Evren Eker MD^*, 
3. Oya Yalcin Cok MD, 
4. Anis Aribogan MD, PhD, 
5. Gulnaz Arslan MD, PhD
6. 1. Article first published online: 7 FEB 2012
      DOI: 10.1111/j.1526-4637.2011.01323.x
      Abstract
      Objective.  Peripheral nerve blocks with methylprednisolone may provide effective pain therapy by decreasing ectopic neuronal discharge and the release of local inflammatory mediators at the site of nerve injury. In this study, we aimed to compare the efficacy of lidocaine alone with a combination of depo-methylprednisolone plus lidocaine in the management of neuropathic pain due to peripheral nerve damage.

Design.  Randomized, double-blind comparator trial

Setting.  Group control (N = 44) received 0.5% lidocaine and group methylprednisolone (N = 44) received 80 mg depo-methylprednisolone + 0.5% lidocaine proximal to the site of nerve injury with a total amount of 10–20 mL solution according to the type of peripheral nerve block with nerve stimulator.

Outcome Measures.  Demographic data, preblock numerical rating scales (NRSs), the Leeds assessment of neuropathic symptoms and signs (LANSS₀) score, accompanying symptoms, and analgesic requirements were recorded. Postblock NRS scores were noted following peripheral nerve block and after 3 months. LANSS₁, accompanying symptoms, and analgesic requirements were also reevaluated 3 months after the injection.

Results.  Demographic data, preblock NRS (8 ± 1.5 and 8.1 ± 1.2, respectively), postblock NRS (2.1 ± 1.2 and 2.4 ± 1.4, respectively), LANSS₀ (18.4 ± 2.2 and 18.2 ± 2.1, respectively), and accompanying symptoms were comparable between groups. Scores for the methylprednisolone group were significantly improved at 3-month postblock for NRS (2 ± 1.4 vs 5.2 ± 1.7) and LANSS₁ scores (4.14 ± 2.7 vs 14.1 ± 2.8), accompanying symptoms, and analgesic requirements (P < 0.0001).

Conclusions.  Our results suggest that peripheral nerve block with 80 mg depo-methylprednisolone plus 0.5% lidocaine provides effective management in the treatment of neuropathic pain due to peripheral nerve damage.

Treatment of neuropathic pain with 5% lidocaine-medicated plaster: Five years of clinical experience

	July/August 2011, Volume 16 Issue 4: 259-262
C Delorme, M Navez, V Legout, R Deleens, D Moyse BACKGROUND: Neuropathic pain is often severe and adversely affects patients' quality of life. OBJECTIVE: To perform a retrospective, observational study investigating the efficacy and safety of treating refractory chronic neuropathic pain with 5% lidocaine-medicated plaster, in patients attending pain centres. METHODS: Medical records from 467 patients treated with 5% lidocaine- medicated plaster were evaluated for efficacy (maximum and minimum pain intensities and coanalgesic consumption) and adverse events. Data from an initial assessment and at least one follow-up visit had to be available, and separate analyses were conducted for the general population and the subpopulation older than 70 years of age. RESULTS: Of the patients enrolled, 25.0% were older than 70 years of age. While 20.6% had postherpetic neuralgia, 76.3% had other types of peripheral pain. Approximately 78.1% of cases of peripheral neuropathic pain followed surgery, and 23% were post-traumatic pain. The time from onset to referral was more than one year in two- thirds of cases. All patients experienced pain of at least moderate severity (mean [± SD] 11-point numerical rating scale score 5.2±2.4 to 8.2±1.6). Treatment with 5% lidocaine-medicated plaster reduced pain intensity by more than 50% in 45.5% of patients, and by at least 30% in 82.2%. Of note, the consumption of analgesics and coanalgesics was significantly reduced. Results were similar in both the general population and the subpopulation older than 70 years of age, at high risk and often receiving multiple medications. CONCLUSIONS: Treatment of refractory neuropathic pain with 5% lidocaine-medicated plaster clearly demonstrated efficacy and an excellent safety profile in patients with refractory neuropathic pain.

Maldynia: Pathophysiology and Management of Neuropathic and Maladaptive Pain—A Report of the AMA Council on Science and Public Health

• Pain Medicine

  Volume 11, Issue 11, pages 1635–1653, November 2010

  1. Barry D. Dickinson PhD, 
  2. C. Alvin Head MD, 
  3. Stuart Gitlow MD, 
  4. Albert J. Osbahr, III MD

  Article first published online: 2 NOV 2010

  DOI: 10.1111/j.1526-4637.2010.00986.x

Abstract

Background.  Because of disparate taxonomic arrays for classification, the American Academy of Pain Medicine has proposed categorizing pain on a neurobiologic basis as eudynia (nociceptive pain), Greek for “good pain,” or maldynia (maladaptive pain), Greek for “bad pain.” The latter has been viewed as maladaptive because it may occur in the absence of ongoing noxious stimuli and does not promote healing and repair.

