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Many patients with chronic diseases suffer pain as a component of the disease process. This is especially true for patients with sickle cell disease, with 90% of hospitalizations for this population being due to sickle pain. Like other populations of patients with chronic illness, there are both physical and psychosocial factors involved in the management approach to pain control.
The Nature of Sickle Cell Pain
Sickle cell painful episodes are thought to be caused by ischemic tissue injury from obstruction of blood flow by sickled red blood cells. Lack of blood flow results in regional hypoxia and acidosis, which perpetuate the sickling process. Considerable evidence also supports the hypothesis that interactions between sickle cells and vascular endothelium contribute to the clinical manifestations of sickle cell disease. Adherence of sickle cells to endothelial cells may augment circulatory flow and promote deoxygenation of red blood cells resulting in sickling. Up-regulation of adhesive and hemostatic properties of endothelial cells by certain viruses may explain how viral infections often precipitate vaso-occlusive episodes.
Painful episodes usually last 4-7 days but can persist for weeks. Hypoxia, infection, dehydration, acidosis, menstruation, sleep apnea, and exposure to cold temperatures can precipitate vaso-occlusive pain episodes. Commonly, no precipitating factors can be identified. Understandably, anxiety, depression, and physical exhaustion are also identified as contributing factors.
A painful crisis can occur in the absence of known precipitating events or any objective clinical findings. The frequency and severity of pain episodes is extremely variable among patients with sickle cell disease. Indeed, one of the great puzzles regarding understanding sickle cell disease is how a single DNA deviation which causes a change in a single amino acid in a single protein in a single type of cell (RBC) can cause such variability in the clinical course.
Sickle cell related pain usually involves the low back, legs, arms, chest, or abdomen. The pain may migrate or be very localized. It may be sharp or dull; stabbing or throbbing. Patients with sickle cell disease can have chronic pain syndromes and additionally experience acute painful episodes.
Dactylitis (painful swelling of the hands or feet) is often the first manifestation of sickle cell disease seen in affected infants. In older children and adults, musculoskeletal pain is the most common complaint. It may be difficult to distinguish a vaso-occlusive pain episode from osteomyelitis, septic arthritis, toxic synovitis, rheumatic fever, or gout. For patients with abdominal complaints, pancreatitis, cholecystitis, urinary tract infection, pelvic inflammatory disease, pneumonia, or malignancy must be ruled out.
Syndromes of chronic pain associated with sickle cell disease include:
- Avascular necrosis
- Vertebral body collapse
- Leg ulcers
Acute pain syndromes associated with sickle cell disease include:
- Vaso-occlusive episodes
- Acute chest syndrome
- Right upper quadrant syndrome
- Dactylitis (hand-foot syndrome)
- Splenic sequestration
- Cholecystitis with calculus (gallstones)
- Renal colic
The NIH practice guidelines for management and therapy of sickle cell disease recommend immediate medical evaluation for complaints of pain associated with any of the following:
- Fever >101 F, lethargy, pallor, recurrent vomiting, and dehydration
- Acute pulmonary symptoms
- Acute neurologic symptoms
- Pain associated with extremity weakness or loss of function
- Acute joint swelling
- Pain which is unrelieved with oral analgesics and routine supportive measures
- Priapism (persistent or reoccurring)
- Acute flank or back pain
Lab Monitoring as Part of the Pain Evaluation
It is NOT possible to diagnose a painful vaso-occlusive episode with a specific clinical finding or laboratory test. Certain lab tests can help discern precipitating or complicating factors.
During a pain episode, the patient’s CBC will usually be normal relative to their baseline.
If the hemoglobin and reticulocyte counts are lower than baseline, an underlying viral process or aplastic crisis may be the cause. This could also signal liver or splenic sequestration. In cases of dehydration, the hemoglobin may seem falsely elevated. If the white count is elevated with a differential shift to the left, infection should be suspected. If the platelet count is low, splenic sequestration should be considered.
