Pain Management and Antiemetic Therapy in Hematologic Disorders

Initial Evaluation

Effective pain management requires a comprehensive assessment of the patient’s pain. The clinical presentation of a patient with chronic pain is very different from that of a patient in acute pain. The patient with chronic pain does not present with the common autonomic manifestations of acute pain (e.g., tachycardia, sweating, elevated blood pressure) or facial grimacing, but often appears withdrawn, quiet, depressed, or irritable; moves very little spontaneously; and experiences discomfort when moved. When the pain is relieved, these patients often exhibit completely different behaviors, becoming mobile, engaged, and involved with other people. The first component in the assessment is to believe the patient’s complaint.

Patient reports of pain are valid, reliable, and reproducible. A variety of assessment tools are available, and most can be completed in 5 to 10 minutes or less. A commonly-used example is the “Brief Pain Inventory.” The pain complaint should be characterized by a number of descriptors, including the pain location, intensity, quality, onset, and duration; location and patterns of radiation; and what relieves or exacerbates the pain and its functional consequences (including how the pain affects the patient's function, including their ability to sleep or eat and how it affects physical activity, relationships with others, emotions, and concentration). Most patients with chronic cancer pain also experience periodic flares of pain, or “breakthrough pain.” An important subtype of breakthrough pain is “incident pain,” which is caused by voluntary activity. The initial evaluation should determine the extent to which the patient has breakthrough pain and if it is provoked by movement (nociceptive) or tends to be paroxysmal in nature (neuropathic). This subjective information, combined with the physical examination and diagnostic studies, may identify a specific pain syndrome and its implied pathophysiology.

In a patient with a hematologic disorder, the cause of pain may be the disease itself, the specific therapy for the disease, diagnostic procedures related to the disease, or unrelated disorders ( Table 99.1 ). Splenomegaly, bone injury (e.g., infarction, infection, hemarthroses, and infiltration), leptomeningeal infiltration, and spinal cord compression frequently accompany hematologic diseases. Chemotherapy and radiation therapy can cause mucositis, typhlitis, hemorrhagic cystitis, and peripheral neuropathy; corticosteroid withdrawal may cause myalgias. Immunosuppression, caused by the diseases themselves or by the therapies used to treat them, may lead to painful infections such as perirectal abscesses, herpetic or candidal esophagitis, and herpes zoster. Patients with sickle cell disease have a number of causes for both acute and chronic pain ( Table 99.2 ).

Distress, however, may arise from nonanatomic sources. The pain complaint may represent the patient's only means of expressing nonspecific feelings of distress to the clinician. Chapman recognized three categories of this distress: anxiety, arising from fear of disfigurement or of uncontrollable pain, fear of loss of social position or of self-control, or fear of death; anger at the failure of the physicians to provide a cure; and depression from the loss of physical ability, a sense of helplessness, and the impact of financial problems. In addition to these psychological, social, and financial contributions, spiritual concerns may exacerbate any concomitant painful sensations. Alleviating them may significantly reduce distress and decrease the need for pain medications or other interventions.

Sometimes there may be a disparity between the patient's expression of pain and the patient’s family or friends’ appreciation of the impact of the pain. The following script may help to begin a conversation around this issue: “You seem to show a different perspective about the pain from those of your family and friends. Help me to understand what the pain is like for you and why you think your family and friends feel differently.” Differences in cultural backgrounds may also affect the expression of pain, and thus may vary within a family as well as in different families.

Continued Assessment

A standardized measurement tool, such as a verbal rating scale (VRS) or a visual analog scale (VAS), should be consistently used during follow-up visits. These measurements are thought to be more accurate than mere qualitative descriptors, such as: “The pain is better.” Using, for example, a scale of 0 (no pain) to 10 (the worst pain one can imagine), a decrease in pain intensity from 10 to 8 indicates that the patient could benefit from additional dose titration, but a decrease from 10 to 3 suggests that the current dose is effective. A pain goal should be assessed by asking the patient, “What level of pain would be acceptable to you?” Negotiating this goal together is often necessary, and helpful, as the complete elimination of pain is often not possible. The ongoing assessment should also pay attention to changes in the phenomenology of the pain, new occurrences of pain, or a change in the location of pain—all of which may suggest progression of disease in the patient with a hematologic disorder.

