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Practical Guide to
Chronic Pain
Syndromes
Practical Guide to
Chronic Pain
Syndromes
Edited by
Gary W. Jay
Pfizer, Inc.
New London, Connecticut, USA
Informa Healthcare USA, Inc.
52 Vanderbilt Avenue
New York, NY 10017
c 2010 by Informa Healthcare USA, Inc.

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No claim to original U.S. Government works

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10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 1-4200-8045-8 (Hardcover)

International Standard Book Number-13: 978-1-4200-8045-2 (Hardcover)
This book contains information obtained from authentic and highly regarded sources. Reprinted
material is quoted with permission, and sources are indicated. A wide variety of references
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author and the publisher cannot assume responsibility for the validity of all materials or for the
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Library of Congress Cataloging-in-Publication Data
Practical guide to chronic pain syndromes / edited by Gary W. Jay.

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Includes bibliographical references and index.
ISBN-13: 978-1-4200-8045-2 (hardcover : alk. paper)
ISBN-10: 1-4200-8045-8 (hardcover : alk. paper) 1. Chronic pain. I. Jay,
Gary W.
[DNLM: 1. Pain. 2. Chronic Disease. 3. Syndrome.
WL 704 P8949 2009]
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Foreword
Pain specialists, noninterventionalists, primary care physicians, medical special-

ists, fellows, residents, and medical students all want to make clinical decisions
about pain efficiently, often with an incomplete knowledge of underlying patho-
physiology, while addressing global needs of their patients. Pain management is
not part of the routine training for most physicians, yet the majority of patients
seek medical attention because they have pain. Pain is typically addressed by
primary care practitioners on an acute, time-limited basis, but when first- and
second-level strategies fail, patients are referred to pain specialists and/or dis-
ease or body system specialists for more thorough evaluation and management.
Primary care physicians, typically the first stopping point for patients in pain, as
well as specialists from anesthesiology, internal medicine subspecialties, neurol-
ogy, physical medicine, and psychiatry must be prepared to help people suffering
with chronic pain disorders.
Pain and other medical specialists as well as primary care physicians man-
aging patients having chronic pain know that usual acute pain management
strategies do not address complex needs of people having many years of con-
tinuous pain. Interventionalists focus on performing procedures intended to
interrupt pain processing, while medically oriented practitioners skillfully blend
multiple medications, many of which primary care physicians are not comfort-
able prescribing (especially methadone). The field of modern pain management
has become highly procedural, often relying upon opioids, involving the use of
polypharmacy and the management of patients within multidisciplinary pain
clinics.
Dr. Gary Jay and contributors to this book, Practical Guide to Chronic Pain Syn-
dromes, have collectively demystified chronic pain, bringing the management of
people with persisting pain into the understanding of pain medicine and other
specialists. The chapter authors have prepared essential reviews focusing on the
information most needed by specialists, fellows, residents, and medical students
to confidently and competently manage complex people in pain. In the vari-
ous pain disorder sections, chapters focus on common, but potentially vexing
painful disorders: soft tissue pain syndromes, neuropathic pain, rheumatologic
pain, urologic pain, back pain, cancer pain, end-of-life pain, and pain from other
causes. In the second section, pharmacologic options are discussed: nonopioid
analgesics and adjuvants, opioids, antidepressants, and anticonvulsants, with
special attention to the legal aspects for prescribing controlled substances.
Today’s specialists evaluating and treating people in pain are medical detec-
tives. They make sense out of painful complaints by following clues, seeing pat-
terns, laying their hands upon their patients, using scientific methods, while
v
vi Foreword
balancing clinical suspicion, intuition, and compassion. People living with

chronic pain may wish for absolute pain relief, but they are grateful for any pain
relief and the opportunity to receive care from clinicians demonstrating concern
and ability.
Practical Guide to Chronic Pain Syndromes is a “go to” book when information is
needed concisely about some aspect of chronic pain. This book focuses on what
matters most for busy clinicians: presentation of chronic pain syndromes, com-
mon causes and underlying pathophysiologic mechanisms, differential diagno-
sis, diagnostic assessment methods (e.g., laboratory studies, imaging, and elec-
trodiagnostic testing), and recommended treatments. While much is said about
the importance of evidence-based treatment, for many chronic pain syndromes
there are limited well-controlled and randomized studies. The contributors have
taken care to keep their messages practical, and readers are sure to find this book
one they will keep close at hand.
B. Eliot Cole, MD, MPA

Montclair, New Jersey, U.S.A.
Preface
Chronic pain syndromes (CPS) are complex problems that present a major chal-
lenge to health care providers. They are biological, psychological, and sociolog-
ical in nature, may have an unclear etiology, and, frequently, poor responses to
therapy. CPS, if treated in a typical mono- or bimodality manner may not give
the patient the best treatment outcome, but as things are now, that may be the
best that can be done for these difficult patients. Even the definition of a CPS (of
any kind) may be considered unsettled, as some look at it as pain that persists
more than three months, while others consider chronic pain to begin after six
months. Pain that persists after physiological healing has occurred, typically in
three months, posttreatment, for example, tells us nothing new—it becomes an
entity in and of itself. The best way to treat it is to understand the complex inter-
actions of the pathophysiology of pain as well as the issues of the psychological
and sociological aspects of an individual patient’s pain, and deal with it all as
best as one can.
The purpose of this book is to give the practitioner the basics and more regard-
ing a number of important, not uncommon, CPS that pain specialists, as well as
other medical specialists see. Sometimes the most difficult issue is diagnosis—
Clinically speaking, pain is what the patient says it is, and it is up to the clinician
to determine what the patient means. Then the treatment phase begins and this
may engender the use/need of chronic opioids, physical therapy, and psycholog-
ical therapy—whatever it may take to help your patient’s chronic pain problems.
Chronic pain can be considered to be like diabetes or hypertension—a disease
that can be treated and controlled, but not necessarily cured.
Practical Guide to Chronic Pain Syndromes has been written for the noninterven-
tional pain specialist as well as for other physicians who treat chronic pain of
one, two, or multiple types. All of the pain syndrome chapters have information
on a specific disorder, the pathophysiology, the treatment, any evidence-based
medicine issues and, of course, up to date references.
I have elected to place the largest section, “Neuropathic Pain,” first. This is
followed by a section on probably the most common pain problems: the soft
tissue pain syndromes including myofascial pain and fibromyalgia. One of the
most frequently missed problems in my longer than a quarter century of patient
care is the piriformis syndrome, which is also discussed in detail. Mechanical and
neuropathic low back pain are also discussed in detail.
Many times, pain specialists are asked to deal with visceral pain syndromes
such as interstitial cystitis and vulvovestibulitis, which are discussed by experts,
along with prostatitis.
vii
viii Preface
Cancer pain and palliative care are ever-growing issues and separate chapters
dealing with both are included.
The section titled “Other Pain Syndromes” includes chapters on osteoarthritis,
electrical injury, and neurogenic thoracic outlet syndrome.
Finally, no book would be complete, practical, and useful if it did not include
a medications section.
I want to thank the many erudite, patient focused, and excellent contributors
to this textbook. It was an honor and a pleasure to work with you!
It was a long road to get to here, and I believe it has been well worth it for
the pain specialists, neurologists, anesthesiologists, physiatrists, urologists, rheu-
matologists, oncologists, general practitioners, internists, psychologists, nurses,
physical therapists, as well as the residents and fellows and others who may
benefit from the knowledge contained in these books.
Most of all, our patients should receive the ultimate benefit of this work.
Gary W. Jay, MD
Acknowledgments
First, as always, I want to thank my wonderful wife Suzanne and my incredi-

ble daughter Samantha for their love and patience with me during the extended
period of time I spent working on this book. Many thanks also go to Byron Scott,
R.Ph., my brother by choice, and one of the smartest and best people in the world
to talk to; David Longmire, MD, another brother by choice, for his rather droll wit
and strange ability to look just like my doppelganger with neither ability getting
in the way of his amazing knowledge of neurology (with, of course, special atten-
tion to the Autonomic Nervous System); to my new friends at Pfizer (you know
who you are) and, of course, to the thousands of patients I had the good fortune
to meet, diagnose and treat- you were all my best teachers. After 25 years of clin-
ical practice, when I made the choice to go into Pharma, I knew I would miss you
all and I do.
Finally, this book is dedicated to Jim Kapp, who left us all too soon.
ix
Contents
Foreword B. Eliot Cole . . . . v

Preface . . . . vii
Acknowledgments . . . . ix
Contributors . . . . xv
PART I NEUROPATHIC PAIN SYNDROMES

1. Diabetic Peripheral Neuropathy 1
Gordon Irving and Richard Irving
2. HIV/AIDS Neuropathy 15
Vasanthi Arumugam and Maurice Policar
3. Central Poststroke Pain 23

Gary W. Jay
4. Postherpetic Neuralgia 30
Rajbala Thakur, Annie G. Philip, and Jonathan C. Weeks
5. Management of Pain Related to Amputation 50

Steven Stanos
6. Pathophysiology of Complex Regional Pain Syndrome 62

Robert J. Schwartzman
7. Meralgia Paresthetica 81
Elizabeth A. Sekul
8. Compression Neuropathies 85
Gabriel E. Sella
9. Quantitative Clinical, Sensory, and Autonomic Testing

of Chronic Neuropathic Pain 102
David R. Longmire
PART II SOFT TISSUE PAIN SYNDROMES

10. The Myofascial Pain Syndrome 115
Gary W. Jay
xi
xii Contents
11. Piriformis Syndrome 140

Gary W. Jay
12. Fibromyalgia 144

Gary W. Jay
PART III LOW BACK PAIN

13. Low Back Pain and Sciatica: Pathogenesis, Diagnosis
and Nonoperative Treatment 181
Anthony H. Wheeler
14. Neuropathic Low Back Pain 206

Joseph F. Audette, Joseph Walker III, and Alec L. Meleger
PART IV GENITOURINARY PAIN SYNDROMES

15. Interstitial Cystitis 228
Neel Shah, Hossein Sadeghi-Nejad, and Robert Moldwin
16. Chronic Prostatitis/Chronic Pelvic Pain Syndrome—A Urologist’s

Perspective 242
Richard A. Watson and Hossein Sadeghi-Nejad
17. Female Chronic Pelvic Pain 261

Frank F. Tu, Sangeeta Senapati, Gregory Goldstein, and Alexandra Roybal
PART V CANCER PAIN AND PALLIATIVE CARE

18. Cancer Pain 271
Judith A. Paice
19. Palliative Care Pain Management 285

Kathleen Broglio
PART VI OTHER CHRONIC PAIN SYNDROMES

20. Chronic Pain Following Electrical Injury 301
Elena N. Bodnar
21. Neurogenic Thoracic Outlet Syndrome—A Biopsychosocial Approach

312
Allen J. Togut
22. Osteoarthritis 318

Thomas J. Romano
Contents xiii
PART VII MEDICATIONS

23. Nonopiate Analgesics and Adjuvants 327
Gary W. Jay
24. Opioid Medications and Correct Medical Usage—An Update 343

Gary W. Jay
25. Legal Issues in Pain Management 367

Jennifer Bolen
26. Antidepressant Medications 391

Gary W. Jay
27. Anticonvulsant Medications 397

Gary W. Jay
Index . . . . 407
Contributors
Vasanthi Arumugam Elmhurst Hospital Center, Mount Sinai School of

Medicine, Elmhurst, New York, U.S.A.
Joseph F. Audette Department of Physical Medicine and Rehabilitation,
Spaulding Rehabilitation Hospital, Harvard Medical School, Boston,
Massachusetts, U.S.A.
Elena N. Bodnar Electrical Trauma Program, Department of Surgery, The
University of Chicago, Chicago, Illinois, U.S.A.
Jennifer Bolen The Legal Side of Pain
R
, The J. Bolen Group, LLC, Knoxville,
Tennessee, U.S.A.
Kathleen Broglio New York University School of Medicine, Bellevue Pain
Center, New York, New York, U.S.A.
Gregory Goldstein Northwestern University, Evanston, Illinois, U.S.A.
Gordon Irving Swedish Pain and Headache Center and University of
Washington Medical School, Seattle, Washington, U.S.A.
Richard Irving Department of Electrical Engineering, University of
Washington, Seattle, Washington, U.S.A.
Gary W. Jay Clinical Disease Area Expert-Pain, Pfizer, Inc., New London,
Connecticut, U.S.A.
David R. Longmire Department of Internal Medicine, University of Alabama
at Birmingham School of Medicine, Huntsville Regional Medical Campus,
Huntsville, Alabama, U.S.A.
Robert Moldwin Pelvic Pain Center, The Arthur Smith Institute for Urology;
Long Island Jewish Medical Center, New Hyde Park, New York, U.S.A.
Alec L. Meleger Department of Physical Medicine and Rehabilitation,
Judith A. Paice Cancer Pain Program, Division of Hematology–Oncology,
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, U.S.A.
Annie G. Philip Department of Anesthesiology, University of Rochester
School of Medicine and Dentistry, Rochester, New York, U.S.A.
xv
xvi Contributors
Maurice Policar Elmhurst Hospital Center, Mount Sinai School of Medicine,

