Section 3 Cancer Pain

*From Conventional to Innovative Approaches for Pain Treatment*

[60] Paoloni J, de Vos RJ, Hamilton B, Murrell GA, Orchard J. Platelet-rich plasma treatment for ligament and tendon injuries. Clinical Journal of Sport

[61] Filardo G, Kon E, Di Matteo B, Di Martino A, Tesei G, Pelotti P, et al. Platelet-rich plasma injections for the treatment of refractory Achilles tendinopathy: Results at 4 years. Blood Transfusion. 2014;**12**(4):533-540

[62] Filardo G, Kon E, Di Matteo B, Merli ML, Cenacchi A, Fornasari PM, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: Study design and preliminary results of a randomized controlled trial. BMC Musculoskeletal Disorders. 2012;**13**:229

[63] Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: A prospective, double-blind, randomized trial. The American Journal of Sports Medicine. 2013;**41**(2):354-364

Medicine. 2011;**21**(1):37-45

**86**

**89**

**Chapter 7**

**Abstract**

chapter.

**1. Introduction**

Cancer Pain

*Arūnas Ščiupokas, Liuda Brogienė and Dalia Skorupskienė*

In 1986, the World Health Organization (WHO) has published a document entitled "A Declaration of the Rights of Patients with Chronic Cancer," which says that according to the WHO, three-step analgesic ladder pain relief should be adequate for 70–90% of patients. However, despite increased attention on assessment and management, pain continues to be a prevalent symptom for patients with cancer. That is why refreshment of knowledge in cancer pain is necessary for every active practitioner. Broad overview of current understanding in cancer pain is presented in the chapter. Cancer pain syndromes are analyzed in between acute or chronic, and in among various causes occurred. Cancer pain assessment was presented with challenges meeting clinical practitioners. For cancer pain treatment, principles of multimodal approach are used. The pharmaceutical treatment presented in detail included rational use of opioids. Big attention is paid on palliative care of cancer pain patients and hospice-based palliative care model is presented too. New technologies of breakthrough cancer pain management are disclosed in detail including special questionnaire for patients. Cancer survivors' pain treatment and general practitioner's role among cancer pain problems are new topics presented in the

**Keywords:** cancer pain syndromes, assessment and treatment principles, multimodal

Cancer is diagnosed for more than 10 million people worldwide each year, and the illness of a malignant tumor is often associated with pain. The consequences of unrelieved cancer pain are devastating [1]. During the established diagnosis of cancer, the pain is present for 40% of tumor patients. The number increases up to 75–80% with the disease spread. About 4 million people in the world each day suffer from pain that comes due to oncological diseases, meaning that almost half of them do not receive

Despite increased attention on assessment and management, pain continues to be a prevalent symptom in patients with cancer. With reference to types of cancer, lower pain prevalence rates were demonstrated in prostate cancer compared to head and neck, lung, and breast cancer. Higher prevalence rates were seen in studies from Asia compared to Europe, in studies that used point or week prevalence rates

Over the past few decades, we succeeded a better understanding of mechanisms underlying cancer pain, new developments achieved in pharmacologic cancer pain management, and increase in global opioid consumption becoming evident. Nevertheless, one-third of the patients worldwide still did not receive pain

approach, basic and breakthrough cancer pains, palliative care

proper treatment, and one-third live in severe or unbearable pain [2].

compared to recall periods of a month or year [3].

#### **Chapter 7**

## Cancer Pain

*Arūnas Ščiupokas, Liuda Brogienė and Dalia Skorupskienė*

#### **Abstract**

In 1986, the World Health Organization (WHO) has published a document entitled "A Declaration of the Rights of Patients with Chronic Cancer," which says that according to the WHO, three-step analgesic ladder pain relief should be adequate for 70–90% of patients. However, despite increased attention on assessment and management, pain continues to be a prevalent symptom for patients with cancer. That is why refreshment of knowledge in cancer pain is necessary for every active practitioner. Broad overview of current understanding in cancer pain is presented in the chapter. Cancer pain syndromes are analyzed in between acute or chronic, and in among various causes occurred. Cancer pain assessment was presented with challenges meeting clinical practitioners. For cancer pain treatment, principles of multimodal approach are used. The pharmaceutical treatment presented in detail included rational use of opioids. Big attention is paid on palliative care of cancer pain patients and hospice-based palliative care model is presented too. New technologies of breakthrough cancer pain management are disclosed in detail including special questionnaire for patients. Cancer survivors' pain treatment and general practitioner's role among cancer pain problems are new topics presented in the chapter.

**Keywords:** cancer pain syndromes, assessment and treatment principles, multimodal approach, basic and breakthrough cancer pains, palliative care

#### **1. Introduction**

Cancer is diagnosed for more than 10 million people worldwide each year, and the illness of a malignant tumor is often associated with pain. The consequences of unrelieved cancer pain are devastating [1]. During the established diagnosis of cancer, the pain is present for 40% of tumor patients. The number increases up to 75–80% with the disease spread. About 4 million people in the world each day suffer from pain that comes due to oncological diseases, meaning that almost half of them do not receive proper treatment, and one-third live in severe or unbearable pain [2].

Despite increased attention on assessment and management, pain continues to be a prevalent symptom in patients with cancer. With reference to types of cancer, lower pain prevalence rates were demonstrated in prostate cancer compared to head and neck, lung, and breast cancer. Higher prevalence rates were seen in studies from Asia compared to Europe, in studies that used point or week prevalence rates compared to recall periods of a month or year [3].

Over the past few decades, we succeeded a better understanding of mechanisms underlying cancer pain, new developments achieved in pharmacologic cancer pain management, and increase in global opioid consumption becoming evident. Nevertheless, one-third of the patients worldwide still did not receive pain medication proportional to their pain intensity levels [4]. Data from Asia and North America revealed comparable prevalence rates, which imply that opioid availability alone is not an explanation for the high prevalence rates [3]. Even after implementation into clinical practice of rapid release opioids (ROOs), which provide faster relief than immediate-release preparations of other opioids, the prevalence of breakthrough pain is still 59% [5]. All these mean the importance of skilled use of opioid analgesics in the relief of cancer pain but also acknowledge the lack of evidence to support clinical practice and guidelines, which in turn causes recommendations in practice guidelines to be based on expert consensus.

In 1986, the World Health Organization (WHO) has published a document entitled "A Declaration of the Rights of Patients with Chronic Cancer." According to the WHO three-step analgesic ladder, in combination with appropriate dosage guidelines, pain relief should be adequate for 70–90% of patients. A systematic review on pain relief based on the WHO ladder, 20 years after its introduction, demonstrated adequate pain relief in 45–100% of patients [6, 7]. Among subjects of debates to improve the analgesic ladder the benefit of paracetamol (acetaminophen) with Step III opioids for which the evidence is "weak if any," as well as the use of adjuvant analgesics for which outcomes are generally modest [8]. On the other hand, not only drugs are a guarantee of success in the cancer pain. It is widely accepted that a biopsychosocial approach in assessment and management is needed for treatment of pain in patients with cancer. Cicely Saunders elaborated on the concept of "total pain," stating that pain is not purely a physical experience but involves various other components of human functioning including personality, mood, behavior, and social relations. A systematic review has identified an association between psychological distress, lack of social support, and cancer pain [9].

Different barriers have been acknowledged in relation to adequate pain management in patients with cancer. One of the most important reasons is lack of knowledge regarding the assessment and management of cancer pain. Health professionals are cautious when prescribing opioids because of fear of adverse effects, tolerance, and addiction. Otherwise, patients struggle with misconceptions about analgesic use, concerns about pain communication, and a belief that pain is inevitable and uncontrollable [10]. All reasons for the lack of adequate pain control are varied: (a) personal—fear of drug addiction, (b) legal issues by issuing a higher dose of these medicines, (c) material—with regard to the price and quantity of medicinal products, (d) organizational—regular supply and storage of medicines, (e) psychological—the conviction of the patient or his family members that narcotic analgesics can be used only in the last stages of the illness, (f) causes of medical staff in the absence of sufficient knowledge of analgesia and the principles for its administration, and (g) poor adherence to pain medication and poor pain relief, which appear to be more country-specific problems [11].

#### **2. Cancer pain syndromes**

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain is always subjective [the International Association for the Study of Pain (IASP)]. Cancerinduced pain may be acute or chronic. Cancer-induced pain may be nociceptive or neuropathic or psychogenic, but often it is mixed because there are several causes causing it to occur. The main (basic) is constant pain of controlled intensity. A breakthrough pain occurs when a basic pain is controlled. Breakthrough pain is a

**91**

*Cancer Pain*

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

**2.1 Acute pain syndromes**

**2.2 Chronic pain syndromes**

basic pain was adequately treated with opioids [12].

temporary exacerbation with high intensity pain, which is felt in patients whose

Cancer pain is not a single entity. It incorporates a range of etiological, pathophysiological, and anatomical subtypes, all requiring unique descriptive terminology, assessment techniques, and treatment modalities [13]. Among patients with cancer, there is substantial heterogeneity in how pain is experienced and in how it appears. In many cases, the constellation of symptoms and signs can suggest a specific cancer pain syndrome [14]. The identification of such a syndrome may help to elucidate the etiology of the pain, direct the diagnostic evaluation, clarify the prognosis for the pain or the disease itself, and guide therapeutic intervention.

Most acute cancer pain syndromes are primary as related to a diagnostic test or treatment. However, some are secondary as they are disease related, such as pain due to acute hemorrhage into a tumor, bone pain from a pathologic fracture, etc. Although some tumor-related pains have an acute onset (as after pathological fracture), most of these will persist unless effective treatment for the underlying lesion is provided. Generally, acute cancer pain syndromes are divided: (1) directly related to cancer, (2)

A clinical picture of directly related to various cancer syndromes depends on cancer's etiology, location, surrounding tissues involved, growing speed, and other factors. Cancer-diagnostic-related syndromes also have miscellaneous presentation and can be presented as: (a) headache after lumbar puncture, (b) prostate pain after biopsy, (c) breast pain after mammography; (d) pain after any other intervention, and some others. Acute pain associated with antineoplastic treatments can be presented as: (a) pain related to chemotherapy and (b) pain after radiotherapy [15]. Related to chemotherapy pain has various causes depending on an agent used, a method of inclusion into organism, etc. Most typical are intravenous infusion pain (due to venous spasm, chemical phlebitis, vesicant extravasation, and anthracyclineassociated flare), intraperitoneal chemotherapy pain (chemical serositis or infection), mucositis (due to cytotoxicity of cytarabine, doxorubicin, methotrexate, and others), painful peripheral neuropathy (toxicity associated with vinca alkaloids, cisplatinum, oxaliplatin, and paclitaxel), headache (after intrathecal methotrexate), myalgias/arthralgias interferon induced, and others. Pain after radiotherapy can be incident pain precipitated by transport and positioning of the patient for radiotherapy, or it can be caused by acute radiation toxicity. Most typical are: oropharyngeal mucositis, early-onset brachial plexopathy, subacute radiation myelopathy, radiation enteritis and proctitis, and others. Some more acute cancer pain syndromes can be

cancer diagnostics related, and (3) associated with antineoplastic treatments.

related to infection (herpes zoster) or venous thrombotic events.

Chronic cancer pain syndromes usually are directly related to the neoplasm itself

or to an antineoplastic therapy. The classification is presented in **Table 1** [16]. Bone metastases are the most common cause of chronic pain in cancer patients. Bone pain should be differentiated from non-neoplastic causes including osteoporotic fractures (such as associated with multiple myeloma), focal osteonecrosis (due to chemotherapy or corticosteroids, or radiotherapy), and osteomalacia. Vertebrae are the most common sites of bony metastases pain. Typical locations are atlantoaxial destruction and odontoid fracture, C7–T1 syndrome, and T12–L1 (thoracolumbar junction) syndrome. Epidural compression of the spinal cord or cauda equina is a common neurologic complication

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

mendations in practice guidelines to be based on expert consensus.

medication proportional to their pain intensity levels [4]. Data from Asia and North America revealed comparable prevalence rates, which imply that opioid availability alone is not an explanation for the high prevalence rates [3]. Even after implementation into clinical practice of rapid release opioids (ROOs), which provide faster relief than immediate-release preparations of other opioids, the prevalence of breakthrough pain is still 59% [5]. All these mean the importance of skilled use of opioid analgesics in the relief of cancer pain but also acknowledge the lack of evidence to support clinical practice and guidelines, which in turn causes recom-

In 1986, the World Health Organization (WHO) has published a document entitled "A Declaration of the Rights of Patients with Chronic Cancer." According to the WHO three-step analgesic ladder, in combination with appropriate dosage guidelines, pain relief should be adequate for 70–90% of patients. A systematic review on pain relief based on the WHO ladder, 20 years after its introduction, demonstrated adequate pain relief in 45–100% of patients [6, 7]. Among subjects of debates to improve the analgesic ladder the benefit of paracetamol (acetaminophen) with Step III opioids for which the evidence is "weak if any," as well as the use of adjuvant analgesics for which outcomes are generally modest [8]. On the other hand, not only drugs are a guarantee of success in the cancer pain. It is widely accepted that a biopsychosocial approach in assessment and management is needed for treatment of pain in patients with cancer. Cicely Saunders elaborated on the concept of "total pain," stating that pain is not purely a physical experience but involves various other components of human functioning including personality, mood, behavior, and social relations. A systematic review has identified an association between psychological distress, lack of social support,

Different barriers have been acknowledged in relation to adequate pain management in patients with cancer. One of the most important reasons is lack of knowledge regarding the assessment and management of cancer pain. Health professionals are cautious when prescribing opioids because of fear of adverse effects, tolerance, and addiction. Otherwise, patients struggle with misconceptions about analgesic use, concerns about pain communication, and a belief that pain is inevitable and uncontrollable [10]. All reasons for the lack of adequate pain control are varied: (a) personal—fear of drug addiction, (b) legal issues by issuing a higher dose of these medicines, (c) material—with regard to the price and quantity of medicinal products, (d) organizational—regular supply and storage of medicines, (e) psychological—the conviction of the patient or his family members that narcotic analgesics can be used only in the last stages of the illness, (f) causes of medical staff in the absence of sufficient knowledge of analgesia and the principles for its administration, and (g) poor adherence to pain medication and poor pain relief, which appear to be more country-specific

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain is always subjective [the International Association for the Study of Pain (IASP)]. Cancerinduced pain may be acute or chronic. Cancer-induced pain may be nociceptive or neuropathic or psychogenic, but often it is mixed because there are several causes causing it to occur. The main (basic) is constant pain of controlled intensity. A breakthrough pain occurs when a basic pain is controlled. Breakthrough pain is a

**90**

and cancer pain [9].

problems [11].

**2. Cancer pain syndromes**

temporary exacerbation with high intensity pain, which is felt in patients whose basic pain was adequately treated with opioids [12].

