Introduction
Pain is one of the most common symptoms reported in cancer patients. This pain can be nociceptive (somatic or visceral) or neuropathic, or a combination of these. Chronic pain can arise secondary to the tumor burden itself or to cancer-related treatments, comprising radiation or chemotherapy that lead to radiation fibrosis and peripheral nerve damage, respectively. , This chapter will discuss the evaluation of patients with cancer who suffer from chronic pain, outline the assessment of cancer-related pain, and provide an overview of the pharmacologic and interventional treatment options available for managing chronic pain.
Evaluating the Patient With Cancer-Related Pain
Cancer pain can be nociceptive or neuropathic, or a combination of these two types of pain. Nociceptive pain can be either somatic or visceral (originating from internal organs mediated by the autonomic nervous system) and arises when receptors at the distal end of axons sense noxious mechanical, chemical, or thermal stimuli that subsequently produce electrical activity. By contrast, neuropathic pain is characterized by lesions or dysfunction of the pain-sensing nervous system.
Medical History and Physical Examination
Pain assessment for a patient with cancer-related pain begins with a thorough medical history. Specifically, the following information should be elicited in detail: location of the pain, the onset of pain, and whether the pain is constant or intermittent (essential to guide whether the patient may benefit from long-acting pain medication versus short-acting analgesics “as needed” [prn] pain medication), description of the pain in the patient’s own words (i.e., sharp, dull, achy, gnawing, throbbing, etc.), factors that alleviate or aggravate the pain, and if there are any other systemic or autonomic symptoms associated with the pain. Most cancer pain is continuous, with some variation in intensity; the severity of pain is often worse at night. A thorough pain medication history should also be elicited. Specifically, an inquiry should elicit whether the patient is currently using or has used any pain medications in the past and whether this provided pain relief.
Information should also be gathered regarding the patients’ cancer diagnosis, including documenting the cancer type, cancer stage, metastatic disease, and past and current cancer treatments (e.g., chemotherapy, radiation, immunotherapy, stem cell transplant).
An extensive physical examination should then follow history taking. For a new patient, the recommendation is to perform a complete multisystem examination. A more focused examination of the patient’s pain complaint site could be considered for an established patient.
Radiologic and Electrophysiologic Studies
Radiologic studies are the mainstay tools for guiding cancer diagnosis, establishing disease progression or regression, or disease surveillance. Pertaining specifically to cancer diagnoses, x-ray images are used when there is a concern of fractures, bony spurs or overgrowth, or concern for bone metastases or disease involvement of the bone marrow. Computerized tomography (CT) and magnetic resonance imaging (MRI) are both high-resolution imaging modalities, with the latter proven to be more beneficial for disease in the soft tissue or spinal cord. In addition, nuclear imaging bone scans can help diagnose and localize pathologies affecting the skeletal bones.
In addition to diagnostic studies, several types of electrophysiologic study can further assist in diagnosing the etiology of pain. For example, a nerve conduction study (NCS) is a diagnostic test that can evaluate nerve function by assessing electrical conduction in both sensory and motor nerves. The NCS stimulates a specific nerve and records its ability to send impulses to the muscle. NCSs are usually performed along with electromyography (EMG), an electrodiagnostic modality for evaluating the electrical activity produced within skeletal muscles. Unlike NCSs, which typically test large fibers, quantitative sensory testing (QST) is a dependable way of assessing both large and small nerve fiber function. Quantitative sensory testing is a psychophysical test that tests the integrity of the entire sensory neuraxis; however, the results are subject to changes based on the patient’s mental alertness.
