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Posts Tagged ‘Pain management’


New Neuromodulation Device to Treat Migraines

Reporter: Irina Robu, PhD

Theranica, Israeli startup is developing a non-invasive medical device that treats migraine pain through smartphone-controlled electric pulses unlike existing pharmaceutical solutions like triptans and ergotamine. The company recently received FDA De-novo clearance on Nerivio Migra, a class II medical device to treat acute migraine pain.

The non-invasive medical device, Nerivio Migra contains a bioelectric patch which is placed on the upper arm and a linked smartphone app which controls the electrical impulses and records data. The device’s electric pulses excite C-fiber nerves, generating an analgesic mechanism in the brain that lightens migraine pain.

In order to diminish the overuse of painkillers, the company developed the non-invasive device and tested it among acute migraine patients both two and 48 hours after treatment. Side effects from the device were mild and resolved within 24 hours.

Theranica’s product is lower in price than the existing alternatives and it is using existing smartphone technology. Their initial focus is on marketing to headache clinics as a start. And hoping to expand the indications for its device to the pediatric migraine population and finally use its platform to treat other idiopathic pain conditions like cluster headaches.

SOURCE

Israeli startup gets FDA nod for neuromodulation device to treat migraines

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Pain Management

Larry H Bernstein, MD, FCAP, Curator

LPBI

 

Pain Management Health Center

http://www.webmd.com/pain-management/

 

Pain Management Overview

Pain management is important for ongoing pain control, especially if you suffer with long-term or chronic pain. After getting a pain assessment, your doctor can prescribe pain medicine, other pain treatments, or psychotherapy to help with pain relief.

Nearly any part of your body is vulnerable to pain. Acute pain warns us that something may be wrong. Chronic pain can rob us of our daily life, making it difficult and even unbearable. Many people with chronic pain can be helped by understanding the causes, symptoms, and treatments for pain – and how to cope with the frustrations.

You know your pain better than anyone — and as hard as it’s been to handle it, your experience holds the key to making a plan to treat it.

Each person and their pain are unique. The best way to manage your case could be very different from what works for someone else. Your treatment will depend upon things such as:

  • The cause
  • How intense it is
  • How long it’s lasted
  • What makes it worse or better

It can be a process to find your best plan. You can try a combination of things and then report back to your doctor about how your pain is doing. Together, you can tweak your program based on what’s working and what needs more help.

All Pain Is Not the Same

In order to make your pain management plan, your doctor will first consider whether you have sudden (“acute”) or long-term (“chronic”) pain.

Acute pain starts suddenly and usually feels sharp. Broken bones, burns, or cuts are classic examples. So is pain after surgery or giving birth.

Acute pain may be mild and last just a moment. Or it may be severe and last for weeks or months. In most cases, acute pain does not last longer than 6 months, and it stops when its underlying cause has been treated or has healed.

If the problem that causes short-term pain isn’t treated, it may lead to long-term, or “chronic” pain.

Chronic pain lasts longer than 3 months, often despite the fact that an injury has healed. It could even last for years. Some examples include:

  • Headache
  • Low back pain
  • Cancer pain
  • Arthritis pain
  • Pain caused by nerve damage

It can cause tense muscles, problems with moving, a lack of energy, and changes in appetite. It can also affect your emotions. Some people feel depressed, angry, or anxious about the pain and injury coming back.

Chronic pain doesn’t always have an obvious physical cause.

What Can I Do to Feel Better?

1. Keep moving. You might think it’s best to rest on the sidelines. But being active is a good idea. You’ll get stronger and move better.

The key is knowing what’s OK for you to do to get stronger and challenge your body, without doing too much, too soon.

Your doctor can let you know what changes to make. For instance, if you used to run and your joints can’t take that now because you have a chronic condition like osteoarthritis, you might be able to switch to something like biking or swimming.

2. Physical and occupational therapy. Take your recovery to the next level with these treatments. In PT, you’ll focus on the exact muscles you need to strengthen, stretch, and recover from injury. Your doctor may also recommend “occupational therapy,” which focuses on how to do specific tasks, like walking up and down stairs, opening a jar, or getting in and out of a car, with less pain.

3. Counseling. If pain gets you down, reach out. A counselor can help you get back to feeling like yourself again. You can say anything, set goals, and get support. Even a few sessions are a good idea. Look for a counselor who does “cognitive behavioral therapy,” in which you learn ways that your thinking can support you as you work toward solutions.

4. Massage therapy. It’s not a cure, but it can help you feel better temporarily and ease tension in your muscles. Ask your doctor or physical therapist to recommend a massage therapist. At your first appointment, tell them about the pain you have. And be sure to let them know if the massage feels too intense.

5. Relaxation. Meditation and deep breathing are two techniques to try. You could also picture a peaceful scene, do some gentle stretching, or listen to music you love. Another technique is to scan your body slowly in your mind, and consciously try to relax each part of your body, one by one, from head to toe. Any healthy activity that helps you unwind is good for you and can help you feel better prepared to manage your pain.

