Cleveland Clinic

View the Disease Management Project
Table of Contents

Cancer Pain

Published December 6, 2002

Reviewed
December 29, 2003

Mellar P.
Davis, MD

Mellar P. Davis, MD

Department of
Hematology and
Medical Oncology

Print Chapter

Copyright 2002
The Cleveland Clinic Foundation

   Cancer will occur in 1.2 million people in the United States each year and nearly ½ will die as a result of their cancer. Pain is experienced in over half and most of these will have pain so severe as to interfere with normal daily activities.1,2 There is limited knowledge of the basic neurobiological mechanisms which generates cancer pain. However empiric strategies for treating cancer pain have been validated and highly successful in relieving pain.3,4 Guidelines for managing cancer pain, although widely published, have not been universally applied and as a result there is considerable variation in the treatment of pain.

 

Chapter Outline

Definition

Prevalence and
Pain Interference

Pathophysiology

Signs and
Symptoms

Breakthrough
Pain

Diagnosis

Treatment

Outcomes

Conclusion

References

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
DEFINITION

Pain is an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage.5 Pain is a state of discomfort (sensory) and distress (affective). Pain corresponds poorly to the degree of tissue destruction and pain intensity is not proportional to the type or extent of tissue damage. Classical pain categories are chronic and acute, nociceptive and neuropathic, within nociceptive classification, somatic and visceral.1 The experience of pain is complex. Pain is modulated at several different central nervous system levels (Figure 1): 1) At the dorsal horn of the spinal cord, 2) descending tracts through the bulbospinal pathways from the periaqueductal grey and rostral ventral medulla, 3) at the level of the cingulate cortex, within the amygdala, medial thalamus and limbic cortex.6 Pain is also influenced by past experience and cognitive function.7 Psychological factors rarely initiate pain but greatly influence intensity. There is a general tendency to separate malignant from non-malignant pain and view cancer pain within a biomedical model and non-cancer pain within a biopsychosocial model. However there is no difference anatomically, physiologically, by biochemical substrate or through mechanisms of nociception which justifies separating the two.8 Pain for the cancer patient is a subjective experience since nociceptive stimuli capable of eliciting pain is modified by genetics, past history, mood, expectation and culture just as it is for those with non-malignant pain.8
PREVALENCE AND PAIN INTERFERENCE

The prevalence of cancer pain directly correlates with stage of disease.9 Patients with breast and prostate cancer, both of which have a propensity to spread to bone, more often experience pain than patients with uterine and cervical cancer.9 Pain as an initial presenting symptom will occur in 20-40% of patients.9 Severe pain (that is greater than 5 on a numerical scale) occurs in 20-35% of the cancer population and significantly impairs activities of daily living. The impact of pain for a given severity will vary depending upon the perceived cause of pain.9 Patients who believe their pain is a result of cancer will have a greater pain interference with activities of daily living for the same degree of pain severity than patients who believe their pain is of a benign etiology.10 Interference with enjoyment of life is greatest when pain is caused by cancer, intermediate when caused by unknown factors and least when seen as caused by treatment.9

Despite the direct association of pain prevalence with stage, pain poorly corresponds to the observed tumor burden. For instance only a minority of radiograph apparent bony metastases are painful. Interestingly high dose single fraction radiation produces rapid analgesia usually within days at lower than tumorcidal doses and more rapidly than projected for tumor response. This indicates that radiation therapy significantly alters the "inflammatory soup" as a means of analgesia which is independent of antitumor activity.

Most pain experienced by cancer patients is a result of their underlying cancer, 20% is a result of treatment sequelae and less than 10% is due to co-morbidities. This is different in the pediatric cancer population where a greater frequency of pain is a result of treatment and also in the bone marrow transplant population due to significant stomatitis. One-third have one pain, one-third will have two separate pain syndromes and one-third will have three or more pains.10 The most common cause of cancer pain is bone metastases. One-third of patients will have neuropathic pain either alone or combined with nociceptive pain.10 A list of common causes of pain is found on Table 1. Pain generally changes very little in severity in the last four to six weeks of life.

