**4. Pain management of patients with sickle cell disease with chronic and neuropathic pain**

#### **4.1. Chronic pain**

In addition to the acute crises, patients with SCD also suffer from chronic pain, which often times overlap with acute pain crises and create difficulty in designing a treatment plan. These individuals can find management of their pain very difficult and therefore change providers frequently, resulting in a higher degree of misdiagnosis and misperception of their pain. Identifying the presenting syndrome can help individualize a treatment plan and therefore understanding the signs and symptoms of chronic pain is crucial for aggressive and effective therapy.

Chronic pain is generally defined as pain that is present for 3 or more months. As opposed to the acute pain, which is sharp and throbbing in nature with a sudden onset, chronic pain is often vague, deep, and achy there is present for a longer period. Approximately 5–10% of adult patients with sickle cell disease are affected with chronic pain [44]. However, a recent study from Pain in Sickle Cell Epidemiology Study reported the incidence of chronic pain in 29% of 292 adult patients [45]. These patients tend to be older and use more opioids [46]. The chronic pain is categorized into two types. The first type is objective and is due to visible signs such as leg ulcers and avascular necrosis which is associated with deep somatic pain. The second type is due to recurrent acute attacks of painful crises. Failure to treat these acute attacks can lead to chronic pain syndrome and resultant neuropathic pain. The exact pathophysiologic mechanism is not fully understood, however central component has been described in which the threshold for the perception of pain is lowered, resulting in pain from typically nonpainful stimuli (allodynia) and severe pain generated by mildly painful stimuli (hyperalgesia) (**Figure 2**).

This figure depicts the age distribution of SCD patient with chronic pain. As demonstrated by the figure, the larger proportion of SCD patients with chronic pain is between 20 and 29 years old.

#### **4.2. Pathophysiology and mechanism**

most commonly used for this purpose; it is commonly administered either intravenously or intramuscularly at a dose of 0.5 mg kg−1 for a maximum of 30 mg every 6 h for 5 days. NSAIDs partly inhibit the inflammatory cascade involved in VOE (see above). Although usually not sufficient to resolve a pain crisis as a sole treatment, it works synergistically with opioids. For moderate VOE pain, a single dose of 30 mg IV is typically sufficient. Opioids are limited by their propensity to cause gastritis and gastric bleeding. The drug should be used cautiously in patients with peptic ulcer disease or a history of gastrointestinal bleeding. NSAIDs can impair kidney function and accelerate the renal injury produced by sickle cell disease itself. For these

Ketamine is gaining a lot of popularity for the treatment of VOE refractory to opioids. A lot of institutions have integrated its use in their algorithm of VOE treatment and strong evidence exists regarding its efficacy as an adjuvant to opioids and NSAIDs. Ketamine is a noncompetitive antagonist at the *N*-methyl-d-aspartate (NMDA) receptor. This property has been shown to modulate opioid tolerance and opioid-induced hyperalgesia. The use of ketamine is limited by its psychiatric side effects such as hallucinations, abnormal dreams, nightmares and abnormal behavior. Randomized controlled trials are still necessary for the regular implementation

**4. Pain management of patients with sickle cell disease with chronic** 

signs and symptoms of chronic pain is crucial for aggressive and effective therapy.

In addition to the acute crises, patients with SCD also suffer from chronic pain, which often times overlap with acute pain crises and create difficulty in designing a treatment plan. These individuals can find management of their pain very difficult and therefore change providers frequently, resulting in a higher degree of misdiagnosis and misperception of their pain. Identifying the presenting syndrome can help individualize a treatment plan and therefore understanding the

Chronic pain is generally defined as pain that is present for 3 or more months. As opposed to the acute pain, which is sharp and throbbing in nature with a sudden onset, chronic pain is often vague, deep, and achy there is present for a longer period. Approximately 5–10% of adult patients with sickle cell disease are affected with chronic pain [44]. However, a recent study from Pain in Sickle Cell Epidemiology Study reported the incidence of chronic pain in 29% of 292 adult patients [45]. These patients tend to be older and use more opioids [46]. The chronic pain is categorized into two types. The first type is objective and is due to visible signs such as leg ulcers and avascular necrosis which is associated with deep somatic pain. The second type is due to recurrent acute attacks of painful crises. Failure to treat these acute attacks can lead to chronic pain syndrome and resultant neuropathic pain. The exact

reasons, many specialists avoid NSAIDs in patients with sickle cell disease.

