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Posts Tagged ‘Transition from Acute to Chronic Pain States’


Opioids, Pain, And Palliative Care [6.3.9]

Curator: Stephen J. Williams, Ph.D.

As written by Hrachya Nersesyan and Konstantin V Slavin in Current approach to cancer pain management: Availability and implications of different treatment options in Ther Clin Risk Manag. 2007 Jun; 3(3): 381–400

According to statistics published by the American Cancer Society in 2002, “50%–70% of people with cancer experience some degree of pain” (ACS 2002), which usually only intensifies as the disease progresses. Less than half get adequate relief of their pain, which negatively impacts their quality of life. The incidence of pain in advanced stages of invasive cancer approaches 80% and it is 90% in patients with metastases to osseous structures (Pharo and Zhou 2005).

Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain). However, there has been difficulty in modeling cancer-induced pain in animals. This has hampered our understanding and therapeutic intervention of the clinical situation, especially concerning ovarian cancer patients.   It has been shown that 85% of ovarian cancer patients in palliative care (during last two months of life) still report severe pain although 54% of these women were given high intensity pain medications such as morphine, still the mainstream pain medication for severe cancer-associated pain. Admittedly, more research into the ability of cancer to provoke pain and sensitize the central nervous system, is warranted, as well as development of new methods of analgesia for cancer-associated pain at end-of-life. Therefore, in collaboration with several colleagues, in vivo models of nociceptive and neuropathic pain will be integrated with my co-developed in vivo tumor models of ovarian cancer. This tumor model allows for noninvasive monitoring of tumor burden without the need for anesthesia, as necessitated by imaging strategies to quantitate tumor burden, such as bioluminescence and MRI.

Even in an era of promising new cancer therapies, cancer pain is one of the highest concerns for the patient, their clinician, and surrounding loved ones, especially impacting quality of life during palliative care. Over half of cancer patients have reported severe pain in the course of their disease (List MA J Clin Oncol 2000 18:877-84) and the statistics are worse for ovarian cancer patients, regardless whether during treatment or in palliative care (see below review).

Journal of Pain and Symptom Management Volume 33, Issue 1 , Pages 24-31, January 2007

Pain Management in the Last Six Months of Life Among Women Who Died of Ovarian Cancer

Sharon J. Rolnick, PhD, MPH, Jody Jackson, RN, BSN, Winnie W. Nelson, PharmD, MS, Amy Butani, BA, Lisa J. Herrinton, PhD, Mark Hornbrook, PhD, Christine Neslund-Dudas, MA, Don J. Bachman, MS, Steven S. Coughlin, PhD

HealthPartners Research Foundation (S.J.R., J.J., A.B.), Minneapolis, Minnesota; Applied Health Outcomes (W.W.N.), Palm Harbor, Florida; Division of Research (L.J.H., D.J.B.), Kaiser Permanente Northern California, Oakland, California; Kaiser Permanente Center for Health Research (M.H.), Portland, Oregon; Josephine Ford Cancer Center (C.N.-D.), Henry Ford Health System, Detroit, Michigan; and National Center for Chronic Disease Prevention and Health Promotion (S.S.C.), Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Abstract Previous studies indicate that the symptoms of many dying cancer patients are undertreated and many suffer unnecessary pain. We obtained data retrospectively from three large health maintenance organizations, and examined the analgesic drug therapies received in the last six months of life by women who died of ovarian cancer between 1995 and 2000. Subjects were identified through cancer registries and administrative data. Outpatient medications used during the final six months of life were obtained from pharmacy databases. Pain information was obtained from medical charts. We categorized each medication based on the World Health Organization classification for pain management (mild, moderate, or intense). Of the 421 women, only 64 (15%) had no mention of pain in their charts. The use of medications typically prescribed for moderate to severe pain (“high intensity” drugs) increased as women approached death. At 5–6 months before death, 55% of women were either on no pain medication or medication generally used for mild pain; only 9% were using the highest intensity regimen. The percentage on the highest intensity regimen (drugs generally used for severe pain) increased to 22% at 3–4 months before death and 54% at 1–2 months. Older women (70 or older) were less likely to be prescribed the highest intensity medication than those under age 70 (44% vs. 70%, P<0.001). No differences were found in the use of the high intensity drugs by race, marital status, year of diagnosis, stage of disease, or comorbidity. Our finding that only 54% of women with pain were given high intensity medication near death indicates room for improvement in the care of ovarian cancer patients at the end of life.

