Clinical manifestations

Presentation and course

Cancer pain has 3 components: (1) nociception, (2) pain, and (3) suffering. Although there may be a psychological element, an organic lesion can be identified as a potential explanation of pain in most cases. Cancer pain can be acute or chronic. Major causes of acute pain in cancer include:

	• Pressure on or infiltration by cancer of various components of the nervous system.
	• Diagnostic procedures, eg, lumbar puncture, bone marrow biopsy. • Therapeutic interventions, eg, epidural injection. • Acute toxicity of cancer chemotherapy. • Vascular events associated with cancer, eg, deep vein thrombosis in the leg.

Various chronic cancer pain syndromes are listed in Table 1. In approximately 10% of cancer patients, the pain is unrelated to the disease or treatment and is most often caused by muscles and connective tissue.

Table 1. Chronic Cancer Pain Syndromes

I. Tumor infiltration of the viscera
	A. Abdominal pain
		1. Chronic intestinal obstruction 2. Peritoneal carcinomatosis 3. Ovarian cancer pain 4. Epigastric pain from pancreatic cancer 5. Right upper quadrant pain from hepatic distention syndrome 6. Suprapubic pain from bladder infiltration 7. Retroperitoneal tumor with neuropathic pain due to involvement of nerves
	B. Chest pain due to lung cancer
II. Tumor infiltration of musculoskeletal structures
	A. Bone pain due to metastases
		1. Neck pain due to atlantoaxial destruction 2. Backache due to epidural compression 3. Hip joint syndrome 4. Pathological fractures
	B. Muscle pain
III. Tumor involvement of the cranium
	A. Headache due to intracranial tumors B. Multiple cranial nerve syndromes due to skull base infiltration
		1. Sphenoid sinus syndrome 2. Orbital syndrome
IV. Tumor infiltration of the peripheral nervous system
V. Peripheral neuropathic pain
	A. Mononeuropathies B. Cervical plexopathy C. Brachial plexopathy D. Lumbar plexopathy
VI. Paraneoplastic pain syndromes
VII. Postchemotherapy pain syndromes
	A. Chemotherapy-induced peripheral neuropathy B. Peripheral vascular ischemic complications of intra-arterial chemotherapy C. Chronic abdominal pain due to intraperitoneal chemotherapy
VIII. Postradiotherapy pain syndromes
	A. Chronic radiation myelopathy B. Radiation-induced brachial and lumbosacral plexopathies C. Radiation-induced peripheral nerve tumors D. Radiation-induced necrosis of the head of femur or humerus
IX. Postsurgical pain syndromes
	A. Neck pain following radical neck dissection B. Postthoracotomy pain syndrome C. Postmastectomy syndrome D. Postnephrectomy syndrome E. Postoperative frozen shoulder F. Phantom pain syndromes due to amputations
		1. Phantom limb pain 2. Phantom breast pain

Cancer pain is often described as somatic, visceral, or neuropathic, but multiple types of pain are common in cancer patients. Neoplastic invasion of bone, joint, muscle, or connective tissue is the most common cause of somatic cancer pain of which bone pain is the most common type. The second most common type is neuropathic pain, which occurs in one third of patients, and may be a mix of nociceptive and neuropathic pain due to peripheral nerve infiltration. The third most common type is pain due to hollow viscus involvement, or visceral pain. Pain is the most frequent symptom among neurologic complications of cancer.

It is important to determine if the pain is nociceptive or neuropathic because the former is responsive to opioids, whereas the response of the latter is less predictable.

Breakthrough cancer pain. Breakthrough pain, defined as transient exacerbation of pain after baseline pain, has been reduced to a mild or moderate level by treatment with opioids and occurs in about 63% of cancer patients. It has a rapid onset and a variable duration with an average of approximately half an hour. The presence of breakthrough pain is a marker of a generally more severe pain syndrome and is associated with both pain-related functional impairment and psychological distress. It is considered a negative prognostic factor. Breakthrough pain may develop into opioid-insensitive pain, which is defined as pain that does not respond to progressively increasing doses of opioids.

Prognosis and complications

This is determined by the nature and location of malignancy.

