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Experience of and Alleviation of Pain

Curator:  Larry H. Bernstein, MD, FCAP

 

A Thousand Words

Stories of medicine unfold on canvas

STEADY PROGRESS: Warren and Lucia Prosperi's <i>Ether Day</i> painting, which captures the first successful use of ether as an anesthetic, hangs in the domed amphitheater in which the historic event occurred more than 150 years ago.
STEADY PROGRESS: Warren and Lucia Prosperi’s Ether Day painting, which captures the first successful use of ether as an anesthetic, hangs in the domed amphitheater in which the historic event occurred more than 150 years ago.

In Carolus-Duran’s The Convalescent, a bearded man leans back, exhausted, into a pillow. Carolus-Duran, the name used by nineteenth-century French artist Charles Auguste Émile Durand, brings the viewer into the sickroom, rendering the emotions of illness through light, feature, and posture.

Studying this and other such paintings and recognizing elements of her own clinical experience in them has enriched Alice Flaherty’s appreciation of sickrooms and deathbeds. It is an appreciation that translates to the clinic.

“I was rounding on a woman who was dying of breast cancer,” says Flaherty ’90, an HMS associate professor of neurology at Massachusetts General Hospital. “I felt this empathic pain, so I asked her about her suffering. She calmly said she felt at peace, that she had been contemplating the quiet, lovely light in the room.”

“I realized that some of my empathy had been the projection of my own distress,” Flaherty continues. “Her description of the calm, empty, white spaces of her sickroom gave me the aesthetic distance that allowed me to see more of what was going on with her than I had seen when my eyes were screwed tight with imagined pain.”

Whether it’s a sickroom tableau, a portrayal of a surgery, or a portrait of a clinician or researcher, depictions of medicine in art have wide-ranging effects on those who view them. In addition to revealing the beauty in everyday clinical care, art inspired by medicine can connect doctors with the history of their profession, encourage them to confront ambiguities or consider alternative points of view, help situate their experiences within a larger context, soothe or sharpen emotions, and lead them to improve patient care in unexpected ways.

Alice Flaherty

Alice Flaherty

Artists, subjects, and viewers connect on another level when the process for reconstructing a historical event in medicine or capturing the character of a portrait subject entails the same meticulous collection of data and keen observational skills practiced in medicine. That physicians and painters should find one another kindred spirits is not surprising given the intertwined histories and philosophies of naturalist art, science, and medicine.

Nature Studies

Ask Massachusetts-based artists Warren and Lucia Prosperi whether they feel an affinity with physicians and scientists, and they will elaborate on how they share a fascination with the nature of the human experience. To capture this fascination in their paintings, they allow themselves to be endlessly curious about the subject, struggle to balance involvement with detachment, and pursue their desire to craft scientifically accurate images based on close observation.

“We’re empiricists,” says Warren, a painter who, in collaboration with his wife, a photographer, has produced dozens of paintings for HMS-affiliated institutions. Most notable, perhaps, is their Ether Day, a work completed in 2001 and displayed in a surgical amphitheater, dubbed the Ether Dome, in the Bulfinch Building at Mass General. In that room in 1846, the use of inhaled ether as a surgical anesthetic was first demonstrated successfully.

The Prosperis adhere to the principles of naturalism, a movement that arose in Europe in the mid-nineteenth century as writers, visual artists, and filmmakers, inspired by advances in natural science, sought to apply scientific methods to their work. Reacting against the idealism and symbolism of romanticism, naturalist painters presented realistic depictions of everyday life with as little distortion as possible. An example of this style, and one that is among the more pervasive images of the caring physician in art, is the late-nineteenth century painting The Doctor by British artist Sir Samuel Luke Fildes. In the work, Fildes portrays a pensive clinician keeping watch over an ailing girl while her parents look on helplessly.

Naturalist artists gather vast amounts of data to ensure accuracy, and the Prosperis are no exception. They spend hours talking with and photographing portrait subjects until they’re satisfied that they’ve captured not only minute physical details but also the person’s essential character. For posthumous portraits and historical scenes, they conduct exhaustive archival research, consult experts on the period, and interview anyone who might have known the person or experienced an event firsthand.

“They sucked my bone marrow for details,” says Donald Barnett, a former HMS assistant clinical professor of medicine and now curator of the Joslin Diabetes Center Historical Commission. Barnett has advised the Prosperis on seven paintings depicting landmarks in Joslin’s history.

