Williams Hematology



Multidimensional Nature of Pain
Pain Mechanisms
Cancer Pain


Treatment for Cancer Pain


Adjuvant Analgesics

Route of Drug Administration

Specific Opioids

Other Pain Therapies
Pain in Sickle Cell Disease

Pharmacologic Management of Painful Crises in Sickle Cell Disease

Route of Administration
Pain in Myeloma
Pain in Acquired Immunodeficiency Syndrome
Chapter References

Hematologic disorders comprise a wide range of disease entities, many with the capacity to produce acute and chronic pain. In addition to pain associated with procedures and complications related to hematologic diseases, such as biopsies, catheter insertions, severe infections, splenic infarctions, and their treatment, pain is a frequent and central problem in sickle cell disease, myeloma, and acquired immunodeficiency syndrome. When present, pain in patients with lymphoma is typical of the somatic and neuropathic pains that accompany the progression of solid tumors. In addition, patients with leukemia and receiving stem cell transplantation often describe persistent low-grade migratory pain that is idiopathic in nature. The guidelines described here for assessment and treatment are applicable to pain problems that coexist in patients with other underlying hematologic disorders.

Acronyms and abbreviations that appear in this chapter include: AIDS, acquired immunodeficiency syndrome; CNS, central nervous system; HIV, human immunodeficiency virus; INF, interferon; NSAID, nonsteroidal anti-inflammatory drug.