Biological basis

	• Various pathomechanisms are involved in the development of cancer pain.
	• Pathophysiology should be identified in an individual patient as a guide to personalized management.

Pathophysiology

In managing the cancer patient with pain, it is useful to be familiar with the characteristics of the typical syndrome found in association with different tumor types and anatomic locations.

Various pathomechanisms are involved in the development of cancer pain, and assessment involves identification of the pathophysiology in an individual patient as a guide to management. Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Genetic variation in the catechol-O-methyltransferase gene can influence the efficacy of morphine and can explain differences in morphine requirements in individual cancer patients with pain (17).

Chemotherapy-induced peripheral neuropathy is a multifactorial disorder with diverse pharmacological mechanisms and a number of common pathologies, including altered ion channel functions, oxidative stress, axonal degeneration, impaired calcium homeostasis, neuroinflammation, and activation of the immune system (19). As many as three fourths of the pain syndromes in these patients are due to direct effects of cancer; others are related to the therapies for cancer. Cancer-related pain syndromes may be due to involvement of musculoskeletal tissues, viscera, or neuropathic syndromes associated with the involvement of the nervous system.

The tumor mass produces inflammatory mediators that cause continuous stimulation of peripheral nociceptors. Other causes of somatic cancer pain include bone fractures, reactive spasm of muscle overlying an area of tissue damage, radiotherapy, and chemotherapy.

Bone pain may be due to invasion of bone by the tumor or the development of bony metastases. Nociceptive afferents are most abundant in the periosteum, whereas bone marrow and cortex are less sensitive to pain. Bone pain can be correlated with osteoclastic activity or bone resorption, which normally equals the bone-forming activity of osteoblasts. In metastatic disease, there is evidence of increased osteoclastic activity. The enhanced turnover of bone leads to an increase of undermineralized bone, predisposing to fractures.

Animal experimental studies have shown that morphine may accelerate cancer growth and inhibit the immune response. Opiates also induce angiogenesis, which further promotes tumor growth and spread.

Epidemiology

• Pain is reported by more than 70% of the 18 million patients diagnosed with cancer worldwide.

Worldwide, there were approximately 18 million patients diagnosed with cancer. Cancer-related pain is reported by more than 70% of patients with cancer, and despite available treatments, is inadequately controlled in approximately 50% of the cases (13). Cancer pain is neuropathic in about 20% of the patients.

Differential diagnosis

Confusing conditions

Recognition of various cancer pain syndromes is important for planning the management. Most of these syndromes are easy to detect if the diagnosis of cancer has already been established. A few present diagnostic challenges exist, particularly if they precede the diagnosis of cancer. The main differential diagnosis is between tumor-related pain syndromes and treatment-related pain syndromes. Further distinction needs to be made between nociceptive and neuropathic pain syndromes.

Nociceptive syndromes. Nociceptive syndromes are related to direct tumor involvement. Characteristics of some examples of these syndromes are as follows:

Skull base infiltration. The pattern of pain and the associated neurologic deficits, (eg, cranial nerve palsies) suggest the location of the lesion associated with metastases to the base of the skull. This can often be confirmed by CT.

Vertebral syndromes. Atlantoaxial fracture or dislocation can cause severe neck and occipital pain and may be associated with neurologic deficits. Involvement of the vertebrae at other levels produces pain radiation in the appropriate location and may be accompanied by radiation of pain in the distribution of the nerve roots.

Bone pain. Multiple bony metastases can lead to generalized pain. The lesions are detected by bone scintigraphy or radiography.

Pains to visceral involvement with cancer. Distinction between visceral pain and nociceptive pain or neuropathic pain is not clear. Generalized abdominal pain may be considered visceral if due to peritoneal metastases, but may be neuropathic if due to retroperitoneal tumors that infiltrate multiple nerves. Neuropathic syndromes are due to tumor infiltration. Examples of these are as follows:

Peripheral neuropathy. Chest wall and paravertebral lesions can cause mononeuropathies. These syndromes are highly variable, and the patient may have pain or, less often, dysesthesias anywhere in the region supplied by the nerve.

