Download Cancer pain: Classification and pain syndromes

/REVIEW ARTICLE
UDK 616.8-009.7:616-006
Cancer pain (classification and pain syndromes)
........
.................................
rezime
E. Slavik, S. Ivanovi}, D. Gruji~i}
Institute of Neurosurgery, Clinical Center of Serbija,
Belgrade,
Inspite the new informations about the physiology and biochemistry of pain, it remains true
that pain is only partially understood. Cancer
pain is often experienced as several different
types of pain, with combined somatic and
neuropathic types the most frequently. If the
acute cancer pain does not subside with initial
therapy, patients experience pain of more constant
nature, the characteristics of wich vary with the
cause and the involved sites. Chronic pain related to
cancer can be considered as tumor-induced pain,
chemotherapy-induced pain, and radiation therapyinduced pain. Certain pain mechanisms are present
in cancer patients. These include inflammation due
to infection, such as local sepsis or the pain of herpes zoster, and pain due to the obstruction or occlusion of a hollow organ, such as that caused by large
bowel in cancer of colon. Pain also is commonly due
to destruction of tissue, such as is often seen with
bony metastases. Bony metastases also produce
pain because of periostal irritation, medullary pressure, and fractures. Pain may be produced by the
growth of tumor in a closed area richly supplied
with pain receptors (nociceptors). Examples are tumors growing within the capsule of an organ such
as the pancreas. Chest pain occurring after tumor
of the lung or the mediastinum due to invasion of
the pleura. Certain tumors produce characteristic
types of pain. For example, back pain is seen with
multiple myeloma, and severe shoulder pain and
arm pain is seen with Pancoast tumors.
Key words: cancer pain, tumor-induced pain,
chemotherapy induced-pain, radiation
therapy-induced pain.
CLASSIFICATION OF CANCER PAIN
atients with advanced malignancy often have pain
as their chief complaint. The pain is present in 20%
to 50% of all patients in early stages to 55% to 95%
in the latter stages of cancer desease. Approximately
60% to 80% of all patients have tumor-related pain,
20% to 30% have treatment-related pain, and 10% to
15% have pain unrelated to the cancer1. Because of its
subjective nature, pain, especially chronic pain, is very
difficult to classify. Pain may be classified according to
its neurophysiologic mechanisms and to pain duration.
According to neurophysiologic mechanisms underlaying in pain, all pain syndromes are classified as nociceptive, neuropathic, reffered, and sympathetic pain2.
Nociceptive pain is generated by activation of ending
of primary afferent neurons responsive to noxious stimuli (nociceptors) that have been situated in somatic
(skin, muscle) or visceral (lung, liver, intestine) tissue.
Nociceptors are not found in the central nervous system. Nociceptive pain that originates from somatic
structures is also termed as somatic pain3; it is caraterized as well-localized, sharp, aching, or pressure like.
Somatic pain is carried along the sensory fibers. Pain
originating from viscera is also known as visceral pain
and is described as deep, dull, vague, difficult to locate,
cramping or gnawing, often radiating away from the affected organ when due to obstruction of a hollow viscus, and sharp, or aching, when due to involvement of
organ capsules or other mesentery 4. It is usually accompanied by an increase in sympathetic outflow and
spasm of adjacent musculature.
P
10
E. Slavik i sar.
Visceral pain may be transmited by autonomic (sympathetic) fibers. Neuropathic pain is defined as pain
produced by an alteration of neurological structure
and/or function of neurons5. Direct injury to neuronal
tissue from tumor infiltration or from cancer therapies
(radiation, chemotherapy) can result in this condition.
A high frequency of cancer pain is associated with
neuropathic pain. The main difference between
neuropathic and nociceptive pain is the absence of a
continuous nociceptive input. A lesion in the central
nervous system causes a central neuropathic pain, such
as thalamic pain, post-paraplegia pain, or post quadriplegia pain6. Lesions in the peripheral nervous system
produces a peripheral neuropathic pain (diabetic painful neuropathies, metastatic neuropathies). Reffered
pain, or viscero-somatic reflex - the pain is referred to
the dermatomes represented by the spinal segments
supplying the effected viscera7. Sympathetic pain can
occur after pathological fractures, thrombosis due to
hypercoagulable states, and lymphedema of extremities. This condition is characterized by constant burning, alodynic pain with associated sudomotor and vasomotor changes, edama and coldness of the affected
area8.
