Fundamentals of Cancer Pain Management

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Editors
Andrew Leitner Christine Chang
Departments of Supportive Care Medicine New York, NY, USA
and Anesthesiology
City of Hope National Medical Center
Duarte, CA, USA

ISSN 0927-3042 ISSN 2509-8497 (electronic)

Cancer Treatment and Research
ISBN 978-3-030-81525-7 ISBN 978-3-030-81526-4 (eBook)
https://doi.org/10.1007/978-3-030-81526-4
© Springer Nature Switzerland AG 2021
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In remembrance of Dr. Lisa Stearns,
a pioneer in cancer pain management
and relentless advocate for care to enhance
quality of life.
This book is dedicated to our patients, for
whom we strive to ease suffering, and to our
families, who support us steadfastly in this
work.
Andrew Leitner
Christine Chang
Preface

Those of us privileged to work in the care of cancer patients have seen significant
treatment advances over the past several years. The utilization of targeted inter-
ventions for cancer pain has also gained more acceptance over time. Unfortunately,
despite these advances, pain remains the most common, and the most feared,
symptom of patients with cancer. As medicine and oncologic care become more
specialized, we increasingly need to address areas, such as pain management, that
cut across disciplines. This book is one such effort, from a group of experts who
share the challenges and rewards of caring for the cancer patient in pain.
The founder of the hospice movement, Cicely Saunders, developed the phrase
“total pain” to describe the suffering that patients may experience across the entire
biopsychosocial spectrum. If pain is a multifactorial experience, so must be its
management. Though opioid therapy has relieved the suffering of countless
patients, the opioid epidemic—and the regulatory response to it—has meant a
re-evaluation of monotherapy approaches to pain. This is particularly relevant for
cancer survivors. Indeed, those of us who practice in the field of cancer pain
management recognize that few patients are helped by a single pill or needle alone.
For this reason, a primer on a spectrum of treatment modalities is offered here.
This text is intended as both a reference for the oncology professional and an
introduction for those who may be interested in specializing in this patient popu-
lation. The first part explores the history and epidemiology of cancer pain and
introduces the common presentations of pain from cancer or its treatments. Special
attention is given to the fortunately growing proportion of long-term cancer sur-
vivors. The remainder of the text focuses on therapeutic areas, with an under-
standing that many, if not all, may come to bear on the treatment of our most
complex patients. There are several excellent texts with broader coverage of these
modalities—here we focus on their specific application to patients with cancer. The
part on pharmacologic therapies devotes considerable attention to opioid analgesia,
which remains a core treatment modality in cancer pain. Of key importance as well
are the non-opioid analgesics, which are addressed alongside a growing list of
emerging therapies. Interventional and locoregional therapies continue to expand in
scope, and the coverage in this part is intended to be an advanced primer, partic-
ularly in understanding patient selection for these therapies. Finally, we conclude

vii
viii Preface

with the recognition that pain is a biopsychosocial experience requiring a holistic

approach to rehabilitation. Topics include psycho-oncology, physical medicine, and
integrative therapies.
We are fortunate to have the contribution of North American as well as Euro-
pean authors, providing valuable perspective on the practice of cancer pain man-
agement in various healthcare systems. Finally, it should be noted that this project
was brought to completion during the international COVID-19 pandemic, with
many of the authors finding themselves on the front lines of care. It would seem that
the same sense of urgency that has driven us to care for the cancer patient in pain
has called many of us to take on pandemic roles as well. We remain inspired by the
efforts of our colleagues and the collaboration that resulted in this book.

Duarte, CA, USA Andrew Leitner MD

New York, NY, USA Christine Chang MD
Contents

Part I Background and Assessment of Cancer Pain

1 History and Epidemiology of Cancer Pain . . . . . . . . . . . . . . . . . . . 3
David J. Copenhaver, Ming Huang, Jasmine Singh,
and Scott M. Fishman
2 Cancer Pain Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
David Y. Lee, John J. Lee, and Steven H. Richeimer
3 Cancer Treatment Related Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Purvi Patel
4 Cancer Pain Management—A European Perspective . . . . . . . . . . . 39
Denis Dupoiron
5 Pain in the Cancer Survivor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Matthew R. D. Brown, Paul Farquhar-Smith, and David J. Magee

