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Multiple factors related to initial trial design may predict low patient accrual for cancer clinical trials

Posted in Cancer and Current Therapeutics, Cancer Prevention: Research & Programs, Cancer Screening, Clinical & Translational, Clinical Diagnostics, Health Economics and Outcomes Research, tagged , , , , , , , , , , , , , on December 30, 2015| Leave a Comment »

 

Multiple factors related to initial trial design may predict low patient accrual for cancer clinical trials

Reporter: Stephen J. Williams, Ph.D.

UPDATED 5/15/2019

A recently published paper in JCNI highlights results determining factors which may affect cancer trial patient accrual and the development of a predictive model of accrual issues based on those factors.

To hear a JCNI podcast on the paper click here

but below is a good posting from scienmag.com which describes their findings:

Factors predicting low patient accrual in cancer clinical trials

source: http://scienmag.com/factors-predicting-low-patient-accrual-in-cancer-clinical-trials/

Nearly one in four publicly sponsored cancer clinical trials fail to enroll enough participants to draw valid conclusions about treatments or techniques. Such trials represent a waste of scarce human and economic resources and contribute little to medical knowledge. Although many studies have investigated the perceived barriers to accrual from the patient or provider perspective, very few have taken a trial-level view and asked why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants. According to a study published December 29 in the JNCI: Journal of the National Cancer Institute, a number of measurable trial characteristics are predictive of low patient accrual.

Caroline S. Bennette, M.P.H., Ph.D., of the Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, and colleagues from the University of Washington and the Fred Hutchinson Cancer Research Center analyzed information on 787 phase II/III clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011. After excluding trials that closed because of toxicity or interim results, Bennette et al. found that 145 (18%) of NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The authors identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy. Bennette et al. then developed a multivariable prediction model of low accrual using 12 trial-level risk factors, which they reported had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

The researchers conclude that “Systematically considering the overall influence of these factors could aid in the design and prioritization of future clinical trials…” and that this research provides a response to the recent directive from the Institute of Medicine to “improve selection, support, and completion of publicly funded cancer clinical trials.”

In an accompanying editorial, Derek Raghavan, M.D., Levine Cancer Institute, writes that the focus needs to be on getting more patients involved in trials, saying, “we should strive to improve trial enrollment, giving the associated potential for improved results. Whether the basis is incidental, because of case selection bias, or reflects the support available to trial patients has not been determined, but the fact remains that outcomes are better.”

###

Contact info:

Article: Caroline S. Bennette, M.P.H., Ph.D., cb11@u.washington.edu

Editorial: Derek Raghavan, M.D., derek.raghavan@carolinashealthcare.org

Other investigators also feel that initial trial design is of UTMOST importance for other reasons, especially in the era of “precision” or “personalized” medicine and why the “basket trial” or one size fits all trial strategy is not always feasible.

In Why the Cancer Research Paradigm Must Transition to “N-of-1” Approach

Dr. Maurie Markman, MD gives insight into why the inital setup of a trial and the multi-center basket type of  accrual can be a problematic factor in obtaining meaningful cohorts of patients with the correct mutational spectrum.

The anticancer clinical research paradigm has rapidly evolved so that subject selection is increasingly based on the presence or absence of a particular molecular biomarker in the individual patient’s malignancy. Even where eligibility does not mandate the presence of specific biological features, tumor samples are commonly collected and an attempt is subsequently made to relate a particular outcome (eg, complete or partial objective response rate; progression-free or overall survival) to the individual cancer’s molecular characteristics.

One important result of this effort has been the recognition that there are an increasing number of patient subsets within what was previously—and incorrectly—considered a much larger homogenous patient population; for example, non–small cell lung cancer (NSCLC) versus EGFR-mutation–positive NSCLC. And, while it may still be possible to conduct phase III randomized trials involving a relatively limited percentage of patients within a large malignant entity, extensive and quite expensive effort may be required to complete this task. For example, the industry-sponsored phase III trial comparing first-line crizotinib with chemotherapy (pemetrexed plus either carboplatin or cisplatin) in ALK-rearrangement–positive NSCLC, which constitutes 3% to 5% of NSCLCs, required an international multicenter effort lasting 2.5 years to accrue the required number of research subjects.1

But what if an investigator, research team, or biotech company desired to examine the clinical utility of an antineoplastic in a patient population representing an even smaller proportion of patients with NSCLC such as in the 1% of the patient population with ROS1 abnormalities,2 or in a larger percentage of patients representing 4%-6% of patients with a less common tumor type such as ovarian cancer? How realistic is it that such a randomized trial could ever be conducted?

