Acta Clin Croat (Suppl.

2) 2022; 61:103-108 Review

doi: 10.20471/acc.2022.61.s2.13

CANCER PAIN AND THERAPY

Gordana Brozović1,2, Nikola Lesar1, Dimitar Janev1, Tomislav Bošnjak1 and Burim Muhaxhiri1

1
Division of Anaesthesiology, Reanimatology and Intensive Care Medicine, University Hospital for Tumors,
Sestre milosrdnice University Hospital Center, Zagreb, Croatia
2
Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek

SUMMARY – Cancer pain is not a homogenous and clearly understood pathological process. The
best treatment is a combination of drug and non-drug measures. Pain is divided into visceral, bone or
neuropathic pain and has characteristics of continuous or intermittent pain. Cancer bone pain therapy
remains centered on strong opioid, radiotherapy and bisphosphonates. Invasive procedures are aimed
to improve neurological function, ambulation and pain relief. Solid tumors often demand surgery.
Treatment of acute postoperative pain is crucial for the prevention of chronic pain. Chemotherapy
and radiation sometimes also cause pain. The management of cancer pain has improved because of
rapid diagnosis and treatment, understanding of analgesics and the cooperation of patients and their
family. The presence of special pain centers in hospitals also raise standard of cancer pain management.
Drug therapy with non-opioid, opioid and adjuvant drugs is the base of such management. The side
effects must be monitored and timely treated. Methods of regional nerve blockade in pain control are
numerous. Placement of epidural, intrathecal and subcutaneous catheters, conductive nerve blocks
with continuous delivery of mixed local anesthetics are very successful for selected patients. Con-
ventional physical therapy involving lymphatic drainage is useful. Acupuncture, psychotherapy and
similar methods are also applicable.
Key words: cancer pain, opioids, non-opioids, adjuvant drugs, regional nerve block, integrative
medicine

Introduction accounting for nearly 10 million deaths in 2020. Can-

cer survival around the world generally approves but
Not everyone with cancer has cancer pain. Cancer
pain takes many forms. It can be constant, intermit- there is a lot of difference between countries. Croatia
tent, mild, moderate or severe and dull, sharp or burn- is unfortunately at the bottom of European countries
ing. The form of pain depends on a number of factors, for the majority of types of cancer. The most import-
including the type of cancer, how advanced it is, local- ant future job will be to improve preventive campaigns,
ization and pain tolerance. Every patient has differ- treat cancer patient as soon as possible after diagnosis,
ent pain sensitivity and we must apply individual pain improve, and apply all complementary forms of treat-
treatment. With more than 2.7 million new cases in ment like pain control, nutrition, physical therapy etc.
Europe, cancer is a leading cause of death worldwide
Cancer pain
Pain is the commonest presenting feature that
Correspondence to: Gordana Brozović MD, PhD, Division of leads to a diagnosis of cancer and remains the most
Anaesthesiology, Reanimatology and Intensive Care Medicine,
feared symptom by patients throughout the course of
University Hospital for Tumors, Sestre milosrdnice University
Hospital Center, Ilica197, Zagreb, Croatia the disease. Beuken-van Everdingen showed that pain
E-mail: brozovic.gordana@gmail.com prevalence rises with disease progression and affect

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G. Brozović et al. Cancer pain and therapy