Part II Pharmacologic Therapies

6 Opioid Therapy in Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Jakun Ing, Samantha Wong, Helen Chan, and Eric Hsu
7 Opioid-Related Side Effects and Management . . . . . . . . . . . . . . . . . 97
Andrea Poon, Jakun Ing, and Eric Hsu
8 Clinical Implications of Opioid Therapy . . . . . . . . . . . . . . . . . . . . . 107
Christy Anthony, Armen Haroutunian, Eric Hsu, James Ashford,
Rene Przkora, Teresa Ojode, and Andrea Trescot
9 Non-opioid Analgesics and Emerging Therapies . . . . . . . . . . . . . . . 125
Marga Glasser, Jeffrey Chen, Mohammed Alzarah, and Mark Wallace

Part III Interventional and Locoregional Therapies

10 Palliative Radiation for Cancer Pain Management . . . . . . . . . . . . . 145
Arya Amini, Ashwin Shinde, and Jeffrey Wong

ix
x Contents

11 Ablation Techniques in Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . 157

Jonathan Kessler
12 Interventional Treatments for Cancer Pain . . . . . . . . . . . . . . . . . . . 175
Manisha Trivedi and Jaisha Mathew
13 Peripheral Nerve Entrapments in Cancer Pain . . . . . . . . . . . . . . . . 203
Rene Przkora, Pavel Balduyeu, Juan Mora, Andrew McNeil,
and Andrea Trescot
14 Intrathecal Analgesia in Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . 225
Denis Dupoiron
15 Neurosurgical Treatments for Cancer Pain . . . . . . . . . . . . . . . . . . . 239
Sharona Ben-Haim, Zaman Mirzadeh, and William S. Rosenberg

Part IV Total Pain and Rehabilitation

16 Physical Medicine and Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . 255
Carolina Gutierrez and Megan B. Nelson
17 Psychosocial Aspects of Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . 273
Mary Morreale
18 Integrative Therapies in Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . 281
Anna Woodbury and Bati Myles
 Part I
Background and Assessment
of Cancer Pain
History and Epidemiology of Cancer
Pain 1
David J. Copenhaver, Ming Huang, Jasmine Singh,
and Scott M. Fishman

1.1 Cancer Pain Prevalence and Etiology

Pain is indelibly associated with the cancer experience. A systematic review and
meta-analysis indicate that the prevalence of cancer pain is 55% during anticancer
treatment, 66.4% in advanced, metastatic, or terminal disease, and 39.3% after
curative treatment [1]. Further, moderate to severe pain is present in 38% of all
patients afflicted with cancer, highlighting the broad need for safe and efficient pain
care [1]. Those who have been treated for cancer and continue to survive are esti-
mated to be 12 million in the USA [2]. Therefore, as cancer treatment becomes more
efficacious and quantity of life extended, one can observe a perceptible shift. Cancer
has become in many instances a chronic illness that is often associated with pain.
Etiologies of cancer-related pain appear to be multifactorial. Sources of pain
include the tumor itself including metastatic lesions directly causing nociceptive
pain, visceral pain, and/or neuropathic pain. Anticancer treatments themselves may
cause various specified pain conditions secondary to chemotherapeutics, radio-
therapy, and surgery.
It is important to note that tumors can secrete noxious chemical irritants,
inflammatory mediators, and immunomodulators that act upon peripheral noci-
ceptors [3]. Nociceptive pain is due to mechanical, thermal, or chemical stimulation
of nociceptors that are located in skin, connective tissue, muscles, and bones [3].

D. J. Copenhaver (&)
S. M. Fishman

Department of Anesthesiology and Pain Medicine, UC Davis Medical Center, 4860 Y Street,
Suite 2700, Sacramento, CA 95817, USA
e-mail: dcopenhaver@ucdavis.edu
M. Huang
J. Singh
Division of Pain Medicine, UC Davis Medical Center, Sacramento, USA

© Springer Nature Switzerland AG 2021 3

A. Leitner and C. Chang (eds.), Fundamentals of Cancer Pain Management,
Cancer Treatment and Research 182,
https://doi.org/10.1007/978-3-030-81526-4_1
4 D. J. Copenhaver et al.

