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| | Cancer Pain
Causes,
symptoms and management of cancer pain
Pain is one of the most common symptoms cancer patients experience; Cancer
pain affects approximately nine million people worldwide annually (Bonica
JJ, 1990). The incidence of pain varies during the different stages of cancer,
with pain occurring in 20%-50% of patients with
newly diagnosed malignancies, in 33% of patients during treatment and in
75%-90% of those
with advanced cancer (Grossman SA, 1994). Most patients with advanced cancer
have two or
more types and/or aetiologies of cancer-related pain (Foley KM, 1985).
Aetiology of cancer pain
The causes of cancer pain fall into five categories:
1. Direct tumour invasion of bone, nerves, viscera or soft tissue, which
accounts for pain in the majority of patients.
2. Changes in body structure due to the tumour or its treatment, usually
resulting in muscle spasm, muscle imbalance
or structural body changes.
3. Anticancer therapy: surgery, chemotherapy, radiation therapy, immunotherapy
and biological response modifiers. This pain is
often neuropathic, resulting from nerve damage caused by
the treatment.
4. Causes unrelated to cancer or its therapy, often caused by pre-existing
painful medical conditions such as rheumatoid
arthritis and diabetic neuropathy.
5. No cause that can be immediately established.
Pain in Cancer Patients
Caused by cancer
Bone involvement, visceral involvement, soft tissue involvement, spinal
cord compression, nerve compression, nerve infiltration, raised intracranial
pressure, muscle spasm, ulceration, infection.
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| Related
to cancer therapy |
| Postoperative
pain syndromes |
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Thoracotomy,
mastectomy, radial neck dissection, amputation, nephrectomy |
| Postchemotherapy
pain syndromes |
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Peripheral
polyneuropathy, mucositis, cranial neuralgia, phlebitis, optic neuritis
(rare) |
| Postradiation
pain syndromes |
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Fibrosis of brachial or
lumbosacral plexus, myelopathy, mucositis, necrosis of bone, ustioni cutanee,
esophagite |
Related
to cancer
Constipation, bedsores, herpetic neuralgia, candidosis, lymphoedema |
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The
World Health Organization (WHO) three-step analgesic ladder
Although cancer pain cannot always be entirely eliminated, appropriate
use of simple
therapies can effectively relieve pain in the majority of patients. In
1986, the World Health Organization (WHO) published guidelines for cancer
pain management based on a three-
step analgesic ladder, whereby increasingly severe pain is treated with
increasingly potent analgesics. The three rungs of this ladder include
non-opioids (such as acetaminophen and
non-steroidal anti-inflammatorydrugs, or NSAIDs) for mild pain; weak opioids
(such as codeine and propoxyphene) for moderate pain; and potent opioids
(such as morphine and methadone)
for severe pain. As treatment progresses, adjuvant drugs and interventional
therapies may
also be added as needed to alleviate pain. Studies have shown that 70%-90%
of cancer
patients' pain can be effectively treated using this system.
Pharmacological
management of cancer pain
Just as the sensation of pain can manifest itself in a variety of ways,
there is a broad range
of options for managing cancer pain. According to the WHO three-step analgesic
ladder,
treatment with analgesics forms the basis of pain management for cancer
patients.
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Three-step analgesic ladder
*
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Step
|
Pain |
Medication |
|
I
|
Mild pain |
Non-opioids |
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II
|
Mild to moderate pain |
Non-opioids plus
opioids for moderate pain |
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III
|
Moderate to severe pain |
Non-opioids plus
strong opioids |
| * In each step, adjuvants
should be prescribed according to the clinical situation |
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Non-opioid
analgesics
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen
are the mainstay of initial drug treatment for mild pain (Eisenberg E,
1994; Beaver WT, 1990). A wide variety of NSAIDs are available, all of
which have antipyretic and anti-inflammatory activity. Aspirin and other
NSAIDs are frequently combined in fixed doses with opioids for moderate
to severe pain. Combining NSAIDs with opiates is a rational approach to
pain management because the two groups of drugs have different mechanisms
of action. Studies have shown that the augmented effect is more than merely
the sum of the analgesic potencies of the two drugs. NSAIDs are particularly
useful for treating pain from bone metastases. When pain from bone metastasis
is moderate to severe,
it is often necessary to use an NSAID-opioid combination. Some soft tissue
metastases have surrounding inflammation that also responds well to NSAIDS.