Further, considering the resources required to initiate and successfully conduct a multicenter international phase III registration study, it is more than likely that in the near future only the largest pharmaceutical companies will be in a position to definitively test the clinical utility of an antineoplastic in a given clinical situation.

One proposal to begin to explore the benefits of targeted antineoplastics in the setting of specific molecular abnormalities has been to develop a socalled “basket trial” where patients with different types of cancers with varying treatment histories may be permitted entry, assuming a well-defined molecular target is present within their cancer. Of interest, several pharmaceutical companies have initiated such clinical research efforts.

Yet although basket trials represent an important research advance, they may not provide the answer to the molecular complexities of cancer that many investigators believe they will. The research establishment will have to take another step toward innovation to “N-of-1” designs that truly explore the unique nature of each individual’s cancer.

Trial Illustrates Weaknesses

A recent report of the results of one multicenter basket trial focused on thoracic cancers demonstrates both the strengths but also a major fundamental weakness of the basket trial approach.3

However, the investigators were forced to conclude that despite accrual of more than 600 patients onto a study conducted at two centers over a period of approximately 2 years, “this basket trial design was not feasible for many of the arms with rare mutations.”3

They concluded that they needed a larger number of participating institutions and the ability to adapt the design for different drugs and mutations. So the question to be asked is as follows: Is the basket-type approach the only alternative to evaluate the clinical relevance of a targeted antineoplastic in the presence of a specific molecular abnormality?

Of course, the correct answer to this question is surely: No!

– See more at: http://www.onclive.com/publications/Oncology-live/2015/July-2015/Why-the-Cancer-Research-Paradigm-Must-Transition-to-N-of-1-Approach#sthash.kLGwNzi3.dpuf

The following is a video on the website ClinicalTrials.gov which is a one-stop service called EveryClinicalTrial to easily register new clinical trials and streamline the process:

 

UPDATED 5/15/2019

Another possible roadblock to patient accrual has always been the fragmentation of information concerning the availability of clinical trails and coordinating access among the various trial centers, as well as performing analytics on trial data to direct new therapeutic directions.  The NIH has attempted to circumvent this problem with the cancer trials webpage trials.gov however going through the vast number of trials, patient accrual requirements, and finding contact information is a daunting task.  However certain clinical trial marketplaces are now being developed which may ease access problems to clinical trials as well as data analytic issues, as highlighted by the Scientist.com article below:

Scientist.com Launches Trial Insights, A Transformative Clinical Trials Data Analytics Solution

The world’s largest online marketplace rolls out first original service, empowering researchers with on demand insights into clinical trials to help drive therapeutic decisions

SAN DIEGO–(BUSINESS WIRE)–Scientist.com, the online marketplace for outsourced research, announced today the launch of Trial Insights, a digital reporting solution that simplifies data produced through clinical trial, biomarker and medical diagnostic studies into an intuitive and user-friendly dashboard. The first of its kind, Trial Insights curates publicly available data nightly from information hubs such as clinicaltrials.gov and customizes it to fit a researcher or research organization’s specific project needs.

Trial Insights, new clinical trial reporting solution, allows researchers to keep track of the evolving landscape of drugs, diseases, sponsors, investigators and medical devices important to their work.

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“Trial Insights offers researchers an easy way to navigate the complexity of clinical trials information,” said Ron Ranauro, Founder of Incite Advisors. “Since Trial Insights’ content is digitally curated, researchers can continuously keep track of the evolving landscape of drugs, diseases, sponsors, investigators and medical devices important to their work.”