Elmhurst, New York, U.S.A.
Thomas J. Romano Private Practice, Martins Ferry, Ohio, U.S.A.
Alexandra Roybal Northwestern University, Evanston, Illinois, U.S.A.
Hossein Sadeghi-Nejad UMDNJ New Jersey Medical School, Newark;
Hackensack University Medical Center, Hackensack; and VA NJ Health Care
System, East Orange, New Jersey, U.S.A.
Robert J. Schwartzman Department of Neurology, Drexel University College
of Medicine, Philadelphia, Pennsylvania, U.S.A.
Elizabeth A. Sekul Medical College of Georgia, Augusta, Georgia, U.S.A.
Gabriel E. Sella Department of Community Medicine, Faculty of Medicine,
West Virginia University, Morgantown, West Virginia, U.S.A.
Sangeeta Senapati NorthShore University HealthSystem, Evanston, and
Pritzker School of Medicine, Chicago, Illinois, U.S.A.
Neel Shah UMDNJ New Jersey Medical School, Newark, New Jersey, U.S.A.
Steven Stanos Center for Pain Management, Rehabilitation Institute of
Chicago, Department of Physical Medicine and Rehabilitation, Northwestern
University Medical School, Feinberg School of Medicine, Chicago, Illinois,
U.S.A.
Rajbala Thakur Department of Anesthesiology, University of Rochester
Allen J. Togut The Commonwealth Medical College of Pennsylvania,
Wilkes-Barre, Pennsylvania, U.S.A.
Frank F. Tu NorthShore University HealthSystem, Evanston, and Pritzker
School of Medicine, Chicago, Illinois, U.S.A.
Joseph Walker III Department of Physical Medicine and Rehabilitation,
Richard A. Watson Touro University College of Medicine & Hackensack
University Medical Center, Hackensack; and UMDNJ New Jersey Medical
School, Newark, New Jersey, U.S.A.
Jonathan C. Weeks Department of Anesthesiology, University of Rochester
Anthony H. Wheeler Pain and Orthopedic Neurology, Charlotte, North
Carolina, U.S.A.
1 Diabetic Peripheral Neuropathy
Gordon Irving
Swedish Pain and Headache Center and University of Washington Medical School,
Seattle, Washington, U.S.A.
Richard Irving
Department of Electrical Engineering, University of Washington, Seattle,
Washington, U.S.A.
THE DISORDER
Diabetes is currently on the rise around the globe. In 2007, the estimated total
prevalence of diabetes (diagnosed and undiagnosed) in the United States was
7.8%, with the majority of affected individuals being 60 years and older. As the
rate of diabetes has increased there has been an associated rise in prevalence of
diabetic neuropathy (1).
Diabetic peripheral sensory polyneuropathy is one of the most common
ailments associated with diabetes. Although it is possible to reverse the effects
if treated early, diabetic neuropathy often results in permanent loss of function
and death of the small nerve fibers, most commonly affecting the feet. It affects
approximately 50% of the patients who have diabetes mellitus.
Despite its prevalence, the onset of symptoms is often mild and can go
unnoticed for long periods of time, with most patients not experiencing any pain.
However, approximately 11% experience chronic, painful symptoms (2).
Painful diabetic peripheral neuropathy (DPN) is associated with sub-
stantial patient burden due to interference with daily function, especially in
those with suboptimal pain management. The severity of neuropathic pain is
significantly associated with overall patient burden, employment disruption,
and productivity. Not surprisingly, most interference is reported to result from
reduced walking ability (3). The medical costs of DPN may account for up to
27% of the direct medical costs of diabetes, although the proportion due to pain
is unclear (2).
Neuropathy is present in over 80% of diabetic patients with foot ulcers.
Ulcers are more common because of decreased sensation perception of pressure
and impairment of the microcirculation and integrity of the skin. Muscle imbal-
ances may lead to anatomic deformities. Once an ulcer has occurred, aggressive
therapy and protective measures should be taken to avoid secondary infection.
The risk of lower limb amputation is high if there is a history of a previous foot
ulcer, neuropathy, peripheral vascular disease, or poor glycemic control (4).
DIAGNOSIS
The diagnosis of DPN is based on the history. The pain may be spontaneous, con-
tinuous, or intermittent and is often worse at night. It affects the long nerve fibers
1
2 Irving and Irving
of the extremities, so the pain tends to be felt first in the toes and may progress
to the hands. The pain is usually described as burning, stabbing, tingling, numb,
hot, cold, or itchy.
General Examination of the Feet

Visual inspection may reveal several abnormalities such as claw toes due to atro-
phy of the small intrinsic muscles, allowing unopposed action of the larger mus-
cles. Charcot arthropathy may be present and is characterized by a collapse of
the midfoot arch and bony prominences. Sweating may be diminished or absent
resulting in dry, scaly, cracked skin, allowing access to infection.
The feet or hands may reveal sensory abnormalities with diminution or
heightened perception to touch, pinprick sensation, or hot and cold. Allodynia
(nonpainful stimulation perceived as painful) may be present with patient com-
plaints of being unable to have their feet under the bedclothes at night as the
pressure of the sheet irritates them.
Testing Methods
r The Semmes-Weinstein monofilament is a simple calibrated nylon filament. It
is inexpensive, easy to use, and rapid and reproducible, with a specificity of
90%. It should be placed at right angles to the skin and the pressure increased
until it buckles. This indicates that a 10-g pressure has been applied. Unfor-
tunately, the sensitivity has been reported to be only 44% to 71% depending
on how many skin areas are tested, and the prevalence between examiners
varied between 3.4% and 29.3% (5).
r Vibration testing is done with a 128-Hz tuning fork placed at the bony promi-
nence at the base of the first toe and is quick and easy to do. The sensitivity
and specificity have been reported to be 53% and 99%, respectively (6). If no
vibration is felt, the diagnosis is probably DPN. Loss of vibration sense pre-
dicts a high probability of foot ulceration and has been suggested as predict-
ing mortality from diabetic complications (7, 8).
Pain Scales
There are several neuropathic pain scales, such as the Leeds Assessment of Neu-
ropathic Symptoms and Signs (LANSS) Pain Scale and the Neuropathic Pain
Scale, that have been devised to aid the diagnosis. Young et al. described the
simple patient-completed questionnaire below (9).
1. What is the type of sensation felt? (maximum 2 points)
a. Burning, numbness, or tingling (2 points)
b. Fatigue, cramping, or aching (1 point)
2. Where is the location of symptoms? (maximum 2 points)
a. Feet (2 points)
b. Calves (1point)
c. Elsewhere (no points)
3. Have the symptoms ever awakened you at night?
a. Yes (1 point)
4. When is the pain worse? (maximum 2 points)
a. At night (2 points)
b. Day and night (1 point)
c. Present only during the day (0 points)
Diabetic Peripheral Neuropathy 3
5. What makes the pain better? (maximum 2 points)

a. Walking around (2 points)
b. Standing (1 point)
c. Sitting or lying or no relief (0 points)
Total score:
0–2: Normal
3–4: Mild
5–6: Moderate
7–9: Severe
Additional Tests
Nerve conduction velocity (NCV) tests may be normal, as they only measure
large fiber function and the majority of abnormalities are at the small fiber level.
Thermal thresholds in isolation or as part of quantitative sensory nerve
testing may be more appropriate indicators of dysfunction of small-diameter sen-
sory nerve fibers but are not widely available. Nerve or skin biopsies are useful
only where the etiology is unclear or for research purposes.
Corneal confocal microscopy is a noninvasive evaluation of the middle
layer of the cornea at a depth of 62 ␮m. Pictures taken of the corneal fiber den-
sity in this layer have been reported to closely correlate with the peripheral fiber
density as measured by the much more invasive skin biopsy (10).
If the presentation of neuropathy is not symmetrical, another cause should
be considered. Other differential peripheral neuropathic pain diagnoses to con-
sider include the following:
r Entrapment neuropathy
r Alcoholism
r HIV infection
r Paraneoplastic syndrome
r Monoclonal gammopathy
r Vitamin deficiencies
r Amyloidosis
r Drugs and toxins: vincristine, cisplatin, isoniazid, arsenic, thallium
r Vasculitic neuropathy
r Fabry disease
PATHOPHYSIOLOGY
The pathophysiology of DPN is complex and not fully understood. Most theories
involve interactions between metabolic and ischemic factors have been shown to
create nerve damage. Several studies have begun to uncover the specific patho-
genesis of diabetic neuropathy.
Hyperglycemia
By comparing animal axonal models that mimic the human disorders, it has
become clear that hyperglycemia, or insulin deficiency, is a major culprit of DPN
(11). The resulting damage occurs in DPN for both type 1 and type 2 diabetics.
Common metabolic factors include the following:
r Advanced glycosylation end products—Glycosylation of tissue and plasma pro-
teins can result in advanced glycosylation end products, which tend to
4 Irving and Irving
increase in concentration in diabetic patients. These end products are thought

to play a major role in diabetic microvascular complications.
r Sorbitol—Glucose metabolism is more pronounced in patients with hyper-
glycemia. Accumulation of sorbitol interferes with cell metabolism by raising
cell osmolarity and decreasing intracellular myoinsitol.
r Oxidative stress—Reduced antioxidants and prolonged exposure to reactive
oxygen species lead to peripheral nerve damage and degeneration.
In the more severe type 1 DPN, insulin and C-peptide deficiencies augment
the deficits in Na+ /K+ -ATPase and endothelial nitric oxide. These deficiencies
result in gene regulatory abnormalities of neurotrophic factors, their receptors,
and cell-adhesive proteins (12).
Disease Progression
In both experimental models and human diabetic subjects, there is an initial
metabolic phase that is responsive to metabolic corrections. During this ini-
tial phase, damage, as caused by the processes described above, can often be
reversed (13).
Progression of disease leads to a structural phase that is increasingly nonre-
sponsive to therapeutic interventions. Abnormalities during the structural phase
add to the severity of axonal pathology and result in severe consequences with
respect to nerve function (14).
Metabolic Changes
One of the earliest metabolic abnormalities is shunting of excessive glucose
through the polyol pathway, resulting in intracellular accumulation of sorbitol
and fructose with depletion of other osmolytes such as taurin and myoinos-
itol. The latter interferes with phosphoinositide turnover, resulting in insuffi-
cient diacylglycerol for activation of Na+ /K+ -ATPase. In type 1 DPN, the more
severe effect on Na+ /K+ -ATPase is accounted for by additional insults caused
by insulin and C-peptide deficiencies (15).
Unmyelinated fiber abnormalities occur early and are reflected in thermal
hyperalgesia and allodynia. Damage to small myelinated A␦ and unmyelinated
C-fibers underlies these functional abnormalities, which translate to abnormal
pain sensation—a common symptom in diabetic patients with DPN. Damage to
the axonal membranes of C-fibers induces increased formation of Na+ channels
and ␣-adrenergic receptors, facilitating ectopic discharges (16, 17).
The initial damage to small peripheral fibers appears to be coupled with
impaired neurotrophic support by nerve growth factor and insulin, itself, both
of which are specifically neurotrophic for small nociceptive ganglion cells of the
dorsal root ganglia. This may explain the more severe degenerative changes of
these fibers in type 1 versus type 2 diabetes (18).
TREATMENT
Prevention of Progression of DPN