Table 1:
Common Causes of Pain
  1. Bone metastasesVisceral metastasesImmobilityNeuropathic painSoft tissueConstipationEsophagitisLymphedemaMuscle cramps
  2. Chronic Postoperative Scar
Adapted from reference 10.
PATHOPHYSIOLOGY

Nociceptors are primary sensory neuron activated by stimuli capable of causing tissue damage. They are high threshold receptors and may remain "silent" until significantly stimulated.11 These nociceptors are polymodal, that is they are capable of responding to both physical and chemical stimuli. Various mediators are capable of depolarizing nociceptors (Table 2).

Table 2:
Mediators Capable of
Depolarizing Nociceptors
  1. Nerve growth factorBradykininSerotoninProtonsLipids (prostaglandin)Heat
  2. Pressure

Afferents arise from small and medium diameter cell bodies within dorsal ganglia and trigeminal ganglia and have either unmyelinated (C-fibers) or thinly myelinated (A-delta fibers) axons. Interneurons within lamina I and II of the dorsal horn amplify or dampen neurotransmission of nociceptors. Afferent axons terminate on lamina I or II within the dorsal horn and second order neurons extend processes to the contralateral spinalthalamic tract through the ventral lateral thalamus to the cerebral cortex (Figure 1). Sensory fibers associated with affective response also ascend in the contralateral dorsolateral spinal cord to the medial thalamus and then to the cingulate cortex and limbic lobe. Spinothalamics extend axons into the medulla and hypothalamus. Downward modulation occurs through the periaqueductal grey (PAG) and rostral ventral medulla (RVM) with axons which transverse the dorsal lateral funiculus to modulate pain directly by connections to secondary afferent neurons in the dorsal horn or via connections with interneurons in lamina I and II (Figure 1).

Somatic pain is experienced as a fast (A-delta) localizing pain and a slow (C-fiber) noxious sensation. Visceral pain is unique as there is not a fast or slow component and is poorly localized compared to somatic pain.

Peripheral sensitization results from nerve ending exposure to products of tissue damage and inflammation. Nociceptors also contribute to persistent pathological pain as seen with allodynia in the setting of nerve injury or due to central sensitization as a result of neuroplasticity and lowered nociceptor thresholds. Central centralization particularly when nerves are damaged results from activation of central algesic receptors such as N-methyl-D-aspartate (NMDA) receptors and nerve sprouting from lamina IV into lamina I and II which previously were occupied by secondary sensory neurons. The gate control theory involves facilitating and inhibitory interneurons which are modulated through multiple descending pathways. Whether the gate is "opened" or "closed" influences pain intensity dependent upon inhibitory influences from the PAG and RVM on spinal cord interneurons.12 Central modulation of pain severity by the PAG and RVM is mediated by monoamines neurotransmitters (serotonin, norephinephrines) and endogenous opioids (enkephalins and dynorphin). Interneurons generate gamma aminobutyric acid (GABA), analgesic amino acids (glycine), algesic amino acids (aspartate, glutamate), and prostaglandins (Figure 2). Experimental studies demonstrate that pain generated by bone cancer, inflammation or neuropathy produce a unique set of behaviors (sensations) and neurochemical changes.13

Cognition and memory play a large role in the experience of pain.7 Fear and depression reduce pain thresholds and produce anatomical changes which alter pain pathways. Long-term neuroanatomical changes have been discovered involving the amgydala and hippocampus, sites of affect and pain memory, and involve calcium-calmodulin-dependent protein kinases.14

