Cancer Pain

Epidemiology and Syndromes

RUSSELL K. PORTENOY, MD

Medical practitioners face the challenge of assuring that pain management has a central place in the
treatment of patients with cancer. To meet this challenge, they must understand the prevalence of pain
in cancer patients, the frequency with which cancer pain goes untreated or is inadequately managed, and
the numerous causes and manifestationsof cancer pain. With the goal of contributing to this understanding,
this article summarizes the current knowledge about the epidemiology of cancer pain and its syndromes.
Cancer 63:2298-2307, 1989.

P AIN is an extremely prevalent symptom in patients

with cancer. Although this is intuitively grasped by
clinicians and patients alike, there is a frustrating degree
bias inherent in surveying a subjective complaint in se-
lected populations, may cause inaccuracies. Nonetheless,
a review of these data reveals remarkable consistency
of misconception about the epidemiology of cancer pain among survey results.
and its treatment. Clinicians generally fail to understand
the high prevalence of cancer pain and, more importantly, Prevalence of Cancer Pain
do not recognize the great frequency with which it remains
untreated or inadequately managed. I In contrast, the Bonica' has provided a comprehensive compilation of
public views pain as a virtual constant among the symp- cancer pain statistics. His review, summarized in Table
toms associated with cancer and anticipates that it will be 1, includes nearly all the survey data published in 15
more severe than survey data suggest that it actually is.' countries during the last decade and provides the most
Implicit in the latter perception is the belief that the as- detailed analysis of cancer pain epidemiology currently
sessment and management of this most dreaded symptom available.
receives little clinical emphasis and is often unsuccessful. The pooling of data from many reports yields global
The challenge to medical practitioners is to alter this view statistics useful as a starting point in the evaluation of
by advancing pain management to a central place in on- cancer pain epidemiology. Overall, pain is reported by
cologic practice, thereby mitigating the fear of cancer and about 50% of patients at all stages of disease and by over
its treatment. 70% with advanced neoplasms. Applied to 1983 cancer
statistics for the United States,' these data indicate that
Epidemiology of Cancer Pain 297,000 of patients dying of cancer and 1,027,000of can-
cer patients who survived that year had pain. Application
The magnitude of the cancer pain problem must be of these prevalence rates to worldwide cancer statistics
understood from the perspective of two related sets of from 19843suggests further that 3 million of the 4.3 mil-
survey data. One set derives from the natural history of lion patients who died from cancer and 16 million of the
the neoplasm and includes the relationshipsbetween pain surviving patients experienced cancer-related pain that
and tumor type, extent of disease, and lesion location. year. The estimated worldwide cancer pain prevalence
However, the more important data set is on the efficacy for 1984 is thus a staggering 19 million patients.
of current management approaches. Clearly, these data These data reveal two important characteristics of can-
sets intersect, and this fact, together with the potential cer pain. First, its prevalence is far higher in patients with
advanced disease than in those at an earlier stage. Thus,
From the Pain Service, Memorial Sloan-KetteringCancer Center, and
the incidence of cancer pain increases with the extent of
the Department of Neurology, Cornell University Medical College, New disease. Second, there is a relationship between the type
York. of neoplasm and the prevalence of pain. For example,
Address for reprints: Russell K. Portenoy, MD, Department of Neu- bone cancer and pancreatic cancer are much more likely
rology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue,
New York, NY 10021. to be associated with pain than are the lymphomas or
Accepted for publication February 20, 1989. leukemias. These differences are far greater in patients

2298
No. I 1 EPIDEMIOLOGY
AND SYNDROMES OF CANCER PAIN * Purtenuy 2299

TABLE1. Prevalence of Cancer Pain* miologic investigations are needed to evaluate these hy-
Stage of No. of Prevalence %
potheses.
Tumor type disease studies (range) Although many epidemiologic studies fail to assess pain
~ e v e r i t y , ~it, ~
is,evident
'~ that such information is needed
All All 18 50 (1 1-75) to understand the impact of pain on function and quality
All Advanced 33 71 (52-96)
Bone Advanced 3-5 75-80 (70-85) of life. Although cancer pain is mild to moderate in most
Pancreas Advanced 3-5 79 (72-100) patients,13 there is compelling evidence that overall se-
Stomach Advanced 3-5 75 (67-77) verity vanes according to tumor typei4and increases with
Uterus/cervix Advanced 3-5 75 (40-100)
Lung Advanced 5 72 (58-85) the extent of Additional investigations are
Breast Advanced 3-5 72 (56-94) needed to clarify these relationships.
Prostate Advanced 3-5 70 (55-80)
Colon Advanced 3-5 69 (47-95)
Understanding of cancer pain epidemiology will also
Lymphoma Advanced 3-5 58 (20-69) require additional information about the influence of me-
Leukemia Advanced 3-5 52 (5-58) tastasis on the experience of pain. Bone pain, which is
* Adapted from Bonica.' usually due to metastasis, has been reported to be the
single most common type of pain:7 and involvement of
bone increases the likelihood of pain, regardless of the
with limited disease, but they exist even in those with primary site of the neoplasm. Moreover, pain due to bone
advanced cancer (Table 1). metastases is reported by 67% to 80% of patients with a
These statistics illustrate the enormity of the cancer variety of primary neoplasms, most commonly lung and
pain problem, but illuminate only a few of the important breast cancer.16 This relationship between metastasis and
epidemiologicissues. For example, the distinctionbetween pain has important implications for the assessment and
acute and chronic pain cannot be recognized from these treatment of cancer patients; future surveys must endeavor
data, and it is likely that inclusion of acute pain syndromes to define this aspect of cancer pain epidemiology more
would greatly increase the prevalence rate. Furthermore, precisely.
there is evidence that most cancer patients experience
more than one type of pain. One survey, for example, Eflectiveness of Cancer Pain Treatment
revealed two or more distinct pain complaints in 8 1% of
patients with pain from advanced cancer. Thirty-four The use of analgesic medications has been advanced
percent of these patients experienced more than three as an essential element in the medical care of the cancer
types.4 pain patient by the World Health Organization and var-
The data presented above also fail to distinguish age- ious medical organizations in the United In
related differences in cancer pain prevalence. There is, for expert hands, this approach can provide substantial pal-
example, an unfortunate dearth of survey data on the liation of symptoms to the great majority of patients.l l ~ ~ ,
prevalence, severity, and impact of cancer pain in chil- Unfortunately, despite this advocacy and eloquent de-
d r e ~ which
~ , ~ may be part of a more general failure to scriptions of the role played by pain relief in efforts to
attend to the analgesic needs of the pediatric population.6 reduce the suffering and maintain the dignity of the dying
Although the available information suggests that cancer patient,2' abundant data suggest that cancer pain is often
pain is common in children, particularly in those with inadequately treated.
bony lesion^,^ it is clear that further epidemiologic studies Although a pain-free state for most patients with
are required to define the problem adequately. advanced cancer may be an unattainable goal cur-
Substantially more is known about the relationship be- r e n t l ~ , * ,the
~ ~prevalence
-~~ and severity of pain among
tween advanced age and cancer pain. The results of several patients treated at home or in routine medical settings
surveys have suggested that pain prevalence and analgesic are far greater than necessary with current approaches to
use decrease in the elderly.*-" These data, however, are analgesia. For example, of 100 patients with cancer pain
correlative and do not clarify the nature of this association. interviewed on admission to a hospice, 73 had experienced
The elderly may report pain less often because of alteration pain for more than 8 weeks and 54 for more than 16
of the sensorineural apparatus, which results in reduced weeks; pain was described as severe, very severe, or ex-
pain perception, or because of the development of stoicism cruciating by most of these patients." A number of other
or "slowness to respond." Analgesic use may decline due surveys have revealed unrelieved pain in 50% to 75% of
to changes in the absorption, metabolism, and elimination these
of drugs in the elderly, which may result in greater effec- Although these data are compelling evidence of the un-
tiveness with smaller doses. Furthermore, clinicians may dertreatment of cancer pain, it must be recognized that
not prescribe the doses usually given the young from fear few reports offer enough detail about patient outcome to
of increased side effects in the aged. Additional epide- provide a truly adequate assessment of treatment efficacy.
2300 June 1 Supplement 1989
CANCER Vol. 63

