In the United States in 2010, it was estimated that there were more than 1.5 million new cancer cases and 569,490 deaths from cancer.

 In patients with advanced cancer, pain is the most commonly reported symptom with a prevalence of 60% to 70%, and unrelieved pain is the most feared symptom in 70% to 80% of these patients.

 Despite advances in pain management and palliative care, intractable cancer pain remains a significant clinical, social, and financial burden in treating the oncologic population.

In advanced stages of cancer, tumors are often incurable and treatment is targeted to controlling pain symptoms and improving a patient’s quality of life.

 Often radiotherapy, chemotherapy, targeted therapy, and surgery are all used to treat and palliate cancers.

 According to the World Health Organization (WHO) analgesic ladder, pharmacologic management is the mainstay for malignancy-related pain.

 However, when patients develop tolerance or side effects to analgesics, interventional pain techniques can better manage a patient’s pain and improve the patient’s quality of life.

In this article, we introduce the reader to various causes of cancer pain, discuss pharmacologic management, and focus on interventional techniques for patients suffering from intractable pain secondary to cancer.

The presence of the tumor itself can cause pain in 4 different ways: (1) nociceptive pain, caused by direct activation of nociceptors (eg, stretched skin or bone), (2) inflammatory pain, caused by release of chemical modulators (ie, growth factor, bradykinin-1, substance P) in response to tissue damage and inflammation resulting in increased nociceptor sensitivity, (3) neuropathic pain, caused by injury of peripheral or central nerves by direct tumor infiltrative etiology or damage by chemotherapy, and (4) functional pain, caused by a derangement in central processing of pain (Table).

 Although most patients with cancer receive multimodal treatment, understanding the different causes of malignancy-related pain can guide targeted pharmacologic and interventional treatments.7

In 1986, the WHO first introduced an analgesic ladder as a pharmacologic algorithm for addressing the management of malignancy-related pain.

 Studies have shown that application of the 3-step approach to administering an appropriate drug at the right dose at the right time is inexpensive and 80% to 90% effective

 The first step of the WHO ladder includes non-opioid analgesics and adjuvant medications, which are often used in combination.

 Commonly used medications to treat nociceptive and inflammatory causes of cancer pain include nonsteroidal anti-inï¬‚ammatory drugs, acetaminophen, and corticosteroids. Adjuvant medications, such as antidepressants (eg, nortriptyline and duloxetine) and anticonvulsants (eg, gabapentin and pregabalin) are also used to treat neuropathic cancer pain.

 Bisphosphonates and monoclonal antibodies (ie, denosumab), may improve pain in patients with bony metastases or may delay worsening of pain control.

 Baclofen and benzodiazepines can help treat pain associated with spasticity.

The second step of the analgesic ladder includes using weaker opioids, such as codeine, tramadol, hydrocodone, and oxycodone for mild to moderate pain

 The third step includes stronger opioids, such as morphine, hydromorphone, oxymorphone, fentanyl, and methadone for severe pain.

 Transdermal opioids are safe, effective, and produce significantly fewer side effects than oral medications when used for moderate-to-severe cancer pain. However, transdermal opioids require a long lag period for dose stabilization and elimination.

Patient Selection for Interventional Techniques Patient selection is important in determining who should pursue interventional techniques for pain management. Patients with pain refractory to medical management or with intolerable side effects to systemic pain medications should be considered for interventional procedures. Accounting for disease-related survival is crucial in deciding if a patient is a suitable candidate for a particular procedure. Patients with shorter life expectancy may be more appropriate for less expensive procedures (eg, intercostal nerve block). However, other procedures (eg, intrathecal pump placement) are generally reserved for patients with longer life expectancy. In performing certain procedures, the cost and benefits of the interventional techniques should be weighed against risks of the procedures, especially for patients with active infections or bleeding diathesis.

During the past decade, advances in chemotherapy, radiotherapy, and other cancer treatments have improved survival but have also resulted in more complex syndromes of cancer pain.

 Recent studies indicate that 20% to 40% of cancer pain is not adequately relieved by solely applying the analgesic ladder.

 In addition, the role of high-dose opioids in pain management is under scrutiny. Thus, new interventional approaches are necessary to help control a patient’s pain when the 3-step WHO analgesic ladder proves limited. These new approaches may allow for better control of a patient’s pain symptoms.