When used as monotherapy, there is a ceiling on the analgesic potential
of NSAIDs: additional increments above the recommended dosage do not provide
greater pain relief (Eisenberg E, 1994). Toxicity resulting from prolonged
use limits the role of NSAIDs in cancer pain management.
Opioid
analgesics
Opioids are the primary analgesics used in the management of moderate
to severe pain.
Opioids bind to specific receptors within and outside the central nervous
system (CNS) and produce analgesia. Opioid analgesics are categorized
as agonists, partial agonists or mixed agonist-antagonists depending upon
binding affinity, specific receptor binding and activity at the specific
receptor. Opioid analgesics are classified according to their ability
to control mild to moderate pain (codeine, tramadol, dextropropoxyphene),
and those used for moderate to severe pain (morphine, methadone, oxycodone,
buprenorphine, hydromorphone, phentanyl and heroin). Unlike non-opioid
analgesics, most opioids do not have an upper limit of effectiveness.
Oral morphine is the drug of choice in the management of moderate or severe
chronic cancer
pain. The administration of short-release morphine tablets allows fast
absorption, with plasma concentrations peaking after 20 to 90 minutes,
with effective analgesia lasting approximately four to six hours (Glare
PA, 1999). Using slow-release tablets, morphine administration can be
reduced to twice a day. Twelve-hour administration of slow-release oral
morphine and four-hour administration of short-release oral morphine provides
similar analgesic efficacy and side-effect profiles in the treatment of
chronic pain (Finn JW, 1993). Morphine can also be administered via rectal,
subcutaneous and spinal routes.
Adjuvant
drugs
Although opioid analgesics are effective in reducing the pain intensity
that most cancer patients experience, they frequently cause side effects
such as sedation, nausea and constipation, and
in some patients they may not completely control pain syndromes. Consequently,
adjuvant drugs have emerged to increase the opioid-induced analgesia,
and to decrease opioid-induced toxicity. Frequently used adjuvant drugs
include tricyclic antidepressants, corticosteroids, anticonvulsants and
bisphosphates (Bruera E, 1993).
Tricyclic
antidepressants
Tricyclic antidepressants, such as amitriptyline, imipramine and despramine,
have intrinsic analgesic properties and are most useful for the relief
of neuropathic pain syndromes.
These drugs may work by stimulating descending inhibitory pathways, or
by increasing the bioavailability of circulating opioids (Feinman C, 1985;
Ventafridda V, 1987; Ventafridda V, 1990). Prospective, double-blind,
placebo-controlled trials have shown that amitriptyline and desipramine
are effective in the management of post-therapeutic neuralgia (Watson
CP, 1982; Kishore-Kumar R, 1990). Furthermore, cross-over, placebo-controlled
trials have demonstrated the efficacy of chlorimipramine and nortriptyline
in the management of central pain syndromes (Panerai AE, 1990). The toxic
effects of these drugs are mainly autonomic (dry mouth, postural hypotension)
and centrally mediated (somnolence, confusion).
Corticosteroids
Corticosteroids are extremely useful in the treatment of bone pain and
any pain caused by
swelling around pain-sensitive structures. Uncontrolled studies suggest
that the administration
of corticosteroids to selected patients with advanced cancer results in
decreased pain and an improvement in appetite and activity (Shell H, 1972).