Currently, DPN is treated symptomatically, but studies have shown a link
between glycemic control and microvascular complications such as neuropathy.
Although there does not appear to be a close link to pain control, getting the
HbA1c down to 7or less should be a priority.
Encouraging the patient to develop a list of achievable goals may assist
with lifestyle changes. These goals should include, where relevant, smoking ces-
sation, weight loss, and regular exercise. Getting the patient to want to change
and to believe he or she can change may require a different type of therapeutic
approach such as motivational interviewing (19).
Described in this section are several nonpharmacological and pharmaco-
logical treatments that have been shown to be effective in a number of trials. By
one estimate, most therapies for DPN result in a 30% to 50% reduction in pain.
This level of improvement may be disappointing to patients (20).
Nonpharmacological Treatment
There are several nonpharmacological treatments that have been shown to have
some efficacy in small trials. Treatment should also include foot care.
Transcutaneous Electrical Nerve Stimulation

TENS versus sham stimulation had positive results in 31 patients (21). Pain,
numbness, and allodynia improved significantly in a small, randomized, double-
blind study of 19 patients with mild to moderate DPN in the group treated with
TENS (22).
Acupuncture
There have been no large placebo-controlled studies evaluating the efficacy of
acupuncture for DPN, but small open-label trials have reported some benefit (23).
Spinal Cord Stimulation

Spinal cord stimulation has been reported to provide long-term relief for some
patients with DPN, but there have been no placebo-controlled studies (24).
Transcranial Magnetic Stimulation

TMS is a noninvasive technology whereby an electric current is passed through
an insulated circular or figure-eight coil to produce a magnetic pulse. When the
coil is applied to the head, the magnetic pulse is capable of passing uninterrupted
through the skin, skull, and ultimately to the cortex.
Repetitive transcranial magnetic stimulation (rTMS) has been shown to
produce long-lasting effects in some small-scale clinical trials. According to one
trial, it might be effective in alleviating DPN (25).
Foot Care Advice

When discussing the care of the DPN foot, advice should include the following:
1. Avoiding walking barefoot.
2. Wearing well-fitted, not tight shoes.
3. Feeling the inside of the shoes before putting them on in case there is a stone
or anything that may cause skin damage.
4. Washing feet twice a day to ensure that patients examine their feet at least
that often.
6 Irving and Irving
5. The importance of careful nail cutting, even having a podiatrist do the cutting
to avoid cutting the skin.
6. Treating all blisters and abrasions early.
Pharmacological Treatment
Frequently, patients take more than one drug for their pain. A cross-sectional,
community-based survey of 255 patients with DPN found that a majority of
patients (79.2%) had taken at least one medication and more than half (52.1%)
had taken at least two for DPN during the preceding week (26).
Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most com-
monly used medications, with 46.7% reporting their use, although there is lit-
tle evidence to support their efficacy. NSAIDs have a high potential for renal
impairment in patients with diabetic neuropathy. Other frequently used med-
ications were short- and long-acting opioids (43.1%), anticonvulsants (27.1%),
second-generation antidepressants (18%), and tricyclic antidepressants (TCAs)
(11.4%) (26).
Acetyl-L-Carnitine
Acetyl-l-carnitine (ALC) has reported beneficial effects on the metabolic abnor-
malities underlying the acute nerve conduction velocity slowing in experimental
diabetes, such as Na+ /K+ -ATPase activity, endoneurial blood flow, and oxida-
tive stressors (27).
A European and North American multicenter trial of 1346 patients with
type 1 and type 2 diabetes and DPN received ALC, either 1500 or 3000 mg/day.
None of the NCV or amplitude measures showed any significant improvement,
but vibratory perception in the lower and upper extremities showed highly sig-
nificant improvements. Pain also improved significantly in patients taking ALC
3000 mg/day both at 26 weeks and at the end of the trial at 52 weeks. Sural nerve
biopsies also demonstrated increased nerve fiber regeneration (28).
ALC has a good safety profile and should be considered early in the dis-
ease, as results appear to be better the earlier the patient is treated (29).
ACE Inhibitors
The ACE inhibitor trandolapril was shown to improve peripheral neuropathy
even in normotensive patients with diabetes. In general, the ACE inhibitor class
of medications appears to have some protective effect against microvascular
complications and organ damage from diabetes (30).
Lipid-Lowering Agents
Hypertriglyceridemia is a risk factor for development of diabetic neuropathy,
and there is evidence that lipid-lowering agents may prevent DPN microvascular
complications (31).
The lipid-lowering HMG-CoA reductase inhibitors (statins) may also pos-
sess neuroprotective properties in their own right (32).
Aldose Reductase Inhibitors

Metabolism of blood glucose via the polyol pathway, where aldose reductase
is a key enzyme, may be important in the development of diabetic neuropathy.
Therefore, blocking aldose reductase may reduce this risk of diabetic neuropathy.
In a one-year, placebo-controlled study, the aldose reductase fidarestat has

been reported to be superior to placebo for reducing pain as well as the progres-
sion of peripheral diabetic neuropathy (33).
A postmarketing surveillance of more than 5000 patients on epalrestat,
another aldose reductase inhibitor, was reported to show improvement of
subjective symptoms, including spontaneous pain, in patients with DPN (34). In
a three-year study, epalrestat was effective in slowing down the development
of neuropathy as measured by changes in median nerve conduction velocity
compared with controls. However, there was no significant difference in pain
between the treated and untreated group (35).
␣-Lipoic Acid
A meta-analysis of 1258 patients with DPN reported that infusions of ␣-
lipoic acid (600 mg/day intravenously) ameliorated neuropathic symptoms and
deficits after three weeks (36).
The ALADIN III (Alpha-Lipoic Acid in Diabetic Neuropathy) study
showed that oral treatment with 600 mg three times a day resulted in a favor-
able effect on neuropathic deficits after six months (37).
The SYDNEY 2 (Symptomatic Diabetic Neuropathy 2) trial suggests that
treatment for five weeks using 600 mg of ␣-lipoic acid orally every day reduces
the paresthesias and numbness to a clinically meaningful degree (38).
All studies have reported a highly favorable safety profile. The drug is
licensed in Germany, but not in the United Kingdom or the United States, for
the treatment of DPN; however, it is sold as a food supplement in the latter two
countries.
Tricyclic Antidepressants
Despite their widespread use, none of the TCAs has been approved by the FDA
for treatment of DPN or any type of pain. A review found the total number of
patients in clinical trials of the various TCAs for treatment of DPN to be less than
200, with no single study having more than 50 patients (39). That review found no
difference in efficacy among the various kinds of TCAs, with an number needed
to treat (NNT) of 3 (95% CI, 2.4–4.0) for improvement of pain of 50% or more. A
2005 Cochrane Collaborative analysis of five diabetic neuropathic pain trials of
antidepressants reported that the NNT for amitriptyline’s effectiveness was 1.3
(95% CI, 1.2–1.5; relative risk, 12.4; 95% CI, 5.2–29.2) (40).
Amitriptyline is the best studied TCA in DPN; other agents in this class
include imipramine, clomipramine, desipramine, and nortriptyline. Their anal-
gesic effect is independent of their antidepressant effect. Analgesia is thought to
be the result of the inhibition of serotonin and norepinephrine reuptake, as well
as sodium channel modulation.
The pain-relieving effect of amitriptyline is correlated with the total plasma
concentration. If the plasma concentration exceeded 300 nmol/L, 70% of patients
were responders on the daily rating of pain and 90% were responders on
the global rating. Only 20% were responders at plasma concentrations below
300 nmol/L. This is lower than the reported corresponding level for the treat-
ment of depression, which is 500 nmol/L (41).
Because of variable absorption, blood levels of amitriptyline should be
taken. In a randomized controlled trial (RCT) of amitriptyline, it was found that
total plasma levels of amitriptyline at a daily dose of 75 mg/day ranged from
56 to 925 nmol/L (42).
8 Irving and Irving
TCAs have a considerable adverse event burden. Ray et al. reported a slight
increase in sudden cardiac death with TCA doses greater than 100 mg/day. There
was no evidence that TCA doses lower than 100 mg increased the risk of sudden
cardiac death (43). This is of obvious concern in the patient with diabetes who has
a higher risk of heart disease. Some authors recommend baseline and follow-up
electrocardiograms (ECGs) throughout treatment with TCAs (44).
Serotonin Norepinephrine Reuptake Inhibitors

There is general agreement that serotonin norepinephrine reuptake inhibitors
(SNRIs) such as duloxetine, velafaxine and the newer SNRI’s milnacipran,
desvenlafaxine and venlafaxine are safer to use than TCAs and are a better option
in patients with cardiac disease. However, the risk of hyponatremia due to the
syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is thought
to be greater in elderly patients using selective serotonin reuptake inhibitors
(SSRIs/SNRIs) than in those using TCAs (45). Hyponatremia should be consid-
ered in all patients who develop drowsiness, confusion, or convulsions while
taking an antidepressant.
Venlafaxine
Results for the primary end point of pain intensity on the VAS showed that the
150 to 225 mg of venlafaxine ER significantly reduced pain intensity compared
with placebo at week 6. Results with 75 mg were not different from those with
placebo (46).
Another trial compared venlafaxine with imipramine for treatment of
painful neuropathies. Treatment with either venlafaxine or imipramine signifi-
cantly reduced pain compared with placebo; no significant difference was seen
between the venlafaxine and imipramine groups (47).
In a multicenter, prospective, open-label study of 97 patients older than
80 years with depressive syndrome, not DPN, extended-release venlafaxine was
found to be safe and effective in the elderly. Adverse events were reported by
seven patients, but no serious events were reported. The most frequent adverse
events were dizziness, gastric pain, and nausea. Treatment with venlafaxine over
24 weeks did not produce any clinically significant changes in blood pressure,
heart rate, or other variables. The authors suggest that venlafaxine is particu-
larly useful in the treatment of the elderly due to a low potential for drug–drug
interaction (48).
Duloxetine
The efficacy of duloxetine in the treatment of DPN was established in three
double-blind, placebo-controlled RCTs that included a total of 1139 patients.
Patients with comorbid depression were excluded (49, 50).
The FDA-approved dosage of duloxetine 60 mg daily demonstrated rapid
onset of action (within the first week of treatment) and sustained pain relief. All
doses of duloxetine were well tolerated, with no significant changes in concen-
trations of hemoglobin A1C or triglycerides. Adverse events that were reported
more often in the duloxetine group than in the placebo group were somnolence
and constipation; these were mild to moderate (51).
Milnacipran and Desvenlafaxine

There have been no studies reported as yet on the efficacy of these drugs on DPN.
Antiepileptic Drugs
In the elderly, antiepileptic drugs may cause significant central nervous system
side effects, especially dizziness and drowsiness, which not infrequently lead
to discontinuation of treatment. Cognitive side effects are common and may
go unrecognized in older patients, particularly in patients with communication
problems.
Pregabalin
The efficacy of pregabalin in DPN has been established in three double-blind,
placebo-controlled RCTs that included a total of 730 patients. It demonstrated
early and sustained improvement in pain and a beneficial effect on sleep with
dosages ranging from 150 to 600 mg daily. The most common treatment-related
adverse events in the 300- and 600-mg/day groups were dizziness (27.2% and
39%, respectively), somnolence (23.5% and 26.8%, respectively), and peripheral
edema (7.4% and 13.4%, respectively) (52–54).
Gabapentin
In one randomized trial of DPN, gabapentin was initiated at a dosage of 300 mg,
three times daily, and increased during a period of four weeks in increments
of 300 mg (from 900 to a maximum of 3600 mg/day). Beginning at week 2 and
continuing throughout the trial, patients treated with gabapentin showed statisti-
cally significant improvements in pain scores compared with those who received
placebo (55).
Sodium Channel Blockers

Sodium channel blockers have not been shown to be effective in patients with
painful diabetic neuropathy. Carbamazepine cannot be recommended due to
inadequate evidence in painful diabetic neuropathy. The successor drug, oxcar-
bazepine, has been withdrawn from clinical trials because of lack of efficacy (56).
Neither topiramate nor lamotrigine has been shown to be effective (57, 58).
Opioids
The weak opioid, tramadol, is effective in painful DPN, but more severe pain
often requires stronger opioids such as oxycodone (59). Two trials over four and
six weeks have demonstrated significant pain relief and improvement in quality
of life following treatment with controlled-release oxycodone, in a dose range of
10 to 100 mg (mean 40 mg/day). In these trials, antidepressants and anticonvul-
sants were not discontinued throughout the trial. As expected, adverse events
were frequent and typical of opioid-related side effects (60, 61).
Combination therapy is common in treating DPN but has been poorly
researched. In a study that titrated the maximum tolerable dose of a combina-
tion treatment of gabapentin and morphine compared with monotherapy of each
drug, the maximum tolerable dose was significantly lower but efficacy was bet-
ter, suggesting an additive interaction between the two drugs (62).
Isosorbide Dinitrate Spray

In a study of 22 DPN patients, 11 patients using topical isosorbide dinitrate had
benefit and continued with the spray before bedtime compared with only four
patients receiving placebo. There were virtually no adverse effects (63).
10 Irving and Irving
TABLE 1 Pharmacological Treatment Tier Recommendations
Dworkin et al. Attal et al. Argoff et al. Moulin et al.

