Experience of and Alleviation of Pain
Curator: Larry H. Bernstein, MD, FCAP
A Thousand Words
Stories of medicine unfold on canvas
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
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 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.
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
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
Please See VIDEOs on Cancer, Pain and Palliative Care
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
- Local injection of endothelin-1 produces pain-like behavior and excitation of nociceptors in rats. Gokin AP, Fareed MU, Pan HL, Hans G, Strichartz GR, Davar G J Neurosci. 2001 Jul 15; 21(14):5358-66.
- Expression and localization of endothelin receptors: implications for the involvement of peripheral glia in nociception.Pomonis JD, Rogers SD, Peters CM, Ghilardi JR, Mantyh PW J Neurosci. 2001 Feb 1; 21(3):999-1006.
- Endothelin and the tumorigenic component of bone cancer pain.[Neuroscience. 2004]
- Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Rosanò L1, Varmi M, Salani D, Di Castro V, Spinella F, Natali PG, Bagnato A. Cancer Res. 2001 Nov 15;61(22):8340-6.
- Endothelin-1 is required during epithelial to mesenchymal transition in ovarian cancer progression. Rosanò L1, Spinella F, Di Castro V, Decandia S, Nicotra MR, Natali PG, Bagnato A. Exp Biol Med (Maywood). 2006 Jun;231(6):1128-31.
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.
- Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway. Lam DK, Schmidt BL. Pain. 2010 May; 149(2):263-72.
- Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Grisaru-Granovsky S, Salah Z, Maoz M, Pruss D, Beller U, Bar-Shavit R. Int J Cancer. 2005 Jan 20;113(3):372-8.
Bradykinin
Sevcik MA, Ghilardi JR, Halvorson KG, Lindsay TH, Kubota K, Mantyh PW
J Pain. 2005 Nov; 6(11):771-5
- T-kinin in human ovarian carcinoma ascites. Adv Exp Med Biol. 1989;247B:109-14. Wunderer G1, Walter I.
Nerve Growth Factor
- Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.[J Clin Oncol. 1999]
- Role of nerve growth factor and FSH receptor in epithelial ovarian Bose CK. Reprod Biomed Online. 2005 Aug;11(2):194-7. Review.
Tumor Necrosis Factor
- Nociceptive characteristics of tumor necrosis factor-alpha in naive and tumor-bearing mice. Wacnik PW, Eikmeier LJ, Simone DA, Wilcox GL, Beitz AJ Neuroscience. 2005; 132(2):479-91.
- Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). Simonitsch I, Krupitza G. Br J Cancer. 1998 Oct;78(7):862-70.
Opioids: A Reference
Opioid analgesics: analgesia without loss of consciousness
Three main uses of opioids
- Analgesia
- Antitussive
- 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:
|
| Nociceptin receptor NOP OP4 |
ORL1 |
|
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
- Analgesia – raise threshhold for pain
- Euphoria – pleasant floating feeling but sometimes dysphoria (agitation)
- Sedation –drowsiness but no amnesia; more frequent in elderly than young but can disrupt normal REM sleep
- 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
- Cough suppression – tolerance can develop; may increase airway secretions
- Miosis – constriction of pupils; seen with ALL agonists; treat with atropine
- Rigidity – mostly seen with fentanyl; treat with opioid antagonist like nalozone
- Emesis; naseua, vomiting
- Peripheral
- Cardiovascular – no real major effects; some specific compounds may have effects on blood pressure
- 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
- Biliary system – minor, may cause constriction of bile duct
- GU (genitourinary) – reduced urine output by increased antidiuretic hormone
- Uterus – may prolong labor
- Neuroendocrine – opioid analgesics can stimulate release of ADH, prolactin
- 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
- Nalbulphine – strong kappa agonist and mu antagonist.. Analgesic
- Buprenorphine – analgesic. Partial mu agonist has long duration. Slow dissocation from receptor makes resistant to naloxone reversal
- Buterphanol – analgesia with sedation, kappa agonist
- Pentazocine – kappa agonist with weak mu antagonism.Is an irritant so do no inject s.c.
Antagonists
- 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
- Naltrexone – well absorbed orally can be used in maintenance therapy because of long duration of action
Antitussives
- Codeine
- Dextromethorphan
- Levoproposyphen
- 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 |
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
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
Frason
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
zraviv06
zs22
Leave a Reply