**3. Acute pain: the vaso-occlusive event**

The vaso-occlusive event (VOE) is the most common cause of morbidity in the patients with SCD [10]. VOE also account for the most common cause of hospital admissions and missed school days. Some data report that up to 95% of hospital admissions related to SCD are for acute painful crises [11, 12]. Multicellular aggregates leading to blood flow obstruction in small blood vessels, depriving downstream tissues of oxygen and nutrient constitute the painful pathway of VOE, which was described earlier in this chapter. Although VOE-related pain can affect any part of the body and often cause generalized pain, it more commonly presents as pain in the extremities in the pediatric population, as opposed to being more commonly seen as headache, chest pain, abdominal and back pain in older individuals [13]. The average duration of an acute pain crisis, based on hospital length of stay, is about 7 days [7]. Fever and leukocytosis typically accompany the patient's presentation and the extent of WBC tends to correlate with the degree of pain [14, 15]. Also, the higher the level of Hb and hematocrit is, the more likely it is that a VOE will occur [9]. Even if leukocytosis associated with VOE does not necessarily signify an infectious process, careful evaluation should be undertaken, as these individuals are highly susceptible to pathogens. A careful and thorough history and physical examination should be undertaken. Inquiring about the onset, location, radiation, quality, relieving and aggravating factors associated with the current painful episode, any differences between the current episode and previous episodes, the presence of fever, transfusion history, medications, baseline hemoglobin level, and a thorough physical exam can assist in making a more definite diagnosis. Any atypical presentation should prompt further investigation (**Table 1**). The triggers of VOE can be physical, psychological, physiological and environmental among many. At any age group, a painful crisis typically begins with sudden onset of pain.

thrombocytopenia. The third phase, the established phase, is when the pain level is at its peak. The patient will show signs of frustration, depression, will tend to complain about hospital staff due to lack of appropriate treatment. Physical exam will show an elevated temperature, signs of inflammation, joint effusions. Laboratory signs will consist of elevated WBC, decreased Hb, and elevated reticulocyte count, elevated LDH, CPK and CRP. This phase is the longest for an average of about 4–5 days. The fourth and final phase, lasting 3 days on average, is the resolving phase; patients start showing signs of decreasing pain, RBC deformability increases, as well as fibrinogen, orosomucoid, ESR, platelets and plasma viscosity. The blood level of sickled RBC is decreased during the final phase. The increase in plasma viscosity leads to a hypercoagulable state that becomes a culprit for recurrence of another painful crisis. In fact, about 16% of hospital admissions because of VOE get readmitted with recurrence within 1 week of discharge [11, 19]. The reasons for readmissions include, but not limited to, withdrawal syndrome, premature discharge, inadequate pain management during hospital admission, development of tolerance to opioid medications, opioid-induced hyperalgesia (OIH). Analysis of children admitted to hospitals with VOE show that patients typically show a blunted response to pain relief after the fourth to sixth day of admission [20]. The reason for this phenomenon is unknown but could be related to OIH, tolerance or provider inexperience with prolonged VOE pain. This subset of patients is more likely to return to the hospital and get readmitted. Special attention should be paid to readmitted patient since these tend a have a higher morbidity and mortality rate. Also, care should be taken not to under treat patients in the resolving phase of the VOE; Even if the pain seems to subside during this phase, it is important to continue aggressive pain management, provide patients with appropriate discharge instructions to avoid overdose or

Pain Management for the Sickle Cell Patient http://dx.doi.org/10.5772/intechopen.79495 19

This table points out important factors to consider when doing a primary investigation of a SCD patient presenting to the ED in pain. It is important to perform a full assessment of the patient to rule out any serious adverse events that are commonly associated with SCD.

The first time SCD was recognized as its own disease was in 1910 when a medical resident observed the sickle appearing cell under a microscope [21]. Since then, many more discoveries about the disease were made, and its treatment still remains a dynamic process with changes constantly occurring. The therapeutic research initially consisted of finding ways to prevent the blockage of small blood vessels by the sickles shape RBC [22]. It was not until the 1960s that pain was recognized as a major symptom in SCD.Among the first pharmacological approaches used to treat it figured papaverine and acetaminophen [23]. It was not until later that opioid medications were used for the treatment of SCD and now represents the cornerstone of treatment for acute painful crisis. Appropriate treatment of VOE crisis is crucial since the consequences associated with the latter are many. Those involve acute chest syndrome in about 50% of VOE-related hospitalization, acute multi-organ failure and sudden death [24–26]. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage [16]. A wide range of treatment modalities exists for the treatment of acute sickle cell pain. Nonpharmacological approaches such as acupuncture, heat, ice, relaxation techniques and hypnosis but are not covered in detail in this chapter [9, 27–30]. Pharmacological approaches for the treatment of VOE around the globe consist predominantly of opioid

withdrawal after discharge, arrange for appropriate follow-up.