Since the complete eradication of pain, especially in pa- known as somatogenic) and that which is predominantly
tients with advanced disease, is uncommon,23the results psychologic. Although the precise prevalence of these types
of analgesic interventionsmust be viewed in relative terms. of pain is unknown, it is generally agreed that the vast
A reduction of pain from severe to mild, accompanied majority of cancer pain syndromes have a major organic
by improvement of function, may be construed by patient component. Although the influence of psychologic factors
and clinician alike as adequate pain control but may not on pain and associated impairments should not be min-
appear as such in statistics that show only the prevalence imized, it is highly desirable in the clinical setting to iden-
of pain. To provide a fair assessment, future outcome tify the organic lesion underlying the pain complaint. This
studies will need to integrate measures of pain duration, identification may alter the known extent of disease,
pain severity, and the impact of pain on functioning and change the prognosis, or provide an opportunity for pri-
patient satisfaction. mary therapy. Recognition of the pain syndromes de-
These important considerations notwithstanding, there scribed below provides a guide for the evaluation of the
are evident inadequacies in the current management of organic lesions responsible for the pain.
cancer pain. Although some pain syndromes clearly re- Organic pain may be due to one or more of a variety
spond poorly to available treatment^,^^ the data reviewed of mechanisms. The additional classification of a patient’s
above suggest that inappropriate, misapplied, or under- pain according to these putative mechanisms may have
utilized clinical techniques of pain management underlie important therapeutic implications. Pain may be noci-
most of the problem. This disheartening observation can ceptive, that is, explicable on the basis of ongoing acti-
largely be attributed to two factop: ignorance of the phar- vation of peripheral nerve fibers sensitive to noxious
macology of analgesic drugs; and inappropriate concerns stimuli. The nociceptive stimulus may be somatic (e.g.,
about psychologic dependence on opioids. Both
1926928329 metastasis to bone) or visceral (e.g.. distended bowel
are perpetuated and compounded by a striking lack of proximal to obstruction), and chemical mediators of in-
emphasis in medical education on pain and its flammation, which activate and sensitize these nocicep-
management’ and the limited availability of opioid drugs, tors, probably play a major ro1e.35,36Organic pain can
both internationally and within the United state^.^'-^* also be neuropathic, a result of aberrant processes in the
Although some progress has been made in the last two peripheral or centrd nervous system that result from in-
decades, there continues to be little appreciation for the jury to neural pathways. Some of these neuropathic pains
enormous prevalence of cancer pain or its destructive im- are due to deaf€erentati~n,~~-~~ and may result from tumor
pact on the life of the patient. This situation will hopefully infiltration of nerves (e.g., brachial plexopathy due to
improve with persistent efforts to educate clinicians, pa- Pancoast’s tumor) or surgical intervention (e.g., phantom
tients, and individuals in government about the scope limb pain). Compared with the more common nociceptive
and nature of the problem and the availability of the pain types, deafferentation pain responds less readily to
means to manage it. opioid drugs and is less amenable to procedures, such as
cordotomy, that are intended to further interrupt afferent
Cancer Pain Syndromes impulses from the painful part.
A third classification distinguishes among discrete pain
The epidemiology of cancer pain can be clarified by syndromes.Although accurate data relating the prevalence
classification systems that delineate the various types of of each syndrome to the pain population as a whole are
pain and pain syndromes.33Cancer pain can be classified, unavailable, syndrome recognition has great clinical util-
for example, according to its etiology. Several studies have ity. It may suggest the differential diagnosis for the organic
established that more than two thirds of cancer patients component of the pain, provide guidance in its evaluation,
develop pain as a direct result of the n e ~ p l a s m . ~ , In-
’ , ~ ~ and allow a more accurate assessment of prognosis. Cancer
vasion of bone or neural structures is the most common pain syndromes can be divided into those due directly to
cause, but pain may also follow infiltration of soft tissues, tumor involvement, those related to cancer treatment,
distortion or occlusion of blood vessels, or obstruction of and those unrelated to the tumor or its treatment (Ta-
a hollow viscus. Up to 25% of patients experience pain ble 2).
as a consequence of antineoplastic and less
than 10%have pain unrelated to the neoplasm or efforts Syndromes Related to Direct Tumor Involvement
to treat it. A large number of syndromes related to specific lesions
A second method of classification, which has been can be delineated. The best characterized and the most
termed pathophysi~logic,~~ empirically integrates known common are caused by neoplastic involvement of bone
pain mechanisms and clinical observation of cancer pain or neural tissues.
syndromes. In the broadest terms, this system divides Pain due to bony involvement: Most bony lesions are
cancer pain into that which is predominantly organic (also asymptomatic, and the specific mechanical, humoral, and
No. 11 EPIDEMIOLOGY
AND SYNDROMES OF CANCER PAIN * POrtenOy 230 1