approximately 64% of patients with advanced cancer. antiepileptic and antidepressant drugs. This is contrary
Approximately 45% of all patients with advanced can- to good evidence of effectiveness in no cancer patients
cer experience pain of moderate to severe intensity1. 7, 8
. Cancer-related pain is divided by anatomical origin
Greco et al estimated that approximately 32% of pa- into visceral, bone or neuropathic pain and has char-
tients were not receiving analgesia proportionate to acteristics of continuous (background) or intermittent
their pain severity2. Although patients understandably (episodic) pain.
express that they want to be pain free, in general, they Vardeh et al. have recently proposed a concept
do not actually expect their pain to go completely3. for pain assessment for all etiologies which forms a
Bender et all identified that patients are keen to un- hierarchy comprising pain state (e.g. inflammatory
derstand the cause of their cancer pain, what to expect, or neuropathic) pain mechanism (e.g. peripheral or
options for pain control and how to cope with cancer central sensitization), and, finally, molecular targets
pain including talking with others and finding help4. (e.g. nerve growth factor or N-methyl-D-aspartate
The key priorities in pain management strategies for receptors)9. However, basic science research in can-
patients with advanced cancer should be to help them cer pain has demonstrated a complex and incom-
achieve a balance between pain and adverse effects of pletely understood picture. Bones metastases are the
analgesia to optimize physical function and support most common cause of cancer pain. It can happen
for self-management. when cancer starts in or spreads. This type of pain is
Cancer pain does not represent a homogenous a unique mixture of inflammatory and neuropathic
and clearly understood pathological process. There is mechanisms with a large number of potential mo-
a large range of different cancer types requiring in- lecular targets. Treatments developed against these
dividual assessment and treatments. In addition, not molecular targets include denosumab, which inter-
every pain in cancer patients is caused by active tu- feres with the receptor activator of nuclear factor
mor. Around two-thirds to three-quarters of pains kappa-b ligand, and tanezumab, which inhibits nerve
are related to tumor, and around 10-20% are related growth factor10, 11. In routine clinical practice, effec-
to cancer treatments (particularly chemotherapy end tive cancer bone pain therapy remains centered on
surgery) with around 10% related to comorbid pain5. strong opioids, radiotherapy and bisphosphonates.
A mechanism-based discussion of pain therapies Interventional procedures may have a role for select-
is confined to pathophysiological processes occur- ed patients. Recording a pain assessment and ensur-
ring at a molecular or cellular level and the conse- ing that health care professionals use this within the
quent biological targets for treatment. Physiological consultation with patient can result in a significant
mechanisms in cancer pain are broadly described as decrease in usual pain. Pain assessment data need to
nociceptive, inflammatory or neuropathic. The prin- be integrated into pain management decision.
cipal approach to cancer-pain management has been
based on the World Health Organization’s (WHO) Useful techniques for pain relief
method for cancer pain relief. The foundation of this
approach is the concept of matching the strength of Pain from the cancer can be caused by tumor
analgesia to severity of pain, ranging from basic an- pressing on nerves, bones or organs. When a tumor
algesics to strong opioids. Other approaches include spreads to the spine, it can press on the nerves of the
adjuvant analgesia, corticosteroids, radiotherapy and spinal cord. The first symptom of spinal cord com-
interventional procedures. This approach can result in pression is usually back or neck pain and sometimes
satisfactory pain control for around 73% of patients it is severe. Numbness or weakness may also hap-
with cancer pain, leaving at least a quarter of patients pen in an arm or leg. Coughing, sneezing or other
with inadequate control6. Strong opioids are generally movements often make the pain worse. Spinal cord
effective with approximately 75% of patients achiev- compression must be treated right away to keep one
ing satisfactory pain control after first or second line from losing control of one’s bladder or bowel or be-
opioid treatment, with no significant differences in ing paralyzed. Treatment for spinal cord compression
efficacy between morphine, oxycodone, fentanyl and involves radiotherapy, steroids, sometimes surgery.
buprenorphine. This results in approximately a 3-point External radiation may be used to treat the weakened
mean reduction on a 0 to 10 pain rating scale. Unfor- bone. Sometimes a radioactive medicine is given to
tunately, data supporting the use of adjuvant analgesia strengthen a bone. Bisphosphonates are drugs that
in tumor-related cancer pain are weak, particularly for can also help make weakened bones stronger and