Interventional techniques target many different neural mechanisms involved in cancer pain.

 Since patients can undergo various treatment options to block pain transmission anywhere from peripheral nerves to the spinal cord, interventional pain strategies are divided between peripheral and neuraxial interventions.

Although early application of interventional techniques is encouraged, a combination of both pharmacologic and interventional therapy may provide patients with superior quality of analgesia over either strategy alone.

Peripheral therapies block pain transmission from peripheral and sympathetic nerves involved in afferent somatic pain signals or sympathetic and visceral afferent pathways. These nerves can be blocked using local anesthetics that provide temporary diagnostic relief. Once a diagnostic block has been shown to be effective, prolonged pain relief can be achieved by performing blocks using steroids in combination with local anesthetics and/or neurolytic techniques (ie, cryoablation,

Peripheral Nerves: Targeted nerve blocks are used when pain is limited to the distribution of specific nerves. The targets for these blocks include: trigeminal nerve branches, sphenopalatine ganglion, brachial plexus, lumbar plexus, sacral plexus, intercostal nerves, ilioinguinal and iliohypogastric nerves, and saphenous and pudendal nerves. By using image guidance (eg, ultrasound, fluoroscopy, and computed tomography), the accuracy of the procedure can be improved and the rate of complications can be limited.

However, patients are still at risk for sensory-motor deficits and deafferentation pain after neurolysis.

 Because of the risk of motor deficits causing loss of functionality, it is recommended to perform peripheral neurolytic blocks on primarily sensory nerves (eg, ilioinguinal nerve) compared with mixed motor-sensory nerves (eg, brachial plexus).24 Another complication of neurolysis is deafferentation pain, which appears to result from aberrant nerve fiber regeneration and neuroma formation. Deafferentation pain can occur from any procedure resulting in neurolysis.

 Local and regional sympathetic blocks are used to block sympathetically mediated pain signals involving the viscera. These blocks include: stellate ganglion block, celiac plexus block, lumbar sympathetic and splanchnic nerve block, superior hypogastric plexus block, and ganglion of Impar block. Neurolysis can interrupt efferent sympathetic fibers, afferent pain fibers traveling in the sympathetic chain, and somatic or visceral pain fibers.

 The stellate ganglion block is used to treat neuropathic pain of the upper extremities and chest (ie, cancers of the breast, thorax, head/neck), postradiation pain, postoperative neuropathy, atypical neuropathic facial pain, and phantom limb pain. The ganglion is formed by fusion of the inferior cervical sympathetic ganglion and the first thoracic sympathetic ganglion and is located anterior to the transverse process of C6 to C7, superior to the neck of the first rib, and below the subclavian artery. Complications of the block include Horner’s syndrome (eg, ptosis, miosis, conjunctival injection, ipsilateral facial warmth, anhidrosis, and ipsilateral vasodilation).

The celiac plexus block (Figure 1) is used to treat pain related to pancreatic cancer, bile duct cancer, gastric cancer, and primary liver neoplasm, and for visceral pain originating from all upper abdominal structures. The plexus is located at the level of the upper part of the first lumbar vertebra and surrounds the celiac artery. It lies between the suprarenal glands, in front of the crura of the diaphragm and abdominal aorta, and behind the stomach and omental bursa. Complications of this block include hypotension, diarrhea, the need for intravascular injection, spinal/epidural injections, back/shoulder pain, leg weakness, sensory deficits, paresthesias, and paraplegia.

Lumbar Sympathetic and Splanchnic Nerve Block:

 The lumbar sympathetic and splanchnic nerves can be targeted for pain from the lower abdominal structures, lower extremities, and for ipsilateral pelvic visceral pain. The lumbar sympathetic ganglion is located along the anterolateral surface of the lumbar vertebral bodies and anteromedial to the psoas muscle. The vena cava lies just anterior to the right sympathetic chain and the aorta lies anterior to the left sympathetic chain. The splanchnic nerves and lumbar splanchnic chain are usually medial to the lumbar sympathetic chain and may travel around the large blood vessels of the abdomen. Complications from this block include hypotension, back/shoulder pain, intravascular injections, spinal/epidural injections, genitofemoral neuralgia, psoas, and lumbar plexus damage.