ARTISTS-IN-RESIDENCE: Warren and Lucia Prosperi's studio contains several of the historical works on which they have collaborated, including <i>The First Casualty at Bunker Hill</i>, shown here, in part.

ARTISTS-IN-RESIDENCE: Warren and Lucia Prosperi’s studio contains several of the historical works on which they have collaborated, including The First Casualty at Bunker Hill, shown here, in part.

As a clinician, Barnett appreciates thorough information gathering. “Historical records tell the ‘what,’ not the ‘how,’” he says. “We brought in the details to turn a painting into a story, and we had a fanaticism for telling the story correctly.”

Details, Details

Demonstrating the effective use of ether during surgery launched U.S. medicine into the international spotlight. Little wonder that when planning to commemorate the 150th anniversary of that landmark event, the hospital’s service chiefs and physicians commissioned the Prosperis to paint a historically accurate version of what happened that day. The research the Prosperis undertook for Ether Day illustrates their dedication to telling stories correctly.

Although written documents and photographs yielded plenty of facts, crucial questions remained: Was surgeon John Collins Warren right- or left-handed? What was the nature of the incision he made? To what extent would red blood cells have oxidized and begun to separate from plasma in the basin used to capture the blood that flowed from the incision? Where would Warren and dentist William T. G. Morton, who administered the ether, have stood relative to the patient?

Over time, a detailed picture took shape. Whenever the Prosperis reached the limits of evidence, they and their consultants made logical deductions. Daguerreotypes in Harvard’s Fogg Museum, for example, show Warren holding his glasses in a manner that suggests he was right-handed. If true, that would mean he should be positioned to the patient’s right in the painting. The fact that blood would flow from the incision—this was a time before cauterization was used—meant someone would probably be there to sop it up, so given Warren’s position, the Prosperis put that person on the patient’s left along with a basin on a table. The possibility that ether wouldn’t work would have meant that the surgical team not only used restraints at the patient’s elbows and ankles but also assigned someone to hold the patient’s head still, likely from behind to remain out of Warren’s way. Thus, each decision about how to compose the scene helped another fall into place.

Reconstructing events feels like time travel, the Prosperis say, and that sense of witnessing the past with nearly photographic precision gets shared with the viewers.

“I remember being alone in the Ether Dome, feeling the history of that moment, and thinking that we had to do honor to what came before,” says Lucia. “It was a heavy responsibility.”

Adds Warren, “It was also great fun.”

Shades of Meaning

Beyond authenticity, the choices made in paintings of medical topics take on symbolic value and convey what it means to be a doctor, a patient, or part of an institution.

The doctor’s worried expression in Fildes’ iconic painting reminds practitioners that sometimes medicine reaches its limit and all it can offer is empathy with the human experience. When English artist John Collier turns the physician away from the viewer in his 1908 painting Sentence of Death, he is subtly directing the viewer’s gaze to the young male patient and his shocked expression, emphasizing how personally devastating the receipt of a terminal diagnosis can be. In Science and Charity, executed by the Spanish painter Pablo Picasso when he was 15 years old, the artist presents the doctor as the scientific observer of symptoms, focusing on his timepiece as he takes his patient’s pulse while a nurse provides compassionate care.

Paintings can also capture the moment a clinical procedure was first put into practice, such as the 1816 introduction of the stethoscope depicted in Ernest Board’s sunlit Laënnec Listening to the Chest of a Patient. In Board’s 1908 work, the early monaural cylinder itself and inventor René Laënnec take center stage. Although such paintings can boost present-day doctors’ and researchers’ confidence that their contributions could likewise change the course of medical history, artistic works can also be used to warn that not all new ideas pan out. For better or worse, French physician Simon Bernheim immortalized his hypothesis for curing tuberculosis using interspecies blood transfusions by hiring French naturalist artist Jules Adler to advertise his idea, which Adler did in The Transfusion of a Goat’s Blood.

EYE TO INNOVATION: In a mural for the Joslin Diabetes Center, Warren Prosperi depicted HMS faculty William Beetham, a surgeon; Lloyd Aiello, an ophthalmology professor; and Priscilla Holman, a nurse, performing a laser surgery procedure developed by Beetham and Aiello. The revolutionary procedure prevented bleeding-induced blindness in patients with diabetes.

EYE TO INNOVATION: In a mural for the Joslin Diabetes Center, Warren Prosperi depicted HMS faculty William Beetham, a surgeon; Lloyd Aiello, an ophthalmology professor; and Priscilla Holman, a nurse, performing a laser surgery procedure developed by Beetham and Aiello. The revolutionary procedure prevented bleeding-induced blindness in patients with diabetes.