The mechanism by which corticosteroids produce beneficial effects in patients
with cancer is unclear, but may involve their euphoriant effects or the
inhibition of prostaglandin (PG) metabolism. While reductions in peritumoral
oedema and inflammation may contribute to relief of pain, the degree to
which the beneficial effects of corticosteroids on mood, appetite and
weight contribute to improved subjective
pain reports is unclear. Corticosteroid treatment produces limiting side
effects, particularly immunosuppression (candidiasis), proximal myopathy
and psychiatric symptoms in 3%-
50% of cancer patients, with severe symptoms occurring in 5% of patients
(Stiefel FC, 1989).
Anticonvulsants
Anticonvulsant drugs, such as carbamazepine, phenytoin, valproic acid
and clonazepam,
have been proposed mainly for the management of the lancinating neuropathic
pain similar
to pain associated with trigeminal neuralgia (Swerdlow M, 1985; Sweet
WH, 1986). However, considerable anecdotal experience has accumulated
for the use of these agents for neuropathic cancer pain syndromes, including
neural invasion by tumour, radiation fibrosis or surgical scarring, herpes
zoster and deafferentation. Side effects of therapy can be serious, particularly
in patients with advanced cancer, and include bone marrow depression,
hepatic dysfunction, ataxia and diplopia.
Bisphosphates
Bisphosphates (disodium pamidroante) represent a new class of drugs that
affect the bone metabolism by inhibiting bone reabsorption by means of
osteoclasts (Boonenkamp PM, 1986). These drugs are used for treatment
of metastatic bone disease as well as for analgesic
purposes. Studies in patients with multiple myeloma (Berenson JR, 1996),
breast cancer
(Lipton A, 1994; Conte PF, 1994) and prostate cancer (Lipton A, 1994)
have shown analgesic efficacy and, to a variable degree, an initial repair
of bone lesions.
Interventional
pain therapy
Although most cancer-related pain can be managed by taking oral analgesics
accompanied by adjuvant drugs, some patients may experience little pain
relief or intolerable side effects with traditional systemic therapy.
Common drug-related side effects such as constipation, nausea, vomiting
and drowsiness - even if they are transitory or episodic - can often discourage
use of
what is otherwise a viable pain management option. When this occurs, interventional
techniques are necessary for providing adequate pain control. Some of
the most significant developments in pain management have occurred in
the area of more advanced delivery systems of established drugs. These
interventional methods of administration are intended to minimize side
effects and target their use more precisely.
Intrathecal drug delivery
Intrathecal drug delivery (IDD) delivers opioids or local anesthetics to
the intrathecal or epidural space of the spine, using a pump that is surgically
placed just under the skin of the abdomen. Direct, intrathecal delivery
of medication to the spine can offer significant pain control for long-
term pain management, with substantially smaller doses than are required
for oral analgesia.
One study approximates that the equivalent daily dose of morphine via intrathecal
administration
is as little as 1/300th of an oral dose (Lamer TJ, 1994). Furthermore, side
effects such as sedation, lethargy, mental clouding, constipation, nausea
and vomiting can be reduced,
affording patients a significant improvement in their activities of daily
living and overall quality
of life. According to one nursing study, the use of intrathecal narcotics
can yield fewer side effects and complications, as well as a reduction in
the number of hospitalisation days required for pain control, compared with
traditional therapy. Studies have also found that in appropriately selected
cancer patients, 70%-80% experienced good to excellent pain relief with
intrathecal drug infusion. Another study of 200 patients, demonstrated that
over four weeks, patients receiving intrathecal drug delivery with SynchroMed
Implantable Programmable Pump experienced a greater reduction in pain as
measured by mean VAS pain score (51,5% reduction), compared with standard
medical management (39,1% reduction), p=0.055. In addition, a significantly
greater proportion of patients survived at 6 months in the IDD group (53,9%)
compared with the standard medical management group (37,2%), p=0,06 (Smith
TJ, 2002).
Injection techniques
and neurosurgical treatment
Two further interventional therapies include the use of non-neurolytic
and neurolytic nerve blocks, in which targeted nerves are injected with
agents such as phenol or anaesthetics that either destroy or numb them.