Cancer pain is not a single entity. It incorporates a range of etiological, pathophysiological, and anatomical subtypes, all requiring unique descriptive terminology, assessment techniques, and treatment modalities [13]. Among patients with cancer, there is substantial heterogeneity in how pain is experienced and in how it appears. In many cases, the constellation of symptoms and signs can suggest a specific cancer pain syndrome [14]. The identification of such a syndrome may help to elucidate the etiology of the pain, direct the diagnostic evaluation, clarify the prognosis for the pain or the disease itself, and guide therapeutic intervention.

#### **2.1 Acute pain syndromes**

Most acute cancer pain syndromes are primary as related to a diagnostic test or treatment. However, some are secondary as they are disease related, such as pain due to acute hemorrhage into a tumor, bone pain from a pathologic fracture, etc. Although some tumor-related pains have an acute onset (as after pathological fracture), most of these will persist unless effective treatment for the underlying lesion is provided. Generally, acute cancer pain syndromes are divided: (1) directly related to cancer, (2) cancer diagnostics related, and (3) associated with antineoplastic treatments.

A clinical picture of directly related to various cancer syndromes depends on cancer's etiology, location, surrounding tissues involved, growing speed, and other factors. Cancer-diagnostic-related syndromes also have miscellaneous presentation and can be presented as: (a) headache after lumbar puncture, (b) prostate pain after biopsy, (c) breast pain after mammography; (d) pain after any other intervention, and some others. Acute pain associated with antineoplastic treatments can be presented as: (a) pain related to chemotherapy and (b) pain after radiotherapy [15].

Related to chemotherapy pain has various causes depending on an agent used, a method of inclusion into organism, etc. Most typical are intravenous infusion pain (due to venous spasm, chemical phlebitis, vesicant extravasation, and anthracyclineassociated flare), intraperitoneal chemotherapy pain (chemical serositis or infection), mucositis (due to cytotoxicity of cytarabine, doxorubicin, methotrexate, and others), painful peripheral neuropathy (toxicity associated with vinca alkaloids, cisplatinum, oxaliplatin, and paclitaxel), headache (after intrathecal methotrexate), myalgias/arthralgias interferon induced, and others. Pain after radiotherapy can be incident pain precipitated by transport and positioning of the patient for radiotherapy, or it can be caused by acute radiation toxicity. Most typical are: oropharyngeal mucositis, early-onset brachial plexopathy, subacute radiation myelopathy, radiation enteritis and proctitis, and others. Some more acute cancer pain syndromes can be related to infection (herpes zoster) or venous thrombotic events.

#### **2.2 Chronic pain syndromes**

Chronic cancer pain syndromes usually are directly related to the neoplasm itself or to an antineoplastic therapy. The classification is presented in **Table 1** [16].

Bone metastases are the most common cause of chronic pain in cancer patients. Bone pain should be differentiated from non-neoplastic causes including osteoporotic fractures (such as associated with multiple myeloma), focal osteonecrosis (due to chemotherapy or corticosteroids, or radiotherapy), and osteomalacia. Vertebrae are the most common sites of bony metastases pain. Typical locations are atlantoaxial destruction and odontoid fracture, C7–T1 syndrome, and T12–L1 (thoracolumbar junction) syndrome. Epidural compression of the spinal cord or cauda equina is a common neurologic complication


#### **Table 1.**

*The classification of cancer chronic pain syndromes.*

of cancer. Breast, lung, and prostate cancers each account for 20–25% of events [17]. And back pain is the initial symptom in almost all patients with epidural compression. The pelvis and hip are also common sites of metastatic involvement. Lesions may involve any of the three anatomic regions of the pelvis (ischiopubic, iliosacral, or periacetabular), the hip joint itself, or the proximal femur [18]. Leptomeningeal metastases, which are characterized by diffuse or multifocal involvement of the subarachnoid space by metastatic tumor, occur in 1–8% in patients with systemic cancer [19]. The most common presenting symptoms are headache, cranial nerve palsies, and radicular pain in the low back and buttocks. Gadolinium-enhanced MRI imaging of the neuroaxis is the investigation of choice when leptomeningeal metastases are suspected. Base of skull metastases can be presented with various syndromes: orbital syndrome, parasellar syndrome, middle cranial fossa syndrome, jugular foramen syndrome, trigeminal neuralgia, and others. Neuropathic pains can be presented as painful radiculopathy, postherpetic neuralgia, malignant brachial plexopathy (lymphoma, beast, lung cancers). Brachial plexopathy also is typical for radiation-induced syndromes. Radiation changes in the skin and lymphoedema are commonly associated. Malignant lumbosacral plexopathy is most frequently associated with colorectal, cervical, breast cancers, sarcoma, and lymphoma [20]. Paraneoplastic painful peripheral neuropathy can be related to injury to the dorsal root ganglion (also known as subacute sensory neuronopathy or ganglionopathy) or injury to peripheral nerves [21]. Subacute sensory neuronopathy is usually associated with small cell carcinoma of the lung. Even in the absence

**93**

his family.

**3.1 Pain measurement scales**

pain, severe pain, and unbearable pain.

chosen smile with the expression of the patient's face.

*Cancer Pain*

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

**3. Cancer pain assessment**

of involvement of the chest wall or parietal pleura, lung tumors can produce a

Most treatment-related pains are caused by tissue-damaging procedures. Chronic-treatment-related pain syndromes are associated with either a persistent nociceptive complication of an invasive treatment (such as a postsurgical abscess), or more commonly, neural injury. Toxic peripheral neuropathy, avascular (aseptic) necrosis of femoral, or humeral head are among most common treatment-related chronic cancer pain syndromes. Breast surgery pain syndromes are very prevalent, too. Chronic neuropathic pain of variable severity is common for those patients, and severity of pain is correlated positively with the number of lymph nodes removed

Despite significant medical, pharmacological, and technological advances in the area of cancer pain assessment and management, up to 90% of patients with advanced cancer experience pain [23], which means careful pain assessment is essential for successful pain management. Cancer pain assessment is a complex undertaking. The evaluation begins with a thorough history of both the pain and the underlying malignancy as well as its treatment. A localization and intensity of pain have to be analyzed in detail, constantly indicating it in the diary. After initial treatment, the effect of treatment pain intensity is to be re-evaluated. Because of the potential impact of pain on quality of life, it is also essential to determine the adverse effects of pain on physical and psychosocial well-being, as well as the spiritual impact of the pain. Also, it is important to remember that cancer pain may linger after the cancer is removed (as examples, postmastectomy, postamputation, or postthoracotomy syndrome), and this may have important psychological and spiritual impact. Other factors that may influence the pain experience should be overestimated and discussed with the patient and

Current recommendations advise that pain severity should be assessed on an 11-point numerical rating scale (NRS) (0–10), with more comprehensive tools including the Brief Pain Inventory (BPI) and McGill Short Form Questionnaire reserved for occasions when more detailed assessment is required [24, 25]. Newer tools including the Alberta Breakthrough Pain Assessment Tool, specifically designed for breakthrough pain, also could be used in the clinical trial setting [26].

Numerical rating scale (NRS)—the intensity of pain is measured by asking the patient to select a number from 0 to 10 that describes the intensity of his pain: "0" means "no pain" and "10" means "unbearable pain." The numbers are arranged in one line. This method is easily understood by many patients, eliminates linguistic and cultural barriers between the investigator and patient, and is most often recommended for pain assessment. The lingual version of NRS can be easily adapted to ill patients who cannot write. In Verbal Rating Scale (VRS), patients are asked to choose the word best suited to describe their pain: no pain, mild pain, moderate

In Faces pain scale (FPS), five smileys are given, starting from a smiley face to the left (no pain) to a sad, and crying right ("unbearable pain") (**Figure 1**). The patient points out the smile that most reflects the pain. The researcher compares the

visceral pain syndrome, being unilateral or bilateral (less common).

[22] both with tumor location (upper outer quadrant of the breast).

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

Tumor-related visceral pain syndromes

Headache

**Table 1.**

**Chronic cancer pain syndromes Clinical presentation** Tumor-related somatic pain syndromes Multifocal bone pain

Tumor-related neuropathic pain Leptomeningeal metastases

Pain related to antineoplastic treatments Chemotherapy-related neuropathy

Postradiation pain syndromes Plexopathies

*The classification of cancer chronic pain syndromes.*

Postsurgical pain syndromes Pain and phantom sensation after amputation

Myelopathy GI tract disorders Lymphedema Osteonecrosis

Soft tissue pain

Cranial neuralgias Radiculopathies Plexopathies

Peripheral mononeuropathies Paraneoplastic syndromes

Bone complications and glucocorticoids Antiandrogens and gynecomastia

of cancer. Breast, lung, and prostate cancers each account for 20–25% of events [17]. And back pain is the initial symptom in almost all patients with epidural compression. The pelvis and hip are also common sites of metastatic involvement. Lesions may involve any of the three anatomic regions of the pelvis (ischiopubic, iliosacral, or periacetabular), the hip joint itself, or the proximal femur [18]. Leptomeningeal metastases, which are characterized by diffuse or multifocal involvement of the subarachnoid space by metastatic tumor, occur in 1–8% in patients with systemic cancer [19]. The most common presenting symptoms are headache, cranial nerve palsies, and radicular pain in the low back and buttocks. Gadolinium-enhanced MRI imaging of the neuroaxis is the investigation of choice when leptomeningeal metastases are suspected. Base of skull metastases can be presented with various syndromes: orbital syndrome, parasellar syndrome, middle cranial fossa syndrome, jugular foramen syndrome, trigeminal neuralgia, and others. Neuropathic pains can be presented as painful radiculopathy, postherpetic neuralgia, malignant brachial plexopathy (lymphoma, beast, lung cancers). Brachial plexopathy also is typical for radiation-induced syndromes. Radiation changes in the skin and lymphoedema are commonly associated. Malignant lumbosacral plexopathy is most frequently associated with colorectal, cervical, breast cancers, sarcoma, and lymphoma [20]. Paraneoplastic painful peripheral neuropathy can be related to injury to the dorsal root ganglion (also known as subacute sensory neuronopathy or ganglionopathy) or injury to peripheral nerves [21]. Subacute sensory neuronopathy is usually associated with small cell carcinoma of the lung. Even in the absence

**92**

of involvement of the chest wall or parietal pleura, lung tumors can produce a visceral pain syndrome, being unilateral or bilateral (less common).

Most treatment-related pains are caused by tissue-damaging procedures. Chronic-treatment-related pain syndromes are associated with either a persistent nociceptive complication of an invasive treatment (such as a postsurgical abscess), or more commonly, neural injury. Toxic peripheral neuropathy, avascular (aseptic) necrosis of femoral, or humeral head are among most common treatment-related chronic cancer pain syndromes. Breast surgery pain syndromes are very prevalent, too. Chronic neuropathic pain of variable severity is common for those patients, and severity of pain is correlated positively with the number of lymph nodes removed [22] both with tumor location (upper outer quadrant of the breast).

#### **3. Cancer pain assessment**

Despite significant medical, pharmacological, and technological advances in the area of cancer pain assessment and management, up to 90% of patients with advanced cancer experience pain [23], which means careful pain assessment is essential for successful pain management. Cancer pain assessment is a complex undertaking. The evaluation begins with a thorough history of both the pain and the underlying malignancy as well as its treatment. A localization and intensity of pain have to be analyzed in detail, constantly indicating it in the diary. After initial treatment, the effect of treatment pain intensity is to be re-evaluated. Because of the potential impact of pain on quality of life, it is also essential to determine the adverse effects of pain on physical and psychosocial well-being, as well as the spiritual impact of the pain. Also, it is important to remember that cancer pain may linger after the cancer is removed (as examples, postmastectomy, postamputation, or postthoracotomy syndrome), and this may have important psychological and spiritual impact. Other factors that may influence the pain experience should be overestimated and discussed with the patient and his family.

Current recommendations advise that pain severity should be assessed on an 11-point numerical rating scale (NRS) (0–10), with more comprehensive tools including the Brief Pain Inventory (BPI) and McGill Short Form Questionnaire reserved for occasions when more detailed assessment is required [24, 25]. Newer tools including the Alberta Breakthrough Pain Assessment Tool, specifically designed for breakthrough pain, also could be used in the clinical trial setting [26].

#### **3.1 Pain measurement scales**

Numerical rating scale (NRS)—the intensity of pain is measured by asking the patient to select a number from 0 to 10 that describes the intensity of his pain: "0" means "no pain" and "10" means "unbearable pain." The numbers are arranged in one line. This method is easily understood by many patients, eliminates linguistic and cultural barriers between the investigator and patient, and is most often recommended for pain assessment. The lingual version of NRS can be easily adapted to ill patients who cannot write. In Verbal Rating Scale (VRS), patients are asked to choose the word best suited to describe their pain: no pain, mild pain, moderate pain, severe pain, and unbearable pain.

In Faces pain scale (FPS), five smileys are given, starting from a smiley face to the left (no pain) to a sad, and crying right ("unbearable pain") (**Figure 1**). The patient points out the smile that most reflects the pain. The researcher compares the chosen smile with the expression of the patient's face.

#### *From Conventional to Innovative Approaches for Pain Treatment*

**Figure 1.**

These three pain scales (NRS, VRS, and FPS) are useful clinical tools to assess pain intensity if they are integrated in **Table 1**, which allows a comparative assessment of the patient's pain intensity [27].

In Visual analogue scale (VAS), patients are asked to pinpoint their pain in the 10 cm section (in the straight line) as accurately as possible. The end of the left line indicates "no pain" and the right is "unbearable pain." The method is widely used in scientific research, but not all patient groups are easy to understand.

Inferred pathophysiology or types of cancer pain (nociceptive/neuropathic) are also core in diagnostics, that is why neurological somatosensory examination using specific sensory stimuli tools (von Frey filament, brush, pin prick, hot/cold water tubes, tuning fork) is essential.

In diagnosing a breakthrough in cancer pain, first is necessary to ask the patient to describe his/her baseline pain over 24 hours, including description of location, intensity, quality, and other features. If continuous pain has fluctuations and breakthrough pain suspected, it is necessary to ask the patient how many different types of breakthrough pains the patient experiences in a 24 hour period following pain variables: location, provocation, quality, etiology, etc. Finally, asking the patient about three most bothersome breakthrough pains allows us to determine what is a breakthrough pain really wearying the patient. Breakthrough pain intensity should be rated by NPS and filled in the pain diary. It also have to be investigated in detail including such characteristics as localization, number of episodes, possible irritant, beginning of pain outbreak, strength, quality, distribution, effectiveness of the medication used. It is also important to evaluate other symptoms of the patient's pain breakthrough: psychological stress, spiritual suffering, craving for chemicals and medications, and cognitive function.

To conclude the evaluation of cancer pain, it is necessary to agree with the patient what the aim of the intended treatment is, what is the analgesia (score from…to), and what pain intensity is tolerated.