When Barnett led the team choosing the subjects for the Joslin paintings, he tried to select caregivers and researchers who represented progress in diabetes research and treatment and to tell stories that embodied the Joslin’s values. One of the physicians selected was Priscilla White, a founding member of Joslin Clinic. White, who collected data from pregnant women for half a century, helped raise the survival rate of babies born to diabetic mothers from 56 percent to over 90 percent.

Another painting depicts a twentieth-century health care team conferring around the bed of a woman with diabetes and a foot infection. Although some people recoil from the “blood and guts” nature of the gangrenous limb, Barnett says, he believes it’s important to portray real patients who lose their legs to the disease. “Looking at the painting reminds doctors of the importance of taking care of the whole person,” he says.

Viewers’ reactions can be emotional as well as intellectual. For Barnett, standing in the Joslin lobby surrounded by the Prosperis’ paintings brings back fifty years of memories of caring for patients with juvenile diabetes.

“Tears would come to my eyes to see kids in their twenties going blind,” he says. “This art can make people aware of what it was like to be a patient or a doctor in those days, when diabetes was a war.”

Face Values

The walls of Flaherty’s office are papered with taped-up printouts of artwork by and about doctors and patients. Art books and sculptures crowd all available horizontal surfaces. Flaherty believes that repeated exposure to artistic renderings of bodies and illness can make them less threatening in reality, help health care practitioners process difficult clinical experiences, and reassure practitioners that their work fits into an older, larger context.

Nonetheless, she worries about putting too thick an aesthetic gloss on medicine.

“It makes our patients more interesting and less painful for us when we aestheticize their experience, but that also can over-anesthetize our ability to feel their pain,” she says.

Art, cautions Flaherty, can encourage doctors to ignore the messiness in real patients’ stories or to infer emotions that may not reflect patients’ actual experiences and feelings. It can, she adds, perpetuate an approach of treating patients like objects to be contemplated rather than as active participants in their own care.

At the same time, Flaherty is among those who believe that art serves doctors well when it “takes something that we encounter every day, and thought we knew, and makes us see that it is unique.”

Having witnessed physicians refer to a terrified-looking patient as “resting comfortably,” Flaherty thinks that art can teach doctors to pay attention.

“Doctors often see the jaundiced sclera but not the sad expression,” she says, “because it saves time if we ignore the pain. Looking closely at portraits can help us remember how to look at people.”

Flaherty says that close attention to facial expression helps her tell the impassivity of depression from that of Parkinson’s disease, Botox treatments, or simply personal demeanor. Occasional attempts to draw—Flaherty has taken some lessons from Warren Prosperi—have engaged her with patients’ affect even more. She has learned, for instance, that if an eyelid’s position changes by even a hundred microns, a face can be transformed from sadness to fear.

“I was talking to a patient once and said, ‘Oh, the light’s in your face,’ ” Flaherty remembers. “He said, ‘That’s so thoughtful of you.’ Don’t thank me, I thought, thank an artist.”

Stephanie Dutchen is a science writer in the HMS Office of Communications and External Relations.

Images: John Soares

 

 

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

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

Phenanthrenes –all are used for analgesia

  • Morphine
  • Hydromorphone
  • Oxymorphone
  • Heroin

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

Phenyllpiperidines

  • Meperidine
  • Fentanyl (also sufentanil) which is 5-7 more times potent than fentanyl. Negative inotropic (contractile force) effects on heart

Levorphanol

 

Mild to Moderate Agonist

Phenanthrenes – most given in combo with NSAID

  • Codeine – antitussive, some analgesia
  • Oxycodone
  • Dihydrocodone
  • Hydrocodone

Propoxyphene – Darvon, low abuse and low analgesia compared to morphine

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

 

What was the drug in Clinical Trial Tragedy In France Jan 2016

by DR ANTHONY MELVIN CRASTO Ph.D

09404-notw1-BIA2

BIA 10-2474

3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide

BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor[1] developed by the Portuguese pharmaceutical company Bial-Portela & Ca. SA. The drug was developed to relieve pain,[2][3] to ease mood and anxiety problems, and to improve movement coordination linked to neurodegenerative illnesses.[4] It interacts with the humanendocannabinoid system.[5][6] It has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.[7]

French newspaper Le Figaro has obtained Bial study protocol documents listing the the chemical name of BIA-10-2474 as 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.[8] A Bial news release described BIA-10-2474 as “a long-acting inhibitor of FAAH”.[9]

Fatty acid amide hydrolase (FAAH) is an enzyme which degrades endocannabinoid neurotransmitters like anandamide,[10] which relieves pain and can affect eating and sleep patterns.[11][12] FAAH inhibitors have been proposed for a range of nervous-system disorders including anxiety, alcoholism, pain and nausea.