SIGNS AND SYMPTOMS

Pain intensity is pivotal to therapeutic decision making (Figure 2). The temporal pattern quality and location of pain suggests its pathophysiology. Somatic pain is well localized, sharp, aching, throbbing or pressure like in quality. Visceral pain on the other hand is gnawing, crampy, diffuse and not well localized. Colic occurs with obstruction of a hollow viscus and achy, sharp or throbbing pain with internal organ capsule invasion or mesenteric infilitration.1,15 Neuropathic pain is frequently associated with allodynia, hyperpathia, dyesthesia and/or neurological deficits in the area of pain. Pain usually courses in the distribution of the motor, sensory or autonomic nerve except when pain is funicular as with an impending spinal cord compression or sympathetically mediated as in complex regional pain syndromes. Neuropathic pain is associated with spontaneous, transient breakthrough pain which is lancinating in quality. Pain may involve injury to a single nerve or the cervical, brachial, celiac, lumbar or sacral plexus. Pain may be generated from spinal cord damage and experienced first as radicular pain then as ascending levels of sensory loss.1 Central mediated pain may be sympathetic, (as in causalgia) or deafferentational as in phantom limb pain. Cancer pain may be acute, and associated with generalized sympathetic hyperactivity resulting in diaphoresis, hypertension and tachycardia. Tolerance to sympathetic hyperactivity develops quickly as pain becomes chronic, recurrent over months, or persists greater than three months. Overt pain behavior such as grimacing, moaning and splinting as well as sympathetic hyperactivity are often not present with chronic pain and are derived from personality characteristics.16 Acute pain occurring upon a background of chronic pain is usually associated with complications related to the cancer or its treatment. Chronic pain if unrelieved will produce depression, anxiety, anorexia, asthenia, and insomnia. The combination of pain quality, location, and radiation is used to classify pain into recognized cancer pain syndromes.1,17

BREAKTHROUGH PAIN

Episodic pain may be intermittent only or a transient worsening of chronic stable background pain. Few will have only intermittent pain, the majority will have continuous pain and most with chronic pain will also have transient worsening of their pain. Incident pain may be voluntary or involuntary but most often occurs with activity, weight bearing, cough or bowel movement and is usually predictable and somatic in origin. Spontaneous lightning like pain of short duration is characteristic of neuropathic pain. End-of-dose failure (that is pain that occurs prior to the next dose of analgesia) is due to undertreatment of chronic pain.
DIAGNOSIS
Accurate assessment is rate limiting to good pain management. Pain severity can be assessed by unidimensional pain scales such as the visual analog, numerical or category scale.1,17 Pain relief scales have the advantage of gauging benefits to treatment but do not correlate with unidimensional scales and tend to be more therapeutically optimistic than evaluation by serial unidimensional scales. Patients may have pain relief but still have severe pain which interferes with daily activities.1,18 Comprehensive multidimensional scales are more burdensome for patients to complete but provide evaluation of the affective component of pain and pain interference with activities. Several general quality of life scales include pain intensity or pain relief scales. Examples are the QLQ-C30 of the European Organization for Research of Cancer and the Functional Assessment of Cancer Therapy Scale.19

Adequate assessment requires a thorough history and physical examination prior to radiographic studies or physiological testing. Bypassing a good history and physical for radiographs may be misleading as there is not a simple one to one correspondence between the report of pain and the presence of underlying pathology.1,17 The location, radiation quality, intensity of pain along with the palliative and worsening factors associated with pain frequently locates the pain source and provides clues to possible etiology. The date of onset, associated symptoms, and pain trajectory indirectly and crudely measures disease course and prognosis. Past trials of therapy including over-the-counter medications and home remedies should be recorded. Crescendo pain or altered pain patterns upon "usual" chronic pain means recurrence until proven otherwise. For example crescendo pain along the course of post-thoracotomy pain is indicative of recurrence of lung cancer.

Physical examination is directed to the area of pain but should not be misguided by radiating patterns of pains. Shoulder pain may be referred from hepatic metastases or splenomegaly for instance. Anatomical examinations is followed by maneuvers to elicit or ameliorate pain. Bone metastases are most common and spinal cord compression most feared. Hence a neurological examination, manual muscle testing, percussion tenderness, joint mobility and inspection for muscle symmetry are important parts of the physical examination.