As we review our current understanding of cancer-related pain, it can only be

placed into perspective by assessing the historical context of how humanity has
qualified pain and cancer.

1.1.1 The Early Greeks

Pain is a complex human experience that has been well documented since ancient
times. Since the beginning, there has always been an attempt to find the origin,
mechanism, and treatment of pain. According to the ancient Greek philosophers,
pain is punishment from the gods; it is a necessity for the development of
self-control and a testament to one’s character. Enduring severe pain allowed one to
demonstrate courage and wisdom [4].
Plato, like many Greek philosophers, believed pain originated from the center of
the heart. He viewed pain and pleasure as opposite to each other and as a product of
an interaction with the soul. The experiences of pain and pleasure can cloud one’s
judgment and prevent one from knowing what was real [4]. Aristotle believed that
the heart was the center of the five senses including sight, hearing, smell, taste, and
touch. Pain was not included in his five senses; rather, it was believed to be a part of
one’s emotions and not a function of one’s sensory experiences [5].
Hippocrates, wildly recognized as the father of medicine, used the word pain for
the first time as a medical condition. He believed the nature of the body to be made
up of four humors or liquids (blood, black bile, yellow bile, and phlegm). Imbalance
in these humors was thought to be the source of pain. In his own words, “pain is felt
when one of these elements is in deficit or excess, or is isolated in the body without
being compounded with all the others” [6].

1.1.2 Rene Descartes

One of the lasting legacies of Descartes is his concept of mind–body dualism. He

reached the conclusion that the mind is a non-physical entity with self-awareness
that is separated from the body, a physical entity. Different from his predecessors,
he believed pain originated from the brain instead of the heart. He is also credited as
being one of the first philosophers to describe the detailed somatosensory pathway
and attempted to make the distinction between sensory transduction and perception
of pain [7]. In Treatise of Man, he described nerves as hollow tubes that connect
and deliver sensory and motor information [8].

1.1.3 Early Twentieth Century

The early twentieth century was filled with advances in the treatment of cancer. The
first use of radiation therapy to cure cancer was reported in 1903 by Goldberg and
London for the eradication of basal cell carcinoma of the skin. Halsted’s surgical
1 History and Epidemiology of Cancer Pain 5

approach to radical dissection of breast tumor, which was developed in late nine-
teenth century, continued to gain wider use in the early twentieth century. Radiation
and surgical therapy gradually became mainstream treatment options for cancer
patients. However, there was inadequate attention directed toward the control of
pain in cancer patients by the medical community. Hospital facilities or medical
clinics specialized in the treatment of pain were nonexistent. Physicians who were
involved in the care of dying patients were often hesitant and unwilling to use
opioids to treat even advanced cancer pain due to fears of addiction and euphoria
[9]. Instead, cancer patients who suffered from severe pain were praised for their
heroic efforts in not using opioids. The use of morphine as a painkiller was further
restricted with governmental regulations with the passing of Harrison Narcotics Act
of 1914.

1.1.4 Post-World War II

By the end of World War II, cancer had become the second leading cause of death
in the USA. Government establishments, major pharmaceutical companies, elite
universities, and research institutes started waging war on cancer as public attention
turned to treating cancer as a potential curable disease. When the federal govern-
ment established the National Cancer Institute in 1937, the initial annual research
fund was approximately $700,000, but that number had increased substantially in
the next two decades after World War II. By 1968, its annual research budget had
exceeded over 185 million [10].
The National Cancer Act of 1971 signed by President Nixon continued
government-organized efforts to fight cancer. The act helped create new cancer
centers and training programs, and award contracts for research, increased collab-
oration between public agencies and private industry, established an international
cancer research data bank, and improved public understanding of cancer as a
biological disease [11].