The Portuguese pharmaceutical company Bial holds several patents on FAAH enzyme inhibitors.[12][13][14][15]

No target organ was identified during toxicology studies and few adverse clinical findings were observed at the highest dose tested. For the single ascending dose part [of the clinical trial], a starting dose of 0.25 mg was judged to be safe for a first-in-human administration.[8]

The protocol defines no starting dose for the multi-dose treatment groups, noting that this will be based on the outcome of the single dose portion of the trial (an approach known as adaptive trial design). The authors note that nonetheless, the starting dose will not exceed 33% of the maximum tolerated dose (MTD) identified in the single dose groups (or 33% of the maximum administered dose if the MTD is not reached).[8]

In July 2015 Biotrial, a contract research organization, began testing the drug in a human phase one clinical trial for the manufacturer. The study was approved by French regulatory authority, the Agence Nationale de Sécurité du Médicament (ANSM), on June 26, 2015, and by the Brest regional ethics committee on July 3, 2015.[20] The trial commenced on July 9, 2015,[21] in the city of Rennes, and recruited 128 healthy volunteers, both men and women aged 18 to 55. According to French authorities, the study employed a three-stage design with 90 of the volunteers having received the drug during the first two stages of the trial, with no serious adverse events being reported .[17][20] Participants of the study were to receive €1,900 and, in turn, asked to stay at Biotrial’s facility for two weeks during which time they would take the drug for ten days and undergo tests.[22]

In the third stage of the trial evaluating multiple doses, six male volunteers received doses by mouth, starting on 7 January 2016. The first volunteer was hospitalized at theRennes University Hospital on January 10, became brain dead,[17][23][24][25] and died on January 17.[26] The other five men in the same dosage group were also hospitalized, in the period of January 10 through January 13[27] four of them suffering injuries including deep hemorrhagic and necrotic lesions seen on brain MRI.[7] The six men who were hospitalised were the group which received the highest dose.[26] A neurologist at the University of Rennes Hospital Center, Professor Pierre-Gilles Edan, stated in a press conference with the French Minister for Health, that 3 of the 4 men who were displaying neurological symptoms “already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap” and were being given corticosteroids to control the inflammation.[27] The sixth man from the group was not showing adverse effects but had been hospitalized for observation.[25][28][29] Biotrial stopped the experiment on January 11, 2016.[4]

Le Figaro posted a 96-page clinical study protocol for BIA 10-2474 that the French newspaper procured from an unnamed source.

According to the document, BIA 10-2474 is 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.

BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.”

The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.

The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana.

Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes.

The French health minister has stated the drug acted on natural receptors found in the body known as endocannibinoids, which regulate mood and appetite. It did not contain cannabis or anything derived from it, as was originally reported. All six trial participants were administered the doses simultaneously.

The trial was being performed at Biotrial, a French-based firm that was formed in 1989 and has conducted thousands of trials. A message on the company’s website stated that they are working with health authorities to understand the cause of the accident, while extending thoughts to the patients and their families. Bial has disclosed the drug was a FAAH (fatty acid amide hydrolase) inhibitor, which is an enzyme produced in the brain and elsewhere that breaks down neurotransmitters called endocannabinoids. Two scientists from the Nottingham Medical School who have worked with FAAH tried over the weekend to try and identify the drug by examining a list of drugs Bial currently has in its pipeline. They believe the culprit is one identified by the codename BIA 10-2474.

While safety issues like this are rare, they are not unheard of. In 2006, a clinical trial in London left six men ill. All were taking part in a study testing a drug designed to fight auto-immune disease and leukemia. Within hours of taking the drug TGN1412, all experienced a serious reaction, were admitted to intensive care, and had to be treated for organ failure.

The Duff Report, written in response to the TGN1412 trial, noted the medicine should have been tested in one person at a time. It also helped to put additional safety measures in place. The Medicines and Health Products Regulatory Agency (MHRA) now requires committees to look at pre-clinical data to determine the proper initial dose, and rules are in place to stop the trial if unintended reactions occur.