6. Consider complementary treatments such as acupuncture, biofeedback, and spinal manipulation. In acupuncture, a trained practitioner briefly inserts very thin needles in certain places on your skin to tap into your “chi,” which is an inner energy noted in traditional Chinese medicine. It doesn’t hurt.

Biofeedback trains you to control how your body responds to pain. In a session of it, you’ll wear electrodes hooked up to a machine that tracks your heart rate, breathing, and skin temperature, so you can see the results.

When you get spinal manipulation, a medical professional uses their hands or a device to adjust your spine so that you can move better and have less pain. Some MDs do this. So do chiropractors, osteopathic doctors (they have “DO” after their name instead of “MD”), and some physical therapists.

Are There Devices That Help?

Although there are no products that take pain away completely, there are some that you and your doctor could consider.

TENS and ultrasound. Transcutaneous electrical nerve stimulation, or TENS, uses a device to send an electric current to the skin over the area where you have pain. Ultrasound sends sound waves to the places you have pain. Both may offer relief by blocking the pain messages sent to your brain.

Spinal cord stimulation. An implanted device delivers low-voltage electricity to the spine to block pain.  If your doctor thinks it’s an option, you would use it for a trial period before you get surgery to have it permanently implanted. In most cases, you can go home the same day as the procedure.

What About Medicine?

Your doctor will consider what’s causing your pain, how long you’ve had it, how intense it is, and what medications will help. They may recommend one or more of the following:

These may include over-the-counter pain relievers such as acetaminophen, aspirin, ibuprofen, or naproxen. Or you may need stronger medications that require a prescription, such as steroids, morphine, codeine, or anesthesia.

Some are pills or tablets. Others are shots. There are also sprays or lotions that go on your skin.

Other drugs, like muscle relaxers and some antidepressants, are also used for pain. Some people may need anesthetic drugs to block pain.

Will I Need Surgery?

It depends on why you’re in pain. If you’ve had a sudden injury or accident, you might need surgery right away.

But if you have chronic pain, you may or may not need an operation or another procedure, such as a nerve block (done with anesthetics or other types of prescription drugs to halt pain signals) or a spinal injection (such as a shot of cortisone or an anesthetic drug).

Talk with your doctor about what results you can expect and any side effects, so you can weigh the risks and the benefits. Also ask how many times the doctor has done the procedure they recommend and what their patients have said about how much relief they’ve gotten.

WebMD Medical Reference

Reviewed by Jennifer Robinson, MD on September 20, 2015

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Outstanding Achievement in Anesthesiology

Curator: Larry H Bernstein, MD, FCAP

 

Thomas J. Rick, MD, for Outstanding Achievements in Anesthesiology and Pain Management

The International Association of HealthCare Professionals has carefully selected Thomas J. Rick, MD, to represent anesthesiology in their publication, The Leading Physicians of the World.  Dr. Rick’s selection is a significant representation of his enduring passion and complete dedication for the field of anesthesiology and pain management. He is considered to be among the best throughout his 19 years in practice.

A well versed and respected anesthesiologist and pain management physician practicing in Phoenix, Arizona, Dr. Rick features a track record of achievements that have marked his 19-year professional journey in his challenging specialty. In a relaxed and friendly setting with accommodating support staff, Dr. Rick receives his at Thomas J. Rick, MD PC, his well equipped private office where he deals with anesthetic and pain management services for patients undergoing surgeries. While he primarily devotes his time to his office in Phoenix, he additionally provides anesthesiology-related services to patients of the St. Joseph’s Hospital and Medical Center and Banner Good Samaritan Medical Center, also in Phoenix, Arizona.

Dr. Rick embraced a career in medicine upon completing his medical degree in 1994 at Hahnemann University Hospital. His postgraduate training led him to the University of Arizona and his continuing learning enhanced his certification in anesthesiology by the American Board of Anesthesiology. As an affirmation of his commitment to education and his desire to advance by adapting his practice to the latest discoveries and technologies in his field, Dr. Rick joined the American Society of Anesthesiology and the Arizona Society of Anesthesiology. An active man in his free time, passionate by tennis, fitness, and drums, he attributes his exceptional success to his availability, as well affordability and accessibility of service.

Stanford Medical School

Myer “Mike” Rosenthal

  • Ellis N. Cohen Award for Outstanding Achievement in Anesthesiology, Stanford University Department of Anesthesia (1980)
  • Jack R. Collins Memorial Award for Outstanding Leadership in Anesthesia Education, Dannemiller Society (1990)
  • Kaiser Award for Clinical Teaching, Stanford University School of Medicine (1991, 2004)
  • Board of Directors (President and Chairman of Board – 2001-2004), Foundation for Anesthesia Education and Research (2000 – 2009)
  • Director (President – 1997-1998), American Board of Anesthesiology (1986 – 1998)
  • Medical Director of Intensive and Intermediate Intensive Care Units, Stanford University Hospital (1975 – 1997)

Arthur Bert, MD

Senior staff anesthesiologist, Rhode Island Hospital

Arthur Bert, MD, has served as director of cardiac anesthesia (1986-2002) at Rhode Island Hospital and as director of pediatric cardiac anesthesia (1996-2005) at Hasbro Children’s Hospital. Bert continues to pursue his interests in adult and pediatric cardiovascular and thoracic anesthesia as a senior staff anesthesiologist. He is a clinical professor of surgery (anesthesiology) at the the Warren Alpert Medical School at Brown University. He also holds the position of director of experimental cardiac surgery, anesthesiology and cardiac imaging at the cardiac surgery research laboratories of Children’s Mercy Hospital, in Kansas City, MO, where he is part of a funded research team that is growing tissue-engineered heart valves. He is a consultant anesthesiologist at Women & Infants Hospital for neonatal anesthesia.