As the velocity, variety and veracity of data available on sites like clinicaltrials.gov continues to increase, the ability to curate it becomes more valuable to different audiences. With the advancement of personalized medicine, it is important to make the data accessible to the health care and patient communities. Information found on the Trial Insights platform can help guide decision making across the pharmaceutical, biotechnology and contract research organization industries as clinical trial data is a primary information source for competitive intelligence, research planning and clinical study planning.

“We are extremely excited to launch the first Scientist.com exclusive, original service offering to our clients in the life sciences,” said Mark Herbert, Scientist.com Chief Business Officer. “Our goal at Scientist.com is to help cure all diseases by 2050, and we believe solutions like Trial Insights, which greatly simplifies access to and reporting of clinical trial data, will get us one step closer to reaching that goal.”

source: https://www.businesswire.com/news/home/20190416005362/en/Scientist.com-Launches-Trial-Insights-Transformative-Clinical-Trials?utm_source=TrialIO+List

 

Other article on this Open Access Journal on Cancer Clinical Trial Design include:

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Patients First

Posted in Hospital reputation, Patient Experience, Reputation of Interventionist, Support Staff, tagged , , , , , on November 15, 2015| Leave a Comment »

Patients First

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Office of Patient Experience

http://my.clevelandclinic.org/patients-visitors/patient-experience

 

Cleveland Clinic defines our patient experience as putting “Patients First”.

http://my.clevelandclinic.org/ccf/media/Images/Patient%20Experience/carousel/patients_first.jpg

 

Putting patients first requires more than world-class clinical care – it requires care that addresses every aspect of a patient’s encounter with Cleveland Clinic, including the patient’s physical comfort, as well as their educational, emotional, and spiritual needs. Our team of professionals serves as an advisory resource for critical initiatives across the Cleveland Clinic health system. In addition, we provide resources and data analytics; identify, support, and publish sustainable best practices; and collaborate with a variety of departments to ensure the consistent delivery of patient-centered care.

Cleveland Clinic was the first major academic medical center to make patient experience a strategic goal, appoint a Chief Experience Officer, and one of the first to establish an Office of Patient Experience.

 

Patient Experience Measurement

http://my.clevelandclinic.org/ccf/media/Images/Patient%20Experience/launchpads/programs-lp.jpg

How We Measure Patient Experience

All acute care hospitals throughout the United States participate in a patient survey process designed and regulated by the Centers for Medicare and Medicaid Services (CMS). This HCAHPS survey (Hospital Consumer Assessment of Healthcare Providers and Systems) measures patients’ perspectives of their hospital care.

Public results are available at hospitalcompare.hhs.gov. Eligible adult patients are surveyed after hospital discharge and results displayed represent four consecutive calendar quarters.

Due to a time lag of the published HCAHPS survey results, we believe it is important for you to see our most recent feedback. View our HCAHPS scores from the last public reported period as well as our recent performance.

HCAHPS Education and Data Coordination

The Intelligence Team in the Office of Patient Experience plays a vital role in coordinating survey data transmission between the survey vendor and the Cleveland Clinic system. Real-time survey results, complete with benchmark comparisons and performance indicators, are maintained on an internal web-based dashboard program available to all staff in leadership and management roles. The team also provides survey education, particularly for the CMS-required inpatient HCAHPS survey process, and works together with leadership to uncover feedback trends and help prioritize experience improvement efforts.

 

Patient Experience: Empathy & Innovation Summit

Patient Experience: A Key Differentiator

Visit the Empathy +
Innovation Summit website

Patient experience has emerged as a dynamic issue for healthcare executives, physicians, nursing executives and industry leaders. No provider can afford to offer anything less than the best clinical, physical and emotional experience to patients and families. As patients become savvier, they judge healthcare providers not only on clinical outcomes, but also on their ability to be compassionate and deliver excellent, patient-centered care.

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Opioids, Pain, And Palliative Care

Posted in Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Health Economics and Outcomes Research, Pain: Etiology, Genetics & Innovations in Treatment, tagged , , , , , , , , , , , , , on September 14, 2015| Leave a Comment »

Opioids, Pain, And Palliative Care [6.3.9]

Curator: Stephen J. Williams, Ph.D.

