24 Pain Management in Sickle Cell Disease
The Massachusetts General Hospital Handbook of Pain Management
Pain Management in Sickle Cell Disease
Jatinder S. Gill
Pain is not just a symptom demanding our compassion; it can be an aggressive disease that damages the nervous system.
II. Clinical features and contemporary management
III. Acute pain crisis
1. Management of mild vaso-occlusive crisis
2. Hospital management of painful sickle cell crisis
IV. Management of chronic pain
3. Nonpharmacologic interventions
V. New therapies
Sickle cell disease is an inherited hemoglobinopathy primarily affecting individuals descending from equatorial Africa, around the Mediterranean Sea, Saudi Arabia, and some parts of India. It is a multisystem, chronic, debilitating disease with variable phenotypic expression. Acute pain is often the first symptom and the most common reason patients seek medical attention.
One third of the patients enjoy a benign course, one third have two to six hospital admissions for pain per year, and one third have more than six pain-related hospitalizations per year. Hospital personnel often develop biased views about the genuine nature of painful crises in the latter group, especially since pain is a subjective sensation. It is, however, this group that is most in need of medical help. The extreme variability in severity of clinical phenotype remains unexplained and probably relates to genetic, microvascular, rheologic, and hematologic factors.
Hemoglobin S (HbS) has a tendency to polymerize when deoxygenated but rapidly reverts with oxygenation. Repeated cycles of polymerization cause oxidative damage to the red cell membrane and lead to irreversibly sickled cells, adhesion to the endothelium of the vessel, and vascular occlusion. The resultant hypoxia causes further sickling and starts a vicious cycle leading to tissue infarction and pain. Increased intramedullary pressure secondary to inflammation and necrosis within the bone is an important cause of the pain. Sickling seems to correlate directly with high hemoglobin levels and neutrophil counts, and indirectly with fetal hemoglobin (HbF) values.
II. CLINICAL FEATURES AND CONTEMPORARY MANAGEMENT
Sickle cell disease is a multisystem disease. Infants and children are at risk for overwhelming infection from encapsulated bacteria such as Pneumococcus. The function of the spleen, and therefore immune function, is deficient even before the eventual autoinfarction. Penicillin prophylaxis, vaccination, and a high index of suspicion are advocated. Meningitis, bacterial pneumonias, cholecystitis, and osteomyelitis are common in adults.
Sickle cell patients are chronically anemic, and profound anemia may occur in the setting of splenic sequestration, exaggerated hemolysis, or aplastic crisis requiring transfusion. Folic acid supplementation is required to support high turnover rates.
Neurologic complications resulting from cerebrovascular occlusion occur in up to 25% of patients. A schedule of monthly transfusions is recommended for children to prevent recurrent stroke. Primary prevention using magnetic resonance imaging and transcranial Doppler screening and initiation of transfusion programs for at-risk patients have been suggested.
These patients often have restrictive lung disease, hypoxemia, and pulmonary hypertension, probably secondary to past pulmonary occlusions and infarctions. They are at risk for acute chest syndrome, with infection usually due to atypical agents. Acute chest syndrome has a high mortality and requires treatment in the intensive care setting. A high index of suspicion is required in patients presenting with chest pain and fever, especially in the presence of hypoxemia.
Hepatobiliary complications are common, with up to 70% of patients demonstrating gallstones. Many patients eventually need a cholecystectomy. Hepatic dysfunction may relate to transfusionassociated iron overload or infection. Hyperbilirubinemia secondary to benign cholestasis (no fever or pain) should be differentiated from hepatic crisis presenting with fever, pain, abnormal liver function tests, and hepatic failure.
Poor medullary flow in the kidneys leads to papillary infarctions, hematuria, and renal tubular acidosis. In addition, patients may develop glomerular dysfunction. Proximal tubular dysfunction may lead to hyperuricemia especially in the setting of heavy analgesic use. These patients eventually develop chronic renal failure.
Proliferative sickle cell retinopathy with the potential of bleeding leading to blindness should be appropriately treated with laser photocoagulation.