Brachial neuropathy. Brachial neuropathy is manifested by paraspinal and shoulder pain with radiation to the arm. The tumor mass may be demonstrable by CT and needs to be differentiated from an extradural lesion.

Lumbosacral neuropathy. Lumbosacral neuropathy may cause backache and pelvic pain with radiation to the lower extremity. These lesions may also extend to the extradural space and can be demonstrated by CT or myelography.

Spinal cord and nerve root compression. This usually results from an extension of the vertebral metastases and manifests as bone pain plus neuropathy with pain radiating in the territory of the involved spinal nerve. Backache is a constant feature, and other neurologic deficits including paraplegia may occur.

Treatment-related pain syndromes. Postoperative, postchemotherapy, and postradiation nociceptive pain syndromes are rare and more commonly neuropathic. Some examples are:

	• Postoperative pain syndromes. Chronic pain can follow any surgical procedure. These syndromes usually manifest as pain and dysesthesias over the area of surgery. Neuroma of the intercostal nerve may be responsible for the pain after thoracotomy. It needs to be differentiated from this because of the recurrence of the tumor. Phantom limb pain may follow amputation of a limb or the breast.
	• Postradiation syndromes. Radiation may produce fibrosis of the peripheral nerves, resulting in peripheral neuropathic pain. This needs to be differentiated from recurrence of the tumor or tumor formation in the peripheral nerve as a result of radiation. Radiation myelopathy is uncommon and accompanied by pain in one fifth of the cases. This can be differentiated from recurrent tumor by imaging procedures.
	• Postchemotherapy syndromes. Drug-induced peripheral neuropathy is a well-recognized syndrome that can follow chemotherapy. The pain usually improves following discontinuation of chemotherapy, but may persist.

Diagnostic workup

The diagnostic workup varies according to the location of the malignancy and findings of the physical, as well as neurologic, examination. Some of the diagnostic tests are:

• Tumor biomarker studies • Bone scintigraphy • CT of bone, soft tissues, and viscera • MRI of spine and brain • Electrophysiological studies, eg, electromyography • Assessment of pain is the first step in planning the management of cancer pain

Assessment of cancer pain. Although the McGill Pain Questionnaire has been extensively evaluated in cancer pain patients, the utility of the subscale scores has not been demonstrated for cancer pain. Two other instruments have been used more frequently for assessment of cancer pain:

The Memorial Pain Assessment Card is a brief validated measure that uses 100 mm visual analog scales to characterize pain intensity, pain relief, and mood, and a further 8-point verbal rating scale to characterize pain intensity. This instrument does not provide a detailed account; its simplicity and brevity facilitate compliance.

The Brief Pain Inventory is a simple and easily administered tool that provides information about pain history, intensity, location, and quality. A numerical scale indicates the intensity of pain and a percentage scale indicates relief from current therapies.

Management

	• Ideal management of cancer pain is multidisciplinary and should be personalized for individual patients.
	• Pharmacological approaches include World Health Organization Analgesic Ladder, which starts with nonopioid medications; opioids and adjuvant medications are added as necessary.
	• Radiation therapy may be used for relief of bone pain.
	• Targeted delivery, including use of delivery devices, enables lower doses of analgesics to be delivered closer to pain pathways for improving efficacy and reducing adverse effects.
	• Surgical methods of pain relief, including neuroablative procedures, are used in cancer patients in whom other methods of pain control have failed.

The ideal management of a cancer pain patient is by multidisciplinary approach including oncology, neurology, anesthesia, nursing, psychology, and pharmacy. The limitation of this approach is that access to such a wide range of specialists is available only at large medical centers.

Pharmacological approaches. Various pharmacologic approaches are shown in Table 2. The World Health Organization Analgesic Ladder is a well-validated approach for the selection of appropriate analgesic therapy for cancer pain. Three major classes of drugs used are (1) opioid analgesics, (2) nonnarcotic or nonsteroidal antiinflammatory drugs, and (3) adjuvant analgesics. It is recommended to begin with nonopioid medications and add the opioid narcotics and adjuvant medications as necessary. In addition, 5 essential concepts of the World Health Organization approach to drug therapy are (1) oral administration, (2) by-the-clock, (3) by the ladder, (4) for the individual, and (5) with attention to detail. The drug is chosen to match the intensity of pain. A direct move to the third step enables management of 80% of cancer pain but also requires careful management of side effects.