**3.1. Treatment of acute sickle cell pain**

Although most individuals with SCD presenting to the healthcare professional with VOE will exhibit different types complains as far as onset, location, quality and intensity of their pain, the painful crisis will typical last between 7 and 10 days and can be described as possessing four different phases: A prodromal phase, initial phase, established phase and resolving phase [16–18]. A prodromal phase lasts 1–2 days and consists of aches, numbness or paresthesia in the area that will subsequently become painful. Physical signs of the prodromal phase include loss of usual appearance of the eyes (loss of luster or yellowing of the eyes). Laboratory values are significant for a decrease in erythrocyte deformability and increase density of erythrocytes. The second phase, initial phase, also lasting 1–2 days, is characterized by an increase in pain level and laboratory findings such as decreased RBC deformability, increase in the number of dense cells, red cell distribution width (RDW), reticulocytosis, leukocytosis, and relative

	- Body temperature
	- Areas of tenderness
	- Cardiac, pulmonary, skin, CNS, abdominal

**Table 1.** Primary investigation upon initial presentation of a SCD patient in pain.

<sup>1.</sup> Detailed history:

thrombocytopenia. The third phase, the established phase, is when the pain level is at its peak. The patient will show signs of frustration, depression, will tend to complain about hospital staff due to lack of appropriate treatment. Physical exam will show an elevated temperature, signs of inflammation, joint effusions. Laboratory signs will consist of elevated WBC, decreased Hb, and elevated reticulocyte count, elevated LDH, CPK and CRP. This phase is the longest for an average of about 4–5 days. The fourth and final phase, lasting 3 days on average, is the resolving phase; patients start showing signs of decreasing pain, RBC deformability increases, as well as fibrinogen, orosomucoid, ESR, platelets and plasma viscosity. The blood level of sickled RBC is decreased during the final phase. The increase in plasma viscosity leads to a hypercoagulable state that becomes a culprit for recurrence of another painful crisis. In fact, about 16% of hospital admissions because of VOE get readmitted with recurrence within 1 week of discharge [11, 19]. The reasons for readmissions include, but not limited to, withdrawal syndrome, premature discharge, inadequate pain management during hospital admission, development of tolerance to opioid medications, opioid-induced hyperalgesia (OIH). Analysis of children admitted to hospitals with VOE show that patients typically show a blunted response to pain relief after the fourth to sixth day of admission [20]. The reason for this phenomenon is unknown but could be related to OIH, tolerance or provider inexperience with prolonged VOE pain. This subset of patients is more likely to return to the hospital and get readmitted. Special attention should be paid to readmitted patient since these tend a have a higher morbidity and mortality rate. Also, care should be taken not to under treat patients in the resolving phase of the VOE; Even if the pain seems to subside during this phase, it is important to continue aggressive pain management, provide patients with appropriate discharge instructions to avoid overdose or withdrawal after discharge, arrange for appropriate follow-up.

This table points out important factors to consider when doing a primary investigation of a SCD patient presenting to the ED in pain. It is important to perform a full assessment of the patient to rule out any serious adverse events that are commonly associated with SCD.