Objective.  To address recent findings on the pathogenesis of pain following neural injury and consider whether the development of maladaptive pain justifies its classification as a disease and to briefly discuss the scope of pharmacologic and non-pharmacologic approaches employed in patients with such pain.

Methods.  English language reports on studies using human subjects were selected from a PubMed search of the literature from 1995 to August 2010 and from the Cochrane Library. Further information was obtained from Internet sites of medical specialty and other societies devoted to pain management.

Results.  Neural damage to either the peripheral or central nervous system provokes multiple processes including peripheral and central sensitization, ectopic activity, neuronal cell death, disinhibition, altered gene expression, and abnormal sprouting and cellular connectivity. A series of neuro-immune interactions underlie many of these mechanisms. Imaging studies have shown that such damage is characterized by functional, structural, and chemical changes in the brain. Such pain is maladaptive in the sense that it occurs in the absence of ongoing noxious stimuli and does not promote healing and repair.

Conclusion.  As defined, maldynia is a multidimensional process that may warrant consideration as a chronic disease not only affecting sensory and emotional processing but also producing an altered brain state based on both functional imaging and macroscopic measurements. However, the absolute clinical value of this definition is not established.

Neuroma Removal for Neuropathic Pain: Efficacy and Predictive Value of Lidocaine Infusion

Clinical Journal of Pain:

              Nikolajsen, Lone MD, PhD

      November/December 2010 - Volume 26 - Issue 9 - pp 788-793

             doi: 10.1097/AJP.0b013e3181ed0823

Abstract

Objective: Injury to peripheral nerves associated with trauma, amputation, or surgery may lead to the formation of neuromas that can produce severe pain refractory to pharmacotherapy. Ectopic impulse activity arising in blindly ending axons within the neuroma, which contain abnormal accumulations of sodium channels, is thought to be a major contributor to this pain. The effect of surgical excision has remained controversial. Here we report a prospective study on the effect of neuroma removal on pain.

Methods: A series of 6 patients with chronic neuropathic pain owing to neuromas after nerve injury were studied before and 3 months after neuroma excision. Quantitative sensory testing included measurement of areas of brush-evoked allodynia, pinprick hyperalgesia, and mechanical and thermal thresholds. The hypothesis that the analgesic response to a preoperative, intravenous infusion of the sodium channel blocker lidocaine can predict outcome of surgery was also tested.

Results: Surgery only relieved spontaneous pain in 2 out of the 6 patients. One of those patients had a prior poor response to neuroma removal. In one patient the pain worsened. Response to surgical removal of neuromas was not predicted by the response to preoperative infusion of intravenous lidocaine.

Discussion: Our findings suggest that, as a therapeutic maneuver, surgical excision of neuromas should be reserved for only those patients with intractable pain, who have failed to respond to other therapies. However, prior poor response to neuroma removal does not preclude relief of pain after a new excision.

Contribution of Primary Afferent Channels to Neuropathic Pain

Current Pain and Headache Reports 2009, 13:197-207 Current Medicine Group  LLC ISSN 1531-3433 Copyright © 2010 by Current Medicine Group LLC

Andrea M. Harriott, BS and Michael S. Gold, PhD

Corresponding author:
Michael S. Gold, PhD
Department of Anesthesiology, University of Pittsburgh, 3500 Terrace Street, Room E1440 BST, Pittsburgh, PA 15213, USA.
Email: msg22@pitt.edu

Neuropathic pain remains a serious medical problem because of patient morbidity and the absence of effective therapeutic interventions.

Recent evidence suggests that this type of pain may be particularly difficult to manage because underlying mechanisms are influenced by a variety of factors, including type of injury, site of injury, and time after injury.

This situation is exacerbated by the fact that different mechanisms may contribute to unique aspects of neuropathic pain, including ongoing pain as well as mechanical and thermal hypersensitivity. The different ion channels present in primary afferent neurons implicated in each of these aspects of neuropathic pain are reviewed.

Capsaicin jelly against migraine pain

International Journal of Clinical Practice Volume 64 Issue 4, Pages 457 - 459
Published Online: 5 Feb 2010
C. Cianchetti
Neuropsichiatria Inf., University, Azienda Ospedaliero-Universitaria, Cagliari, Italy
Correspondence to Carlo Cianchetti, MD, Neuropsichiatria Inf., University, Azienda Ospedaliero-Universitaria, via Ospedale 119, 09124 Cagliari, Italy
Tel.: + 39 070 609 3425
Fax: + 39 070 609 3415
Email: cianchet@unica.it
Copyright © 2010 Blackwell Publishing Ltd

ABSTRACT
Objective: Recent studies support the role of extracranial perivascular afferents in a substantial percentage of migraineurs. Perivascular afferent fibres of the superficial temporal artery contain peptides, like calcitonin gene-related peptide (CGRP) and substance P (SP). CGRP and SP are considered relevant in the genesis of migraine pain. Capsaicin is an agonist of the transient receptor potential vanilloid type 1. It causes membrane depolarisation of sensory neurons, which release CGRP, SP and other pain peptides; excitation is followed by a refractory state, causing inactivation. Topical capsaicin has been found to be efficacious in several types of neuropathic pain. We attempted to verify whether topical periarterial capsaicin could ameliorate pain in absence of and during a migraine attack.