**3.5. Ketamine**

of ketamine in SCD protocols.

24 Pain Management in Special Circumstances

**and neuropathic pain**

**4.1. Chronic pain**

Although the exact mechanism underlying the transition from acute to chronic pain is not fully understood, some contributing factors include chronic inflammation, organ damage, and opioid-induced hyperalgesia [47]. According to a study presented at the Annual Meeting of American Society of Hematology, patients with chronic pain (defined as >50% of days reported as painful crises collected over 6 months) tend to be older (41 vs. 32 years), use more opioids (11.45 mg/day vs. 2.92 mg/day), and have higher levels of mast cell activation [48].

Opioid-induced hyperalgesia is a state of sensitization caused by repetitive exposure to opioids resulting in paradoxical response to pain. Although there is no understanding or consensus on the biomolecular mechanism, it is believed to be secondary to neuroplastic changes in the central and peripheral nervous system [49]. Despite it being a controversial topic, patients with sickle cell disease with chronic pain do require increasingly higher dosage adjustments.

Recent research demonstrates clear evidence that chronic inflammation and mast cell activation plays a role in the chronic pain state of patients with sickle cell disease. Mast cells release the neuropeptide substance P, which promotes neurogenic inflammation and nociceptive

**Figure 2.** Distribution of SCD patient with chronic pain.

activation [48]. Additionally, tryptase, a serine proteinase found within mast cells appears far more elevated in patients with chronic pain in sickle cell disease. This can help guide future therapy directed toward inhibition of mast cell activation, and implementation of medications such as Cromolyn. This can also help identify and diagnose patients with sickle crises who present to the emergency department and are sadly mistaken as drug seeking opportunists.

Lastly, it important to note that patients with SCD are not immune to non-hemoglobinopathic pain. Excluding other disease processes is essential and misdiagnosis can be life threatening. Conditions that can mimic the chronic pain state include but are not limited to ischemic colitis, pancreatitis, bone marrow infarction, hepatobiliary disorders, and vertebral

Pain Management for the Sickle Cell Patient http://dx.doi.org/10.5772/intechopen.79495 27

In addition to acute and chronic pain, a neuropathic component of pain plays a large and undiagnosed constituent of chronic disease. Data suggest that the development of neuropathic pain is responsible for the transition from acute to chronic pain with aging [54]. The general understanding is that multiple components of central sensitization and peripheral nerve injury are responsible. Types of neuropathic pain include peripheral neuropathic (caused by vaso-occlusive crises and neuropathies) and central neuropathic (caused by CNS damage, ictus, and central sensitization). Peripheral nerve injury and prostaglandin release can sensitize peripheral nerve endings and facilitate the transmission of pain along the A-delta and C fibers to the cerebral cortex [44]. The exact mechanism, however, is poorly understood, which

Neuropathic pain from SCD occurs more commonly in older adults and females, which is hypothesized to be secondary to abnormalities in pain signaling pathways. These patients have extreme sensitivity to tactile touch (allodynia), increased pain from a normally painful stimulus (hyperalgesia) and extreme sensitivity to temperature [45]. Some studies demonstrate the prevalence to be approximately 20% of the chronic pain population. In a 2013 article published in Pediatric Blood and Cancer, 37% of patients with SCD were identified to have neuropathic pain and only 5% were reported to be taking a neuropathic pain drug (gabapentin), which highlights the lack of diagnosis and treatment [55]. Thus, appropriate screening tools such as the pain DETECT questionnaire could help identify patients with neuropathic

Although no single treatment therapy exists, a multimodal pharmacologic approach can be instituted in patients diagnosed with neuropathic pain. Treatment may include tricyclic antidepressants (TCA, SSRI, SNRIs, MAOIs) or anticonvulsants (pregabalin, gabapentin), although there is no data supporting its use in patients with SCD [56]. With a better safety profile and less side effects than opioids, tramadol (a typical analgesic with weak opioid receptor agonism and SNRI activity) can act centrally and be helpful in treating neuropathic

Until SCD can be fully cured (possibly with gene therapy), new and improved treatment modalities are necessary. The information currently available about SCD is that rapid and aggressive therapy at the first sign of a VOE help reduce the length of the event and even

pain, but should be used with caution in patients with renal failure [57, 58].

hinders our progression toward achieving novel therapies.

body necrosis [53].