Drug (66) (67) (68) (69)
Antidepressants
TCA 1 1 1 1
Duloxetine NR 2 1 2
Venlafaxine 2 2 2 2
Bupropion 2 NR —a NR
Paroxetine 2 NR NE NR
Citalopram 2 NR NE NR
Antiepileptics
Gabapentin 1 1 2 1
Pregabalin 1 1 1 1
Lamotrigine NR NR 2 NR
Valproate NR 2 NR 4
Topiramate NR NE NR 4
Phenytoin NR NR —a NR
Opioids
Tramadol 1 2 2 3
Oxycodone/methadone 1 2 1 3
Topicals
Lidocaine 5% 1 2 —b 2
Capsaicin 3 2 —b 3
Others
Mexilitine 3 NE NR 4
Clonidine 3 NE NR 4
1 = first tier, 2 = second tier, 3 = third tier, 4 = fourth tier.

a >1 RCT.
b Mechanism of action.
Abbreviations: NR, no recommendations; NE, not considered effective.
Local Anesthetics
Lidocaine 5% patches may be effective for treating patients with DPN (64, 65).
Some patients find that cutting the patch and wrapping it around their toes and
then putting socks on will decrease their nighttime pain and allow a better night’s
sleep.
Summary of Pharmacological Treatments

There have been three published task force recommendations for pharmacolog-
ical therapies in neuropathic pain and one consensus guidelines published on
DPN. Drugs were evaluated and ranked based on recommendations from tier
1 to 4, with tier 1 drugs being the most recommended, as shown in Table 1.
Comorbidities
When deciding which medication to choose, other factors must play a role.
r Obesity: Avoid or monitor carefully TCAs or a gabapentinoid (gabapentin,
pregabalin), all of which have significant risk of weight gain.
r Poor sleep: Consider any of the tier 1 medications in Table 1.
r Smoking: To encourage smoking cessation consider bupropion to assist in
decreasing withdrawal symptoms.
r Polypharmacy: Consider a gabapentinoid and/or venlafaxine.

r Depression or anxiety: Consider duloxetine, venlafaxine, or TCAs because of
fewer drug to drug interactions.
Surgical Treatment
If the presentation of pain is atypical, with pain felt over individual nerve der-
matomes, entrapment neuropathy should be considered. A Tinel sign should be
looked for over the deep peroneal or posterior tibial nerve. The superficial per-
oneal nerve, as it goes around the head of the fibula, may also be tender to touch,
leading to a possibility of entrapment at this site. Although there are advocates of
decompression in these cases, there is controversy as to whether surgical nerve
decompression surgery is effective (70, 71).
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2 HIV/AIDS Neuropathy
Vasanthi Arumugam and Maurice Policar
Elmhurst Hospital Center, Mount Sinai School of Medicine, Elmhurst,
New York, U.S.A.
THE DISORDER
There are several forms of peripheral neuropathy related to HIV/AIDS, but the
most common is distal sensory polyneuropathy (DSP). DSP has become the most
frequent neurologic syndrome associated with HIV infection, and the pain asso-
ciated with this condition can be debilitating. Several factors such as age, use
of antiretroviral medication (ARV), severity of HIV infection, diabetes, and alco-
hol abuse have been related to an increased risk of developing DSP (1). However,
studies of subgroups who received highly active antiretroviral therapy (HAART)
have not shown a relationship between virologic and immunologic status, and
the development of symptomatic sensory neuropathies (2). There are two sub-
types of DSP: the type solely associated with HIV infection and the type associ-
ated with antiretroviral treatments, sometimes referred to as antiretroviral toxic
neuropathy (ATN) (3). When caused by ARV, the clinical presentation may be
the same except for a temporal relationship with ARV use. Neuropathy in HIV
can also result from other causes, such as chronic hepatitis C infection, vitamin
deficiency, or chemotherapy.
Occurring in the middle and late stages of HIV infection, DSP commonly
presents as painful feet. Neuropathy related to ARV toxicity may occur at any
stage of HIV infection. When DSP is caused by medications, the most common
culprits are antiretroviral agents, but medications such as dapsone, isoniazid,
and chemotherapeutic agents have also been implicated. Nucleoside reverse
transcriptase inhibitors (NRTIs) are the class of drugs most frequently associated
with peripheral neuropathy.
Prevalence
The prevalence of DSP varies from 9% to 63% in different series (4). Although the
incidence has progressively decreased since the introduction of HAART (5), DSP
has become more prevalent. This increase in prevalence is most likely due to the
increased survival of those infected with HIV, the occurrence of comorbidities
with similar complications, and the use of antiretroviral therapy (6).
DIAGNOSIS
The diagnosis of the peripheral neuropathy syndrome in HIV-infected patients
is generally based upon the clinical picture.
DSP commonly presents as tingling and numbness in the toes bilaterally,
and then gradually spreads proximally from the lower extremities, rarely involv-
ing the upper extremities. Early painful dysesthesias of the lower extremities
are common, but patients may also complain of numbness. These symptoms
15
16 Arumugam and Policar
are typically most severe on the soles of the feet and are worse at night or after
walking (7). There is sensory loss in a stocking distribution, and ankle jerks are
decreased or absent. Knee jerks are occasionally decreased and may be absent
in severe cases. Vibratory, pain, and temperature sensation is usually decreased,
but muscle weakness is not a prominent symptom of DSP and generally occurs
only in advanced disease.
Compared with DSP that is related to HIV infection, that related to
antiretroviral toxicity is indistinguishable, except for the temporal relationship
of ARV use with onset, and eventual resolution with discontinuation. Whereas
HIV-related DSP may take weeks to months to develop, ATN generally occurs
shortly after exposure and may not be related to cumulative exposure to ARV (8).
Specific agents in the NRTI class are most commonly associated with DSP, par-
ticularly the so-called “d” drugs: ddI (didanosine), ddC (zalcitabine), and d4T
(stavudine). As a result of the frequency of ATN, and other adverse drug reac-
tions, prescribing patterns in the developed world have changed to limit the use
of these agents. In developing countries, however, ARV regimens still commonly
contain stavudine. Concern about a possible relationship of ATN and the class of
ARV known as protease inhibitors led to a recent study by Ellis and colleagues.
The investigators concluded that the independent risk of DSP attributable to pro-
tease inhibitors, if any, is very small (9).
It can be clinically difficult to distinguish between HIV-associated and
drug-induced neuropathy. Numbness, tingling, and pain are common in both
types. Both predominantly affect the distal extremities, mostly in the lower limbs.
The upper extremities may become involved late in the course and may be more
commonly affected with drug toxicity. A beneficial response after withdrawal of
the offending agent can help identify ARV as the cause. It has been noted that
a transient intensification of symptoms (“coasting”) can occur for four to eight
weeks after drug withdrawal and before improvement begins (6).
In patients with significant weakness, or an asymmetric presentation,
additional diagnoses should be considered. Electrodiagnostic studies including
electromyography and nerve conduction studies may be helpful when there
is doubt about the diagnosis (4). Nerve biopsy is rarely indicated, and a skin
biopsy may be helpful in some cases. A careful history of antiretroviral therapies
with a review of other medications should be done to exclude possible iatrogenic
causes.
Laboratory evaluation in DSP is relatively unrevealing, but it should
exclude other causes of this type of neuropathy. Testing should include the fol-
lowing:
Vitamin B12 and folate levels

Thyroid-stimulating hormone assay
Fasting blood sugar
Liver function tests
Blood urea nitrogen and creatinine
Serum protein electrophoresis and immunoelectrophoresis
Screening test for syphilis
Electrophysiologic findings show small or absent sural sensory nerve acti-

vation potentials. Nerve conduction studies usually confirm a length-dependent
HIV/AIDS Neuropathy 17
axonal polyneuropathy. Needle electromyography shows acute or chronic partial

denervation of distal lower limb muscles.
Nerve biopsy is rarely indicated to exclude other neurologic diagnoses.
Features include loss of myelinated and unmyelinated fibers with axonal degen-
eration and macrophage activation (10).
Skin biopsy may be positive in some patients with negative electrodiagnos-
tic studies (4).
The presence of a low epidermal nerve fiber density (<11 fibers/mm) has
been noted in persons with DSP. This finding was associated with an increased
likelihood of developing DSP in one study (11).
PATHOPHYSIOLOGY
The pathogenesis of DSP is not well understood and is thought to be
multifactorial.
There is little evidence to support direct infection of the neurons by
HIV-1, suggesting that this is not likely to be an important mechanism for neu-
ronal injury (12). In vitro studies suggest roles for viral proteins such as gp120 in
the indirect stimulation of axonal degeneration and/or cell death (3).
The envelope glycoprotein gp120 may produce neurotoxicity within the
dorsal root ganglion, and in vitro studies have suggested that gp120 induces
apoptosis in rodent dorsal root ganglion cultures and lowers the threshold for
excitation (7).
Neuropathologic changes of the dorsal root ganglia include inflammatory
infiltrates of lymphocytes and activated macrophages and low numbers of neu-
rons. The amount of macrophage activation in the dorsal root ganglion relates
with symptomatic DSP (7).
The prominent presence of proinflammatory cytokines including
TNF-alpha, interferon alpha, interleukin 6, and other inflammatory media-
tors including nitric oxide has been shown in dorsal root ganglia in AIDS. This
may lead to neuronal hyperexcitability as has been seen in animal models (7).
In patients receiving NRTIs, therapy interferes with DNA synthesis and
causes mitochondrial abnormalities (13). These abnormalities are thought to
underlie the pathogenesis of antiretroviral-related DSP. This view is supported
by the evidence showing increased serum lactate concentrations and decreased
serum concentrations of acetylcarnitine in patients with this condition (7). Ele-
vated blood lactate levels occurred in 90% of those with DSP who were using
stavudine (14).
A prospective study of 509 patients again identified older age and receipt
of stavudine and didanosine as being more frequent in those developing DSP,
but the mitochondrial haplogroup T was also more frequent in this group (15).
TREATMENT
Distal Sensory Polyneuropathy

Management of DSP is largely symptomatic and usually aimed at ameliorat-
ing the painful dysesthesias. Correcting nutritional and metabolic abnormalities
when present may be helpful. Various classes of medication have been used in
the treatment of DSP.
Tylenol/NSAIDs
Acetaminophen or nonsteroidals (NSAIDs) are the initial treatment for mild
pain. If this is inadequate, other treatment should be considered.
Tricyclic Antidepressants
Tricyclic antidepressants are still used for the treatment of HIV-associated neu-
ropathies, despite the absence of efficacy noted in two small studies (16, 17).
Either nortriptyline or amitriptyline may be used. In patients who experience
nighttime pain primarily, amitriptyline is a sound alternative. Treatment may
be initiated with lower doses to reduce possible side effects such as sedation,
urinary retention, dry mouth, and orthostatic hypotension. A starting dose of
25 mg at night is gradually increased to 75 mg or as high as 100 to 150 mg if
needed. For patients with daytime pain, oral nortriptyline is often used, since it
has a less sedative effect. A starting dose of 10 mg/day is gradually increased to
30 mg three times a day.
Anticonvulsants
Gabapentin
Gabapentin has been widely used in the treatment of DSP. The use of gabapentin
for the treatment of painful HIV-related neuropathy was found to reduce pain
better than placebo in small groups of patients in two studies (18, 19). Beneficial
effects begin with higher doses. The usual starting daily dose is 300 mg/day in
three divided doses, but doses can be increased to a maximum of 3600 mg/day.
Slow escalation of doses should allow for tolerance to side effects such as som-
nolence and dizziness.
Pregabalin
Pregabalin is an anticonvulsant designed as a more potent successor to
gabapentin. Although pregabalin may be used for the treatment of patients
with HIV-associated painful peripheral neuropathy, a randomized, double-blind,
placebo-controlled study (20) showed no long-term difference in end point mean
pain score between pregabalin and placebo groups. Important to note is that
there was a larger-than-usual placebo effect in this study compared with simi-
lar studies, possibly negating the effect of pregabalin.
Lamotrigine
Lamotrigine has also been studied in HIV-DSP. In a randomized, placebo-
controlled trial (21), lamotrigine alone showed improved pain control over
placebo, but only in patients receiving neurotoxic antiretroviral therapy. There
was a seven-week dose escalation phase, followed by a maintenance phase. In a
different double-blind, placebo-controlled trial (22), lamotrigine, 200 to 400 mg
daily, when used in combination with other medications for neuropathic pain,
did not demonstrate medication efficacy better than placebo.
Other Agents
Memantine
The use of memantine for the treatment of HIV-associated peripheral neuropa-
thy was evaluated in a placebo-controlled study enrolling 45 subjects. This
N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of