Methods: On 23 migraineurs showing pain at pressure on scalp arteries, we administered topical capsaicin 0.1% or vaseline jelly on painful arteries in absence of migraine attack. In those having pain reduction > 50%, we made the same comparison during a migraine attack.

Results: Topical capsaicin caused > 50% reduction of arterial pain in absence of attack in 17/23 patients, as opposed to two with vaseline. During attacks of mild- to moderate-intensity, > 50% improvement was obtained in 11/17 with capsaicin and in one with vaseline.

Conclusions: Although referring to a small number of patients, our data show that topical capsaicin may relieve arterial pain in absence of and during a migraine attack in a substantial number of patients experiencing scalp arterial tenderness. More active capsacinoids might be tried in the future and could provide a new method for treating migraine attacks.

α2δ Modulators for management of compression neuropathic pain: A review of three case series

Indian Journal of Palliative Care  
ORIGINAL ARTICLE
Year : 2009 | Volume : 15 | Issue : 2 | Page : 132--136
Tariq A Tramboo1, Showket Gurkhoo

Context: The α2δ modulators gabapentin and pregabalin are effective against neuropathic pain. Numerous brands of α2δ modulators are available in India, and are expected to have equivalent clinical effects. They are routinely used for management of neuropathic pain associated with radiculopathy.  

Aim: To describe clinical outcomes in three series of cases of neuropathic pain treated with three available brands of a2d modulators.
 
Settings and Design: Retrospective analysis of clinical outcomes in patients attending an interventional pain clinic
Patients and Methods: One hundred and ninety-four consecutive patients with neuropathic pain secondary to Magnetic Resonance Imaging (MRI)-documented compression radiculopathy received either LYRICA (LYR), a locally available generic brand of pregabalin (PGN), or a locally available generic brand of gabapentin (GBN), respectively. Drug treatment was continued till adequate pain relief was achieved. In each of the three groups, mean pain scores were analyzed at Days 0, 15, 60 and 90, and daytime sedation scores at Days 1, 15, 60 and 90.

Statistical Analysis used: Analysis of variance (ANOVA) followed by pair-wise comparison using two-tailed unpaired t-test (if P value was significant).

Results: Mean pain score was significantly lower in the LYR series as compared to the PGN and GBN series at Days 15, 60 and 90. As compared to the PGN and GBN series, a greater proportion of patients in the LYR series could discontinue drug therapy following adequate pain relief, by Day 90. Daytime sedation scores were significantly lower in the LYR series as compared to the PGN and GBN series at Days 1, 15 and 60, and as compared to the PGN series at Day 90. 

Conclusion: These results indicate the effectiveness of a2d modulators for management of neuropathic pain secondary to compression radiculopathy. The results also suggest a possible therapeutic superiority of LYRICA over locally available generic brands of pregabalin and gabapentin. These findings need to be further examined in randomized, controlled trials.

Brain Anatomy Changes Associated with Persistent Neuropathic Pain Following Spinal Cord Injury

Cerebral Cortex Advance Access published online on October 8, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp205
© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

S. M. Gustin1,2, P. J. Wrigley1, P. J. Siddall1 and L. A. Henderson2
1 Pain Management Research Institute, Kolling Institute, University of Sydney, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia, 2 Department of Anatomy and Histology, University of Sydney, Sydney, NSW 2006, Australia

Address correspondence to Luke A. Henderson, Department of Anatomy and Histology, F13, University of Sydney, Sydney, NSW 2006, Australia. Email: lukeh@anatomy.usyd.edu.au
Persistent neuropathic pain commonly occurs following spinal cord injury (SCI). It remains one of the most challenging management problems in this condition. In order to develop more effective treatments, a better understanding of the neural changes associated with neuropathic SCI pain is required. The aim of this investigation was to use diffusion tensor imaging (DTI) to determine if persistent neuropathic pain following SCI is associated with changes in regional brain anatomy and connectivity. In 23 subjects with complete thoracic SCI, 12 with below-level neuropathic pain and 11 without pain, and 45 healthy control subjects, a series of whole-brain DTI scans were performed. The mean diffusivity (MD) of each voxel was calculated and values compared between groups. This analysis revealed that neuropathic pain following SCI is associated with significant differences in regional brain anatomy. These anatomical changes were located in pain-related regions as well as regions of the classic reward circuitry, that is, the nucleus accumbens and orbitofrontal, dorsolateral prefrontal, and posterior parietal cortices. The right posterior parietal cortex projected to most regions that displayed an anatomical change. Analysis of the fiber tracts connecting areas of MD differences revealed no significance differences in MD values between the SCI pain, SCI no pain, and control groups.