Evidence-Based Practice of Palliative Medicine

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EVIDENCE-BASED PRACTICE OF PALLIATIVE MEDICINE ISBN: 978-1-4377-3796-7

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Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional practices,
or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge
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Library of Congress Cataloging-in-Publication Data

Evidence-based practice of palliative medicine / [edited by] Nathan E. Goldstein,
R. Sean Morrison.
   p. ; cm.
Includes bibliographical references.
ISBN 978-1-4377-3796-7 (pbk. : alk. paper)
I. Goldstein, Nathan E. II. Morrison, R. Sean (Rolfe Sean)
[DNLM: 1. Palliative Care. 2. Evidence-Based Medicine. WB 310]
616.02'9--dc23
2012039834

Content Strategist: Helene Caprari

Senior Content Development Specialist: Jennifer Shreiner
Publishing Services Manager: Anne Altepeter
Senior Project Manager: Doug Turner
Designer: Steve Stave

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

To our patients and their families, who have taught us so much,
And to our partners, Mitchell and Elizabeth, who palliate us in
their own ways
 Preface

What Is Palliative Care? How Can We Not Thank the Following People?
Palliative care is specialized medical care for ­people Publishing a textbook is a daunting task, and we
with serious illnesses, and the goal is to improve have numerous people to thank. First, thanks to all
quality of life for both the patient and the family. It is of our contributors. We are so impressed with their
provided by a team of doctors, nurses, social work- hard work and dedication to our book. Each was
ers, chaplains, and other specialists who work with given a clinical question and an outline to help orga-
a patient's other clinicians to provide an added layer nize the material, but it took an incredible amount
of support. Palliative care is appropriate at any age of work on their part to turn this into the outstand-
and at any stage in a serious illness, and it can be pro- ing book that you now hold in your hands. Special
vided together with curative and disease-directed thanks go to the team at Elsevier; without our editor,
treatments. Palliative care is different from hospice in Pam Hetherington, and our amazing developmental
that (1) palliative care is given at the same time as life- editor, Jennifer Shreiner, we would never have been
sustaining or curative treatments whereas h ­ ospice able to complete this book. Thanks to Doug Turner at
is only for patients who have chosen to forego life- Elsevier for his work on the proofs, as well. We appre-
sustaining treatments and (2) palliative care is for ciate the work of Dr. Kathy Foley on the Foreword; we
patients who are at any point in their i­ llness trajectory never considered anyone else to author this section
whereas hospice is for patients who have 6 months or and are honored that she would agree to introduce
less to live if the disease runs its usual course. our book in this way. Nate also thanks his partner,
Mitchell, and Sean his partner, Elizabeth, and his
sons, Kyle and Corey—who help each of us innumer-
Why Do We Need a New Book About Palliative Care? able ways and are always there for us. And last and
most important, thanks to our patients and their fam-
Since the early 1990s, the field of palliative medicine ilies, who have taught us so much.
has seen exponential growth. In fact, 63% of all hos-
pitals and 85% of mid- to large-size hospitals now Nathan E. Goldstein and R. Sean Morrison
report having a palliative care team.1,2 As the field Mount Sinai School of Medicine
has grown, so has the evidence base supporting its
benefit to patients and their families. Indeed, there is
clear evidence that palliative care improves symptom References
control, helps patients maximize quality of life, and 1. Voelker R. Hospital palliative care programs raise grade to B in
in some cases may help patients live longer.3–7 As a new report card on access. JAMA. Dec 7 2011;306(21):2313–2314.
result of these benefits, palliative care simultaneously 2. Morrison RS, Maroney-Galin C, Kralovec PD, Meier DE. The
reduces costs to hospitals and health care systems.4,8 growth of palliative care programs in United States hospitals.
J Palliat Med. Dec 2005;8(6):1127–1134.
However, many clinicians may not be familiar with 3. Casarett D, Pickard A, Bailey FA, et al. Do palliative consul-
the most recent evidence demonstrating the benefits tations improve patient outcomes? J Am Geriatr Soc. Apr
of palliative care. This book provides the most up-­to- 2008;56(4):593–599.
date evidence (at the time of publication) related to 4. Morrison RS, Penrod JD, Cassel JB, et al. Cost savings associ-
the key, relevant topics encountered during the day- ated with US hospital palliative care consultation programs.
Arch Intern Med. Sep 8 2008;168(16):1783–1790.
to-day clinical practice of palliative medicine. It is 5. Norton SA, Hogan LA, Holloway RG, Temkin-Greener H, Buckley MJ,
organized in the form of clinical questions, making Quill TE. Proactive palliative care in the medical intensive care unit:
it more user friendly for the busy practitioner. Each effects on length of stay for selected high-risk patients. Crit Care
chapter ends with a table that summarizes the key Med. Jun 2007;35(6):1530–1535.
6. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care
“take-home” points, so the reader can quickly glean intervention on clinical outcomes in patients with advanced
the main recommendations or read the entire chap- cancer: the Project ENABLE II randomized controlled trial.
ter to get a more in-depth discussion of the topic that JAMA. Aug 19 2009;302(7):741–749.
includes references to the literature. The chapters 7. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care
are written by clinicians, educators, and research- for patients with metastatic non-small-cell lung cancer. N Engl J
Med. Aug 19 2010;363(8):733–742.
ers across a broad range of disciplines to p ­ rovide an 8. Morrison RS, Dietrich J, Ladwig S, et al. Palliative care consulta-
approach to the practice of palliative medicine from tion teams cut hospital costs for Medicaid beneficiaries. Health
different perspectives. Aff (Millwood). Mar 2011;30(3):454–463.
 Foreword

The role of palliative medicine has grown and ­rofessionals want and need to know the facts
p
expanded since the early 1990s. The demand for quickly and accurately as they contextualize medical
health care professional education and training in information and plan strategies. This text provides
this new field of medicine is enormous, which is a framework to make palliative medicine routinized,
­gratifying to those of us who have advocated for the prescriptive, evidence based, and integrated. This
professionalization of palliative care practice. compendium of questions and answers demonstrates
We know that educating health care professionals how the field of palliative medicine has advanced and
in palliative medicine starts with identifying the com- how the practice of improving the quality of life for
mon and frequently challenging issues clinicians face seriously ill patients and their families has evolved
as they care for a seriously ill patient. Drs. Goldstein into sophisticated, complex, evidence-based proto-
and Morrison, the editors of this new textbook in pal- cols and roadmaps focused on addressing the phys-
liative medicine, have adapted a unique and user- ical, psychological, and spiritual needs of the sick
friendly approach that is similar to that of frequently person and his or her family.
asked questions, and they have assembled a cadre With the increasing demand for palliative care
of expert clinicians to provide the evidence-based ­consultations and a limited number of trained special-
answers to these common and important questions ists to deliver such care, this textbook fills a dual role.
in palliative medicine. It is a powerful teaching tool for nursing and medicial
More than 80 questions define this textbook's students and trainees, and it is a reliable reference text
domain. They span a diverse range of topics from how for senior clinicians who have not been formally trained
to start dosing opioids in an outpatient ­setting to in palliative medicine but are committed to improving
specific questions about dosing steroids, the use of their patients’ symptoms and addressing their commu-
bisphosphonates, prognostication and difficult con- nication, psychosocial, and spiritual needs.
versations, as well as what models of palliative care Clearly, we will succeed in the goal of improving
are appropriate in different settings and what the care for those with life-limiting illnesses when health
benefits are of palliative care. In addition to answer- care professionals begin to embrace the answers to
ing a specific question, each chapter provides con- the questions raised in this book and integrate them
text, discussion, and pertinent references based on into their daily practice. This textbook will help them
the current available research, coupled with the achieve this goal.
the authors’ clinical expertise and best practices
­recommendations that give attention to the need for
­individualized care. Kathleen Foley, MD
All of the chapters provide substantive information Professor of Neurology, Neuroscience, and
for the busy clinician, and some add a further ele- Clinical Pharmacology
ment to help clinicians advocate for the field of pallia- Weill Medical College of Cornell University;
tive medicine, as evidenced in chapters that address Attending Neurologist
why palliative care is beneficial and needed. Memorial Sloan-Kettering Cancer Center;
This text's format lends itself to an educational Medical Director
style that is direct, efficient, and practical for busy International Palliative Care Initiative
clinicians and essential for the field. Health care
­ Open Society Foundations
 Contributors