104 Acta Clin Croat, Vol. 61, (Suppl. 2) 2022

G. Brozović et al. Cancer pain and therapy

help keep the bones from breaking. Invasive proce- itself as pain, burning, tingling, numbness, weakness,
dures are aimed at maintaining or improving a neu- clumsiness, trouble walking or unusual sensations in
rological function and ambulation, spinal stability, the hand, arms, legs and/or feet. It is due to nerve
durable tumor control, and pain relief. Percutaneous damage caused by certain types of chemotherapy, vita-
vertebroplasty (PVP) is the treatment of multiple min deficiencies, a tumor pressing on a nerve or other
vertebral metastases and has a good analgesic effect. problems such as diabetes and infection. Chemother-
PVP not only improves the quality of life of patients apy can cause mouth sores (stomatitis or mucositis)
significantly, but also prevents further vertebral col- and pain in the mouth and throat, which cause prob-
lapse and the invasiveness of intraspinal tumors, lems with eating, drinking and even talking. Radia-
avoiding the nerve dysfunction caused by spinal cord tion mucositis and other radiation injuries cause pain
compression. Surgery for spinal metastases consists depending on the part of the body that is treated and
of simple decompressive laminectomy. You may still cause skin burns, and scarring. Glutamine is a major
need pain medicines, but sometimes these treatments dietary amino acid that is both a fuel and nitrogen
themselves, can greatly reduce your pain. Lumbar donor for healing tissues damaged by chemotherapy
epidural steroid injections under fluoroscopic guid- and radiation. Evidence supports the benefit of oral
ance are used very commonly for the treatment of glutamine to reduce symptoms and improve quality
low back and lower extremity radicular pain. These of life of cancer patients. Benefits include not only
procedures have been shown to be effective for pain better nutrition, but also decreased mucosal damage
relief in the short term and are relatively safe12,13. (mucositis, stomatitis, pharyngitis, esophagitis, and
Bone pain can also happen as a side effect of med- enteritis) 15. Intestine and bladder are also prone to
icines known as growth factor drugs or colony-stim- radiation injury and patients may have pain in these
ulating factors. These drugs may be given to help areas if these areas are treated.
prevent white blood cell counts from dropping after
treatment. They help body to produce more white Control of cancer pain
blood cells, which are made in the bone marrow. Be-
cause the bone marrow activity is higher bone, pain The management of cancer pain has improved over
can occur. the last 20 years. The reason is better cancer diagnosis
Surgical pain is often part of the treatment for and treatment, a greater understanding of analgesic
cancers that grow as solid tumors. Depending on the drug therapy, insistence of patients and their families
kind of surgery, some amount of pain is usually ex- that pain be better controlled, and a consensus that
pected and can last a few days to weeks. Treatment adequate symptom control and a good quality of life
of acute postoperative pain is of crucial importance are particularly important in patients with advanced
for the prevention of chronic pain. Algometry can be disease. The presence of a special center also serves to
used in preoperative stage to estimate the intensity raise the standard of cancer pain management in hos-
and strength of postoperative pain and to adjust the pitals. Drug therapy with non-opioid, opioid, and ad-
analgesia protocol. Pressure algometer is an instru- juvant drugs is the base of such management. As a first
ment for measuring sensitivity to pressure or to pain step, we must take a detailed history of the complaint
and it attempts to objectify sensitivity to pain of a of pain and perform a careful physical examination.
particular patient. The wound catheter placement at Investigations should be reserved for cases where there
the end of the operation and administration of local is doubt about the cause of pain, or where a decision
anesthetics completes the multimodal intravenous about further anticancer treatment depends upon the
analgesia14. precise localization of the disease. Assessment is a vi-
Phantom pain is a longer-lasting effect of surgery. tal preliminary step toward the satisfactory control of
If you had an arm, leg or even a breast removed, you cancer pain. It includes understanding not only the
may still feel pain or another unusual or unpleasant physical but also the psychological, spiritual, inter-
feelings that seem to be coming from the absent body personal, social, and financial components that make
part. Many methods have been used to treat this type up the patient’s “total pain”. Characterization of the
of pain, including pain medicine, physical therapy, patient’s pain as mild, moderate, or severe provides a
antidepressant medicines and TENS. basis for appropriate drug therapy. Information about
Chemotherapy and radiation treatments some- past illnesses, current level of anxiety and depression,
times also cause pain. Peripheral neuropathy manifest suicidal thoughts, and the degree of functional inca-

