Gary Deng, Amitabh Gulati, and Barrie R. Cassileth
Pain can significantly decrease patients’ quality of life during and after radiotherapy, but appropriate and adequate pain management remains imperfect. More than half of patients who undergo radiotherapy experience pain,1 and the majority of patients and physicians feel that patients’ pain is inadequately controlled.2
Pain may result from tissue damage caused by the tumor, such as bone destruction by a metastasis from prostate cancer or invasion of the celiac plexus by pancreatic cancer, or from the delivery of radiotherapy and subsequent complications. Irradiation of normal tissues, especially those with a rapid growth turnover rate, causes cell death and triggers a cascade of proinflammatory cytokines and thrombotic and growth factors, propagating local painful reactions.3,4 Radiation oncologists must be knowledgeable about pain management during and after radiotherapy. In this chapter we discuss the pathophysiology of pain, treatment options, and practice guidelines for developing a stepwise, integrated treatment plan.
Radiotherapy is also a valuable modality in the treatment of cancer pain. It is commonly used in the palliative setting when a radiosensitive cancer invades bone, soft tissue, or nerves.5 Radiotherapy for the palliation of pain caused by various types of cancer is covered in their respective chapters elsewhere in this book.
TYPES OF PAIN
Pain generally can be defined as either nociceptive or nonnociceptive. Nociceptive pain refers to the nervous system response that is proportionate to the tissue damage initiating the response. Nociceptive pain is divided into somatic pain and visceral pain, depending on the location and symptoms of the painful stimulus. Typically, somatic pain presents as a well-localized sharp, stabbing (knifelike), and achy pain as a response to skin, muscle, and connective tissue damage. Conversely, patients typically find it difficult to localize visceral pain, which also may have a somatic referral pattern, often complaining of cramping or a dull ache.6
Nonnociceptive pain encompasses both neuropathic and psychogenic (or idiopathic) pain syndromes. In these cases, nervous system responses are not what would be expected from the damage causing the response. In fact, responses may occur without tissue damage. Neuropathic pain involves abnormal pain processing by the peripheral or central nervous system. Patients may complain of burning, shooting, tingling, or numbness, which generally occurs along a nerve distribution.7 Patients also may experience pain that is out of proportion to physical injury. Psychogenic causes such as depression and anxiety may exacerbate the perception of painful stimuli.
Understanding a patient’s symptoms allows the physician to determine the pathophysiology of the pain syndrome. Each type of pain syndrome is amenable to treatment with different modalities. For example, somatic pain, localized sharp pain, may be better treated with opioid medications, whereas anticonvulsants or antidepressants may be more effective against neuropathic pain. Other modalities, such as acupuncture, have been shown to help either type of pain.8
FIGURE 96.1. World Health Organization (WHO) guidelines for initial medical treatment for cancer pain. A three-tiered system broadly indicating the use of opiate medications for continued pain control is shown. As pain symptoms worsen, a physician may enter a higher tier of medications for pain control. (Adapted from World Health Organization. WHO guidelines cancer pain relief, 2nd ed. Geneva: World Health Organization, 1996.)
TABLE 96.1 GUIDE TO COMMON NONOPIATE MEDICATIONS AND STARTING DOSES FOR ADULTS
MEDICAL MANAGEMENT
Many national and international organizations have developed guidelines for pain management. Despite variations in the details, the principles and approaches are consistent across guidelines. The World Health Organization (WHO), American Pain Society (APS), and National Comprehensive Cancer Network (NCCN) guidelines are discussed here.
WHO Pain Ladder
The WHO guidelines for analgesic management of cancer pain, first described in the early 1980s,9,10 consist of a three-step approach that has been validated in recent trials.11 Despite some debate on its effectiveness,12 it establishes a widely practiced, stepwise approach in the treatment of various levels of pain severity.
The first tier involves the use of nonopiate medications, primarily nonsteroidal anti-inflammatory drugs (NSAIDs) (Table 96.1). These medications include acetaminophen, nonspecific cyclo-oxygenase inhibitors (including ibuprofen, diclofenac, aspirin), and cyclo-oxygenase-2 inhibitors (celecoxib).13 NSAIDs are considered the first group of medications to administer. If the patient’s pain persists or worsens, the second tier adds a weak opioid in addition to the nonopiate. Finally, continued treatment for worsening pain includes the addition of a strong opioid to replace the weak opiate, the third tier (Fig. 96.1).