Amy P. Abernethy, MD Susan Block, MD

Associate Professor of Medicine Chair, Department of Psychosocial Oncology
Division of Medical Oncology and Palliative Care
Duke University Medical Center Dana-Farber Cancer Institute;
Durham, North Carolina Professor of Psychiatry
Department of Medicine
Robert M. Arnold, MD Harvard Medical School;
Professor of Medicine Co-Director, HMS Center for Palliative Care
Division of General Internal Medicine Boston, Massachusetts
University of Pittsburgh School of Medicine;
Chief, Section of Palliative Care and Medical Ethics Barton T. Bobb, MSN, FNP-BC, ACHPN
Assistant Director, Institute to Enhance Palliative Care Advanced Practice Nurse
Director, Institute for Doctor-Patient Communication Thomas Palliative Care Services
Leo H. Criep Chair in Patient Care Virginia Commonwealth University
UPMC Montefiore Hospital Massey Cancer Center
Pittsburgh, Pennsylvania Richmond, Virginia
Deborah D. Ascheim, MD Jason C. Brookman, MD
Associate Professor Assistant Professor
Division of Cardiology Department of Anesthesiology and Critical Care
Samuel Bronfman Department of Medicine and Medicine
Department of Health Evidence and Policy The Johns Hopkins University School of Medicine
Mount Sinai School of Medicine Baltimore, Maryland
New York, New York
Melissa D.A. Carlson, PhD, MBA
Rebecca Aslakson, MD Assistant Professor
Assistant Professor Brookdale Department of Geriatrics and Palliative
Department of Anesthesiology and Critical Care Medicine
Medicine Mount Sinai School of Medicine
The Johns Hopkins University School of Medicine New York, New York
Baltimore, Maryland
Thomas Carroll, MD, PhD
Anthony L. Back, MD Palliative Medicine Fellow
Professor of Medicine Center for Ethics, Humanities, and Palliative
Division of Medical Oncology; Care
Director, Program in Cancer Communication University of Rochester School of Medicine
Fred Hutchinson Cancer Research Center Rochester, New York
University of Washington School of Medicine
Seattle, Washington Emily J. Chai, MD
Medical Director
Vickie E. Baracos, PhD Lilian and Benjamin Hertzberg Palliative Care
Professor of Palliative Care Medicine Institute
Department of Oncology Brookdale Department of Geriatrics and Palliative
University of Alberta Faculty of Medicine Medicine
and Dentistry Mount Sinai School of Medicine
Edmonton, Alberta, Canada New York, New York
xii Contributors

Harvey M. Chochinov, MD, PhD, OM, FRCPC Kathleen Foley, MD

Distinguished Professor of Psychiatry Professor of Neurology, Neuroscience, and Clinical
University of Manitoba Faculty of Medicine; Pharmacology
Director, Manitoba Palliative Care Research Unit Weill Medical College of Cornell University;
CancerCare Manitoba Attending Neurologist
Winnipeg, Manitoba, Canada Memorial Sloan-Kettering Cancer Center;
Medical Director
Jessica Cook-Mack, MD International Palliative Care Initiative
Assistant Professor Open Society Foundations
Samuel Bronfman Department of Medicine New York, New York
Mount Sinai School of Medicine
New York, New York Laura P. Gelfman, MD
Instructor
Kenneth E. Covinsky, MD, MPH Lilian and Benjamin Hertzberg Palliative Care
Edmund G. Brown, Sr., Professor of Medicine Institute
Division of Geriatrics Brookdale Department of Geriatrics and Palliative
University of California, San Francisco Medicine
San Francisco, California Mount Sinai School of Medicine
New York, New York
Christopher E. Cox, MD, MPH
Assistant Professor of Medicine Eric M. Genden, MD
Division of Pulmonary, Allergy, and Critical Care Professor and Chair
Medicine Department of Otolaryngology
Duke University School of Medicine Professor of Neurosurgery
Durham, North Carolina Mount Sinai School of Medicine;
Chief, Division of Head and Neck Oncology
David C. Currow, BMed, MPH, FRACP Mount Sinai Medical Center
Professor of Palliative and Supportive Services New York, New York
Flinders University
Adelaide, South Australia, Australia Gabrielle R. Goldberg, MD
Medical Director
J. Randall Curtis, MD, MPH The Wiener Family Palliative Care Unit
Professor of Medicine Assistant Professor
Division of Pulmonary and Critical Care Brookdale Department of Geriatrics and Palliative
Medicine Medicine and Samuel Bronfman Department of
University of Washington School of Medicine Medicine
Seattle, Washington Mount Sinai School of Medicine
New York, New York
Linda V. DeCherrie, MD
Assistant Professor Nathan E. Goldstein, MD
Samuel Bronfman Department of Medicine and Associate Professor
Brookdale Department of Geriatrics and Palliative Director of Research and Quality
Medicine Lilian and Benjamin Hertzberg Palliative Care
Mount Sinai School of Medicine Institute
New York, New York Brookdale Department of Geriatrics and Palliative
Medicine
Ronald M. Epstein, MD Mount Sinai School of Medicine
Professor of Family Medicine, Psychiatry, Oncology, New York, New York;
and Nursing Physician Investigator
Director, Center for Communication and Disparities Geriatric Research, Education, and Clinical
Research Center
University of Rochester Medical Center James J. Peters VA Medical Center
Rochester, New York Bronx, New York
Mary Ersek, PhD, RN, FAAN Rick Goldstein, MD
Director Attending Physician
National PROMISE (Performance Reporting and Division of Pediatric Palliative Care
Outcomes Measurement to Improve the Standard Department of Psychosocial Oncology and Palliative
of Care at End-of-Life) Center Care
Philadelphia Veterans Affairs Medical Center; Dana-Farber Cancer Institute
Associate Professor Children's Hospital Boston
University of Pennsylvania School of Nursing Harvard Medical School
Philadelphia, Pennsylvania Boston, Massachusetts
 Contributors xiii

Robert Gramling, MD, DSc Vicki A. Jackson, MD, MPH

Associate Professor Assistant Professor of Medicine
Schools of Medicine and Nursing Division of Palliative Care
Fellowship Director and Co-Director of Research Harvard Medical School;
University of Rochester Chief of Palliative Care
Rochester, New York Massachusetts General Hospital
Boston, Massachusetts
Corita R. Grudzen, MD, MSHS
Assistant Professor Arif Kamal, MD
Department of Emergency Medicine and Brookdale Assistant Professor of Medicine
Department of Geriatrics and Palliative Medicine Division of Medical Oncology
Mount Sinai School of Medicine Department of Medicine
New York, New York Duke Cancer Institute
The Reverend George Handzo, MA, MDiv, BCC Durham, North Carolina
Senior Consultant Kenneth L. Kirsh, PhD
Chaplaincy Care Leadership & Practice Director of Behavioral Medicine and Ancillary
HealthCare Chaplaincy Services
New York, New York The Pain Treatment Center of the Bluegrass
Paul Hernandez, MDCM, FRCPC Lexington, Kentucky
Associate Professor of Medicine
Division of Respirology Kimberly G. Klipstein, MD
Faculty of Medicine Assistant Professor
Dalhousie University; Department of Psychiatry;
Respirologist Director, Behavioral Medical and Consultation
Department of Medicine Psychiatry
Queen Elizabeth II Health Sciences Centre Mount Sinai Medical Center
Halifax, Nova Scotia, Canada New York, New York

Aluko A. Hope, MD, MSCE Fred C. Ko, MD

Assistant Professor of Medicine Assistant Professor
Division of Critical Care Medicine Brookdale Department of Geriatrics and Palliative
Albert Einstein College of Medicine of Yeshiva Medicine
University; Mount Sinai School of Medicine
Attending Intensivist New York, New York
Jay B. Langer Critical Care System
Jean S. Kutner, MD, MSPH
Bronx, New York
Godon Meiklejohn Endowed
Robert Horton, MD Professor of Medicine
Faculty, Division of Palliative Medicine Division Head, General Internal Medicine
Faculty of Medicine University of Colorado School of Medicine
Dalhousie University; Denver, Colorado
Queen Elizabeth II Health Science Centre
Halifax, Nova Scotia, Canada Alexandra E. Leigh, MD
Assistant Professor of Medicine
Ula Hwang, MD, MPH Division of Gerontology, Geriatrics, and Palliative
Assistant Professor Care
Department of Emergency Medicine and Brookdale University of Alabama at Birmingham;
Department of Geriatrics and Palliative Medicine Palliative Care Physician
Mount Sinai School of Medicine Birmingham VA Medical Center
New York, New York Birmingham, Alabama
Scott A. Irwin, MD, PhD Stacie K. Levine, MD
Chief of Psychiatry Associate Professor
Vice President of Psychosocial Services Section of Geriatrics and Palliative Medicine
San Diego Hospice and the Institute for Palliative University of Chicago
Medicine Chicago, Illinois
San Diego, California
xiv Contributors