Alzheimer’s disease was not effective at reducing HIV-associated peripheral
neuropathy (23).
Prosaptide
A randomized trial evaluating the polypeptide prosaptide for HIV-associated
sensory neuropathies (24) showed that, although prosaptide was safe, it is not
an effective agent in the treatment of HIV-associated peripheral neuropathy.
Tramadol
Tramadol 50 mg po bid or narcotics are reserved for those with breakthrough
pain, as part of a broader treatment regimen. In refractory cases of peripheral
neuropathy, the patient may respond to combinations of medications.
Topical
Lidocaine gel
In a double-blind, placebo-controlled multicenter study, lidocaine 5% gel was a
safe but ineffective agent in the treatment of pain in HIV-associated DSP (25). The
gel was applied once daily to skin over the area of pain.
Capsaicin patch
A double-blind multicenter study randomized 307 subjects with HIV-related
peripheral neuropathy to compare high-concentration capsaicin patch versus a
low-concentration capsaicin patch. The high-concentration patch had a greater
reduction of pain intensity over a 12-week period, 23% versus 11% (26), when
applied for 30 to 90 minutes once daily.
Cannabis
Cannabis may be useful in the management of painful HIV-associated sensory
neuropathy. A prospective, randomized, placebo-controlled trial of 50 patients
with painful HIV-associated sensory neuropathy (27) showed that smoked
cannabis reduced daily pain better than placebo (34% vs. 17%). Fifty-two per-
cent of the group treated with cannabis reported a reduction in pain greater than
30% as opposed to the placebo group who experienced a 24% reduction in pain.
The first cannabis cigarette reduced chronic pain by a median of 72% vs. 15%
with placebo ( p < 0.001). The patients smoked up to one cigarette three times a
day, containing approximately 1 g of cannabis with 3.56% tetrahydrocannabinol
(THC).
Acupuncture
In a case series, 21 subjects with HIV-related neuropathy received acupuncture
treatment, which demonstrated that subjective pain and symptoms of neuropa-
thy were reduced during the period of acupuncture. The total subjective periph-
eral neuropathy summary score was reduced by approximately 50% (28).
Healing Touch
A review of anecdotal reports of healing touch (29) found that there are many
positive outcomes, but none of the findings were conclusive.
Plasmapheresis/Intravenous Gamma Globulin

Kiprov et al. (30) treated HIV neuropathy with plasmapheresis and intravenous
gamma globulin. It appears that the combination of plasmapheresis and intra-
venous gamma globulin was a potent immunomodulatory therapy for patients
with HIV-related neuropathy.
It has been recognized that unhealthy behaviors may be employed by
HIV-positive patients suffering from DSP. As part of a larger study on self-
care and HIV (31), investigators identified specific unhealthy self-care behaviors
such as cigarette smoking, alcohol consumption, and illicit drug use which were
employed to alleviate pain. It was concluded that the clinician must partner with
the patient to address any unhealthy behavior that may exacerbate DSP.
Antiretroviral Toxic Neuropathy

Treatment of ATN should include the discontinuation of drugs that cause periph-
eral neuropathy. About two-thirds of these patients will eventually respond to
the NRTI discontinuation.
Two large studies (32, 33) demonstrated the beneficial effect of using lamot-
rigine in patients with ATN rather than DSP. Dose escalation occurred over seven
weeks to reach a maximum of 400 to 600 mg/day in two divided doses.
Acetyl-l-carnitine has been used as treatment for painful ATN in HIV
patients. In an open-label study (34), acetyl-l-carnitine was found to be effective
in symptomatic treatment of painful neuropathy but had no observable effect on
neurophysiologic parameters. In another double-blind, placebo-controlled, mul-
ticenter study (35), investigators looked at acetyl-l-carnitine in the symptomatic
treatment of ATN. Using the Visual Analog Scale, acetyl-l-carnitine was found
to significantly reduce the subject’s pain rating in comparison to placebo.
Amitriptyline, mexiletine, topical capsaicin, 5% lidocaine, and gabapentin
may also be useful therapeutic modalities for treating ATN.
In a prospective study (36), 11 HIV/AIDS patients with a drug-induced
neuropathy were enrolled. Noninvasive skin electrodes were placed on the leg,
and low-voltage current was passed for 20 minutes every day for 30 days.
Although only seven individuals completed the study, the results support the
notion that low-voltage electroacupuncture improves the condition of the neuro-
pathic HIV/AIDS patient.
General Measures
Podiatrist evaluation (to develop plan of care, including exercise, care of feet,
etc.)
Loose shoes or no shoes
Soak feet
Short walks
Blanket bridge to protect feet while sleeping
Initiation of HAART may help in DSP
Vitamin supplements may be considered—mainly B1 , B12 , and folate
Other supplements including magnesium, ␣-lipoic acid, ␥ -linolenic acid
Avoidance of alcohol
Control blood sugar if applicable
Alternative therapy: massage, yoga, hypnosis, and meditation
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3 Central Poststroke Pain
Gary W. Jay
Clinical Disease Area Expert-Pain, Pfizer, Inc., New London, Connecticut, U.S.A.
THE DISORDER
Central poststroke pain (CPSP) was originally thought to be “thalamic” pain, as
described by Dejerine and Roussy (1), although it was described even earlier in
1883 (2). Dejerine and Roussy (1) characterized their eponymous thalamic pain
syndrome as including hemiplegia; hemiataxia and hemiastereognosis; difficul-
ties with both superficial and deep sensation; persistent, paroxysmal, typically
intolerable pain; and choreoathetoid movements. This syndrome is now known
as central poststroke pain syndrome.
DIAGNOSIS
The reported incidence of CPSP varies widely from 2% (3) to 8% (4) in stroke
patients and to 25% (5) in patients with lateral medullary infarctions (Wallen-
berg’s syndrome).
CPSP is broadly defined as central neuropathic pain, secondary to lesions
or dysfunction in the central nervous system. It is typically characterized by con-
stant or intermittent pain and sensory abnormalities, most commonly of thermal
sensation (6).
The pain is typically described as burning, scalding, or freezing and burn-
ing. Early diagnosis can be difficult, as the patients who develop CPSP may
develop the problem long after their cerebral vascular accident (CVA), causing
misdiagnosis or significant delay prior to treatment. Also, as these patients may
have cognitive or speech difficulties, as well as depression, anxiety, and sleep
problems, diagnosis may be further complicated. They may also develop sponta-
neous dysesthesias and stimulus-evoked sensory disturbances including dyses-
thesia, hyperalgesia, and allodynia (6, 7).
The onset of the pain may be immediate or be delayed for months to years
(7–9). In 40% to 60% of CPSP patients, the onset of their centrally related pain
post stroke may occur more than one month after the CVA (10). The pain may
encompass a large part of the contralateral body, but it may also involve only a
small area.
Sensory abnormalities are also associated with CPSP. These may include
altered sensory processing: warm and cold stimulation applied to the skin may
be perceived as paresthesias or dysesthesias rather than cold or warm (4,7). Allo-
dynia is found in 55% to 70% of patients (11, 12). Hyperalgesia and dysesthesia
are also frequently seen (13).
Evaluation of the CPSP patient may be more complex than that of the typ-
ical pain patient, at least in part for reasons noted above. The pain history must
be accompanied by a pain-specific sensory examination, musculoskeletal and
23
24 Jay
myofascial evaluation, and basic psychological evaluation. Specialized sensory

testing may also be needed, something that a neurologist can easily learn but
may need specialized tools (14).
PATHOPHYSIOLOGY
Locations of the lesions inducing the CPSP have been demonstrated to be refer-
able to the spinothalamocortical tract/pathway, typically associated with abnor-
mal evoked sensations in the peripherally affected area (10,15,16). While at least
three thalamic regions, which directly or indirectly receive spinothalamic pro-
jections, appear to be involved in the development of CPSP—the ventroposte-
rior thalamus including the posteriorly and inferiorly located nuclei bordering
on that region, the reticular nucleus, and the medial intralaminar region—it is
the ventroposterior thalamic region that is proposed to be most significantly
involved in central pain (17–19). It should also be noted that cerebrovascular
lesions located above the diencephalon, that is, in the parietal lobe, may also
induce CPSP (11,17,20).
While damage to the spinothalamocortical pathway appears to be a neces-
sary condition in CPSP, it is thought that the spontaneous pain linked to CPSP is
secondary to hyperexcitability or spontaneous discharges in thalamic or cortical
neurons that have lost part of their normal input (21).
CPSP is most typically associated with a single lesion, associated with
either a focal gray or white matter lesion; the lesion may be at the spinal, brain
stem, or cerebral level, but it is always contralateral to the pain of CPSP; CPSP
is associated with abnormal somatic senses, particularly thermal and/or pain
sensations—most commonly, a loss of sensation is seen, but one may also see an
exaggerated sensation of pain or temperature. The pain of CPSP may unilaterally
involve the contralateral (to the lesion) face, body, and extremities, or it may be
focal, involving only a limb, part of a limb, or the face; it is almost always within
the region of somatic motor or sensory impairment; it may begin at the time of
the CVA or be delayed for months (22).
Studies using magnetic resonance imaging and positron emission tomog-
raphy (PET) scan have demonstrated anatomical lesions and associated infor-
mation. One study using functional magnetic resonance imaging and diffusion
tensor imaging found that in CPSP, there is an important role of damage of lat-
eral nociceptive thalamoparietal fibers, along with release of activity of anterior
cingulate and posterior parietal regions (23). An older study using single-photon
emission computerized tomography found a contralateral relative hyperactivity
in a central region corresponding with the thalamic region in patients with CPSP
(24).
The “disinhibition hypothesis” of CPSP suggests that there is an excessive
response (including dysesthesias/hyperalgesia/allodynia) associated with a loss
of sensation secondary to a lesion of a “lateral nucleus” of the thalamic or “corti-
cothalamic pathways.” It was also thought that injury to a cool-signaling lateral
thalamic pathway disinhibits a nociceptive medial thalamic pathway, producing
both burning, cold, ongoing pain and cold allodynia. Using quantitatively evalu-
ated sensory testing, it was found that, in CPSP, tactile allodynia occurs in distur-
bances of thermal/pain pathways that can spare the tactile signaling pathways,
and that cold hypoesthesia itself is not necessary or sufficient for cold allodynia
(25).
Central Poststroke Pain 25
Another way of evaluating CPSP using PET scan technology revealed a