The successful outcome of pain therapy should be more than simply the lowering of pain intensity scores, but the impact on function, the minimization of side effects from treatment, and the prevention of opioid misuse. Passik and Weinreb developed a useful mnemonic device for the assessment of pain therapy in chronic nonmalignant pain known as the “4 As”: analgesia, activities of daily living, adverse events, and aberrant drug-taking behaviors (e.g., repeated dose escalation or non-adherence, hoarding medications, or acquiring controlled substances from other medical sources or even non-medical avenues). By focusing on these relevant domains in the continued assessment of the pain therapy, the clinician is able to determine if the therapy makes a true difference in the patient’s life, stabilizes or improves psychosocial functioning, manages side effects, and provides a means of assessing for aberrant behaviors. Ultimately, the goal should be to lower the pain to a level acceptable to the patient and to improve the patient’s level of functioning.

Cognitive-Behavioral Interventions

Cutaneous Techniques

Acupuncture, massage, vibration, and applying cold or heat to the skin over injured areas are often very effective. Cold wraps, ice packs, or cold massage using a cup filled with water that has frozen into a solid piece of ice relieve the pain of muscles that are in spasm from nerve injury. Heat from heating pads, hot wraps, or paraffin treatments can soothe injured joints but should not be used over areas of vascular insufficiency.

EMLA, a cream containing two topical anesthetics (2.5% lidocaine and 2.5% prilocaine) is used, especially in children, to decrease the pain of superficial cutaneous procedures (e.g., venous cannulation or skin anesthesia before lumbar puncture, bone marrow aspiration, or biopsy). In adults, it is sometimes used before access of implanted vascular access devices or CNS ports. To achieve anesthesia, the EMLA cream must be applied 1 to 1.5 hours before the planned procedure in a mound under a semipermeable dressing such as Opsite or Tegaderm. When EMLA is used as directed, methemoglobinemia has not been a problem even in infants as young as 3 months old. Skin blanching occurs, sometimes exceeding or equaling the frequency of that found with placebo moisturizing cream placed under the occlusive dressing. ELA-Max, a cream containing 4% lidocaine, is available over the counter and is an alternative to EMLA cream. Because it does not contain prilocaine, there is no risk of methemoglobinemia.

Lidocaine patches can be used over areas of hyperesthesia, as can occur in patients with postherpetic neuralgia (PHN) or nerve entrapment by vertebral body collapse. The patch is applied to the affected area for no more than 12 consecutive hours a day and can be cut to size. Use should be avoided over areas of broken skin and in patients undergoing radiation therapy. Lidocaine patches have been safely applied for up to 24 hours/day for up to 4 days with minimal systemic absorption in healthy volunteers and in patients with PHN.

Neuromodulation

Transcutaneous electrical nerve stimulation (TENS) devices are indicated for patients with dermatomal pain, such as PHN or radiculopathy from spinal cord compression. For optimal effect, a physiatrist or physical therapist familiar with the device should train the patient in its use. The efficacy of TENS therapy for patients with cancer pain remains controversial.

Radiation Therapy

Radiation therapy is commonly used in the management of painful bone lesions, spinal cord compression, bulky lymphadenopathy, and symptomatic splenomegaly in patients with hematologic malignancies. Radiotherapy is the treatment of choice for local metastatic bone pain in most situations, although patients with underlying pathologic fractures may require surgical fixation before radiotherapy. Randomized trials have shown that single-fraction radiotherapy is as effective as multifraction radiotherapy in relieving pain caused by metastases. However, there are higher rates of retreatment, and single-fraction radiotherapy may not prevent pathological fractures or spinal cord compression. In patients with poor performance status or a short life expectancy, a single dose (8 Gy) of radiation or a hypofractionated course (20 Gy/5 fractions) may be preferable and less burdensome. Some hematologic malignancies can be more sensitive to radiation therapy than are most solid organ tumors, with effective palliation of cancer-related symptoms occurring at lower radiation doses in many cases of lymphoma, for example.

Vertebroplasty and Kyphoplasty

Vertebroplasty and kyphoplasty are both minimally invasive techniques used to stabilize vertebral compression fractures and reduce pain. Vertebroplasty is a procedure in which bone cement, usually polymethylmethacrylate, is injected into the vertebral body. With kyphoplasty, a balloon is first inserted into the vertebral body followed by inflation and then deflation before cement is added. Balloon kyphoplasty has been shown to stabilize pathologic vertebral fractures caused by multiple myeloma and significantly reduce pain, though there remains some debate about its efficacy amid other negative studies.