Barriers to cancer
pain management
Despite the consensus that most cancer pain can be treated effectively,
and the availability of published guidelines for pain management, many
cancer patients still experience considerable pain. Approximately half
of them are thought to receive inadequate analgesia (Larue F, 1995; Cleeland
CS, 1994; Zenz M, 1995). Some of the current barriers to cancer pain management
are shown in the table below.
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| Heath Care Professional
Barriers |
- Lack of education regarding pain assessment
and treatment
- Belief that only patients who are "terminal"
should receive maximal analgesia
- Belief that patients are not good judges of
severity of their pain
- Lack of knowledge of the distinction between
tolerance, physical dependence
(addiction)
- Fear of opioid toxicity
- Fear of opioid addiction
- Fear of regulatory scrutiny
- Inadequate use of multimodality approach to
treatment
- The high cost of analgesic medications that
are non-refundable and not readily
available in some countries
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| Patient and Family Barriers |
- Lack of awareness that pain can be treated and
how best to access such therapy
- Under-reporting of pain to avoid possible confirmation
of disease progression
- Poor access to care
- Fear of opioid toxicity - confusion, personality
change
- Fear of opioid addiction
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Conclusion
Adherence to the treatment guidelines proposed by the WHO results
in adequate long-term
pain control in most patients with advanced cancer. However, many cancer
patients still suffer
as a result of inappropriate pain management, insufficient knowledge and
education, physicians' limited experience regarding the management of
cancer pain and the perception of the laws that govern opioid prescription
and use.
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JR, et al. Efficacy of pamidronate in reducing skeletal events in patients
with advanced
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- Bonica JJ. Cancer Pain. In: Bonica
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- Bruera E, et al. Adjuvant to opioid
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- Cancer Pain Relief and Palliative
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- Cleeland CS, et al. Pain and its
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- Conte PF, et al. Delayed progression
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- Daut RL, et al. The prevalence
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- Eisenberg E, et al. Efficacy and
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- Feinmann C. Pain relief by antidepressants:
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- Finn JW, et al. Placebo-blinded
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- Foley KM. The treatment of cancer
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- Foley KM. Pain syndromes in patients
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- Gilmer-Hill HS, et al. Intrathecal
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- Glare PA, et al. Clinical pharmacokinetics
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- Jadad AR, et al. The WHO analgesic
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- Kishore-Kumar R, et al. Desipramine
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- Lipton A, et al. Pamidronate in
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patients
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- Mercadante S. Pain treatment and
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at
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- Panerai AE, et al. A randomized,
within-patient, cross-over, placebo-controlled trial on the efficacy
and tolerability of the tricyclic antidepressants chlorimipramine
and nortriptyline in central pain.
Acta Neurol Scand 1990;82:34-38.
- Schug SA, et al. A long-term survey
of morphine in cancer pain patients. J Pain Symptom Manage
1992;7:259-266.
- Smith TJ, et al. An implantable
drug delivery system (IDDS) for refractory cancer pain improves pain control,
drug related toxicity, and survival compared to comprehensive
medical management (CMM).
ASCO, 38th Annual Meeting. Abstract number 1436, May 21,
2002
- Stiefel FC, et al. Corticosterodis
in cancer: neuropsychiatric complications. Cancer Invest 1989;7:479-491.
- Ventafridda V, et al. Studies
on the effects of antidepressant drugs on the antinociceptive action of
morphine
and on plasma morphine in rat and man. Pain 1990;43:155-162.
- Ventafridda V, et al. Cancer pain
management. Pain Rev 1996;3:153-179.
- Zech DF, et al. Validation of
World Health Organisation guidelines for cancer pain relief: a 10 year
prospective
study. Pain 1995;63:65-76.
- Zenz M, et al. Severe undertreatment
of cancer pain: a 3-year survey of the German situation. J Pain Symptom
Manage 1995;10:187-191.
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