Elizabeth Lindenberger, MD R. Sean Morrison, MD

Program Director Director, National Palliative Care Research Center
Palliative Medicine Fellowship Director, Lilian and Benjamin Hertzberg Palliative
Education Director Care Institute
Lilian and Benjamin Hertzberg Palliative Care Hermann Merkin Professor of Palliative Medicine
Institute; Brookdale Department of Geriatrics and Palliative
Assistant Professor Medicine
Brookdale Department of Geriatrics and Palliative Mount Sinai School of Medicine
Medicine New York, New York;
Mount Sinai School of Medicine Physician Investigator
New York, New York Geriatric Research, Education, and Clinical Center
James J. Peters VA Medical Center
Mara Lugassy, MD Bronx, New York
Medical Director
MJHS Hospice and Palliative Care Alvin H. Moss, MD, FAAHPM
New York, New York Director
Center for Health Ethics and Law
Jennifer M. Maguire, MD Professor of Medicine
Clinical Fellow, Pulmonary and Critical Care Medicine, Section of Nephrology
Medicine West Virginia University;
Department of Medicine Medical Director
University of North Carolina Supportive Care Service
School of Medicine West Virginia University Hospital
Chapel Hill, North Carolina Morgantown, West Virginia
Deborah B. Marin, MD Ryan R. Nash, MD, MA
Associate Professor Assistant Professor of Medicine
Department of Psychiatry and Brookdale UAB Center for Palliative and Supportive Care
Department of Geriatrics and Palliative Department of Internal Medicine
Medicine University of Alabama, Birmingham
Mount Sinai School of Medicine Birmingham, Alabama
New York, New York
Lynn B. O'Neill, MD
Diane E. Meier, MD
Assistant Professor
Director, Center to Advance Palliative Care
Department of Medicine
Professor and Vice-Chair for Public Policy
Duke University School of Medicine
Brookdale Department of Geriatrics and Palliative
Durham, North Carolina
Medicine
Gaisman Professor of Medical Ethics Steve Pantilat, MD
Mount Sinai School of Medicine Professor of Clinical Medicine
New York, New York Department of Medicine;
Rabbi Edith M. Meyerson, BCC Director, Palliative Care Program
Palliative Care Chaplain University of California, San Francisco
Lilian and Benjamin Hertzberg Palliative San Francisco, California
Care Institute Steven D. Passik, PhD
Brookdale Department of Geriatrics and Palliative Professor
Medicine Departments of Psychiatry and Anesthesiology
Mount Sinai School of Medicine Vanderbilt University Medical Center
New York, New York Nashville, Tennessee
Drew Moghanaki, MD, MPH
Assistant Professor Michael W. Rabow, MD, FAAHPM
Department of Radiation Oncology Professor
Virginia Commonwealth University; Department of Medicine
Director of Clinical Research University of California, San Francisco;
Department of Radiation Oncology Attending Physician
Hunter Holmes McGuire VA Medical Center General Medical Practice and Inpatient Palliative
Richmond, Virginia Care Service
UCSF Medical Center at Mount Zion;
Lori P. Montross, PhD Director
Director of Psychology and Integrative Medicine Symptom Management Service
San Diego Hospice and The Institute for Palliative UCSF Helen Diller Family Comprehensive Cancer
Medicine Care Center
San Diego, California San Francisco, California
 Contributors xv

Kavitha J. Ramchandran, MD Kristofer L. Smith, MD, MPP

Clinical Assistant Professor Department of Internal Medicine
Department of Medicine Hofstra North Shore-LIJ Medical School
Stanford University School of Medicine Hofstra University
Stanford, California Hempstead, New York;
Medical Director, Post Acute Care
Aditi Rao, PhD(c), MSN, RN Department of Internal Medicine
John A. Hartford Foundation Building Academic North Shore-LIJ Health System
Geriatric Nursing Capacity Scholar Manhasset, New York
University of Pennsylvania School of Nursing
Philadelphia, Pennsylvania Lorie N. Smith, MD
Instructor in Medicine
Thomas Reid, MD, MA Division of Palliative Care
Assistant Clinical Professor Harvard Medical School;
Department of Medicine Massachusetts General Hospital
University of California, San Francisco Boston, Massachusetts
San Francisco, California
Thomas J. Smith, MD, FACP
Lynne D. Richardson, MD Director of Palliative Medicine
Professor The Johns Hopkins University Medical Institutions;
Departments of Emergency Medicine and Health Professor of Oncology
Evidence and Policy Sidney Kimmel Comprehensive Cancer Center
Mount Sinai School of Medicine Baltimore, Maryland
New York, New York
Theresa A. Soriano, MD
Christine S. Ritchie, MD, MSPH Associate Professor
Professor of Medicine Department of Medicine
Harris Fishbon Distinguished Professor Associate Professor
Department of Medicine Brookdale Department of Geriatrics and Palliative
Division of Geriatrics Medicine
University of California, San Francisco Mount Sinai School of Medicine
San Francisco, California New York, New York
Graeme Rocker, MD Lynn Spragens, MBA
Professor of Medicine President
Head, Division of Respirology Spragens & Associates, LLC
Faculty of Medicine Durham, North Carolina
Dalhousie University; Knox H. Todd, MD, MPH
Queen Elizabeth II Health Science Centre Professor and Chair
Halifax, Nova Scotia, Canada Department of Emergency Medicine
Justine S. Sefcik, MS, RN The University of Texas MD Anderson Cancer Center
National Harford Centers of Gerontological Houston, Texas
Nursing Excellence Patricia G. Archbold Rodney O. Tucker, MD, MMM
Scholar Associate Professor of Medicine
University of Pennsylvania School of Nursing Division of Gerontology, Geriatrics, and Palliative
Philadelphia, Pennsylvania Medicine
Joseph W. Shega, MD University of Alabama at Birmingham
Associate Professor of Medicine Birmingham, Alabama
Sections of Geriatrics and Palliative Medicine Martha L. Twaddle, MD
University of Chicago Associate Professor
Chicago, Illinois Department of Medicine
Cardinale B. Smith, MD, MSCR Rush University Medical Center
Assistant Professor Chicago, Illinois;
Division of Hematology/Medical Oncology Chief Medical Officer
Tisch Cancer Institute; Midwest Palliative & Hospice CareCenter
Assistant Professor Glenview, Illinois
Lilian and Benjamin Hertzberg Palliative Jamie H. von Roenn, MD
Care Institute Professor of Medicine
Brookdale Department of Geriatrics and Palliative Division of Medical Oncology
Medicine Robert H. Lurie Comprehensive Cancer Center
Mount Sinai School of Medicine Northwestern University Feinberg School of Medicine
New York, New York Chicago, Illinois
xvi Contributors

Ania Wajnberg, MD Eric Widera, MD

Assistant Professor Associate Professor
Samuel Bronfman Department of Medicine Division of Geriatrics
Mount Sinai School of Medicine University of California, San Francisco;
New York, New York Director, Hospice and Palliative Care Service
San Francisco VA Medical Center
Deborah Waldrop, PhD, MSW
San Francisco, California
Associate Professor and Associate Dean for Faculty
Development Joanne Wolfe, MD, MPH
School of Social Work Division Chief, Pediatric Palliative Care
University at Buffalo Department of Psychosocial Oncology and
Buffalo, New York Palliative Care
Jeremy D. Walston, MD Dana-Farber Cancer Institute;
Raymond and Anna Lublin Professor of Geriatric Director, Pediatric Palliative Care
Medicine Department of Medicine
Division of Geriatric Medicine and Gerontology Children's Hospital Boston;
The Johns Hopkins University School of Medicine; Associate Professor
Co-Principal Investigator Pediatrics
Older American Independence Center; Harvard Medical School
Co-Director Boston, Massachusetts
Biology of Healthy Aging Program Gordon Wood, MD, MSCI
Baltimore, Maryland Assistant Professor
Department of Medicine
Monica Wattana, MD
University of Pittsburgh School of Medicine
Resident, Department of Emergency Medicine
Pittsburgh, Pennsylvania
University of California, Los Angeles
Los Angeles, Californnia Meng Zhang, MD
Assistant Professor
Michelle T. Weckmann, MD Samuel Bronfman Department of Medicine
Assistant Professor Visiting Doctors Program
Departments of Family Medicine and Psychiatry Mount Sinai School of Medicine
University of Iowa New York, New York
Iowa City, Iowa
Jane L. Wheeler, MS
Medical Instructor
Division of Medical Oncology
Duke University School of Medicine
Durham, North Carolina
 PAIN
Chapter How Should Opioids Be Started and