Other pharmaceutical companies, including Merck, Pfizer, Johnson & Johnson, Sanofiand Vernalis, have previously taken other FAAH inhibitors into clinical trials without experiencing such adverse events (e.g. respectively, MK-4409,[35][36] PF-04457845,JNJ-42165279,[37] SSR411298 and V158866.[38][39] Related enzyme inhibitor compounds such as URB-597 and LY-2183240 have been sold illicitly as designer drugs,[40][41] all without reports of this type of toxicity emerging, so the mechanism of the toxicity observed with BIA 10-2474 remains poorly understood.

Clinical Trial Tragedy, France, Jan 2016, PHASE 1 | Categories: Uncategorized | URL:http://wp.me/p38LX5-4ut

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Pharmacological Action of Steroid Hormones

Curator: Larry H. Bernstein, MD, FCAP

 

Hormone Receptors

Steroid hormone receptors are found on the plasma membrane, in the cytosol and also in the nucleus of target cells. They are generally intracellular receptors (typically cytoplasmic) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A)[1] and 3-ketosteroids (group NR3C).[2] In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

 

Steroid Hormone Receptors and their Response Elements

Steroid hormone receptors are proteins that have a binding site for a particular steroid molecule. Their response elements are DNA sequences that are bound by the complex of the steroid bound to its Steroid receptor.

The response element is part of the promoter of a gene. Binding by the receptor activates or represses, as the case may be, the gene controlled by that promoter.

It is through this mechanism that steroid hormones turn genes on (or off).

 

steroid hormone receptor

steroid hormone receptor

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/Sigler.jpg

 

This image (courtesy of P. B. Sigler) shows a stereoscopic view of the glucocorticoid response element (DNA, the double helix shown in yellow at the left of each panel) with the glucocorticoid receptor (a protein homodimer, right portion of each panel) bound to it.

 

The DNA sequence of the glucocorticoid response element is

  • 5′ AGAACAnnnTGTTCT 3′
  • 3′ TCTTGTnnnACAAGA 5′

where n represents any nucleotide. (Note the inverted repeats.)

 

The glucocorticoid receptor, like all steroid hormone receptors, is a zinc-finger transcription factor; the zinc atoms are the four yellow spheres. Each is attached to four cysteines.

 

For a steroid hormone to regulate (turn on or off) gene transcription, its receptor must:

  1. bind to the hormone (cortisol in the case of the glucocorticoid receptor)
  2. bind to a second copy of itself to form a homodimer
  3. be in the nucleus, moving from the cytosol if necessary
  4. bind to its response element
  5. bind to other protein cofactors

Each of these functions depend upon a particular region of the protein (e.g., the zinc fingers for binding DNA). Mutations in any one region may upset the function of that region without necessarily interfering with other functions of the receptor.

Positive and Negative Response Elements

Some of the hundreds of glucocorticoid response elements in the human genome activate gene transcription when bound by the hormone/receptor complex. Others inhibit gene transcription when bound by the hormone/receptor complex.

Example: When the stress hormone cortisol — bound to its receptor — enters the nucleus of a liver cell, the complex binds to

the positive response elements of the many genes needed for gluconeogenesis — the conversion of protein and fat into glucose resulting in a rise in the level of blood sugar.

the negative response element of the insulin receptor gene thus diminishing the ability of the cells to remove glucose from the blood. (This hyperglycemic effect is enhanced by the binding of the cortisol/receptor complex to a negative response element in the beta cells of the pancreas thus reducing the production of insulin.)

Note that every type of cell in the body contains the same response elements in its genome. What determines if a given cell responds to the arrival of a hormone depends on the presence of the hormone’s receptor in the cell.

Visual Evidence of Hormone Binding

This autoradiograph (courtesy of Madhabananda Sar and Walter E. Stumpf) shows the endometrial cells from the uterus of a guinea pig 15 minutes after an injection of radioactive progesterone. The radioactivity has concentrated within the nuclei of the endometrial cells as shown by the dark grains superimposed on the images of the nuclei. The same effect is seen when radioactive estrogens are administered.

The cells of the endometrium are target cells for both progesterone and estrogens, preparing the uterus for possible pregnancy. [Link to discussion]

 

Endometrium

Endometrium

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Endometrium.jpg

Nontarget cells (e.g. liver cells or lymphocytes) show no accumulation of female sex hormones. Although their DNA contains the response elements, their cells do not have the protein receptors needed.