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

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

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

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

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

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

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

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

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

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

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

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

Palliative Care

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

Palliative Care_4.6

Please See VIDEOs on Cancer, Pain and Palliative Care

https://youtu.be/88ri3VNOd2E

 

https://youtu.be/B1_Ui3f4AI4

https://youtu.be/-KOSinGapUg

From ACS Guideline: Developing a plan for pain control

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

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

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

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

You can use the rating scale to describe:

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

Tell your cancer care team and your family or friends:

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

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

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

The attached PDF gives information on

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

Table. Important Points in NCCN Guidelines for Pain Management

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

– Consider specific pain syndrome problem and consultation

– continue analgesic titration
Mild (0-3) Adjuvant analgesics

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

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

Ovarian cancer stem cells and mediators of pain

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

Some Known Pain Mediators Secreted from Ovarian Tumor Cells

Endothelin-1

Proteases and Protease-Activated Receptors

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

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

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

Bradykinin

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

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

Nerve Growth Factor

Tumor Necrosis Factor

Opioids: A Reference

Opioid analgesics: analgesia without loss of consciousness

Three main uses of opioids

  1. Analgesia
  2. Antitussive
  3. Diarrhea

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

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

2) synthetic: meperedine, methadone

Chemistry

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

Pharmaookinetics

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

 

Metabolism

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

 

Receptors

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

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

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

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

μ2:

μ3:

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

Tolerance and Physical Dependence

Tolerance: gradual loss of effectiveness over repeated doses

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

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

Major effects of opioids on Organ Systems

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

 

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

 

Specific Agents

Strong Agonists

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

Mild to Moderate Agonist

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

Mixed Agonist-Antagonist & Partial Agonists

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

Antagonists

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

Antitussives

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

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

Palliative Care_4.6

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

Cancer and Nutrition

Thyme Oil Beats Ibuprofen for Pain Management.

Pain Management Drug Market: Insight Pharma Reports

New target for chronic pain treatment found

The Genetics of Pain: An Integrated Approach

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The Unseen Pathologist

Posted in Interviews with Scientific Leaders, tagged , , , , , , , on October 11, 2013| 1 Comment »

The Unseen Pathologist

Reporter: Larry Bernstein, MD, FCAP

 

This was reported to Larry Bernstein, MD, FCAP

The Unseen Pathologist: Why You Might Want To Meet Yours

Dr. Michael Misialek

Aug 7, 2013
http://commonhealth.wbur.org/2013/08/meet-your-pathologist#more-33236
http://pharmaceuticalintelligence.com/2013-10/11/The_Unseen_Pathologist

Dr. Michael Misialek is Associate Chair of Pathology at Newton-Wellesley Hospital and Assistant Clinical Professor of Pathology at Tufts University School of Medicine.

Screen-shot-2013-08-06-at-4.33.03-PM-140x140 Dr. Michael Misialek

“How much time do I have?” was the first question Mrs. C asked.

She had called me in a panic. Earlier in the week, I had diagnosed her with breast cancer. She called me after learning the bad news from her radiologist. A whirlwind of appointments with oncology, surgery and radiation oncology ensued, overwhelming her with information.

I knew her case — these cells and her pathology — well, having just presented the pathology at our weekly breast cancer conference.

I struggled to reassure her, telling her that treatment has advanced and catching it early was very encouraging.

But there was silence. I envisioned her on the other end of the line, nervous fingers playing with the phone cord. Finally she said, “It would give me great comfort to meet with you since you are a pathologist. I would like to review my slides along with you.”

I am a pathologist. I spend more time studying your cells and developing a diagnosis then your other doctors spend with you. For particularly tough cases, I ask my partners for help, even send images for another opinion to my academic specialist colleagues, who may in turn show them to still more pathologists.

Many eyes have likely seen your cells. Yet, I am often unseen by you, maybe even unknown. But it doesn’t have to be that way. You can request a meeting with me, you can ask — as Mrs. C did — to review your pathology, whatever the diagnosis, benign or malignant. No request is too small.