Anesthetic Techniques

Trigger-point injections, nerve blocks, and neurolytic procedures are useful for acute and chronic localized pain. After excisional biopsy of an axillary lymph node, for example, a burning, constricting pain in the posterior arm and chest wall may develop; this pain is often promptly relieved by trigger-point injection.

Lymphoma or multiple myeloma may involve the spine and lead to vertebral collapse or pain from progressive disease that is refractory to antineoplastic therapy. Such pain is often particularly difficult to manage. Insertion of temporary or permanent indwelling epidural or intrathecal catheters to deliver opioids, local anesthetic agents, clonidine, or combinations of these and other agents can be very effective, especially in relieving lower thoracic or lumbar spine pain, as well as pelvic and lower extremity pain. Reviews of the indications for and techniques of the anesthetic and neurolytic procedures are available. Consultation with an expert in anesthesiology and/or palliative medicine can be helpful in these situations, to obtain expert guidance about appropriate indications for these procedures.

Management of Mild-to-Moderate Pain

Nonopioid analgesics should be given to patients with mild-to-moderate pain. Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, are especially useful as antiinflammatory agents because they decrease local prostaglandin release through the inhibition of COX (although the mechanisms for their analgesic properties are not as clear). Acetaminophen is an effective analgesic but only a weak antiinflammatory agent. Daily intake of acetaminophen should not exceed 3 to 4 g because of the potential hepatic toxicity. It is important to prescribe an adequate dose of acetaminophen or NSAID at regular intervals, switching to another nonopioid analgesic only when maximal doses of the first have become ineffective.

Ketorolac tromethamine (Toradol) is an NSAID of particular value in relieving moderate-to-severe acute pain. A parenteral dose of 30 mg of ketorolac equals the pain-relieving potency of a parenteral dose of 15 mg of morphine, and acute toxicity is minimal if the total daily dose is under 100 mg. Oral ketorolac is considered less potent. Ketorolac has all of the side effects of the NSAIDs and is not recommended for use beyond 5 days because of an increased risk of renal toxicity. If that degree of pain relief is needed chronically, an opioid agent should be substituted.

Because NSAIDs can cause renal insufficiency in a significant number of patients, renal function should be assessed 1 to 2 weeks after initiation of any of these agents. NSAIDs should be used with caution in patients with a history of aspirin allergy or asthma because they can precipitate bronchospasm in as many as 20%. Significant edema can occur in patients with cirrhosis or congestive heart failure. The relatively selective COX-2 inhibitors, such as meloxicam, celecoxib, and nabumetone, have been shown to cause similar gastrointestinal side effects as nonselective NSAIDs. If NSAIDs are required in patients with a history of significant gastritis or ulcer disease, or who are older than 70 years, COX-2 inhibitors or a concomitant proton pump inhibitor should be considered. Cardiotoxicity is well described in the literature for COX-2 selective inhibitors. Recently, the cardiac risk associated with traditional NSAIDs has been questioned. In a meta-analysis that included naproxen, ibuprofen, diclofenac, and several COX-2–specific inhibitors, ibuprofen and diclofenac demonstrated an increased risk of stroke. Diclofenac was also associated with an increased risk of cardiovascular death. Naproxen was not noted to increase risk in this study. Nonopioid analgesics should be continued when opioid analgesics are added because they can potentiate the pain-relieving effect of the opioid (see Fig. 99.1 ). However, when aspirin or acetaminophen is included in a fixed drug combination (e.g., Percodan, Percocet), toxicities may develop if the patient uses the medication more frequently than prescribed. The metabolism of salicylates is limited by the capacity of the hepatic microsomal system. After it is saturated, salicylate levels are dependent on renal clearance. Small increases in maintenance doses can lead to serious salicylism. Patients with low albumin levels or acid urine are particularly susceptible to the development of salicylate toxicity.