Priapism develops in many individuals, and if prolonged it may lead to impotence. If this is poorly responsive to conservative treatment for 12 hours, exchange transfusions, corporal aspiration, the use of alpha-adrenergic agents, and even surgical creation of fistula may be required to prevent impotence.
Osteonecrosis, leading to vertebral fractures or necrosis of the femoral head, can be acutely painful. In patients with advanced disease of the joints who fail to rehabilitate, major reconstructive surgery may be required. Bone marrow infarction may be differentiated from osteomyelitis by scans. Arthritis may result from periarticular infarction or from gout. Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful adjuncts in patients with bone pain.
Chronic bilateral leg ulcers are common over the shins. In addition to causing chronic pain, these may also lead to osteomyelitis and septicemia. Subdermal vascular occlusions can lead to chronic myofascial pain.
Mean life expectancy is about 42 years in men and 48 years in women. Patients with severe disease and multiple crises tend to have a shorter lifespan.
III. ACUTE PAIN CRISIS
Despite the multiple problems associated with sickle cell disease, the most common reason for these patients to be hospitalized is for an acute pain crisis requiring aggressive inpatient management. The usual precipitants are exposure to cold, dehydration, alcohol intake, infections, stress, and menstruation. In more than half the cases, there is no clear cause of the pain.
About 5% of patients account for one third of hospital admissions, and regrettably, caregiver hostility toward this group of patients is common. It is important to remember that these are the patients who tend to die young, and pain is a direct marker for mortality. The incidence of pain is highest in young male adults.
Pain typically affects one region of the body. Common sites of pain include the back, bilateral large joints, chest, sternum, ribs, and abdomen. In children, the smaller joints of the hand and feet may be involved. In about half the patients, fever is present. Patients are usually able to tell whether a new crisis feels like their typical crisis.
The cause of the pain is probably related to ischemia of the tissue undergoing infarction and an increase in intramedullary pressure due to inflammation. The pain of sickle cell disease is often described as excruciating, commonly rating more than nine on the visual analog scale. It is important to rule out any catastrophic events, being alert for acute chest syndrome in a patient with acute chest pain, osteomyelitis or septic arthritis in a patient with bone or joint pain, or acute abdomen in a patient with abdominal pain. Further workup may be needed (e.g., chest films in a dyspneic patient with chest pain, diagnostic aspiration of an acutely tender joint). A good history and a physical, together with a review of previous admissions, are indispensable.
1. Management of mild vaso-occlusive crisis
Old admissions records, previous treatments, complications of the disease, and baseline pain medications are very helpful in directing treatment. Once it has been established that the patient does not require emergent investigation or intervention, aggressive hydration and pain treatment should be instituted. Fluids may be taken by mouth or given intravenously. Opioid medication may be given by mouth if tolerated, but the intravenous (IV) route is usually preferable at least in the initial period. For oral use, oxycodone, hydromorphone, and morphine are good choices. NSAIDs are very useful for bone pain and should be freely used if no contraindications exist. For the latter, a fixed dose regime is preferable to an asneeded regimen.
If the patient can be stabilized, he or she may be discharged home with a tapering supply of oral opioids. Failure to adequately manage pain is likely to result in readmission, so it is important that the patient be provided with an adequate supply of analgesics. If the pain does not improve, or if the patient has other symptoms (e.g., fever or severe nausea), a longer hospital admission may be required.
2. Hospital management of painful sickle cell crisis
The pain of sickle cell crisis is described as excruciating, and narcotics are often the first-line treatment. There is no benefit to trying alternative analgesics before opioids in the acute situation. Adjuncts may, however, be used simultaneously.
The care team must take patient reports of pain seriously and administer medications in a timely manner. This fosters trust in the patient and prevents undue suffering.
a) Route of administration
Opioids may be given orally if tolerated, but in most situations parenteral narcotics are needed in the initial stages. In patients with chronic pain using opioids on a long-term basis, the baseline (chronically used) medications can be continued to provide continuous background analgesia, supplemented with the regimen chosen to treat the acute episode. Alternatively, the chronic analgesic requirement can be given intravenously after calculating the equivalent IV dose, further supplemented with additional medication to cover the acute pain. Transdermal fentanyl can be used in the later stages of the crisis, but in the initial acute setting, slow onset and difficulty with titration make this a poor choice.