Pain is defined by the International Association for the Study of Pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage.1 Acute pain is usually associated with signs of sympathetic nervous system hyperactivity (e.g., tachycardia, hypertension, and diaphoresis) and heightened distress.2 Chronic pain persists for weeks or months, and usually the source has been investigated and is known or suspected. Chronic pain implies that the underlying cause cannot be readily eliminated and requires some combination of palliative treatment, especially with analgesics and adjustment of lifestyle.3
Pain is regarded as either nociceptive or neuropathic.13 This distinction signifies the presence or absence of an intact nervous system, and indicates that its functional status does or does not directly influence the cause of symptoms. Nociceptive pain may be somatic or visceral in origin. Somatic pain emanates from skin, bone, muscle, and other soft tissue, is characteristically localized, and is usually described with familiar adjectives (e.g., dull, aching, gnawing, or sharp). Visceral pain tends to be vague, less well localized, and is characteristically described as deep, dull, aching, dragging, squeezing, or pressure-like. Nociceptive pain of both somatic and visceral origin tends to respond to treatment with the opioids and, despite a ceiling effect, the nonsteroidal anti-inflammatory drugs (NSAIDs).10 Bone pain of mild or moderate intensity, as well as pain that is accompanied by inflammation, tends to be especially responsive to treatment with the NSAIDs. In addition, bisphosphonates (classified as adjuvant analgesics; see Adjuvant Analgesics, below) have recently been observed to be efficacious for neoplastic bone pain.4
Neuropathic pain results from injury to the peripheral or central nervous system.5 Pain is often accompanied by altered sensation, with or without objective findings of nerve injury, and is expressed in unfamiliar, sometimes bizarre terms that are distinct from prior experiences of pain. Complaints are dysesthetic in nature, and sensations are commonly described as burning, tingling, numbing, pressing, squeezing, or itching. Neuropathic pain may be constant, intermittent, or shocklike. The latter phenomenon has been likened to seizures, and may be characterized as shooting, lancinating, electrical, or jolting in nature. In contrast to nociceptive pain, neuropathic pain is less responsive to treatment with opioids and NSAIDs, but often responds favorably to adjuvant analgesics or coanalgesics, including the heterocyclic antidepressants, anticonvulsants, oral local anesthetics, and others (see below).6 Despite the utility of the above clinical distinctions, the underlying mechanisms of pain, especially when due to progressive cancer are often mixed. The presence of mixed pain together with more obscure features that influence clinical responses idiosyncratically often call for implementing trials of analgesics on an individualized empiric basis. This is best achieved when drugs are introduced in low doses, ideally on an around-the-clock schedule, after which doses are rapidly titrated to achieve the optimal balance between therapeutic effect and toxicity.
Pain accompanies a diagnosis of cancer in about two-thirds of cases, including about 25 percent of patients being treated with antineoplastic therapies and up to 90 percent of those with advanced disease.7,8 About 80 percent of patients will respond with analgesia when oral and transdermal medications are used carefully to achieve a favorable balance between comfort and side effects. Most patients with moderate to severe pain who do not respond to conservative management with oral or transdermal medications can achieve comfort with parenteral opioids,11,12 adjuvant medications,13 or combined approaches offered by anesthesiologists or neurosurgeons.14 It is the rare individual who will not respond to appropriate interventions. Surprisingly, despite the availability of effective treatment, unrelieved cancer pain remains an epidemic public health problem in the United States8 and abroad.9 Undertreatment is more closely related to cultural than medical factors. Prominent among these barriers are a failure to distinguish medical treatment from drug abuse, providers’ exaggerated concerns regarding addiction and regulatory reprisal, a failure to embrace the principle of titration to effect, inadequate skills in treating side effects and using adjuvant medications, and an overall lack of accountability.11,15 These issues are being addressed by legislation, scientific-based guidelines, and consumer-based initiatives. Pain associated with diagnostic procedures is a frequent problem in patients with hematologic disorders, especially children. Venipuncture, lumbar puncture, and bone marrow sampling are typical examples of tests that can be performed with little pain or distress with adequate planning.16,17
A pain history is intended to determine the etiology of pain. Given the subjective nature of symptoms, the process includes evaluation of factors that are unique to the individual and may influence therapeutic recommendations, an endeavor that is best undertaken with a team approach that includes nursing staff. Questionnaires are available that are simple to administer and have been validated in patients with cancer pain.18,19
Clinicians should document pain intensity based on patient self-report and apply the same schema on return visits to guide therapy. Options include numerical rating scales (e.g., zero to ten, with zero an absence of pain and ten the worst pain a given patient can imagine), visual analgesic scales, or categorical scales that rate pain as absent, mild, moderate, severe, or excruciating. Easily incorporated into daily practice, these schema permit patients to guide clinicians in establishing the need to modify therapies.
When tolerated, around-the-clock administration of an NSAID may relieve pain that is mild. The NSAIDs may be combined with stronger analgesics for moderate to severe pain. The NSAIDs interfere with prostaglandin synthesis and thus are particularly effective in the management of pain of inflammatory and bony metastatic origin. The potential benefits of traditional NSAIDs should be weighed against their toxicity (gastrointestinal, renal, hematologic, and masking of fever), particularly in the presence of hematologic disorders and older age.20 The nonacetylated salicylates (e.g., sodium salicylate and choline magnesium trisalicylate) have less effect on platelet aggregation, have less risk of gastrointestinal bleeding, and are well tolerated by asthmatics.21,22 Parenteral ketorolac is equianalgesic with low doses of morphine, but is associated with the same range of potential side effects as oral NSAIDs, and treatment with oral or parenteral formulations is restricted to five days.23 In contrast to opioids, treatment with the NSAIDs has a ceiling effect, above which dose escalations do not result in further analgesia but may result in increased toxicity. Regular, as opposed to intermittent, use promotes anti-inflammatory effects that may enhance analgesia. Although structurally distinct, NSAIDs are indistinguishable in most respects. Selection is based on the patient’s prior experience, toxicity profiles, physician experience, schedule of administration, and cost. A new class of NSAIDs, referred to as COX-2 inhibitors (e.g., celecoxib and rofecoxib), has been introduced. These agents promise efficacy similar to that of less-sensitive NSAIDs with minimal toxicity and are currently being evaluated for potential chemopreventative roles, especially in colon cancer.24,25
When NSAIDs provide insufficient relief of pain, are poorly tolerated, or are contraindicated, the addition or substitution of a combination codeine-type preparation (e.g., codeine, oxycodone, hydrocodone, or dihydrocodeine combined with aspirin or acetaminophen) is an analgesic of intermediate potency. Although these agents comprise the “second step” of the World Health Organization–endorsed analgesic ladder, practitioners rely excessively on these agents, continuing their use after they are no longer effective in an attempt to avoid prescribing more potent opioids, which are also more highly regulated.26 This practice may result in acetaminophen or aspirin toxicity, persistent pain, or side effects when symptoms would be more appropriately managed with “stronger” opioid analgesics. While continuing NSAIDs or adjuvants to exploit additive or synergistic effects to achieve an opioid-sparing effect is sometimes reasonable, this approach should be weighed against toxicities. The demonstration of equianalgesic activity for single-entity preparations of oxycodone substituted for morphine, together with the acceptance of transdermal preparations of fentanyl, which, although 100 times more potent than morphine, is prescribed in micrograms, has established that, overall, characterizing this class of drugs as “weak” is medically germane only insofar as the inclusion of acetaminophen or aspirin imposes a ceiling dose above which toxicity can be anticipated.
Individualization and Dosing Guidelines for Opioid Analgesics Therapeutic and adverse effects of opioids vary widely based on factors such as age, previous drug history, drug metabolism and clearance, extent of disease, neuropathic pain, pain on movement, and other factors.27,28 Effective doses may exceed guidelines recommended for acute pain in standard texts, and the correct opioid dose is the one that relieves the pain without inducing intolerable side effects (Table 21-1 and Table 21-2).10 Because the early appearance of side effects erodes compliance, treatment is instituted in low doses that are gradually increased until either pain control is achieved or side effects occur.