Cancer pain is a complexity concerning not only the peripheral and central nervous systems but the cancer cell, the tumor microenvironment, and tumor infiltrating immune cells and inflammatory mediators. The goal of this article is to briefly introduce these factors governing pain in the cancer patient and a discussion of animal models of pain in relation to cancer.

Pain is considered as either termed nociceptive pain (activations and sensitization of primary afferent “nociceptor” neurons or neuropathic pain (damage to sensory nerves). Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain).

For a great review please see Dr. Kara’s curation The Genetics of Pain: An Integrated Approach.

Palliative Care

For a good review please see the following LINK on Palliative Care

Palliative Care_4.6

Please See VIDEOs on Cancer, Pain and Palliative Care

https://youtu.be/88ri3VNOd2E

 

https://youtu.be/B1_Ui3f4AI4

https://youtu.be/-KOSinGapUg

From ACS Guideline: Developing a plan for pain control

The first step in developing a pain control plan is talking with your cancer care team about your pain. You need to be able to describe your pain to your family or friends, too. You may want to have your family or friends help you talk to your cancer care team about your pain, especially if you’re too tired or in too much pain to talk to them yourself.

Using a pain scale is a helpful way to describe how much pain you’re feeling. To use the Pain Intensity Scale shown here, try to assign a number from 0 to 10 to your pain level. If you have no pain, use a 0. As the numbers get higher, they stand for pain that’s getting worse. A 10 means the worst pain you can imagine.

0 1 2 3 4 5 6 7 8 9 10
No pain Worst pain

For instance, you could say, “Right now, my pain is a 7 on a scale of 0 to 10.”

You can use the rating scale to describe:

  • How bad your pain is at its worst
  • What your pain is like most of the time
  • How bad your pain is at its least
  • How your pain changes with treatment

Tell your cancer care team and your family or friends:

  • Where you feel pain
  • What it feels like – for instance, sharp, dull, throbbing, gnawing, burning, shooting, steady
  • How strong the pain is (using the 0 to 10 scale)
  • How long it lasts
  • What eases the pain
  • What makes the pain worse
  • How the pain affects your daily life
  • What medicines you’re taking for the pain and how much relief you get from them

NCCN Adult Cancer-Associated Pain Guidelines (see PDF)NCCN adult pain guidelines

NCCN gives a comprehensive guideline to Cancer Patient Pain Management for Caregivers, physicians, and educational materials for patients.

The attached PDF gives information on

  • Pain Definition and Pain Management Principles
  • Pain Screening, Rating and Assessment Guidelines
  • Management of Patients with Differing Opioid Tolerance
  • Opioid Titration Guidelines
  • Adjuvant Analgesia
  • Psychosocial Support

Table. Important Points in NCCN Guidelines for Pain Management

Pain Severity (pain scale level) guideline
All pain levels – Opioid maintenance, – psychosocial support, – caregiver education
Severe Pain (7-10) – Reevaluate opioid titration
Moderate (4-6) – Continue opioid titration

– Consider specific pain syndrome problem and consultation

– continue analgesic titration

Mild (0-3) Adjuvant analgesics

The clinical presentation of cancer pain depends on the histologic type of cancer, the location of the primary neoplasm, and location of metastases. (for example pain in breast cancer patients have different pain issues than patients with oral.cancer).

However, high grade serous ovarian cancer, the most clinically prevalent of this disease, usually presents as an ascitic carcinomatosis, spread throughout the peritoneum and mesothelium.

Ovarian cancer stem cells and mediators of pain

Although not totally accepted by the field, a discussion of ovarian cancer stem cells is warranted, especially in light of this discussion. Cancer stem cells are considered that subpopulation of cells in the bulk tumor exhibiting self-renewing capacity, generally resistant to chemotherapy, and therefore repopulate the tumor with new tumor cells. In this case, ovarian cancer stem cells could be more pertinent to the manifestations of pain than bulk tumor, as these cells would survive chemotherapy. This may be the case, as ovarian cancer pain may not be associated with overall tumor burden? Are there PAIN MEDIATORS secreted from ovarian cancer cells?