TABLE2. Cancer Pain Syndromes Orbital syndrome. A lesion within the orbit typically
presents with retroorbital, periorbital, or frontal headache,
Pain associated with direct tumor involvement
Due to invasion of bone which may be associated with diplopia and/or visual loss.
Base of skull Proptosis and extraocular palsies may be evident on ex-
Orbital syndrome amination. These lesions may be quite small, and com-
Parasellar syndrome
Sphenoid sinus syndrome puterized tomography (CT), including orbital views and
Clivus syndrome thin slices of the base with bone windows, is usually re-
Jugular foramen syndrome quired to visualize them. Experience with magnetic res-
Occipital condyle syndrome
Vertebral body onance imaging (MRI) is limited, but it is likely that this
Atlantoaxial syndrome technique will also prove to be an effective method of
C7-TI syndrome visualization. Given current experience, CT and MRI
L, syndrome
Sacral syndrome must be viewed as the imaging procedures of choice in
Generalizedbone pain the evaluation of all base-of-skull syndromes. Plain ra-
Multiple metastases
Intramedullary neoplasm
diography, plain tomography, and bone scintigraphy
Due to invasion of nerves should be viewed as adjunctive procedures for these le-
Peripheral nerve syndromes sions.
Paraspinal mass Parasellar syndrome. Masses in this location invade
Chest wall mass
Retroperitoneal mass the cavernous sinus and the adjacent sphenoid bone. Pain
Painful polyneuropathy and neurologic findings may be identical to those observed
Brachial, lumbar, sacral plexopathies with lesions affecting the orbit, although proptosis is less
Leptomeningeal metastases
Epidural spinal cord compression likely to occur.
Due to invasion of viscera Sphenoid sinus syndrome. Neoplastic invasion of the
Due to invasion of blood vessels sphenoid sinus itself may be accompanied by unilateral
Due to invasion of mucous membranes
Pain associated with cancer therapy or bilateral headache, which may be retroorbital, perior-
Postoperative pain syndromes bital, or frontal. Patients usually experience a sensation
Postthoracotomysyndrome of fullness or nasal stuffiness. Local extension of the lesion
Postmastectomy syndrome
Postradical neck dissection syndrome ultimately compromises nearby cranial nerves, usually
Postamputationsyndromes beginning with the abducens. Diplopia is thus the first
Postchemotherapy pain syndromes neurological symptom reported.
Painful polyneuropathy
Aseptic necrosis of bone Middle cranial fossa syndrome. Lesions lateral to the
Steroid pseudorheumatism sella may involve one or more of the branches of the tri-
Mucositis geminal nerve or the gasserian ganglion itself. Ipsilateral
Postradiation pain syndromes
Radiation fibrosis of brachial or lumbosacral plexus facial pain may be continuous or may mimic trigeminal
Radiation myelopathy neuralgia. Pain may be accompanied by trigeminal sen-
Radiation-inducedperipheral nerve tumors sory loss or diminution of the corneal reflex.
Mucositis
Radiation necrosis of bone Clivus syndrome. Neoplastic invasion of the clivus often
Pain indirectly related or unrelated to cancer refers pain to the vertex. This pain may be markedly ex-
Myofascial pains acerbated by neck flexion. Recognition of this referral
Postherpetic neuralgia
Osteoporosis pattern is essential in evaluating cancer patients with pro-
gressive vertex pain. Progression of the lesion eventually
compromises cranial nerves, with the specific deficits de-
neural processes that convert a quiescent lesion into a site pendent on the location of the lesion relative to the sella
of pain are unknown. Local elaboration of prostaglandins, and neural foramina.
particularly PGE2,may play a central role in this process.39 Jugular foramen syndrome. This well-described neu-
Clinically, involvement of prostaglandins is suggested by rologic syndrome, which is characterized by dysfunction
the especial efficacy of the nonsteroidal antiinflammatory of cranial nerves IX, X, and XI, may be accompanied by
drugs. one or more distinct pain complaints. Glossopharyngeal
Many pain syndromes related to bony infiltration have neuralgia, a lancinating pain experienced in the throat,
been identified. These can be summarized as follows: may be the sole pain complaint or may occur in con-
Base-of-skull syndrome^^^.^': Neoplastic involvement junction with pain referred to the ipsilateral occiput or
of the base of the skull is most often due to a metastatic postauricular region. The latter pains are usually contin-
deposit. The resulting syndromes comprise a spectrum of uous and often are exacerbated by neck flexion.
clinical disorders characterized by specific pain referral Occipital condyle syndrome. Neoplastic involvement
patterns and concomitant neurologic signs. of the occipital condyle produces severe occipital pain,
2302 June 1 Supplement 1989
CANCER Vol. 63