Education

Bert graduated as president of Alpha Omega Alpha Medical Honor Society from Mount Sinai School of Medicine in New York City. He served as a resident in internal medicine at Beth Israel Deaconess Medical Center in Boston and was awarded the Dr. Nathan Sidel Prize for outstanding achievement. He completed his anesthesia residency and an adult cardiac anesthesia fellowship at Beth Israel Hospital in Boston, followed by a pediatric anesthesia fellowship at Children’s Hospital Boston.

Board Certification

Diplomate of the American Board of Anesthesiology (1985) and re-certified in 2008

Testamur of the National Board of Echocardiography in Perioperative Transesophageal Echocardiography (1998)

Diplomate (2006) and re-certified in 2007

Awards

Top Physicians, Rhode Island Monthly magazine (2000, 2002, 2004, 2006 and 2008)

Guide to America’s Top Physicians, Consumers’ Research Council of America, Washington, DC (2005, 2006)

Teaching Recognition Award, Brown Medical School (2005)

Dr. Charles A. Hill Award from the RI Medical Society (2006)

Interests

Applications of transesophageal echocardiography to intraoperative patient management

Techniques of reducing blood product transfusions during surgery

Cerebral function monitoring during general anesthesia

Research: Echocardiographic evaluation of tissue-engineered valve function

ASA Award for Excellence in Research

Henrik Kehlet, M.D., Ph.D.

The annual ASA Award for Excellence in Research recognizes an individual for outstanding achievement in research that has or is likely to have an important impact on the practice of anesthesiology.

The individual’s work must represent a body of original, mature and sustained contribution to the advancement of the science of anesthesiology. The nominee need not be a physician, an anesthesiologist or a member of ASA, but must be presently engaged in research related to anesthesiology, academically accomplished with peer-reviewed publications and funded research, and nominated in response to a call for nominations. The completed application must include the nominee’s current curriculum vitae, a letter of nomination and a seconding letter from two individuals with an understanding of the research contributions of the individual.

The 2014 Award for Excellence in Research was presented to Henrik Kehlet, M.D., Ph.D., at the ANESTHESIOLOGY™ 2014 annual meeting in New Orleans on Monday, October 13, 2014. Dr. Kehlet is a Professor at Rigshospitalet, Copenhagen University, Denmark.

Dr. Kehlet is known for his research and writing in surgical pathophysiology, surgical stress response and the transition from acute to chronic pain, among other topics.

Henrik Kehlet, M.D., Ph.D. is perhaps the most well-known surgeon among physician anesthesiologists around the world due to his substantial contributions toward the understanding of surgical pathophysiology. After Dr. Kehlet completed his medical studies and surgical residency at the University of Copenhagen, Denmark, he enrolled in a Ph.D. program within the same institution, authoring a thesis pertaining to the study of the hypothalamic-pituitary-adrenocortical function in glucocorticoid-treated surgical patients. Dr. Kehlet served as the Chief of Surgery and Professor of Surgery, Copenhagen University at Hvidovre University Hospital from 1989 to 2004. He was subsequently appointed as a Professor of Perioperative Therapy and Head of the Section for Surgical Pathophysiology at the Rigshospitalet in Copenhagen. Dr. Kehlet continues to be an extremely prolific writer, having authored more than 950 scientific articles covering topics of surgical pathophysiology, acute pain physiology and pharmacotherapy, surgical stress response, regional anesthesia and analgesia, perioperative immune function, fast-track surgery and the transition from acute to chronic pain.

Dr. Kehlet’s research led to the creation of the concept of fast-track surgery, or enhanced recovery after surgery (ERAS), with the aim of painless and safe surgeries. His work related to pain relief and surgical outcomes led to the multimodal analgesia approach of combining different analgesics for better pain control and fewer side effects that is widely used today. Dr. Kehlet also is credited with the concept of pre-emptive analgesia, or administering an analgesic prior to surgical injury in order to decrease the intensity and duration of postoperative pain. In addition to his many contributions to perioperative pain management, Dr. Kehlet is responsible for establishing the first nationwide hernia database in Denmark, with the purpose of optimizing outcomes and documenting different approaches to improve care.

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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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The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

Curator and Interviewer: Stephen J. Williams, Ph.D.