Some Known Pain Mediators Secreted from Ovarian Tumor Cells

Endothelin-1

Proteases and Protease-Activated Receptors

Hoogerwerf WA, Zou L, Shenoy M, Sun D, Micci MA, Lee-Hellmich H, Xiao SY, Winston JH, Pasricha PJ

J Neurosci. 2001 Nov 15; 21(22):9036-42.

Alier KA, Endicott JA, Stemkowski PL, Cenac N, Cellars L, Chapman K, Andrade-Gordon P, Vergnolle N, Smith PA.J Pharmacol Exp Ther. 2008 Jan; 324(1):224-33.

Bradykinin

Sevcik MA, Ghilardi JR, Halvorson KG, Lindsay TH, Kubota K, Mantyh PW

J Pain. 2005 Nov; 6(11):771-5

Nerve Growth Factor

Tumor Necrosis Factor

Opioids: A Reference

Opioid analgesics: analgesia without loss of consciousness

Three main uses of opioids

  1. Analgesia
  2. Antitussive
  3. Diarrhea

1954 – nalorphine, partial antagonists had analgesic effect. Morphine: Morpheus – Greek God of dreams

1) opiates: opium alkaloids including morphine, codeine, thebaine, papavarine

2) synthetic: meperedine, methadone

Chemistry

  • Antagonist properties associated with replacement of the methyl substituent on nitrogen atom with large group (naloxone and nalorphine replaced with allyl group)
  • Pharmacokinetic properties affected by C3 and C6 hydroxyl substitutions
  • CH3 at phenolic OH at C3 reduces first pass metabolism by glucoronidation THEREFORE codeine and oxycodeine have higher oral availability
  • Acetylation of both OH groups on morphine : heroin penetrates BBB : rapidly hydrolyzed to give monoacetylmorphine and morphine

Pharmaookinetics

  • Well absorbed from s.c., i.m., oral
  • Codeine and hydrocodeine higher absorption from oral:parental ratio because of extensive first pass metabolism
  • Most opioids are well absorbed orally but DECREASE potency due to first pass
  • Variable plasma protein binding
  • Brain distribution is actually low but opioids are very potent
  • Well distributed and may accumulate in skeletal muscle
  • Fentynyl (lipophilic) may accumulate in fat

 

Metabolism

  • Most opioids converted to polar metabolites so excreted by kidney ;IMPORTANT prolonged analgesia in patients with renal disease
  • Esters like meperidine and herion metabolized by tissue esterases
  • Glucoronidated morphine may have analgesic properties

 

Receptors

All three (mu, kappa, and delta) activate pertussis toxin sensitive G protein {Gi}

Opioids quiet pain (nociceptive) neurons by inhibiting nerve conduction (decrease entry of calcium or increase entry of potassium)

There are four major subtypes of opioid receptors:[12]

Receptor Subtypes Location[13][14] Function[13][14]
delta (δ)
DOR
OP1 (I)
δ1,[15] δ2
kappa (κ)
KOR
OP2 (I)
κ1, κ2, κ3
mu (μ)
MOR
OP3 (I)
μ1, μ2, μ3 μ1:

μ2:

μ3:

  • possible vasodilation
Nociceptin receptor
NOP
OP4
ORL1
  • anxiety
  • depression
  • appetite
  • development of tolerance to μ-opioid agonists

Tolerance and Physical Dependence

Tolerance: gradual loss of effectiveness over repeated doses

Physical Dependence: when tolerance develops continued administration of drug required to prevent physical withdrawal symptoms

  • With opioids see tolerance most with the analgesic, sedative, and antitussive effects; not so much with antidiarrheal effects

Major effects of opioids on Organ Systems

  • CNS
    1. Analgesia – raise threshhold for pain
    2. Euphoria – pleasant floating feeling but sometimes dysphoria (agitation)
    3. Sedation –drowsiness but no amnesia; more frequent in elderly than young but can disrupt normal REM sleep
    4. Respiratory depression – ALL opioids produce significant resp. depression by inhibiting the brain stem; careful in patients with impaired respiratory function like COPD or increased intracranial pressure
    5. Cough suppression – tolerance can develop; may increase airway secretions
    6. Miosis – constriction of pupils; seen with ALL agonists; treat with atropine
    7. Rigidity – mostly seen with fentanyl; treat with opioid antagonist like nalozone
    8. Emesis; naseua, vomiting

 

  • Peripheral
    1. Cardiovascular – no real major effects; some specific compounds may have effects on blood pressure
    2. GI – Constipation most common; loperamide (Immodium); pentazocine may cause less constipation; problem for treating cancer patients for pain; opioid receptors do exist in the GI tract but effect may be CNS as well as local
    3. Biliary system – minor, may cause constriction of bile duct
    4. GU (genitourinary) – reduced urine output by increased antidiuretic hormone
    5. Uterus – may prolong labor
    6. Neuroendocrine – opioid analgesics can stimulate release of ADH, prolactin
    7. Other – opioid analgesics may cause flushing and warming of skin; release of histamine?