Tramadol, which both weakly inhibits norepinephrine and serotonin reuptake, and weakly binds to μ-opioid receptors and has opioid-like side effects, can be used for mild-to-moderate pain. A dose of 100 mg is more effective than 60 mg of codeine. Tapentadol (Nucynta) also has both μ-receptor agonism and norepinephrine reuptake inhibition. Studied in moderate-to-severe acute postoperative pain, osteoarthritis, and low back pain, doses of 50 to 100 mg every 4 to 6 hours are comparable to oxycodone 10 to 15 mg every 4 to 6 hours with less nausea, vomiting, and constipation.

Management of Moderate-to-Severe Pain

Opioid therapy is the cornerstone of management of patients with moderate-to-severe pain.

In patients with acute moderate-to-severe pain (i.e., ≥4/10 on VRS), intravenous dosing should be started with the goal of rapid titration (see, for example, National Comprehensive Cancer Network [NCCN] guidelines for Adult Cancer Pain). In opioid-naïve patients, morphine 2 to 5 mg or its equivalent (see box on Relative Potencies of Commonly Used Opioids ) should be dosed every 15 minutes (peak effect ∼15 minutes). The patient should be reassessed for analgesic effect and side effects. If pain is not relieved, then the dose can be increased by 50% to 100%; if the pain score decreases to an acceptable level, then the same dose can be continued and given as a standing dose “around the clock.” Alternatively, a patient-controlled analgesia (PCA) can also be used in these situations and can provide the patient with significant control over their pain experience. Similarly, the PCA demand dose can be calculated over a 24-hour period to determine the “basal dose” of opioid the patient will need for stable analgesia. This can be provided as a basal rate on the PCA, or given the clinical situation, as a long-acting formulation equivalent to the amount of demand doses received. In opioid tolerant patients, a dose equivalent to 10% to 20% of the patient’s total 24-hour oral requirement should be administered as an intravenous bolus (see box on Relative Potencies of Commonly Used Opioids ) and titrated, as above, every 15 minutes until pain is controlled and acceptable to the patient. For example, a patient receiving oxycodone sustained release 60 mg twice daily, should be prescribed morphine 5 to 10 mg intravenously every 15 minutes as needed (oxycodone 120 mg is approximately equivalent to 180 mg of oral morphine, or 60 mg of intravenous morphine; take 10% to 20% of this dose). The long-acting opioid should be continued or converted to a continuous infusion, or given as a basal rate via a PCA.

Once the patient has an acceptable level of analgesia, this dose can be converted to a sustained release formulation, or to another equivalent long-acting opioid. If morphine is used, for example, the patient will need three times the parenteral dose that was effective. For example, a patient who requires 10 mg of morphine per hour (i.e., 240 mg/24 hours given intravenously) will need 720 mg/day of the oral sustained-release agent (240 mg every 8 hours). This can also be given orally as 360 mg every 12 hours. Short-acting immediate-release morphine should be available for rescue dosing at 10% of the total daily dose. For this patient, 60 to 90 mg every 3 to 4 hours is recommended. If the amount of opioid taken as a rescue dose is significant (>25% of the daily dose) for 1 or 2 days, the total dose of long-acting agent is adjusted upward accordingly.

In the outpatient setting, patients with chronic, moderate-to-severe pain can be treated with oral pain medications, e.g., morphine 5 to 15 mg (or an equianalgesic dose, e.g., oxycodone 5 to 10 mg), and titrated in a similar fashion. The peak effect of most oral opioids is approximately 60 minutes, so the patient should be reassessed 60 minutes following the dose for analgesic efficacy and side effects. The same strategy as above can be used for opioid-tolerant patients, i.e., 10% to 20% of the basal dose can be given for additional analgesia and titrated to effect.

Agents to prevent side effects should be started once opioids are initiated. All patients should be prescribed a stimulant laxative, for example, senna (one or two tablets orally daily to twice daily, up to a maximum of eight pills per day), plus or minus a stool softener, for example, Colace 100 mg three times per day. If a more potent laxative effect is needed, lactulose (15 to 30 mL) or polyethylene glycol (17 g) is added. In opioid-naïve patients, prochlorperazine (Compazine 10 mg taken orally two or three times daily) is prescribed as needed to treat nausea. Other antiemetics may be prescribed instead, depending on the desired side effect profile; 5HT3 blocking medications, for example, are constipating and can cause QTc prolongation and headaches, but are not sedating like prochlorperazine.

Opioid Analgesics