which often worsens with movement of the head. Infil- to the possibility of an occult spinal lesion located further
tration of the hypoglossal nerve produces ipsilateral rostrally, even if one is not apparent on plain radiographs.
weakness and atrophy of the tongue. The propinquity of Bone scintigraphy may assist in targeting additional ra-
the occipital condyle to the jugular foramen may be re- diographic procedures, in particular CT or MRI. Also,
flected in the coexistence of this syndrome with the jugular CT and MRI can be useful in assessing the possibility of
foramen syndrome. pain referred from an extraspinal site, such as the para-
Vertebral syndromes: The early recognition of pain spinal gutter.
syndromes due to neoplastic invasion of vertebral bodies LI syndrome. Lesions involving the L, vertebra, and
is essential. Pain usually precedes compression of adjacent sometimes TI*,can refer pain to the ipsilateral iliac crest
neural structures, and primary therapy directed at the le- or the sacroiliacjoint. Imaging procedures directed at pel-
sion during the period in which pain is the sole manifes- vic bones will therefore miss the source of the pain. Delay
tation may prevent the development of potentially cata- in diagnosis may result in the development of a conus
strophic neurologic deficits. This recognition often re- medullaris or cauda equina syndrome. Recognition of this
quires substantial clinical acumen; referral of pain is referral pattern will lead to the selection of radiographic
common, and the associated symptoms and signs can procedures targeted to the appropriate level of the spine.
mimic a variety of other disorders, both malignant (e.g., Sacral syndrome. Severe focal pain radiating to the
paraspinal masses) and nonmalignant (e.g., osteoarthritis buttocks, perineum, or posterior thighs may accompany
or osteoporosis with collapse). destruction of the sacrum. Such pain often is precipitated
Atlantoaxial syndrome. Destruction of the atlas or or exacerbated by sitting or lying and is improved by
fracture of the odontoid process with secondary sublux- standing or walking. Compression of sacral nerve roots
ation of the atlas on the axis typically causes severe pain results in bladder and bowel dysfunction, the earliest as-
experienced in the occiput and the nuchal region. Pain sociated neurologic deficits.
often worsens with movement of the neck, particularly Diffuse or multifocal bone pain: Multiple bony metas-
flexion. The ensuing compression of the spinal cord at tases are by far the most common cause of generalized
the cervicomedullary junction may be acute or progres- bone pain. Rarely, such pain may be due to diffise marrow
sive. If compression is progressive, symptoms and signs involvement by malignant cells; the latter has been ob-
may begin in the hands and arms and progress to involve served in both hematologic malignancies and solid tu-
sensory, motor, and autonomic function in all the ex- mors. In one notable case, for example, bone marrow
tremities. This distribution of deficits, ie., early involve- biopsy revealed marrow replacement by carcinoma in a
ment of the upper extremities, and the occasional ap- patient who presented with generalized bone pain without
pearance of so-called “pseudo-levels” suggestive of more other signs or symptoms of systemic disease, radiographic
caudal spinal lesions, may present a clinical picture much findings, or laboratory abnormality (except mild anemia).
different from those usually seen with compression of the In this patient, pain lessened markedly after initial che-
spinal cord at other sites. A high degree of suspicion is motherapy.
therefore needed to avoid undue delay in diagnosis. Clin- Pain due to neural involvement:Neoplastic involvement
ical experience again suggeststhat CT is a sensitive method of peripheral nerve, nerve plexus, nerve root, or spinal
for visualizing the upper cervical spine, although early cord may result in specific pain syndromes. Similar to the
data indicate that MRI may be superior in providing views vertebral syndromes, the recognition of pain patterns as-
of the cervicomedullaryjunction.42Plain radiography, to- sociated with infiltration of neural structures can suggest
mography, and bone scintigraphy should be viewed as sites and methods of evaluation and offer the possibility
ancillary procedures. Patients with neurologic deficits, or for the early application of primary therapy. Pain caused
those in whom spinal lesions at the upper cervical spine by neural involvement can be classified as follows:
have been identified, usually require myelography as Peripheral nerve syndromes: Peripheral nerve syn-
we11.43 dromes can be divided into the painful mononeuropathies
C,-Tl syndrome. Invasion of vertebra C7 or TI can and painful polyneuropathy. Best characterized among
result in pain referred to the interscapular region. Such the former group are those related to paraspinal masses
lesions are commonly missed, because radiographic eval- (spinal nerve involvement), chest wall or rib lesions (in-
uation may be mistakenly targeted inferior to the site of tercostal nerve involvement), and retroperitoneal masses.
damage. Additionally, visualization of the appropriate re- Paraspinal masses may envelop one or more spinal
gion on routine radiographs may be inadequate due to nerves as they exit the spinal column and produce a pain
obscuration by overlying shadows. Patients with inter- syndrome that mimics radiculopathy, thereby posing a
scapular pain should therefore undergo spinal radiography diagnostic challenge. Indeed, proximal growth into the
of both the cervical and thoracic spine. In the absence of epidural space, resulting first in a coexistent radiculopathy
a midthoracic spinal lesion, consideration should be given and ultimately in spinal cord or cauda equina compres-
No. I 1 EPIDEMIOLOGY
AND SYNDROMES OF CANCER PAIN - POrtenOy 2303