According to duration a pain may be defined as acute
and chronic pain. All pain syndromes begin as acute
and remain acute during the time of the course of expected healing of the causative stimulus9. Acute pain
syndromes generally have either somatic or visceral
nocicep tive sources, but a neurogenic causa may be a
component of some of them10,11. Somatic sources of
acute pain include injuries to skin, muscle, fascia, periosteum and joints12,13. Visceral sources of acute pain
include distention, stretching, inflammation, and ischemia of the peritoneum, hollow abdominal and pelvic organs, solid organ capsules, pleura, myocardium,
and pericardium14,15. Chronic pain is defined as persisting a month beyond the usual course of an acute
disease or a reasonable time period for an injury to heal
(Bonica). Chronic persistent pain may impose sever
physical, emotional, or socioeconomical influences on
the patients and his relevants16. Cancer pain may result
from direct infiltration, or pressure, or stretching of
nerve fibers. Also, it may be induced by secondary infection, for example pyelonephritis, pyometria or aspiration pneumonia in patients suffering from tumours of
the mouth, pharynx or larynx.
There may be infection within the tumour itself. Obstruction of a hollow viscus, such as the ureter in carcinoma of the bladder or cervix, can give rise to ureteric
or renal colic, while the obstruction of the bowel, in gynaecological or pelvic malignancy, may produce subacute bowel obstruction and pain. Tissue damage secondary to a malignancy treatment may be a source of
ACI Vol. LI
intractable pain, as radiation-therapy and chemotherapy-induced pain16. In essence, the cancer pain may be
thought of as a combination of chronic and continually
recurring acute pain, but during a progression of malignancy disease a neuropathic and sympathetic pain
may be accompanied17.
PAIN SYNDROMES
Tumor-induced pain
Pain may occur at the site of the primary tumor or at
the site of the metastasis, or it may be referred to a distant area.
Bone Pain - Bone metastasis are the most common
cause of chronic pain in cancer patients. The pain is
caused by endosteal or periosteal nociceptor activation
on two ways: b yrealizing chemical mediators or by direct mechanical distortion. Direct tumor invasion into
adjacent soft tissue and nerves may be also very painful18.
Tumor-induced osteolytic activity produces prostaglandins, specifically PGE2, wich may sensitize peripheral nerve endings, thus priming the organism for
nociceptive input. Other tissue autocoids are also released as a result of osteolytic activity (tumor necrosis
factor, potassium, bradykinin). These tissue hormones
leads to sensitization of neurons to mechanical, chemical, and thermal stimuli. They also lower discharge
thresholds of the neuronal membrane, produce exaggerated responses to suprathreshold stimuli, and provoke tonic impulse discharges in normally silent nociceptors. The primary nociceptive source of input
from the bone is the periosteum. Joint pain often arises
as a reaction to inflammatory processes provoked by
the malignant process and may be classified as a paraneoplastic syndrome19.
The most frequent metastases to bone are cancers of
lung, brest and prostate. The vertebrae are the most
common sites of bony metastases. In the thoracic spine
are located more then 30% of all vertebral metastases;
lumbosacral and cervical metastases account for approximately 20% and 10%. Multiple vertebral metastasis occurs in more then 85% of patients, but some of
them are very difficult for visualization. Magnetic resonance imaging (MRI) is probably the best method for
imaging this microlesions. Computed tomography
(CT), plain radiography, tomography and bone scintigraphy are the complementary procedures.