Adverse Effects of Opioid Analgesics Constipation is very frequent and should be treated prophylactically, usually with a mild stimulant and softener. Alternative laxatives (e.g., lactulose, a prokinetic agent, or enemas) can be used until regular bowel habit is reestablished.29 When constipation is not relieved or alternates with diarrhea, fecal impaction or bowel obstruction should be excluded. When a new opioid is started or the dose is increased, tolerance to respiratory depression occurs rapidly, but transient nausea and sedation are common. With continued use, symptoms usually resolve spontaneously over a few days.29 Unless symptoms are dramatic, patients should be encouraged to adhere to their analgesics and, if necessary, use an antiemetic (e.g., haloperidol, chlorpromazine, metoclopramide, scopolamine, glucocorticoids, odansetron, etc.), which should be gradually tapered. The possibility of severe constipation as an etiology of nausea and vomiting should be considered. Sedation that is related to opioid use may respond to an alternate opioid or treatment with a psychostimulant (methylphenidate, commencing with 10 mg on awakening and 5 mg with the noon-time meal, or dextroamphetamine).30 Sudden cognitive changes in patients maintained on relatively stable opioid doses are unlikely to be related to the analgesic, and other causes should be considered.31
When side effects persist, a trial of a different opioid analgesic is warranted, since side effects are often idiosyncratic and may not be triggered by even pharmacologically similar agents.32 The presence of intractable side effects may be an indication for invasive therapeutic modalities, such as nerve blocks or intraspinal opioids.14
Although a feared side effect of opioid therapy, addiction (Table 21-3) is an uncommon outcome of medical treatment. It has been reported in less than one of 3000 exposures for cancer-related pain33 and in less than 3 percent of patients treated for sickle cell–related pain.34 Addiction refers to a behavioral pattern of aberrant drug use aimed at achieving psychic, and not analgesic, effects of opioids, and implies loss of control and interference with routine activities.40 Addiction is considered to be synonymous with psychological dependence and is unrelated to physical dependence and tolerance, pharmacologic phenomena that are, to some extent inevitable with chronic use.35 Although common, tolerance appears to be a less dramatic phenomenon than was once thought and clinically is rarely problematic, since the dose can be raised, as tolerance also occurs to most side effects. Patients should be taught to expect that physical dependence will lead to withdrawal syndrome if treatment is abruptly stopped or an antagonist is administered and should be reassured that if pain remits, doses can be tapered without difficulties. The term pseudoaddiction has been used to refer to an iatrogenic syndrome of drug seeking resulting from underprescribing.36