Serum electrolytes may not give the practitioner a real indication of renal function. Many people with sickle cell disease have renal salt wasting. Most also have some degree of hyposthenuria, or inability to concentrate urine efficiently. Hydration status is not accurately measured by serum electrolytes or urine specific gravity. Hyperuricemia is another common finding. This occurs due to increased urate production associated with accelerated red cell production/turnover and diminished renal clearance of uric acid. Hematuria is a common finding among patients with sickle cell disease. Pain with hematuria warrants further evaluation for renal or ureteral stones, infection, clots, or malignancy. Abdominal pain (right upper quadrant syndrome) accompanied by elevated liver transaminases may indicate a need for further hepatitis evaluation. Most patients with sickle cell disease have elevated indirect bilirubin as a result of chronic hemolysis. Because of increased bile production, gallstones are quite common in sickle cell disease (occurring in 75% of adults by age 30). Elevations of direct bilirubin suggest obstruction and warrant further evaluation.
Other lab monitoring should include chest X-ray and oxygen saturation reading for complaints of pain when acute chest syndrome is being considered. If the peripheral circulation is normal, the oxygen saturation measured by pulse oximetry should be within 3% of the person’s baseline. Most patients with sickle cell disease have a low Pa02 during their steady state, but an 02 saturation of below 90% indicates acute hypoxia in most cases.
Evaluation of abdominal pain may include KUB radiographs or ultrasound to rule out gallstones, severe constipation (due to use of narcotic analgesia), liver, spleen, or pancreatic enlargement which could be contributing to the patient’s complaints of pain. An acutely enlarged and painful liver (right upper quadrant syndrome) may suggest red cell sequestration during a vaso-occlusive crisis. This is also usually accompanied by increased jaundice and decreased hemoglobin and hematocrit.
If osteomyelitis or septic arthritis is suspected, cultures from a direct bone or joint aspiration should be done. In addition, radiographs and/or radioisotope scans can sometimes be helpful to differentiate infarction from infection. Blood cultures should be obtained for fever >101 F.
Measurement of Pain and Relief
For older children and adults, a verbal pain scale is quite helpful during periods of acute pain. This simply involves asking the patient to rate the pain from 0 (no pain) to 10 (worst pain imaginable). Written assessments of pain and relief, such as a Visual Analog Scale have been helpful tools to use during inpatient hospitalizations. This involves marking the level of pain and percentage of pain relief achieved on a scale and identifying the location of the pain on a drawn body figure. Interestingly, reports from these scales confirm that many patients continue to have moderate pain at the time of discharge. It is important to note that many patients with sickle cell disease experience a great deal of anxiety over anticipatory pain or improper pain management, which tends to make treatment more difficult.
For younger children, pain can be measured in small interval categorical scales using visual markers. One such scale uses tokens to represent amounts of pain or “hurt”. Another uses colored crayons to shade on a body outline where the pain is located and how much it hurts. The “Faces” and “Oucher” scales use 5 pictures or drawings of children depicted in various stages from happy (no pain) to sobbing and upset (severe pain). It is important to realize that expression of pain is very individual. Many children remain active at play while in pain as a coping mechanism.
Management of Pain – Outpatient
When patients feel that a painful episode is impending, early treatment with analgesics, warmth, rest, and oral hydration can ameliorate the process.
Home-based management includes the following guidelines:
Step 1: mild pain
Use non-opioid medications + adjuvant measures:
- Oral hydration: at least 150cc/kg/day for children and 3-4 liters per day for adults
- 10-15mg/kg every 4 hours for children
- 325-1000mg every 4 hours for adults (max dose 65mg/kg/24 hrs)
- 10-15mg/kg every 6-8 hours for children
- 400-800mg every 6-8 hours for adults (max dose 2400mg/24 hrs)
- OR other NSAIDS as indicated
- Use of heating pads, massage, relaxation therapy, diversion, self-hypnosis
Step 2: moderate pain
Weak opioid + non-opioid adjuvant measures: use fixed doses around the clock
- 1mg/kg every 4 hours for children
- 30-60mg every 4 hours for adults
- 0.2mg/kg every 4 hours for children
- 5-10mg every 4 hours for adults
*If using acetaminophen and codeine/oxycodone preparations, do not exceed recommended amounts of acetaminophen on an every 4-hour schedule
*Continue NSAID dosing around the clock. Toradol is a good choice for patients with moderate or severe pain. It is available in PO, IM, and IV forms. Do not use Toradol in conjunction with other NSAIDs. Adequate hydration is mandatory. Do not use Toradol for more than 5 days. The dosing is 10-30mg every 6 hours, not to exceed 60mg/day in children or persons weighing less than 50kg (110lb).