#### **3.2 Challenges in cancer pain assessment**

There are a number of significant challenges associated with the precise assessment of a cancer patients' pain [28]. They include: (1) multiple cancer pain mechanisms, patients often have multiple coexiting pain disorders even in the one cancer as the example of breast cancer, pain can be caused by surgical outcome, tumor spread, chemotherapy and bony metastases to the spine, (2) lack of a universal cancer pain classification system, (3) lack of objective testing modalities, (4) time constraints of staff that failing in continuous reassessment of pain as this is a vital sign to be fully controlled, and (5) individual differences in cancer pain sensitivity.

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*Cancer Pain*

including cancer [29].

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

**4. Cancer pain treatment principles**

therapy, and (g) complementary.

provider agreements or contracts.

suppositories, transdermal patches, or injections.

The National Cancer Institute (NIH, USA) has funded a Patient Reported Outcome Measurement System (PROMIS). This aims to develop a widely available set of standardized instruments to measure subjective outcomes in illnesses,

Adequate pain relief can be achieved in 70–90% of patients when well-accepted

Methods of pain control in cancer pain can be divided into: (a) pharmacological,

(b) oncological, (c) surgical, (d) interventional, (e) psychological, (f) physio-

The WHO analgesic ladder provides a structured starting point for the pharmacological treatment of the patient with cancer pain. It is not without controversy, however, some authors questioning the need to start all patients with severe pain on the bottom rung (i.e., managing with paracetamol alone rather than proceeding directly to stronger drugs). Some also have suggested that the second step (weak opioids) should be omitted in favor of low-dose strong opioids for the sake of both clinical effectiveness and simplicity [31]. For mild to moderate cancer pain, simple analgesic medications such as paracetamol or nonsteroidal anti-inflammatory medications (e.g., ibuprofen or aspirin) can usually provide effective pain relief. Nevertheless, opioid analgesics are mainstream in treating the cancer pain as in most cases it is severe or even unbearable [32]. Some important rules must be followed before starting with the prescription with opioids. Careful assessment of the pain and its effect on function, and of the possible risks associated with use of an opioid, are the first step. When opioids are considered, providers should assess every patient for risk factors for addiction. Providers should also employ strategies to reduce the risk of misuse for all patients who are taking opioids. These strategies may include urine testing, checking state prescription drug monitoring programs to evaluate a person's history of filling prescriptions for controlled substances, doing pill counts, and using patient-

Long-acting opioids may be administered orally or can be given in the form of a transdermal patch. Long-acting opioids are usually started at an initial low dose and titrated upward every 2–3 days for oral formulations and 5–6 days for patches. Short-acting opioid preparations may be used to treat breakthrough pain. One-sixth of the daily opioid requirement is commonly prescribed, and is often a useful starting point. Well-documented side-effects of opioid therapy include sedation, constipation, confusion, nausea and vomiting, pruritus, urinary retention, and occasionally, respiratory depression is necessary. Chronic administration

Medications are mainstream in the treatment of cancer pain and taken on a regular basis to provide pain relief. They are mostly given by oral administration as this increases ease of use and is usually the most cost-effective solution. Other forms of pain relief medication may be required in some cases, including rectal

treatment guidelines for cancer pain are followed (World Health Organization [30]). Therefore, pain management techniques should be implemented as early as possible to prevent the development of persistent pain, which can lead to a significant reduction in quality of life. Unfortunately, the availability of effective therapy and updated guidelines from reliable leading societies has not eliminated the problem of undertreatment of cancer pain [3]. The causes of undertreatment are multifactorial and reflect the combined effects of clinician-, patient-, and systemrelated barriers as been provided in this chapter previously (p.2, Introduction).

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

ment of the patient's pain intensity [27].

**Figure 1.**

tubes, tuning fork) is essential.

and cognitive function.

from…to), and what pain intensity is tolerated.

**3.2 Challenges in cancer pain assessment**

These three pain scales (NRS, VRS, and FPS) are useful clinical tools to assess pain intensity if they are integrated in **Table 1**, which allows a comparative assess-

*Lithuanian pain scales (Decree of the Lithuanian MOH V-608, 26-08-2004 [27], English version).*

In Visual analogue scale (VAS), patients are asked to pinpoint their pain in the 10 cm section (in the straight line) as accurately as possible. The end of the left line indicates "no pain" and the right is "unbearable pain." The method is widely used in

Inferred pathophysiology or types of cancer pain (nociceptive/neuropathic) are also core in diagnostics, that is why neurological somatosensory examination using specific sensory stimuli tools (von Frey filament, brush, pin prick, hot/cold water

In diagnosing a breakthrough in cancer pain, first is necessary to ask the patient to describe his/her baseline pain over 24 hours, including description of location, intensity, quality, and other features. If continuous pain has fluctuations and breakthrough pain suspected, it is necessary to ask the patient how many different types of breakthrough pains the patient experiences in a 24 hour period following pain variables: location, provocation, quality, etiology, etc. Finally, asking the patient about three most bothersome breakthrough pains allows us to determine what is a breakthrough pain really wearying the patient. Breakthrough pain intensity should be rated by NPS and filled in the pain diary. It also have to be investigated in detail including such characteristics as localization, number of episodes, possible irritant, beginning of pain outbreak, strength, quality, distribution, effectiveness of the medication used. It is also important to evaluate other symptoms of the patient's pain breakthrough: psychological stress, spiritual suffering, craving for chemicals and medications,

To conclude the evaluation of cancer pain, it is necessary to agree with the patient what the aim of the intended treatment is, what is the analgesia (score

There are a number of significant challenges associated with the precise assessment of a cancer patients' pain [28]. They include: (1) multiple cancer pain mechanisms, patients often have multiple coexiting pain disorders even in the one cancer as the example of breast cancer, pain can be caused by surgical outcome, tumor spread, chemotherapy and bony metastases to the spine, (2) lack of a universal cancer pain classification system, (3) lack of objective testing modalities, (4) time constraints of staff that failing in continuous reassessment of pain as this is a vital sign to be fully controlled, and (5) individual differences in cancer pain sensitivity.

scientific research, but not all patient groups are easy to understand.

**94**

The National Cancer Institute (NIH, USA) has funded a Patient Reported Outcome Measurement System (PROMIS). This aims to develop a widely available set of standardized instruments to measure subjective outcomes in illnesses, including cancer [29].

#### **4. Cancer pain treatment principles**

Adequate pain relief can be achieved in 70–90% of patients when well-accepted treatment guidelines for cancer pain are followed (World Health Organization [30]). Therefore, pain management techniques should be implemented as early as possible to prevent the development of persistent pain, which can lead to a significant reduction in quality of life. Unfortunately, the availability of effective therapy and updated guidelines from reliable leading societies has not eliminated the problem of undertreatment of cancer pain [3]. The causes of undertreatment are multifactorial and reflect the combined effects of clinician-, patient-, and systemrelated barriers as been provided in this chapter previously (p.2, Introduction).

Methods of pain control in cancer pain can be divided into: (a) pharmacological, (b) oncological, (c) surgical, (d) interventional, (e) psychological, (f) physiotherapy, and (g) complementary.

Medications are mainstream in the treatment of cancer pain and taken on a regular basis to provide pain relief. They are mostly given by oral administration as this increases ease of use and is usually the most cost-effective solution. Other forms of pain relief medication may be required in some cases, including rectal suppositories, transdermal patches, or injections.

The WHO analgesic ladder provides a structured starting point for the pharmacological treatment of the patient with cancer pain. It is not without controversy, however, some authors questioning the need to start all patients with severe pain on the bottom rung (i.e., managing with paracetamol alone rather than proceeding directly to stronger drugs). Some also have suggested that the second step (weak opioids) should be omitted in favor of low-dose strong opioids for the sake of both clinical effectiveness and simplicity [31]. For mild to moderate cancer pain, simple analgesic medications such as paracetamol or nonsteroidal anti-inflammatory medications (e.g., ibuprofen or aspirin) can usually provide effective pain relief. Nevertheless, opioid analgesics are mainstream in treating the cancer pain as in most cases it is severe or even unbearable [32]. Some important rules must be followed before starting with the prescription with opioids. Careful assessment of the pain and its effect on function, and of the possible risks associated with use of an opioid, are the first step. When opioids are considered, providers should assess every patient for risk factors for addiction. Providers should also employ strategies to reduce the risk of misuse for all patients who are taking opioids. These strategies may include urine testing, checking state prescription drug monitoring programs to evaluate a person's history of filling prescriptions for controlled substances, doing pill counts, and using patientprovider agreements or contracts.

Long-acting opioids may be administered orally or can be given in the form of a transdermal patch. Long-acting opioids are usually started at an initial low dose and titrated upward every 2–3 days for oral formulations and 5–6 days for patches. Short-acting opioid preparations may be used to treat breakthrough pain. One-sixth of the daily opioid requirement is commonly prescribed, and is often a useful starting point. Well-documented side-effects of opioid therapy include sedation, constipation, confusion, nausea and vomiting, pruritus, urinary retention, and occasionally, respiratory depression is necessary. Chronic administration may lead to problems such as tolerance, physical dependence, and addiction. It must be noticed that by case, opioids may worsen pain—a phenomenon known as opioid-induced hyperalgesia. Management principles of side effects include: (a) opioid reduction or cessation, (b) opioid rotation, where one therapeutic opioid is substituted for an equivalent dose of another, (c) symptomatic treatment, and (d) administration of a specific antagonist.

Another group of pharmaceuticals used for the treatment of cancer pain is adjuvants (**Table 1**). Common adjuvants are antidepressants, anticonvulsant, biphosphonates, and others [33]. An adjustment of adjuvants to the treatment plan of cancer pain is typical if the pain has a neuropathic element or is wholly neuropathic. In such cases, antidepressants and anticonvulsants may be more effective in providing balanced analgesia and better tolerance than the high doses of opioids. Bisphosphonates are helpful in reducing the severity of bone pain secondary to both osteoporotic vertebral collapse and metastatic deposit. They are incorporated into the structure of mineralized bone as pyrophosphate analogues, to be then taken up by active osteoclasts, which are then inhibited. High-dose steroids can be given to reduce inflammation and edema associated with tumor growth, and to partially mitigate local mass effect. Capsular distension of intra-abdominal visceral can be very painful, and steroids may be helpful in this situation. They are also used for the immediate management of metastatic spinal cord compression and in the palliation of intracerebral lesions.

Chemotherapy, radiotherapy, endocrinotherapy, and immunotherapy are oncological methods used for cancer pain relief. Chemosensitive tumors include small-cell lung carcinoma, myeloma, colorectal, and breast cancers. These drugs are designed to target rapidly dividing cells, but can lead to the well-known side-effects of hair loss, mucositis, and diarrhea. Also, many chemotherapeutic agents are neurotoxic and cause varying degrees of temporary and permanent nerve damage, resulting in peripheral neuropathy.

Radiotherapy is particularly useful in the treatment of bony metastases and nonoperable pathological fractures, but may be used in various other contexts where the tumor type is known to be radiosensitive. Several types of radiotherapy exist: (a) localized external beam radiotherapy, (b) wide-field external beam radiotherapy, (c) brachytherapy, and (d) radioisotope treatment. Certain types of tumor may be dependent on circulating hormones to affect growth, and therefore susceptible to manipulation of the endocrine system, for example, prostate cancer. The use of immunotherapy in cancer treatment has shown to improve survival even in some advanced cancers, such as breast tumor.

Surgery can be undertaken with curative or palliative intent. If a cancerous tumor is responsible for causing the pain, techniques to reduce the size or obstruction of the tumor offer the greatest benefit. This may involve surgical removal of the tumor or shrinking of the tumor with radiation therapy. Neurosurgery to cut or block the nerves involved in the pain pathways can also help to reduce severe neuropathic pain. Bone fixation may be necessary to palliate a pathological fracture or decompress the spinal cord.

The aim of interventional cancer pain management is to interrupt nociceptive transmission at one or more points between periphery and cortex to achieve adequate analgesia. This can be achieved via reversible, nondestructive techniques for diagnostic purposes and short-term analgesia, or offer a longer-lasting solution via the physical or chemical destruction of the nervous tissue.

The diagnosis of a life-threatening illness has a huge psychological impact on patients and their families. Grief reactions, anxiety, and depression are particularly problematic at nodal points in the cancer pathway: at diagnosis, starting treatment, recurrence, failure of treatment, and facing the prospect of dying. Such

**97**

*Cancer Pain*

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

psychological states exacerbate, and also are exacerbated by, uncontrolled pain, and addressing them is often of paramount importance in beginning to manage pain and improve the quality of life. Multidisciplinary input, with the use of evidencebased interventions such as cognitive behavioral therapy, distraction and relaxation techniques, graded exercise, and goal setting can be delivered with the involvement

There are some complimentary medicinal techniques that can be used as additional complex in the treatment of cancer pain. These include: (a) acupuncture, which can help to relieve pain through the manipulation of pressure points in the body, (b) biofeedback is a technique that promotes awareness of bodily processes such as heart rate and blood pressure to influence the severity of the pain, (c) distraction techniques such as music therapy can be useful to shift attention away from the pain to a more pleasant stimulus, (d) hot or cold packs can be helpful to regulate pain and provide relief, (e) hypnosis can be used to manage pain by focusing the patient's consciousness to process pain information more effectively, and (f) relaxation exercises can be used to refocus the attention of the patient on a

In general, an effective strategy for cancer pain management is predicated on

• A detailed assessment of the pain should be performed initially; careful reassessment is indicated whenever a change occurs. The initial assessment of the patient with cancer pain always includes a history and examination, and often requires imaging or laboratory tests. The approach may be conceptualized as collecting data are sufficient to characterize key elements of the pain (a specific pain syndrome, the inferred pathophysiology, the etiology of

• The second principle recognizes that pain may be addressed by diseasemodifying antineoplastic therapy and other interventions directed against the etiology of the pain. Treatments that address the underlying etiology of pain, such as radiation therapy, surgery, or in some cases, chemotherapy can be integrated into a broader plan of care for symptom control. Treatment of cancer-related pain usually requires close consultation with an oncology specialist, who can provide the necessary information about the availability

• Whether or not primary disease-modifying therapy is possible, a large proportion of patients with pain due to active cancer require symptomatic treatment. Beginning in the early 1980s, a worldwide consensus has evolved that considers opioid-based pharmacotherapy as the mainstay approach for the symptomatic treatment of cancer patients with active disease and pain that is moderate

to severe. This conclusion was originally codified in the World Health Organization's (WHO) "analgesic ladder" approach, which was originally published in the mid-1980s and has had a global influence on clinical practice

In 1986, the World Health Organization (WHO) declared cancer pain manage-

and policies pertaining to medication availability.

ment algorithm, so called three-step analgesic ladder (**Figure 2**) [35].

**5. WHO analgesic ladder in twenty-first century**

of psychologists, physiotherapists, and occupational therapists.

specific task, such as breathing, to lessen the pain.

several broad principles [34]:

pain, etc.).

of antineoplastic therapy.