 

Specific Agents

Strong Agonists

  1. Phenanthrenes –all are used for analgesia
  • Morphine
  • Hydromorphone
  • Oxymorphone
  • Heroin
  1. Phenylheptylamine
  • Methadone – longer acting than morphine; tolerance and physical dependency slower to develop than with morphine; low doses of methadone may be used for heroin addict undergoing withdrawal
  1. Phenyllpiperidines
  • Meperidine
  • Fentanyl (also sufentanil) which is 5-7 more times potent than fentanyl. Negative inotropic (contractile force) effects on heart
  1. Levorphanol

Mild to Moderate Agonist

  1. Phenanthrenes – most given in combo with NSAID
  • Codeine – antitussive, some analgesia
  • Oxycodone
  • Dihydrocodone
  • Hydrocodone
  1. Propoxyphene – Darvon, low abuse and low analgesia compared to morphine
  2. Phenylpiperidines
  • Diphenoxylate –used for diarrhea; not for analgesia and no abuse potential
  • Loperamide – antidiarrheal (Imodium), low abuse potential

Mixed Agonist-Antagonist & Partial Agonists

  1. Nalbulphine – strong kappa agonist and mu antagonist.. Analgesic
  2. Buprenorphine – analgesic. Partial mu agonist has long duration. Slow dissocation from receptor makes resistant to naloxone reversal
  3. Buterphanol – analgesia with sedation, kappa agonist
  4. Pentazocine – kappa agonist with weak mu antagonism.Is an irritant so do no inject s.c.

Antagonists

  1. Naloxone – quick reversal of opioid agonist action (1-2 hours); not well absorbed orally; pure antagonist so no effects by itself; no tolerance problems; opioid antidote
  2. Naltrexone – well absorbed orally can be used in maintenance therapy because of long duration of action

Antitussives

  1. Codeine
  2. Dextromethorphan
  3. Levoproposyphen
  4. Noscapine

Other posts related to Pain, Cancer, and Palliative Care on this Open Access Journal Include

Palliative Care_4.6

Requiem for Palliative Cardiology: The Voice of Dr. Esselstyn on Plant-Based Nutrition

Cancer and Nutrition

Thyme Oil Beats Ibuprofen for Pain Management.

Pain Management Drug Market: Insight Pharma Reports

New target for chronic pain treatment found

The Genetics of Pain: An Integrated Approach

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Reporter: Aviva Lev-Ari, PhD, RN

http://www.paintherapeuticsummit.com/agenda

Agenda

 
WEDNESDAY OCTOBER 3, 2012

7:45 Registration and Continental Breakfast

8:30 Chairperson’s Opening Remarks

William K. Schmidt, Ph.D. (biography), President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical Development, CrystalGenomics (CG Pharmaceuticals)

8:45 Pain, Addiction, Abuse and Psychiatric Co-morbidities
Dr. Medve will discuss managing critical interplays and putting the patient at the center of the treatment team.
The session will cover:

  • Addiction – what is it?
  • Animal models – can they predict human addiction?
  • Psychiatric illness vs pain vs addiction – how do these interplays work?
  • Opioids and the future of pain care
  • How best to manage patients in a complicated care system

Dr. Medve will also discuss Nektar’s recently Fast Tracked NCE opioid NKTR-181, which is designed to have a slow rate of entry into the brain to reduce the attractiveness of the molecule as a target of abuse and to reduce its CNS-mediated side effects.