Metastatic destruction of the atlas or pathological
fracture of the odontoid process demonstrate a typical
nuchal or occipital pain, exacerbating by movement of
the neck, especially by flexion. Metastases of the C7
or Th1 vertebra result in pain referred to the interscapular region. Unfortunately, a radiographic evaluation
could be targeted to the painful area caudal to the site
Br. 4
Cancer pain (classification and pain syndromes)
of lesion. Patients with interscapular pain have to undergo MRI of both the cervical and the thoracic spine.
Similary, a Th12 or L1 vertebral metastases can refer
pain to the ipsilateral iliac crest or the sacroiliac joint.
Invasion of the sacrum is manifested by severe focal
pain radiating to buttocks, perineum, or posterior
thighs, exacerbating by sitting or lying and relieving by
standing or walking. The metastatic invasion to surrounding structures can results in other pain syndromes. Spreading laterally to m. pyriformis, a pyriformis pain syndrome could be appeared; it characterized
a pain located in buttock or posterior leg, exacerbating
by internal rotation of the hip.
Metastatic involving of the sacral plexus, may leads
to a sacral neuropathic pain syndrome20. Epidural compression of the spinal cord or cauda equina is the common cause of cancer pain. This pain usually precedes
neurological signs by a prolonged period and should be
viewed as a indicator of growing of epidural metastasis.
Because the back pain is a nonspecific symptom that
can result not only from bony or paraspinal metastases,
with or without epidural progression, but from many
benign conditions also, a early systematic evaluation is
necessary. The options for definitive imaging include
MRI and CT myelography21.Metastatic invasion of the
pelvis commonly provokes a incidental pain by ambulantion. Tumor involvement of the acetabulum or head
of the femur typically produces localized hip pain radiating to the knee or medial thight; the pain is aggravated by weight bearing and movement of the hip. Metastatic spreading in pelvic region frequently leads to
compression of lumbosacral plexus inducing chronic
pain in the leg or lumbal region22.
Cancer of breast, lung, and prostate freaquently send
metastasis in base of skull. These pain syndromes often
represent a combination of nociceptive and neuropathic
pain
HEADACHE
The prevalence of headache in patients with brain
metastases is 60% to 90%. The pain may be local, at
the site of tumor, or generalized. The intracranial mass
lesions produced headache by stimulation of nociceptors in dural and vascular tissue. Especialy the stretching of these structures are painful. Such effects of tumors may be, directly or indirectly, due by increased
intracranial pressure23. Maneuvers that transiently increase intracranial pressure can cause episodes of sever
headache. Patients with multiple metastases and those
with posterior fossa lesions are more likely to experience headache. Posterior fossa metastases often cause
a bifrontal headache24.
11
According to the site of intracranial metastatic involvement there are various pain syndromes. Parasellar
syndrome supraorbital or frontal headache which may
be associated with some of other neurological dysfunction (diplopia, external ophtalmoparesis, quadrantopsia). Orbital syndrome progressive pain in the retroorbital and supraorbital area and associated symptoms
(blurred vision, chemosis, proptosis, external ophtalmoparesis). Jugular foramen syndrome refered pain to
the posterior pharynx, ipsilateral ear, mastoid region or
ipsilateral neck or shoulder; occasionally, a pain may
mimics idiopathic glossopharyngeal neuralgia. Occipital condyle syndrome - unilateral occipital pain worsening with neck flexion, ipsilateral hypoglossal nerve
paralysis and sternocleidomastoid weakness. Clivus
syndrome pain localized in vertex area and worsened
by neck flexion, accompanied by dysfunction of cranial
nerves (V-Xll). Sphenoid sinus syndrome - bifrontal or
retroorbital pain with radiation to the temporal region,
diplopia and abducens paresis. Middle cranial fossae
syndrome - pain in the cheek or jaw, occasionally can
mimics idiopathic trigeminal neuralgia; hypesthesia in
the trigeminal nerve distribution and the weakness in
the ipsilateral muscules of mastication25.
VISCERAL PAIN
Gastric cancer has a high mortality rate, especially
adenocarcinoma. The clinical presentation may be asymptomatic or with vague, epigastric pain, associated
with vomiting, weight loss and hematemesis26,27.