Step 3: severe pain
Strong opioid + non-opioid adjuvant measures: use fixed doses around the clock
- Oral morphine:
- 0.3-0.6mg/kg every 3 hours (dose may depend on prior use)
- Usual dose: 30-60mg every 3 hours for adults (half-life 2-3.5 hrs)
- Oral hydromorphone (Dilaudid):
- .02-.04mg/kg every 4 hours
- Usual dose: 4-8mg every 4 hours for adults (half-life 2-3 hrs)
- Meperidine (Demerol) is not recommended for analgesic use in patients with sickle cell disease due to high incidence of seizures and accumulation of drug leading to renal failure
To add longer acting pain relief agents to short acting analgesia:
- MS Contin (morphine sulfate controlled release) is available in 30 and 60mg tablets. 30mg of MS Contin every 12 hours equals a dose of oral immediate release morphine at 10mg every 4 hours.
- Fentanyl transdermal (Duragesic) patches come in a 25mcg/24-hour delivery system (also available in 50, 75, and 100mcg/24 hr. strengths). The patch provides 72 hours worth of continuous release fentanyl. A fentanyl 25mcg patch is equal to between 45-135mg of immediate release morphine over a 24-hour period.
Other adjuvant oral medications may include:
- Antihistamines (Hydroxyzine or Diphenhydramine) to manage opioid induced pruritus.
- Antiemetics (Phenergan, Compazine, Ondansetron, Granisetron) to manage narcotic induced nausea.
- Laxatives and stool softeners (Colace, Peri-colace, Senekot, Sorbitol) to manage constipation.
- Benzodiazephines (Valium, Ativan, Xanax, Halcion) to manage short term anxiety and sleep disorders.
- Tricyclic antidepressants (Elavil, Sinequan, Tofranil, Pamelor) to manage depression, sleep disorders and as pain adjuvant therapy.
- Anticonvulsants (Dilantin, Clonidine, Tegretol) as adjuvant pain medications.
Management of Pain in the Emergency Room and Inpatient Hospital Setting
It is important to realize that most patients with sickle cell disease only present to the hospital for pain relief after other measures have failed at home. Patients often report fear of not being believed about their pain, being labeled a “drug seeker” or receiving inadequate pain control when presenting to urgent care. These additional concerns can exacerbate the pain already being experienced. Acute pain in patients with sickle cell disease is often treated in a standard fashion by medical staff: a dose of opioid that would seem to be appropriate is given. The dose may be excessive for opioid-naïve patients leading to oversedation, or insufficient in the opioid-tolerant patient leading to inadequate relief. It is often wrongly assumed that if the patient did not receive the expected relief from a “standard” dose of opioid that they must have addictive or “drug seeking” behavior. Individualizing the loading dose of narcotic based on the patient’s history and use of measurable pain scales to document relief are very helpful to change this experience.
The goal of emergency room care is to assess the clinical problem, initiate a trial of analgesic therapy, assess the outcome, and decide with the patient whether or not hospitalization is necessary.
Steps to ER evaluation for pain
Step 1: Assessment
- Believe the patient
- History and physical exam, including prior experience with pain management agents
- Document location and intensity of pain on a simple measurement scale
- Note that symptoms of opioid withdrawal can mimic a pain crisis (hyperalgesia)
- Vital signs with oxygen saturation measurement
- CBC with differential, reticulocyte, and platelet count
- Chemistry studies if H&P raises concerns over a specific organ system
- Blood cultures for fever >101 F
- Serum or urine pregnancy test for pre-menopausal women
- Radiographs as indicated
Step 2: Action
Correct dehydration and electrolyte imbalances with IV fluids.