Table 2. Pharmacologic Approaches to the Management of Cancer Pain

Opioid analgesics
	For mild-to-moderate pain:
		• Codeine • Dihydrocodone • Oxycodone
	For moderate-to-severe pain:
		• Morphine • Hydromorphone • Fentanyl • Methadone • Levorphanol • Tramadol
Nonopioid, nonsteroidal, anti-inflammatory drugs
		• Acetaminophen • Acetyl salicylic acid • Ibuprofen • Ketoprofen • Meclofenamate • Naproxen
Adjuvant drugs
		• Antidepressants • Antiepileptic drugs • Cannabis and cannabinoids • Corticosteroids • Neuroleptics

Opioid analgesics. Opioids remain the cornerstone of pharmacotherapy for cancer pain. Various factors taken into consideration for selection of an opioid include severity of pain, response to previous therapy, the drug's pharmacokinetics, and the available formulations. Drugs such as morphine, hydromorphone, fentanyl, oxycodone, and oxymorphone, which have a short half-life, are generally used initially as they are easier to titrate than long half-life agents. For clinical purposes, oxycodone or morphine can be used as first-line oral opioids for relief of cancer pain in adults. Although pain relief with oxycodone is like other strong opioids, there are less hallucinations with controlled-release oxycodone than with controlled-release morphine, which is usually the first-line opioid of choice because it is cheaper (21).

Tapentadol is a novel, centrally acting analgesic medicine acting at the mu-opioid receptor and inhibiting noradrenaline reuptake. The efficacy of tapentadol is comparable to morphine and oxycodone for the management of moderate to severe cancer pain; however, information from randomized controlled trials on the effectiveness and tolerability of tapentadol is limited (24). For long-term management, sustained-release opioid preparations can reduce the inconvenience of around-the-clock administration of drugs with a short duration of action. A systematic review tried to assess the role of tapentadol given at medium-high doses in opioid-tolerant patients for management of pain in cancer instead of step 3 analgesics (10). Results showed that tapentadol, when used at 60 mg or more of oral morphine equivalents in opioid-tolerant patients with cancer pain, was well tolerated as well as effective and can be used for management of moderate-to-severe cancer pain.

Besides morphine, common opioids include meperidine, methadone, hydromorphone, oxycodone, fentanyl, and buprenorphine. Oral morphine is available and can be used for chronic pain. For long-term outpatient management, controlled-release oxycodone hydrochloride, methadone, or sustained-release morphine are recommended. Methadone has been a preferred choice for the management of cancer-related neuropathic pain, but its mechanism of action still needs to be established. Because it has no known active metabolites, is well absorbed by oral and rectal routes, and is inexpensive, methadone is an important alternative for those who have side effects related to the use of other opioids. One complication of the use of methadone is accumulation in some patients due to its unpredictable half-life, which may lead to delayed onset of adverse effects. In an assessment of use of methadone over 28 days, there was a higher rate of withdrawal due to side effects in the methadone group, and dose adjustment as well as monitoring is recommended for long-term use (14). Buprenorphine is a broad-spectrum, highly lipophilic, and long-acting partial mu opioid receptor agonist that is non-cross tolerant to other opioids and is used extensively in the management of cancer pain. A transdermal preparation of buprenorphine is available in Europe and has been approved by the FDA in the United States.