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G. Brozović et al. Cancer pain and therapy

pacity help to detect patients who may require more morphine by mouth every four hours. The patient tak-
specific psychological support. Depression may occur ing medication orally is not restricted in activity by the
in as many as 25% of cancer patients. The therapeu- route of administration but the parenteral administra-
tic strategy varies from country to country and from tion of a drug restricts the patient to either hospital
patient to patient. The integration of the method into or home and requires additional people to perform it.
a more comprehensive program of care for cancer Chronic pain and breakthrough cancer pain have
patients is recommended16. While complete relief of a high prevalence in all cancer types and stages. First,
pain is not always possible, the method can be used to we must prescribe the lowest initial dose of imme-
help all patients considerably. The Croatian Pain Soci- diate release opioids; oxycodone or hydromorphone.
ety currently promotes a multidisciplinary pain man- The combination of oxycodone/naloxone could reduce
agement program as the standard of care for patients opioid-induced constipation17,18. Transdermal admin-
with chronic pain. This Society issued guidelines for istration of fentanyl or buprenorphine is indicated
therapy of cancer pain aimed at equalizing pain thera- for the treatment of severe chronic pain that requires
py of patients in different hospitals. continuous administration of long-term opioid. The
The use of analgesic drugs is the mainstay of cancer most often used tablets for the breakthrough cancer
pain management. When used correctly, analgesics are pain is morphine sulphate, which can be combined
effective in a high percentage of patients. A three-step with paracetamol or nonsteroidal analgesics. Pain is
“analgesic ladder’’ is suggested. In patients with mild often worse at night and disables patient’s sleep. The
pain, non-opioid drugs such as aspirin, paracetamol, or use of a larger dose of morphine at bedtime, compared
any of the non-steroidal anti-inflammatory drugs will with the daytime, results in more prolonged relief of
be adequate. In patients with moderately severe pain, if pain and better sleep. Morphine can be combined
non-opioids do not provide adequate relief when given with pregabaline or tramadol for better pain relief. The
on a regular basis, codeine or an alternative weak opi- common side effects of the strong opioid are consti-
oid should be prescribed. Non-opioid drugs, specifi- pation, nausea and vomiting and must be monitored
cally the nonsteroidal anti-inflammatory drugs, appear and treated with antiemetics and laxatives. Clinical-
to act peripherally by inhibiting prostaglandin systems, ly important respiratory depression is rare. An initial
whereas the opioids act centrally by binding to specific treatment review is sometimes necessary within hours,
opioid receptors. Because of this difference, combina- normally within one or two days, and always after the
tions of these two types of drug produce additive an- first week. Pain monitoring could be performed by vis-
algesic effects. In patients with severe pain, morphine, iting clinicians or by phone call. Additionally, a nurse
as a strong opioid, is the drug of choice. Paracetamol calls patients and checks symptoms and possible side
is currently recommended for mild-to-moderate pain. effects.
However, patients with moderate-to-severe cancer
pain that is already being treated with a strong opioid The adjuvant drugs
are unlikely to gain any additional benefit. Morphine
has a relatively short half-life, its pharmacokinetics is The adjuvant drugs mainly include antiepilep-
linear, and it is relatively easy to titrate the dose against tic, antidepressants and corticosteroids. These drugs
the pain. Corticosteroids are commonly used in pa- have different chemical structure and should not be
tients with cancer both as chemotherapeutic agents prescribed routinely. Combining antidepressant or an-
and as analgesics. Several studies have reported relief tiepileptic drugs with opioids has resulted in increased
of pain by corticosteroids in patients with epidural spi- pain relief when used for neuropathic pain in non-can-
nal cord compression or infiltration of a nerve by the cer conditions. However, evidence to support their ef-
tumor, and in metastatic bone disease. The effective fectiveness in cancer pain is lacking. Clinicians should
analgesic dose varies considerably from patient to pa- balance the small likelihood of benefit in patients with
tient. The right dose of an analgesic is that which gives tumor-related cancer pain against the increased risk
adequate relief for a reasonable period of time, prefer- of adverse effects of combination therapy19. An anti-
ably four hours or more. Unlike the doses of non-opi- depressant is indicated for patients who remain de-
oids, weak opioids, and mixed opioid agonist-antago- pressed despite improved pain control. An anxiolytics
nists, the doses of morphine and other strong opioids may be used for very anxious patients. Multiple cur-
can be increased indefinitely. Published data indicate rent guidelines recommend corticosteroids for some
that it is rare for a patient to need more than 200 mg of types of cancer pain, particularly where pain is relat-