 

philly2nightThis post is the third in a series of posts highlighting interviews with Philadelphia area biotech startup CEO’s and show how a vibrant biotech startup scene is evolving in the city as well as the Delaware Valley area. Philadelphia has been home to some of the nation’s oldest biotechs including Cephalon, Centocor, hundreds of spinouts from a multitude of universities as well as home of the first cloned animal (a frog), the first transgenic mouse, and Nobel laureates in the field of molecular biology and genetics. Although some recent disheartening news about the fall in rankings of Philadelphia as a biotech hub and recent remarks by CEO’s of former area companies has dominated the news, biotech incubators like the University City Science Center and Bucks County Biotechnology Center as well as a reinvigorated investment community (like PCCI and MABA) are bringing Philadelphia back. And although much work is needed to bring the Philadelphia area back to its former glory days (including political will at the state level) there are many bright spots such as the innovative young companies as outlined in these posts.

In today’s post, I had the opportunity to talk with both Dr. William Kinney, Chief Scientific Officer and Thoma Kikis, Founder/CMO of KannaLife Sciences based in the Pennsylvania Biotech Center of Bucks County.   KannaLifeSciences, although highlighted in national media reports and Headline news (HLN TV)for their work on cannabis-derived compounds, is a phyto-medical company focused on the discipline surrounding pharmacognosy, the branch of pharmacology dealing with natural drugs and their constituents.

Below is the interview with Dr. Kinney and Mr. Kikis of KannaLife Sciences and Leaders in Pharmaceutical Business Intelligence (LPBI)

 

PA Biotech Questions answered by Dr. William Kinney, Chief Scientific Officer of KannaLife Sciences

 

 

LPBI: Your parent company   is based in New York. Why did you choose the Bucks County Pennsylvania Biotechnology Center?

 

Dr. Kinney: The Bucks County Pennsylvania Biotechnology Center has several aspects that were attractive to us.  They have a rich talent pool of pharmaceutically trained medicinal chemists, an NIH trained CNS pharmacologist,  a scientific focus on liver disease, and a premier natural product collection.

 

LBPI: The Blumberg Institute and Natural Products Discovery Institute has acquired a massive phytochemical library. How does this resource benefit the present and future plans for KannaLife?

 

Dr. Kinney: KannaLife is actively mining this collection for new sources of neuroprotective agents and is in the process of characterizing the active components of a specific biologically active plant extract.  Jason Clement of the NPDI has taken a lead on these scientific studies and is on our Advisory Board. 

 

LPBI: Was the state of Pennsylvania and local industry groups support KannaLife’s move into the Doylestown incubator?

 

Dr. Kinney: The move was not State influenced by state or industry groups. 

 

LPBI: Has the partnership with Ben Franklin Partners and the Center provided you with investment opportunities?

 

Dr. Kinney: Ben Franklin Partners has not yet been consulted as a source of capital.

 

LPBI: The discipline of pharmacognosy, although over a century old, has relied on individual investigators and mainly academic laboratories to make initial discoveries on medicinal uses of natural products. Although there have been many great successes (taxol, many antibiotics, glycosides, etc.) many big pharmaceutical companies have abandoned this strategy considering it a slow, innefective process. Given the access you have to the chemical library there at Buck County Technology Center, the potential you had identified with cannabanoids in diseases related to oxidative stress, how can KannaLife enhance the efficiency of finding therapeutic and potential preventive uses for natural products?

 

Dr. Kinney: KannaLife has the opportunity to improve upon natural molecules that have shown medically uses, but have limitations related to safety and bioavailability. By applying industry standard medicinal chemistry optimization and assay methods, progress is being made in improving upon nature.  In addition KannaLife has access to one of the most commercially successful natural products scientists and collections in the industry.

 

LPBI: How does the clinical & regulatory experience in the Philadelphia area help a company like Kannalife?

 

Dr. Kinney: Within the region, KannaLife has access to professionals in all areas of drug development either by hiring displaced professionals or partnering with regional contract research organizations.

 

LPBI  You are focusing on an interesting mechanism of action (oxidative stress) and find your direction appealing (find compounds to reverse this, determine relevant disease states {like HCE} then screen these compounds in those disease models {in hippocampal slices}).  As oxidative stress is related to many diseases are you trying to develop your natural products as preventative strategies, even though those type of clinical trials usually require massive numbers of trial participants or are you looking to partner with a larger company to do this?

 

Dr. Kinney: Our strategy is to initially pursue Hepatic Encephalophy (HE) as the lead orphan disease indication and then partner with other organizations to broaden into other areas that would benefit from a neuroprotective agent.  It is expected the HE will be responsive to an acute treatment regimen.   We are pursuing both natural products and new chemical entities for this development path.

 

 

General Questions answered by Thoma Kikis, Founder/CMO of KannaLife Sciences

 

LPBI: How did KannaLife get the patent from the National Institutes of Health?

 

My name is Thoma Kikis I’m the co-founder of KannaLife Sciences. In 2010, my partner Dean Petkanas and I founded KannaLife and we set course applying for the exclusive license of the ‘507 patent held by the US Government Health and Human Services and National Institutes of Health (NIH). We spent close to 2 years working on acquiring an exclusive license from NIH to commercially develop Patent 6,630,507 “Cannabinoids as Antioxidants and Neuroprotectants.” In 2012, we were granted exclusivity from NIH to develop a treatment for a disease called Hepatic Encephalopathy (HE), a brain liver disease that stems from cirrhosis.