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

administration of a specific antagonist.

resulting in peripheral neuropathy.

or decompress the spinal cord.

in some advanced cancers, such as breast tumor.

may lead to problems such as tolerance, physical dependence, and addiction. It must be noticed that by case, opioids may worsen pain—a phenomenon known as opioid-induced hyperalgesia. Management principles of side effects include: (a) opioid reduction or cessation, (b) opioid rotation, where one therapeutic opioid is substituted for an equivalent dose of another, (c) symptomatic treatment, and (d)

Another group of pharmaceuticals used for the treatment of cancer pain is adjuvants (**Table 1**). Common adjuvants are antidepressants, anticonvulsant, biphosphonates, and others [33]. An adjustment of adjuvants to the treatment plan of cancer pain is typical if the pain has a neuropathic element or is wholly neuropathic. In such cases, antidepressants and anticonvulsants may be more effective in providing balanced analgesia and better tolerance than the high doses of opioids. Bisphosphonates are helpful in reducing the severity of bone pain secondary to both osteoporotic vertebral collapse and metastatic deposit. They are incorporated into the structure of mineralized bone as pyrophosphate analogues, to be then taken up by active osteoclasts, which are then inhibited. High-dose steroids can be given to reduce inflammation and edema associated with tumor growth, and to partially mitigate local mass effect. Capsular distension of intra-abdominal visceral can be very painful, and steroids may be helpful in this situation. They are also used for the immediate management of metastatic

spinal cord compression and in the palliation of intracerebral lesions.

Chemotherapy, radiotherapy, endocrinotherapy, and immunotherapy are oncological methods used for cancer pain relief. Chemosensitive tumors include small-cell lung carcinoma, myeloma, colorectal, and breast cancers. These drugs are designed to target rapidly dividing cells, but can lead to the well-known side-effects of hair loss, mucositis, and diarrhea. Also, many chemotherapeutic agents are neurotoxic and cause varying degrees of temporary and permanent nerve damage,

Radiotherapy is particularly useful in the treatment of bony metastases and nonoperable pathological fractures, but may be used in various other contexts where the tumor type is known to be radiosensitive. Several types of radiotherapy exist: (a) localized external beam radiotherapy, (b) wide-field external beam radiotherapy, (c) brachytherapy, and (d) radioisotope treatment. Certain types of tumor may be dependent on circulating hormones to affect growth, and therefore susceptible to manipulation of the endocrine system, for example, prostate cancer. The use of immunotherapy in cancer treatment has shown to improve survival even

Surgery can be undertaken with curative or palliative intent. If a cancerous tumor is responsible for causing the pain, techniques to reduce the size or obstruction of the tumor offer the greatest benefit. This may involve surgical removal of the tumor or shrinking of the tumor with radiation therapy. Neurosurgery to cut or block the nerves involved in the pain pathways can also help to reduce severe neuropathic pain. Bone fixation may be necessary to palliate a pathological fracture

The aim of interventional cancer pain management is to interrupt nociceptive transmission at one or more points between periphery and cortex to achieve adequate analgesia. This can be achieved via reversible, nondestructive techniques for diagnostic purposes and short-term analgesia, or offer a longer-lasting solution

The diagnosis of a life-threatening illness has a huge psychological impact on patients and their families. Grief reactions, anxiety, and depression are particularly problematic at nodal points in the cancer pathway: at diagnosis, starting treatment, recurrence, failure of treatment, and facing the prospect of dying. Such

via the physical or chemical destruction of the nervous tissue.

**96**

psychological states exacerbate, and also are exacerbated by, uncontrolled pain, and addressing them is often of paramount importance in beginning to manage pain and improve the quality of life. Multidisciplinary input, with the use of evidencebased interventions such as cognitive behavioral therapy, distraction and relaxation techniques, graded exercise, and goal setting can be delivered with the involvement of psychologists, physiotherapists, and occupational therapists.

There are some complimentary medicinal techniques that can be used as additional complex in the treatment of cancer pain. These include: (a) acupuncture, which can help to relieve pain through the manipulation of pressure points in the body, (b) biofeedback is a technique that promotes awareness of bodily processes such as heart rate and blood pressure to influence the severity of the pain, (c) distraction techniques such as music therapy can be useful to shift attention away from the pain to a more pleasant stimulus, (d) hot or cold packs can be helpful to regulate pain and provide relief, (e) hypnosis can be used to manage pain by focusing the patient's consciousness to process pain information more effectively, and (f) relaxation exercises can be used to refocus the attention of the patient on a specific task, such as breathing, to lessen the pain.

In general, an effective strategy for cancer pain management is predicated on several broad principles [34]:


#### **5. WHO analgesic ladder in twenty-first century**

In 1986, the World Health Organization (WHO) declared cancer pain management algorithm, so called three-step analgesic ladder (**Figure 2**) [35].

#### **Figure 2.**

*Cancer pain management—three step WHO analgesic "ladder" [35].*

**Figure 3.**

*Modified WHO ladder approach for cancer pain (Fine P G, 2005).*

I step: main medication—aspirin, acetaminophen, and nonsteroidal antiinflammatory drugs (NSAIDs) are used for the treatment of mild pain (score 1–3 in NAS). Nonopioids can be used as adjuvants in II and III steps analgesia.

II step: medication—weak opioids: codeine, dihydrocodeine, and tramadol are used for moderate intensity pain relief (4–6 by NAS). The upper tramadol daily (ceiling) dose is 400 mg. If oral or parental route of administration is not possible, for moderate pain treatment, one can use strong opioids in low doses, e.g., transdermal fentanyl patches.

III step: medication—strong opioids: morphine, fentanyl, methadone, and others are used for severe and intolerable cancer pain (NAS-7-10) relief [36].

Adjuvants may be administered in all steps together with main analgesics. They enhance pain relief and decrease or prevent opioids side effects. In 2000, algorithm was revised in decreasing limitations of opioid use, enabling to start treatment with

**99**

*Cancer Pain*

**6. Pharmaceuticals**

breakthrough pain relief.

decrease in analgesic effect;

opioid to another and adapting the dosage).

The use of opioid analgesics may induce [39]:

**6.1 Analgesics**

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

opioids for refractory pain (see **Figure 3**).

opioids and nonopioids and (2) adjuvants.

strong opioids if patient is suffering from severe cancer pain. Other modifications of WHO three-step analgesic ladder were later applied (2005), introducing spinal

There are two groups of medication for cancer pain management: (1) analgesics:

Opioid analgesics are: (a) weak: tramadol, codeine (and dihydrocodeine) and (b) strong: morphine, fentanyl, methadone, buprenorphine, pethidine [37]. The route of administration are as follows: (a) noninvasive (oral, rectal, transdermal, nasal, sublingual), (b) invasive-parenteral (intramuscular, intravenous, subcutaneous, etc.), including long acting devices such as "morphine pumps "with subcutaneous or epidural catheters and PCA-patient-controlled analgesia option, allowing patient to determine and regulate the needed day and night doses of opioids. The day dose is determined by giving short-acting (immediate release) opioids, such as morphine hydrochloride 1% or morphine sulfate, 1–2% solution injections or tablets (e.g., 10 mg every 4 hours), day dose correction is made after 24–48 hours. After the needed day dosage is achieved (after 3–4 days), we switch to long-acting (slow release) (12–24 hours) morphine medication—tablets, suspension, suppositories, or fentanyl patches (72 hours) [38]. If morphine was administered parenterally, the needed daily oral or rectal dose of morphine should be three times bigger than the injected one earlier. Short-acting (immediate release) opioids should be used for

(a) tolerance—a state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drugs' effects over time, which is while using opioid, one has to increase its dose after some time due to the

(b) physiologic dependence—a state of adaptation that is manifested by a drugclass-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration

of an antagonist. It can be avoided by gradual opioid dose reduction;

(c) psychologic dependence (addiction)—a primary chronic, neurobiologic

disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behavior that includes one or more of the following: impaired control over drug use, compulsive use, and continued use despite harm and craving (AAPM, APS, ASAM, 2001).

Adverse effects of opioids: constipation, nausea/vomiting, respiratory depression, urinary retention, pruritus, sedation, and more rarely, neurotoxic disordershallucinations, seizures, delirium, hyperalgesia. To evade or decrease these effects, one uses adjuvants (laxatives, antiemetics) or opioid rotation (changing one strong strong opioids if patient is suffering from severe cancer pain. Other modifications of WHO three-step analgesic ladder were later applied (2005), introducing spinal opioids for refractory pain (see **Figure 3**).

### **6. Pharmaceuticals**

There are two groups of medication for cancer pain management: (1) analgesics: opioids and nonopioids and (2) adjuvants.

#### **6.1 Analgesics**

*From Conventional to Innovative Approaches for Pain Treatment*

**98**

**Figure 3.**

**Figure 2.**

*Modified WHO ladder approach for cancer pain (Fine P G, 2005).*

*Cancer pain management—three step WHO analgesic "ladder" [35].*

transdermal fentanyl patches.

I step: main medication—aspirin, acetaminophen, and nonsteroidal antiinflammatory drugs (NSAIDs) are used for the treatment of mild pain (score 1–3 in

II step: medication—weak opioids: codeine, dihydrocodeine, and tramadol are used for moderate intensity pain relief (4–6 by NAS). The upper tramadol daily (ceiling) dose is 400 mg. If oral or parental route of administration is not possible, for moderate pain treatment, one can use strong opioids in low doses, e.g.,

III step: medication—strong opioids: morphine, fentanyl, methadone, and oth-

Adjuvants may be administered in all steps together with main analgesics. They enhance pain relief and decrease or prevent opioids side effects. In 2000, algorithm was revised in decreasing limitations of opioid use, enabling to start treatment with

NAS). Nonopioids can be used as adjuvants in II and III steps analgesia.

ers are used for severe and intolerable cancer pain (NAS-7-10) relief [36].

Opioid analgesics are: (a) weak: tramadol, codeine (and dihydrocodeine) and (b) strong: morphine, fentanyl, methadone, buprenorphine, pethidine [37]. The route of administration are as follows: (a) noninvasive (oral, rectal, transdermal, nasal, sublingual), (b) invasive-parenteral (intramuscular, intravenous, subcutaneous, etc.), including long acting devices such as "morphine pumps "with subcutaneous or epidural catheters and PCA-patient-controlled analgesia option, allowing patient to determine and regulate the needed day and night doses of opioids. The day dose is determined by giving short-acting (immediate release) opioids, such as morphine hydrochloride 1% or morphine sulfate, 1–2% solution injections or tablets (e.g., 10 mg every 4 hours), day dose correction is made after 24–48 hours. After the needed day dosage is achieved (after 3–4 days), we switch to long-acting (slow release) (12–24 hours) morphine medication—tablets, suspension, suppositories, or fentanyl patches (72 hours) [38]. If morphine was administered parenterally, the needed daily oral or rectal dose of morphine should be three times bigger than the injected one earlier. Short-acting (immediate release) opioids should be used for breakthrough pain relief.

The use of opioid analgesics may induce [39]:


Adverse effects of opioids: constipation, nausea/vomiting, respiratory depression, urinary retention, pruritus, sedation, and more rarely, neurotoxic disordershallucinations, seizures, delirium, hyperalgesia. To evade or decrease these effects, one uses adjuvants (laxatives, antiemetics) or opioid rotation (changing one strong opioid to another and adapting the dosage).

#### *From Conventional to Innovative Approaches for Pain Treatment*


*\*Methadone/morphine, if morphine day dose: (a) >30 mg 1:4, (b) >100 mg 1:8, and (c) >300 mg 12:1. \*\*Fentanyl/morphine, if morphine day dose: (a) 30 mg—12 mcg/hours, (b) 60 mg—25 mcg/hours, (c) 90 mg—37 mcg/hours, (d) 120 mg—50 mcg/hours, etc.*

#### **Table 2.**

*Opioid equianalgesic day doses.*

#### **6.2 Opioid rotation**

Opioid rotation is a change of one opioid drug to another due to acquired tolerance or unmanageable side effects. These are the rules of opioid rotation:


Opioid rotation is applied according to opioids equianalgesic doses table, thus changing the daily dose of the new drug [40].

In the event of opioid overdose antagonist, naloxone is applied.

The adequate pain control is achieved gradually, by dose titration and administration of various treatment options. Preliminary period of time to achieve:


**101**

haloperidol.

*Cancer Pain*

**6.3 Adjuvant drugs**

purpura, etc.

and myorelaxants (baclofen).

somnolence and hypotension.

ataxia, dizziness, disorientation) occur.

tremor, dyspepsia (better use while eating).

both—nociceptive and neuropathic—together).

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

increased but the adverse effects are progressing.

Nonopioids: aspirin, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs). They are effective in treating mild pain (score 1–3 by number analogue pain intensity scale (NAS)), due to bone metastases, soft tissue or muscular irritation, and damage. They are treating inflammation and decreasing fever and pain. NSAIDs are COX-1 and COX-2 also COX-3 inhibitors. They can be quite toxic to the GI tract (dyspepsia, erosions, ulcers, bleeding, constipation), slowing thrombocytes aggregation, impairing renal and liver function, enhancing hypervolemia, provoking rashes, headaches, dizziness, and allergic reactions. These drugs have their upper dose limit so-called "ceiling effect" when the analgesic effect cannot be

Glucocorticoids ( dexamethasone, prednisolone, hydrocortisone)—indications: increased intracranial pressure, spinal cord compression, nerve compression or infiltration, bone metastases, extended liver capsule, soft tissue cancer infiltration (head and neck, abdominal, and pelvic tumors). Contraindications: no absolute contraindications, dose is limited by adverse effects, and being cautious with peptic ulcers, diabetes, cardiovascular dysfunction, and endemic situations. Adverse effects: Cushing syndrome, gastric ulcers, erosions, bleeding, increased appetite, weight, hyperglycemia, diabetes complications, muscle wasting, euphoria, dysphoria, emotional lability, depression, steroidal psychosis, edemas, hypertension, thrombosis, myopathies, decreased immunity to infections, potassium blood levels, liquid detention in the body, insomnia, skin

Drugs for neuropathic pain: antidepressants, anticonvulsants, local anesthetics,

Antidepressants—not always effective for neuropathic pain treatment and is better to prescribe tricyclic antidepressants (TCAs). Start with amitriptyline — 10–25 mg dose in the evening and then increase to 50–100 mg/day. If no effective pain relief is achieved, it is discontinued after 1 week of use. Adverse effects:

Anticonvulsants—for neuropathic pain—gabapentin, carbamazepine, and clonazepam. The starting dose is the same as treating epilepsy. Increase until pain relief is achieved, or unmanageable adverse effects (nausea, vomiting, somnolence,

Local anesthetics (lidocaine, mexiletine)—for neuropathic pain systemic treatment when other options are not working. Adverse effects: somnolence, nausea,

NMDA receptors antagonists (ketamine)—for persistent neuropathic pain and other chronic pain when opioids are not tolerated. Routes of administration of ketamine: oral, intravenous, starting with 100 mg/day, and titration till 500 mg/ day. Adverse effects: psychomimetic can be reversed by benzodiazepines and

According to medical literature, about 20% of women have neuropathic pain after mastectomy and about 1/3 of cancer patients suffer from neuropathic pain (or

Bisphosphonates (pamidronate, zoledronic acid)—decrease bone resorption, effective in treating cancer hypercalcemia, decrease bone pain and occurrence of pathologic bone fractures for the patients with bone metastases, inhibit activity of

Radionuclides—Stroncium 89 systemic administration effectively relieves pain due to bone metastases, better works for osteoblastic metastases, and helps about

osteoclasts, and are useful with ineffective radiotherapy and analgesics.