Other routes of administration are being developed for various opioids. These include controlled-release morphine suppositories, transmucosal fentanyl, and transdermal fentanyl. Various commercially available fast-acting fentanyl preparations have improved the management of breakthrough cancer pain (09). Transdermal fentanyl (Duragesic) allows dosing every 3 days and avoids the first-pass effect of the liver. Compared with oral opioids, the advantages of transdermal fentanyl include a lower incidence and impact of adverse effects (constipation, nausea and vomiting, and daytime drowsiness), more patient satisfaction, improved quality of life, improved convenience and compliance resulting from administration every 72 hours, and decreased use of rescue medication. Transdermal fentanyl is a useful analgesic for cancer patients who are unable to swallow or have gastrointestinal problems. An intranasal fentanyl spray is now approved and offers improved onset of analgesia compared to other oral therapies, which may closely mimic the typical time course of a break-through episode of cancer pain (05). Transdermal buprenorphine has been introduced in Europe for the treatment of moderate to severe cancer pain. This system provides potent analgesia with a low incidence of adverse events. A prospective, open label, observational study has shown that intranasal sufentanil can provide intense but relatively short-acting analgesia for cancer-associated breakthrough pain in palliative care setting (06).

Although morphine is the only opioid approved by the FDA for intraspinal use, other opioid analgesics are being used intraspinally, including hydromorphone, fentanyl, sufentanil, meperidine, and methadone, in the treatment of cancer pain. Intrathecal morphine is helpful in cancer pain and the complication of mass formation at the catheter tip is rare.

Breakthrough pain is currently managed with oral or parenteral breakthrough pain medications given in addition to the around-the-clock analgesic regimen. Fentanyl with new delivery methods seems to be the best option to cover the temporal pattern of this pain. An oral transmucosal fentanyl formulation (Actiq) is the first product indicated only for the management of breakthrough cancer pain in patients with malignancies who are already receiving, and who are tolerant to, opioid therapy for their underlying persistent cancer pain. Fentanyl transmucosal delivery system (ONSOLIS) using buccal soluble film is also approved for the treatment of breakthrough pain in cancer. A systematic review to identify evidence-based drugs for adequate management of breakthrough cancer pain revealed that transmucosal immediate-release fentanyl was effective (02). Oral transmucosal fentanyl citrate is an effective treatment for breakthrough pain management, and its use should be considered in any patient experiencing breakthrough pain related to cancer. In comparison with oral opioids, fentanyl preparations appear to have a short onset and offset of analgesic effect, which fits the temporal characteristics of breakthrough cancer pain, but further studies are needed to assess the net benefit of these drugs to assist decision-making by patients, clinicians, and payers, according to individual clinical conditions (11).

Clinical trials have shown efficacy of a nasal spray formulation of fentanyl for breakthrough pain in cancer (08).

Fentanyl pectin nasal spray (PecFent), which uses an innovative delivery system and is approved in the European Union, has been shown to be superior to oral transmucosal fentanyl citrate in clinical trials (12).

Before making a change in the around-the-clock analgesic dosage, the physician should consider analgesic side effects, the number of episodes of breakthrough pain per day, and the best ways to balance side effects against analgesia. The treatment should be personalized to provide the best for an individual’s needs.

Opioids are well-accepted treatments for cancer pain. The pharmacology of opioid use for treatment of pain is different from that of use in normal subjects where they can lead to addiction. Careful use, titrated against pain, is safe in patients with severe pain. Benefits and risks of opioid use in cancer patients and the non-cancer population are quite different, and opioid-associated deaths are 10 times less likely in the former than the latter population (25). Opioid analgesics, used for relief of cancer pain and prescribed in accordance with established dose guidelines, are unlikely to cause accidental death or dependence. Nevertheless, to protect patients with cancer from the problems of opioid abuse/misuse, an evaluation of risk and the monitoring of aberrant behaviors should be done. The liberal use of opioids can cause neurotoxicity as a major side effect of the treatment of cancer pain; the neurotoxicity can manifest as delirium, hallucinations, myoclonus, and seizures. Opioid-related cognitive dysfunction tends to occur in the earlier stages of cancer, whereas delirium is likely to be present in the advanced stages of cancer. An optimal management approach requires objective monitoring of cognition, maintenance of adequate hydration, and either dose reduction or switching to a different opioid. There is strong evidence for the efficacy of naloxone to reverse respiratory depression or constipation but weak evidence for the effectiveness of changing from the oral to epidural route of morphine administration to manage sedation.

Adjuvant drugs. Use of adjuvant drugs in the management of cancer pain is supported by anecdotal experience.