Five simple principles are recommended to make the pharmacologic treatments effective: (a) oral administration of analgesics should be used whenever possible; (b) analgesics should be given at regular intervals; (c) analgesics should be prescribed according to pain intensity as evaluated with a pain scale; (d) dosing of analgesics should be adapted to the individual; and (e) analgesics should be prescribed with a constant concern for detail.14
Physicians using the WHO guidelines may find it difficult to select among opioids or other medications to start with and to determine dosages to use when changing medications (Table 96.2). Often a patient may not respond to a weak opioid but may respond well to a strong opioid. When pain control becomes inadequate, the physician can climb a higher tier for guidance for better pain control.14 In light of advances in pharmacogenomics, it is increasingly clear that genetics plays a role in each individual’s sensitivity to an analgesic.15,16 If a patient does not respond or develops tolerance to a particular agent, the current medical regimen should be increased to the maximum tolerated dose or the patient rotated to a different agent.
Over time, adaptations of the WHO ladder have been proposed. In refractory pain or crises of chronic pain, a fourth step may be considered, which includes invasive techniques such as nerve blocks, neurolysis, or surgical or other interventions.9,17 Adjuvant medications including steroids, anxiolytics, antidepressants, hypnotics, anticonvulsants, antiepileptic-like gabapentinoids (gabapentin and pregabalin), membrane stabilizers, sodium channel blockers, N-methyl-D-aspartate receptor antagonists, and cannabinoids may be used in the treatment of neuropathic pain.18,19
TABLE 96.2 GUIDE TO COMMON WEAK AND STRONG OPIOID MEDICATIONS AND POTENTIAL STARTING DOSESA
APS and NCCN Guidelines
As the understanding of pain physiology and treatments expands, so does the management strategy. Although the WHO guidelines are a good initial step in pain management, other organizations have modified and expanded these strategies to improve treatment for cancer pain. These guides provide initial medication dosages, the addition of adjuvant medications, and information on appropriate dose increases, allowing the radiation oncologist to further develop pain management skills.
The 2005 APS Guideline for the Management of Cancer Pain in Adults and Children contains detailed discussions of cancer pain management algorithms, pharmacologic strategies, coanalgesics, psychological strategies, supportive therapy, integration of nonpharmacologic and pharmacologic treatments, physical strategies, nerve blocks, surgical strategies, radiation therapy, chemotherapy, and pain management in special populations. It also discusses patient education and the importance of patients’ adherence to the pain management plan, as well as how to improve quality of care in pain management.4
The latest (2010) NCCN guidelines for adult cancer pain contain the following required components: (a) pain intensity must be quantified by the patient (whenever possible); (b) a formal comprehensive pain assessment must be performed; (c) reassessment of pain intensity must be performed at specified intervals to ensure that the therapy selected is having the desired effect; (d) psychosocial support must be available; and (e) specific educational material must be provided to the patient. The guidelines also acknowledge the range of complex decisions faced in caring for these patients. They provide specific suggestions for dosing of NSAIDs, opioids, and coanalgesics; titrating and rotating of opioids; escalation of opioid dosage; management of opioid adverse effects; and when and how to proceed to other techniques/interventions for the management of cancer pain.20
Universal screening of pain should take place for cancer patients, followed by comprehensive assessment of the characteristics, underlying pathophysiology and etiology, psychosocial issues, and risk factors for undertreatment of pain. Patients’ goals and expectations should be sought for any patient whose pain score is not zero (on a visual analog or a numerical rating scale). Patients are then stratified based on the urgency and severity of the pain and treated with escalating aggressiveness. Repeat reassessments are done frequently to adjust treatment plans until patients’ goals and expectations in comfort and function are met. It is preferable to convert short-acting opioids to long-acting ones when the dose required to provide adequate pain control is determined. Rescue dosing with short-acting agents should be provided for breakthrough pain during maintenance therapy.