Patients with sickle cell disease become easily dehydrated due to reduced oral intake during pain episodes or nausea from analgesic medications. They also may have insensible losses from fever. Hyposthenuria (inability to concentrate the urine) is common, so measurement of the specific gravity of the urine does not adequately reflect hydration status. D5W.25NS at 1.5 times maintenance rate is appropriate. Care must be given to avoid iatrogenic congestive heart failure or electrolyte imbalances. Due to the chronic nature of salt wasting in most patients, serum sodium levels of 130-135mg/d do not usually need correction.
Oxygen therapy most likely does not help in management of vaso-occlusive pain episodes unless hypoxemia (compared to the patient’s baseline) is present (oxygen saturation <92%).
Sodium bicarbonate therapy does not improve the clinical course of a painful episode. It should only be used to correct acidosis.
Vasodilator therapy has no role in management of painful episodes with the exception of severe priapism (see section on priapism).
Administer an oral or parenteral (prefer IV) analgesic agent mutually agreed upon with the patient, taking into consideration prior experiences and use of home medications. The oral route of administration for opioids is about one third as effective as the parenteral route. Synthetic opioids (pentazocine, butorphanol, nalbuphine) should be avoided because of antagonist induction of withdrawal symptoms or psychomimetic effects. Most patients with sickle cell disease require an initial dose of morphine 2-10 mg or hydromorphone 0.5-2mg to control pain.
Step 3: Assessment of efficacy
After administration of narcotic analgesia, monitor for side effects of respiratory depression, nausea, vomiting, pruritus, hypotension, secretion of antidiuretic hormone, urinary retention, or changes in the seizure threshold. A respiratory rate < 10/min. is a sign of opioid induced respiratory depression.
10-15 minutes after initial administration of IV opioid analgesic reassess pain location and intensity with a simple measurement scale. Believe the patient. If there has been no relief of pain, 50% o initial dose should be given. If the patient is mildly sedated but still reporting pain, 25% o initial dose should be given.
If the patient remains comfortable for 3 hours, administer an oral narcotic and observe for another hour. If moderate or severe pain returns within 30 minutes of the oral narcotic dose, administer a repeat dose of the initial IV narcotic. If pain persists, the patient should be admitted to the hospital for pain control.
If the patient is discharged to home, a prescription for a 1-week supply of narcotic analgesia and adjuvant medications is appropriate.
Narcotic Tolerance, Pseudo-Addiction, and Withdrawal
The pain in sickle cell disease has similarities to pain produced by trauma, surgery, acute ischemia, and cancer. However, the occurrence of sudden and severe pain for patients with sickle cell disease is a lifelong experience. Health care professionals often do not exhibit the same degree of empathy for patients with sickle cell pain. This may contribute to under-treatment, patient dissatisfaction, mistrust, and maladaptive learned coping behaviors.
The prevalence of addiction in sickle cell patients is about 10% in two studies. Addiction is compulsive use, loss of control, and continued use of the substance despite harm. Opioid use has been more widely studied in cancer populations. Tolerance and physical dependence do not equal addiction in the cancer population. Euphoria varies inversely with analgesia. Analgesia can occur in the absence of mood elevation. There are differences in the metabolism of opioids among certain individuals and groups.
Inadequate pain management initiates pseudo-addiction syndrome. This phenomenon is identified by behaviors directly or indirectly taught by health care workers to patients with sickle cell pain. The fear over not receiving adequate pain control perpetuates behaviors which are often viewed as “drug seeking” by medical staff. The result is often maladaptive coping strategies, anger and isolation for the patient. This in turn leads to frustration and avoidance behaviors on the part of the healthcare providers.