• for patients experiencing anxiety and depression—3–4 weeks.

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

Nonopioids: aspirin, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs). They are effective in treating mild pain (score 1–3 by number analogue pain intensity scale (NAS)), due to bone metastases, soft tissue or muscular irritation, and damage. They are treating inflammation and decreasing fever and pain. NSAIDs are COX-1 and COX-2 also COX-3 inhibitors. They can be quite toxic to the GI tract (dyspepsia, erosions, ulcers, bleeding, constipation), slowing thrombocytes aggregation, impairing renal and liver function, enhancing hypervolemia, provoking rashes, headaches, dizziness, and allergic reactions. These drugs have their upper dose limit so-called "ceiling effect" when the analgesic effect cannot be increased but the adverse effects are progressing.

#### **6.3 Adjuvant drugs**

*From Conventional to Innovative Approaches for Pain Treatment*

Opioid rotation is a change of one opioid drug to another due to acquired toler-

*\*\*Fentanyl/morphine, if morphine day dose: (a) 30 mg—12 mcg/hours, (b) 60 mg—25 mcg/hours, (c) 90 mg—37* 

**Medication Route of administration Equivalent of 10 mg morphine dose**

Codeine Oral 100 mg Tramadol Oral/parenteral 50–100 mg/25–50 mg Oxycodone Oral/parenteral 5–7.5 mg/3.33–5 mg Pethidine Parenteral 25 mg Methadone Oral 5 mg\* Fentanyl Patch 0.067 mg\*\* Morphine Parenteral 3.33–5 mg *\*Methadone/morphine, if morphine day dose: (a) >30 mg 1:4, (b) >100 mg 1:8, and (c) >300 mg 12:1.*

• adaptation of the day dosage for the newly prescribed opioid (in 24 hours period);

• decrease the determined dose of newly applied opioid by 25–50% to avoid cross-

• if after applying new opioid, the pain relief is not enough and its dose is increased

ance or unmanageable side effects. These are the rules of opioid rotation:

• additional clinical assessment of pain and its diagnostics;

• determine the equianalgesic dose of the new opioid (**Table 2**);

tolerance of both drugs and possible inadequacy of the dosage;

In the event of opioid overdose antagonist, naloxone is applied.

tration of various treatment options. Preliminary period of time to achieve:

• no pain while not in movement (seated or lying in bed)—3–5 days;

• for patients experiencing anxiety and depression—3–4 weeks.

• evaluate side effects and drugs' effectivity; and

• pain re-assessment for every 2–3 days.

changing the daily dose of the new drug [40].

• no awakening at night due to pain—2–3 days;

• titrate new drugs' dose for 24 hours until good pain control is achieved;

Opioid rotation is applied according to opioids equianalgesic doses table, thus

The adequate pain control is achieved gradually, by dose titration and adminis-

• no pain while moving—3–7 days (not for patients with multiple vertebral and pelvic bone metastases—for them total pain control may not be achieved); and

**6.2 Opioid rotation**

*Opioid equianalgesic day doses.*

**Table 2.**

*mcg/hours, (d) 120 mg—50 mcg/hours, etc.*

by 100–125%;

**100**

Glucocorticoids ( dexamethasone, prednisolone, hydrocortisone)—indications: increased intracranial pressure, spinal cord compression, nerve compression or infiltration, bone metastases, extended liver capsule, soft tissue cancer infiltration (head and neck, abdominal, and pelvic tumors). Contraindications: no absolute contraindications, dose is limited by adverse effects, and being cautious with peptic ulcers, diabetes, cardiovascular dysfunction, and endemic situations. Adverse effects: Cushing syndrome, gastric ulcers, erosions, bleeding, increased appetite, weight, hyperglycemia, diabetes complications, muscle wasting, euphoria, dysphoria, emotional lability, depression, steroidal psychosis, edemas, hypertension, thrombosis, myopathies, decreased immunity to infections, potassium blood levels, liquid detention in the body, insomnia, skin purpura, etc.

Drugs for neuropathic pain: antidepressants, anticonvulsants, local anesthetics, and myorelaxants (baclofen).

Antidepressants—not always effective for neuropathic pain treatment and is better to prescribe tricyclic antidepressants (TCAs). Start with amitriptyline — 10–25 mg dose in the evening and then increase to 50–100 mg/day. If no effective pain relief is achieved, it is discontinued after 1 week of use. Adverse effects: somnolence and hypotension.

Anticonvulsants—for neuropathic pain—gabapentin, carbamazepine, and clonazepam. The starting dose is the same as treating epilepsy. Increase until pain relief is achieved, or unmanageable adverse effects (nausea, vomiting, somnolence, ataxia, dizziness, disorientation) occur.

Local anesthetics (lidocaine, mexiletine)—for neuropathic pain systemic treatment when other options are not working. Adverse effects: somnolence, nausea, tremor, dyspepsia (better use while eating).

NMDA receptors antagonists (ketamine)—for persistent neuropathic pain and other chronic pain when opioids are not tolerated. Routes of administration of ketamine: oral, intravenous, starting with 100 mg/day, and titration till 500 mg/ day. Adverse effects: psychomimetic can be reversed by benzodiazepines and haloperidol.

According to medical literature, about 20% of women have neuropathic pain after mastectomy and about 1/3 of cancer patients suffer from neuropathic pain (or both—nociceptive and neuropathic—together).

Bisphosphonates (pamidronate, zoledronic acid)—decrease bone resorption, effective in treating cancer hypercalcemia, decrease bone pain and occurrence of pathologic bone fractures for the patients with bone metastases, inhibit activity of osteoclasts, and are useful with ineffective radiotherapy and analgesics.

Radionuclides—Stroncium 89 systemic administration effectively relieves pain due to bone metastases, better works for osteoblastic metastases, and helps about

80% of patients. The response lasts from 3 to 6 months and is evident already after 2–3 weeks. Adverse effects: myelosuppression, monitored by blood tests. Trials with radioisotopes of samarium and rhenium were also performed.

Psychotropic drugs—neuroleptics. Common neuroleptics (e.g., haloperidol) have no analgesic effect but decrease anxiety, insomnia, treat nausea, and delirium. Levopromazine has analgesic effect: 20 mg dose is equivalent to 10 mg of morphine. Adverse effects: somnolence and hypotension. Benzodiazepines (diazepam, lorazepam, oxazepam) are useful for muscle spasms or acute bone-muscular pain. Adverse effects: hypotension, somnolence, and fatigue. Psychostimulants: metilphenidate has no analgesic effect and may be used to decrease severe opioidinduced somnolence. Adverse effects: dysphoria, tolerance, and dependence.

Myorelaxants—baklofen (act on spinal cord level, start with 5 mg/day dose, and increase till 100 mg/day, for severe hiccup (hiccough)). Adverse effects: fatigue and somnolence. It should be discontinued slowly due to possible withdrawal syndrome and convulsions. Dantrolene—primary effect on muscles. Start with 25 mg/ day, and continue with maximal titration till 400 mg/day. Adverse effects: fatigue, somnolence, and hepatotoxicity.

#### **7. Invasive cancer pain management**

In most patients, cancer pain can be adequately controlled with pain medication; however, in 5–14% of oncological patients', invasive pain management is needed [41]. Invasive procedures are the part of the option available for cancer pain management. Anesthetic, neurosurgical, or other invasive procedures can be given. Interventional pain management can improve pain control and reduce the amount of systemically administered drugs and their side effects. Also, invasive procedures can be an option when it is not possible to administer oral or parenteral medications. Final decision maker is a physician (anesthetist, pain specialist, and neurosurgeon) who will perform the procedure. He is main person that will decide about indications and contraindications for intervention treatment and will explain and talk with the patient or his relatives about the possibility of intervention and of course risk factors and possible complications. Invasive cancer pain procedures can be divided in to nondestructive and destructive.

Nondestructive procedures are such that the pain signal is modulated or interrupted (blocked) by the administration of a pharmacological agent to a source of pain. The pharmacological preparation may be administered by a single shot dose or via a catheter for long-term administration of the medication. Usually, the catheter is placed neuroaxially (into the spinal canal) or near the peripheral nerves or plexuses. Peripheral nerve blocks/injections can be used, but they are effective for short term and are usually performed in patients with limited survival when the pain source is one or more nerves or when the pain is caused by pathological fractures or vascular occlusion. As a first-line treatment, these blockades are rarely used and, if applicable, it is necessary to combine with systemic analgesics.

Neuraxial invasive procedures can be: intrathecal or epidural. For example, an epidural medication injection (transforaminal or translaminar) or catheter/devise placement is applied in most of the cases when the nerve structures are involved in pain cause.

In case of complicated cases and intolerable pain, opioid analgesics can also be delivered through neuraxial delivery systems. The use of neuraxial system for long term can range from simple percutaneous (tunneled) patient controlled to implantable complex programmable medication delivery systems. Implantable systems are expensive, but safe and their application is always justified, if patient need pain

**103**

*Cancer Pain*

pain [47].

and glycerol.

symptoms [48].

15–20% of patients).

for depression [50].

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

not generally apply to everyday cases.

control longer than 3 months and other medical treatments are not effective [42, 43]. These techniques may be on an oncological pain management plan, but they do

neurolysis (phenol), and (c) radio-frequency ablation [45, 46].

**8. Nonpharmacological cancer pain treatment**

number of radiation fractions (1–5) [49].

**9. Cancer pain and palliative care**

Destructive procedures can be applied in cases where pharmacological preparations cannot modulate the pain signal. For example, in case of small cell lung cancer and mesothelioma, chest pain is poorly localized, severe, and intolerable. This is because intercostal nerves and their branches can be infiltrated in cancer cells, during metastatic spread and making it difficult to manage the source of pain. Then, the cordotomy can be applied—a neurosurgical procedure in which the spinal cordspinothalamic tract ablation is performed in the area opposite to the pain. After the ablation pain disappears, but along with the disappearing of pain on the part of the body below, the ablation area develops temperature and paresthesia [44]. Another destructive procedure is rhizotomy, segmental or multisegmental destruction of spinal cord nerve roots. It can be done in several ways: (a) surgically, (b) chemical

Chemical neurolysis is widely used in the treatment of intractable cancer-related pain, especially in abdominal and pelvic cancer-related pain. These procedures can provide prolonged pain relief (3–6 month) and decrease the need of opioids. High evidence is for coeliac plexus neurolysis in pancreatic cancer-related

Neurolytic agents that often used for chemical neurolysis are alcohol, phenol,

All procedures can be done under ultrasound, X-ray, or CT scan. After the procedure, patient may experience significant pain relief and opioid withdrawal

Palliative radiotherapy is effective for the treatment of cancer pain caused by bone and brain metastases, metastatic skin ulcerations, and infiltrative growth of tumor in soft tissues. The summary dose of palliative radiotherapy is smaller than the dose for radical radiotherapy; maximal effect is achieved giving minimal

Transcutaneous electroneurostimulation (TENS)-nerve stimulation via electrodes put on skin, thus, inhibits pain signal in spinal cord. Optimal dose varies for different patients. TENS is used for the treatment of mild and moderate cancer pain but is not effective for visceral pain. TENS is contraindicated for the patients with pacemaker (ECS). Pain relief effect is quick but usually not long-lasting (only for

Psychotherapy-introducing patients psychological support groups, delivering enough information; relaxation therapies, meditation; cognitive therapy, autotraining, hypnosis, short psychotherapy seances with psychotherapist. Drug is administered if there is a need to correct renal, liver failure, and antidepressants

Palliative care includes palliative cancer treatment options, such as palliative radio therapy, palliative surgery, palliative chemotherapy, also pain relief and

Acupuncture, physical therapy, mild massage can also be applied.

control of other symptoms caused by advanced cancer [51].

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

somnolence, and hepatotoxicity.

**7. Invasive cancer pain management**

be divided in to nondestructive and destructive.

applicable, it is necessary to combine with systemic analgesics.

radioisotopes of samarium and rhenium were also performed.

80% of patients. The response lasts from 3 to 6 months and is evident already after 2–3 weeks. Adverse effects: myelosuppression, monitored by blood tests. Trials with

Psychotropic drugs—neuroleptics. Common neuroleptics (e.g., haloperidol) have no analgesic effect but decrease anxiety, insomnia, treat nausea, and delirium. Levopromazine has analgesic effect: 20 mg dose is equivalent to 10 mg of morphine. Adverse effects: somnolence and hypotension. Benzodiazepines (diazepam, lorazepam, oxazepam) are useful for muscle spasms or acute bone-muscular pain. Adverse effects: hypotension, somnolence, and fatigue. Psychostimulants: metilphenidate has no analgesic effect and may be used to decrease severe opioidinduced somnolence. Adverse effects: dysphoria, tolerance, and dependence.

Myorelaxants—baklofen (act on spinal cord level, start with 5 mg/day dose, and increase till 100 mg/day, for severe hiccup (hiccough)). Adverse effects: fatigue and somnolence. It should be discontinued slowly due to possible withdrawal syndrome and convulsions. Dantrolene—primary effect on muscles. Start with 25 mg/ day, and continue with maximal titration till 400 mg/day. Adverse effects: fatigue,

In most patients, cancer pain can be adequately controlled with pain medication; however, in 5–14% of oncological patients', invasive pain management is needed [41]. Invasive procedures are the part of the option available for cancer pain management. Anesthetic, neurosurgical, or other invasive procedures can be given. Interventional pain management can improve pain control and reduce the amount of systemically administered drugs and their side effects. Also, invasive procedures can be an option when it is not possible to administer oral or parenteral medications. Final decision maker is a physician (anesthetist, pain specialist, and neurosurgeon) who will perform the procedure. He is main person that will decide about indications and contraindications for intervention treatment and will explain and talk with the patient or his relatives about the possibility of intervention and of course risk factors and possible complications. Invasive cancer pain procedures can

Nondestructive procedures are such that the pain signal is modulated or interrupted (blocked) by the administration of a pharmacological agent to a source of pain. The pharmacological preparation may be administered by a single shot dose or via a catheter for long-term administration of the medication. Usually, the catheter is placed neuroaxially (into the spinal canal) or near the peripheral nerves or plexuses. Peripheral nerve blocks/injections can be used, but they are effective for short term and are usually performed in patients with limited survival when the pain source is one or more nerves or when the pain is caused by pathological fractures or vascular occlusion. As a first-line treatment, these blockades are rarely used and, if

Neuraxial invasive procedures can be: intrathecal or epidural. For example, an epidural medication injection (transforaminal or translaminar) or catheter/devise placement is applied in most of the cases when the nerve structures are involved in

In case of complicated cases and intolerable pain, opioid analgesics can also be delivered through neuraxial delivery systems. The use of neuraxial system for long term can range from simple percutaneous (tunneled) patient controlled to implantable complex programmable medication delivery systems. Implantable systems are expensive, but safe and their application is always justified, if patient need pain

**102**

pain cause.

control longer than 3 months and other medical treatments are not effective [42, 43]. These techniques may be on an oncological pain management plan, but they do not generally apply to everyday cases.