1 Titrated in Routine Outpatient Settings?

Gabrielle R. Goldberg and Cardinale B. Smith

be further classified as either somatic (resulting

INTRODUCTION AND SCOPE OF THE PROBLEM from injury to skin and deep tissue) or v
­ isceral pain
RELEVANT PATHOPHYSIOLOGY (resulting from injury to internal organs). Visceral
End Organ Function pain is often described as dull, vague, or diffuse,
Patient Age
SUMMARY OF EVIDENCE REGARDING TREATMENT
whereas somatic pain is more likely to be well local-
RECOMMENDATIONS ized and described as sharp or intense. The cause
Pain Assessment of a patient's pain should always be assessed, and
Choosing a Starting Dose disease-specific treatments must be considered11
Severity of Pain and offered where appropriate and consistent with
Approach to the Opioid-Naïve Patient patients’ goals of care. The goal of this chapter is
Approach to the Opioid-Tolerant Patient to familiarize the reader with an approach to the
Assessment for Response ­treatment of pain with opioids; it will not address
Opioid Titration ­disease-specific therapies.
Opioid Side Effects
Opioid Rotation
Opioid Agreements End Organ Function
KEY MESSAGES TO PATIENTS AND FAMILIES
CONCLUSION AND SUMMARY Morphine is metabolized in the liver to morphine-
6-glucuronide and morphine-3-glucuronide, both of
which are excreted by the kidneys.12 In the ­setting
INTRODUCTION AND SCOPE OF THE PROBLEM of renal failure, these metabolites can accumulate,
resulting in a lowering of the seizure threshold.
Despite recognition of the importance of pain man- Morphine should therefore be used with caution
agement, availability of effective pain medications in with mild renal impairment and be avoided in the set-
the United States,1 and multiple published guidelines ting of renal failure.13 Opioid metabolism is ­generally
for the management of pain,2 the undertreatment of impaired in the setting of liver disease, with an
pain in patients with advanced illness continues to be increase in oral bioavailability and an increase in
an ongoing and highly prevalent problem.3 Although elimination half-life.14 In the setting of severe liver
numerous organizations such as the World Health disease, opioids should be used with caution, with
Organization (WHO),4 the American Pain Society,5 a decrease in dose and increased (i.e., longer time
the European Association for Palliative Care, and the between) dosing intervals.14
American Geriatrics Society6 have developed guide- Fentanyl and methadone have few active metabo-
lines, uncontrolled pain in seriously ill patients per- lites and are therefore likely to be safer than other
sists. The p­ revalence of undertreatment of cancer pain opioids for the treatment of patients with renal or
in particular remains unacceptably high, with nearly hepatic dysfunction.13 The most commonly avail-
half of patients receiving inadequate treatment for their able nonparenteral formulation of fentanyl in the
pain.7 The high prevalence of poorly managed pain is United States is transdermal. As discussed later,
often attributed to barriers to opioid use related to transdermal fentanyl should be administered only
the health care provider, patients and families, and the to a patient who is opioid tolerant, and it should
health care system.8 Poorly controlled pain has been be avoided in patients for whom the opioid dose is
associated with functional impairment, anxiety, depres- being actively titrated. For an in-depth discussion on
sion, insomnia, and diminished quality of life.9 the use of methadone in treating patients with pain,
see Chapters 7 and 8.
RELEVANT PATHOPHYSIOLOGY
Patient Age
Pain is defined as “an unpleasant sensory and emo-
tional experience associated with actual or p ­ otential Several changes in pharmacokinetics and pharmaco-
tissue damage.”10 Pain can be ­classified as ­nociceptive, dynamics occur with increasing age. Physiological
neuropathic, or idiopathic. Nociceptive pain can decline in organ function (e.g., decreased ­glomerular

2
 Opioid Use in Outpatient Settings 3

filtration with increased age) and an increased Inpatient settings allow for rapid titration of opioids
­volume of distribution as a result of relative increase because the m ­ edications can be administered intra-
in body fat content over skeletal muscle mass can venously and may be repeated and increased over
affect the pharmacology of analgesics, and therefore minutes to hours. The inpatient setting also allows
the onset of action, rate of elimination, and half-life of for controlled dispensing of medication with minimal
these medications may be altered in older patients.15 concern for misuse or diversion. Challenges in the
Because of these changes, the prescribing philoso- outpatient setting include ensuring that the patient
phy should be “start low and go slow” (i.e., start at can obtain the prescribed medications (in terms of
a low dose and increase with caution) when treat- being able to both afford the medication and find a
ing older patients with opioids. To be clear, however, pharmacy that dispenses opioids18), difficulties in
older age is not a contraindication to opioid use. monitoring for side effects, and a delay in being able
to assess the patient's responses to the medications
prescribed (Table 1-2).
SUMMARY OF EVIDENCE REGARDING TREATMENT
RECOMMENDATIONS
Severity of Pain
Pain Assessment
The WHO developed guidelines for the management
The experience of pain is subjective, and therefore of cancer pain in the mid-1990s, and as of 2011 it is
a patient's report of pain is the gold standard for currently developing treatment guidelines for the
­assessment. The first step in treating a patient is to management of acute pain, chronic pain in adults,
perform a comprehensive pain assessment. A full and chronic pain in children.4 In the absence of guide-
pain assessment should take into account the onset, lines for pain management in the noncancer popula-
precipitating or alleviating factors, quality, ­presence tion, the WHO Pain Relief Ladder for ­cancer has been
or absence of radiation, severity, and timing of the applied to the management of pain in other diseases
patient's pain. A variety of tools may be used for as well. The WHO recommends a ­stepwise approach
the assessment of pain severity, including numeric to pain management, with choice of m ­ edication
pain intensity rating scales (0 = no pain and 10 = based on pain severity, using nonopioids (­aspirin
worst possible pain) and the verbal descriptor scales and acetaminophen) for mild pain, mild opioids
(mild, moderate, or severe). The numeric rating scale (codeine or oxycodone with acetaminophen) for
offers several advantages, including ease of adminis- mild to moderate pain, and strong opioids such as
tration and scoring, multiple response options, and morphine for moderate to severe pain.4 The weak-
no reported age-related difficulties in its use.16 For ness of this approach is that the mild opioids may
younger patients, the Faces Pain Scale may be more become limited by the nonopioid component (e.g.,
effective than verbal report.17 (For more informa- in combination medications containing acetamino-
tion on treating pediatric patients, see Chapter 65.) phen, the total acetaminophen dose for a healthy
Clinicians should assess pain intensity regularly, individual is less than 4 g per 24 hours, and it may be
because this helps guide the initial approach to treat- lower in older patients or those with liver disease).19
ment, response to treatment, and need for further Because of concerns about hepatotoxicity with the
titration of medications. use of combination opioid agents, the FDA has recom-
mended banning these ­combination ­medications.20
Given these c ­ oncerns, combination medications will
Choosing a Starting Dose not be f­ urther ­discussed in this chapter. For patients
When considering starting a patient on opioids for presenting in severe pain, the clinician should
­
the treatment of pain in the outpatient setting, sev- ­consider whether the patient would benefit from inpa-
eral factors must be considered, including the sever- tient admission to ensure more rapid relief by titrat-
ity of pain, end organ function, patient age, and ing intravenous opioids as opposed to ­dose-finding
history of opioid use (Table 1-1). These factors will with oral opioids in an ­outpatient setting.
influence the initial opioid to be used, the starting
dose, and the interval of administration. Treatment of
pain in the outpatient setting often poses more chal- TABLE 1-2. Issues to Consider When Prescribing
lenges than pain management in the inpatient setting. Opioid Medications in the Outpatient Setting
• Does the medication come in the dose you want to
prescribe?
TABLE 1-1. Issues to Consider When Starting • What is the cost of the medication? Does the patient have
a Patient on an Opioid prescription coverage? Will the patient be able to afford the
prescription?
• Is the patient opioid naïve? • Where will the patient be filling the prescription?
• What opioids have been effective for the patient in the past? • Is the medication available at the patient's local pharmacy?
• What is the patient's age, and does this have an effect on • Did you start the patient on a bowel regimen?
either dose or interval of administration? • Have you arranged for a short interval for follow-up with
• What is the patient's renal function? the patient to assess for response to treatment, tolerability,
• What is the patient's liver function? and presence of side effects?
4 Pain