Pharmacologic Management of Cancer-Related Pain
The World Health Organization has developed a three-step ladder to treat cancer-related pain systematically. While the three-step ladder is a treatment algorithm based on the severity of pain (mild, moderate, severe), the ultimate goal should be to assist with pain management while minimizing patient symptoms and maximizing their functionality. Step 1 pertains to treating mild pain with aspirin, acetaminophen, and nonsteroidal antiinflammatory drugs (NSAIDs) along with “adjuvant” medications. Adjuvant medication is an umbrella term for nonopioid medicines used to assist with pain control and to minimize the use of opioids. Adjuvants can be antiinflammatories, muscle relaxants, anticonvulsants/antidepressants, local anesthetics, alpha-2 agonists, and many others. Step 2 is geared toward treating patients experiencing moderate pain, using “weak opioids,” such as codeine, hydrocodone, or oxycodone, along with other adjuvants. Step 3 aims to manage patients’ severe pain using strong opioids such as morphine, hydromorphone, methadone, or fentanyl, along with adjuvants. Unlike opioids, acetaminophen and NSAIDs have an analgesic ceiling effect and have no tolerance or addiction potential.
Acetaminophen
Although acetaminophen is widely used for its analgesic and antipyretic properties, its exact mechanism is unknown. Because of its antipyretic effect, acetaminophen is generally avoided in cancer patients who are actively undergoing chemotherapy, stem cell therapy, or immunotherapy to avoid masking fevers, thereby allowing early detection of neutropenic sepsis. In addition, acetaminophen should be used with caution in patients with liver dysfunction, as it may cause liver toxicity. The maximum dose is 4 g in a 24-h period.
Nonsteroidal AntiinflammatoryDrugs (NSAIDs)
NSAIDs inhibit the cyclooxygenase (COX) enzyme, which can be found in either COX-1 (a constitutive form) or COX-2 (inducible under conditions of inflammation) analogs, and are responsible for the conversion of arachidonic acid to thromboxanes and prostaglandins. As such, NSAIDs help minimize the formation of inflammatory mediators that sensitize nerve endings.
The side effects of NSAIDs are associated with their mechanisms of action. Inhibition of the enzyme leads to inhibition of platelet aggregation and vasoconstriction, increasing the risk of gastric erosion and bleeding in the gastrointestinal tract and ischemic kidney injury. The risk of stomach ulcers and platelet inhibition is decreased with COX-2 specific medications. NSAIDs should be taken with food and used with caution in cancer patients with cachexia, reduced fluid intake, or dehydration.
Opioids
Opioids elicit their analgesic effects by binding to the central and peripheral mu-, kappa-, and delta-opioid receptors. Opioids can be full agonists, partial agonists, or mixed agonist-antagonists. However, to treat cancer-specific pain, we primarily focus on full agonists. Opioids can be administered via multiple routes, including oral, buccal, rectal, subcutaneous, transdermal, intravenous, epidural, and intraspinal, with a preference for the oral route due to ease of administration. Table 42.1 details the recommended doses for opioids.
| Drug | Dosage | Routes |
|---|---|---|
| Codeine | 15–60 mg, Q4–Q6H, PRN | PO |
| Tramadol | 50–300 mg, Q4–Q6H, PRN | PO |
| Tapentadol | 50–100 mg, Q4–Q6H, PRN | PO |
| Morphine | Dose individualized 15–30 mg, Q4H, PRN 2.5–10 mg, Q2–Q6H, PRN 10–20 mg, Q4H, PRN 0.5–2.5 mg, IV-PCA, Q6–20 min, PRN | PO Subcutaneous/IM/IV Rectal IV-PCA |
| Oxycodone | Dose individualized, start 5–15 mg, Q4–Q6H, PRN | PO |
| Hydromorphone | Dose individualized = 2–3 mg immediate-release (IR), Q4–Q6H = 1–4 mg, Q3-Q6H, PRN 8 mg extended-release (ER), Q24H 3 mg, Q6-Q8H, PRN 0.05–0.4 mg, Q6–20 min, IV-PCA | PO IV/IM, subcutaneous IV-PCA |
| Methadone | 2.5 mg, Q8–Q12H for moderate-severe pain | PO/subcutaneous/IM/IV |
| Fentanyl transdermal | 12.5–100 µg/h | Transdermal |
Codeine
Codeine is a prodrug metabolized by CYP2D6 to its active form to achieve its analgesic effect. There are known variations in the CYP2D6 enzyme. Some variations have reduced enzymatic activity, with the formation of low levels of the active metabolite, providing insufficient pain relief in some patients. By contrast, some individuals are ultra-rapid metabolizers with overactivity of CYP2D6 and can experience symptoms of opioid overdose secondary to an overproduction of the active metabolite. Due to the variability in the CYP2D6 enzyme, patients can often fail therapy, which requires switching to another opioid or alternate analgesic medication.