Traditionally, these patients have been treated with intramuscular injections of meperidine and hydroxyzine (Vistaril). However, in light of the improved understanding of meperidine toxicity, and the ease with which IV therapy can be used, there is very little rationale for continuing to recommend this treatment. Intramuscular injections should probably be reserved for situations where there is no IV access, or before IV access is obtained. Intramuscular injections are painful and may lead to myositis and abscesses; in addition, the rate of drug absorption is unpredictable.
Intravenous narcotics can be given by continuous infusion, by nurse-administered bolus injection, or by using a patient-controlled analgesia (PCA) pump. Patient-controlled analgesia is a very attractive option in the acute management of sickle cell crisis, and it is probably the treatment of choice. Unfortunately, it is not widely available and may not be an option in some settings. Patients can be maintained on a safe low basal rate of opioid, especially at night, and demand doses titrated to comfort and safety.
b) Choice of opioid
Morphine and hydromorphone are the first-line narcotic agents. Hydromorphone may be preferred in patients with renal dysfunction because morphine-6-glucuronide, an active metabolite of morphine, may accumulate in renal failure. Formerly, meperidine was considered the opioid of choice in sickle cell patients, but it should no longer be used as a first-line opioid (see Chapter 9). However, some patients tolerate other opioids poorly and prefer meperidine. In these patients, it is reasonable to consider meperidine but with due caution for its potential toxicity (especially in patients with renal involvement and seizure disorder) and its potential for producing addiction.
Narcotics often give rise to adverse side effects such as nausea, itching, and sedation. Different medications and dosing intervals may be tried to get the best match in terms of side-effect profile. Side effects should be treated with appropriate medications such antiemetics and psychostimulants.
The typical crisis last for about 4 to 7 days and its course is often unpredictable. However, some patients with a typical crisis may repeat the course of their last crisis. As pain improves, the demand for analgesics and reports of pain decrease. At this point, the patient may be switched to an oral regimen. The total IV dose used by the patient over the last 24 hours is measured, then converted to an equivalent oral dose (using an approximately 1:3 ratio; see Table 2, Appendix VIII). Other routes could also be chosen at this point, including rectal and transdermal. The dose is gradually reduced, as tolerated.
For a successful change from parenteral to oral narcotics, it is critical (a) that a plan be individualized for the patient and (b) that an adequate amount of medication be prescribed. Prompt attention to the patient’s reports of pain at this juncture will go a long way toward achieving a successful weaning.
d) Tolerance and addiction
Tolerance to narcotics is a well-known and poorly understood phenomenon. It usually develops over weeks, but acute tolerance in the setting of high doses can also occur. The analgesic effects as well as the sedative and respiratory depressant effects of these medications are decreased. Thus these patients may require high doses of narcotics to achieve adequate pain control. This phenomenon should not be interpreted as addictive behavior.
Sickle cell patients are also at risk of withdrawal if their narcotic regimen is abruptly discontinued. Reducing opioid dose by no more than 20% per day prevents withdrawal in most individuals. If a withdrawal syndrome does occur, it can be reversed by reintroducing the opioid at 25% to 40% of the original dose.
The term addiction is employed when medication is used primarily for its mind-altering effects and not for its intended analgesic effect. Addiction is a behavioral problem, and addicted patients always display compulsive drug-seeking behavior that is distinct from the drug-seeking behavior of patients in pain (see Chapter 35). Sickle cell patients are not more prone to addiction than any other group of patients. The incidence of addiction in the opioid-treated population as a whole, and in the sickle cell population, ranges from 2% to 3%. Wrongly assuming addiction in sickle cell patients plays a negative role in effectively treating their pain.