Approach to the Opioid-Naïve Patient suggested that the effective dose of breakthrough
pain medication is a percentage of the patient's total
When starting a patient on opioids in the outpatient daily opioid dose, most commonly 10% to 20% of the
setting, a short-acting medication that is available 24-hour dosage.2,23 However, current evidence sug-
orally should be selected; the choices most readily gests that the dose of opioid for breakthrough pain
available in the United States are morphine, oxyco- should be determined by individual titration.24–26 A
done, and hydromorphone. The use of short-acting useful clinical rule of practice is:
oral medication allows for active titration. Morphine
is generally the opioid of first choice because of Breakthrough dose = 10% of total 24 - hour dosage
its relatively low cost and availability.2 The recom-
mended starting dose for an opioid-naïve patient The time to peak effect of a short-acting oral opioid
is ­morphine 5 to 10 mg intravenously (IV), which is is 60 to 90 minutes. Based on the pharmacokinetics
approximately equivalent to morphine 15 to 30 mg of opioids, breakthrough doses of oral opioids can
orally (PO) (Table 1-3). The clinician should start at therefore be prescribed every 1 to 2 hours as needed
the lower end of this range and reevaluate the patient for pain. For example, a patient prescribed morphine
frequently (either via phone or in subsequent office 30 mg PO every 4 hours around the clock (a total of
visits) to determine the optimal starting dose of med- 180 mg of morphine in 24 hours) should also receive
ication to control the patient's pain. For an older morphine 18 mg PO every hour as needed for pain.
or more debilitated patient, starting at the low end To make administration of this easier, it should be
or below this range should be considered.6 As dis- rounded to 15 mg PO every hour as needed.
cussed earlier, oxycodone or hydromorphone would
be the preferred oral opioid in patients with a history
of renal or liver failure, because their metabolites are Approach to the Opioid-Tolerant Patient
not as active as those of morphine. For patients with Tolerance is defined pharmacologically as loss of drug
incident pain that is not constant or that occurs at effect with chronic dosing.27 Patients currently on opi-
specific times during the day, the medication should oid therapy or with a prior (or current) history of opi-
be started on an as-needed basis. For patients with oid use will have higher requirements than those who
continuous pain, the medication should be pre- are opioid naïve. Initial dose ­finding should follow the
scribed on a standing basis, dosed every 4 hours for same guidelines as in the opioid-naïve patient; how-
patients with normal renal and hepatic function.21 ever, the starting dose will be higher.
In addition to a standing order, patients should also
be provided with medications to treat breakthrough
pain.2 Breakthrough pain refers to a transitory Assessment for Response
increase in pain to greater than moderate intensity
that occurs on a baseline or pain of moderate inten- Assessment for response to an opioid dose should be
sity or less in a patient receiving chronic opioid ther- made at the time of peak effect. Based on the phar-
apy.22 This pain can be incident (pain is provoked by macokinetics of the short-acting oral opioids, if relief
an event) or may occur spontaneously. The typical has not been obtained in 60 to 90 minutes with an
dosing recommendations for rescue medications are oral opioid, the patient will not receive additional
based largely on anecdotal experience. It has been relief despite the fact that the duration of action is
4 hours. Patients should be instructed that if they are
requiring the breakthrough doses more frequently
TABLE 1-3. Opioid Analgesic Equivalences* than two or three times per day, they should contact
their clinician for further titration of the standing
INTRAVENOUS/ medication.
SUBCUTANEOUS/ ORAL/ DURATION OF
INTRAMUSCULAR RECTAL EFFECT
OPIOID AGONISTS (mg) (mg) (hr)
Opioid Titration
Morphine 10 30 4
Hydrocodone — 30 4
Patients should be encouraged to keep a pain jour-
Oxycodone — 20 4 nal documenting their use of pain medications and
Oxymorphone 1 10 4 their pain scores. There should be a short time to
Hydromorphone 1.5 7.5 4 the next follow-up visit, preferably within 1 week of
Fentanyl †
  ‡ 1-2 starting a patient on opioids. This follow-up may
Codeine 130 200 4
occur either in person or by telephone. The ­clinician
should review the patient's use of breakthrough
Modified from Horton JR. Hospital-based opioid analgesia. In: Dunn A,
Klotman P, Kathuria N, eds. Handbook of Hospital Medicine. Hackensack NJ: medications, response to the treatment, and p ­ resence
World Scientific. In press. of side effects (including sedation and c ­ onstipation).
*This table provides a conversion ratio when converting from one opioid
medication to another or from one route of administration to another.
The clinician should also review and calculate the
†
Convert morphine 2 mg PO/24 hr to fentanyl 1 mcg/hr transdermal patch; total 24-hour opioid use. Patients with ­well-controlled
transdermal fentanyl should never be prescribed for an opioid-naïve pain, requiring no more than 3 breakthrough doses
patient.
‡
Oral fentanyl preparations are available, but their use is complicated and per day, can be started on l­ong-acting opioids, with
simple conversion ratios do not exist. the total 24-hour opioid dosage divided into 2 daily
 Opioid Use in Outpatient Settings 5

doses of long-acting opioid administered every 12 50% to sustained-release morphine 200 mg PO every 12
hours. Long-acting opioids will ­ maintain the level hours (400 mg in 24 hours).
of pain control, lessen the pill burden, and decrease Another option for long-acting opioid adminis-
the need to wake up at night to take pain medica- tration for a patient with well-controlled pain on a
tions. Occasionally, patients may report increased stable, standing opioid regimen is the use of trans-
pain in the 3 to 4 hours before the next standing dermal fentanyl. Transdermal administration is par-
dose, requiring the frequent use of breakthrough ticularly useful in patients who are unable to take
opioids. This phenomenon is known as end-of-dose oral medications or who have enteral feeding tubes.
failure. In this circumstance, it is reasonable to con- Transdermal fentanyl patches are changed every
sider prescribing the long-acting opioid every 8 hours, 72 hours, although some patients may need them
rather than every 12. The majority of ­long-acting or changed as frequently as every 48 hours. Because of
­sustained-release opioid oral ­formulations cannot be the longer half-life of transdermal fentanyl, it is not
split or crushed, so doses prescribed must be sums the best choice of opioid for a patient who is still
or m­ ultiples of the available pill sizes. (Crushing or requiring active titration of the analgesic regimen.2
splitting long-acting preparations may counteract the Transdermal fentanyl is lipophilic and requires a
mechanism that ensures delayed, controlled release patient to have adequate adipose tissue for effective
and thus crushing these medications can potentially absorption; it is not recommended for use in patients
result in overdose.) However, select brand-name who are cachectic or very thin. The transdermal
formulations of long-acting morphine are avail- absorption can be altered by temperature and mois-
able in capsules that may be opened and adminis- ture, so patients who sweat frequently or live in
tered via enteral feeding tubes. For example, the environments without adequate temperature con-
patient started on morphine 30 mg PO every 4 hours trol may not be good candidates for the transdermal
(180 mg in 24 hours) is taking 1 or 2 breakthrough patch. Additionally, the patches should be removed
doses and reports her pain is well controlled. This and replaced with an alternative opioid regimen if the
is a total of 195 to 210 mg of oral morphine daily. patient develops a high fever. Transdermal fentanyl
Sustained-release morphine tablets are available in takes 12 to 24 hours to reach peak effect; therefore
15, 30, 60, 100, and 200 mg. She may be prescribed (1) transdermal fentanyl is never an appropriate first-
sustained-release morphine 90 mg PO every 12 hours line option for the management of pain in a patient
(180 mg in 24 hours), with continuation of morphine who is opioid naïve and (2) the patient's prior opioid
15 mg PO every 1 to 2 hours as needed for break- regimen should be continued for the first 12 hours
through pain. A 90-mg long-acting morphine prep- after application of the first fentanyl patch. Each time
aration is not available, so the clinician will need the clinician evaluates a patient prescribed transder-
to write prescriptions for both sustained-release mal fentanyl, the physical examination should verify
morphine 60 mg and sustained-release morphine that the patch has been placed in an area to ensure
30 mg to ensure the patient can take the dose of 90 mg appropriate absorption.
every 12 hours.
If the patient requires multiple doses of break-
through medication in a 24-hour period, her pain is Opioid Side Effects
not optimally controlled and the entire 24-hour opi-
oid requirement should be totaled and converted to Common opioid side effects are listed in Table 1-4.
a long-acting formulation. For example, the patient Tolerance develops to all opioid side effects, with
started on morphine 30 mg PO every 4 hours (180 mg the exception of constipation, an expected and pre-
in 24 hours) is requiring 4 breakthrough doses of dictable consequence of taking opioids. At the time
morphine 15 mg per day (an additional 60 mg in of prescribing opioids, all patients should also be
24 hours) to control her pain. The patient's total started on a prophylactic bowel regimen unless the
24-hour opioid requirement is 240 mg. She may be patient is having diarrhea or has another contraindi-
prescribed sustained-release morphine 100 mg (note cation to being on a bowel regimen. One of the most
the available formulations reviewed earlier) PO every commonly used regimens is senna (Senokot) (1 or
12 hours. 2 tablets at bedtime) and docusate (100 mg two or
Alternatively, if the patient's pain is not well con- three times per day), although evidence is lacking
trolled, dose adjustments may be made based on the
severity of the pain. Adjustments typically allow for
a 25% to 50% dose increase for a patient with mild to TABLE 1-4. Opioid Side Effects
moderate pain and a 50% to 100% dose adjustment
TIME ON STABLE OPIOID DOSE TO THE
for a patient with moderate to severe pain. For exam- SIDE EFFECT DEVELOPMENT OF TOLERANCE
ple, a patient started on morphine 30 mg PO every
4 hours (180 mg in 24 hours) has taken 6 rescue doses Constipation Never
of morphine 15 mg per day for the previous 5 days Nausea/vomiting 7-10 days
(an additional 90 mg in 24 hours), and she reports her Pruritus 7-10 days
Sedation 36-72 hr
pain is still 10 on a pain scale of 0 to 10. The patient Respiratory depression Extremely rare when opioids
is tolerating a total of 270 mg of morphine in 24 hours; are dosed appropriately
thus her dose can be safely increased by ­approximately
6 Pain