Once a drug regimen has been established, it is the clinician’s responsibility to reassess adequacy. Patients may be reluctant to ask for more potent analgesics and may not describe changes in the character of pain that signify new events, such as impending spinal cord compression or fracture. Pharmacologic tolerance is first manifested by decreased duration of analgesic effect and is best managed by an upward dose adjustment rather than decreasing the interval between administration. Increased drug requirements after a period of stable analgesia are most commonly related to disease progression or recurrence.
A time-contingent (around-the-clock) schedule for the administration of analgesics is usually preferred to symptom-contingent (prn) administration. When withheld until pain becomes severe, analgesics may be ineffective due to sympathetic arousal and established patterns of anticipation and memory of pain. Most cancer pain is relatively constant, with intermittent exacerbations (breakthrough pain), and is ideally treated with a combination of maintenance therapy with a basal, long-acting analgesic (e.g, controlled-release morphine or controlled-release oxycodone or transdermal fentanyl) and “escape doses” or “rescue doses” of a short-acting agent (e.g., immediate-release morphine, hydromorphone, oxycodone, or oral transmucosal fentanyl citrate) administered as necessary for breakthrough and incident pain.37 The frequency with which rescue doses are utilized serves as a gauge of the efficacy of maintenance therapy. Patients are instructed to maintain records that reflect analgesic use: a need for rescue doses in excess of three to four times over a 24-h period signifies the need to raise the dose of the long-acting analgesic, whereas the absence of a need for rescue doses may permit maintenance doses to be lowered. Rescue doses are usually commenced at a dose equivalent to 5 to 15 percent of the 24-h dose of the long-acting analgesic, administered ideally at 4-h, but sometimes as often as 2-h, intervals as necessary.10 Although the empirically derived “5 to 15 percent rule” is safe and usually effective, studies of oral transmucosal fentanyl citrate failed to reveal such a correlation,38 presumably reflecting the heterogeneity of breakthrough pain. A common clinical oversight involves gradually raising the background dose of basal analgesic without considering altering the rescue dose. This dilemma is often best resolved by allowing reliable patients to use a range of prn dosing predicated on the breakthrough event.
Breakthrough pain that is predominantly movement-related (incident pain, as opposed to end-of-dose failure or idiopathic breakthrough pain), as in the case of an unstable fracture or decubitus ulcer, is the most clinically challenging of pain syndromes.33,34 and 35 Rapid changes in pain intensity and in dose requirements are not readily addressed by most oral agents. The need for erratic dosing that is contingent on activity may not allow patients to tolerate side effects. Oral transmucosal fentanyl citrate (OTFC) a sweetened lozenge impregnated with fentanyl38 and mounted on a stick may provide pain relief within 5 to 10 min after patients start to consume a unit. Available in doses ranging from 200 to 1600 µg, units usually require 15 min for complete consumption. Rapid onset relates to the proportion of drug that is rapidly absorbed across the highly vascular buccal mucosa. While this route is not subject to first-pass hepatic metabolism, the remaining drug is inevitably swallowed, providing a duration of relief ranging from 2 to 4 h.
Adjuvant analgesics are drugs developed for purposes other than pain relief that have been observed to promote pain relief in specific clinical settings. Because efficacy is contingent on the underlying mechanism of pain, the adjuvants are generally reserved for specific settings, usually neuropathic pain. Other indications for adjuvant analgesics include the use of psychostimulants (e.g., methylphenidate or amphetamines) to enhance arousal and the use of glucocorticoids for bone pain and other syndromes.
Selected antidepressants relieve pain, especially when neuropathic, independent of mood, a property that has been confirmed in controlled clinical trials.5,6 Amitriptyline and its analogs (e.g., nortriptyline and imipramine) induce pain relief in doses inadequate to combat depression (10–100 mg nightly). The tricyclics appear most likely to be effective in the presence of constant neuropathic pain that is dysesthetic (e.g., burning, numb, or tingling) in character. Pain that is predominantly intermittent, shocklike, or stabbing may be best treated first with an anticonvulsant,39 such as carbamazepine, gabapentin phenytoin, valproic acid, and clonazepam. Specific applications for these agents include postherpetic neuralgia, diabetic neuropathy, phantom limb pain, and postmastectomy or postthoracotomy pain, chemotherapy-mediated polyneuropathy, and tumor invasion of neural structures. Gabapentin has garnered considerable favor because, when doses are raised gradually from 100 mg tid, adverse effects are infrequent, even in doses of up to 3600 mg/day.40 Mexiletene, an antiarrhythmic and oral local anesthetic, has been shown to be useful as a second-line agent for refractory neuropathic pain.41 Oral glucocorticoids are effective for various cancer pain syndromes, especially when bulky tumor is present (e.g., rectal, pelvic, and esophageal cancer, and brachial and lumbosacral plexopathy), presumably due to reduction of peritumoral edema and inflammation.42 There are few data to support a direct analgesic effect of antihistamines, antipsychotics, or anxiolytics. Since adjuvant analgesics are not as consistently effective as opioids, treatment is usually in sequential drug trials. Most require regular use for up to one week before efficacy is established, and thus these agents should not be relied on in the presence of a “pain emergency.” They are typically used in conjunction with opioid therapy and must be carefully titrated to avoid adverse effects and drug interactions.