Opiate Side Effects
Patients taking opioids also should be provided with a bowel regimen. Side effects may limit the maximal tolerable dose of opioid analgesics. Treating a patient’s pain is a balance of maximizing analgesic effects and minimizing side effects.21 Common opioid side effects include gastrointestinal (constipation, nausea, and emesis), respiratory (decreased respiratory rate), dermatologic (pruritus and dry mouth), and central nervous system (sedation, hallucinations, and seizures) effects. Many strategies are implemented in balancing analgesic effects and side effects.22,23 Although no consensus exists, physicians can manage side effects with the following strategies:
1. Pharmacologic treatment of the side effects (e.g., high water intake, dietary fiber, stool softeners, laxatives, or the peripherally acting opioid antagonist methylnaltrexone for constipation);
2. Reduction of opiate dose;
3. Addition of adjuvant medications for pain management (see following discussion), and opioid rotation.
Opioid rotation refers to drug-switching within a group, for example, changing hydrocodone to codeine because of nausea.24 Medications should be changed every 2 to 3 months so that the patient does not become tolerant to an agent.
Adjuvant Therapy
Using the WHO ladder, pain related to cancer can be managed with oral medications in 70% to 85% of patients.11,25 At any point on the WHO analgesic ladder, adjuvant therapy can be initiated to supplement NSAIDs and opioid treatment. Benefits of adjuvant therapy include use of medications tailored to specific causes of nociceptive responses (i.e., neuropathic pain) and reduction of opiate side effects.
Because neuropathic pain generally is not responsive to opioid medications unless high doses are applied, other classes of medications often are prescribed.26 Anticonvulsants, such as gabapentin, carbamazepine, and pregabalin, are effective in managing neuropathic symptoms.7 Both gabapentin and pregabalin are renally excreted and have minimal drug–drug interactions, which renders these medications effective first-line treatments for neuropathic pain.7
Like anticonvulsants, antidepressants are a broad category of medications that stabilize neurons involved in neuropathic pain. Tricyclic antidepressants in low doses, such as amitriptyline, have been well studied for pain relief.27Serotonin reuptake inhibitors and newer classes of antidepressants, including selective serotonin and norepinephrine reuptake inhibitors (milnacipran, duloxetine, and venlafaxine), are less well studied but often prescribed for neuropathic pain. Because many patients with neuropathic pain experience depression or anxiety, antidepressants may play a dual treatment role, resulting in improved efficacy in pain control.27
When faced with a patient with neuropathic pain, the radiation oncologist may prescribe an anticonvulsant, such as gabapentin, at low doses and titrate the medication to improve analgesia while monitoring side effects. Some physicians may initiate antidepressant treatment, especially if patients also exhibit signs of depression or anxiety, and then add the anticonvulsant as a secondary medication. In any case, both medications can be used synergistically to improve analgesia for neuropathic pain.
The NMDA (N-methyl-D-aspartate) receptor has received much attention for its role in modulating pain signals throughout the nervous system. Methadone is a long-acting opioid receptor antagonist, which may act also as an NMDA receptor antagonist, preventing morphine tolerance and NMDA hyperalgesia effects.28 Pain management specialists have also used ketamine, a specific NMDA receptor antagonist, to relieve cancer and neuropathic pain, especially refractory pain.29
Other adjuvant analgesic drug classes used in cancer therapy include local anesthetics, steroids, muscle relaxants, benzodiazepines, α-adrenergic agonists, and bisphosphonates.29 In recent years there has been a resurgence in clinical trials of cannabis extracts and analogs in the treatment of refractory cancer pain.30 Many of these medications are used in specific pain syndromes, which may be useful for the radiation oncologist (Table 96.3).
Nonoral Routes of Administration
Chemotherapy, surgery, and radiotherapy often produce significant side effects. Pain medications given by mouth may not be the most appropriate mode of delivery. When changing from oral to another delivery mode, care must be taken to give equipotent analgesic doses. Conversion charts for opioids are readily available in the literature.22
Some pain medications come in formulations that can be delivered rectally, intramuscularly, intravenously, or topically. NSAIDs and opioids are commercially available in suppository form. Intramuscular delivery of morphine and other medications shows variable efficacy and is not recommended.31 Patient-controlled analgesia allows patients to regularly administer intravenous medications without nursing assistance, especially in the inpatient setting. Both fentanyl and lidocaine are available in a transdermal patch.32 Capsaicin cream and a newer transdermal patch are effective for the local treatment of neuropathic pain.33,34
TABLE 96.3 COMMON ADJUVANT MEDICATIONS WITH STARTING DOSAGES AND COMMON SIDE EFFECTS
INTERVENTIONAL MANAGEMENT
Although most cancer pain can be managed medically, some patients require interventional procedures to achieve pain relief. Such interventions include peripheral nerve blocks, neuroablation, and neuroaxial and implantable techniques.