#### **3.1. Treatment of acute sickle cell pain**

seen as headache, chest pain, abdominal and back pain in older individuals [13]. The average duration of an acute pain crisis, based on hospital length of stay, is about 7 days [7]. Fever and leukocytosis typically accompany the patient's presentation and the extent of WBC tends to correlate with the degree of pain [14, 15]. Also, the higher the level of Hb and hematocrit is, the more likely it is that a VOE will occur [9]. Even if leukocytosis associated with VOE does not necessarily signify an infectious process, careful evaluation should be undertaken, as these individuals are highly susceptible to pathogens. A careful and thorough history and physical examination should be undertaken. Inquiring about the onset, location, radiation, quality, relieving and aggravating factors associated with the current painful episode, any differences between the current episode and previous episodes, the presence of fever, transfusion history, medications, baseline hemoglobin level, and a thorough physical exam can assist in making a more definite diagnosis. Any atypical presentation should prompt further investigation (**Table 1**). The triggers of VOE can be physical, psychological, physiological and environmental among many. At any age group, a painful crisis typically begins with sudden onset of pain. Although most individuals with SCD presenting to the healthcare professional with VOE will exhibit different types complains as far as onset, location, quality and intensity of their pain, the painful crisis will typical last between 7 and 10 days and can be described as possessing four different phases: A prodromal phase, initial phase, established phase and resolving phase [16–18]. A prodromal phase lasts 1–2 days and consists of aches, numbness or paresthesia in the area that will subsequently become painful. Physical signs of the prodromal phase include loss of usual appearance of the eyes (loss of luster or yellowing of the eyes). Laboratory values are significant for a decrease in erythrocyte deformability and increase density of erythrocytes. The second phase, initial phase, also lasting 1–2 days, is characterized by an increase in pain level and laboratory findings such as decreased RBC deformability, increase in the number of dense cells, red cell distribution width (RDW), reticulocytosis, leukocytosis, and relative

• Pain: onset, location, radiation, quality, frequency, progressiveness, alleviating and aggravating factors,

4. Radiologic imaging based on history and physical (i.e., Abdominal CT for abnormal abdominal pain, Head CT if

5. Initiate pain management algorithm (**Figure 1**) after serious complications rules out (stroke, acute chest

• Associated factors (Cough and respiratory symptoms, GI symptoms, neurological changes)

1. Detailed history:

home medications. • Presence of fever • Transfusion history • Baseline hemoglobin

18 Pain Management in Special Circumstances

2. Thorough physical exam • Body temperature • Areas of tenderness

3. Laboratory results (BMP, CBC)

any CNS manifestation present)

• Cardiac, pulmonary, skin, CNS, abdominal

syndrome, splenic sequestration, pneumococcal sepsis, priapism)

**Table 1.** Primary investigation upon initial presentation of a SCD patient in pain.

The first time SCD was recognized as its own disease was in 1910 when a medical resident observed the sickle appearing cell under a microscope [21]. Since then, many more discoveries about the disease were made, and its treatment still remains a dynamic process with changes constantly occurring. The therapeutic research initially consisted of finding ways to prevent the blockage of small blood vessels by the sickles shape RBC [22]. It was not until the 1960s that pain was recognized as a major symptom in SCD.Among the first pharmacological approaches used to treat it figured papaverine and acetaminophen [23]. It was not until later that opioid medications were used for the treatment of SCD and now represents the cornerstone of treatment for acute painful crisis. Appropriate treatment of VOE crisis is crucial since the consequences associated with the latter are many. Those involve acute chest syndrome in about 50% of VOE-related hospitalization, acute multi-organ failure and sudden death [24–26]. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage [16]. A wide range of treatment modalities exists for the treatment of acute sickle cell pain. Nonpharmacological approaches such as acupuncture, heat, ice, relaxation techniques and hypnosis but are not covered in detail in this chapter [9, 27–30]. Pharmacological approaches for the treatment of VOE around the globe consist predominantly of opioid analgesic including full agonists, partial agonists, mixed agonists-antagonists, antagonists but also include opioid adjuvants as well as nonopioid analgesics such NSAIDs, acetaminophen and other adjuvants [9]. As previously mentioned, VOE is the most common presentation (up to 90%) of patients with SCD to the healthcare facilities (i.e., Emergency Department). The first step in management focuses on immediate pain control with fluids and analgesics as evidence exists demonstrating that rapid and efficient control of acute pain related to VOE reduces pain scores, length of hospital stay, improve patient satisfaction [28, 31], reduce hospitalization in patients with SCD and also a decrease in the development of chronic pain syndromes, which is commonly seen in the sickle cell population [9, 32].

However, managing the pain could be more difficult than anticipated by the healthcare provider, as the SCD patient's pain management differs from that of the rest of the population. Indeed, the patient with sickle cell disease tends to be more tolerant to opioid medications then the rest of the population due to chronic administration, VOE pain can appear out of proportion for most providers and necessitates higher doses of narcotics which most emergency department providers are not accustom to administer. This underlines the reason why most patients with sickle cell disease report that their pain is undertreated in the emergency department and that the providers lack understanding and compassion [9, 33–38]. Additionally, VOE-related pain more exaggerated than expected, every patient possesses his own unique sensation, perception and expression of pain.