Radiographic studies are guided by the history and physical examination as well as the stage of disease, patient performance status, therapeutic options and goals of care. Patients terminally ill or in whom little is gained by defining radiographic pathology should be treated palliatively and not subject to painful unnecessary testing for curiosity sake. Plain radiographs of painful areas are still valuable sources of information. Prior to examination, pain should be treated so that patients are both comfortable and able to complete their radiographic procedures. Magnetic resonance scanning for the spine and brain and computer tomography for the chest and abdomen are primary choices and provide the greatest amount of information. Ultrasonography for pericardial effusions, biliary and urinary tract obstructions are easily accomplished, portable and without radiation exposure. Electrophysiological studies can separate mononeuropathies or entrapment neuropathies from plexopathies; ulnar and peroneal entrapment syndromes from brachial, and lumbar plexopathies respectively. Conduction velocities, specific latencies, amplitudes, duration and configuration of sensory and motor evoked potentials identify and locate neuropathology. However electrophysiological studies can be normal in the face of significantly damaged non-myelinated fibers.

TREATMENT

Cancer pain can be relieved in 80-90% of patients using an opioid-based analgesic regimen20 and the WHO stepladder as21 guidelines (Figure 2).22-24 Opioids are used preferably by mouth, around the clock, by the analgesic ladder with individualized treatment based upon pain patterns and with attention to details.24 Use morphine as the first opioid of choice. Low doses can be combined with a NSAID as a substitution for a "weak" opioid in the second step of the analgesic ladder (Figure 2). Avoid codeine which has excessive side effects, meperidine due to its neuroactive metabolites and mixed agonists-antagonists because of a ceiling effect. Use oxycodone, fentanyl and methadone as second line opioids for patients intolerant to morphine. Drug interactions are least with morphine and more problematic with second line potent opioids. Use around-the-clock dosing with either normal release morphine every fours hours or sustained release morphine every 12 hours for continuous pain. Rescue doses of normal release morphine should be provided for breakthrough or incident pain. Doses are based upon pain severity, dosing patterns are varied according to pain pattern and diural variations in pain severity. Alternate routes of administration eg, rectal, subcutaneous, intravenous or spinal need to be identified particularly in dying patients or those unable to take oral medications (Table 3). Analgesic response is quantified by degree, duration and dose adjustments are made based upon both. Individualized dosing will need to take into account age, perhaps gender, renal, liver and cognitive function. Alternative opioids may be chosen depending upon organ failure. Methadone is relatively safe with little dose adjustments necessary for renal failure whereas morphine is one of the safest opioids in cirrhosis. Oxycodone pharmacokinetics are significantly altered by hepatic and renal failure. Identify dose limiting side effects and those at risk for respiratory failure and titrate doses slowly in this group of patients. An opioid switch is necessary for opioid toxicity particularly with neurotoxicity (myoclonus, hallucinations or confusion) and poorly controlled pain. Alternatively, adjuvant analgesics and simultaneous opioid reduction (opioid sparing) may accomplish the same (Table 4). Anticipate constipation with proactive use of laxatives such as docusate plus either bisacodyl, senna or osmotic laxatives. It is important to be aware of pain syndromes which are relatively opioid resistant and will require early use of adjuvants such as antiseizure medications or tricyclic antidepressants (as in the case of neuropathic pain). Interventions such as surgery, radiation, or kyphoplasty will be required for optimal analgesia for some patients with bone metastases. Tables 5 and 6 define equianalgesic dosing, opioid rotation and opioid conversion.21

Opioid side effects are relatively common. There are several ways of managing the more common dose limiting symptoms (Table 7). The most feared side effect is respiratory depression, which fortunately is uncommon.21,22 Respiratory compromise when accompanied by tachypnea or anxiety is never primarily caused by opioids.22 Tolerance to respiratory depression occurs quickly with repeated opioid dosing. However, care must be taken in those who are frail, opioid naïve, have comorbid conditions which predispose respiratory failure such as chronic obstructive lung disease or who are given sedative medications. Respiratory depression from opioids is always associated with sedation and miosis. Naloxone is given only if sedation is accompanied by badypneia and only in doses that reverse respiratory depression and not analgesia if possible. A 0.4 mg vial of naloxone is diluted in 10 ml of saline. A 1 ml aliquot is given every 3 minutes and titrated to the level of consciousness. Patients on sustained release opioids or methadone may require 0.4 mg per hour as a continuous infusion since the half-life of naloxone is 30 minutes.