sion, is such a common c ~ m p l i c a t i o n that

~ ~ , ~myelog-
~ and intervals greater than 6 months between pain onset
raphy has been advocated as part of the evaluation of and diagnosis are common.52 Evaluation of the plexus
most patients with paraspinal masses.43The pain from should be considered in all patients, with or without
these lesions may be aching or dysesthetic in quality, and known cancer, who develop persistent or progressive pain
may be experienced focally in the back or referred along of this type, or neurologic findings in a distribution con-
the distal course of the nerve. Again, CT and MRI are forming to the C8-TI segments (rare in benign cervical
the procedures of choice for establishing the existence of spine disease, in which the C5-C6 roots are usually in-
a lesion and determining its extent. volved).
Chest wall or rib lesions may infiltrate intercostal nerves Cross-sectional imaging with CT is currently the best
and produce unilateral pain in the chest. These pains, too, method of detection in these patients4’ Proximal exten-
may be aching or dysesthetic, located superficial to the sion of the mass through the intervertebral foramen and
lesion or referred along the distal course of the nerve. Pain into the epidural space occurs commonly with Pancoast
may be continuous, paroxysmal, or both. Sensory distur- lesions, and up to 50%of untreated patients develop spinal
bances are often evident in the area of distribution of the cord c o m p r e ~ s i o nClinical
.~~ clues of epidural extension
affected nerves. include progressive pain and evidence of panplexopathy
Retroperitoneal masses, many of which extend to the or Horner’s syndrome on e ~ a m i n a t i o nThese
. ~ ~ findings
paraspinal gutter, produce protean pain complaints and in the setting of a known plexus lesion, or evidence of
neurologic findings, some of which may mimic radicular paraspinal extension on CT or MRI, justify further eval-
lesions. Pain may be localized in the back, flank, abdomen, uation with myelography.
buttocks, or legs and is sometimes distributed widely. Malignant lumbosacral plexopathy also usually begins
Similar to other peripheral nerve lesions, the quality and with pain, which is typically aching in quality. Some pa-
temporal characteristics are variable. In addition, a sub- tients also describe dysesthesias, which may be coincident
type of retroperitoneal lesion, believed to be due to infil- or independent of the aching discomfort and may be con-
tration of the celiac plexus, may produce a deep boring tinuous or have a paroxysmal component. Although pain
discomfort experienced in the epigastrium or midback. may be experienced in the back, the most prominent
This pain responds extremely well to celiac plexus symptoms are usually in the ipsilateral leg. Leg pain can
blockade.46 occur in a segmental or nonsegmental distribution, and
Painful polyneuropathy: Although polyneuropathy is depending on the specific region of the plexus affected,
a common remote effect of cancer, associated pain is a can predominate in the anterior or lateral thigh or in the
relatively rare manifestation. The most notable exception posterior aspect of the leg extending below the knee. Para-
occurs in the neuropathies associated with the plasma cell spinal encroachment of the tumor mass again predisposes
dyscrasias, including multiple myeloma, solitary plas- the patient to the development of epidural spinal cord
macytoma, and Waldenstrom’s macr~globulinemia.~~compression (a risk as high as 35% was found in one
Like other painful polyneuropathies, dysesthesias in this study5’), and myelography must be strongly considered
disorder are usually first experienced in the feet, progress in patients with evidence of a coexistent radiculopathy or
to the distal legs, and then may involve the hands. The paraspinal disease on CT or MRI.43
association between painful polyneuropathy and these Leptomeningeal metastases: Pain is a symptom in less
malignancies, and the observation that the neuropathy than 50% of patients with leptomeningeal m e t a s t a s e ~ . ~ ~ . ~ ~
may precede clinical evidence of disease by years, suggest Headache, back pains, segmental pains that can mimic
that painful polyneuropathy in a middle-aged individual compressive radiculopathy, and nonsegmental pains all
should prompt a search for one of the plasma cell dys- may occur in this syndrome. The protean neurologic and
crasias. If the search is fruitless, it should be followed by pain manifestations suggest that examination of the ce-
reevaluation at intervals of several months until a cancer rebrospinal fluid should be considered early in cancer pa-
is identified or an alternative explanation is found. tients with unexplained pains or neurologic signs.
Brachial and lumbosacral p l e ~ o p a t h y ~ ’ -Pain
~ ~ : is the Epidural spinal cord compression: Over 95% of patients
most common symptom associated with the malignant with epidural spinal cord compression report pain, which
plexopathies. Neoplastic invasion of the brachial plexus, may be focal or referred.55-57 Referred pain may be related
usually originating in the lung (Pancoast’s syndrome), to vertebral body involvement (see “Vertebral Syn-
typically presents with some combination of aching in the dromes” above), nerve root infiltration with radicular
shoulder, upper back, paraspinal region, and elbow, often symptoms, or rarely, spinal cord compression with referral
associated with burning dysesthesias of the medial aspect to the distal legs. Although the vast majority of patients
of the hand. Progression of the tumor results in loss of have pain as the first symptom of this lesion, most have
motor and sensory function in the arm. Identification of some degree of motor, sensory, or autonomic dysfunction
malignant brachial plexopathy is often unduly delayed, by the time diagnosis is made. This delay is unfortunate
2 304 CANCERJune I Supplement 1989 Vol. 63

I I I Back Dain t I

Without neurologic
signs or symptoms

Coexistent
radiculopathy
suspected
Malignant-appearing
progressing signs lesion on spine

yes
pDarasDinal
z zmassk q

r-l
Suspicious lesion
Admit to hospital
Dexamethasone 100 mg
Obtain spine radio-
. yes
Malignant-appearing
radiograph or
on bone scintigram

graphs suspicious lesion

Emergency myelo- on bone scintiaram

bony or paraspinal
Bony or paraspinal
lesion on CT
I
I
I
lesion on CT
no
Follow clinicallv

I
insider admission Obtain spine radiographs If k strongly suspected or
I I myelography delayed, give dexarnethasone Myelography as soon as possible

>8Oo/a Block I t 8 0 % Block Follow CII cally

High-dose Low-dose
dexamethasone dexamethasone
Emergency RT Routine RT
A

in light of data indicating that neurologic outcome is in- Postoperative pain syndromes: Surgical incision at vir-
versely related to the degree of deficit at the time definitive tually any location occasionally results in chronic pain.
treatment is ~ n d e r t a k e nThe
. ~ ~need for prompt diagnosis Although persistent pain is occasionally encountered after
suggests that definitive imaging of the epidural space nephrectomy, sternotomy, inguinal dissection, and other
should be performed in patients with back pain and clin- procedures, these pain syndromes have not been well de-
ical evidence of radiculopathy or myelopathy, back pain fined. In contrast, the following postoperative pain syn-
without neurologic findings but with radiographic evi- dromes have been described in detail:
dence of a neoplastic lesion at the appropriate level, and Postthoracotomy pain syndrome: A survey5*identified
pain associated with paraspinal masses (Fig. l).43 three postthoracotomy pain patterns. One group of pa-
tients with persistent pain had early improvement, fol-
Syndromes Related to Antineoplastic Therapy lowed by later recurrence. A second group experienced
progressive pain from the time of surgery. In both, tumor
Chronic pain may be a sequela of cancer treatment. recurrence was extremely prevalent. A third, smaller group
Specific pain syndromes can follow chemotherapy, sur- also had prolonged pain, which was stable or decreased
gery, or radiotherapy. from the time of surgery. These patients seldom had tumor
No. I 1 EPIDEMIOLOGY
AND SYNDROMES OF CANCER PAIN * PO~tenOy 2305