Pancreatic cancer is a lethal disease and less than 2%
of the patients survival over five years. The clinical
presentation is that of an epigastric, gnawing, dull, aching pain that radiates to the back in 25% of the patients.
It is associated with anorexia, weight loss and vomiting28.
Extensive intrahepatic metastases may produce a local dull and aching pain in the right subcostal region or
a referred pain in the right neck, shoulder and scapula29. The nociceptive structures in the liver are the
capsule, vessels and biliary tract; they are inervated
from celiac plexus, phrenic nerve and lower right intercostals nerves30
Early primary cancer of the pelvic viscera rarely produces pain. Its initialy spread to lumbosacral plexus
and bones leading to intensive pain31. Retroperitoneal
and pelvic lesions involving the deep somatac structures of the posterior abdominal wall, the sensitive connective tissue or the celiac plexus may produce mixed
nociceptive and neuropathic pain. The pain is dull and
located in the epigastrium and the low thoracic region
in the back. It is exacerbated by movement or deep inspiration, and improved by sitting or lying in a lateral
decubitus position32,33.
12
E. Slavik i sar.
The abdominal and pelvic cancers may produce the
continous or colickly pains as a result of chronic intestinal obstruction with consecutive intestinal distension,
mesenteric tension, and mural ischemia. The pain is referred to the dermatomes represented by the spinal segments supplying the effected viscera. Peritoneal carcinomatosis can cause a diffuse abdominal or low back
pain or stretching pain in the anterior abdominal
wall34.
Malignant tumors of the colon, rectum, female reproductive tract, and distal genitourinary system cause a
perineal constant or aching pain, often aggravated by
sitting or standing. It may involve mixed nociceptive
or neurapthic mechanisms. In patients with urinary,
colonic, or gynecological carcinomas, involvement and
compression of lumbosacral plexus (L5-S1) produces
pain in the anterior thigh , or at compression of upper
lumbal plexus (L1-L3) pain is located in the groin. At
the lower lumbal plexus compression, pain is distributed from the posterior part of the leg to the heel. Metastatic involvement of sacral plexus is characterized
by perineal sensory loss associated with dull, aching,
medline pelvic pain35,36.
Cancers of the cervix, ovary, prostate, and rectum are
most commonly associated with a tipically dull chronic
discomfort in the flank, wich may radiate into the inguival region or genitalia. In advanced stages of malignant desease a infiltration and compression of lumbosacral plexus are possible. If that occurs a intractable
chronic pain in the lumbosacral region or leg appears37,38.
Carcinoma of the lung is the very freaquent cancer
site and cause of death. There are three main types of
pain arising from lung cancer within the thorax. Mediastinal pain from mediastinal lymph node involvement,
or direct extension of the primary tumour into the mediastinum. It is a dull, borning, central persistent pain.
Chest wall pain arising from direct involvement of the
chest wall and malignant invasion of ribs or intercostals nerves. It is a very severe pain which may radiate some distance from the site of origin.
Pancoasts syndrome is present when a carcinoma at
the lung apex makes invasion and erosion of one or
more of the upper ribs, expanding directly into the brachial plexus. As a result of involvement of the brachial
plexus these patients suffer very severe pain irradiating
into shoulder, the ipsilateral upper extremity, medial
two fingers and medial upper arm, adjacent thorax, or
scapula, with or without neurological physical signs.
The pain is characteristically persistent. Clinical signs,
as Horners syndrome, sympathetic denervation and
sensory or motor involvement of the lower brachial
plexus, are present in 34% of these patients39.
ACI Vol. LI
RADIATION THERAPY
INDUCED PAIN
Postradiation pain may occurs after few weeks,
months or years of radiation therapy as neuropathic
pain or as nociceptive pain (the rectum and rectosigmoid are more commonly involved).
Postradiation plexopathy of brachial, cervical, or
lumbosacral nerve plexuses is accompanied by diffuse,
constant, burning neuropathic pain with dysesthesias
and paresthesias developing from 6 months to 20 years
after therapy.