 The Nuclear Receptor Superfamily

 

Retinoids

Retinoids

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/R/Retinoids.png

 The zinc-finger proteins that serve as receptors for glucocorticoids and progesterone are members of a large family of similar proteins that serve as receptors for a variety of small, hydrophobic molecules. These include:

  1. other steroid hormones like
  2. the mineralocorticoid aldosterone
  3. estrogens
  4. the thyroid hormone, T3
  5. calcitriol, the active form of vitamin D
  6. retinoids: vitamin A (retinol) and its relatives
    1. retinal
    2. retinoic acid (tretinoin — also available as the drug Retin-A®); and its isomer
  7. isotretinoin (sold as Accutane® for the treatment of acne).
  8. bile acids
  9. fatty acids.
The three dimensional crystal structure of holo-retinol binding protein (RBP–ROH)

The three dimensional crystal structure of holo-retinol binding protein (RBP–ROH)

 

 

 

 

 

vitamin_d_synthesis

 

Chemical structures of vitamin A (retinol)

Chemical structures of vitamin A (retinol)

 

vit D and receptor complex

vit D and receptor complex

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

These bind members of the superfamily called peroxisome-proliferator-activated receptors (PPARs). They got their name from their initial discovery as the receptors for

  • drugs that increase the number and size of peroxisomes in cells.

In every case, the receptors consist of at least

  • three functional modules or domains.

From N-terminal to C-terminal, these are:

  1. a domain needed
  2. the zinc-finger domain needed for DNA binding (to the response element)
  3. the domain responsible for binding the particular hormone as well as the second unit of the dimer.
  4. for the receptor to activate the promoters of the genes being controlled

The Steroid Hormone Receptors

Klinge, C, Rao, C, Glob. libr. women’s med.,

(ISSN: 1756-2228) 2008;
http://dx.doi.org:/10.3843/GLOWM.10281
Structure of The Steroid Hormone Receptor Protein

In order to understand how steroid hormone receptors regulate gene function, it is important to know the structure of the receptor proteins as well as the identity and cellular function of the genes that they regulate. Members of the steroid receptor superfamily share direct amino acid homology and a common structure (Fig. 1).

Fig. 1 Relative lengths of several members of the steroid/nuclear hormone receptor superfamily, shown schematically as linearized proteins with common structural and functional domains. Variability between members of the steroid hormone receptor family is due primarily to differences in the length and amino acid sequence of the amino (N)-terminal domain. Adapted from Wahli W, Martinez E. Superfamily of steroid nuclear receptors: Positive and negative regulators of gene expression. FASEB J 1991;5:2243-2249.

lengths of steroid hormone receptor superfamily

lengths of steroid hormone receptor superfamily

http://resources.ama.uk.com/glowm_www/graphics/figures/v5/0040/001f.gif

Molecular cloning of the complementary DNA (cDNA) for each of the major steroid receptors has greatly enhanced our understanding of the structure–function relationships for these molecules. The receptor proteins have five or six domains called A–F from N- to C-terminus, encoded by 8–9 exons.  The receptors contain three major functional domains that have been shown experimentally to operate as independent “cassettes”,13 unrestricted as to position within the molecule. The three major functional domains (Fig. 2) of the receptor are:

 

  1. A variable N-terminus (domains A and B) that confers immunogenicity and modulates transcription in a gene and cell-specific manner through its N-terminal Activation Function-1 (AF-1);
  2. A central DNA-binding domain (DBD, consisting of the C domain), comprised of two functionally distinct zinc fingers through which the receptor physically interacts directly with the DNA helix;
  3. The ligand-binding domain (LBD, domains E and in some receptors F) that contains Activation Function-2 (AF-2).

 

Fig. 2 Schematic representation of the common structural and functional domains of the steroid hormone receptors. The horizontal lines indicate the domains of the receptor. Adapted from Wahli W, Martinez E. Superfamily of steroid nuclear receptors: Positive and negative regulators of gene expression. FASEB J 1991;5:2243-2249.

 

http://resources.ama.uk.com/glowm_www/graphics/figures/v5/0040/002f.gif

 

The F domain is thought to play a role in distinguishing estrogen agonists from antagonists, perhaps through interaction with cell-specific factors. Domain-swapping experiments in which the DBD of estrogen receptor α (ERα) was switched with that of the glucocorticoid receptor (GR), yielded a chimeric receptor that bound to specific DNA sequences bound by GR, but up-regulated transcription of glucocorticoid-responsive target genes when treated with estrogen, thus demonstrating the specificity of the DNA-binding domain in target gene regulation.