Indicators of adequate VOE management consist, but not limited to, admission to the hospital (indicates poor pain control in the ED), readmission to the hospital (indicator that pain was not well controlled during hospital stay), length of stay (indicator of effective pain management during hospital stay), pain intensity felt during ED visit or hospitalization (different pain measurement assessment available), patient and parents satisfaction, increase or decrease in VOE/SCD-related complications (**Table 2**).

The indicators of an effective treatment of SCD patients during their visit to the ED or admission to the hospital are shown here. Signs of ineffective treatment are admission from the ED to the hospital, readmission to the hospital after discharge, increased length of stay in the ED or the hospital, elevated pain assessment score, poor patient and/or parent satisfaction.

> This figure outlines our guidelines for the recommendation of the treatment of VOE in the ED. Alternatively, institution that do not typically encounter individuals with SCD and that do not have an algorithm in place for the management of a patient that presents to their healthcare facility for the first time should involve starting with the lowest dose for the shortest duration possible in order to control the symptoms if the pain is mild to moderate and the patient has not been opioid naïve [39]. If the pain is moderate to severe and the patient has previously attempted an opioid medication without relief, a higher dose of opioid is preferred. From that baseline, the physician should titrate the dose, and duration of the analgesic medications upwards until adequate pain relief is achieved. On the other hand, as discussed earlier, the patient who presents for a subsequent visit to the same healthcare facility should initially be restarted on the same analgesic regimen with which adequate pain relief was obtained in the

Pain Management for the Sickle Cell Patient http://dx.doi.org/10.5772/intechopen.79495 21

**Figure 1.** Management of SCD patient presenting to the ED with VOE.

previous visits for VOE crises.

Facilities that have taken into account these indicators of effective VOE pain management have demonstrated benefice in rapid treatment of patients presenting to their healthcare facility with VOE with an individualized plan for each patient. An individualized plan results in decreased hospital admissions, readmissions, length of ED and hospitalization, substantial decrease in pain scores, increased patient and parent satisfaction. Although no single plan or approach is perfect for all patients, there are different algorithms that are available to the healthcare provider that serve as helpful guide for the patient presenting with VOE. Using an algorithm has shown to be simple, cost-effective and beneficial for the patient's generalized well-being. Institutions that commonly encounter patients with VOE are encouraged to either follow an existing effective algorithm or create their own. Every patient presenting to the healthcare provider with VOE-related pain would require his or her own individualized treatment plan [39]. Our preferred algorithm is inspired by the American Pain Society and is detailed in the following paragraph.

**Figure 1.** Management of SCD patient presenting to the ED with VOE.

analgesic including full agonists, partial agonists, mixed agonists-antagonists, antagonists but also include opioid adjuvants as well as nonopioid analgesics such NSAIDs, acetaminophen and other adjuvants [9]. As previously mentioned, VOE is the most common presentation (up to 90%) of patients with SCD to the healthcare facilities (i.e., Emergency Department). The first step in management focuses on immediate pain control with fluids and analgesics as evidence exists demonstrating that rapid and efficient control of acute pain related to VOE reduces pain scores, length of hospital stay, improve patient satisfaction [28, 31], reduce hospitalization in patients with SCD and also a decrease in the development of chronic pain syndromes, which

However, managing the pain could be more difficult than anticipated by the healthcare provider, as the SCD patient's pain management differs from that of the rest of the population. Indeed, the patient with sickle cell disease tends to be more tolerant to opioid medications then the rest of the population due to chronic administration, VOE pain can appear out of proportion for most providers and necessitates higher doses of narcotics which most emergency department providers are not accustom to administer. This underlines the reason why most patients with sickle cell disease report that their pain is undertreated in the emergency department and that the providers lack understanding and compassion [9, 33–38]. Additionally, VOE-related pain more exaggerated than expected, every patient possesses his own unique

Indicators of adequate VOE management consist, but not limited to, admission to the hospital (indicates poor pain control in the ED), readmission to the hospital (indicator that pain was not well controlled during hospital stay), length of stay (indicator of effective pain management during hospital stay), pain intensity felt during ED visit or hospitalization (different pain measurement assessment available), patient and parents satisfaction, increase or decrease in

The indicators of an effective treatment of SCD patients during their visit to the ED or admission to the hospital are shown here. Signs of ineffective treatment are admission from the ED to the hospital, readmission to the hospital after discharge, increased length of stay in the ED or the hospital, elevated pain assessment score, poor patient and/or parent satisfaction.