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G. Brozović et al. Cancer pain and therapy

ed to inflammation and oedema20. Corticosteroids, control in cancer patients. Physical therapists design
anticonvulsants, and neuroleptic drugs have a role to personalized exercise and treatment programs to help
play only in selected cases. Some guidelines include cancer survivors increase their physical activity. Physi-
the option to use ketamine but acknowledge the lack cal activity has been shown to reduce or prevent many
of evidence to support its routine use. There is lim- cancer-related problems. It is not limited only to exer-
ited data that intravenous lidocaine may reduce pain cise but includes magnetotherapy, TENS, ultrasound
intensity in some patients but a lack of efficacy has electrotherapy and lymphatic drainage. Some people
been seen in other trials. Use of lidocaine comes with find some pain relief through acupuncture, infiltration
a risk of frequent adverse effects and therefore special- trigger points, massage, psychotherapy, relaxation exer-
ist supervision is needed. Lidocaine could therefore cises, music-based interventions, meditation and hyp-
be considered as an option for the treatment of opi- nosis24. In some cases, it may be legal to use medical
oid-refractory cancer pain. Pre-clinical experiments marijuana for cancer pain25.
show that tetrahydrocannabinol (THC) enhances the
anti-nociceptive effect of morphine, and preliminary Conclusion:
studies indicated a role as an adjuvant treatment for
pain in cancer patients21. Further research is needed in Adequate pain assessment and management are
patients with moderate and severe cancer pain because critical to improve the quality of life and health out-
it is not clear if there is benefit. The patient’s progress comes in this population. A strong opioid remains the
should be monitored carefully. drug of choice for treating moderate or severe pain in
patients with advanced cancer. Future research should
Regional analgesia focus on defining the efficacy of NSAIDs, anti-de-
pressants, anticonvulsants, corticosteroids and the
A nerve block procedure can be used to stop pain likely role for non-pharmacological approaches in
signals from being sent to the brain. In this context the management of pain in patients with advanced cancer.
methods of regional anesthesia and analgesia is very
useful for pain relief. Furthermore, a large number of
patients are afraid of taking opioids. They have a fear of
addicting to opioids, fear of side effects and developing
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Sažetak
KARCINOMSKA BOL I TERAPIJA
G. Brozović, N. Lesar, D. Janev, T. Bošnjak i B. Muhaxhiri

Karcinomska bol nije homogen i potpuno razjašnjen patološki proces. Najbolja terapija je kombinacija medikamentozne
terapije i nemedikametoznih postupaka. Možemo je podijeliti na visceralnu, koštanu i neuropatsku bol i ima karakteristike
kontinuirane ili povremene boli. Terapija koštane boli fokusirana je na jake opioide, radioterapiju i bifosfonate. Cilj invazivnih
metoda liječenja boli je poboljšati neurološku funkciju, pokretljivost i olakšanje boli. Solidni tumori često zahtjevaju operaciju.
Liječenje akutne poslijeoperacijske boli je od iznimne važnosti u prevenciji nastanka kronične boli. Kemoterapija i radioterapija
ponekad također uzrokuju bol. Liječenje karcinomske boli je poboljšano bržom dijagnostikom i terapijom, boljim poznavanjem
analgetika i suradnjom s pacijentom i njegovom obitelji. Postojanje specijaliziranih centara za bol u bolnicama također je podiglo
standard u liječenju boli. Liječenje boli medikamentozno neopioidima, opioidima i drugim pomoćnim lijekovima je osnova
liječenja boli. Nuspojave lijekova moraju se neprestano pratiti i na vrijeme liječiti. Metode regionalne nervne blokade u liječenju
boli su brojne. Plasiranje epiduralnih, intratekalnih i supkutanih katetera s kontinuiranom isporukom mješavine lokalnih aneste-
tika veoma su uspješne kod određenih bolesnika. Fizikalna terapija s limfnom drenažom je korisna. Akupunktura, psihoterapija
i slične metode su također primjenjive.
Ključne riječi: Karcinomska bol, opioidi, non-opioidi, adjuvantni lijekovi, regionalni živčani blok, integrativna medicina

108 Acta Clin Croat, Vol. 61, (Suppl. 2) 2022