Destructive procedures can be applied in cases where pharmacological preparations cannot modulate the pain signal. For example, in case of small cell lung cancer and mesothelioma, chest pain is poorly localized, severe, and intolerable. This is because intercostal nerves and their branches can be infiltrated in cancer cells, during metastatic spread and making it difficult to manage the source of pain. Then, the cordotomy can be applied—a neurosurgical procedure in which the spinal cordspinothalamic tract ablation is performed in the area opposite to the pain. After the ablation pain disappears, but along with the disappearing of pain on the part of the body below, the ablation area develops temperature and paresthesia [44]. Another destructive procedure is rhizotomy, segmental or multisegmental destruction of spinal cord nerve roots. It can be done in several ways: (a) surgically, (b) chemical neurolysis (phenol), and (c) radio-frequency ablation [45, 46].

Chemical neurolysis is widely used in the treatment of intractable cancer-related pain, especially in abdominal and pelvic cancer-related pain. These procedures can provide prolonged pain relief (3–6 month) and decrease the need of opioids.

High evidence is for coeliac plexus neurolysis in pancreatic cancer-related pain [47].

Neurolytic agents that often used for chemical neurolysis are alcohol, phenol, and glycerol.

All procedures can be done under ultrasound, X-ray, or CT scan. After the procedure, patient may experience significant pain relief and opioid withdrawal symptoms [48].

#### **8. Nonpharmacological cancer pain treatment**

Palliative radiotherapy is effective for the treatment of cancer pain caused by bone and brain metastases, metastatic skin ulcerations, and infiltrative growth of tumor in soft tissues. The summary dose of palliative radiotherapy is smaller than the dose for radical radiotherapy; maximal effect is achieved giving minimal number of radiation fractions (1–5) [49].

Transcutaneous electroneurostimulation (TENS)-nerve stimulation via electrodes put on skin, thus, inhibits pain signal in spinal cord. Optimal dose varies for different patients. TENS is used for the treatment of mild and moderate cancer pain but is not effective for visceral pain. TENS is contraindicated for the patients with pacemaker (ECS). Pain relief effect is quick but usually not long-lasting (only for 15–20% of patients).

Psychotherapy-introducing patients psychological support groups, delivering enough information; relaxation therapies, meditation; cognitive therapy, autotraining, hypnosis, short psychotherapy seances with psychotherapist. Drug is administered if there is a need to correct renal, liver failure, and antidepressants for depression [50].

Acupuncture, physical therapy, mild massage can also be applied.

#### **9. Cancer pain and palliative care**

Palliative care includes palliative cancer treatment options, such as palliative radio therapy, palliative surgery, palliative chemotherapy, also pain relief and control of other symptoms caused by advanced cancer [51].

*Palliative surgical procedures—*palliative operations such as tumor mass reduction, stomas: colostomy, tracheostomy, gastrostomy, nephrostomy, etc., and drainage of pleural effusion and ascites.

*Palliative chemotherapy* is effective while treating pain, caused by chemotherapysusceptible tumor and metastases. The main goal is to minimize its side-effects. Monotherapy of drug combination in reduced doses can be applied [52].

Most common symptoms control [53].

Anorexia is a loss of appetite, usually with decreased food intake. *Cachexia*-lack of nutrition and wasting. Causes maybe disease-related (bowel obstruction, etc.), psychological or treatment-related (intoxication due to chemotherapy, radiation esophagitis, etc.). Treatment-dietary consultation, parental/enteral nutrition, medications (e.g., megestrol acetate suspension), odor control, and counseling.

Constipation is a common symptom in palliative care. The key should be prevention. Causes can be diseases related to GI obstruction, neurologic (spinal cord compression), hypercalcemia, inactivity; or treatment related-opioids, other medication. Treatmentlaxatives, other medication, increasing fluid intake, and dietary consultation.

*Nausea and vomiting*—common in advanced disease. Assessment of etiology is important, maybe acute, anticipatory (e.g. before chemotherapy) and delayed. Causes can be physiological (GI pathology, metabolic dysfunction, brain metastases, alsotreatment related (opioids), psychological. Treatment—both pharmacological (anticholinergics, antihistamines, steroids, prokinetic agents, etc.) and non-drug treatment (small/slow feeding, dietary consultation, relaxation/distraction techniques).

*Lymphedema*—chronic, progressive swelling due to failure of lymph drainage. Patients limbs and whole body can be affected. Treatment—skin care, compression, limb elevation, education, etc. For those patients trophic ulcers and bedsores occur more often.

**105**

fixed scheme

*Cancer Pain*

be considered.

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

options are exhausted (**Figure 4**).

General principles of palliative care:

1.patient and family as unit of care;

3.interdisciplinary team approach;

6.bereavement support [55].

**10. Cancer basic pain relief**

4. education and support of patient and family;

to improve the quality of life, still left for the patient.

**Basic pain Breakthrough pain**

Treatment—long acting, slow release opioids,

Start—slow, gradual increase in intensity Start—acute, not predictable

Type—dull, pressing, gnawing… Type—acute, shooting, irradiating

Duration—no less 12 hours/day Duration—from several seconds to 30 minutes

demand basis

Treatment—short acting, immediate release opioids, on

5. extends across illnesses and settings; and

2. attention to physical, psychological, social, and spiritual needs;

The main idea of palliative care-no matter how much the disease is advanced, and what complex treatment has been applied, one always can do something more

Planning pain relief for cancer pain patients one should take into the consideration possible mechanisms and types of pain (nociceptive, neuropathic, mixed), patients' wishes, former treatment. If psychological distress is present, talking about pain assessment is needed, if there is suffering, help from the clergymen may be useful. If the signs of drug addiction appear, drug release should be more controlled, physical aspects of pain relief introduced. With cognitive disorders depression and anxiety should be treated, also opioid rotation should be available.

Advanced cancer patients at the end of life also often exhibit *delirium* (acute change in cognition/awareness) with *agitation and confusion* (disorientation, inappropriate behavior, hallucinations). The causes vary, most common-medications, infection, bladder distention, hypoxemia. As treatment option medication reevaluation, hydration, oxygen therapy, reorientation, psychotropic drugs should

Aging population and increasing number of long time cancer survivors, some of them finally ending as advanced cancer patients, now especially increase the need of *hospice and palliative care* [54]. It should be patient-oriented, and not related to artificial prolongation of life and failure to acknowledge the limits of medicine with inappropriate use of aggressive curative treatment. Palliative care should help with all patients' problems (physical, psychological, social, spiritual), include interdisciplinary team approach (doctors, nurses, social workers, psychologists, other specialists and volunteers) and is oriented to achieve better quality of life for the patient and his/her family members. Palliative care should start for the cancer patients still receiving specific anti-cancer therapies, not waiting until all treatment

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

age of pleural effusion and ascites.

Most common symptoms control [53].

*Palliative surgical procedures—*palliative operations such as tumor mass reduction, stomas: colostomy, tracheostomy, gastrostomy, nephrostomy, etc., and drain-

*Palliative chemotherapy* is effective while treating pain, caused by chemotherapysusceptible tumor and metastases. The main goal is to minimize its side-effects.

Anorexia is a loss of appetite, usually with decreased food intake. *Cachexia*-lack of nutrition and wasting. Causes maybe disease-related (bowel obstruction, etc.), psychological or treatment-related (intoxication due to chemotherapy, radiation esophagitis, etc.). Treatment-dietary consultation, parental/enteral nutrition, medications (e.g., megestrol acetate suspension), odor control, and counseling.

Constipation is a common symptom in palliative care. The key should be prevention. Causes can be diseases related to GI obstruction, neurologic (spinal cord compression), hypercalcemia, inactivity; or treatment related-opioids, other medication. Treatment-

*Nausea and vomiting*—common in advanced disease. Assessment of etiology is important, maybe acute, anticipatory (e.g. before chemotherapy) and delayed. Causes can be physiological (GI pathology, metabolic dysfunction, brain metastases, alsotreatment related (opioids), psychological. Treatment—both pharmacological (anticholinergics, antihistamines, steroids, prokinetic agents, etc.) and non-drug treatment

*Lymphedema*—chronic, progressive swelling due to failure of lymph drainage. Patients limbs and whole body can be affected. Treatment—skin care, compression, limb elevation, education, etc. For those patients trophic ulcers and bedsores occur

Monotherapy of drug combination in reduced doses can be applied [52].

laxatives, other medication, increasing fluid intake, and dietary consultation.

(small/slow feeding, dietary consultation, relaxation/distraction techniques).

**104**

**Figure 4.**

more often.

*Palliative care models (WHO directives, 2002) (adapted by Skorupskiene (2018)).*

Advanced cancer patients at the end of life also often exhibit *delirium* (acute change in cognition/awareness) with *agitation and confusion* (disorientation, inappropriate behavior, hallucinations). The causes vary, most common-medications, infection, bladder distention, hypoxemia. As treatment option medication reevaluation, hydration, oxygen therapy, reorientation, psychotropic drugs should be considered.

Aging population and increasing number of long time cancer survivors, some of them finally ending as advanced cancer patients, now especially increase the need of *hospice and palliative care* [54]. It should be patient-oriented, and not related to artificial prolongation of life and failure to acknowledge the limits of medicine with inappropriate use of aggressive curative treatment. Palliative care should help with all patients' problems (physical, psychological, social, spiritual), include interdisciplinary team approach (doctors, nurses, social workers, psychologists, other specialists and volunteers) and is oriented to achieve better quality of life for the patient and his/her family members. Palliative care should start for the cancer patients still receiving specific anti-cancer therapies, not waiting until all treatment options are exhausted (**Figure 4**).

General principles of palliative care:

1.patient and family as unit of care;

2. attention to physical, psychological, social, and spiritual needs;

3.interdisciplinary team approach;

4. education and support of patient and family;

5. extends across illnesses and settings; and

6.bereavement support [55].

The main idea of palliative care-no matter how much the disease is advanced, and what complex treatment has been applied, one always can do something more to improve the quality of life, still left for the patient.

#### **10. Cancer basic pain relief**

Planning pain relief for cancer pain patients one should take into the consideration possible mechanisms and types of pain (nociceptive, neuropathic, mixed), patients' wishes, former treatment. If psychological distress is present, talking about pain assessment is needed, if there is suffering, help from the clergymen may be useful. If the signs of drug addiction appear, drug release should be more controlled, physical aspects of pain relief introduced. With cognitive disorders depression and anxiety should be treated, also opioid rotation should be available.


Cancer pain treatment algorithm [2]:


#### **10.1 Basic cancer pain drug treatment principles**

After the cause and type of cancer pain is determined, the constant analgesia is started by the easiest route, the patient-oral or transdermal, individualizing the dose, and also providing drugs for relief from other symptoms. The drug is selected taking into consideration the type and intensity of pain, WHO "analgesic ladder,", also drug combinations, but combined medications should not be used and no placebo drugs as well [56].

To prevent pain becoming chronic, cancer pain relief should be started as soon as pain appears, as it helps to reduce drugs doses, adverse effects, and achieve better drug tolerance. It also reduces the cost of pain treatment, enhances the trust between patient and doctor, and patient is socially active for a longer time. The pain relief effect should be quick, so we can start with stronger medications and later pass on the weaker ones. Different medication is used for different types of pain: (a) nociceptive pain, due to soft tissue, bone damage, and visceral pain are treated by combinations of nonopioids and opioids and (b) neuropathic pain, due to nerve compression—by opioids, glucocorticoids, when nerve is damaged—by antidepressants, anticonvulsants, and NMDA receptor antagonists [57].

#### **11. Cancer breakthrough pain management**

Breakthrough cancer pain (BTCP) is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain [58]. The frequency is less than four times/day, if it takes more than four times/day, we need to think about lack in background cancer pain control.

Leading doctor in BTCP management should preform regular assessments and repeatedly investigate pain management after 1–4 weeks dependably on patient's complexity.

It is important to understand that the BTCP management is different compared with background cancer pain, which is managed according to the ladder and "by the clock," while for BTCP, "rescue medication" should be given as needed. Main feature is that the breakthrough cancer pain should be started when background cancer pain is well controlled (**Figure 5**) [59]. This type of pain can take about from 30 minutes but not more than 60 minutes. The highest intensity of the pain can be reached at tenth minute, and it can take 1–4 episodes/day [60]. For that reason, for BTCP should be given very strong, short-acting opioids.

**107**

**Table 3.**

*Fentanyl short acting formulations.*

*Cancer Pain*

background cancer pain.

**Figure 5.**

*cancer pain.*

soluble film [61].

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

It is better to use the same chemical opioid structure, which is chosen to manage

*Association of Palliative Medicine of Great Britain and Ireland (APM) algorithm for assessing breakthrough* 

When fentanyl plasters/patches is used, the short-acting medication (buccal or sublingual tablet) for BTCP control can be prescribed. The dose should be titrated up to effective one, because of the lipophilic structure and the absorption, which is through the mucous of the mouth and gastrointestinal tract. There is a variety of short-acting fentanyl forms (**Table 3**). For example, BTCP management can be started with 200 μg of oral transmucosal fentanyl citrate tablet or 100 μg buccal-

If for BTP management, immediate-release morphine is chosen, usually one BTP episode is needed, part of 1/6 injecting medication of all morphine day dose. Their pharmacokinetic characteristics have limitations, with a relatively slow onset of

BTCP management consists of other approaches as setting of pain management goals, education of the patient, and depending on the cause of breakthrough pain, occupational therapist, physiotherapist can be involved. Other acute causes as

Fentanyl pectin intranasal spray

Sublingual fentanyl tablet

action (30–45 minutes) and duration of action of up to 4–6 hours [62].

Sublingual Sublingual fentanyl orally disintegrating tablet

**Formulation Description**

Nasal spray Phosphate-buffered solution

Oromucosal Oral transmucosal fentanyl citrate

Buccal tablet Effervescent formulation Buccal soluble film Fentanyl buccal soluble film

#### **Figure 5.**

*From Conventional to Innovative Approaches for Pain Treatment*

1. assessment of pain reason, type, and intensity;

4. evaluation of results and correction of treatment plan; and

5.providing constant pain relief and palliative care.

**10.1 Basic cancer pain drug treatment principles**

**11. Cancer breakthrough pain management**

to think about lack in background cancer pain control.

BTCP should be given very strong, short-acting opioids.