Facilities that have taken into account these indicators of effective VOE pain management have demonstrated benefice in rapid treatment of patients presenting to their healthcare facility with VOE with an individualized plan for each patient. An individualized plan results in decreased hospital admissions, readmissions, length of ED and hospitalization, substantial decrease in pain scores, increased patient and parent satisfaction. Although no single plan or approach is perfect for all patients, there are different algorithms that are available to the healthcare provider that serve as helpful guide for the patient presenting with VOE. Using an algorithm has shown to be simple, cost-effective and beneficial for the patient's generalized well-being. Institutions that commonly encounter patients with VOE are encouraged to either follow an existing effective algorithm or create their own. Every patient presenting to the healthcare provider with VOE-related pain would require his or her own individualized treatment plan [39]. Our preferred algorithm is inspired by the American Pain Society and is

is commonly seen in the sickle cell population [9, 32].

20 Pain Management in Special Circumstances

sensation, perception and expression of pain.

VOE/SCD-related complications (**Table 2**).

detailed in the following paragraph.

This figure outlines our guidelines for the recommendation of the treatment of VOE in the ED.

Alternatively, institution that do not typically encounter individuals with SCD and that do not have an algorithm in place for the management of a patient that presents to their healthcare facility for the first time should involve starting with the lowest dose for the shortest duration possible in order to control the symptoms if the pain is mild to moderate and the patient has not been opioid naïve [39]. If the pain is moderate to severe and the patient has previously attempted an opioid medication without relief, a higher dose of opioid is preferred. From that baseline, the physician should titrate the dose, and duration of the analgesic medications upwards until adequate pain relief is achieved. On the other hand, as discussed earlier, the patient who presents for a subsequent visit to the same healthcare facility should initially be restarted on the same analgesic regimen with which adequate pain relief was obtained in the previous visits for VOE crises.


**Table 2.** Indicators of effective/ineffective VOE treatment.

Whenever initiating opioid analgesia, it is mandatory to monitor for respiratory and sedation status. Useful questionnaires such as the Richmond Agitation Sedation Scale (RASS), the visual analogue scale (VAS) exist for sedation and pain assessment respectively. Respiratory status is typically monitored by pulse oximetry and visual assessment although some institution advocate for continuous end-tidal carbon dioxide monitoring (EtCO2 ), especially when using high doses of opioids.

painful stimuli. Additionally, there exists a multitude of different receptors that each mediates the desired analgesic differently. Thus, the response to opioids depends not only on the type of opioid used, but also on the number and activity of the opioid receptors that a certain patient has. An opioid that binds a low number of receptors and has poor affinity, for example, is unlikely to produce effective analgesia in certain patients even if the dose is high. On the other hand, an opioid binding to an elevated number of receptors and with moderate or high binding affinity would provide effective analgesia even if used in small doses. This is part of the reason, among many others, why there is an immense variability to the pain response in patients with SCD. A dose considered an under treatment for a particular patient could overdose another patient.

Pain Management for the Sickle Cell Patient http://dx.doi.org/10.5772/intechopen.79495 23

Unfortunately, opioids are not without side effects. The long list of mild to moderate adverse effects includes pruritus, nausea, vomiting, constipation, urinary retention, seizures, hives and the notorious respiratory depression. As mentioned earlier, seizures are mostly associated with meperidine. Other opioids have also possessed a potential for albeit a lot smaller and thought to be derived from the neuroexcitation related to metabolite of the opiate. Opioid-induced pruritus is one of the most prevalent complications with the use of opioids and is typically well controlled by either hydroxyzine, diphenhydramine, low dose naloxone and, now recognized as the most effective treatment, nalbuphine. The more serious complications, some of which are very popular topic of debates in the world today include addiction, tolerance, withdrawal, physical dependence and pseudoaddiction. A condition feared by many providers in today's world is addiction; a condition that is influenced by genetic, psychological and environmental factors that lead to compulsive use despite harm. Opiates are strong stimulants of the reward/ pleasure system, increasing the level of dopamine in the system, which in turn enhances the desire to achieve the reward/pleasure. Addiction can ultimately lead to overdose and death. Tolerance, on the other hand, represents a state of adaptation in which exposure to the same amount of the drug results in a lower effect than previously obtained. Physical dependence also happens frequently and is the cause of the known withdrawal syndrome that manifests with abrupt cessation or an exaggerated reduction in the dose of opiate administered. Signs and symptoms of withdrawal include tremor, shakiness, anxiety, depression, lacrimation, rhinorrhea, fatigue, irritability, and diarrhea. Pseudoaddiction is very common in patients with SCD.It is a state, in which the patient appears to be seeking for excessive amount of medication, but is due to under-treatment of pain and resolves when the pain is treated properly. Opioid-induced hyperalgesia (OIH) results from chronic administration of opioid medications. A process that is not totally proven and well understood yet but is thought to result from a minor excitatory pathway that becomes magnified with chronic use of the opiates and, ultimately, becomes the dominant effect. The sites of pain from OIH are typically the same as the sites perceived during