1.1.5 Cancer Patients’ Autonomous Voice

Government-led organized efforts to fight cancer partly stemmed from the change
of public opinions about cancer treatment. Starting in the 1960s, there was an
increase in the publication of narratives from the cancer patient perspective. These
narratives focused on the frustration surrounding inadequate pain control and lack
of patient autonomy. Prominent writers and journalists frequently published stories
of the struggle they encountered in managing the cancer pain of their dying friends
and family members. Stewart Alsop, a renowned journalist, frequently wrote col-
umns and books to describe his battle with leukemia and death and dying from the
patient perspective. He called for patient autonomy and spoke to how patients
should have a voice and choice regarding their analgesia. In his own words, “a
terminal patient in full command of his faculties should be permitted to ask a
6 D. J. Copenhaver et al.

committee of experienced doctors about his future, and if he is told it holds nothing
but suffering, and death at the end, he should have the right to demand, and to
receive, a pill or some other painless means of ending his life” [12].

1.1.6 1950–1960s

Progress and development of cancer treatment with chemotherapy drugs were

significant in the 1950–1960s. Prior to this, treatment of cancer was by either
surgical resection or radiotherapy. In 1956, methotrexate was successfully used to
cure gestational choriocarcinoma. This marked the first time that cancer could be
eradicated by a pharmacological agent. In the next decade, patients with Hodgkin
disease and acute lymphoblastic leukemia were also first reported to be cured or put
into remission with chemotherapy [13]. By the late 1960s, chemotherapy had
become one of three major treatment modalities along with surgery and
radiotherapy.

1.1.7 Ray Houde Memorial Sloan Kettering

Shortly after World War II, the search for an ideal powerful analgesic (but also
non-addictive) medication began. Research programs and laboratories, created
under the Committee on Drug Addiction and Narcotics (a subdivision of the US
National Research Council), had developed over hundreds of morphine derivatives
awaiting testing [14]. The need for a standardized approach to the testing of the
pharmacological agents became apparent. Ray Houde, with colleagues Ada Rogers
and Kathleen Foley at Memorial Sloan Kettering, developed methods and research
programs to assess pain and the efficacy of analgesic therapy for cancer patients.
The methods they used continue to serve as models for standard analgesic trials for
many decades [14].

1.1.8 John Bonica

John Bonica is often considered as the founding father of pain medicine. Before his
time, there was little mention of the evaluation and treatment of patients with pain
in medical textbooks. With his firsthand experiences of treating wounded soldiers
who suffered severe pain in the Madigan Army Hospital during World War II, he
recognized pain as a complex condition and called for the integration of opinions
from multiple disciplines including, but not limited to, neurosurgery, neurology,
orthopedics, and psychiatry for treatment of acute and chronic pain [15, 16]. The
book The Management of Pain, which he wrote in 1953, was considered the first
comprehensive medical textbook devoted entirely to practice of pain medicine. He
pushed for pain to be recognized and treated as a medical condition and brought
awareness to the medical world. By transforming the way pain was perceived,
1 History and Epidemiology of Cancer Pain 7

evaluated, and treated, he created a framework for pain medicine that accounts for
psychological, biological, and social aspects of the disease. This biopsychosocial
model continues to be influential in the modern practice of pain medicine.

1.1.9 Ren Leriche and Other Neurosurgical Approaches

to Cancer Pain

The French surgeon Rene Leriche was a pioneer in inventing surgical procedures
that provided pain relief for soldiers who suffered from pain related to reflex
sympathetic dystrophy or causalgia. It was well documented that he performed the
first periarticular sympathectomy on a patient who developed painful paresthesia
after a gunshot wound to the axilla and resulted in patient getting pain relief
15 days later [17].
Other neurosurgical approaches were also developed to interrupt the transmis-
sion of pain in the early twentieth century. Neurosurgeons Edward Martin per-
formed the first division of the anterior lateral column for treatment of severe
intolerable cancer pain related to tumor invasion of cauda equina in the early
twentieth century. The procedure achieved pain relief of the lower extremities after
surgery [18]. The first use of neurolysis of the celiac plexus (transcutaneous
splanchnic nerve block) was described in 1914 by Kappis and colleagues. He was
able to demonstrate that abdominal pain can be blocked via nerve block of the
splanchnic nerves [19].