2.pharmacological pain treatment: basic pain relief, breakthrough pain relief,

After the cause and type of cancer pain is determined, the constant analgesia is started by the easiest route, the patient-oral or transdermal, individualizing the dose, and also providing drugs for relief from other symptoms. The drug is selected taking into consideration the type and intensity of pain, WHO "analgesic ladder,", also drug combinations, but combined medications should not be used and no

To prevent pain becoming chronic, cancer pain relief should be started as soon as pain appears, as it helps to reduce drugs doses, adverse effects, and achieve better drug tolerance. It also reduces the cost of pain treatment, enhances the trust between patient and doctor, and patient is socially active for a longer time. The pain relief effect should be quick, so we can start with stronger medications and later pass on the weaker ones. Different medication is used for different types of pain: (a) nociceptive pain, due to soft tissue, bone damage, and visceral pain are treated by combinations of nonopioids and opioids and (b) neuropathic pain, due to nerve compression—by opioids, glucocorticoids, when nerve is damaged—by antidepressants, anticonvulsants, and NMDA receptor

Breakthrough cancer pain (BTCP) is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain [58]. The frequency is less than four times/day, if it takes more than four times/day, we need

Leading doctor in BTCP management should preform regular assessments and repeatedly investigate pain management after 1–4 weeks dependably on patient's

It is important to understand that the BTCP management is different compared with background cancer pain, which is managed according to the ladder and "by the clock," while for BTCP, "rescue medication" should be given as needed. Main feature is that the breakthrough cancer pain should be started when background cancer pain is well controlled (**Figure 5**) [59]. This type of pain can take about from 30 minutes but not more than 60 minutes. The highest intensity of the pain can be reached at tenth minute, and it can take 1–4 episodes/day [60]. For that reason, for

Cancer pain treatment algorithm [2]:

3.nonpharmacological treatment of pain;

and adjuvants;

placebo drugs as well [56].

antagonists [57].

complexity.

**106**

*Association of Palliative Medicine of Great Britain and Ireland (APM) algorithm for assessing breakthrough cancer pain.*

It is better to use the same chemical opioid structure, which is chosen to manage background cancer pain.

When fentanyl plasters/patches is used, the short-acting medication (buccal or sublingual tablet) for BTCP control can be prescribed. The dose should be titrated up to effective one, because of the lipophilic structure and the absorption, which is through the mucous of the mouth and gastrointestinal tract. There is a variety of short-acting fentanyl forms (**Table 3**). For example, BTCP management can be started with 200 μg of oral transmucosal fentanyl citrate tablet or 100 μg buccalsoluble film [61].

If for BTP management, immediate-release morphine is chosen, usually one BTP episode is needed, part of 1/6 injecting medication of all morphine day dose. Their pharmacokinetic characteristics have limitations, with a relatively slow onset of action (30–45 minutes) and duration of action of up to 4–6 hours [62].

BTCP management consists of other approaches as setting of pain management goals, education of the patient, and depending on the cause of breakthrough pain, occupational therapist, physiotherapist can be involved. Other acute causes as


**Table 3.** *Fentanyl short acting formulations.*

#### *From Conventional to Innovative Approaches for Pain Treatment*

bone fractures, bowel perforation, etc. should be excluded, and if the BTCP can be predicted, pain medication should be given before the coming pain event.

The evaluation of the effectiveness of the pharmacological treatment of BTCP has a four-factor rule [63]:


Possible inappropriate use of opioids is very important factor in pain management, and it should be carefully investigated. It manifests as addiction or pseudoaddiction for strong opioids and can be associated with mental disease. Clinically, it can be seen as seeking for opioids and/or problematic opioid use. In order to correct the possible misconduct in the use of opioids, it is important that these requirements are met before they are given:


#### **12. Cancer pain treatment for children and elderly patients**

While treating cancer pain in children and elder patients, one should take into consideration the differences in metabolism, concurrent diseases. Children receive different adapted opioid doses, and opioid rotation is also different (e.g., better pain relief with methadone and not morphine).

Elderly patients more easily overdose opioids; one cannot double their opioid dose quickly for them. Also, one should be aware of elder persons' liver and renal function; if there is some failure, the correction is essential before prescribing opioid medication. There are usually a lot of tablets and other oral drugs prescribed for the concurrent diseases, so there is necessary to determine daily opioid dosage very carefully.

#### **13. Cancer survivors pain treatment**

Chronic pain can be a serious, negative consequence of surviving cancer. As a result of remarkable advances in cancer diagnosis and therapy, today there are a record 14 million cancer survivors in the United States. However, an estimated 40% of survivors continue to experience persistent pain as a result of treatment, which can be detrimental to their quality of life [3]. Two-thirds of these individuals are surviving more than 5 years after diagnosis, supporting the need to study pain in this growing population [65]. National Cancer Institute's Office of Cancer Survivorship characterizes the survivor as a person with a history of cancer who is beyond the acute diagnosis and treatment phase. Risk factors for chronic pain in survivors include the

**109**

*Cancer Pain*

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

type and invasiveness of the tumor, the treatment regimen used, the time since the cancer treatment has started, and the efficacy of initial pain therapy. Continuous pain is associated with impaired quality of life in this population [66]. As the population of cancer survivors expands, all clinicians, including oncologists, advanced practice providers, and primary care physicians who interact with these individuals, will require the knowledge and skills to implement best practices in the management of chronic pain. When analgesic drugs are used, the imperative to prescribe safely must expand beyond immediate adverse effects, such as the resulting respiratory depression or constipation associated with opioids, to incorporate awareness and mitigation

Clinical practice guidelines are issued recently, and they deal comprehensively with the pain people experience after cancer treatment, and are unique in its focus on chronic pain among cancer survivors. Key guideline recommendations include: (1) clinicians should screen for pain at each encounter with a patient. Recurrent disease, second malignancy, or late onset treatment effects should be evaluated, treated, and monitored; (2) clinicians may prescribe nonpharmacologic interven-

of the long-term consequences of these and other analgesic agents.

tions such as physical medicine and rehabilitation, integrative therapies (e.g., acupuncture and massage), interventional therapies, and psychological approaches (e.g., guided imagery, hypnosis, and meditation); (3) systemic nonopioid analgesics (NSAIDS, acetaminophen) and adjuvant analgesics (selected antidepressants and anticonvulsants), may be prescribed to relieve chronic pain and/or improve physical function; (4) clinicians may prescribe a trial of opioids in carefully selected cancer patients who do not respond to more conservative pain management and who continue to experience pain-related distress or impairment of physical function [67]. The management of cancer survivors suffering chronic pain requires greater consideration of a multimodality plan of care that balances pharmacologic and nonpharmacologic techniques and may necessitate the involvement of an interdisciplinary team; the goals of treatment in these populations may focus on improving function and limiting the long-term adverse effects of pain and

of its treatment, as much or more as they do on improving comfort [68].

As therapeutic treatment options and outcomes improve, patients with cancer are living longer. Chronic pain can develop from a variety of sources: peripheral neuropathy, muscle or bone pain, surgery, radiation, and other conditions.

Comorbidity with other conditions or syndromes can make assessing chronic pain more difficult. Different chronic pain syndromes may be present for cancer survivors. Chronic inflammatory polyneuropathy is one of many well-recognized pain disorders, together with other treatment-related pain syndromes, such as postsurgical and postradiation pain. Hormonal therapies, such as aromatase inhibitors, can produce arthralgias. As the use of hematopoietic stem-cell transplantation expands, graft-versus-host disease (GVHD) is seen with greater frequency, leading to pain syndromes that can affect almost any organ system. In addition, immunosuppressive agents used to treat GVHD can lead to painful complications (e.g., corticosteroids and avascular necrosis). The recent validation of a tool specific to musculoskeletal symptoms in hematopoietic stem cell transplantation will allow better characterization of this painful phenomenon [69–71]. The important consideration when designing an usage of analgesics is the potential for harm, and drug-drug interactions with cancer therapies, or other treatments should be considered. Cytochrome P450 CYP 3A and CYP2D6 inhibitors can increase concentrations of opioids, such as codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone, metabolized by this system [72, 73]. Methadone and buprenorphine can prolong the QT interval, an effect that can be potentiated by many chemotherapeutic agents, notably doxorubicin [74]. If pain is severe and disabling, and long-term opioid therapy is being considered, the potential for

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

has a four-factor rule [63]:

3. adverse effect of medications; and

ments are met before they are given:

4.possible inappropriate use of opioids.

gambling, having mental problems); and

relief with methadone and not morphine).

**13. Cancer survivors pain treatment**

1.pain relief;

2.day activity;

bone fractures, bowel perforation, etc. should be excluded, and if the BTCP can be

The evaluation of the effectiveness of the pharmacological treatment of BTCP

Possible inappropriate use of opioids is very important factor in pain management, and it should be carefully investigated. It manifests as addiction or pseudoaddiction for strong opioids and can be associated with mental disease. Clinically, it can be seen as seeking for opioids and/or problematic opioid use. In order to correct the possible misconduct in the use of opioids, it is important that these require-

1.to distinguish between people with risk factors (drug users, alcohol dependent,

2.modifying the use of drugs for the prevention of BTCP (by giving a slightly higher dose of slow-release opioid to relieve background pain, try to use nonopioids for BTCP reduction, and family support-controlled home care, etc.) [64].

While treating cancer pain in children and elder patients, one should take into consideration the differences in metabolism, concurrent diseases. Children receive different adapted opioid doses, and opioid rotation is also different (e.g., better pain

Elderly patients more easily overdose opioids; one cannot double their opioid dose quickly for them. Also, one should be aware of elder persons' liver and renal function; if there is some failure, the correction is essential before prescribing opioid medication. There are usually a lot of tablets and other oral drugs prescribed for the concurrent diseases, so there is necessary to determine daily opioid dosage very

Chronic pain can be a serious, negative consequence of surviving cancer. As a result of remarkable advances in cancer diagnosis and therapy, today there are a record 14 million cancer survivors in the United States. However, an estimated 40% of survivors continue to experience persistent pain as a result of treatment, which can be detrimental to their quality of life [3]. Two-thirds of these individuals are surviving more than 5 years after diagnosis, supporting the need to study pain in this growing population [65]. National Cancer Institute's Office of Cancer Survivorship characterizes the survivor as a person with a history of cancer who is beyond the acute diagnosis and treatment phase. Risk factors for chronic pain in survivors include the

**12. Cancer pain treatment for children and elderly patients**

predicted, pain medication should be given before the coming pain event.

**108**

carefully.

type and invasiveness of the tumor, the treatment regimen used, the time since the cancer treatment has started, and the efficacy of initial pain therapy. Continuous pain is associated with impaired quality of life in this population [66]. As the population of cancer survivors expands, all clinicians, including oncologists, advanced practice providers, and primary care physicians who interact with these individuals, will require the knowledge and skills to implement best practices in the management of chronic pain. When analgesic drugs are used, the imperative to prescribe safely must expand beyond immediate adverse effects, such as the resulting respiratory depression or constipation associated with opioids, to incorporate awareness and mitigation of the long-term consequences of these and other analgesic agents.

Clinical practice guidelines are issued recently, and they deal comprehensively with the pain people experience after cancer treatment, and are unique in its focus on chronic pain among cancer survivors. Key guideline recommendations include: (1) clinicians should screen for pain at each encounter with a patient. Recurrent disease, second malignancy, or late onset treatment effects should be evaluated, treated, and monitored; (2) clinicians may prescribe nonpharmacologic interventions such as physical medicine and rehabilitation, integrative therapies (e.g., acupuncture and massage), interventional therapies, and psychological approaches (e.g., guided imagery, hypnosis, and meditation); (3) systemic nonopioid analgesics (NSAIDS, acetaminophen) and adjuvant analgesics (selected antidepressants and anticonvulsants), may be prescribed to relieve chronic pain and/or improve physical function; (4) clinicians may prescribe a trial of opioids in carefully selected cancer patients who do not respond to more conservative pain management and who continue to experience pain-related distress or impairment of physical function [67]. The management of cancer survivors suffering chronic pain requires greater consideration of a multimodality plan of care that balances pharmacologic and nonpharmacologic techniques and may necessitate the involvement of an interdisciplinary team; the goals of treatment in these populations may focus on improving function and limiting the long-term adverse effects of pain and of its treatment, as much or more as they do on improving comfort [68].

As therapeutic treatment options and outcomes improve, patients with cancer are living longer. Chronic pain can develop from a variety of sources: peripheral neuropathy, muscle or bone pain, surgery, radiation, and other conditions. Comorbidity with other conditions or syndromes can make assessing chronic pain more difficult. Different chronic pain syndromes may be present for cancer survivors. Chronic inflammatory polyneuropathy is one of many well-recognized pain disorders, together with other treatment-related pain syndromes, such as postsurgical and postradiation pain. Hormonal therapies, such as aromatase inhibitors, can produce arthralgias. As the use of hematopoietic stem-cell transplantation expands, graft-versus-host disease (GVHD) is seen with greater frequency, leading to pain syndromes that can affect almost any organ system. In addition, immunosuppressive agents used to treat GVHD can lead to painful complications (e.g., corticosteroids and avascular necrosis). The recent validation of a tool specific to musculoskeletal symptoms in hematopoietic stem cell transplantation will allow better characterization of this painful phenomenon [69–71]. The important consideration when designing an usage of analgesics is the potential for harm, and drug-drug interactions with cancer therapies, or other treatments should be considered. Cytochrome P450 CYP 3A and CYP2D6 inhibitors can increase concentrations of opioids, such as codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone, metabolized by this system [72, 73]. Methadone and buprenorphine can prolong the QT interval, an effect that can be potentiated by many chemotherapeutic agents, notably doxorubicin [74]. If pain is severe and disabling, and long-term opioid therapy is being considered, the potential for

opioid-related harm over time must also be evaluated. Persistent adverse effects such as constipation are well recognized, and risk of sleep-disordered breathing suggests that these conditions must be considered when opioid therapy is initiated and later during the course of treatment. The potential for neurotoxicities, such as persistent mental clouding, increased risk of falls in the elderly, and other phenomena may occur. Opioid-induced hyperalgesia is well described in preclinical models but has uncertain clinical importance; the potential is considered when a patient reports escalating pain in tandem with opioid dose escalation in the absence of identifiable worsening of a pain cause. Opioid-related harm may also result from misuse or abuse, the development of opioid addiction, or the occurrence of drug diversion within the community. The problem of prescription drug abuse is serious, leading to an increase in opioid-related deaths [75]. The treatment of patients with additional chronic conditions, a situation in which the patient may have two or more such conditions, referred to as multiple chronic conditions, is challenging. Insomnia and psychological distress are common conditions in patients with chronic pain, present in 17–90% of adult sufferers, respectively. The most common psychiatric disorders comorbid with chronic pain include depression, anxiety, personality disorders, and PTSD [76]. Evidence also suggests that patients with comorbid conditions are less likely to improve with standard chronic pain treatment [77].