During Radiotherapy Procedure
Most patients tolerate the radiotherapy procedure, but occasional individuals may not tolerate proper positioning secondary to pain. Most patients can be managed with oral or intravenous pain medications, primarily with opioids such as morphine or fentanyl. When these methods fail, the radiation oncologist may need the assistance of an anesthesiologist.
If the region of radiotherapy is an extremity, the specific nerves to an extremity may be anesthetized with local anesthetic or peripheral nerve block.35 For multiple-day procedures, a peripheral nerve catheter may be placed for delivery of continuous anesthetic.36 Patients with abdominal or thoracic pain may benefit with local anesthetic delivered through an epidural catheter.37 If these methods are contraindicated, general anesthesia may be the only option.
Neuroablative Techniques
Although most pain symptoms can be managed with oral and intravenous medications, the regimen may become insufficient (e.g., due to medication tolerance), or side effects may become intolerable. Interventional pain management specialists offer a myriad of neurolytic procedures that reduce pain medication requirements.
Peripheral nerves, once leaving the spinal cord, can be visualized with magnetic resonance imaging or ultrasound and are amenable to various neurolytic procedures. Common nerves targeted include intercostal nerves for thoracic chest wall or abdominal wall pain, maxillary and mandibular nerves for facial pain, and median branch nerves for facet arthropathy.38 Cryoanalgesia techniques apply subzero temperatures to induce wallerian degeneration of neurons, while allowing normal regrowth of axons. Radiofrequency techniques use heat to cause nerve damage. Chemical neurolysis can be achieved with phenol or alcohol preparations.
Pain signals initiating from the perineal, pelvic, and abdominal regions may be transmitted via visceral afferents following the sympathetic nervous system. Along with these fibers, the sympathetic nerves coalesce at specific ganglia (impar, superior and inferior hypogastric, and celiac plexus). At these sites, image-guided neurolytic procedures can be performed.39 When pain fibers are destroyed in this process, the associated region also is sympathetically denervated.
Not all cancer patient pain is caused by tumors and somatic in nature. Sympathetically mediated pain, complex regional pain syndromes (CRPSs) I and II, may present in an extremity with symptoms of swelling, redness, and temperature change. These typically result from nerve injury and consequent dysautomania of the sympathetic system. Chronic skin changes, hair loss, and muscle atrophy and disuse may follow.40 Along with pharmacologic treatment, neuroablative techniques targeting sympathetic fibers to the upper extremity (stellate ganglion) and lower extremity (lumbar sympathetics) can be used to treat these syndromes.41
Neuroaxial Techniques
Neuroaxial procedures involving drug delivery systems are indicated when oral opioid doses are escalated without significant pain relief or when side effects are intolerable.42 Either semipermanent epidural systems or permanent intrathecal delivery systems can be used to deliver local anesthetic and opiate medications in low concentrations to appropriate spinal cord root levels.43 The benefits of these methods include the use of local anesthetics in concentrations that are not toxic but can provide analgesia at the spinal cord level and the use of adjuvants (such as clonidine, baclofen, and ziconotide). These should not be given at equivalent oral doses because of side effects.44
Electrostimulation techniques also may be applied to disrupt the flow of pain signals in the spinal cord. Transcutaneous electrical nerve stimulation, spinal cord stimulation at thoracic and lumbar regions, and deep-brain stimulation at the thalamus or motor cortex can interfere with the conduction of pain signals.23 The stimulation of large motor fibers inhibits the conduction of pain signals by small nerve fibers and has shown efficacy for various pain syndromes.45
Neurosurgical techniques are generally reserved for refractory pain and specific indications. Plexus root avulsions may be responsive to dorsal root entry zone lesioning, but the indications and success rates are limited.46 More specific lesions at the spinal cord and central nervous system (e.g., thalamotomy and deep-brain stimulation) have also been used with variable success and significant side effects.47 Finally, various chemoneurolytic medications can be delivered intrathecally for destruction of specific nerve roots or parts of the spinal cord for the treatment of refractory cancer pain.48
COMPLEMENTARY THERAPIES
Conventional medical regimens may not satisfactorily treat cancer-related pain syndromes. Several complementary modalities such as hypnosis, biofeedback, massage, music therapy, mind–body exercises, and dietary supplementation have been shown to reduce anxiety and chronic pain,49 yet more multi-institutional, randomized, controlled trials are needed to confirm their effectiveness in this setting.50
Acupuncture is perhaps the most extensively studied method for pain control.51 Acupuncture relieves both acute pain (e.g., postoperative dental pain) and chronic pain (e.g., headache, osteoarthritis).52–54 Acupuncture appears effective against cancer-related pain. A randomized, placebo-controlled trial tested auricular acupuncture for patients with cancer pain despite stable medication. Pain intensity decreased by 36% at 2 months from baseline in the treatment group, a statistically significant difference compared with the two control groups for whom little pain reduction was seen.8 Most patients in this study had neuropathic pain, which is often refractory to conventional treatment.