The superior hypogastric plexus block is used to treat pain from the entire pelvis with the exception of the Fallopian tubes and ovaries. It is useful in treating pain from cervical cancer or any type of pelvic pain (eg, bladder spasm/pain, testicular pain), except for ovarian pain. The plexus is located in the retroperitoneal space, starts at the lower part of the fifth lumbar vertebral body and reaches the upper part of the first sacral vertebral body, close to the aortic bifurcation. It transfers visceral impulses from the upper vagina, cervix, uterus, bladder, and right colon to the dorsal horns of the spinal cord through sympathetic thoracic lumbar fibers. Complications from this block include infection, damage to the aorta/iliac vein/lumbar nerves, and retroperitoneal bleeding.

 The ganglion of Impar block is used to treat rectal pain, perineal pain, rectal spasm, or coccydynia. The ganglion is located anterior to the sacrococcygeal junction where the 2 pelvic sympathetic trunks converge at the cranial base and travel retroperitoneal to form the solitary median ganglion. It is usually targeted anterior to the sacrococcygeal or coccygeal ligament. Complications from this block include infection, accidental perforation of the rectum, impaired bladder or bowel function, impaired sexual function, impaired motor or sensory function, and postinterventional neuralgia.

Neuraxial techniques focus on directly blocking modulation of afferent, nociceptive fibers, interneurons, and ascending fibers of the spinal cord in the epidural or intrathecal space. Epidural and intrathecal opioids, steroids, and local anesthetics are used to provide pain relief with fewer side effects than oral or parenteral medications.

 These agents can also be used in tunneled epidural catheters and intrathecal pumps.

 Neuromodulation (ie, transcutaneous electric nerve stimulation and spinal cord stimulation) is another technique that can provide pain relief to patients with cancer.

: Intrathecal neurolysis is used to treat intractable cancer pain in a localized area and is thought to be more effective in treating visceral and somatic pain, and less effective in treating neuropathic pain.45 Alcohol and phenol are injected into the intrathecal space with the goal of producing disruption in sensory transmission while preserving motor function, targeting the dorsal rootlets.45 These neurolytic blocks produce an opioids-sparing analgesic effect and decrease the dose of opioid medications used. Side effects from these techniques can include bladder and rectal sphincter dysfunction, but side effects depend on the area of injection.

 For patients with pain that becomes increasingly difficult to manage, intrathecal drug delivery systems are an effective option for pain relief.

 Compared with conventional pharmacologic management, prospective randomized studies have shown improved pain relief and decreased adverse effects in chronic pain patients using intrathecal drug delivery. The placement of opioids delivered by pump to the intrathecal space provides pain relief and improves quality of life for patients with cancer.

Intrathecal drug delivery is used to treat visceral pain from pancreatic, liver, and stomach cancer, and somatic pain from bone metastases.

 Intrathecal medications have been shown to be effective in treating neuropathic pain (ie, postherpetic neuralgia or cancer-related plexopathies), and in some cases, improved survival when compared with conventional medical management.

Intrathecal opioids are about 100 times more potent than intravenous opioids.

 Because of the long duration of action, effectiveness, and ease of use, morphine is the most commonly used medication for intrathecal analgesia. Other medications used intrathecally include hydromorphone, fentanyl, bupivacaine, ziconotide, clonidine, sufentanil, ropivacaine, buprenorphine, midazolam, meperidine, and ketorolac. Experimental agents, such as gabapentin, octreotide, neostigmine, and adenosine, have all been used, though not necessarily shown to be effective.

Before placing an intrathecal pump, the patient undergoes a trial to establish pain relief and to select the most appropriate medications and dosages to be used with the pump. Normally, the trial consists of a single injection or continuous infusions into the epidural or intrathecal space. If the patient has a positive trial, intrathecal drug delivery systems are placed either as a percutaneous short-term intrathecal catheter, a long-term tunneled intrathecal catheter, or an implantable infusion pump and catheter.

 An implantable infusion pump and catheter requires periodic refilling of the pump and assessment of the patient for adequate pain relief and possible complications after implantation of the pump, such as granuloma formation or infections. These patients also have a patient-controlled device providing additional boluses to provide pain relief and improve quality of life.