	• Neuropathic cancer pain may require the use of adjuvant analgesics such as amitriptyline and gabapentin.
	• Use of cannabis and cannabinoids for management of cancer pain is increasing. Preclinical studies and a single double-blind, randomized, placebo-controlled trial of nabiximol showed improvements in cancer pain refractory to opiate therapy practice. However, for adults with advanced cancer being treated with opiate therapy, the addition of cannabis or cannabinoids is not currently supported by evidence-based data (04).
	• Corticosteroids may be helpful in patients with pain due to acute nerve compression, visceral distention, soft tissue infiltration, and raised intracranial pressure.
	• Nonsteroidal anti-inflammatory drugs appear to be more effective than placebo for cancer pain; clear evidence to support superior safety or efficacy of 1 nonsteroidal anti-inflammatory drug compared with another is lacking.

Management of bone pain. The following have been found to be useful:

	• Intravenous pamidronate, a bisphosphonate that inhibits osteoclastic activity, reduces pain or analgesic requirements.
	• Strontium 89, a beta particle-emitting calcium analog, is selectively taken by osteoblasts, and relieves pain or reduces the need for analgesics.
	• A proprietary cancer therapeutic agent has been approved for the relief of pain in patients with metastatic bone lesions that image on conventional bone scan, a routinely performed nuclear medicine procedure in these patients. It consists of a radioactive isotope, samarium 153, which emits beta radiation, and a chelating agent, which targets the drug to sites of new bone formation. By targeting these areas of bone formation, the cancer therapeutic agent delivers site-specific radiation, which may result in significant pain reduction.

Radiation therapy. Radiation therapy can relieve pain associated with local extensions of cancer, as well as metastases. Pain due to peripheral nerve compression or infiltration by tumor may sometimes be relieved by radiation therapy. Radiation therapy may be simply palliative for relief of bone pain.

Alternative nonpharmacological methods. Acupuncture, hypnosis, and biofeedback have been used for the relief of cancer pain and are useful in some cases. No adequately controlled studies have shown their effectiveness in cancer pain, but many ambulatory patients use these methods without the knowledge of their attending physicians. The Cochrane Database systematic review of randomized controlled clinical trials reveals there is insufficient evidence to determine whether acupuncture is effective in treating cancer pain in adults (15).

Implantation of drug delivery devices. Various drug delivery methods have been used to deliver opioid analgesics to the central nervous system in cancer patients. For example, intrathecal by a programmable drug pump and catheter that are surgically placed underneath the skin of the abdomen. Because the medication is delivered directly to the pain pathway, small doses can be effective with intrathecal infusion. Site-specific drug delivery may also help to minimize side effects and limit addiction potential. Intrathecal drug delivery systems, which offer rapid and effective pain relief with less toxicity relative to oral or parenteral administration, are highly effective in a variety of settings.

Anesthetic techniques. Various regional nerve blocks using local anesthetics can be used for pain relief. Local anesthetics and neurolytic agents can be delivered directly to the vicinity of the neural structures affected by tumor. Nerve blocks may be done as diagnostic procedures to predict the outcome of more permanent interventions such as neurolysis or rhizotomy.

Celiac plexus block for pancreatic cancer pain in adults can be performed by the percutaneous approach or guided by endoscopic ultrasonography. Although statistical evidence for the superiority of pain relief by celiac plexus block over analgesic therapy is minimal in a systematic review of clinical trials, it causes fewer adverse effects than opioids, which is important for patients (01).

Neurolytic blocks of the sympathetic axis are considered important cost-effective adjuncts to pharmacologic therapy for the relief of severe visceral pain experienced by cancer patients. However, these blocks rarely eliminate cancer pain because of frequently coexisting somatic and neuropathic pain.