1.1.10 Latter Twentieth Century

1.1.10.1 Increasing Call for Improved Pain Control

The latter half of the twentieth century saw major advances in understanding,
identification, and pharmaceutical management of pain in a patient suffering with
cancer. Despite the advancement in therapeutic approaches, including the devel-
opment of various opioids, most cancer pain patients in the 1970s still died in
severe pain [20]. There were not sufficient guidelines and systematic treatment
approaches for management of cancer pain. As part of an international effort to
address the under-treatment of cancer pain, the World Health Organization
(WHO) in 1986 released the concept of a simple “three-step analgesic ladder” to
standardize the management of cancer pain in a stepwise fashion depending on
severity of pain. The template was not perfect. However, it marked the first time a
simple rule could be applied to the treatment of cancer pain. It helped guide new
and inexperienced clinicians to make practical decisions for their patients in
treatment of pain. This template also legitimized the use of opioids in treatment of
pain and led to a wider adaptation throughout the world.
8 D. J. Copenhaver et al.

1.1.10.2 The Discipline of Hospice and Palliative Care

Palliative care is a relatively young discipline. The modern concept of palliative
care started out as a form of hospice care at St. Joseph’s Hospice in the 1950s where
Dr. Cicely Saunders based her observations of patients dying of cancer. She rec-
ognized there was little known about pain management of cancer patients and
introduced the idea of “total pain” in an attempt to provide a holistic approach to
meet the physical, psychological, and spiritual distress of her dying cancer patients
[21]. Psychological and spiritual aspects of pain experiences were taken into
account with focus on improving overall comfort and quality of life. Gradually,
palliative care as a discipline started to take shape and offered a wider range of
services. It helped to manage the side effects arising from treatment of cancer in
addition to cancer pain. The term palliative care was invented by Dr. Balfour
Mount, a surgical oncologist in Canada to distinguish it from hospice care [22]. The
field continued to evolve and served a unique role in the multi-disciplinary treat-
ment of cancer pain.

1.1.10.3 The Discipline of Pain Medicine

Under the leadership of John Bonica, the International Association for the Study of
Pain was created in 1973 to help promote research, educate, and advance the
understanding of the treatment of pain. The association served as platform for
researchers, clinicians, and policy makers to gather together to share the latest
scientific knowledge in pain medicine and translated that into the clinical practice of
pain management. The organization also helps promote education and training in
the field of pain management worldwide. One of its biggest contributions was
bringing clinicians from various different disciplines together and adopting a uni-
form definition and classification of pain diseases and conditions. Despite the fact
that the field of pain medicine is relatively new compared to other fields in medi-
cine, it has made significant progress in last few decades of twentieth century. From
the specificity theory of pain to a multi-disciplinary approach, the pain community
has come to understand that pain is complex, multi-dimensional with not just
sensory-discriminative, rather with affective–motivational and cognitive–evaluative
components. Treatment of pain gradually changed from a single dimension
involving pharmacologic treatments to include other treatment approaches such as
specialized injections and implants coupled with guided imagery and cognitive
behavioral therapy. Pain medicine has continued to evolve and has slowly emerged
as unique field of its own. Cancer pain management is a natural extension of the
evolution of pain medicine as a discipline.
1 History and Epidemiology of Cancer Pain 9

1.2 Cancer Pain: Historical Perspectives and Current

Thoughts

Recent studies have demonstrated specialized communication between cancer cells

and those of the host’s immune system, peripheral nervous system, and central
nervous system [23]. The intersection of the immune system and the nervous
system has become a fundamental framework for understanding cancer-related
pain. By way of example, precancerous head and neck tumors that are benign
usually do not cause pain; however, once the cells become malignant they do tend
to involve neurological structures and cause pain [23]. Furthermore, squamous cell
cancers release high levels of nerve growth factor (NGF), and the treatment of these
factors with specific antibodies or nerve growth factor inhibitors have been shown
to decrease pain [23]. The extent that the nervous system plays in the development
of cancer pain continues to be studied. More research is needed to elucidate the
unique relationship of the immune system and nervous system in the development
of cancer-associated pain.