 

Cannabinoids are the chemicals that compose the Cannabis plant. There are over 85 known isolated Cannabinoids in Cannabis. The cannabis plant is a repository for chemicals, there are over 400 chemicals in the entire plant. We are currently working on non-psychoactive cannabinoids, cannabidiol being at the forefront.

 

As we started our work on HE and saw promising results in the area of neuroprotection we sought out another license from the NIH on the same patent to treat CTE (Chronic Traumatic Encephalopathy), in August of 2014 we were granted the additional license. CTE is a concussion related traumatic brain disease with long term effects mostly suffered by contact sports players including football, hockey, soccer, lacrosse, boxing and active military soldiers.

 

To date we are the only license holders of the US Government held patent on cannabinoids.

 

 

LPBI: How long has this project been going on?

 

We have been working on the overall project since 2010. We first started work on early research for CTE in early-2013.

 

 

LPBI: Tell me about the project. What are the goals?

 

Our focus has always been on treating diseases that effect the Brain. Currently we are looking for solutions in therapeutic agents designed to reduce oxidative stress, and act as immuno-modulators and neuroprotectants.

 

KannaLife has an overall commitment to discover and understand new phytochemicals. This diversification of scientific and commercial interests strongly indicates a balanced and thoughtful approach to our goals of providing standardized, safer and more effective medicines in a socially responsible way.

 

Currently our research has focused on the non-psychoactive cannabidiol (CBD). Exploring the appropriate uses and limitations and improving its safety and Metered Dosing. CBD has a limited therapeutic window and poor bioavailability upon oral dosing, making delivery of a consistent therapeutic dose challenging. We are also developing new CBD-like molecules to overcome these limitations and evaluating new phytochemicals from non-regulated plants.

 

KannaLife’s research is led by experienced pharmaceutically trained professionals; Our Scientific team out of the Pennsylvania Biotechnology Center is led by Dr. William Kinney and Dr. Douglas Brenneman both with decades of experience in pharmaceutical R&D.

 

 

LPBI: How do cannabinoids help neurological damage? -What sort of neurological damage do they help?

 

Cannabinoids and specifically cannabidiol work to relieve oxidative stress, and act as immuno-modulators and neuroprotectants.

 

So far our pre-clinical results show that cannabidiol is a good candidate as a neuroprotectant as the patent attests to. Our current studies have been to protect neuronal cells from toxicity. For HE we have been looking specifically at ammonia and ethanol toxicity.

 

 

– How did it go from treating general neurological damage to treating CTE? Is there any proof yet that cannabinoids can help prevent CTE? What proof?

 

We started examining toxicity first with ammonia and ethanol in HE and then posed the question; If CBD is a neuroprotectant against toxicity then we need to examine what it can do for other toxins. We looked at CTE and the toxin that causes it, tau. We just acquired the license in August from the NIH for CTE and are beginning our pre-clinical work in the area of CTE now with Dr. Ron Tuma and Dr. Sara Jane Ward at Temple University in Philadelphia.

 

 

LPBI: How long until a treatment could be ready? What’s the timeline?

 

We will have research findings in the coming year. We plan on filing an IND (Investigational New Drug application) with the FDA for CBD and our molecules in 2015 for HE and file for CTE once our studies are done.

 

 

LPBI: What other groups are you working with regarding CTE?

 

We are getting good support from former NFL players who want solutions to the problem of concussions and CTE. This is a very frightening topic for many players, especially with the controversy and lawsuits surrounding it. I have personally spoken to several former NFL players, some who have CTE and many are frightened at what the future holds.

 

We enrolled a former player, Marvin Washington. Marvin was an 11 year NFL vet with NY Jets, SF 49ers and won a SuperBowl on the 1998 Denver Broncos. He has been leading the charge on KannaLife’s behalf to raise awareness to the potential solution for CTE.

 

We tried approaching the NFL in 2013 but they didn’t want to meet. I can understand that they don’t want to take a position. But ultimately, they’re going to have to make a decision and look into different research to treat concussions. They have already given the NIH $30 Million for research into football related injuries and we hold a license with the NIH, so we wanted to have a discussion. But currently cannabinoids are part of their substance abuse policy connected to marijuana. Our message to the NFL is that they need to lead the science, not follow it.

 

Can you imagine the NFL’s stance on marijuana treating concussions and CTE? These are topics they don’t want to touch but will have to at some point.

 

LPBI: Thank you both Dr. Kinney and Mr. Kikis.

 

Please look for future posts in this series on the Philly Biotech Scene on this site

Also, if you would like your Philadelphia biotech startup to be highlighted in this series please contact me or

http://pharmaceuticalintelligence.com at:

sjwilliamspa@comcast.net or @StephenJWillia2  or @pharma_BI.

Our site is read by ~ thousand international readers DAILY and thousands of Twitter followers including venture capital.