recurrence, and pain could usually be attributed to damage velops dysesthesias, which may be severe and character-
to the intercostal nerve. The quality of the pain, which ized by both continuous and paroxysmal elements. Treat-
was often burning, and other characteristicswere identical ment of these patients is symptomatic. Both pain and
in the three groups. neuropathic signs often improve after dscontinuation of
Postmastectomy pain syndrome: In contrast to post- the offending drug.
thoracotomy pain, prolonged pain after mastectomy rarely Painful aseptic necrosis: Painful aseptic necrosis of the
presages tumor recurrence, but rather is related to surgical femoral or humeral head may complicate the use of cor-
damage sustained by the intercostobrachial nerve, a cu- tico~teroids.~~ These lesions must be distinguished from
taneous branch of the TI-TZ spinal nerve.59360 The pain, a metastatic focus.
which is usually burning, is experienced in the axilla, me- Steroid pseudorheumatism: A less well-recognized dis-
dial aspect of the upper arm, and anterior chest wall. It order is steroid pseudorheumatism,66which is character-
can follow any surgery on the breast, including lumpec- ized by myalgias, arthralgias,and constitutionalsymptoms
tomy, and can occur almost immediately or up to months after steroid dose reduction. These symptoms abate rap-
after the procedure. idly after reinstitution of a higher steroid dose.
Postradical neck dissection pain syndrome: The chronic Painful oral mucositis: An acute monophasic pain syn-
pain ensuing in a small subgroup of these patients may drome related to shallow ulcerations of the oral mucosa
be neuropathic or somatic, and may relate to a variety of may follow some therapeutic regimens. For example, al-
causes, including recurrent tumor, damage to cervical cu- most two thirds of patients who undergo bone marrow
taneous nerves or local soft tissues, and the late effects of transplantation have moderate to severe pain for 3 to 4
radiation.61Many patients report a sensation of tightness weeks after the procedure.' Empirical treatment that in-
or burning in the anterolateral neck, jaw, ear, and sur- cludes local measures, antiinflammatory drugs, and sys-
rounding areas, which is commonly associated with lan- temic opioids can usually provide at least partial relief,
cinating pain shooting to the ear, angle of the jaw, or and education about the short-lived nature of the pain
temporal region. Some patients develop specific cranial syndrome can be psychologically helpful.
neuralgias, and some report aching in the shoulder, an- Postradiotherapy pain syndromes: Prolonged pain syn-
terior chest, and scapular region, which may be myofascial dromes after radiation therapy usually involve damage to
or related to a suprascapular mononeuropathy, both as- nerve plexus. Pain may also occur after treatment of the
sociated with drooping of the shoulder. Patients who de- spinal cord, mucosa, or bone. Rarely, pain is due indirectly
velop pain after radical neck dissection require careful to a radiation-induced secondary neoplasm.
imaging of the area by CT or MRI. Radiation fibrosis of brachial or lumbosacral
Postamputation pain syndromes: Two distinct pain p l e x ~ s ~ ' - ~Although
': some discomfort, such as heaviness,
syndromes can be recognized after amputation of a limb. is common in patients with symptomaticradiation fibrosis
Stump pain is due to a traumatic neuroma and is typically in the regions of the brachial or lumbosacral plexus, sig-
experienced in the distal aspect of the stump. Palpation nificant pain occurs in less than 25% of afflicted patients.
of trigger points may precipitate or exacerbate the pain, In contrast, pain is extremely common in plexopathy due
which often has both burning and lancinating compo- to tumor. Among patients with pain and neurologic signs
nents. Instillation of local anesthetics around the neuroma suggestive of plexus damage, this distinction between ra-
can often provide prolonged pain relief. diation fibrosis and recurrent neoplasm has profound im-
In contrast, phantom pain is experienced in the phan- plications for therapy and prognosis. Clinically, radiation
tom and is characterized by both continuous dysesthesias injury is usually accompanied by lymphedema and skin
and lancinating pain. Although phantom sensation and changes. In brachial plexus lesions, radiation plexopathy
some degree of phantom pain in the immediate postop- typically produces signs consistent with upper plexus in-
erative period are almost universal, the incidence of pro- volvement, conforming to a ( 2 4 6 segmental distribution,
longed phantom pain is controversial, with estimates whereas those with recurrent tumor have findings in a
ranging from 5% to more than 75% of patient^.^*,^^ Cs-TI root di~tribution.~~ Electromyography can be help-
Postchemotherapy pain syndromes: The following syn- ful, with the finding of myokymia suggesting radiation
dromes may occur in patients after chemotherapy: damage. CT or MRI may be very useful, delineating a
Painful polyneuropathy: Painful polyneuropathy is mass lesion compatible with neoplasm; more diffuse dis-
most common after treatment with the vinca alkaloids, tortion of tissue planes is a more nonspecific finding, con-
particularly ~ i n c r i s t i n e .Dose-related
~~ neuropathy also sistent with either tumor or radiation fibrosis.48Occa-
complicates the use of cis-platinum, but pain is less often sionally, biopsy provides the only avenue for a definitive
a feature of this syndrome. Virtually all patients who de- diagnosis.
velop clinically apparent neuropathy describe paresthesias, Radiation myelopathy: Radiation myelopathy, which
which themselves can be uncomfortable; a subgroup de- is uncommon, is complicated by pain in less than 20% of
2306 CANCERJune 1 Supplement 1989 Vol. 63