The occasional addicted patient provides a challenge in pain management. On one hand, the need for the opioid medication is clear, but on the other hand the patient is likely to abuse his medication. Management is greatly helped by clear communication, avoiding conflict, a reasonable amount of limit setting, and the involvement of a person who has known the patient for a long time. Acute pain crisis is not the time for initiating detoxification measures.
(ii) Anti-inflammatory drugs
NSAIDs are useful in the treatment of acute crisis, as well as for chronic bone pain. They supplement the opioid analgesia by attacking a different mechanism of pain—that is, by inhibiting prostaglandins at the peripheral level.
Important side effects include decreased platelet adhesiveness (risk of bleeding), renal dysfunction, and gastritis. Ketorolac is available for short-term IV use. These medications are more effective if prescribed as fixed doses and not on an as-needed basis.
The use of steroids is controversial. These drugs may decrease the duration of the episode but can also lead to rebound. Furthermore, their use is complicated by several severe side effects. Hence steroids are not among the first line of drugs in the management of acute crisis.
(iii) Epidural analgesia
Epidural analgesia is a very effective modality for the treatment of pain below the mid-thoracic region. Although it provides excellent regional analgesia, it is not commonly used because adequate analgesia can often be provided by noninterventional techniques. If the pain is widespread, it may not be covered by epidural medication. In a patient with severe pain not responding to parenteral analgesics, epidural anesthesia can be an excellent alternative. Epidural analgesia may also be beneficial in a patient at risk of acute chest syndrome by minimizing systemic medication, respiratory depression, and sedation. Ventilation may be aided with the provision of better analgesia.
(iv) Adjunctive medications
Antihistamines such as hydroxyzine and diphenhydramine (Benadryl) are commonly used in sickle cell patients experiencing pruritus. These medications have been shown to potentiate the analgesic effects of opioids and to increase their sedating effects.
Overall, nausea and vomiting is less a problem in sickle cell patients than in cancer patients. It is often treated with medications such as droperidol, metoclopramide, prochlorperazine, scopolamine, and ondansetron. Ondansetron is a very good choice in a sedated patient because it is free of sedating effects.
Benzodiazepines are used for multiple reasons in sickle cell patients: anxiolysis, sleep induction, myoclonus and muscle spasm, and seizure disorders. Judicious use of these adjuncts is appropriate during an acute episode. They may lead to excessive sedation and inability to properly use PCA. The sedation also limits the amount of opioid that can safely be administered. Alprazolam may induce episodes of mania, hypomania, hostility, and anger.
Analeptics such as methylphenidate (Ritalin) may occasionally be useful in patients experiencing excessive sedation from opioid use.
(v) Other measures
Analgesia and fluid replacement form the cornerstone of the management of acute sickle cell crisis. Fluids may be repleted parenterally or enterally. Although fever is not uncommon during an acute cell crisis, its presence should nevertheless prompt a search for an infective source. These patients remain very vulnerable to infection, and cultures should be done as appropriate. Antibiotics may be used where clinical suspicion of infection is high or in the presence of objective data.
Blood transfusion is restricted to complicated situations such as an acute chest syndrome, a stroke, or a severe and prolonged attack, or if there are frequent recurrent episodes. A hemoglobin level of less than 5 g/dL or a fall of more than 2 g/dL below the baseline may be a rough indication for transfusion. High hematocrit may itself predispose these patients to an acute crisis. Exchange transfusions may be required in the setting of severe, prolonged attack in a patient with a stable hematocrit.
Supplemental oxygen has not been shown to be of any benefit in reducing the pain or the duration of the crisis. This is probably because sickle cell crisis is a vaso-occlusive crisis that has already occurred. Oxygen is, however, essential in a hypoxemic patient.
(vi) Prevention of recurrent crises
Advice on lifestyle (e.g., avoiding extremes of temperature, exercise, and alcohol) may decrease the frequency of these episodes. Patients should be advised to decrease or abstain from smoking, to drink enough fluids on warm days, to wear warm clothing on a cold day, and to obtain early treatment of infections. Medical treatments such as hydroxyurea can significantly lower the incidence of painful crises (see section V, below).