Robert Medve, MD (biography), Vice President & Chief Medical Officer, Nektar Therapeutics

9:15 Allosteric Inhibitors of the NGF/TrkA Pathway: a Novel, Small Molecule Approach to Inhibiting Peripherally Mediated Pain
Nerve Growth Factor (NGF) plays a significant role in the generation and maintenance of the nociceptive pain associated with a variety of human diseases. Array Biopharma has used a structural biology driven approach to develop potent, highly selective small molecules that inhibit TrkA kinase activity through allosteric modulation. The efficacy of TrkA inhibitors in rodent models of peripheral pain will be detailed. Additionally, potential mechanistic differentiation from the anti-NGF strategy will be discussed as will in vivo efficacy and long term safety associated with their small molecule inhibitors.

Steven Andrews, Ph.D., Associate Director, Drug Discovery, Array BioPharma

9:45 New Models of Pain in Freely Moving Rodents
The pain field has been frustrated by the limitations of the current evoked nociception models that are used for screening or target discovery. Regeneron has been working on several non-evoked models of visceral pain and deep tissue pain that are providing some interesting mechanistic insights. Dr. LaCroix-Fralish’s in vivo pharmacology team is seeking to develop therapeutics for the treatment of pain and neurological disability. In this presentation, he will discuss his team’s efforts to develop new models for visceral and deep tissue pain.

Michael LaCroix-Fralish, Ph.D.,(biography) Staff Scientist, Pain Therapeutics Group, Regeneron Pharmaceuticals

10:15 Poster Viewing & Refreshment Break

10:45 TRPA1 as a Pain Target: Progress and Challenge
A gain of function mutation of TRPA1 has been linked to familial episodic pain syndrome in humans. This result, coupled with a growing preclinical literature, has made TRPA1 an attractive pain target. Dr. Chen will address several key biology and drug discovery issues, including physiological/pathological function of TRPA1, species difference, therapeutic profile and drug discovery strategies.

Jun X. Chen, Ph.D. (biography), Principal Research Scientist GPRD, Neuroscience, Abbott Laboratories

11:15 Gene Therapy to Control Intractable Pain in Cancer Patients: A New Paradigm?
A very high proportion (up to 85%) of terminal cancer patients suffer from severe pain; current therapies, principally opioids, are of limited use. Benitec Biopharma Ltd. is developing a gene therapy strategy to control pain in such patients using intrathecal delivery of lentiviral particles expressing shRNA constructs designed to inactivate the Protein Kinase C gamma gene (PKCg) in neurones of the spinal cord. Others have demonstrated the strategy works in neuropathic pain models in rats. Benitec has developed constructs that strongly inactivate PKCg in vitro; these particular shRNAs target sequences within PKCg that are absolutely conserved between rat and humans as well as pre-clinical test species (dogs and macaques), simplifying pre-clinical testing. These new constructs are being validated in rat pain models and protocols for pre-clinical testing are being developed. Benitec believes a gene therapy  approach for pain control in terminal cancer patients is warranted, the approach is relatively low risk and offers the prospect of a single treatment providing long term pain relief.

Peter French, Ph.D. (biography), Chief Executive Officer, Benitec Biopharma

11:45 Pain in Children: Challenges in Conducting Pediatric and Neonatal Pain Studies and Treating Pain in Children
This presentation will cover the following:

  • Developmental physiology and pharmacology, including enzyme maturation and drug metabolism
  • Pain measures: assessments from neonates through adolescents
  • Challenges in clinical study design, including: recruitment, use of placebo, blood volume restrictions and formulations
  • Current concepts in the treatment of pain in children

Ernest A. Kopecky Ph.D, MBA, VP Clinical Development, Head, Neuroscience TA, COLLEGIUM Pharmaceutical

12:15 Luncheon

1:30 Transition from Acute to Chronic Pain States

Tony L. Yaksh, Ph.D. (biography), Professor & Vice Chair for Research, Department of Anesthesiology and Professor of Pharmacology, University of California, San Diego

2:00 Minimizing Experimental Error in Analgesic Research by Reducing Placebo Response and Variability
The properly educated patient can be your greatest ally in producing a positive analgesic clinical trial. A significant portion of an analgesic investigation’s variability is produced secondary to cognitive gaps that the patient may have when interpreting the various protocol mandated scales and questions. All pharmaceutical companies spend a large amount of time perfecting their protocol and selecting/educating quality sites so that the efficacy of their drug can be statistically demonstrated. However, an equal amount of effort is rarely placed on patient education. This piece of the puzzle is the responsibility of the site and as such, we have developed educational materials to reduce placebo response and garner data that is as “true” as possible. This talk will discuss placebo response training and other ways to mitigate variability in analgesic clinical trials.