Neurophysiologic studies show that acupuncture-induced analgesia appears to be mediated by endogenous opioids and other neurotransmitters.55 Functional brain imaging studies suggest that acupuncture also modulates the affective-cognitive aspect of pain perception.56 Correlations between functional magnetic resonance imaging signal intensities and analgesic effects induced by acupuncture have been reported.57
SPECIFIC SCENARIOS
The following section identifies common pain syndromes that radiation oncologists may face.
Muscle Spasm
Muscle fibers, once thought to be radioresistant, may undergo significant change, especially months after radiation exposure.58 One-time muscle exposures to 10 to 20 Gy or fractionated doses >55 Gy are associated with myokymia, pain, and decreased muscle strength and range of motion.58 Specific cancer locations susceptible to muscle complications include head and neck cancers and soft-tissue cancers (e.g., Ewing sarcoma).58 Treatment regimen includes early physical therapy and orthopedic exercises and pharmacologic therapy such as muscle relaxants (e.g., baclofen). Novel treatments involve the use of botulinum toxin injected in small doses (15 to 25 units) into the muscle to relieve contracture or spasm.59,60
Plexopathy
Similar to muscle fibers, nerve bundles exposed to a one-time dose of 28 Gy, or fractionated doses totaling 60 Gy, undergo significant decreases in large nerve fiber density.61 Significant pain may ensue months to years after radiotherapy, especially in the brachial plexus distribution.62 Rates of radiation-induced plexopathy range from 1% to 5%, with 10% of this population having complicated pain syndromes such as CRPSs, dysesthesias, and numbness.63 Treatments involve early physical and occupational therapy, multimodality pain regimens (opioid and neuropathic pain medications as previously discussed), neurolytic procedures (e.g., stellate ganglion), and electrical stimulation (transcutaneous electrical nerve stimulation or spinal cord stimulators).64
Mucositis and Proctitis
Pain associated with mucositis (up to 75% of patients treated with radiation) is debilitating and may result in dose limitations of radiotherapy.65 Pain control strategies include NSAIDs and oral opioids, with intravenous patient-controlled analgesia providing good management of pain when patients are hospitalized. Topical analgesics, such as viscous lidocaine, ice chips, capsaicin, benzydamine (Gelclair, Sinclair Pharma Ltd., United Kingdom), and diphenhydramine, may provide relief prior to ingestion of food.66 Some helpful interventions include good oral hygiene, honey, hydrolytic enzymes, zinc, laser therapy, Gelclair, and povidone.67,68
Similar to oral mucosa, the rectum is susceptible to late radiation damage and proctitis, with patients presenting with tenesmus and rectal pain. Medical treatments involve reducing inflammation with NSAIDs and steroids, such as hydrocortisone cream, and the use of sucralfate.69 Novel therapies, including hyperbaric oxygen and heat therapy (laser therapy), have also been used successfully to heal rectal mucosa and reduce tenesmus.70–72
SUMMARY
Pain is a common problem in patients with advanced cancer. Radiotherapy can be used to treat pain caused by the underlying cancer (e.g., pain from bone metastasis and pain due to treatment side effects). A multimodal management approach should be applied, starting with oral analgesics administered according to clinical practice guidelines, and also confounding factors such as psychological issues should be addressed. For patients who experience refractory pain despite medical management, interventional procedures may be necessary. Complementary therapies may be helpful in some patients, although their efficacy has not been definitively established.
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