to ­recommend the addition of docusate to senna as KEY MESSAGES TO PATIENTS AND FAMILIES
an initial regimen to improve laxation.28,29 Clinicians
should assess for constipation during every follow- Clinicians should reassure patients and their families
up visit after a patient is started on an opioid regimen. that most pain can be effectively treated with available
analgesics. Addiction is a common concern for patients
and their families, and given the frequency of this con-
cern, clinicians may want to address this proactively. It
Opioid Rotation is important to remind patients that the risk for addic-
Opioid rotation involves switching from one opioid to tion (defined as persistent use despite harm to self or
another. The clinician should consider opioid rotation others) in a patient taking opioids for pain who has no
when a patient has (1) difficulty tolerating the initial history of abuse is exceedingly low.19 Likewise, because
opioid prescribed, because of intolerable side effects of misconceptions about opioids, patients and families
(e.g., nausea, pruritus, myoclonus); (2) poor response often have serious concerns about these medications.
to pain control with the initial opioid, despite appro- Clinicians should thus encourage patients and their
priate titration; or (3) worsening of renal or hepatic families to express their concerns about side effects,
function.30,31 When choosing to rotate from morphine because these can pose barriers to effective pain man-
to another opioid, oxycodone and hydromorphone agement. To engage patients and families in their own
are both reasonable alternatives.32 When rotating opi- care, clinicians may want to encourage the use of a
oid medications, the concept of incomplete cross- pain journal documenting the timing of administration
tolerance, which is the idea that the new drug may of standing and breakthrough pain medications and
be more effective because of differences in potency the impact of these medications on pain and function.
or drug bioavailability, must be taken into consider- This information can be very helpful in guiding clini-
ation.9,33 If the patient's pain is well controlled, the cians in pain management.
equianalgesic dose for the new opioid can be calcu-
lated using the Opioid Analgesic Equivalences table
(Table 1-3). This dose is then decreased by 25% to 50% CONCLUSION AND SUMMARY
to adjust for incomplete cross-tolerance.31 Clinical Poor pain management remains a major barrier to
judgment should be used in selecting the appropriate high-quality care for patients facing serious illness.
dose (e.g., if the pain was not well controlled, the clini- Palliative care clinicians have the ability to provide
cian may consider not decreasing the dose or reduc- safe and effective pain control for the majority of
ing the dose by only 25%). The patient should have patients through the appropriate dosing and titration
close follow-up because the dose initially chosen may of opioids. Continued research is required to increase
require titration. the evidence base for the majority of the treatment
recommendations provided in this chapter.

Opioid Agreements
SUMMARY RECOMMENDATIONS
Written opioid agreements are recommended by con-
sensus guidelines to decrease the risk for opioid • Morphine is the opioid of first choice for the
misuse.34 The introduction of an opioid a ­greement treatment of severe pain.
to patients is an opportunity to review potential • Patients on standing opioids should be ­prescribed
­misperceptions the patient may have about the safety of rescue medications for breakthrough pain.
opioids and their potential side effects and to establish • Clinicians should educate patients about the
expected treatment outcomes. This discussion has the ­efficacy and side effects of opioids, as well as
potential to minimize patient ­nonadherence with opi- address any concerns about the use of this
oid regimens.35 Agreements may include stipulations class of medication so as to increase patient
such as the patient must obtain ­opioid prescriptions adherence.
from only one ­prescriber, fill the ­prescription from • All patients started on opioids should be started
only one specified pharmacy, and agree to random on a bowel regimen unless there is a clear
urine drug screens.34 Many opioid agreements also contraindication.
clearly state clinical circumstances and behaviors • Opioid treatment agreements should be consid-
that will lead to ­discontinuation of opioid prescribing ered in outpatient practices.
by the ­clinician or the practice. The limited evidence
base for the efficacy of these treatment agreements
suggests these agreements may be effective.36 Opioid
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agreements should be considered in routine practice
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Support Care Cancer. 2006;14(11):1086–1093.
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objectively applying ramifications of nonadherence opioids in cancer pain: the EAPC recommendations. Br J Cancer.
with ­treatment recommendations. 2001;84(5):587–593.
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3. Apolone G, Corli O, Caraceni A, et al. Pattern and ­ quality 22. Portenoy RK, Hagen NA. Breakthrough pain: definition, preva-
of care of cancer pain management: results from the lence and characteristics. Pain. 1990;41(3):273–281.
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Treatment of Acute Pain and Cancer Pain. 6th ed. Glenview, IL: 3238–3245.
American Pain Society; 2008. 25. Farrar JT, Cleary J, Rauck R, Busch M, Nordbrock E. Oral
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management of persistent pain in older p ­ ersons. J Am Geriatr cancer patients. J Natl Cancer Inst. 1998;90(8):611–616.
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 Chapter How Should Opioids Be Started and

2 Titrated in Hospital or Inpatient Settings?

Cardinale B. Smith and Gabrielle R. Goldberg

RELEVANT PATHOPHYSIOLOGY
INTRODUCTION AND SCOPE OF THE PROBLEM
RELEVANT PATHOPHYSIOLOGY Pain is defined as “an unpleasant sensory and ­emotional
Opioid Pharmacology experience associated with actual or potential ­tissue
SUMMARY OF EVIDENCE REGARDING TREATMENT damage.”13 Pain can be classified as nociceptive,
RECOMMENDATIONS ­neuropathic, or idiopathic. Nociceptive pain can be
Pain Assessment further classified as either somatic (resulting from
Choosing a Starting Dose
injury to skin and deep tissue) or visceral pain (result-
Opioid Use in Patients With End Organ Dysfunction
Approach to the Opioid-Naïve Patient ing from injury to internal organs). Visceral pain is
Approach to the Opioid-Tolerant Patient often described as dull, vague, or diffuse, whereas
Opioid Titration somatic pain is more likely to be well-localized and
Method of Administration described as sharp or intense.
Opioid Side Effects The cause of a patient's pain should always be
Opioid Rotation assessed and disease-specific treatment offered14
KEY MESSAGES TO PATIENTS AND FAMILIES when appropriate and consistent with patients’ goals
CONCLUSIONS AND SUMMARY of care. The focus of this chapter will be on treat-
ing pain in the inpatient setting with opioids; a dis-
cussion of disease-specific therapies is beyond the
INTRODUCTION AND SCOPE OF THE PROBLEM scope of this section.
Pain is the most common symptom experienced by
hospitalized adults.1 Patients with advanced dis-
ease admitted to a hospital setting often have mod- Opioid Pharmacology
erate to severe pain and require intravenous opioid It is important to understand the pharmacology of
therapy.2 Beginning intravenous opioid therapy in opioids because it dictates the way in which opi-
the inpatient setting allows for rapid titration of oids are prescribed and administered. The admin-
pain m­ edication, because medication doses may istration of intravenous opioids is associated with
be repeated or the dose escalated over minutes to the most rapid onset of analgesia. The time to peak
hours. The inpatient setting also allows for ­controlled plasma concentration and therefore peak effect of
dispensing of ­opioid medications with little concern intravenous opioids can vary, although the general
for m
­ isuse or diversion. Acute severe pain requires range is 5 to 30 minutes. The duration of effect is
rapid a­ pplication of analgesic strategies and aggres- usually 3 to 4 hours. Opioids are conjugated in the
sive treatment, which are distinct from chronic liver and excreted (approximately 90% to 95%) by
management techniques that may be done in the out- the kidney.
patient setting. Numerous adverse outcomes exist to
poorly treated pain, including reduced patient satis-
faction,3 depressed mood,4 decreased quality of life,5
increased interference with physical functioning,4 SUMMARY OF EVIDENCE REGARDING TREATMENT
and increased costs resulting from prolongation of RECOMMENDATIONS
hospital stays and delays in return to work.6,7 In the Pain Assessment
postoperative setting, complications of poorly con-
trolled pain may include splinting because of chest The experience of pain is subjective, and therefore
wall pain, leading to atelectasis and ultimately pneu- a patient's report of pain is the gold standard of
monia, and deep venous thrombosis8 resulting from assessment. Treatment begins with a comprehensive
reduced movement because of pain and limiting pain assessment. This includes asking questions to
physical function. Organizations including the World assess time of onset, precipitating or alleviating fac-
Health Organization (WHO),9 the American Pain tors, quality, presence or absence of radiation, sever-
Society,10 the European Association for Palliative ity, and timing of the pain. A variety of tools may be
Care,11 and the American Geriatrics Society12 have used for the assessment of pain severity, including
developed guidelines for the treatment of pain, but numeric pain intensity rating scales (0 = no pain and
untreated and poorly controlled pain remains a 10 = worst possible pain) and the verbal ­descriptor
major problem in hospital settings. scales (mild, moderate, or severe). The numeric