When possible, analgesics should be administered orally or transdermally to promote independence and mobility. Parenteral administration is not more efficacious than oral administration, so treatment by these routes should be reserved for conditions that render oral administration unreliable (e.g., weakness, dry mouth, dysphagia, nausea, vomiting, malabsorption, or intestinal obstruction). Alternative routes should be considered when excessive numbers of tablets must be ingested or when rapid pain control is required. Morphine, because it is easily available in a variety of formulations, has been regarded as the initial opioid of choice for moderate to severe pain, although concerns have arisen regarding the potential for the accumulation of M-6-glucuronide, which can produce refractory nausea or sedation in a minority of patients.43
Preferred agents for prolonged basal analgesia include controlled-release morphine (MS Contin or Oramorph44 q 12–8 h, or Kadian capsules q 24–12 h45), controlled-release oxycodone (Oxycontin q 12–8 h), or transdermal fentanyl (Duragesic patches applied q 72–48 h),46 titrated to effect. While controlled-release tablets should never be broken, crushed, or chewed, the contents of Kadian capsules can be sprinkled in food or placed through feeding tubes. All long-acting agents should be prescribed in adequate doses to avoid the need for shorter intervals between administrations. Transdermal fentanyl is especially well accepted by patients and may be associated with less constipation than other opioids. Conversion factors in Table 21-1 are conservative, thus necessitating upward titration in some patients. A small proportion of patients may need patches changed as often as q 48 h. The epidermis and a subcutaneous depot effect requires a period of time before equilibration occurs for both upward and downward titration. Thus, transdermal therapy is not useful to treat acute pain.
If controlled-release agents are poorly tolerated, short-acting opioids can be used around the clock, or inherently long-acting analgesics, such as methadone or levorphanol, can be considered. Methadone and, to a lesser extent, levorphanol have long half-lives that exceed the duration of analgesia. Patients at increased risk of respiratory depression include those who are opioid naive, patients with receding pain, older patients, and those with altered renal function.47,48 In addition to its opioid effects, methadone binds to the newly recognized n-methyl-D-aspartate (NMDA) receptor,49 and thus may provide better analgesia than other opioids, especially when pain has neuropathic features.
Chronic administration of meperidine should be avoided, particularly when renal function is impaired (see “Pain in Sickle Cell Disease”). When administered chronically, especially in high doses, all opioids have the potential to cause muscle twitching (myoclonus), usually manifest as whole body jerking, but meperidine is the only clinically relevant opioid that may produce seizures. The accumulation of normeperidine may result in naloxone-resistant grand mal seizures.50 Predisposing factors include older age, oral use, prolonged use, and renal dysfunction.
The agonist-antagonist opioids (e.g., pentazocine, nalbuphine and butorphanol) and partial agonist opioids (e.g., buprenorphine and dezocine) are not recommended for cancer pain management10 because of their characteristic ceiling doses, above which further analgesia does not accrue, the potential for physiologic withdrawal when combined with pure opioid agonists, unreliable reversal with naloxone, a higher incidence of dysphoria, and limited formulations.
While sedatives, antidepressants, and anxiolytics have important roles in the management of various symptoms, these agents should not be utilized as substitutes for the more reliable opioid analgesics.
Whenever possible, specific therapies directed at modifying the underlying disease process should be considered for pain relief, although, when the outcome of these strategies is uncertain or is likely to be time consuming, pharmacotherapy should be instituted concomitantly.
Traditional pharmacologic therapies are inadequate in certain settings. In some patients, behavioral and physical modalities, such as relaxation training, guided imagery, hypnosis, therapeutic massage, acupuncture, and music therapy, may be useful. When pharmacologic therapy has failed, consideration should be given to more specialized interventional therapies, including neural blockade, CNS opioid therapy, neurosurgery, and electrical stimulation.13,14
Pain is a very frequent feature of sickle cell disease (see Chap. 47). Although the pain associated with vaso-occlusive crisis is abrupt in onset and severe in intensity, many patients experience lower-level chronic pain between episodes. Pain has been cited as a cause of death in sickle cell patients,51,52 serves as a marker of disease severity,53 and should be treated effectively so that patients may function more effectively.54 Except in the presence of specific evidence, physicians should assume that the patient’s report of pain is reliable and on this basis should evaluate its cause and provide symptomatic relief.55