patients.67A variety of pains can be experienced, including difficult. Bone scintigraphy will not distinguish the two,
focal back pain, radicular pain, and central pains expe- and both may be accompanied by loss of vertebral height
rienced below the level of the lesion. It is extremely im- and paraspinal masses on plain radiographs. A CT scan
portant to distinguish radiation myelopathy from recur- can be extremely helpful in the diagnostic process by
rent tumor. This can usually be accomplished with non- demonstrating a destructive lesion, but some patients will
invasive imaging procedures and myelography. require a biopsy of the vertebral body for a definitive di-
Radiation-induced secondary neoplasm: Radiation fi- agnosis.
brosis may manifest itself clinically from 6 months to 20 Finally, pains common among patients without neo-
years after radiation treatment. If the primary neoplasm plasms occur also in patients with cancer. The stress as-
was one in which late recurrence is rare, a long delay sociated with cancer may exacerbate these conditions. The
between treatment and the onset of symptoms aids in the appropriate management of cancer patients who complain
differential diagnosis. It must be recognized, however, that of chronic headache, backache, arthralgia, or other com-
another possibility in this setting is a radiation-induced mon nonmalignant pain syndromes depends on a detailed
secondary neoplasm. These lesions produce both local history, a directed physical examination, frequent mon-
pain and pain radiating down the course of the affected itoring, and ultimately, good clinical judgment.
nerve. A mass is often palpable. If a mass cannot be dis- REFERENCES
cerned, one must be sought with appropriate imaging 1. Bonica JJ. Treatment of cancer pain: Current status and future
procedures. A tissue diagnosis is needed to confirm the needs. In: Fields HL, Dubner R, Cervero F, eds. Advances in Pain Re-
presence of such a lesion. search and Therapy, vol. 9. Proceedings of the Fourth World Congress
on Pain. New York: Raven Press, 1985; 589-616.
Bone necrosis: Radiation may contribute to necrosis of 2. Levin DN, Cleeland CS, Dar R. Public attitudes toward cancer
the femoral or humeral head. Occasionally, other pain pain. Cancer 1985; 56:2337-2339.
syndromes may be ascribed to this complication, such as 3. StjernswardJ. Cancer pain relief: An important global public health
issue. In: Fields HL, Dubner R, Cervero F, eds. Advances in Pain Research
necrosis of the mandible in patients receiving radiation and Therapy, vol. 9. Proceedings of the Fourth World Congress on Pain.
therapy for head and neck cancers. New York Raven Press, 1985; 555-558.
Mucositis: Similar to chemotherapy, radiation therapy 4. Twycross RG, Fairfield S. Pain in far-advanced cancer. Pain 1982;
14:303-310.
may cause self-limited pain syndromes related to mucosal 5 . Patterson KL, Kopovich PM. Pain in the pediatric oncology patient.
damage. Both oral mucositis and radiation proctitis can In: McGuire DB, Yarbro CH, eds. Cancer Pain Management. Orlando:
be associated with substantial, generally short-lived, local Grune and Stratton, 1987; 259-272.
6. Beyer J, DeGood D, Ashley L, Russel G. Patterns of postoperative
pain. analgesic use in adults and children following cardiac surgery. Pain 1983;
17:7 1-81,
Syndromes Indirectly Related or Unrelated to Cancer 7. Foley KM. Pain syndromes in patients with cancer. In: Bonica JJ,
Ventafridda V, eds. Advances in Pain Research and Therapy, vol. 2.
Myofascial pains are common in patients with cancer, New York: Raven, 1979; 59-75.
particularly in those with advanced di~ease.~ These pains, 8. Moms JN, Mor V, Goldberg RF et al. The effect of treatment
which are usually localized and aching, are generally due setting and patient characteristics on pain in terminal cancer patients:
A report from the National Hospice Study. J Chronic Dis 1986; 39:27-
to an unusual degree of stress on muscles or involuntary 35.
splintingas a consequence of adjacent lesion, such as nerve 9. Portenoy RK, Kanner RM. Patterns of analgesic prescription and
injury, pathologic fracture, or soft tissue infiltration. consumption in a university-affiliated community hospital. Arch Intern
Med 1985; 145:439-441.
Identification of these pains often suggests one or more 10. Goldberg RJ, Mor V, Wiemann M, Greer DS, Hiris J. Analgesic
local measures, including spray and stretch techniques,68 use in terminal cancer patients: Report from the National Hospice Study.
trigger point injections, or physiotherapy. J Chronic Dis 1986; 39:37-45.
11. Ventafridda V, Oliveri E, Caraceni A et al. A retrospective study
Herpes zoster is common among cancer patients, par- on the use of oral morphine in cancer pain. J Pain Syrnpt Manag 1987;
ticularly those with hematologic malignancies. Posther- 2:77-82.
petic neuralgia may follow and become a difficult pain 12. Twycross RG. Clinical experience with diamorphine in advanced
malignant disease. Int J Clin Pharmacol Ther Toxicoll914; 9: 184-198.
management problem. A variety of therapeutic ap- 13. Daut RL, Cleeland CS. The prevalence and severity of pain in
proaches is available, the appropriate selection of which cancer. Cancer 1982; 50:1913-1918.
depends on the duration of the pain and the clinical char- 14. Greenwald HP, Bonica JJ, Bergner M. The prevalence of pain in
four cancers. Cancer 1987; 602563-2569.
acteristics of the patient.69 15. McKegney FP, Bailey LR, Yates JW. Prediction and management
Pain in cancer patients occasionally is attributable to of pain in patients with advanced cancer. Gen Hosp Psychiatry 1981; 3:
the effects of osteoporosis, most often in the setting of a 95-101.
16. Pannuti E, Rossi AP, Marraro D. Natural history of cancer pain.
new compression fracture. The underlying process is ac- In: Twycross RG, Ventafridda V, eds. The Continuing Care of Terminal
celerated in these patients by bed rest, inadequate nutri- Cancer Patients. New York Pergamon, 1980 75-89.
tion, and the use of corticosteroid drugs. Differentiation 17. World Health Organization. Cancer Pain Relief. Geneva: World
Health Organization, 1986; 1-74.
between a compression fracture and pathologic collapse 18. McGivney WT, Crooks GM. The care of patients with severe
in a cancer patient with radiographic osteoporosis can be chronic pain in terminal illness. JAMA 1984; 25 1:1182-1 188.
No. I 1 EPIDEMIOLOGY
AND SYNDROMES O F CANCER PAIN * PUrtenOy 2307