Some patients fail to achieve adequate analgesia despite dose escalation, due to rate limiting side effects. Options in these circumstances include 1) opioid switch since there is non-cross tolerance between various potent opioids, 2) opioid conversion to parenteral or spinal routes, 3) opioid sparing with the addition of an adjuvant analgesic, 4) neuroblockade, neuroablation, or invasive neurostimulation.21,22,25 Adjuvant analgesics are chosen based upon pathophysiology (Figure 3). "Lateral" benefits may influence the choice since several symptoms may be treated by one medication (eg, corticosteroids for bone pain, nausea, and headaches from cerebral metastases). A dramatic reduction of pain can occur with adjuvant analgesics precipitating opioid toxicity and for this reason close observation is necessary when adjuvants are initiated. Adjuvant analgesics may be started prior to opioids (eg, tricyclic antidepressants, valproic acid or gabapentin for neuropathic pain) depending upon the clinical situation and severity of pain. Most adjuvants improve the therapeutic index of opioids but unlike opioids have a ceiling effect. Permanent end-organ damage can occur with certain adjuvant medications unlike opioids. Adjuvants are less flexible and versatile than opioids and serum levels may be helpful in guiding titration which is not the case with opioids.

Adjuvants for somatic pain include non-steroidal antiinflammatory drugs, corticosteroids, and acetaminophen. The preferred NSAID is naproxen due to its twice daily dosing and low cost. Acetaminophen is an alternative for those with a history of gastrointestinal bleeding or renal dysfunction but should be limited to 4 grams daily due to the risk of liver toxicity. Corticosteroids may improve multiple symptoms as well as produce a general sense of well being but will have accumulative side effects with chronic administration which need to be minimized. Doses are reduced to the lowest effective dose once maximum response has been achieved. Cox-2 selective non-steroidal antiinflammatory drugs have a reduced risk of gastrointestinal toxicity and bleeding but may not have the analgesia of non-selective Cox inhibitors.26 Pamidromate and calcitonin reduce bone pain as does single fraction radiation therapy.

Neuropathic pain may respond to opioids alone but frequently requires adjuvant analgesics. If pain is limited to a particular area (eg, a mononeuropathy) a lidocaine 5% patch can be applied for 12 hours to the affected area without systemic absorption. The secondary tricyclic antidepressant despiramine and nortriptyline are preferred over the tertiary tricyclics, amitriptyline and imipramine, due to reduced anticholinergic side effects. Among the antiseizure medications, valproic acid has less drug interactions than classical antiseizure medications and is dosed once or twice daily. Gabapentin has the fewest drug interactions but is extremely sensitive to renal function, costly and less versatile. Mexilitine is a third line adjuvant. Electrocardiograms need to be reviewed before starting mexilitine. Some physicians evaluate the therapeutic response to parenteral lidocaine before considering mexilitine. Ketamine, in low doses either parenterally or orally, blocks NMDA receptors and may reduce pain without psychomimetic side effects. Methadone by virtue of its NMDA receptor blockade may do the same as ketamine and in addition is the least expensive of the opioids.

Celiac plexus blocks are particularly effective in locally extensive pancreatic cancer. Kyphoplasty and vertebroplasty reduce pain associated with unstable vertebral compression fractures. Finally, non-pharmacological therapies such as guided imagery, relaxation techniques, hypnosis and biofeedback compliment pharmacotherapy. Treating depression and delirium (which lowers pain thresholds) with phenothiazines, antidepressants or atypical antipsychotics will reduce pain without the need for opioid titration and may in fact allow for opioid dose reduction.