Will the health care system allow for this? Won’t it resist? My colleagues from other specialties have embraced it. But currently we cannot bill for these patient consults. That’s part of my reason for writing this: We pathologists are advocating to make our consultations with patients billable, like a patient’s consultations with any other specialists. Pathologists are taking on new roles, and the system needs to change to reflect the value of pathology.

My job is not just about diagnosing cancers. Anything that is biopsied, cut out of your body, scraped off, smeared, aspirated, coughed up, excreted or cultured will pass under my microscope.

I discuss treatment plans with every kind of doctor: primary care, surgeons, oncologists, gynecologists, gastroenterologists and more. Pathologists are quarterbacks, calling each play, just as in football.

With nearly 80% of medical care dependent upon lab tests, a care plan can only be developed with this information. This is the world of pathology.

We’re in the midst of great change in medicine. With the information gleaned from sequencing the human genome, we are beginning to unravel the mysteries of cancer and other diseases. Pathologists have been key players in this discovery pipeline. Care can now be individualized. This leads to quicker diagnoses, earlier and more effective treatments and improved outcomes. Buzz words like “personalized healthcare” and “precision medicine” are becoming commonplace.

Screen-shot-2013-08-06-at-4.20.46-PM-620x457 breast cancer

 

‘Is this what breast cancer looks like?’ she asked me.

But this genomic revolution comes with a price tag. Most of these tests cost thousands of dollars, which creates a dilemma. The Affordable Care Act asks us to do more with less. There is emphasis on quality care that is both accountable and cost conscious.

So how do we balance the two? I would argue that the answer is pathologists. We help our clinical colleagues choose the right test, for the right patient, at the right time. Choosing the “right” test often begins when the diagnosis is first made.

Sitting with Mrs. C, I adjusted the light of the multi-headed microscope so she could see her cells more clearly. She was silent, but I could sense her anxiety.

“Is this what breast cancer looks like?” she asked me, as her eyes scanned her cells on a slide.

“These are cancer cells that grow as little donuts invading the tissue,” I said, hoping to make meaning out of the sea of cells for her.

A smile of relief lit up her face. “Dr. Misialek, that’s a great analogy.” Her cancer was starting to make sense to her, she said.

That’s exactly what I’m here for as a pathologist.

Mrs. C was undecided between lumpectomy and mastectomy. Seeing the pathology, seeing her cells, enabled her to make the decision. She chose a mastectomy, in fact a bilateral mastectomy.

Mrs. C was undecided between lumpectomy and mastectomy. Seeing the pathology, seeing her cells, enabled her to make the decision. She chose a mastectomy, in fact a bilateral mastectomy.

Often when a slide is under my microscope I feel a sense of honor knowing I am the first one to make a diagnosis that will be life-altering. Each slide speaks to me. It is my job to listen.

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I imagine the dominoes that will be set in motion when I pick up the phone to report my findings. It is not only bad news. Just the other day I couldn’t wait to report a benign diagnosis of a young woman’s breast biopsy. Her doctor had called me earlier looking for any preliminary information. She said the patient was in tears after the procedure, convinced she had cancer. She did not, and that made my day. A different outcome than Mrs. C., who is starting chemotherapy and radiation soon.

Just recently I received a thank you card in the mail from Mrs. C. She said that having had a tour of our lab, seeing her slides and understanding how a pathologist helped her was the best part of her entire experience. It extended a warmer touch, in a world filled with barcodes, sterile instruments and starched white lab coats.

You might be hesitant to seek out your pathologist. However, with healthcare reform, pathologists are becoming more and more involved with direct patient care. We welcome the opportunity.

What can you do? Ask your doctor who is the pathologist and lab they use. Remember, you can always request a second opinion. Take the opportunity to look at your slides with your pathologist. It will be an enlightening experience. Be your own advocate. And know that if the system resists your efforts to meet with your pathologist, it’s not what your pathologist wants. We want to know you as well as we know your slides.

 

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