IV. MANAGEMENT OF CHRONIC PAIN
Some patients with sickle cell experience chronic pain secondary to multiple causes. Their lives revolve around this all-pervasive pain as they go from physician to physician in search of more successful pain relief. Constant pain eventually leads to psychopathology and they are at greater risk for depression. In addition, they have poor prospects for fruitful employment because of the diseaseinduced physical and emotional impediments. In general, their socioeconomic status is poor at baseline and further complicates their successful rehabilitation.
These patients are too often labeled as drug seekers and difficult patients. It is not difficult to appreciate the reasons for chronic pain in these patients. In the vast majority the pain is of nociceptive origin with diverse causes such as chronic leg ulcers, avascular necrosis of the femur and the humerus, vertebral fractures, chronic osteomyelitis, arthropathies, and constant vaso-occlusive crises.
Neuropathic pain has been very rarely reported in sickle cell patients. Perhaps there is a low incidence of this type of pain in these patients, or more likely, the nociceptive pain is so obvious and the reason so clear that the neuropathic component goes unrecognized. The rich and complex interconnecting blood supply of the nerves may protect them from infarction during a vaso-occlusive crisis. Mental nerve involvement with numbness of the cheek has been most often described in sickle cell patients.
Myofascial pain and fibromyalgia are similarly rarely reported in this group. This may again represent the fact that the predominant nociceptive component overshadows other components.
Since most of the pain in these patients is of nociceptive origin, NSAIDs and opioids are the mainstay of treatment. The medications are preferably prescribed by a single clinic where care is consolidated. Long-term narcotics should be administered using the same principles as for other nonmalignant chronic pain conditions (see Chapter 30). Titration of medications, changes in choice of opioid, and concerns with tolerance and dependence are issues that are best addressed by a single physician or group of physicians. Many sickle cell patients are successfully managed with nonopioid analgesics or with minimal or weak opioids.
Literature regarding the utility of neuropathic pain medications in sickle cell patients is lacking. Anecdotal reports of beneficial effects of tricyclic antidepressants and anticonvulsants warrant trials of these medications in selected patients in combination with other medications. Some conditions such as priapism, seizure disorder, and urine retention in sickle cell patients may contraindicate the use of tricyclics.
Laxatives, antihistaminics, and antiemetics may be required to manage the side effects of medications.
3. Nonpharmacologic interventions
Education goes a long way in helping patients cope with their disease, and in having a compliant patient. Reasonable expectations, knowledge of medications and therapeutic goals, and what to expect from the provider should be clearly explained. Counterirritant measures, such as transcutaneous electrical nerve stimulation (TENS), massage, and heat may be beneficial in selected patients. Intensive physical therapy in a patient with a painful degenerative joint disease helps to ameliorate pain. Biofeedback, coping mechanisms, distraction, and motivation are all valuable adjuncts. Sickle cell patients are poor candidates for interventional pain therapies.
V. NEW THERAPIES
Hydroxyurea is a promising drug that has been shown to reduce the incidence of acute crises by 50%, and it is likely to be more commonly used in the future. Its long-term effects are not clear and therefore warrant close monitoring. Although stem cell transplantation has been used successfully, it carries a 10% risk of periprocedure mortality, and it is largely experimental at present. Gene therapy holds promise but is still elusive. Nitric oxide, by changing the threshold for oxygen dissociation from hemoglobin, can lead to a reversal of sickling during a crisis and is currently being tested.
Sickle cell disease is a chronic multisystem disease that subjects a patient to a life of misery and pain. Most patients are socioeconomically disadvantaged, lack good health insurance coverage, and have poor support systems.
Appreciation of the excruciating pain that these patients experience, and prompt treatment based on the patient report are the essence of their pain management. These patients do not have a higher potential for addiction, and pain medications should not be withheld for such concerns. Management of a difficult patient requires tolerance and clear communication. Contact should be established with a physician who knows the patient well.
At the very least, these unfortunate individuals need to be treated with respect, compassion, and extreme patience.
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