striking loss of opioid receptor availability widely distributed throughout a great
deal of the hemisphere contralateral to the pain (especially in the thalamus, ante-
rior and posterior cingulate cortex, insula, S2, and lateral prefrontal cortex) (26).
It has previously been pointed out that decreased opioid receptor bind-
ing can also indicate the release of endogenous opioids during pain (27). The
authors of the previous study (26) found that the location and distribution of the
diminished receptor binding was more extensive and showed little overlap as
compared to the other group (27). It is thought possible that the loss of opioid
receptor availability in CPSP may be secondary to a reduction or downregula-
tion of opioid receptors, resulting in a reduction of effectiveness of endogenous,
opioid-mediated, analgesic mechanisms (26).
A later study looked at peripheral versus central neuropathic pain (28). The
authors used PET scans to evaluate patients with peripheral (n = 7) and CPSP
(n = 8) neuropathic pain patients. They found that in CPSP patients, interhemi-
spheric comparison indicated a significant decrease in opioid binding in poste-
rior midbrain, medial thalamus, and the insular, temporal, and prefrontal cortices
contralateral to the painful side. The patients with peripheral neuropathic pain
did not show any lateralized decrease in opioid binding. The authors concluded
that decreases in opioid binding were much more extensive than anatomical
cortical lesions and were not colocalized with the lesions: metabolic depression
(diaschisis) and/or degeneration of opioid receptor–bearing neurons secondary
to central lesions appears to be a likely mechanism (28).
Sympathetic dysfunction has also been felt to play a role in central pain sec-
ondary to signs of abnormal sympathetic activity: edema, hypohidrosis, trophic
skin changes, changes in skin color, and decreased skin temperature (12,29). It is
also noted that some or many of these changes may be secondary to “movement
allodynia,” which makes the patient keep the affected limb motionless (9).
Reports of CPSP associated with abnormal “epileptiform” activities in tha-
lamic cells may be involved with central pain (30, 31). This would also indicate
that some aspects of the problem may be secondary to cortical involvement, as
epileptiform discharges are associated with that region, typically. Another group
also noted that central pain may be a manifestation of partial epileptic seizures
(32).
TREATMENT
Treatment of the CPSP is difficult and options are limited.
The most common first-line drug is amitriptyline, with other drugs includ-
ing opiates treated as second line (10). Amitriptyline is thought to be helpful, sec-
ondary to its reuptake inhibition of serotonin and norepinephrine (33). In a con-
trolled trial of amitriptyline and carbamazepine, only patients on amitriptyline
reached a statistically significant reduction in pain compared to placebo. Patients
on carbamazepine did not but had “some pain relief” and more side effects (34).
Aside from amitriptyline, anticonvulsants including lamotrigine and
gabapentin have been reported to provide pain relief with better safety than car-
bamazepine and phenytoin (35–39). In spite of the articles suggesting lamotrig-
ine provided good relief of CPSP, a Cochrane review found that lamotrigine had
only limited evidence that it would be useful, and it was, in fact, unlikely to be
of benefit for the treatment of neuropathic pain (40).
26 Jay
Other antidepressants and anticonvulsants have also been tried in the

treatment of CPSP, but none has become a primary or gold-standard treatment
(41–46).
Intravenous lidocaine appeared to be helpful in patients with CPSP
(47, 48). Intravenous naloxone was not helpful in CPSP (49), while intrathecal
baclofen, an agonist of GABA-B receptors, did provide relief for CPSP patients
(50).
Stimulation of the primary motor cortex for intractable deafferentation
pain, as well as central stroke pain, has been used successfully. The mechanism of
pain relief by this form of electrical stimulation of MI is uncertain (51, 52). How-
ever, motor cortex stimulation is felt to be the treatment of choice in poststroke
pain, thalamic pain, or anesthesia dolorosa of the face (53).
One group looked at the effectiveness of chronic subthreshold stimulation
of the contralateral precentral gyrus in patients with intractable neuropathic pain
for more than 15 years. They found that patients with trigeminal neuralgia had
a greater positive effect than those with CPSP. They note that positive effects can
last for 10 years in long-term follow-up (54).
Repetitive transcranial magnetic stimulation of the primary motor cortex
has also been used successfully, as long as the postcentral gyrus (M1) is stimu-
lated (55). Another group found this modality to give good but transient relief
(56).
Transcutaneous electrical nerve stimulation (TENS), both high and low fre-
quency, was tested on patients with CPSP (n = 15). Four patients obtained pain
relief. Three patients continued to use TENS ipsilaterally with good effect at 23 to
30 months, while in one-third of the patients, TENS temporarily increased their
pain (57).
One undesirable effect of repetitive deep brain stimulation (DBS) is the
reduction of the seizure threshold, known as kindling (58–62). An associate of
the author (personal communication) described a patient whose pain was only
partially reduced with the original stimulus parameters of DBS. In an attempt to
improve pain control, that individual used the external controller to increase the
amount of stimulation above the amount used by the attending neurosurgeon.
After several days of this maneuver, the patient suffered a first-ever focal onset,
secondarily generalized seizure. To the author’s knowledge, this patient may rep-
resent the first case of self-induced kindling of seizures in a human patient using
DBS for pain control. Other treatments include sympathetic blockade, as well as
surgical interventions including cordotomy, dorsal root entry zone lesions, tha-
lamotomy, or cortical and subcortical ablation (63–69).
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now, in one of the comfortable chairs that surrounded a wicker table, sat the
solitary occupant of the portico—Sir Charles. He had been here for an hour
or so, ever since dinner was over, half awake, bored, wishing for amusement,
but without energy to go in search of it. On Virginia's approach he rose,
bowed, and went to the edge of the porch to hand her up.
"Thank you," she said, smiling a little. "It was a condescension. You look
very sleepy."
"And you are, as ever, pleased to make sport of me," he responded,

good-humoredly. "Have you no pity for a man weary of himself, his very
sportiveness, and most mightily tired of the silence of the trees, the shadows,
the sun, and the river yonder?"
"Troth, you are in a bad way," responded the young lady, seating herself
at the table and taking therefrom a reticule which held some silken knitting-
work.
There was a pause before Fairfield observed, idly, "My aunt's roses must
be highly successful this year."
"Yes. These are very perfect."
"And are you going to be so selfish as to keep the two of them, when not
even one is needed to complete your beau—"
"No, no. Stop!"
Sir Charles looked at her in surprise.
"Take both the flowers if you like"—she tossed them over to him—"but
forbear any remarks on my appearance. I—I am not in the mood."
He fastened the roses upon his waistcoat, helped himself to a pinch of

snuff, dusted his coat with a large handkerchief, and leaned towards her.
"How have I offended, O Virginia the fair?" he asked, half lazily, half
curiously.
The young lady shrugged her shoulders. "In no way at all. This is a
Monday. Have you never noticed that I am always vaporish on Mondays?"
"No, I had not noticed. Oh! as I remember it! Tell me, what did you think
yesterday of M. de Mailly? Is't the first time you have seen him?"
"Yes. And I think him a gentleman, and that his English accent is good.
He looked rather pale. For the rest—why should I think of him at all, since
his eyes are only for Deborah?"
"Deborah!" echoed the man, too quickly. He recovered himself, however.

"Ah, well—he has seen her before. You and Lucy were strange to him."
"He has seen her before?" repeated Virginia, surprised.
"Several times. Didn't you know? Carroll told me 'twas her doses—
medicines—that probably saved his life."
"Ah! So that is what has made her so eager over Miriam Vawse."
Virginia gazed thoughtfully out among the trees towards the river, of which a
flashing glimpse was now and then to be caught through the feathery foliage.
"I thought you knew, cousin, or I would not have spoken. There was no
wrong in the matter. Only Deborah is peculiar. She—"
"Oh, have no fear! I will not speak of the matter. But—I am not too fond
of Deborah Travis; therefore I say nothing of her affairs. It might be better
for her if I did."
"I think not," he answered, coolly. "Hark! There is some one coming up
the road. Do you hear the beat of the hoofs?"
"Yes."
At that moment Jim, the groom from the stables, came running to the
portico, and stood there expectantly facing the road, down which the sound
of horses' hoofs was becoming plainly audible.
"Who is it, Jim?" asked Sir Charles.

"Mas' Thompson shout f'um road, minute ago, dat Mistah Rockwell
ridin' up."
"Oh—Mr. Rockwell!" Virginia rose with a cold expression settling over

her face, and Sir Charles shrugged indifferently as the visitor came in sight
and presently halted his mare at the portico.
He was a florid, rotund, sandy-haired fellow, the rector of St. Anne's of

Annapolis; conceited, a large eater, and a fair story-teller, but without brain
enough to make himself obnoxiously disagreeable. He came up the two
steps, wiping his face with an enormous handkerchief. His dress had been
somewhat disturbed by the long gallop, and his bag-wig was awry. Before
bowing to Virginia he stopped to adjust these matters, and then, having
returned the slightly distant salute of the lieutenant, he observed, in a thin,
non-clerical voice:
"Mistress Virginia, if it is not inconvenient, I am bent upon seeing your

brother and Madam Trevor this afternoon."
"Vincent is in the fields, Mr. Rockwell. I will have him sent for."
"Pray do not do so, my dear young lady. I would not for the world put
you to such trouble. No doubt he will be in later. I will see madam, your
mother, first. If you could tell me where I may find her—"
"Will you step into the parlor, please? If Sir Charles will excuse me, I
will call my mother at once."
The lieutenant bowed politely, and the two passed into the house, leaving
Fairfield to sit down again with another shrug at the interruption that left him
once more to his boredom. Presently, to his mild surprise, he perceived
young Charles Carroll hurrying through the shrubbery in the distance, across
the road.
"Carroll! Oh, Carroll!" shouted Fairfield; but, if the boy heard him, he
made no reply, merely quickening his pace a little till he was out of sight.
As a matter of fact, young Charles did not want to hear. It was for
Deborah that he had come to the plantation, and he was going to seek her in
the spot where she was most likely to be found. Having happily escaped the
continued notice of Sir Charles, he reached the back of the Trevor house, and
there came upon the object of his search, seated, Turk-fashion, by the still-
room door, surrounded by a group of black, wide-eyed pickaninnies, to
whom she had been telling ghost-stories in their own dialect. It was one of
her favorite forms of amusement when she was a little lonely; and the small
mental effort required in concocting the endless tales was more than
compensated for by the unwavering devotion to her of every black imp on
the place. It was no great acquisition, perhaps, to one's acquaintance, but it
was one of Mistress Travis' pleasures, and one not yet forbidden by Madam
Trevor.
"SURROUNDED BY A GROUP OF PICKANINNIES"
Young Carroll was close upon her before he was perceived; and when
she beheld his expression, she burst into so sudden a peal of laughter that her
audience jumped in terror, imagining it to be the latest demoniacal
accomplishment of the ghost. At sight of Master Carroll, however, they
realized that their afternoon was over, and all but one ran off to the quarters.
This small fellow, Sambo by name, aged five, elegantly clad in a brown
holland shirt that was many shades lighter than his skin, clung to Miss
Debby's arm, pleading for more; for he was court favorite, and might do as
he chose.
"I'm so glad you've come, Charles," she said, holding out a hand, which
he clasped and shook as he might a man's.
"I have the pinnace. Can you come sailing now?"
"Oh yes! I've finished my spinning"—she made a little grimace—"and

the knitting, and have crushed two bushels of rose-leaves for distilling, and
have told three ghost-stories—and now I may sail, I think."
"Must I ask madam?" he queried, dubiously.
She laughed. "No. There now, Sambo, run away. No, I can go without
asking her."
Very gently Deborah put away the child who still clung to her skirts, and
started off, beside her companion, towards the river. Virginia and Sir
Charles, from the portico, saw them pass the shrubbery. Fairfield repressed
an exclamation. He would have given much to have been in the boy's place;
and Virginia, catching a glimpse of his face, knew it, but was silent.
"I've got that Frencher—de Mailly—in the boat," observed Charles, as if

offering a bit of off-hand information. "I like him, and he asked to come.
What's the matter?"
Deborah had stopped short in her walk. "He there!" she cried, looking
anxiously at her rumpled dress, knowing that her hair was all awry, and
beginning to pull down the sleeves that were rolled to her shoulders. "Oh,
you might have told me! How could you have let me come looking so?"
"You didn't mind me, though," returned Charles, not over-pleasantly.
"Come, let the sleeves stay up, and don't bother with your hair. You're a
thousand times prettier so, if that's what you want."
Deborah looked up at the boy with a little, mischievous smile. "I know
that I'm better so. That's why I let it stay—for you," she said; and Charles,
near enough to manhood to make the inference, had a momentary impulse to
fall then and there at her feet. He did not guess, however, why the added
color had come into Deborah's cheeks, or that there was a quick tremor at
her heart as they approached the boat.
The wharf belonging to the Trevor place was hidden from the house by
the foliage of the peach-orchard on the river-bank. Claude de Mailly, waiting
in the little pinnace, beheld the two figures approaching him among the
trees, and made his way along the bowsprit that he might help the young girl
into the boat. He bowed gravely as she came along the pier, regarding her
dishevelment of attire in surprise as well as admiration. It was but yesterday
noon that he had seen her in very different state, and had thought her
charming then. But now—! She accepted his proffered hand, and stepped
carefully past the boom and down into the pinnace, though Charles had
never seen her do such a thing before. Usually she leaped past him and was
at the tiller before he could cast the painter off.
"Better let me take the steering to-day, Deborah," observed Charles, as

they swung away from the dock.
"Oh—does mademoiselle herself steer at times?" asked Claude, with the

quaintly twisted s's and r's that Deborah loved to hear.
"Sometimes," she replied.
"River or bay, Deb?" inquired Carroll, bluffly.
"The river; and let us beat up along the other shore. 'Tis prettier."
"All right. Mind the sail now."
Deborah obediently ducked her head, but Claude, not understanding the
observation, and being turned from the canvas, sat still as the heavy boom
swung over. Charles shouted, and Deborah seized his arm, pulling him down
just in time. When they were under way again, de Mailly sat straight and
looked curiously at the sail.
"Ma foi comme j'étais bête!" he observed, smiling at the girl, who
returned his glance. The incident had broken the little stiffness of her
manner, a fact which the Frenchman perceived with relief. "You saved my
unfortunate head another blow, Mistress Travis. I thank you for it."
"I am glad that I saw you," she answered. "Charles and I have both been
knocked over with it. One does not always see."
"Faith, I should think not! I had Deborah senseless for a quarter of an

hour here once—"
"Nonsense, Charles. It was not five minutes."
"Humph! It seemed half a day to me. There, are we near enough the bank
now?"
"Yes. Let her out, and run free with the wind."
With this command, and a sigh of content, Deborah sank down at