1.3 Cancer Pain Guidelines, Paradigm Shifts in Opioid

Management, and the Development of Interventional
Approaches and Targeted Analgesic Therapies

Traditionally, the gold standard in managing pain associated with cancer follows a
stepwise plan in accordance with the World Health Organization’s ladder of
analgesia. These guidelines were developed by clinicians that were largely experts
in pain medicine and palliative care from the 1950s to the 1980s and finally with
updates completed into the late 1990s [3]. Opioids have served as the mainstay of
treatment when it comes to cancer pain care. Nonetheless, current studies suggest
that patients with cancer have similar rates of risk for misuse, abuse, and addiction
as the general public [24]. When coupling this information with the graded increase
in survivorship and the perspective of cancer as a chronic illness, there has been a
perceptible paradigm shift. The prescription drug abuse crisis in the USA is a
complex topic, but perhaps one of the most important learning points from the crisis
is the view that clinicians who prescribe opioid therapy should consider themselves
as risk managers. The treatment of pain from cancer has been given a pass in most
contemporary opioid prescribing guidelines. However, cancer patients also suffer
from substance use disorders [24]. The new paradigm suggests that clinicians must
manage pain and risk, harnessing opioids when the benefits outweigh the risks, and
otherwise sparing opioid therapy when it is not the optimal choice. Essentially,
clinicians must remain vigilant of looming risks and always able to assess the risk
of pain versus the risk of treatment.
Non-opioid adjuvant treatments include Tylenol, NSAIDs, neuropathic agents,
NMDA receptor blockers, injections, and surgical procedures. For those patients
with cancer, these classes of medications and interventions were typically
10 D. J. Copenhaver et al.

recommended to be initiated once opioid titration therapy had been optimized—

balancing relief with side effects [23, 25].History has dictated a shift in cancer pain
treatment, as advanced cancer pain management has now relied on various inter-
ventions and medication strategies that are opioid sparing. In many cases, malignant
bone pain may not respond to opioid medications, and as such the following may be
used: NSAID, corticosteroids, bisphosphonates, radiopharmacologic drugs, oral
ketamine therapy, and calcitonin [23, 25]. We are learning cancer-related bone pain
has a direct correlation between the immune system and nervous system leading to
novel therapies such as nerve growth factor inhibitor [26]. Pain due to malignant
bowel obstruction may be reduced with the use of anticholinergic agents, octreo-
tide, and corticosteroids, which all may reduce pain and other symptoms such as
emesis [23, 25].
Plant-derived cannabinoids include THC and CBD [23]. These agents are cur-
rently under study and have been noted to both be analgesic and have anti-tumor
effects. Nabiximols (Sativex) is an oromucosal spray with a 50:50 ratio of THC:
CBD that has been shown to have some effect in relieving cancer-related pain [23].
The history of cancer pain treatment has demonstrated that although opioids may
be a necessary part of pain management in patients with cancer who are at the end
of life, not all will need them, and in some instances, pain may not be responsive to
opioid therapy. In such cases, there may be more effective alternatives to opioids.
For instance, pain from bone metastases is often more responsive to steroids or
NSAIDs than to opioids. Similarly, chest wall pain from a rib fracture, or pleural
tumor, is often more responsive to steroids or NSAIDs than to opioids. At times,
pain may be amplified by psychological etiologies, social stresses, or
spiritual/existential angst. Addressing these pain amplifiers may offer pain reduc-
tion. These biopsychosocial considerations are important to highlight even as the
literature may suggest that 70–90% of cancer-related pain is responsive to the use of
opioids [25]. As such, evaluation and treatment of such type of issues should be
directed to the appropriate experts.
When opioid therapy is prescribed, it is important to consider the use of urine
drug screens and to be particularly astute for results that do not show the opioid that
is being prescribed, as this may suggest an issue with the test or potential diversion.
Clinicians must also be cautious with frequent requests by the patient to increase
opioid dosage as this might indicate worsening pain, opioid tolerance, or potentially
drug abuse. Likewise, frequent prescriptions that are lost or misplaced, concurrent
use of other psychoactive substances, or failure to follow the recommended treat-
ment, may suggest aberrant drug use that needs further investigation.
For those patients who do not benefit in pain reduction with the use of opioid
medications, Davis et al. recommend the following: to those that have never
responded to the use of opioid medications [27], a taper should be instituted and the
sole use of non-opioid medications should be implemented. Furthermore, such
patients should be evaluated for spiritual and existential crises that may be con-
tributing to lack of improvement, as somatization may be present. Pain that, by its
very nature, does not respond to opioid analgesics will require adjuvant therapies
early in the course of treatment, in addition to non-pharmacologic options. Davis