Early after irradiation may develop a painful mucosal
thining or ulceration of oral, gastric, esophageal or
some other mucosa. The rectum and rectosigmoid are
more commonly involved). The damage of small intestine lead to cramping pain, mucosal ulcera and development of fistula. Sometimes, after three months to
three years appear a chronic cramping pain of proctitis
caused by radiation therapy40.
Postradiation myelopathy can be expressed as transient or as chronic form. The first develops over 4
months after radiation and resolves in 2 to 36 weeks.
The second develops over 5 to 13 months after radiation41.
CHEMOTHERAPY
INDUCED PAIN
The oral mucositis, as a sequela to chemotherapeutic
agents, is making a swallowing very difficult. The
chronic steroid use frequently leads to aseptic necrosis
of bone or pathological fracture of the femoral or humeral head which are associated with constant, intractable dull pain. Some of the used chemotherapy agents
may result in the development of chronic pain42.
Treatment of cancer pain with therapeutic doses of
vincristine and vinblastine can result in a painful symmetrical polyneuropathy, arthralgia and myalgia.
REFERENCES
1. Bonica JJ, Ventafridda V, Twycross RG. Cancer
Pain. In Bonica JJ,ed: The Management of Pain,ed
2.Vol 1.Philadelphia, Lea&Fwebiger,1990;401-404.
2. Twycross R. Cancer pain classification. Acta Anaesthesiol Scand , 1997; 41: 141-145.
3. Kerr, FWL.Neuroanatomical substrates of nociception in the spinal cord. Pain 1975;l: 325-356.
4. Willis WD. The pain system. The neural basis of
nociceptive transmission. Pain and headache. Vol 8.
Basel, Switzerland: Karger, 1985;356-376.
Br. 4
Cancer pain (classification and pain syndromes)
5. Johnson BW, Parris WCV. Mechanisms of
neuropathic pain. In Raj PP, ed: Current Review of
Pain. Curr Med ,1994; 179.
6. Bowsher D. Central pain: Clinical and physiological characteristics. J Neurol Neurosurg Psychiatry,
1996; 61:62-69.
7. Lee SI, Phillips LH, Jane JA. Somato-somatic referred pain caused by suprasegmental spinal cord tumor. Neurology, 1991;41:928.
8. Payne R: Pathophysiology of cancer pain. In Foley
KM, Bonica JJ, Ventafrida V, et al, eds: Advances in
Pain Research and Therapy. Vol. 16, New York, Raven Press, 1990; 13-26.
9. Crews JC. Acute Pain Syndrome. In Ray PP, ed:
Practical Management of Pain. St Louis, Mosby , 2000;
14: 169-171.
10. Spence AA. Relieving acute pain. Br J Anaesth
1980; 52:245-246.l
11. Bonica JJ. General consideration of acute pain.
In Bonica JJ, ed: The Management of Pain. Philadelphia, Lea & Febiger, 1990; 159-179
12. Gebhart GF. Visceral pain mechanisms. In Chapman RC, Foley KM, eds: Current and Emerging Issues in Cancer Pain: Research and Practice. New York,
Raven Press, 1993; 99.
13. Cervero F. Mechanisms of visceral pain. In: Lipton S, Miles J,eds: Persistent pain. Vol 4. London:
Academic Press,1983; 1-19.
14. Ness TJ, Gebhart GF. Visceral Pain: a review of
experimental studies. Pain, 1990;41:167-234.
15. Procacci P, Maresca M, Cersosimo R: Visceral
pain: Pathophysiology and clinical aspects. In Costa
Med: Sensory Nervesand Neuropeptides in Gastroenterology, New York, Plenum Press, 1991;98-142.
16. Merskey H, Bogduk N. Classification of Chronic
Pain, ed 2. Seattle, IASP Press, 1994; 56-98.
17. Johnson BW, Paris WCV. Mechanisms of cancer
pain. In Parris WCV, ed: Cancer Pain Management:
Principles and Practice. Newton, Mass, ButterworthHeinemann, 1997; 31-38.