Surgical methods of cancer pain relief. These methods are used in about 10% to 30% of cancer patients in whom other methods of pain control have failed. The aim is to reduce side effects of analgesic therapy and to improve the patient's quality of life. Surgical methods range from procedures to debulk tumors and decompress various pain sensitive structures to interrupting pain pathways. An example of some of these procedures includes spinal decompression and the insertion of a rod to stabilize the spine for bone pain due to metastatic involvement of the spine. Another example includes neuroablative procedures, such as dorsal rhizotomy, spinothalamic tractotomy, and commissural myelotomy. Percutaneous CT-guided cordotomy is a low-risk intervention that can benefit carefully selected patients with cancer-related pain. After cordotomy in patients with bilateral pain, referred pain mechanism causes increased or new pain. Nevertheless, cordotomy can still be indicated for patients with bilateral pain because postoperative pain is better controlled than the original pain (07). For patients with cancer pain, head and neck malignancies, and significant emotional distress, cingulotomy may be a safe treatment option with minimal cognitive changes (23).

Spinal cord stimulation has been used successfully for treatment of intractable cancer pain. Spinal cord stimulation through implanted electrodes in a patient with intractable neuropathic pain due to metastatic cancer has been shown to provide 90% to 100% pain relief and discontinuation of pain medications for 1 year (26). The Cochrane Database systematic review has not identified any randomized clinical trial of spinal cord stimulation (SCS) for refractory cancer pain and has concluded that current evidence is insufficient to establish the role of spinal cord stimulation in treating refractory cancer-related pain (16). It was suggested that future randomized studies should focus on the implantation of spinal cord stimulation in participants with cancer-related pain.

The Congress of Neurological Surgeons has conducted a systematic review and published evidence-based guidelines for neuroablative procedures that may be an option for treating patients with refractory cancer pain (18). Serious complications are relatively uncommon and improved imaging, refinements in technique, as well as the availability of new lesioning modalities may further minimize the risks of neuroablation.

Rehabilitation of the patient with cancer pain. Adequate pain management is a requisite condition for successful rehabilitation of patients with cancer. Opioid pharmacotherapy, adjuvant drugs, disease-modifying therapies, and interventional strategies may be used concurrently to augment pain relief.

Future directions. The current management of pain in cancer patients is inadequate and requires further research.

There is also a need to develop better dosing strategies and evidence-based recommendations for severe cancer pain. Currently, opioid dose titration for severe pain is guided by the experience and opinion of an individual expert. Evidence-based guidelines for the use of opioid analgesics in the treatment of cancer pain are being developed in Europe.

According to evidence-based guidelines, when spinal cord compression is suspected, providers should treat with corticosteroids and evaluate with whole-spine magnetic resonance imaging scan as soon as possible but within 24 hours to make further decisions for definitive treatment.

With increasing length of survival of cancer patients, cancer pain is moving into the category of chronic pain and provides more challenges in management. Although opioids can control moderate and severe cancer pain, their adverse effects remain a cause for concern. To address this problem, neurostimulatory or neuroinhibitive methods are being investigated to reduce the dose by amplifying the analgesic action of opioids. The search continues for endogenous opioids that are as effective as currently available opioids, but without their adverse effects. Other trends in the management of cancer pain include the following:

• Targeted as well as an individualized plan of management of cancer pain is appropriate throughout the course of illness. Variations in the response to drugs is often caused by the genetic make-up of individual patients due to gene mutations. Pharmacogenomics and pharmacogenetics can be used to investigate the analgesic drug metabolizing enzymes or disease genes, RNA expression or protein translation of genes affecting drug response, and interindividual genetic variability in DNA sequence of drug targets (22). This can be a basis for an individualized pain management treatment plan for efficient and safe treatments for patients with cancer pain.

• The conventional cancer pain management algorithms are being modified to include peripheral neural blockade, neurodestructive techniques, neuromodulatory device use, and intrathecal drug delivery systems with sparing of opioids resulting in decrease of medication-induced side effects as well as improvement in quality of life of the patients (03).

Although there is an insight into mechanisms that initiate and maintain chemotherapy-induced peripheral neuropathy, eg that induced by oxaliplatin, this clinical entity currently cannot be prevented. There is a need for new therapeutic approaches for prevention. This research should address genotypic profiles of patients suffering from chemotherapy-induced peripheral neuropathy, and the knowledge regarding genetic susceptibility should be incorporated into clinical trials to enable the prediction of patients’ susceptibility prior to starting chemotherapy (20).