 

Other posts on this site in this VIBRANT PHILLY BIOTECH SCENE SERIES OR referring to PHILADELPHIA BIOTECH include:

The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

RAbD Biotech Presents at 1st Pitch Life Sciences-Philadelphia

The Vibrant Philly Biotech Scene: Focus on Vaccines and Philimmune, LLC

What VCs Think about Your Pitch? Panel Summary of 1st Pitch Life Science Philly

1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

LytPhage Presents at 1st Pitch Life Sciences-Philadelphia

Hastke Inc. Presents at 1st Pitch Life Sciences-Philadelphia

PCCI’s 7th Annual Roundtable “Crowdfunding for Life Sciences: A Bridge Over Troubled Waters?” May 12 2014 Embassy Suites Hotel, Chesterbrook PA 6:00-9:30 PM

Pfizer Cambridge Collaborative Innovation Events: ‘The Role of Innovation Districts in Metropolitan Areas to Drive the Global an | Basecamp Business

Mapping the Universe of Pharmaceutical Business Intelligence: The Model developed by LPBI and the Model of Best Practices LLC

 

 

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Larry H. Bernstein, MD, FCAP, Reporter, Reposted

Leaders in Pharmaceutical Intelligence

DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

https://pharmaceuticalintelligence.com/10/29/2010/larryhbern/Rofecoxib

ROFECOXIB

MK-966, MK-0966, Vioxx

162011-90-7

C17-H14-O4-S
314.3596
\
Percent Composition: C 64.95%, H 4.49%, O 20.36%, S 10.20%
LitRef: Selective cyclooxygenase-2 (COX-2) inhibitor. Prepn: Y. Ducharme et al., WO 9500501; eidem, US5474995 (both 1995 to Merck Frosst).
Therap-Cat: Anti-inflammatory; analgesic.

Rofecoxib /ˌrɒfɨˈkɒksɪb/ is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritisacute pain conditions, and dysmenorrhoea. Rofecoxib was approved by the Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names VioxxCeoxx, and Ceeoxx.

Rofecoxib

Rofecoxib

Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.[1]

On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib’s risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.[2] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[3] Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens.

Rofecoxib was available on prescription in both tablet-form and as an oral suspension. It was available by injection for hospital use.

 

 Mode of action
 Cyclooxygenase (COX) has two well-studied isoforms, called COX-1 and COX-2.
  • COX-1 mediates the synthesis of prostaglandins responsible for protection of the stomach lining, while
  • COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation.
prostaglandin PGE2

prostaglandin PGE2

By creating “selective” NSAIDs that inhibit COX-2, but not COX-1, the same pain relief as traditional NSAIDs is offered, but with greatly reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2 inhibitor, or “coxib”.

Others include Merck’s etoricoxib (Arcoxia), Pfizer’s celecoxib (Celebrex) and valdecoxib (Bextra). Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen.[4]

Pharmacokinetics

The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%.[5][6][7] Rofecoxib crossed the placenta and blood–brain barrier,[5][6][8]and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) of approximately 17 hours.[5][7][9] The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib[5][9] which are primarily excreted through urine.

Fabricated efficacy studies

On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated in order to augment the analgesic effects of the drugs. There is no evidence that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company Pfizer (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union’s regulatory agencies prior to the drug’s approval. Drug manufacturer Merckhad no comment on the disclosure.[10]

Adverse drug reactions

VIOXX sample blister pack.jpg

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs.

Prostaglandin is a large family of lipids. Prostaglandin I2/PGI2/prostacyclin is just one member of it. Prostaglandins other than PGI2 (such as PGE2) also play important roles in vascular tone regulation. Prostacyclin/thromboxane are produced by both COX-1 and COX-2, and rofecoxib suppresses just COX-2 enzyme, so there is no reason to believe that prostacyclin levels are significantly reduced by the drug. And there is no reason to believe that only the balance between quantities of prostacyclin and thromboxane is the determinant factor for vascular tone.[11] Indeed Merck has stated that there was no effect on prostacyclin production in blood vessels in animal testing.[12] Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionized under physiological conditions. (Reddy & Corey, 2005)

 Adverse cardiovascular events

VIGOR study and publishing controversy

The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accidenttransient ischemic attack, or coronary artery bypass).

Merck’s scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks “is primarily due to” this protective effect (Targum, 2001). Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference (Michaels 2005), and some outside scientists warned Merck that this claim was implausible before VIGOR was published.[13] No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin.[14][15] Though Dr. Topol’s 2004 paper criticized Merck’s naproxen hypothesis, he himself co-authored a 2001 JAMA article stating “because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib.” (Mukherjee, Nissen and Topol, 2001.)

The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, “Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).”[16] This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA were not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data.[17] They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.[18]

The editors charged that “more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article.” These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the “aspirin not indicated” group) and the editors noted that the omission “resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups.” The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication.[19]

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the “omitted” table were printed in the text of the article. The authors stood by the original article.[20]

NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks).[19]

Some scientists have accused the NEJM editorial board of making unfounded accusations.[21][22] Others have applauded the editorial. Renowned research cardiologist Eric Topol,[23] a prominent Merck critic, accused Merck of “manipulation of data” and said “I think now the scientific misconduct trial is really fully backed up”.[24] Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying “this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies”.[25]

On May 15, 2006, the Wall Street Journal reported that a late night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that “the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine‘s own role in aiding Vioxx sales.”[26]

“Internal emails show the New England Journal’s expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal’s handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article.” The Journal stated that NEJM‘s “ambiguous” language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; “the New England Journal says it didn’t attempt to have these mistakes corrected.”[26]

APPROVe study

In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for theprophylaxis of colorectal polypsCelecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (includingheart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations.[28]

In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Other studies

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005).

Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.[31]

Other COX-2 inhibitors

Any increased risk of renal and arrhythmia pathologies associated with the class of COX-2 inhibitors, e.g. celecoxib (Celebrex), valdecoxib (Bextra), parecoxib (Dynastat),lumiracoxib, and etoricoxib is not evident,[31] although smaller studies[32][33] had demonstrated such effects earlier with the use of celecoxib, valdecoxib and parecoxib.

Nevertheless, it is likely that trials of newer drugs in the category will be extended in order to supply additional evidence of cardiovascular safety. Examples are some more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), which are currently (circa 2005) undergoing Phase III/IV clinical trials.

Besides, regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:[34]

  • Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease
  • Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking
  • Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment

Other NSAIDs

Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older “trusted” NSAIDs such as ibuprofendiclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties.

Withdrawal

Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.[35]

In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.[36]

On November 5, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004).

In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib’s benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen—though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.[37]

In 2005, Merck retained Debevoise & Plimpton LLP to investigate Vioxx study results and communications conducted by Merck. Through the report, it was found that Merck’s senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team’s overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and showed that Merck intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results and withholding of information was the result of oversight, not malicious behavior….The report was published in February 2006, and Merck was satisfied with the findings of the report and promised to consider the recommendations contained in the Martin Report. Advisers to the US Food and Drug Administration (FDA) have voted, by a narrow margin, that it should not ban Vioxx — the painkiller withdrawn by drug-maker Merck.

They also said that Pfizer’s Celebrex and Bextra, two other members of the family of painkillers known as COX-2 inhibitors, should remain available, despite the fact that they too boost patients’ risk of heart attack and stroke. url = http://www.nature.com/drugdisc/news/articles/433790b.html The recommendations of the arthritis and drug safety advisory panel offer some measure of relief to the pharmaceutical industry, which has faced a barrage of criticism for its promotion of the painkillers. But the advice of the panel, which met near Washington DC over 16–18 February, comes with several strings attached.

For example, most panel members said that manufacturers should be required to add a prominent warning about the drugs’ risks to their labels; to stop direct-to-consumer advertising of the drugs; and to include detailed, written risk information with each prescription. The panel also unanimously stated that all three painkillers “significantly increase the risk of cardiovascular events”.

External links

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Curated by: Dr. V. S. Karra, Ph.D.

Pain is a major symptom in many medical conditions, and can significantly interfere with a person’s quality of life and general functioning.[1]. It is often caused by intense or damaging stimuli, such as stubbing a toe, burning a finger, putting alcohol on a cut, and bumping the “funny bone.”

English: Illustration of the pain pathway in R...

Pain is an absolutely unpleasant one. Knowing the time of onset, location, intensity, pattern of occurrence (continuous, intermittent, etc.), exacerbating and relieving factors, and quality (burning, sharp, etc.) of the pain will help the examining physician to accurately diagnose the problem. For example, chest pain described as extreme heaviness may indicate myocardial infarction, while chest pain described as tearing may indicate aortic dissection.

Acute pain is usually managed with medications such as analgesics and anesthetics. Management of chronic pain, however, is much more difficult and may require an interdisciplinary approach for treating or easing the suffering and improving the quality of life. Psychological factors such as social support, hypnotic suggestion, excitement, or distraction can significantly modulate pain’s intensity or unpleasantness.

The International Association for the Study of Pain (IASP) states that “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.[2].

Following is the IASP’s classification of pain:

(1) region of the body involved (e.g., abdomen, lower limbs),

(2) system whose dysfunction may be causing the pain (e.g., nervous, gastrointestinal),

(3) duration and pattern of occurrence,

(4) intensity and time since onset, and

(5) etiology

This system has been criticized by Clifford J. Woolf and others as inadequate for guiding research and treatment.

According to Woolf, there are three classes of pain :

Nociceptive pain: is caused by stimulation of peripheral nerve fibers and the stimulants could be Thermal, Mechanical and/ or Chemical. For example “heat or cold” (thermal), “crushing, tearing, etc.” (mechanical) and “iodine in a cut, chili powder in the eyes” (chemical).

Inflammatory pain: is associated with tissue damage and the infiltration of immune cells, and

Pathological pain: is a disease state caused by damage to the nervous system (neuropathic pain) or by its abnormal function (dysfunctional pain, like in fibromyalgia, irritable bowel syndrome, tension type headache, etc.).[3]

Pain will have a very detrimental effect on the quality of life. Experimental subjects challenged by acute pain and patients in chronic pain experience impairments in attention control, working memory, mental flexibility, problem solving, and information processing speed.[4]. Acute and chronic pain are also associated with increased depression, anxiety, fear, and anger.[5].