As with other pain states, treatment should be individualized, and relatively large doses of analgesics often are required to control pain. When pain is chronic, it is essential to broaden therapeutic goals to maintain function and comfort. Adequate analgesia implies uninterrupted nighttime sleep, the maintenance of normal daily activities, and relative freedom from side effects such as sedation, nausea, and vomiting. Despite clinician perception,56 the incidence of addiction in sickle cell patients is low, and drug-seeking behavior may be more intimately related to undertreatment (pseudoaddiction).36
Only one nonopioid analgesic is available in the United States in parenteral form (ketorolac), and although efficacy for the management of sickle cell pain has not been specifically demonstrated, when not contraindicated, it is a reasonable nonhabituating therapeutic option.55,57 All opioid analgesics have been used for the management of sickle cell pain. Although meperidine (Demerol) is the most commonly used parenteral therapy, it is a poor choice for repetitive administration, in that it is the least potent of the strong opioids, it has a relatively short duration of effect (2 to 3 h), and its low oral bioavailability renders outpatient treatment ineffective and hazardous.50,58 Normeperidine, a primary metabolite, may accumulate as a result of its half-life of 18 h. Although it is not an analgesic, its stimulant properties can produce nervousness, tremors, agitation, multifocal myoclonus, and generalized seizures, effects that are not reversible with naloxone.50 In addition, mean peak meperidine concentrations are lower in sickle cell patients than in postoperative patients, and unexplained diurnal variations in meperidine plasma levels and efficacy have been noted in patients with painful sickle cell disease.59 These factors taken together indicate that, despite its time-honored role, meperidine should be avoided for the management of acute or chronic pain in the sickle cell patient and should not be a first-line analgesic. Treatment of pain in patients with sickle cell disease is in most respects similar to treatment of cancer-related pain.55
Opioid agonist-antagonists (e.g., butorphanol, pentazocine, and nalbuphine) and partial agonists (e.g., buprenorphine and dezocine) should in general play a very limited role in the treatment of chronic sickle cell disease–related pain. The advantages of less rigorous scheduling and a ceiling effect on respiratory depression are outweighed by various other characteristics of these agents. With the exception of pentazocine, no drugs from these classes are available orally, although butorphanol has recently been introduced for intranasal administration. These agents also are associated with psychotomimetic side effects (e.g., jitteriness, hallucinations, and delirium), which are most pronounced with pentazocine. Buprenorphine may be difficult to antagonize with naloxone, and the potential of other agents to antagonize pure opioid agonists reduces flexibility and enhances the risk of undesirable drug interactions.
Oral opioids can be used in the treatment of acute sickle cell–related pain.60,61 Treatment with oral meperidine or morphine has resulted in significant reductions in the frequency of emergency room visits, lengths of stay, and both the frequency and dose of parenteral opioids.60 In another emergency room–based study,61 88 percent of patients with uncomplicated sickle cell pain achieved relief within 30 min of starting a treatment regimen composed mostly of oral morphine sulfate elixir. After an initial dose of 60 mg oral morphine elixir, additional 15-mg doses were provided q 20 min until analgesia or sedation occurred. Once acceptable analgesia was obtained, 30- to 60-mg doses of oral morphine were administered q 2 h as needed, with aspirin or another NSAID and oral hydration (200–300 ml/h).
Although continuous intravenous infusions of morphine [0.08 mg/(kg · h)] and meperidine [0.58 mg/(kg · h)] are often used in hospitalized children with severe sickle cell pain, treatment should be provided cautiously.62 Reports of three children with signs and symptoms of “acute chest syndrome” experienced respiratory arrest during treatment with opioids administered by a continuous intravenous infusion. A diagnosis of acute chest syndrome should be considered at least a relative contraindication to such treatment.
Patient-controlled analgesia for the management of hospitalized patients with acute sickle cell–related pain has considerable appeal. Use in postoperative and cancer pain management and preliminary experiences in sickle cell–related pain,63,64 suggests that patients will titrate to a minimally effective analgesic concentration without overdose, sedation, or respiratory depression.
Patient-controlled analgesia for sickle cell pain is usually safe and efficacious in children as young as 11 years of age. Although reductions in opioid use typically accompany the resolution of pain, exaggerated concerns may arise regarding the potential for addiction in adolescent populations.59,63 In one study, 30 percent of 46 patients reported problems, which included dislike of treatment and, in one patient, respiratory insufficiency that required the administration of naloxone occurred.63