Neil Singla, MD (biography), Founder & Chief Scientific Officer, Lotus Clinical Research, LLC

2:30 Analgesic Potential of TRPA1 Antagonists
TRPA1 serves as a broad sensor for the detection of both endogenous and exogenous reactive chemicals. This presentation will review the rationale for targeting TRPA1 for the treatment of pain, including peri-operative, inflammatory, visceral and neuropathic conditions. In addition, recent progress on the clinical development of TRPA1 antagonists will be summarized, including data from Cubist and Hydra Bioscience’s clinical development programs.

Magdalene Moran, Ph.D. (biography), Vice President, Biology, Hydra Biosciences

3:00 Poster Viewing & Refreshment Break

3:30 Overview of Analgesic Efficacy and Safety of Tanezumab, a Monoclonal Antibody Targeting Nerve Growth Factor for Treatment of Chronic Pain
Nerve growth factor (NGF) has been increasingly implicated as a facilitator of pain in human diseases and related animal disease models. Monoclonal antibodies targeting NGF have shown compelling efficacy in relieving pain in a number of painful conditions. This presentation will review the current analgesic efficacy and safety profile of tanezumab, a monoclonal antibody in late-stage development for chronic pain.

Mark T. Brown, MD (biography), Executive Director, Clinical Program Leader for Osteoarthritis and Cancer Pain Studies, Pfizer Inc.

4:00 Conotoxins: Molecular Tools to Dissect Pain Pathways
Conotoxins are disulfide-rich peptides isolated from the venom of the predatory cone snail. Millions of years of natural selection fine-tuned this complex mixture of venom peptides to be highly potent and selective to various ion channels, transporters and GPCRs. In particular their subtype selectivity make them preferred tools for the study of receptors (e.g. ionchannels) involved in neuropathic pain. With ready access to sequencers we are now able to mine the transcriptome of the venom ducts, providing us with more sequence information than we can produce, certainly putting the pressure back on developing better synthetic methodologies. In this presentation, Dr. Muttenthaler will describe the discovery, synthesis and application of this class of compounds with a focus on the latest advancement in creating a diverse toolbox for neuroscientists.

Markus Muttenthaler, Ph.D. (biography), Departments of Chemistry and Cell Biology, The Scripps Research Institute

4:30 Making Investment Choices in Pain Management
In this presentation, Dr. Meltzer will walk the audience through some top line discussions of how Purdue Pharma is looking at the current and future marketplace of pain management and how that influences investment choices.

Brian Meltzer, MD(biography) Executive Director, R&D Innovation, Purdue Pharma

5:00 Cocktail Reception

THURSDAY OCTOBER 4, 2012

8:15 Chairperson’s Opening Remarks

William K. Schmidt, Ph.D. (biography), President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical Development, CrystalGenomics (CG Pharmaceuticals)

8:20 Addressing Acute and Persistent Pain at its Origins: Transcription Factor Decoys For Pain Prevention and Treatment
Adynxx Inc. is developing a transformative technology platform addressing pain at its molecular roots – preventing the development of pain following surgery or trauma and resolving established chronic pain syndromes. The Adynxx platform utilizes a proprietary form of oligonucleotide technology – small pieces of DNA that bind to transcription factors and inhibit their activity. Adynxx’s lead compound, AYX1, is designed to prevent acute post-surgical pain and the transition to persistent or chronic pain with a single intrathecal administration at the time of surgery. AYX1 acts by inhibiting the spinal cord activity of transcription factor EGR1, a powerful molecular switch whose function is critical in the establishment and maintenance of post-surgical or trauma-related pain. In this presentation, Dr. Manning will discuss the concept of transcription factor decoys, the preclinical data from several rodent models of post-surgical pain, mechanical hyperalgesia and functional recovery.  AYX1 entered clinical trials in Q2 2012 and data from Phase 1 safety and general development plans will be discussed.

Donald C. Manning, MD, Ph.D. (biography), Chief Medical Officer, Adynxx Inc.

8:50 Overview of Fulranumab, an Anti-NGF Antibody for Treatment of Chronic Pain
A variety of anti-NGF compounds are currently in development.  Fulranumab is a fully human anti-NGF antibody that shows promise in relief of a variety of pain models.  This presentation will review the clinical efficacy and safety profile that has been developed to date.