8
 Opioid Use in Inpatient Settings 9

r­ ating scale offers several advantages, including ease ­insufficiency.20 It is also appropriate to consider an
of administration and scoring, multiple response alternative opioid for a patient receiving morphine
options, and no reported age-related difficulties in who experiences a decrease in renal function and a
its use.15 For younger patients and those with cogni- concomitant increase in undesirable effects. Fentanyl
tive impairments, the Faces Pain Scale may be more is considered relatively safe in renal insufficiency
effective than verbal report.16 (For more informa- because there are no known active metabolites.
tion on treating pediatric patients, see Chapter 65.) However, few pharmacokinetic data exist regard-
Clinicians should assess pain intensity regularly, ing fentanyl in end-stage renal disease.21 Clinicians
because this helps guide the initial approach to should consider starting even the relatively “renal-
treatment, efficacy of current regimen, and need for failure safer” opioids at lower than normal doses to
­further ­titration of medications. ensure patient safety.22,23
In the presence of hepatic impairment, most drugs
are subject to significantly impaired clearance, but
Choosing a Starting Dose this has been poorly studied in the clinical setting.
The elimination of morphine is greatly reduced in
When initiating opioid therapy in the inpatient patients with liver disease, and the recommendations
setting, the severity of pain, end organ function,
­ have been to decrease the frequency of administra-
dose of opioid (if any) currently being taken, the tion in these patients.24,25 A paucity of data exist for
patient's prior experiences with pain, and history the use of hydromorphone in patients with hepatic
of opioid use are all key factors in determining dysfunction, but expert consensus suggests it can be
the ­appropriate regimen. The mu-agonist opioids— used with caution by increasing (i.e., extending) the
morphine, ­ hydromorphone, and fentanyl—are the dosing interval.15 In contrast, fentanyl pharmacoki-
most commonly used intravenous agents in patients netics do not appear to be altered in patients with
with moderate to severe pain. Methadone is avail- cirrhosis and therefore fentanyl may be a reasonable
able in an intravenous formulation, but because of its choice in these patients.25
unique pharmacokinetic profile and the complexity
relating to its dosing and titration, it should not be
used as the initial treatment for pain in the inpatient
­setting. (For more information on the use of metha- Approach to the Opioid-Naïve Patient
done, see Chapters 7 and 8.) In the patient who is opi- The recommended starting dose for an opioid-naïve
oid naïve, morphine is considered the opioid of choice patient is morphine 5 to 10 mg intravenously (IV),
because of its established effectiveness, ­availability, which is approximately equivalent to 15 to 30 mg of
familiarity to physicians, simplicity of administra- oral morphine. An older or more debilitated patient
tion, and relatively lower cost compared to those should be started at the lower end of this range.
of other opioids. It is likewise the most appropriate Although this is the dose commonly used, few stud-
­medication for patients on oral morphine who need ies have evaluated the appropriate starting dose for
either ­titration or ­escalation of their pain regimen in opioid-naïve patients in acute pain. There have been
the inpatient setting. several studies evaluating the utility of beginning
various doses and intervals of morphine to achieve
Opioid Use in Patients With End Organ Dysfunction appropriate analgesia, particularly in the emergency
room setting.26,27 No one defined standard exists,
Caution should be used with the administration of however, and current practice is based on expert
opioids in patients with renal or hepatic d ­ ysfunction. consensus.
The two major morphine metabolites are ­morphine-3 Severe pain is considered a medical emergency and
glucuronide (M3G) and morphine-6 glucuronide should be managed aggressively. Ideally, the starting
(M6G). M6G appears to contribute to the analge- dose of the opioid should be administered as a bolus
sic activity of morphine.17,18 M3G does not have or “intravenous push” dose as opposed to a slow infu-
­analgesic activity and is believed to contribute to sion over 30 minutes. The peak effect of intravenous
the neuroexcitatory side effects. Both M3G and opioids is approximately 8 to 15 minutes after admin-
M6G are eliminated by the kidney and, because of a istration; therefore the analgesic response can be
­longer half-life than the parent compound, will accu- reevaluated at about 15 minutes after an i­ntravenous
mulate faster than morphine itself. The buildup of push. The dose may then be repeated every 15 min-
these metabolites is associated with the most severe utes if the patient is not sedated and adequate analge-
­toxicities observed with the use of opioids (respi- sia has not been achieved (see Chapter 1, Table 1-3).
ratory depression or obtundation, myoclonus, and A rule of thumb for dose increases is to use 25% to
seizures).19 Although evidence regarding the use 50% more morphine for mild to moderate pain and
of opioids in renal and hepatic insufficiency comes 50% to 100% more for moderate to severe pain.
from small group pharmacokinetic studies or case A dose increase of less than 25% is likely to have no
reports, which included patients with wide varia- effect. Repeated intravenous doses are administered
tion in the degree of organ d
­ ysfunction, morphine is in this fashion to titrate to the point of adequate anal-
still not recommended for use in patients with renal gesia. Once the adequate dose has been determined,
10 Pain

that dose can be prescribed for every 4 hours as a the patient has severe pain, the clinician decides to
standing order, assuming there is no hepatic or renal increase the dose by 50% and give a 7.5-mg intrave-
dysfunction. Standing scheduled dosing will main- nous morphine bolus dose to treat the acute pain
tain stable serum drug levels and provide consistent crisis.
relief.
In addition to a standing order, patients also should
be prescribed medications to treat breakthrough Opioid Titration
pain. Breakthrough pain refers to a transitory
increase in pain, to greater than moderate inten- It is important to ensure accurate and continuous
sity, in a patient receiving chronic opioid t­herapy.28 recording of the amount of pain medication neces-
This can be related to incident pain (pain provoked sary to achieve adequate analgesia, because this
by an event) or pain that occurs spontaneously. information will allow safer and more efficient dose
Breakthrough pain is treated with rescue medication, titration. After the patient has been started on a regi-
which is taken as required (i.e., as needed), rather men of standing opioids and a rescue medication,
than on a regular basis.29 The typical dosing recom- the total dose of opioids required for effective anal-
mendations for rescue medications have been based gesia is then assessed. In general, the goal is that
on anecdotal experience. It has been suggested that rescue medications be required no more than two
the effective dose of breakthrough pain medication is or three times per day. If a patient requires a r­ escue
a percentage of the patient's total daily opioid dose medication more frequently, the standing dose
­
(most commonly 10% to 20% of the 24-hour dos- should be increased. The general practice includes
ing).30,31 However, current evidence suggests that the calculating the total opioid doses required in the pre-
dose of opioid for breakthrough pain should be deter- vious 24-hour period. If the patient's pain is well con-
mined by individual titration.32–34 Future studies on trolled, this total calculated dose can then be given in
this topic are warranted because the primary objec- divided doses every 4 hours and a new rescue medi-
tive of previous trials was to evaluate the efficacy of cation dose calculated. If this regimen did not pro-
short-acting formulations, not to determine optimal vide adequate relief, the same general rule of thumb
rescue medication dosing. The dosing interval of the applies as described earlier (25% to 50% increase
rescue medication is based on the pharmacokinetics in dose for mild to moderate pain and 50% to 100%
described earlier. In reality, a rescue dose could be increase in dose for moderate to severe pain). For
given every 8 to 15 minutes, because this is the time example, a patient is prescribed morphine 4 mg IV
to peak effect of the intravenous opioids. However, in every 4 hours and 2 mg IV every hour as needed. The
the inpatient setting it is difficult to have a clinician patient has received a total of 5 of the rescue doses
administer a dose that frequently. In clinical practice, (total 24-hour dose is 34 mg). If the pain was well con-
these authors suggest calculating the rescue dose as trolled on this regimen, the new dose would be 6 mg
10% of the total 24-hour dose, given every hour as IV every 4 hours, with 3 mg IV every hour as needed
needed for pain. This interval should be increased to (doses rounded for ease of administration). If the
2 hours for patients with hepatic or renal dysfunc- pain was only moderately controlled, the dose can be
tion. In a patient requiring frequent administration increased by 25% to 50%. The new dose would then
of rescue doses it is appropriate to consider start- be 8 mg IV every 4 hours, with 4 mg IV every hour as
ing the patient on patient-controlled analgesia (PCA). needed for pain.
For example, if a patient is on morphine 4 mg IV every
4 hours (24-hour dose is 24 mg), the rescue medica- Method of Administration
tion dose is 2.4 mg IV every hour as needed for pain,
although this would be rounded to 2 mg to simplify In addition to administering standing opioid doses
administration. every 4 hours, the inpatient setting allows for
continuous intravenous infusions of pain medica-
­
tions. Depending on the source or severity of pain
Approach to the Opioid-Tolerant Patient and the patient's overall health status, continuous
intravenous infusions may help achieve better effi-
Pharmacologically, tolerance is defined as the loss of cacy. This can be achieved either with a continuous
drug effect with chronic dosing.35 Patients on opioid “drip” or via a PCA pump. PCA allows a patient to
therapy or with a prior history of opioid use will have self-administer opioid therapy (according to a clini-
higher requirements than those who are opioid naïve. cian's order) to control pain. PCA administration can
Initial dose finding should follow the same guidelines include a baseline (continuous) infusion, a patient-
as for the opioid-naïve patient; however, the start- controlled demand (bolus) dose given at some fre-
ing dose will be higher. For example, a patient on quency with a lockout interval, or both; the basal and
long-acting morphine sulfate 45 mg orally (PO) every bolus can each be given alone, or they may be given
12 hours (90 mg in 24 hours) is admitted for progres- together. Lockout interval refers to the time between
sion of disease, with complaints of 10 on a pain scale boluses during which the pump will not allow
of 0 to 10 not relieved by the current oral morphine more bolus doses to be administered. Use of PCA
regimen. This is the equivalent of a 24-hour dose of has several advantages, the primary being patient
morphine 30 mg IV, or 5 mg IV every 4 hours. Because ­convenience. The medication can be administered
 Opioid Use in Inpatient Settings 11