the VOE crisis, but the quality of the pain differs. It is more neuropathic in nature.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main adjuvant of opioid in today's therapeutic guidelines of most healthcare facilities. Ketorolac tromethamine is the NSAID

**3.4. Nonsteroidal anti-inflammatory drugs**

**3.3. Opioids adverse events**

The preferred and recommended primary pharmacological method to treat the VOE crises is the opioid analgesic route and the commonly used medications include codeine, morphine, hydromorphone, fentanyl, hydrocodone/acetaminophen, hydrocodone/ibuprofen, oxymorphone, oxycodone, methadone and diamorphine [9].

#### **3.2. Opioid medications**

The first opiate used for VOE in the ED was meperidine in the 1960s. At home, short-acting oxycodone with acetaminophen was the most often used home medication. Morphine sulfate then got FDA approval in the 1980s and became the opiate of choice for the management of VOE in the 1990s. Not only did morphine show improvement in pain management and decreased hospital admissions related to VOE, it also did not possess the feared seizure side effect related to the meperidine metabolites, Normeperidine. These metabolites reduce the seizure threshold and also accumulate in patient with renal insufficiency, a complication commonly seen in patients with SCD [40–42]. In today's world though, as mentioned earlier, many different types of opioid are used effectively for the treatment of VOE-related pain but in the United States, intravenous hydromorphone is the drug most commonly used in the hospital setting and oral oxycodone as home prescription medications [43]. As a comparison, in the United Kingdom, intravenous morphine, diamorphine and oral oxycodone are the most commonly used pain medications for VOE pain.

Opioid agonists produce their effect by binding into μ receptors. The potency of a particular opioid is dependent on the binding affinity or strength with which that drug binds to its receptors and there is a great amount of variability of potency between different opiates. For example, hydromorphone is 5–7 as potent as morphine while sufentanyl is 500–1000 as potent as morphine. When an opiate binds to its receptors, it initiates a cascade of biochemical events that starts with activation of G-proteins, inhibition of adenylate cyclase activity and extrusion of K++ that result in hyperpolarisation of cell membranes, which delays or prevents the transmission of painful stimuli. Additionally, there exists a multitude of different receptors that each mediates the desired analgesic differently. Thus, the response to opioids depends not only on the type of opioid used, but also on the number and activity of the opioid receptors that a certain patient has. An opioid that binds a low number of receptors and has poor affinity, for example, is unlikely to produce effective analgesia in certain patients even if the dose is high. On the other hand, an opioid binding to an elevated number of receptors and with moderate or high binding affinity would provide effective analgesia even if used in small doses. This is part of the reason, among many others, why there is an immense variability to the pain response in patients with SCD. A dose considered an under treatment for a particular patient could overdose another patient.

#### **3.3. Opioids adverse events**

Whenever initiating opioid analgesia, it is mandatory to monitor for respiratory and sedation status. Useful questionnaires such as the Richmond Agitation Sedation Scale (RASS), the visual analogue scale (VAS) exist for sedation and pain assessment respectively. Respiratory status is typically monitored by pulse oximetry and visual assessment although some institu-

The preferred and recommended primary pharmacological method to treat the VOE crises is the opioid analgesic route and the commonly used medications include codeine, morphine, hydromorphone, fentanyl, hydrocodone/acetaminophen, hydrocodone/ibuprofen, oxymor-