The application of a “cancer pain model” to sickle cell pain has met with considerable success in one inner city hospital. The short-term use of intravenous analgesics and maintenance therapy with controlled release oral morphine resulted in a 67 percent decrease in emergency department visits, a 44 percent reduction in hospital admissions, 57 percent fewer inpatient days, and a 23 percent reduction in length of stay.55
The management of pain in other medical illnesses, such as cancer, headache, and burns, by the chronic administration of opioids need not be complicated by a high prevalence of drug abuse or addiction.33,65,66 Concern among practitioners regarding the risk of addiction as a consequence of treating sickle cell pain is demonstrated by a recent survey documenting that 23 percent and 53 percent of hematologists and emergency physicians, respectively, believed there was a greater than 20 percent incidence of addiction among patients with sickle cell disease.56 While few studies have carefully investigated the risk of addiction in patients with sickle cell disease, several suggest that the perception of risk is exaggerated. One report of more than 600 patients followed in the United Kingdom failed to reveal any evidence of drug addiction, while a U.S. study of 101 patients found three patients with abuse and seven with “drug dependence.” Patients with a prior history of drug abuse are at an increased risk of addiction. A report of 160 patients with sickle cell disease treated for pain found that 14 adults used emergency room facilities and hospitals excessively, tampered with infusion pumps to deliver unauthorized opioids, or engaged in trafficking in prescription drugs or cocaine.
Bone pain occurs in about 70 percent of patients at the time of diagnosis of myeloma (see Chap. 106). Pain is characteristically severe and sudden in onset and predominantly involves the vertebrae, ribs, and long bones. As a result of osteolytic lesions and osteopenia, pathologic fractures occur in nearly two-thirds of patients. Exaggerated secretion of cytokines such as IL-1, IL-6, lymphotoxin, and INF induce osteoclastic activity, with subsequent bone resorption.67,68 Associated pain is often severe. The resultant decreased mobility increases the likelihood of hypercalcemia. Multiple approaches can be used to alleviate pain. Successful cytotoxic therapy is the principal approach. Radiation therapy and surgery are reserved for specific localized sites requiring rapid prophylactic or palliative treatment, especially to prevent or treat fractures. Radiation therapy can relieve pain, even at modest doses, if there are no better, less cytotoxic options.
Direct inhibition of osteoclastic activity with bisphosphonates and related compounds is of significant value, when these drugs are given concurrently with antimyeloma chemotherapy, in decreasing myeloma-induced skeletal complications, including total number of pathologic fractures, delayed onset of new pathologic fractures, a reduced need for palliative radiation therapy, less overall use of analgesics, and more relief of bone pain than on patients treated with chemotherapy alone.69,70 Side effects from recommended monthly doses of 90 mg pamidronate were relatively few, and the drug is quite well tolerated (see Chap. 106).
Patients with the human immunodeficiency virus (HIV) infection experience a broad spectrum of pain syndromes with incidences and severities similar to those observed in cancer patients, although undertreatment is much more prevalent.71 In addition to the impediments to pain control that have been identified in other disease states, pain may be overlooked as a consequence of the overwhelming impact of the disease, its stigma, and a history of drug abuse in some affected individuals. HIV infection is associated with a heterogeneous group of pain syndromes, of which variants of neuropathic pain are especially common. Disease-specific pain syndromes exist,71 and, as is true for cancer, pain severity correlates with disease progression.72 Reports of pain prevalence, intensity, and pain-related interference with function are similar among patients independent of a history of prior injection drug use, although undertreatment is much more prevalent in those with a history of drug abuse.73
About 50 percent of patients admitted to a hospital for care had pain, and 30 percent of hospital admissions were primarily for pain74; and, in a survey of outpatients, pain was identified in about 50 percent of 100 outpatients studied.75 In some communities, pain is the second most frequent reason for hospitalizing patients,76 and persistent or frequent pain over the most recent two-week interval was reported in 226 of 336 patients interviewed; 85 percent had inadequate analgesic therapy.77 In the latter study, less than 8 percent of 110 patients with severe pain were given a “strong” opioid, and adjuvant analgesics were used in only 10 percent of cases.77 Pain and discomfort are even more prevalent during the last two weeks of life. Up to 93 percent of patients developed pain for at least 48 h during this interval, and up to 38 percent experienced no relief.78
Although further studies investigating the relationship between AIDS and pain are needed, the application of established guidelines with a combination of opioid and adjuvant analgesics similar to that described for the management of cancer pain is recommended.10

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology


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