18. Thompson CB, Crawford ME, Sjogren P. Malignant bone pain. Ugeskr Laeger, 1997; 159:2364-2369.
19. Woodforde JM, Fielding JR. Pain and cancer. In
Wiesenberg M, ed:Pain, Clinical and Experimental
Perspectives, St Louis, Mosby, 1975;15:128-145
20. Cherny NI, Portenoy RK. The management of
cancer pain. CA Cancer J Clin , 1994; 44:262-303.
21. Chapman CR. Pain related to cancer treatment. J
Pain Symptom Manage, 1988; 3:188-193.
22. Swerdlow M: Relief of Intractable Pain, ed 3.Amsterdam, Excerpta Med, 1983;68-78.
13
23. Moskowitz MA. The neurobiology of vascular
head pain. Ann Neurol, 1984; 16:157-168.
24. Ho RCS Pain in the cancer patient. Cancer J Clin
, 1994; 44:259.
25. Foley K: Pain syndromes in patients with cancer.
In Bonica JJ, Ventafrida V, eds: Advances in Pain Research and Therapy, Vol 2. New York, Raven Press,
1979; 59-75.
26. Ferrer-Brechner T: Rational management of cancer-related pain. In Raj PP, ed: Practical Management
of Pain. Chicago, Year Book Medical Publichers,
1986;312-328.
27. Ray PP: Practical Management of Pain. Mosby,
St Louis, 2000; 11:119-132.
28. Foley KM.The treatment of cancer pain.N Engl J
Med,1985;313:84-95.
29. Cervero F. Sensory innervation of the viscera:
Peripheral basis of visceral pain. Physiol Rev
1994;74:95-138.
30. Payne R: Anatomy, physiology and neuropharmacology of cancer pain . Med Clin North Am 1987;
71:153-167.
31. Bonica JJ.Neurosurgical operations involving peripheral nerves. In: Bonica JJ, ed.The Management of
Pain. Philadelphia, PA: Lea&Febiger; 1990;2066-44.
32. Tasker RR. Neurosurgical and neuroaugmentative
intervention In: Patt RB, ed. Cancer Pain, Philadelphia:
JB Lippincott, 1993; 471-500.
33. Kerr, FWL. The ventral spinothalamic tract and
other ascending systems of the ventral funiculus of the
spinal cord. J Comp Neurol1975;159:335-356.
34. Giamberardino MA, Vecchiet L. Experimental
studies on pelvic pain. Pain Rev, 1994;1: 1o4-117.
35. Hickey M, Liernen G, Weaver K. Evaluation of
abdominal pain. Emerg Med Clin North Am,
1989;7:437-451.
36. Bridenbaugh LD, Moore DC, Campbell DP.
Management of upper abdominal cancer pain: Treatment with celiac plexus block with alcohol.
JAMA,1964;190:877.
37. Siegfried J, Khner A, Sturm V. Neurosurgical
treatment of cancer pain. Recent results. Cancer Res
1984; 89:148-155.
38. Mulholland MW, Debas H. Disease of the liver,
biliary system and pancreas. In Bonica, JJ, ed: The
Management of Pain, ed 2. Philadelphia, Lea & Febiger, 1990; 1214-1231.
39. Watson PN, Evans RJ. Intractable pain with lung
cancer. Pain, Elsevier.Vol 29.No 2 1987; 163-173.
14
E. Slavik i sar.
40. Raj PP. Practical Management of Pain, 3rd ed.
In: Lema JM, DayRM, Myers PD:
Cancer
Pain.Mosby, St Louis, 2000; 244.
41. Galicich J, Sundaresa N. Metastatic Brain Tumors. In: Wilkins R, Rengachary S, eds. Neurosurgery,
McGraw-Hill Book Company, New York,1985;
67:607-609.
42. Sawaya R, Ligon L, Bindal R. Management of
Metastatic Brain Tunors. In: Tindall G, Cooper P, Barrow D,eds. The Practice of Neurosurgery, Vol l. Williams&Wilkins, Baltimore, 1999; 50:730-731.
ACI Vol. LI