Carroll's feet, laid her head upon the seat, and said no more. Charles could
feel a bit of her calico ruffle over his foot, and her shoulder close to his arm,
and was perfectly happy in watching the sail and feeling the tiller quiver in
his grasp. The stranger reclined on a cushion in the bottom of the boat,
facing the stern, his eyes resting half the time upon Deborah, and half the
time upon the silver wake of the little boat.
A more perfect afternoon the gods never contrived. The sun was by this
time well on its descent, the west was a glare of glory, and the whole river
caught its reflection and poured an endless golden ripple along the shores,
upon whose deep velvet turf the yellow shadows were lengthening. From the
bay, eastward, came a stiff salt breeze that stirred the lazy June air till it had
revealed every flower-breath in the land, and was as rich as only June air can
be. Farther up, the river narrowed and twined between its banks till Charles
was obliged to tack in order to catch the wind. For the most part the shores
were wooded and still; but every now and then came an opening through
which one caught the glimpse of a red brick house with white windows and
pillared portico gleaming through a mist of birch or willow branches.
Occasionally a gull, just in from the ocean, would dart, arrow-like, into the
water, churning it white with his dive, to reappear presently, holding a
captive fish, scales flashing in the light, fast in his beak.
Claude de Mailly noted it all—all this natural beauty and perfumed

silence that his life had lacked. It was entering into his nature at every pore
of the flesh, and was to him as milk to a man dying of hunger and thirst.
Only one unsatisfied desire was in his heart. And yet, was it easy to mourn,
even for that, when, just before him, graceful, unconscious, careless, pure of
brow, clear of eye, and with that mad hair clustering all about her neck, lay
another woman, whose glance, every now and then encountering his own,
would droop so swiftly that he could see the whiteness of her eyelids and the
long, curling lashes that touched her delicately flushed cheeks? A new
feeling was welling up in the courtier's heart—something that had never
come before. He let it stay, nor tried to understand the reason for its being.
But he knew that he was moved by the sight of Deborah, and instinctively he
divined that his emotion was being echoed in her.
Deborah was cold, with a cold which the summer sun had no power to
warm. But she had not found that chill in the salt, eastern wind. She knew
and understood but half that was taking place this afternoon. She had waited
for its like, without knowing what it might be, for a long time. Sir Charles
had brought her something that emanated merely from himself; but here, at
once, in the first glance ever given her by this other, while he had raved in
fever, was all that she had dreamed of, and infinitely more. Had it been some
weight that was crushing out her heart, she could only have opened wide her
arms and fiercely welcomed it. It was not all de Mailly either, she thought,
vaguely, as she felt Charles move the tiller. It was the whole day, the place,
the sunlight, the river, even the imperturbable Carroll, who was silent for the
sake of the air, and the water beneath the keel of his boat. The Severn was
still swollen from heavy spring rains, and the shallows of later summer were
covered now. Young Carroll presently ran the pinnace so close to the high
north bank that a willow, growing in the water, sent out one pale, feathery
arm that brushed Claude's head in passing. Deborah watched a long leaf
draw over his neck, just below the ear. Taking the bough as it reached her,
she pressed it half unconsciously to her forehead, looking up to find de
Mailly smiling into her eyes. But when they emerged from the shadows he
was looking beyond her, down the river, though the smile lingered still about
his lips. Charles Carroll did not notice the incident. He was thinking of his
pretty feat in steersmanship.
"Well, Deb," he said at last, "if I'm to get home for supper, we'll have to
come about."
Deborah sighed, and acquiesced.
"Mind your head, then, sir," cried the boy, laughing.
And as de Mailly bent carefully over, he answered blithely: "Faith, sir,

had you kept me out half an hour longer, I should so have lost my head that
the boom could not have menaced it."
"Ay, the river's pretty."
"The most beautiful spot in the world—and seen with the most charming
companions," returned the Count, bowing towards Deborah, but moving up
to the high side as they came into the wind.
Deborah knew instantly that their afternoon was over, and she was
chagrined that she had allowed him to be weary of her. Pushing Charles from
the tiller, she suddenly took his place.
"There, now you shall rest, or unfasten the sheet and manage that while I
wake myself up!" she said. And young Charles obediently moved up beside
Claude and took unto himself the management of the sail, while Deborah,
sitting straight to the freshening wind, shook herself out mentally, and
fastened her thoughts upon the tiller. Now, indeed, as she brought the boat so
close into the wind that the water swirled gently over the low side, de Mailly
turned towards her again. He was willing to be upset if she liked; but he did
not care to have an accident occur because he had made her absent-minded.
Deborah, however, was not thinking of him at all. Her skilful hand was
making the little vessel fly, and there would be no false moves on her part.
When they came about upon the second tack the sail flapped for but one-
quarter of a second. As it filled with a puff, the little yacht fairly leaped
ahead.
"Jack me, Deb, if that wasn't the prettiest turn I ever saw!" cried young
Charles, as he manipulated the sheet.
"'Twas half you, Charlie. I must have let her go had you not brought her
up just at the right instant."
"And did Mistress Deborah learn the management of a boat under you,
sir?" asked Claude.
"Mine and my father's."
Claude settled back and tried to bring his mind to other subjects; but for
the moment Deborah had completely fascinated him. He could do nothing
better than compare her to all those other women to whom she was indeed
incomparable, to try to fathom the many expressions he had seen in her eyes,
and seek to determine which was the normal one. And so they left behind the
upper windings of the river and neared at last the wharf of the Trevor place.
The sun hung low over the tree-tops as Deborah stepped from the boat and
held out her hand to Charles.
"Indeed, I am beholden to you. We have never had so beautiful a sail."
"I trust, Mistress Travis, that it will not be the last in which I shall be
permitted to join you?" put in Claude, hastily, as she courtesied to him, and
would have been off.
"I trust not; but the pinnace is not mine. It is with Charles and Dr. Carroll
that you must plead."
So, with that small politeness, Deborah turned towards the shore,
wondering a little why she should have finished so perfect an afternoon in
annoyance with herself and those who had been her companions. She passed
slowly up through the orchard and across the road at the top of the bank. The
plantation grounds seemed utterly deserted. The family must be at supper.
Through the trees she caught a glimpse of the empty portico. Hurrying a
little, she went close to the doorway of a small, vine-covered arbor which
was but rarely used. Nevertheless, to-night, as she passed it, there came the
sound of muffled sobs from within. Deborah halted, hesitated for an instant,
and then entered the little place. Inside it was dusky, but she perceived at
once the glimmer of something white in a corner.
"Who is it?" asked the girl, sharply.
The figure stirred, and perhaps made some attempt to reply; but the only
result was another hoarse sob.
"Lucy! Lucy! what is it?" cried her cousin, running to her quickly. "Nay,
now, pray don't cry so! Is't only Mr. Calvert's going with the commissioners,
so that you mayn't have him to take you to Master Whitney's church? Listen!
Virginia told me she'd go herself with you there."
"Oh, Debby dear, no, it's not that at all now," came more quietly.
"What, then? Try and tell me about it, Lucy. See, you are all crumpled
up. Come out of this horrid place, and tell me about it. Come, now—come."
It was seldom that Lucy Trevor would have refused such persuasion, for
she was a gentle little thing, and loved to be led. Now, however, she resisted
all Deborah's kindly efforts to help her to rise, and only crouched closer in
her corner, shaking with grief. Finally Deborah knelt and took the little
dishevelled figure in her arms. Lucy had clung to her for a second, when a
new voice interrupted them.
"Lucy—are you here?"
Virginia stood in the doorway. Lucy made no answer, but Deborah said:
"Lucy's here, Virginia. What has happened?"
The elder daughter of the Trevors came forward and stood looking down
at the two figures on the ground. "The Reverend George Rockwell has asked
for Lucy's hand. She should be most proud. Come, Lucy, supper is standing,
and the wedding's not till to-morrow. Why do you bear yourself like a child?
Good God, Lucy, do you fancy a woman ever gets the man she loves?"
CHAPTER IV
Annapolis
The commissioners left Annapolis for Lancaster on the 18th day of June,
which was three days earlier than had been originally planned. After their
departure Governor Bladen sighed with relief, packed up his black satins and
official orders, and hied him to his country-place to recuperate for the fall
sessions. By the 1st of July Annapolis was deserted. All of the old families
had gone to their summer houses up the river or down the bay, and it was
remarked that Dr. Carroll, who chose to stay in town, and Rockwell, whom
he sincerely hated, must bear each other company through the summer. But
Dr. Charles was not yet reduced to the companionship of a Church-of-
England clergyman. He had taken an immense fancy to Claude de Mailly, of
whom he saw as much as Claude would let him. Indeed, he had given the
Frenchman more than one invitation to leave the tavern of Miriam Vawse to
make a permanent abode in his own house, and could not quite understand
why he had been refused. But Claude was well satisfied where he was; and
had there the indispensable feeling of independence. Few guests ever came
to the little tavern after the close of the spring assembly; and, when an
occasional traveller did stop overnight, monsieur ate in his room, went to the
coffee-house, or remained to make acquaintance of the stranger, as he chose.
On sailing for the English colonies it had been Claude's idea to travel
through them, when he arrived, as rapidly as possible, courting what
adventure and danger he could, and to keep his thoughts enough occupied to
crush, as best he might, his hopeless homesickness. But, after living in
Annapolis for a week, he found that it might be a very endurable thing to
exist in Annapolis for a year. The air was different, in this new land. New
thoughts and new occupations had come, after his illness, and he ended at
last by making a very pleasant salute to the Fate which had cast his lines in
these places, determining to take the goods which the gods and Miriam
Vawse provided (at moderate cost), and remain in the little city till
discontent again knocked upon his door. Certainly, he was not lonely.
Through Dr. Carroll and Vincent Trevor he had made acquaintance with
every gentleman, young or old, in the town. They received him extremely
well, though, it must be confessed, some of them balked at his title. "Bah!
Every Frencher's a count!" he heard Mr. Chase cry out one morning at the
market, and thereafter he requested to be presented simply as M. de Mailly
to what men he chanced to meet. Through the influence of Sir Charles he
had been given the freedom of the coffee-house, which was really the
gentlemen's club; and he was asked to the last assembly of the season, which
had taken place just before the departure of the commissioners, and which he
did not attend.
Upon an afternoon of the first week of July, Charles Fairfield, wofully

bored with the weather and the lack of something to do, rode into town at an
early hour with intent to amuse himself at any cost, and a pruriency towards
a stiff sangaree as the beginning of matters. The second want drove him
down Church Street to the coffee-house. On arriving at the jockey-club-
room he found its only occupant to be George Rockwell. The Queen's
clergyman greeted him with great urbanity. How well would Rockwell have
loved his brethren had all of them been knights, and the eldest sons of
wealthy families! The sangaree was quickly forthcoming. He drank with Sir
Charles, and Sir Charles drank with him, and they drank together, till the
weather was of less importance and spirit acted upon spirit with delightful
effect. Then it was that the divine opened a more intimate conversation.
"Charles—my dear Sir Charles—were you aware—ah—of the fact that it

is my hope and my intention—my intention, sir—to have the honor, at some
day not far distant, of becoming, when two events shall have taken place,
your—ah—brother-in-law, as it were?"
"What the—oh yes! Ha! ha! ha! Oh yes! You're after Lucy. To be sure, I
recollect. Lucy! Well, George, I wish you well—you know that. But she
won't have you."
"Won't have me?—Um. Madam Trevor has all but promised her."
"The more fool Madam Trevor.—Oh, I beg pardon. No offence, sir. But,
as I hear, the affections of the lady in question are already engaged."
"Engaged?" The rector looked startled for an instant. Then he recovered

himself. "You have reference, I presume, to that Puritan psalm-singer, John
Whitney. Oh, I'll engage to cure the pretty child of him! She is coy with me
now; excuses herself when I call, has vapors when her mother insists;
refuses to permit me to salute her hand. But I have no fear, Sir Charles.
Consider my position. I shall get her, have no fear."
"Still, I have observed that she attends your rival's church," remarked Sir
Charles, maliciously.
The rector emptied a glass. "If you'd but help me there," he said.
"I help you! Damme, what can I do, George?"
"Since Benedict Calvert left the city 'tis Mistress Virginia, your future
wife, who takes her sister to the Puritan meetings. Now, Fairfield, if you—if
you would be so monstrous obliging as to speak a word to your young lady
in—ah—my favor, I'd be forever beholden to you."
Sir Charles laughed unpleasantly. "Lord, Master Rockwell, d' ye think