: Since placement of intrathecal drug delivery systems is expensive and there is a risk for serious complications, including granuloma formation and post- dural puncture headaches, tunneled epidural catheters may be theoretically more beneficial for patients with a limited life expectancy. Unfortunately, the disadvantage of epidural port systems is that they become more expensive when survival is prolonged (>3 months). There is limited data for the use of tunneled epidural catheters via a percutaneous port in treating malignancy-related pain.

Transcutaneous Electrical Nerve Stimulation:

 Transcutaneous electrical nerve stimulation (TENS) is a noninvasive intervention used to treat a variety of acute and chronic pain disorders. The mechanism of action of TENS therapy is thought to be related to the gate theory of pain. In this theory, there is a ‘gating mechanism’ in the dorsal horn of the spinal cord that controls the transmission of pain signals. By stimulating large-diameter afferent fibers, the ‘gate’ becomes ‘closed’ and the perception of pain is reduced. The advantages of TENS devices are that they are portable, easy to use, and have few adverse effects. Unfortunately, the use and clinical benefit of TENS devices for oncology and palliative care patients with severe cancer pain remains controversial, and it is unclear which patients benefit from this technique.

 Spinal cord stimulation (SCS) (Figure 2) is a minimally invasive approach to treat neuropathic and nociceptive pain. It is mostly used in patients suffering from chronic pain states, such as post-laminectomy syndrome or complex regional pain syndrome. However, since neuropathic pain is a common component of malignancy-related pain, some researchers suggest that SCS may be a valuable technique in patients suffering from intractable cancer pain.

The use of SCS for the treatment of intractable cancer pain has many advantages. Patients can have a trial of the SCS prior to permanent implantation. Implanting the SCS system is a minimally invasive procedure that can be performed in an outpatient setting. There are few side effects to placement and the spinal cord stimulator can be removed if the SCS is no longer effective or fails to provide the anticipated level of pain relief. The main limitation of SCS is that it is not effective in all patients. Most studies demonstrate only 50% to 60% of patients achieve at least a 50% reduction in pain, and there are no randomized controlled trials addressing the efficacy and safety of SCS in patients with cancer. Another serious limitation with placement of spinal cord stimulators in patients with cancer is that most current devices are not compatible with magnetic resonance imaging (MRI) (although newer devices have some FDA-approved MRI compatibility). Because many patients with cancer need continuous surveillance as part of their treatment, SCS may interfere with a patient’s therapeutic course. Complications of placement in SCS include lead migration, lead connection failure, lead breakage, pain at the generator site, dural puncture, bleeding, and infection.

 Vertebral collapse caused by metastatic disease is a frequent source of pain in cancer patients.3 Vertebroplasty and kyphoplasty are interventional pain procedures of the spine, in which polymethylmethacrylate is injected through a needle into a weakened vertebra with the goal of relieving back pain and symptoms of cord compression.

 Besides pain relief, these procedures provide vertebral stability and prevent progression of the fracture or further vertebral body collapse.54 The risks of these procedures are related to cement extravasations, which can lead to radiculopathy by causing pressure on the spinal cord or nerve roots, cement embolism, infection, and death.3 Unfortunately, studies of these procedures have failed to show significant reduction in pain over control.

 One randomized controlled trial demonstrated balloon kyphoplasty to be superior to nonsurgical management for cancer-related vertebral compression fractures.

Patients with advanced cancer can present with severe intractable pain. Although following the WHO analgesic ladder can help treat most patients, some individuals may need additional interventional pain therapies for pain relief and improvement in their quality of life. Interventional techniques should be used in conjunction with pharmacologic management for treatment of cancer pain symptoms. As patient survival with cancer improves, treating patients with cancer pain syndromes becomes more complex and difficult. Determining which interventional technique to try involves careful understanding of the risks and benefits of each procedure. Although more evidence is needed to determine when and how to apply these interventional pain therapies, utilizing interventional techniques and targets will allow for better pain control in our oncologic patients, often with fewer systemic side effects.

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Amitabh Gulati, MD

Articles

Update on the Management of Pain in Patients With Advanced Cancer