The first opiate used for VOE in the ED was meperidine in the 1960s. At home, short-acting oxycodone with acetaminophen was the most often used home medication. Morphine sulfate then got FDA approval in the 1980s and became the opiate of choice for the management of VOE in the 1990s. Not only did morphine show improvement in pain management and decreased hospital admissions related to VOE, it also did not possess the feared seizure side effect related to the meperidine metabolites, Normeperidine. These metabolites reduce the seizure threshold and also accumulate in patient with renal insufficiency, a complication commonly seen in patients with SCD [40–42]. In today's world though, as mentioned earlier, many different types of opioid are used effectively for the treatment of VOE-related pain but in the United States, intravenous hydromorphone is the drug most commonly used in the hospital setting and oral oxycodone as home prescription medications [43]. As a comparison, in the United Kingdom, intravenous morphine, diamorphine and oral oxycodone are the

Opioid agonists produce their effect by binding into μ receptors. The potency of a particular opioid is dependent on the binding affinity or strength with which that drug binds to its receptors and there is a great amount of variability of potency between different opiates. For example, hydromorphone is 5–7 as potent as morphine while sufentanyl is 500–1000 as potent as morphine. When an opiate binds to its receptors, it initiates a cascade of biochemical events that starts with activation of G-proteins, inhibition of adenylate cyclase activity and extrusion of K++ that result in hyperpolarisation of cell membranes, which delays or prevents the transmission of

), especially when

tion advocate for continuous end-tidal carbon dioxide monitoring (EtCO2

phone, oxycodone, methadone and diamorphine [9].

4. Patient pain assessment (i.e., VAS, Baker-Wong faces scale)

**Table 2.** Indicators of effective/ineffective VOE treatment.

most commonly used pain medications for VOE pain.

using high doses of opioids.

1. Admission to the hospital 2. Readmission to the hospital 3. Length of stay in the ED or hospital

22 Pain Management in Special Circumstances

5. Patient satisfaction 6. Parent satisfaction

**3.2. Opioid medications**

Unfortunately, opioids are not without side effects. The long list of mild to moderate adverse effects includes pruritus, nausea, vomiting, constipation, urinary retention, seizures, hives and the notorious respiratory depression. As mentioned earlier, seizures are mostly associated with meperidine. Other opioids have also possessed a potential for albeit a lot smaller and thought to be derived from the neuroexcitation related to metabolite of the opiate. Opioid-induced pruritus is one of the most prevalent complications with the use of opioids and is typically well controlled by either hydroxyzine, diphenhydramine, low dose naloxone and, now recognized as the most effective treatment, nalbuphine. The more serious complications, some of which are very popular topic of debates in the world today include addiction, tolerance, withdrawal, physical dependence and pseudoaddiction. A condition feared by many providers in today's world is addiction; a condition that is influenced by genetic, psychological and environmental factors that lead to compulsive use despite harm. Opiates are strong stimulants of the reward/ pleasure system, increasing the level of dopamine in the system, which in turn enhances the desire to achieve the reward/pleasure. Addiction can ultimately lead to overdose and death. Tolerance, on the other hand, represents a state of adaptation in which exposure to the same amount of the drug results in a lower effect than previously obtained. Physical dependence also happens frequently and is the cause of the known withdrawal syndrome that manifests with abrupt cessation or an exaggerated reduction in the dose of opiate administered. Signs and symptoms of withdrawal include tremor, shakiness, anxiety, depression, lacrimation, rhinorrhea, fatigue, irritability, and diarrhea. Pseudoaddiction is very common in patients with SCD.It is a state, in which the patient appears to be seeking for excessive amount of medication, but is due to under-treatment of pain and resolves when the pain is treated properly. Opioid-induced hyperalgesia (OIH) results from chronic administration of opioid medications. A process that is not totally proven and well understood yet but is thought to result from a minor excitatory pathway that becomes magnified with chronic use of the opiates and, ultimately, becomes the dominant effect. The sites of pain from OIH are typically the same as the sites perceived during the VOE crisis, but the quality of the pain differs. It is more neuropathic in nature.

#### **3.4. Nonsteroidal anti-inflammatory drugs**

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main adjuvant of opioid in today's therapeutic guidelines of most healthcare facilities. Ketorolac tromethamine is the NSAID 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 reasons, many specialists avoid NSAIDs in patients with sickle cell disease.

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

Pain Management for the Sickle Cell Patient http://dx.doi.org/10.5772/intechopen.79495 25

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.

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

(hyperalgesia) (**Figure 2**).

**4.2. Pathophysiology and mechanism**

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

#### **3.5. Ketamine**

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 of ketamine in SCD protocols.