Tramadol
Tramadol is a weak opioid analgesic used to treat mild to moderate cancer-related pain. Tramadol binds to both mu- and kappa-opioid receptors. Furthermore, one benefit of tramadol is that it prevents the reuptake of norepinephrine and serotonin, which can serve as an effective analgesic for neuropathic pain.
Tapentadol
Tapentadol is a weak opioid involved with mu-agonism and norepinephrine reuptake inhibition, and minor serotonin reuptake inhibition. Tapentadol is more potent than tramadol, with no active metabolites. However, similar to tramadol, there is an increased risk of seizures, with a similar gastrointestinal side effect profile.
Morphine
Morphine is a potent opioid that undergoes glucuronidation and is metabolized into two metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M6G has a high affinity for the mu receptors and provides analgesic relief; however, it also has the potential for respiratory depression. On the other hand, M3G does not provide any analgesia and contributes to different adverse reactions, including seizures, myoclonus, allodynia, and hyperanalgesia. Morphine can be administered via numerous routes, including oral, intravenous, epidural, and intrathecally.
Oxycodone
Oxycodone is a semisynthetic opioid with high bioavailability and is prescribed in an extended-release or immediate-release form. CYP2D6 metabolizes oxycodone into nor-oxycodone and oxymorphone; the latter is 14 times more potent than oxycodone. Oxycodone is sold under different formulations in combination with aspirin or acetaminophen, which amplifies the synergistic properties. Again, caution must be exercised in patients undergoing active cancer treatment using formulations containing aspirin or acetaminophen, as these will mask fevers.
Hydromorphone
Hydromorphone is a strong opioid analgesic four times more potent than morphine, and it is metabolized into the inactive metabolite hydromorphone-3-glucuronide. Due to its high affinity for the opioid receptor, hydromorphone is used for severe cancer pain that is not relieved by other methods. An extended-release formulation of hydromorphone is currently being formulated.
Methadone
Methadone is a mu- and delta-opioid agonist with N -methyl-d-aspartate (NMDA) antagonist properties. Methadone has been used as a drug of choice to treat opioid tolerance/addiction and heroin addiction. While the mechanism of action is not entirely understood, methadone also inhibits the reuptake of norepinephrine and serotonin, which, alongside its NMDA antagonist properties, makes it a good drug for treating neuropathic pain.
Fentanyl
Transdermal patches have been shown to be effective for cancer-type pain, especially in patients who cannot take any oral medications. Fentanyl patches come in different dosages, usually from 12.5 to 100 µg/h. On average, it takes approximately 4–6 h for fentanyl patches to start working, with maximum pain relief achieved after 12–24 h after application. Patches are usually changed every 3 days, and once removed, the medication half-life is approximately 17 h. Because of its slow onset of action, patients should be notified about using other narcotic medications, as opioid toxicity can occur hours later. In addition to the transdermal route, fentanyl can be administered via oral, buccal, and intravenous routes.
Anticonvulsants
Anticonvulsants, such as gabapentin, pregabalin, carbamazepine, valproic acid, and lamotrigine, are typically used as adjuvants along with opioids to manage neuropathic pain. These medications, listed in Table 42.2 , have been shown to improve neuropathic pain resulting from trigeminal neuralgia, nerve root compression, diabetic neuropathy, and chemotherapy-induced peripheral neuropathy, among others. ,
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