**4.4. Neuropathic pain**

pain and help initiate treatment.

**5. Future of SCD pain treatment**

**4.5. Treatment/management**

#### **4.3. Treatment/management**

The cornerstone to therapy involves recognition of the disease state and assessment of the pain intensity, which helps individualize therapy. Prevention of SCD pain is crucial by avoidance of precipitating factors (dehydration, infection, diuretics, altitude, acidosis, and hypoxia), as repetitive acute inflammation can result in chronic pain. The approach to pain management in patients with SCD with chronic pain is multidisciplinary, involving the use of pharmacologic analgesic drugs, nerve blocks, physical therapy, and cognitive behavioral therapy [46]. Discussion of hydroxyurea and other disease modifying therapies is appropriate. Close attention should be made to psychosocial issues including depression and social isolation [45].

Mild chronic pain can be treated with acetaminophen or dihydrocodeine. In patients with liver failure, acetaminophen can be avoided and NSAIDS such as ibuprofen can be used, but should be used with caution in patients with borderline renal function or failure. In patients with moderate pain, consideration of slow release morphine with small amounts of rapid-release morphine for breakthrough pain is advised [46]. Alternatives to Morphine include hydromorphone, oxycodone, methadone, or transdermal fentanyl. Methadone in particular can be efficacious in patients with suspected opioid-induced hyperalgesia due to its N-methyl-D-aspartate (NMDA) antagonism and monoaminue uptake reuptake inhibition. In patients who cannot tolerate opioid side effects and have contraindications the prior listed opioid analgesics, tramadol, a selective Mu-receptor agonist and serotonin–norepinephrine reuptake inhibitor can be considered [44]. The goal of chronic pain management is to maximize the quality of life rather than short-term pain suppression [45]. Other adjuvants include partial opioid agonists such as buprenorphine, topical agents, corticosteroids, antihistamines, benzodiazepines, antidepressants, anticonvulsants, and phenothiazines.

In patients with severe chronic pain, alternative procedures can be considered in addition to opioid therapy. For example, in a patient with deep somatic pain of avascular necrosis of the hip, an interventional nerve block could supply instant relief for 12 h, and potentially 72 h if the injectate is liposomal Bupivacaine [49, 50]. Physiotherapy can help strengthen muscle fibers and loosen stiff joints, preventing contractures and physical disability. Psychological support with cognitive behavioral therapy can help the patient cope with pain or deal with the mental agony and psychosocial stressors associated with sickle cell disease [46]. Adapting to cognitive skills can also help alter the perception of pain as negative thinking has been linked to higher pain scores. Massage therapy, relaxation techniques, and even self-prayer have been reported in published studies to help with chronic pain [51]. The American Pain Society strongly recommends psychological, behavioral and physical modalities as necessary complements to pharmacologic therapy, as a significant effect on pain scores and activities of daily living have been reported [52]. Orthopedic devices for back or leg support can be deployed to reduce chronic pain in the hips or back. Orthopedic surgery, such as total hip replacement should be deferred until the pain is no longer tolerable [46].

Lastly, it important to note that patients with SCD are not immune to non-hemoglobinopathic pain. Excluding other disease processes is essential and misdiagnosis can be life threatening. Conditions that can mimic the chronic pain state include but are not limited to ischemic colitis, pancreatitis, bone marrow infarction, hepatobiliary disorders, and vertebral body necrosis [53].

#### **4.4. Neuropathic pain**

activation [48]. Additionally, tryptase, a serine proteinase found within mast cells appears far more elevated in patients with chronic pain in sickle cell disease. This can help guide future therapy directed toward inhibition of mast cell activation, and implementation of medications such as Cromolyn. This can also help identify and diagnose patients with sickle crises who present to the emergency department and are sadly mistaken as drug seeking opportunists.

The cornerstone to therapy involves recognition of the disease state and assessment of the pain intensity, which helps individualize therapy. Prevention of SCD pain is crucial by avoidance of precipitating factors (dehydration, infection, diuretics, altitude, acidosis, and hypoxia), as repetitive acute inflammation can result in chronic pain. The approach to pain management in patients with SCD with chronic pain is multidisciplinary, involving the use of pharmacologic analgesic drugs, nerve blocks, physical therapy, and cognitive behavioral therapy [46]. Discussion of hydroxyurea and other disease modifying therapies is appropriate. Close attention should be made to psychosocial issues including depression and social isolation [45].