immediately, removing the delay that often exists pain, the clinician decides to start a PCA. The patient
when a clinician is required to bring the rescue medi- received a total of morphine 76 mg IV (6 doses of
cation. For a patient with acute severe pain, PCA will 6 mg plus 10 doses of 4 mg) in 24 hours. Because the
allow for more rapid pain relief and faster titration of patient rates her current pain as a 5 on a pain rating
opioid therapy. Finally, PCA helps to ensure safety; scale of 0 to 10, it is decided that the basal dose will
a patient who becomes sedated can no longer press be 70% of the previous total 24-hour dose. Thus the
the button for additional doses, thus limiting the risk basal rate should be 2.2 mg per hour (76 mg/24 hr ×
for respiratory depression. If other individuals press 70% as basal = 53 mg over 24 hours = 2.2 mg/hr). The
the button to release bolus doses, this can result in orders will be written as follows (note that the doses
administration of potentially unnecessary and unsafe have been rounded to simplify administration and
doses of the medication. setting of the pump):
Finding the appropriate dose for PCA administra- 1. Basal rate: Morphine 2.5 mg per hour
tion is very similar to the methods described earlier. 2. Bolus dose: Morphine 1.5 mg with a lockout inter-
In general, the majority of patients started on PCA val of 10 minutes (50% of the basal dose, adjusted
will have been on opioid therapy previously. The first for rounding)
step is to calculate the total opioid doses required in 3. Maximum hourly dose: 11.5 mg per hour
the previous 24-hour period. Expert opinion suggests When starting a basal rate via the PCA it is impor-
that 50% to 70% of this dose should be used as the tant to remember that it will take several hours for
basal (continuous infusion) rate. If the regimen previ- the dose to reach a steady state. More specifically,
ously used did not provide adequate relief, using the it will take 4 to 5 half-lives of a drug to reach a new
entire 24-hour requirements as the basal dose should steady state. Therefore simply starting the basal rate
be considered. Evidence on the appropriate lockout will take 10 to 15 hours for the drug to reach a steady
interval is lacking. Based on the pharmacokinetics of state. In the inpatient setting, this may be an unac-
the intravenous opioids the lockout can be between ceptably long delay to achieve analgesia. It would not
5 and 30 minutes. In clinical practice the most com- be unusual for a patient to use the bolus doses more
monly used intervals are 6, 8, 10, and 15 minutes. frequently during this period. A clinician-activated
In general, the lockout interval should be based on bolus dose ordered in addition to the basal and bolus
providing adequate analgesic coverage during times rate also can be considered. This dose is usually
when patients need the most coverage (during times written as 10% of the total 24-hour dose every hour
when activities or other factors that precipitate pain as needed for pain. The clinician-activated bolus is
may occur). The American Pain Society recommends administered by the nurse most commonly by PCA,
a lockout interval of 5 to 10 minutes for patients with but can also be given as a separate intravenous
acute pain.36 The bolus dose given is typically 50% dose (bolus or slower infusion). For example, for the
to 150% of the basal dose.37 In the authors’ experi- patient discussed earlier the orders will now be:
ence, the general practice is a lockout of 10 minutes 1. Basal rate: Morphine 2.5 mg per hour
with a bolus dose of 50% of the basal amount. The 2. Bolus dose: Morphine 1.5 mg, with a lockout
amount of the bolus dose depends on the nature of interval of 10 minutes
the pain. Patients who experience severe incident 3. Maximum hourly dose: 11.5 mg per hour
pain may benefit from a relatively higher PCA dose. 4. Clinician-administered dose: 6 mg every hour
When intravenous access is not possible, PCA may as needed × 4 doses (Note: The clinician dose
be administered by the subcutaneous route. Based is based on the 24-hour total basal rate, not
on risk for local irritation and toxicity, there is a max- the maximum hourly dose. The modifier of “×4
imum hourly rate that can be given by the subcuta- doses” is written because if the patient has not
neous route. The maximum rate may be as high as achieved appropriate analgesia with the PCA and
10 mL per hour, although institutional policies vary.38 4 clinician-administered doses, the patient needs
The subcutaneous route may therefore require bags to be reassessed to determine if the entire regi-
with higher than standard concentrations to keep men should be adjusted.)
the hourly maximum volume low. Use of nonstan-
dard concentrations is a potential source of medica-
tion error and should be carefully reviewed with the Opioid Side Effects
pharmacist and nurse administering the medication.
Inappropriate candidates for PCA therapy include Common opioid side effects are listed in Table 2-1.
patients who are physically or cognitively unable Tolerance develops to all opioid side effects, with the
to self-administer demand or breakthrough medica- exception of constipation, which is an expected and
tion. In other words, patients must be able to inter- predictable consequence of taking opioids. At the
pret their own pain and be able to press the button to time of prescribing opioids all patients should also
administer a bolus dose. Patients, families, and clini- be started on a prophylactic bowel regimen, unless
cians should be reminded that the PCA bolus should the patient has diarrhea or another contraindica-
be administered only by the patient. For example, tion to a bowel regimen. One of the most commonly
a patient is on morphine 6 mg IV every 4 hours and used regimens is senna (Senokot) (1 or 2 tablets at
4 mg IV every hour as needed (received 10 doses in ­bedtime) and docusate (100 mg two or three times
last the 24 hours). To better control the patient's per day), although evidence is lacking to r­ ecommend
12 Pain

want to proactively address this topic. It is important

TABLE 2-1. Opioid Side Effects
to remind patients that the risk for addiction (defined
TIME ON STABLE OPIOID DOSE TO THE as persistent use despite harm to self or others) in
SIDE EFFECT DEVELOPMENT OF TOLERANCE a patient taking o
­ pioids for pain who has no history
of abuse is exceedingly low.44 Likewise, because of
Constipation Never misconceptions about opioids, patients and families
Nausea/vomiting 7-10 days often have other concerns about these medications.
Pruritus 7-10 days
Sedation 36-72 hr Clinicians should thus encourage patients and their
Respiratory depression Extremely rare when opioids families to express their concerns about side effects,
are dosed appropriately because these can pose barriers to effective pain
management.

the ­addition of docusate to senna as an initial ­regimen

to improve laxation.39,40 Clinicians should assess CONCLUSIONS AND SUMMARY
for constipation during every follow-up visit after a
patient is started on an opioid regimen. (For further Pain is a significant symptom experienced by hospi-
discussion of treating constipation in the ­setting of talized patients. Opioids are effective at treating pain
opioids, see Chapter 24.) in the hospitalized patient and can lead to improved
patient outcomes. Palliative care practitioners can
provide rapid, effective, and safe pain management
Opioid Rotation for patients in the inpatient setting. The majority of
current evidence surrounding the initiation and titra-
Opioid rotation involves switching from one opioid tion of opioids in the inpatient setting relies on expert
to another in an attempt to limit adverse effects or opinion and consensus. Further investigative work is
improve analgesia. The clinician should consider needed to improve the evidence base for these treat-
opioid rotation when a patient has (1) difficulty with ment recommendations.
the initial opioid prescribed because of i­ntolerable
side effects (e.g., nausea, pruritus, myoclonus),
(2) poor response to pain control with the initial SUMMARY RECOMMENDATIONS
­opioid despite appropriate titration, or (3) ­worsening
of renal or hepatic function.41,42 When choosing to • Morphine is the opioid of first choice for the
rotate from morphine to another opioid, oxycodone treatment of pain.
and hydromorphone are both reasonable alterna- • Patients on standing opioids should be ­prescribed
tives.41 If the patient's pain is well controlled, the rescue medication for breakthrough pain.
equianalgesic dose for the new opioid can be calcu- • Patients in severe pain crisis should be given
lated using the Opioid Analgesic Equivalences table intravenous bolus pain medication until the
(see Chapter 1, Table 1-3). When rotating ­ opioid ­crisis is resolved.
medications, the concept of incomplete cross- • Patient-controlled analgesia should be ­considered
tolerance must be taken into consideration, in which for patients with severe pain requiring frequent
the new drug may be more effective because of bolus doses.
differences in potency or drug bioavailability. An • Opioid rotation should be considered for
appropriate dose reduction is to decrease the new patients with intolerable side effects or poorly
opioid dose by 25% to 50% to allow for this incom- managed pain despite adequate titration.
plete cross-tolerance.43 Clinical judgment should be
used in ­selecting the ­appropriate dose (e.g., if the pain
is not well controlled, the clinician may consider not
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