David Upmalis, MD, Senior Director and Compound Development Team Leader, fulranumab, Janssen Research Foundation

9:20 Selective A3 Adenosine Receptor Agonists for Chronic Neuropathic Pain
The clinical management of chronic neuropathic pain is limited by marginal effectiveness and unacceptable side effects of current analgesics such as opiates, gabapentanoid or drugs that modulate the noradrenergic/serotonergic pathway: novel analgesics are therefore needed. Dr. Salvemini’s findings identify therapeutic use of selective A3 adenosine receptor (A3AR) agonists in chronic neuropathic pain of distinct etiologies including chemotherapy-induced neuropathic pain caused by paclitaxel, oxaliplatin and bortezomib. In addition, A3AR agonists increase the potency and efficacy of morphine, gabapentin and amitriptyline. Her team’s findings provide the pharmacological rationale for therapeutic development of A3AR agonists, as novel analgesics for the management of chronic neuropathic pain.

Daniela Salvemini, Ph.D., Professor, Saint Louis University School of Medicine

9:50 Poster Viewing & Refreshment Break

10:15 Mechanisms and Novel Treatment of Neuropathic Pain

Allan Basbaum, Ph.D. (biography), Professor and Chair, Department of Anatomy, University of California, San Francisco

10:45 Panel Session: Treating Pain in the Clinic – the Physician’s Perspective on Unmet Need and the Challenges Facing Pain Drug Developers

Chair: William K. Schmidt, Ph.D. (biography), President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical Development, CrystalGenomics (CG Pharmaceuticals)

Sean Mackey, MD, Ph.D. (biography), Chief, Division of Pain Management, Stanford University School of Medicine, Associate Professor of Anesthesiology, Director, Stanford Systems Neuroscience & Pain Lab

Lynn Webster, MD, (biographyMedical Director, CRI Lifetree, President-Elect, The American Academy of Pain Medicine

Michael S. Leong, MD, Clinic Chief, Stanford Pain Medicine Center, Clinical Associate Professor, Anesthesia, Stanford University

11:45 Neuroimaging Based Pain Detection: Findings and Applications
Dr. Mackey will cover recent advances in neuroimaging as an objective tool for the detection of pain. He will discuss recent data for both detection of acute and chronic pain, and potential applications.

Sean Mackey, MD, Ph.D. (biography), Chief, Division of Pain Management, Stanford University School of Medicine, Associate Professor of Anesthesiology, Director, Stanford Systems Neuroscience & Pain Lab

12:15 Luncheon

1:15 An NGF Inhibitor Update: Thoughts and Observations Regarding the Future of this Class of Pain Therapeutics
Dr. Lane will discuss results from Phase 2 and 3 studies that have come out in past months. She will also cover status of their development and what the FDA Arthritis Advisory Committee’s recent recommendation to lift the hold on NGF inhibitors in clinical development means for the future of this class of pain therapeutics.

Nancy E. Lane, MD (biography), Endowed Professor of Medicine and Rheumatology, Director, Musculoskeletal Diseases of Aging Research Group Director, Academic Geriatric Resource Program, Co-Director, Building Interdisciplinary Research Careers in Women’s Health (BIRCWH), Co-Director, Center for Translational Research in Osteoarthritis, UC Davis Health System

1:45 Panel Session: NGF Antagonists Back on Track: Clinical Development Challenges and Opportunities Moving Forward

Chair: William K. Schmidt, Ph.D. (biography), President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical Development, CrystalGenomics (CG Pharmaceuticals)

Mark T. Brown, MD (biography), Executive Director, Clinical Program Leader for Osteoarthritis and Cancer Pain Studies, Pfizer Inc.

Nancy E. Lane, MD (biography), Endowed Professor of Medicine and Rheumatology, Director, Musculoskeletal Diseases of Aging Research Group Director, Academic Geriatric Resource Program, Co-Director, Building Interdisciplinary Research Careers in Women’s Health (BIRCWH), Co-Director, Center for Translational Research in Osteoarthritis, UC Davis Health System

David Upmalis, MD, Senior Director and Compound Development Team Leader, fulranumab, Janssen Research Foundation

Steven Andrews, Ph.D., Associate Director, Drug Discovery, Array Biopharma

2:45 End of Conference

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