Mild chronic pain can be treated with acetaminophen or dihydrocodeine. In patients with liver failure, acetaminophen can be avoided and NSAIDS such as ibuprofen can be used, but should be used with caution in patients with borderline renal function or failure. In patients with moderate pain, consideration of slow release morphine with small amounts of rapid-release morphine for breakthrough pain is advised [46]. Alternatives to Morphine include hydromorphone, oxycodone, methadone, or transdermal fentanyl. Methadone in particular can be efficacious in patients with suspected opioid-induced hyperalgesia due to its N-methyl-D-aspartate (NMDA) antagonism and monoaminue uptake reuptake inhibition. In patients who cannot tolerate opioid side effects and have contraindications the prior listed opioid analgesics, tramadol, a selective Mu-receptor agonist and serotonin–norepinephrine reuptake inhibitor can be considered [44]. The goal of chronic pain management is to maximize the quality of life rather than short-term pain suppression [45]. Other adjuvants include partial opioid agonists such as buprenorphine, topical agents, corticosteroids, antihistamines,

In patients with severe chronic pain, alternative procedures can be considered in addition to opioid therapy. For example, in a patient with deep somatic pain of avascular necrosis of the hip, an interventional nerve block could supply instant relief for 12 h, and potentially 72 h if the injectate is liposomal Bupivacaine [49, 50]. Physiotherapy can help strengthen muscle fibers and loosen stiff joints, preventing contractures and physical disability. Psychological support with cognitive behavioral therapy can help the patient cope with pain or deal with the mental agony and psychosocial stressors associated with sickle cell disease [46]. Adapting to cognitive skills can also help alter the perception of pain as negative thinking has been linked to higher pain scores. Massage therapy, relaxation techniques, and even self-prayer have been reported in published studies to help with chronic pain [51]. The American Pain Society strongly recommends psychological, behavioral and physical modalities as necessary complements to pharmacologic therapy, as a significant effect on pain scores and activities of daily living have been reported [52]. Orthopedic devices for back or leg support can be deployed to reduce chronic pain in the hips or back. Orthopedic surgery, such as total hip

benzodiazepines, antidepressants, anticonvulsants, and phenothiazines.

replacement should be deferred until the pain is no longer tolerable [46].

**4.3. Treatment/management**

26 Pain Management in Special Circumstances

In addition to acute and chronic pain, a neuropathic component of pain plays a large and undiagnosed constituent of chronic disease. Data suggest that the development of neuropathic pain is responsible for the transition from acute to chronic pain with aging [54]. The general understanding is that multiple components of central sensitization and peripheral nerve injury are responsible. Types of neuropathic pain include peripheral neuropathic (caused by vaso-occlusive crises and neuropathies) and central neuropathic (caused by CNS damage, ictus, and central sensitization). Peripheral nerve injury and prostaglandin release can sensitize peripheral nerve endings and facilitate the transmission of pain along the A-delta and C fibers to the cerebral cortex [44]. The exact mechanism, however, is poorly understood, which hinders our progression toward achieving novel therapies.

Neuropathic pain from SCD occurs more commonly in older adults and females, which is hypothesized to be secondary to abnormalities in pain signaling pathways. These patients have extreme sensitivity to tactile touch (allodynia), increased pain from a normally painful stimulus (hyperalgesia) and extreme sensitivity to temperature [45]. Some studies demonstrate the prevalence to be approximately 20% of the chronic pain population. In a 2013 article published in Pediatric Blood and Cancer, 37% of patients with SCD were identified to have neuropathic pain and only 5% were reported to be taking a neuropathic pain drug (gabapentin), which highlights the lack of diagnosis and treatment [55]. Thus, appropriate screening tools such as the pain DETECT questionnaire could help identify patients with neuropathic pain and help initiate treatment.

#### **4.5. Treatment/management**

Although no single treatment therapy exists, a multimodal pharmacologic approach can be instituted in patients diagnosed with neuropathic pain. Treatment may include tricyclic antidepressants (TCA, SSRI, SNRIs, MAOIs) or anticonvulsants (pregabalin, gabapentin), although there is no data supporting its use in patients with SCD [56]. With a better safety profile and less side effects than opioids, tramadol (a typical analgesic with weak opioid receptor agonism and SNRI activity) can act centrally and be helpful in treating neuropathic pain, but should be used with caution in patients with renal failure [57, 58].