19. Health and Public Policy Committee, American College of Phy- 44. Graus F, Krol G, Foley KM. Early diagnosis of spinal epidural
sicians. Drug therapy for severe chronic pain in terminal illness. Ann metastasis: Correlation with clinical and radiological findings. J Clin
Intern Med 1983; 992370473. Oncol (in press).
20. NIH Consensus Development Conference. The integrated ap- 45. Haddad P, Thaell JF, Kiely JM, Harrison EG, Miller RH. Lym-
proach to the management of pain. J Pain Sympt Manag 1987; 2:35- phoma of the spinal extradural space. Cancer 1976; 38: 1862-1866.
44. 46. Leung JWC, Bowen-Wright M, Aveling W et a/. Celiac plexus
2 1. Twycross RG, Lack SA. Symptom Control in Far Advanced Can- block for pain in pancreatic cancer and chronic pancreatitis. Br J Surg
cer: Pain Relief. London: Pitman, 1983; 43-55. 1983; 70:730-732.
22. Parkes CM: Home or hospital: Terminal care as seen by surviving 47. McLeod JG. Carcinomatous neuropathy. In: Dyck PJ, Thomas
spouse. J R Coll Gen Pract 1978; 28: 19-30. PK, Lambert EH, Bunge R, eds. Peripheral Neuropathy. Philadelphia:
23. Ventafridda V, Tamburini M, De Conno F. Comprehensive WB Saunders, 1984; 2 180-2 19 I.
treatment of cancer pain. In: Fields HL, Dubner R, Cervero F, eds. 48. Cascino TL, Kori S , Krol G ef a/. CT scanning of the brachial
Advances in Pain Research and Therapy, vol. 9. Proceedings ofthe Fourth plexus in patients with cancer. Neurology 1983; 33:1553-1557.
World Congress on Pain. New York: Raven Press, 1985; 617-628. 49. Kori S, Foley KM, Posner JB. Brachial plexus lesions in patients
24. Kane RL, Bernstein L, Wales L, Rothenberg R. Hospice effec- with cancer: Clinical findings in 100 cases. Neurology 1981; 3 1:45-50.
tiveness in controlling pain. JAMA 1985; 253:2683-2686. 50. Jaeckle KA, Young DF, Foley KM. The natural history of lum-
25. Aitken-Swan J. Nursing the late cancer patient at home. Practi- bosacral plexopathy in cancer. Neurology 1985; 35:8-15.
tioner 1959; 183:64-69. 5 1. Thomas JE, Cascino TE, Earle JD. Differential diagnosis between
26. Marks RM, Sachar El. Undertreatment of medical inpatients with radiation and tumor plexopathy of the pelvis. Neurology 1985; 35:l-7.
narcotic analgesics. Ann Intern Med 1973; 78:173-181. 52. Kanner R, Martini N, Foley KM. Incidence of pain and other
27. Cartwright A, Hockey L, Anderson ABM, eds. Life Before Death. clinical manifestations of superior pulmonary sulcus tumor (Pancoast’s
London: Routledge and Kegan Paul, 1973; 1-300. tumors). In: Bonica JJ, Ventafridda V, Pagni CA, eds. Advances in Pain
28. Shine D, Demas P. Knowledge of medical students, residents and Research and Therapy, vol. 4. New York: Raven Press, 1982; 27-38.
attending physicians about opiate abuse. JMed Educ 1984; 59:50 1-507. 53. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment
29. Charap AD. The knowledge, attitudes and experience of medical of leptomeningeal metastasis from solid tumors: Experience with 90 pa-
personnel treating pain in the terminally ill. Mt Sinai J Med 1978; 45: tients. Cancer 1982; 49:759-772.
561-580. 54. Olson ME, Chernik NL, Posner JB. Infiltration of the leptome-
30. Kanner RM, Portenoy RK. Unavailability of narcotic analgesics ninges by systemic cancer: A clinical and pathological study. Arch Neurol
for ambulatory cancer patients in New York City. J Pain Sympt Manag 1978; 30:122-137.
1986; 1~87-90. 55. Gilbert RW, Klin JH, Posner JB. Epidural spinal cord compression
3 I . Wenk R. Availability of analgesics in Argentina. J Pain Sympt from metastatic tumor: Diagnosis and treatment. Ann Neurol 1978; 5:
Manag 1987; 2:191-192. 40-5 I .
32. Caraceni A. Availability and use of opioids for cancer pain patients 56. Posner JB. Back pain and epidural spinal cord compression. Med
in Italy. JPain Sympt Munag 1987; 2:127-128. Clin North Am 1987; 71:185-206.
33. Portenoy RK. Diagnosis and management of cancer pain syn- 57. Barcena A, Lobato RD, Rivas JJ et ul. Spinal metastatic disease:
dromes. In: Fields HL, ed. Pain Syndromes in Neurologic Practice. New Analysis of factors determining functional prognosis and choice of treat-
York Butterworths (in press). ment. Neurosurgery 1984; 15:820-827.
34. Kanner RM, Foley KM. Patterns of narcotic drug use in a cancer 58. Kanner R, Martini N, Foley KM. Nature and incidence of post-
pain clinic. Ann NYAcadSci 1981; 362:161-172. thoracotomy pain. Proc Am Soc Clin Oncol 1982; 1:152.
35. Janig W. Neurophysiological mechanisms of cancer pain. Recent 59. Assa J. The intercostobrachial nerve in radical mastectomy. J
Results Cancer Res 1984; 89:45-58. Surg Oncol 1974; 6:123-126.
36. Payne R. Anatomy, physiology and neuropharmacology of cancer 60. Granek I, Ashikari R, Foley KM. Postmastectomy pain syndrome:
pain. Med Clin North Am 1987; 71:153-168. Clinical and anatomic correlates. Proc Am Soc Clin Oncol 1983; 3: 122.
37. Wall PD. Cancer pain: Neurogenic mechanisms. In: Fields HL, 61. Greenslade R, Portenoy RK. Pain syndromes in head and neck
Dubner R, Cervero F, eds. Advances in Pain Research and Therapy, cancer. J Pain Sympt Manag 1988; 35.2 1.
vol. 9. Proceedings of the Fourth World Congress on Pain. New York 62. Weis A. The phantom limb. Ann Intern Med 1956; 44:668-677.
Raven Press, 1985; 575-587. 63. Sherman RA, Sherman CJ. Prevalence and characteristics of
38. Tasker RR. Deafferentation. In: Wall PD, Melzack R, eds. Text- chronic phantom limb pain among American veterans: Results of a trial
book of Pain. New York Churchill Livingstone, 1984; 119-1 32. survey. Am J Phys Med 1983; 62:227-238.
39. Galasko CSB. Mechanism of bone destruction in the development 64. Lequesne PM. Neuropathy due to drugs. In: Dyck PJ, Thomas
of skeletal metastasis. Nature 1976; 263507-5 10. PK, Lambert EH, Bunge R, eds. Peripheral Neuropathy. Philadelphia:
40. Greenberg JS, Deck MDF, Vikram B et al. Metastasis to the base WB Saunders, 1984; 2 126-2 179.
of the skull: Clinical findings in 43 patients. Neurology 1981; 31530- 65. Ihde DC,DeVita VT. Osteonecrosisof the femoral head in patients
537. with lymphoma treated with intermittent combination chemotherapy
4 1. Bingas B. Tumors of the base of the skull. In: Vinken PJ, Bruyn (including corticosteroids). Cancer 1975; 36: 1585-1588.
GW, eds. Handbook of Clinical Neurology, vol. 17. Amsterdam: North 66. Rotstein J, Good RA. Steroid pseudorheumatism. Arch Intern
Holland, 1974; 136-233. Med 1957; 99:545-555.
42. Bosley TM, Cohen DA, Schatz NJ et al. Comparison of metriz- 67. Jellinger K, Sturm KW. Delayed radiation myelopathy in man.
amide computed tomography and magnetic resonance imaging in the JNeurolSci 1971; 14:389-408.
evaluation of lesions at the cervicomedullary junction. Neurology 1985; 68. Travel1 JG, Simons DG.Myofascial Pain and Dysfunction: The
351485-492. Trigger Point Manual. Baltimore: Williams & Wilkins, 1983; 45-102.
43. Portenoy RK, Lipton RB, Foley KM. Back pain in the cancer 69. Portenoy RK, Duma C, Foley KM. Acute herpetic and posther-
patient: An algorithm for evaluation and management. Neurology 1987; petic neuralgia: Clinical review and current management. Ann Neurol
37: 134-138. 1986; 20:651-664.