The amino (N)-terminal domain is hypervariable (less than 15% homology among steroid receptors) in both size and amino acid sequence, ranging in length from 25 amino acids to 603 amino acids and constituting the major source of size differences between receptors. The AF-1 domain in this region is involved in activation of gene transcription, but does not depend on ligand binding. In rat GR, the AF-1 region is called tau 1 or enh2 and constitutes aa 108–317. Tau 1 is necessary for transcriptional activation and repression. Deletion of the C-terminal LBD of GR yields constitutive (hormone-independent) transcriptional activation, implying that the N-terminal regions harbor autonomous transcriptional activation functions.

 

Some steroid receptors exist as isoforms, encoded by the same gene, but differing in their N-terminus. The progesterone and androgen receptors (PR and AR) exist in two distinct forms, A and B, synthesized from the same mRNA by alternate splicing. The two PR receptor isoforms differ by 128 amino acids in the N-terminal region, yielding PR-A = 90 kDa and PR-B = 120 kDa, that have strikingly differing capacities to regulate transcription. In contrast, AR-A and AR-B isoforms show minimal differences in activation of a reporter gene in response to androgen agonists or antagonists in transiently transfected cells.

Receptors in this superfamily contain several key structural elements which enable them to bind to their respective ligands with high affinity and specificity, recognize and bind to discrete response elements within the DNA sequence of target genes with high affinity and specificity, and regulate gene transcription.

The central core or DNA-binding domain (DBD) is highly conserved and shows 60–95% homology among steroid receptors.1 The DBD varies in size from 66 to 70 amino acids, and is hydrophilic due to its high content of basic amino acids. The major function of this region is to bind to specific hormone response elements (HREs) of the target gene. DNA-binding is achieved through the tetrahedral coordination of zinc (Zn) by four cysteine residues in each of two extensions, that form two structurally distinct “Zn fingers” (Fig. 3). Zn fingers are common among gene regulatory proteins. Specificity of HRE binding is determined by the more highly conserved hydrophilic first Zn finger (C1), while the second Zn finger (C2) is involved in dimerization and stabilizing DNA binding by ionic interactions with the phosphate backbone of the DNA.18 The D box is involved in HRE half-site spacing recognition. The highly conserved DBD shared by AR, GR, mineralocorticoid receptor (MR), and PR enables them to bind to the same HRE, called the glucocorticoid response element (GRE). The more C-terminal part of the C2 Zn finger and amino acids in the hinge region are involved in receptor dimerization in coordination with amino acids in the hinge region and the LBD.

 

Fig. 3 Schematic diagram of type II zinc finger proteins characteristic of the DNA-binding domain structure of members of the steroid hormone receptor superfamily. Zinc fingers are common features of many transcription factors, allowing proteins to bind to DNA. Each circle represents one amino acid. The CI zinc finger interacts specifically with five base pairs of DNA and determines the DNA sequence recognized by the particular steroid receptor. The three shaded amino acids indicated by the arrows in the knuckle of the CI zinc finger are in the “P box” that allows HRE sequence discrimination between the GR and ERα. The vertically striped aa within the knuckle of the CII zinc finger constitutes the “D box” that is important for dimerization and contacts with the DNA phosphate backbone. Adapted from Tsai M-J, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 1994;63:451-483; Gronemeyer H. Transcription activation by estrogen and progesterone receptors. Annu Rev Genet 1991;25:89-123.

type II zinc finger proteins

type II zinc finger proteins

http://resources.ama.uk.com/glowm_www/graphics/figures/v5/0040/003f.gif

The hinge region or D domain is a 40–50 amino acid sequence separating the DNA-binding and ligand-binding domains that contains sequences for receptor dimerization and ligand-dependent and independent nuclear localization sequences (NLSs). The hinge region interacts with nuclear corepressor proteins, and with L7/SPA, a 27 kDa protein that increases the partial agonist activity of certain antagonist-liganded steroid hormone receptors, i.e., tamoxifen-liganded ERα, RU486-occupied PR, or RU486-occupied GR. ….

The carboxy (C)-terminal or ligand-binding domain (LBD) is poorly conserved, ranging in size from 218 to 264 amino acids and is hydrophobic. This region contains the ligand-binding site and dictates hormone binding specificity.