OUTCOMES

Relief of pain is generally measured using unidimensional or pain relief scales. Ancillary outcomes include improved activities, relief of insomnia and improved appetite even if pain severity is relatively stable. Patient satisfaction with treatment will in addition to pain relief reflect the relationship of the patient to the physician. One will see a resolution of overt pain behavior as seen with pseudoaddiction once pain is relieved. It is generally more difficult to see an improvement in overall quality of life since this is influenced to a significant degree by the burden of multiple symptoms.
CONCLUSION

Pain is one of the most feared symptoms associated with advanced cancer but also can be effectively managed in the great majority of patients. Pain assessment is rate limiting to effective treatment. Multiple opioids are available but morphine remains the drug of choice. Adjuvant analgesics will improve pain control and prevent or amerliorate opioid toxicity by allowing opioid dose reduction. Finally, non-pharmacotherapies as well as treatment of depression and delirium are important in the overall management of advanced cancer pain.

Return to Medicine Index
REFERENCES
  1. Cherny NL. Cancer Pain: Principles of Assessment and Syndromes in Principles and Practice of Supportive Oncology, edited by Ann Berger, Russell Portenoy, David Weissman (Lippincott-Raven Publishers, Philadelphia) 1998 pg 3-42.

  2. Foley KM. Advances in cancer pain. Arch Neurol. 1999;56:413-7.

  3. Ventafridda V, Stejernsward J. Pain control and the World Health Organization Analgesic Ladder. JAMA. 1995;275:835-6.

  4. Dahl JL. Effective pain management in terminal care. Clinics in Geriatric Medicine. 1996;12:279-300.

  5. International Association for the Study of Cancer Classification of Chronic Pain. Pain. 1987;Suppl 3:51-6.

  6. Fields HL, Basbaum. Central nervous system mechanisms of pain modulation in Textbook of Pain edited by Patrick D. Wall, Ronald Melzack (Churchill Livingstone Ediburgh, UK) 1999.

  7. Turk DC, Monarch ES, Williams AD. Cancer patients in pain: Considerations for assessing the whole person. Hematol Oncol Clin N Am. 2002;16:511-25.

  8. Turk DC. Remember the distinction between malignant and benign pain? Well, forget it. Clin J Pain. 2002;18:75-6.

  9. Daut RL, Cleeland CS. The prevalence and severity of pain in cancer. Cancer.1982;50:1913-8.

  10. Twycross R, Harcourt J, Bergl S. A survey of pain in patients with advanced cancer. J Pain Symptom Manage. 1996;12:273-82.

  11. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413:203-10.

  12. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971-99.

  13. Honore P, Rogers SD, Schwei MJ, et al. Murine models of inflammatory neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience. 2000;98:585-98.

  14. Sankuhler J. Fear of pain. Lancet. 2002;360:426.

  15. Grond S, Zech D, Diefenbach C, Radbrunc, Lehman KA. Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred to a pain service. Pain. 1996;64:107-14.

  16. Turk DC, Okifuji A. Assessment of patients' reporting of pain: an integrated perspective. Lancet. 1999;353:1784-8.

  17. Davis M, Walsh D. Cancer pain syndromes. Eur J Pall Care. 2000;7:206-209.

  18. DeConno F, Caraceni A, Gamba A, Marianai L, et al. Pain measurement in cancer patients: a comparison of six methods. Pain. 1994;57:161-6.

  19. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, et al. The European Organization for Research and Treatment of Cancer QLQ-C30; a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-76.

  20. Vielhaber A, Portenoy RK. Advances in cancer pain management. Hematol Oncol Clin N Am. 2002;16:527-41.

  21. Walsh D. Pharmacological management of cancer pain. Seminars in Oncol. 2000;27:45-63.

  22. Cherny NL. Update in the management of cancer pain. Principles and Practice of Supportive Oncology. 1999;1:1-15.

  23. Portenoy RK, Lesage P. Management of cancer pain. Lancet. 1999;353:1695-700.

  24. Twycross R. Opioids in The Textbook of Pain edited by Patrick D. Wall and Ronald Melzack (Churchill Livingstone, Edinburgh UK) 1999.

  25. Guay DR. Adjunctive agents in the management of chronic pain. Phamacotherapy. 2001;21:1070-81.

  26. McCormack K, Twycross R. Are Cox-2 selective inhibitors effective analgescis? Pain Reviews. 2001;813-26.

Disclaimer