Patients who often have a background level of pain controlled by medications and whos pain periodically “breaks through” the medication is called breathrough pain and it is common in cancer patients . The characteristics of breakthrough cancer pain vary from person to person and according to the cause.

Harold Merskey said: “If I have matters right, the consequences of pain will include direct physical distress, unemployment, financial difficulties, marital disharmony, and difficulties in concentration and attention…”

Pain perception (point at which the stimulus begins to hurt) and tolerance thresholds (point at which the individual can’t tolerate the pain any more and when the subject acts to stop the pain) are not the same. The perception of pain is influenced by a multitude of variables including gender, age, mood, ethnicity and genetic factors [6],

Thus it is important to:

  • understand mechanisms of susceptibility to (chronic) pain,
  • Explore the genetics, emphasizing the conservation of pain-related genes, their functions and their advantages if any
  • Understand the role of gene polymorphisms in normal and pathological modulation of pain in models, humans, and as future drug targets
  • Explore the latest findings from human genome-wide investigation of genomic variability and gene expression on pain
  • Understand genetic and genomic techniques to study genetic contribution to (human) pain.
  • Study the progress of cutting-edge clinical trials and translate research findings to clinical practice
  • develop preventative approaches and novel treatment strategies

Advances in molecular, statistical and behavioral methodologies have suddenly allowed genetic investigations of complex biological phenomena, including pain. Genetic studies of pain are already showing their power to identify new molecular targets for drug development and create new animal models of pain pathology, says Jeffrey S. Mogil, PhD who is currently the E.P. Taylor Professor of Pain Studies and the Canada Research Chair in the Genetics of Pain and wrote a book on “The Genetics of Pain“.

Pain genetics can explain why we’re not all alike with respect to pain – why some people hurt more, and receive less benefit from existing analgesics. The knowledge gained holds the promise of allowing truly individualized pain therapy, says Mogil.

Algorithms for accessing and integrating available public data to examine disease-relevant mechanisms are of growing interest as publically available data sets grow at an ever-increasing rate. A meta-analysis of publicly available microarray data from rodents exposed to neuropathic or inflammatory pain was able to efficiently prioritize pain-related genes [7].

A similar approach using human gene expression data could be highly beneficial in generating data-driven hypotheses for pain genetics.

Most recent article, published on June 7, 2012, in open access journal  PLoS Computational Biology, on “Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases” presented a novel integrative approach that combines publicly available molecular data and automatically extracted knowledge regarding pain contained in the literature to assist the discovery of novel pain genes. This study was approved by the Institutional Review Boards of Stanford University and SRI International.

In this meta-analysis, they took advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories and

  • Ranked thousands of diseases according to the Figure shown below.

  • Obtained gene expression profiles of 121 of these human diseases from public sources.
  • Selected ‘genes with expression variation significantly correlated with DSPI across diseases’ as candidate pain genes.
  • Genotyped selected candidate pain genes in an independent human cohort, and finally
  • Evaluated for significant association between variants and measures of pain sensitivity.

In this study, the genes were chosen based on their high correlation with the DSPI and plausible biology as assessed by the available literature and human expression profile across tissue using The Scripps Research Institute BioGPS database [8].

The selected genes were:

  • ABLIM3 (actin binding LIM protein family, member 3),
  • PDE2A (phosphodiesterase 2A, cGMP-stimulated),
  • CREB1 (cAMP responsive element binding protein 1),
  • NAALAD2 (N-acetylated alpha-linked acidic dipeptidase 2), and
  • NCALD (neurocalcin delta).

These genes were selected from the candidate list and were prospectively tested for variants that may be associated with differential pain sensitivity in an independent human cohort.

ABLIM3 was selected as the top candidate as it showed the highest correlation with the DSPI. ABLIM3 is a newly characterized protein-coding gene. ABLIM3 is expressed in various tissues, most prominently in muscle and neuronal tissue [9], [10].

Polymorphisms in ABLIM3 (rs4512126) and NCALD (rs12548828, rs7826700, and rs1075791) showed significant association with the cold pressor pain threshold

The strongest signal was with rs4512126 (5q32, ABLIM3, P = 1.3×10−10)  for the sensitivity to cold pressor pain in males, but not in females – a sex-specific association.”

Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P = 1.7×10−4, 1.8×10−4, and 2.2×10−4 respectively).

Authors said that, “This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.”

Authors have demonstrated the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This approach was validated through a targeted genetic association study in an independent human cohort, where variants of selected pain gene candidates were evaluated for associations with experimental pain sensitivity measures in humans.

Authors hope that “the outlined approach can complement existing research efforts by assisting the formulation of data-driven hypotheses, and may serve as a template to discover genetic components of other clinically important phenotypes.

Further Reading:

Pain Gene Database (PGD)[11]

MeSH: Medical Subject Heading is a comprehensive vocabulary thesaurus organized in a hierarchical structure allowing the indexing of publications with various levels of specificity.

The 20 diseases with the highest disease-pain ratio from the DSPI are listed out of a total of 2962 diseases are

 .

Curated by: Dr. V. S. Karra, Ph.D.

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