Two human GR isoforms, GRα and GRβ, derived from the same gene by differential splicing at the C-terminus, have been reported. While GRα and GRβ share the first eight exons, they differ in their last two exons, i.e., exons 9α or 9β, spliced into the respective mRNA.40 GRβ was reported to localize in the cell nucleus in the absence of ligand and to block hGRα activity. …

Sequences within the LBD form the binding site for hsp90 that blocks the DBD in the cytosolic, nonliganded GR.40 The CII and CIII regions (Fig. 2) show homology among members of the steroid/nuclear receptor superfamily and are important in forming the ligand binding pocket. …

 

The Bifunctional Role of Steroid Hormones: Implications for Therapy in Prostate Cancer

Paul Mathew, MD
Review Article | May 15, 2014 | Oncology Journal, Genitourinary Cancers, Prostate Cancer

In a biomarker-driven study reported in 1941, Drs. Huggins and Hodges of the University of Chicago demonstrated reduction in elevated levels of serum acid phosphatase in five men with metastatic prostate cancer treated with estrogens and orchiectomy, whereas three men who received testosterone injections after orchiectomy exhibited increased serum levels of the enzyme. Hitherto, serum elevations of acid phosphatase had been associated strictly with prostate cancer, and Huggins and Hodges thus concluded that androgens activated prostate cancer. Nevertheless, in the years that followed, several investigators experimented with testosterone injections in prostate cancer. Pearson[3] of the Sloan-Kettering Institute reviewed the inconsistent biochemical and clinical responses to testosterone injections associated with these studies and puzzled over two case studies of his own, one of a hormone-naive patient, another of a castration-resistant patient, both of whom had responded to testosterone injection: “These observations invite the development of new concepts to explain the response of these prostatic cancers to alterations in the endocrine environment.”

Table 1: Sex Steroids as Tumor Suppressors (not shown)

ABSTRACT: Ablation of the androgen-signaling axis is currently a dominant theme in developmental therapeutics in prostate cancer. Highly potent inhibitors of androgen biosynthesis and androgen receptor (AR) function have formally improved survival in castration-resistant metastatic disease. Resistance to androgen-ablative strategies arises through diverse mechanisms. Strategies to preserve and extend the success of hormonal therapy while mitigating the emergence of resistance have long been of interest. In preclinical models, intermittent hormonal ablative strategies delay the emergence of resistant stem-cell–driven phenotypes, but clinical studies in hormone-naive disease have not observed more than noninferiority over continual androgen ablation. In castration-resistant disease, response and improvement in subjective quality of life with therapeutic testosterone has been observed, but so too has symptomatic and life-threatening disease acceleration. The multifunctional and paradoxical role of steroid hormones in regulating proliferation and differentiation, as well as cell death, requires deeper understanding. The lack of molecular biomarkers that predict the outcome of hormone supplementation in a particular clinical context remains an obstacle to individualized therapy. Biphasic patterns of response to hormones are identifiable in vitro, and endocrine-regulated neoplasms that proliferate after prolonged periods of hormone deprivation appear preferentially sex steroid–suppressible. This review examines the relevance of a translational framework for studying therapeutic androgens in prostate cancer.

 

Protection and Damage from Acute and Chronic Stress: Allostasis and Allostatic Overload and Relevance to the Pathophysiology of Psychiatric Disorders

Bruce S. Mcewen*

Annals of the New York Academy of Sciences 12 JAN 2006;
1032 (Biobehavioral Stress Response: Protective and Damaging Effects): Pp1–328

http://dx.doi.org:/10.1196/annals.1314.001

                                             

Keywords:

stress;psychiatric disorders;depression;allostasis;allostatic overload;homeostasis

Abstract: Stress promotes adaptation, but prolonged stress leads over time to wear-and-tear on the body (allostatic load). Neural changes mirror the pattern seen in other body systems, that is, short-term adaptation vs. long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in the brain. Many of these processes are seen in major depressive illness and may be expressed also in other chronic anxiety disorders. The brain controls the physiological and behavioral coping responses to daily events and stressors. The hippocampal formation expresses high levels of adrenal steroid receptors and is a malleable brain structure that is important for certain types of learning and memory. It is also vulnerable to the effects of stress and trauma. The amygdala mediates physiological and behavioral responses associated with fear. The prefrontal cortex plays an important role in working memory and executive function and is also involved in extinction of learning. All three regions are targets of stress hormones. In animal models, neurons in the hippocampus and prefrontal cortex respond to repeated stress by showing atrophy, whereas neurons in amygdala show a growth response. Yet, these are not necessarily “damaged” and may be treatable with the right medications.

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