I'm married yet? What possible right have I to address my cousin on any
subject but—the one I most avoid with her?"
"The one you most avoid? And what, pray, is that?"
"The tender matter of love, George. Love and Virginia are—well—

strangers in my heart."
"Good Heavens! Are you not, then, to wed the lady?"
"Damme, my good fellow, I don't know! I would to Heaven I did know

—the state of another person's affections."
"Another! Oho! Aha! Another—truly this is gallantry! In my ear, I beg,

whisper the name."
"The name? There's only one woman's name in the world," cried Sir
Charles, dramatically, a little overbalanced with the sangaree. "Deborah!
Deborah! Deborah! 'Tis she, the fairest petticoat in the colony. D'ye hear?"
"I've heard that she was dangerous," responded Rockwell, chuckling
with interest. "But is it true, is it possible, Charlie, that you are bewitched
enough by this young—hum—Pomona—by this young Pomona, to be
indifferent to the more glittering charms of Miss Trevor?"
Sir Charles sat him down in a chair and sighed. It was a true love-sigh,
such as there could be no mistaking in those days. "I love her to distraction,"
was his inadequate observation.
"Now I wonder," reflected the rector, aloud, "I wonder if, in such case,
distraction and marriage are terms synonymous?" He lifted his head,
scratched his large neck delicately with his finger-nail, and regarded the
young man from that height with humorous serenity.
"Devil take me—how can I, George? They expect me to take the other—
Virginia. And there's the dower—and my aunt's favor—and my own
dependence—and, egad, I don't know!"
"Then you won't marry her, eh?"
Fairfield grew a little red. "I must. She's a kind of cousin, too, you
know."
"Oh, tut! A difficult matter. Hum!—Ha!—When—a—you are prepared

to assist me in getting Mistress Lucy, my services, or, rather, one of them, is
at yours."
"The marriage? Oh—St. Quentin 'ud do that. He—"
"Not St. Quentin's service, or—one that he would not perform."
"Eh? What are you getting to, Rockwell?"
The divine advanced with large solemnity to where the young man sat,
bent over him, and said, in a broad whisper: "Now look you, Fairfield,
there's a certain ceremony of which the law takes no count, certain words
being left out.—A lady would accept it—" He stepped back a pace. "When
you desire such a service, terms might be got at between us. Once in
England with your bride, the marriage growing cold—" he waved his hand,
shook his head, and so finished the proposition.
Sir Charles gave him a long look. The color had left his face. He rose
slowly, turned his back for a moment, and took a pinch of snuff. As he faced
the other again he remarked, without much expression: "What a cool-headed
beast you are, Rockwell."
"Sir!"
"Yes. But don't fight me to-day. That service—" he stopped, unwilling to

go on.
"You may want it yet," finished the rector, insinuatingly.
But Fairfield did not commit himself. Before he had a chance to reply a
servant of the house opened the door.
"Beg pardon, sirs, but young Mr. Carroll and Mr.—the Frencher, are
below, and, not being regulars—"
"Yes, yes, show them up at once," cried the lieutenant, with relief in his
tone.
The servant disappeared, and George Rockwell turned upon his heel. He
was not a little irritated at the result of the foregoing conversation, and he
remained silent till quick steps sounded on the stairs outside, the door
reopened vigorously, and young Charles, with de Mailly at his shoulder,
gayly entered the room, bringing with them a new atmosphere.
"Good-day, Fairfield! Good-day, Mr. Rockwell!—Faith, you both look

wofully! Is the sangaree ill made?"
The boy was in a gale of spirits, and ran about the room tasting of the
liquor, looking down out of the window, and laughing at the three others.
Claude saluted the gentlemen more quietly, observing to Sir Charles:
"I perceive that we have interrupted you. I crave pardon. I sent the man
to see if you were disengaged."
"You are mistaken, monsieur. I assure you, in my turn, that your arrival
could not have been more agreeable.—Confound it, Charles, have you a
megrim or a frenzy? Where have you been, sir?"
"To a cock-fight in the Prince George Street pit. You should have been
with us. Captain Jordan's bird against Jack Marshe's. Jack's died. The
secretary will be in a rage. I won three pounds, though."
"You see, it was the first I had witnessed," explained de Mailly.
"Devil take me, why didn't you hunt me out, Charles? I've been eternally
bored for a week.—You lost to him, de Mailly?"
Claude nodded. "As he said, a small bet—seventy-five francs."
Fairfield looked at him curiously. Three pounds did not seem to him
small for a cockpit wager; but he would not have voiced this idea to the
foreigner for double the amount. He turned again to young Charles.
"Odds my life, Charlie, you've been drinking. What's it mean? Where's

your tutor?"
Carroll laughed joyously. "Shooting plover in the west marsh with father.
I've a holiday, and M. de Mailly is making it with me."
Rockwell frowned rather ill-humoredly, as though a preachment lay upon

his tongue, and Sir Charles was about to speak again, when from below
came the trampling of horses' hoofs and a little chorus of voices, while
Carroll cried from the window: "Vincent Trevor, William Paca, and Carleton
Jennings! They've stopped here."
"Ah—they'll be up presently. Rockwell, will you risk another tankard?

They'll have apple-brandy and Madeira. Vincent scorns rum."
The rector shrugged, vouchsafing no active consent, and after a moment

or two the three young gentlemen clattered into the room. There was a
chorus of greeting, and Trevor introduced young Paca to Claude, who had
not seen him before. Jennings flung himself into a chair, flicking the dust
from his coat-sleeves with a riding-crop. Paca sat upon the long table; and
Vincent, after drawing off his gloves and flinging them, with his hat and
whip, upon a chair, went to the door and called lustily for a decanter of
Madeira with glasses.
"I ordered a sangaree when we were down," observed Jennings to Paca.

"Trevor's thirst is aristocratic, but too small."
"And we'll all drink with you both," put in Fairfield, with sociable
impudence, while Rockwell smiled approval.
"And now for the affair in hand," pursued Jennings, when the party were
seated. "We've a race in prospect, Fairfield, that will take four months' pay to
back."
"Eh! What's that? I back the winning side, of course."
Trevor laughed. "Nay, then, Charlie, will you desert me?"
"Egad, Vin, you're never going to take to racing! You've no stables."
"Castor needs none."
"Castor! Oh! By my life, Vincent, he might do. Vastly fine points,

gentlemen. Rough-bred; but where you'd find a better—"
"He's pledged already, then," observed Jennings to Paca, smiling.
"Why, who will you run against, sir?" asked Rockwell, interested,
despite his ill-humor; for, of all things, he loved the turf.
"Paca's filly, Doris. She's young for my two-year-old; but Will is to enter
her for the fall cup, and wants to give her practice."
"Pretty beast, Doris. I stake on her, I think. Are the dates fixed?"
"No, deuce take it! there's the bother. Trevor has no jockey. Castor will
carry weight, and there's not a rider in town over four and a half stone. Five
would ride him; no less—eh, Vincent?" queried Paca, and Trevor nodded.
There was a short pause, in the midst of which a servant with the wine
and sangaree appeared. The room drank with Trevor, and two or three
afterwards turned to the pewter mugs which held the planter's favorite
beverage. Claude had been listening intently to the talk concerning the race,
and, his ear being well accustomed to the colonial accent, he had gathered
the gist of all that was said.
"My man, Tom Cree, might know of some fellow who would do for you,
Vincent. I think you could trust him if you cared to look about in that way,"
suggested Paca, after some hesitation.
Vincent bowed. "Certainly I'd trust your man, Will. But I've some
objections to that course. I've no intention of starting stables. I run Castor
merely to try your Doris and test my own animal. I don't want to be known
as deeply interested in the turf. Get a professional rider fastened to you even
by one race, and—poof! You all know what it means."
The group nodded. Vincent Trevor was a man highly respected by all of
them. He was quiet, silent, of excellent judgment, a little given to over-
Toryism, no prig, but holding fast to strong principles. His friends knew his
manner of life, and never expected him to step beyond its bounds. In the
present case they all perceived his position, and his silence was rather
dubious, till Claude de Mailly most unexpectedly broke it.
"This race—it would not be in public?"
"Oh no. Certainly not," responded Sir Charles.
"It would be—on a track, or through the country, à l'anglais?"
"Oh, track, of course—not a steeple-chase—eh, Trevor?" queried

Jennings, and Vincent nodded, looking to de Mailly for more.
"And the leagues—miles, I mean—how many?"
"Track's a mile and a quarter. Shall it be twice round?"
"Castor will hold twice, but would you try Doris so?"
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Practical guide to chronic pain syndromes / edited by Gary W. Jay.

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Pain specialists, noninterventionalists, primary care physicians, medical special-

balancing clinical suspicion, intuition, and compassion. People living with

B. Eliot Cole, MD, MPA

First, as always, I want to thank my wonderful wife Suzanne and my incredi-

Foreword B. Eliot Cole . . . . v

PART I NEUROPATHIC PAIN SYNDROMES

3. Central Poststroke Pain 23

5. Management of Pain Related to Amputation 50

6. Pathophysiology of Complex Regional Pain Syndrome 62

9. Quantitative Clinical, Sensory, and Autonomic Testing

PART II SOFT TISSUE PAIN SYNDROMES

11. Piriformis Syndrome 140

12. Fibromyalgia 144

PART III LOW BACK PAIN

14. Neuropathic Low Back Pain 206

PART IV GENITOURINARY PAIN SYNDROMES

16. Chronic Prostatitis/Chronic Pelvic Pain Syndrome—A Urologist’s

17. Female Chronic Pelvic Pain 261

PART V CANCER PAIN AND PALLIATIVE CARE

19. Palliative Care Pain Management 285

PART VI OTHER CHRONIC PAIN SYNDROMES

21. Neurogenic Thoracic Outlet Syndrome—A Biopsychosocial Approach

22. Osteoarthritis 318

PART VII MEDICATIONS

24. Opioid Medications and Correct Medical Usage—An Update 343

25. Legal Issues in Pain Management 367

26. Antidepressant Medications 391

27. Anticonvulsant Medications 397

Vasanthi Arumugam Elmhurst Hospital Center, Mount Sinai School of

Maurice Policar Elmhurst Hospital Center, Mount Sinai School of Medicine,

General Examination of the Feet

5. What makes the pain better? (maximum 2 points)

increase in concentration in diabetic patients. These end products are thought

Prevention of Progression of DPN

Transcutaneous Electrical Nerve Stimulation

Spinal Cord Stimulation

Transcranial Magnetic Stimulation

Foot Care Advice

Aldose Reductase Inhibitors

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