After an aggressive pain management course with opioid analgesia, the doses should be tapered over 1-2 weeks to avoid symptoms of withdrawal or abstinence syndrome. Tolerance causes changes in the brain that mimic those seen with persistent injury. Symptoms of opioid withdrawal or abstinence syndrome can easily mimic or even precipitate vaso-occlusive pain.
Frequent Utilizers of Care Facilities
Individuals who are felt to overutilize the hospital services create the most difficult management problems. This group is the minority of patients with sickle cell disease, but they account for the majority of ER visits and hospitalizations. In most cases, high utilizers of services are equated with “drug-seeking” behaviors. This stereotyping results in under-treatment of pain with opioids for other patients with sickle cell disease. Frequent utilizers of services (“frequent flyers”, etc.) are often quickly labeled as “problem patients”. They may belong to any of the following subclasses:
These are patients who are not adequately treated for pain as outpatients. Investigating and correcting this issue can change the pattern of service utilization.
These patients rely on medical services because of social, financial, or psychological problems. They may be admitted often, but use minimal amounts of pain medications while their other needs are being met.
These individuals find it easier to use the ER staff than to make and keep regular outpatient visits. They may not have established a trusting rapport with a practitioner who can give them guidance regarding home management of pain.
This is the most difficult group of patients to deal with or help. Investigating these individuals may reveal prescription alteration, selling, or substance abuse. Formulating a treatment plan should include intensive counseling, psychiatric evaluation, rehabilitation, and appropriate pain control for real events.
It is appropriate to make a treatment contract with these types of patients. The goals of such a contract should include relief of pain. It should also include the setting of strict limits within the context of a consistent plan for management of pain. The patient and family must understand that the complaint of pain will be addressed. However, in addition to receiving opioids for the treatment of pain, the importance of a consistent, coordinated plan that includes behavior modification and patient/family involvement is equally important.
Inpatient Pain Management
When attempts at outpatient pain control have failed, hospitalization for pain management is necessary.
A management plan should be documented in the medical record at the time of admission. Documentation of pain measurement scales should be done at regular intervals. The patient should be educated to expect relief of pain and to develop positive coping skills. IV continuous opioid analgesia, bolus dose (“patient controlled analgesia” or PCA), or both are appropriate. Continuation or addition of adjuvant medications such as NSAIDS, antiemetics, antianxiety agents, or antipruretics is also appropriate. Many institutions offer a “short stay” or “day hospital” setting in which patients can receive up to 23 hours of IV analgesia and are discharged to home when comfort on oral medications is achieved. This can avoid congestion in the emergency room. It also encourages patients to seek medical intervention in the early phase of a painful episode in an attempt to avoid an ER visit or hospitalization.
Patient Controlled Analgesia (PCA)
Begin PCA by using 20-25% of the quantity of the opioid bolus that was used in loading the patient to be delivered with a 6-minute lockout interval. Reassess and document the patient’s perception of pain every 4 hours using a simple measurement scale. Determine the hourly use of opioid during the day and give 66% of the hourly dose as a continuous infusion at night to promote sleep and rest.
Continuous Infusion Narcotic Analgesia:
A continuous infusion of opioid analgesia (for an adult) typically uses morphine sulfate in D5W or NS at a concentration of 0.5mg MSO4 per ml D5W or NS. For example: MSO4 125mg in D5W 250ml. Using 250ml IV diluent bags avoids accidental confusion with IV “piggybacks” and accidental overdose. It also permits delivery of MSO4 up to 100mg in a 24-hour period without changing IV bags. Most adult patients with severe pain require MSO4 at a dose of between 2-4 mg per hour continuously with additional bolus or rescue (PCA) doses of 2-4mg as often as every 15 minutes as needed. If the patient is using bolus doses in excess of 1.5 times the basal MSO4 rate every 15 minutes over a 1 hour period without achieving pain relief, and in the absence of adverse side effects, it is reasonable to increase the basal rate or increase the PCA bolus dose, or both. After pain control has been achieved, the basal MSO4 rate can be decreased in 25% increments while oral opioids are added on a scheduled basis. Obviously, these are very patient/practitioner specific interventions, which require very frequent monitoring and titration.