Because cancer posttreatment pain is so complicated; good communication between patients and their medical providers is essential. Cancer survivors may have varying capacities to deal with a great source of information that can sometimes be overwhelming. Some patients may even be reluctant to discuss their pain, seeing it as a sign of weakness or fearing a recurrence; some may see it as an expected and untreatable complication of their cancer treatment. That is why a pain assessment is recommended at every visit. In teasing out how they are coping, clinicians need to ask patients how chronic pain is affecting them and suggest how they can work together to better manage their symptoms and improve their quality of life. The question arises regarding who should provide pain management for the cancer survivor: the oncologist and his or her team, the patient's primary care provider, a multidisciplinary pain service, or any other professional? Oncology teams providing ongoing care for cancer survivors may be the optimal group to address pain, because they routinely manage a complex regimen of cancer therapies and related symptoms.

Comprehensive assessment, including the impact of pain on function and quality of life, is warranted for all survivors. Long-term assessment is also needed after clinical trials to better recognize novel or previously unrecognized painful consequences of treatment, including those syndromes that may occur after treatment is completed. Carefully designed, extended studies of pharmacologic and nonpharmacologic interventions to relieve pain and improve function are indicated in this population. An especially relevant and urgent need is research identifying those cancer survivors who respond optimally to opioid therapy and those at greatest risk of adverse effects.

#### **14. General practitioner's role**

Cancer care generally requires the technical knowledge and skills of specialty physicians such as medical oncologists, surgeons, and radiation oncologists. General practitioners (GP) may play an essential role because they are often the initial point of contact for patients in obtaining screening or evaluating symptoms, and they may make referrals, coordinate care, and manage symptoms or comorbid

**111**

*Cancer Pain*

palliative care [83].

and

medicine [85].

the following cases (indications):

controlled sufficiently;

• pain breakthrough is not treated at all;

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

conditions. One of the main role for GP also is counseling cancer patients about treatment options and monitoring treatment progress and side effects [78].

Most common mistakes in the treatment of cancer pain are as following:

• a prescription of slow release(SR)-form opioids for intake regime "as needed";

• medicine for breakthrough pain is added in the situation where basic pain is not

• adjuvants (antidepressants, anticonvulsants) and related medicine are not used;

• with the prescription of opioids, behavioral aspects of patients are not evaluated.

It goes without saying that controlling such a complex syndrome as cancer pain can lead to other problems that require the help and advice of the pain physician. Therefore, GP should refer the cancer patient to a pain clinic for a clear indication of

A general practitioner, who has diagnosed pain in a cancer patient, starts treatment with analgesics. A ladder analgesia scheme is used. Opioids may even be prescribed for moderate pain, and if the pain is severe and unbearable, the opioid analgesic is the main remedy for pain relief. A sufficient daily dose for baseline (basic) analgesia should be achieved by increasing the dose (titration) of the product [84]. When titrating the product, the following rules should be used: (a) pain is controlled and there are no side effects—treatment to continue the current dose, (b) pain is controlled, but there are side effects—reduce the dose of the product, (c) pain is uncontrolled and there are no side effects—increase the dose of the preparation, and (d) pain is uncontrolled, in case of side effects, change the

• monotherapy (NSAIDs or opioid analgesics only);

• improper treatment of side effects caused by medicines;

The roles of GP's for patients with cancer such as managing comorbid conditions, chronic pain, or depression, and referring patients to hospice were tested in the study and showed that 22% of GPs reported no direct involvement in cancer care roles, while 19% reported heavy involvement, and rural practice location was not associated with greater GP involvement in cancer care [79]. There is a gradual move toward shared care models with GPs playing a central role alongside other healthcare providers. In this context, it will be important to understand the factors influencing the involvement of GPs in cancer care and how to maximize their involvement throughout the spectrum of cancer care [80]. The studies also confirm that the great majority of GPs are familiar with the modern management of pain control problems commonly encountered in practice, but are less aware of the drug options available for less common situations, particularly the use of syringe drivers [81]. Fortunately, there is no evidence of a reluctance to start strong opioids for severe pain, as identified in previous works [82]. However, it is of concern that only minority of GPs still are suggesting immediate-release opioids for breakthrough pain, and laxatives or antiemetics when starting strong opioids, which is a recommended practice in community

#### *Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84452*

*From Conventional to Innovative Approaches for Pain Treatment*

standard chronic pain treatment [77].

opioid-related harm over time must also be evaluated. Persistent adverse effects such as constipation are well recognized, and risk of sleep-disordered breathing suggests that these conditions must be considered when opioid therapy is initiated and later during the course of treatment. The potential for neurotoxicities, such as persistent mental clouding, increased risk of falls in the elderly, and other phenomena may occur. Opioid-induced hyperalgesia is well described in preclinical models but has uncertain clinical importance; the potential is considered when a patient reports escalating pain in tandem with opioid dose escalation in the absence of identifiable worsening of a pain cause. Opioid-related harm may also result from misuse or abuse, the development of opioid addiction, or the occurrence of drug diversion within the community. The problem of prescription drug abuse is serious, leading to an increase in opioid-related deaths [75]. The treatment of patients with additional chronic conditions, a situation in which the patient may have two or more such conditions, referred to as multiple chronic conditions, is challenging. Insomnia and psychological distress are common conditions in patients with chronic pain, present in 17–90% of adult sufferers, respectively. The most common psychiatric disorders comorbid with chronic pain include depression, anxiety, personality disorders, and PTSD [76]. Evidence also suggests that patients with comorbid conditions are less likely to improve with

Because cancer posttreatment pain is so complicated; good communication between patients and their medical providers is essential. Cancer survivors may have varying capacities to deal with a great source of information that can sometimes be overwhelming. Some patients may even be reluctant to discuss their pain, seeing it as a sign of weakness or fearing a recurrence; some may see it as an expected and untreatable complication of their cancer treatment. That is why a pain assessment is recommended at every visit. In teasing out how they are coping, clinicians need to ask patients how chronic pain is affecting them and suggest how they can work together to better manage their symptoms and improve their quality of life. The question arises regarding who should provide pain management for the cancer survivor: the oncologist and his or her team, the patient's primary care provider, a multidisciplinary pain service, or any other professional? Oncology teams providing ongoing care for cancer survivors may be the optimal group to address pain, because they routinely manage a complex regimen of cancer therapies and related

Comprehensive assessment, including the impact of pain on function and quality

Cancer care generally requires the technical knowledge and skills of specialty

physicians such as medical oncologists, surgeons, and radiation oncologists. General practitioners (GP) may play an essential role because they are often the initial point of contact for patients in obtaining screening or evaluating symptoms, and they may make referrals, coordinate care, and manage symptoms or comorbid

of life, is warranted for all survivors. Long-term assessment is also needed after clinical trials to better recognize novel or previously unrecognized painful consequences of treatment, including those syndromes that may occur after treatment is completed. Carefully designed, extended studies of pharmacologic and nonpharmacologic interventions to relieve pain and improve function are indicated in this population. An especially relevant and urgent need is research identifying those cancer survivors who respond optimally to opioid therapy and those at greatest risk

**110**

symptoms.

of adverse effects.

**14. General practitioner's role**

conditions. One of the main role for GP also is counseling cancer patients about treatment options and monitoring treatment progress and side effects [78].

The roles of GP's for patients with cancer such as managing comorbid conditions, chronic pain, or depression, and referring patients to hospice were tested in the study and showed that 22% of GPs reported no direct involvement in cancer care roles, while 19% reported heavy involvement, and rural practice location was not associated with greater GP involvement in cancer care [79]. There is a gradual move toward shared care models with GPs playing a central role alongside other healthcare providers. In this context, it will be important to understand the factors influencing the involvement of GPs in cancer care and how to maximize their involvement throughout the spectrum of cancer care [80]. The studies also confirm that the great majority of GPs are familiar with the modern management of pain control problems commonly encountered in practice, but are less aware of the drug options available for less common situations, particularly the use of syringe drivers [81]. Fortunately, there is no evidence of a reluctance to start strong opioids for severe pain, as identified in previous works [82]. However, it is of concern that only minority of GPs still are suggesting immediate-release opioids for breakthrough pain, and laxatives or antiemetics when starting strong opioids, which is a recommended practice in community palliative care [83].

Most common mistakes in the treatment of cancer pain are as following:


A general practitioner, who has diagnosed pain in a cancer patient, starts treatment with analgesics. A ladder analgesia scheme is used. Opioids may even be prescribed for moderate pain, and if the pain is severe and unbearable, the opioid analgesic is the main remedy for pain relief. A sufficient daily dose for baseline (basic) analgesia should be achieved by increasing the dose (titration) of the product [84]. When titrating the product, the following rules should be used: (a) pain is controlled and there are no side effects—treatment to continue the current dose, (b) pain is controlled, but there are side effects—reduce the dose of the product, (c) pain is uncontrolled and there are no side effects—increase the dose of the preparation, and (d) pain is uncontrolled, in case of side effects, change the medicine [85].

It goes without saying that controlling such a complex syndrome as cancer pain can lead to other problems that require the help and advice of the pain physician. Therefore, GP should refer the cancer patient to a pain clinic for a clear indication of the following cases (indications):


### **15. Conclusion**

Following the International Association for the Study of Pain cancer pain is "unpleasant sensory and emotional experience associate with actual or potential tissue damage resulting either from the treatment of cancer or the cancer itself." Due to the complexity of symptoms and multimodality of treatments, cancer pain is built in the most sophisticated field of medicine, where each patient's stage of disease and diagnosis will require an individualized pain treatment plan to optimize the quality of life. Such tasks can only be carried out using multidisciplinary approach. That is why basic knowledge about cancer pain is essential for every healthcare professional. We believe that the text you have just read will help you to be an active practitioner giving the patients the cancer pain relief.

#### **Acknowledgements**

The authors acknowledge Lithuanian Pain Society for text support.

#### **Notes**

Materials from "Cancer induced pain,"(Lithuanian Pain Society's guidelines) 2nd ed., 2018, are used in the text.

**113**

*Cancer Pain*

**Author details**

Kaunas, Lithuania

Lithuania

Lithuania

Lithuania

Arūnas Ščiupokas1,2\*, Liuda Brogienė

*DOI: http://dx.doi.org/10.5772/intechopen.84452*

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Pain Clinic, Lithuanian University of Health Sciences Hospital Kauno Klinikos,

2 Department of Neurology, Lithuanian University of Health Sciences, Kaunas,

4 Department of Oncology, Lithuanian University of Health Sciences, Kaunas,

\*Address all correspondence to: arunas.sciupokas@lsmuni.lt

3 Department of Anesthesiology, Lithuanian University of Health Sciences, Kaunas,

1,3 and Dalia Skorupskienė

4

*From Conventional to Innovative Approaches for Pain Treatment*

psychological dependence on them is suspected;

is an unadjusted side effect of the drug;

pain is well controlled;

analgesic (opioid rotation);

ists' meeting) is necessary; and

**15. Conclusion**

**Acknowledgements**

2nd ed., 2018, are used in the text.

• when initiating opioid analgesics, basic pain control is not achieved and there

• failure to achieve control over cancer breakthrough pain in cases where basic

• the control of basic pain by an opioid analgesic becomes ineffective, a tolerance to the preparation is suspected, and it needs to be changed to another opioid

• pain must be controlled by combining the pharmaceutical treatment and invasive procedures (patient controlled analgesia, pain relief block);

• inappropriate behavior with opioid analgesics is identified or developing of

• repeated multidisciplinary pain assessment and specialized control (special-

• if a cancer patient is given a palliative care nursing home or nursing home and cannot physically access the pain clinic, according to the above indications, the

Following the International Association for the Study of Pain cancer pain is "unpleasant sensory and emotional experience associate with actual or potential tissue damage resulting either from the treatment of cancer or the cancer itself." Due to the complexity of symptoms and multimodality of treatments, cancer pain is built in the most sophisticated field of medicine, where each patient's stage of disease and diagnosis will require an individualized pain treatment plan to optimize the quality of life. Such tasks can only be carried out using multidisciplinary approach. That is why basic knowledge about cancer pain is essential for every healthcare professional. We believe that the text you have just read will help you to

pain clinic staff can consult on arrival at the place of destination.

be an active practitioner giving the patients the cancer pain relief.

The authors acknowledge Lithuanian Pain Society for text support.

Materials from "Cancer induced pain,"(Lithuanian Pain Society's guidelines)

**112**

**Notes**

#### **Author details**

Arūnas Ščiupokas1,2\*, Liuda Brogienė 1,3 and Dalia Skorupskienė 4

1 Pain Clinic, Lithuanian University of Health Sciences Hospital Kauno Klinikos, Kaunas, Lithuania

2 Department of Neurology, Lithuanian University of Health Sciences, Kaunas, Lithuania

3 Department of Anesthesiology, Lithuanian University of Health Sciences, Kaunas, Lithuania

4 Department of Oncology, Lithuanian University of Health Sciences, Kaunas, Lithuania

\*Address all correspondence to: arunas.sciupokas@lsmuni.lt

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[43] Smith TJ, Coyne PJ, Staats PS, Deer T, Stearns LJ, Rauck RL, et al. An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management

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[61] Janknegt R, Van den Beuken M, Schiere S, Überall M, Knaggs R, Hanley J, et al. Rapid acting fentanyl formulations in breakthrough pain in cancer. Drug selection by means of the system of objectified judgement analysis. European Journal of Hospital Pharmacy: Science and Practice. 2018;**25**(3):e2. DOI: 10.1136/ ejhpharm-2016-001127 (Epub January 11, 2017)

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[65] Henley SJ, Singh SD, King J, et al. Invasive cancer incidence and survival—United States, 2012. Morbidity and Mortality Weekly Report. 2015;**64**:1353-1358

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[83] Doyle D, Hanks G, MacDonald L. Oxford Textbook of Palliative Medicine. Oxford: Oxford University Press; 1998

[84] Davies AN et al. Dose titration to individualise treatment. European Journal of Pain. 2009;**13**:331-333

[85] Raphael J et al. Cancer pain: Part 2: Physical, interventional and complimentary therapies;

management in the community; acute,

habits and knowledge base of general practitioners. Journal of Pain and Symptom Management.

2009;**24**(9):1029-1036

2006;**185**(2):122-124

2002;**23**:383-392

2014;**36**:99-104

1994;**9**:67-72

guideline. Journal of Clinical Oncology;**34**:3325-3345

1990;**66**:1117-1123

2005;**23**:6596-6606

2010;**160**:907-918

11):S276-S287

2010;**5**:105-111

2015;**372**:241-248

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[69] Siegal T, Haim N. Cisplatin-induced peripheral neuropathy. Frequent offtherapy deterioration, demyelinating syndromes, and muscle cramps. Cancer.

[70] Syrjala KL, Langer SL, Abrams JR, et al. Late effects of hematopoietic cell transplantation among 10-year adult survivors compared with case matched controls. Journal of Clinical Oncology.

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[72] Samer CF, Daali Y, Wagner M, et al. The effects of CYP2D6 and CYP3A activities on the pharmacokinetics of immediate release oxycodone. British Journal of Pharmacology.

[73] Overholser BR, Foster DR. Opioid

[74] Keller GA, Ponte ML, Di Girolamo G. Other drugs acting on nervous system associated with QT interval prolongation. Current Drug Safety.

[75] Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic abuse and mortality in the United States. The New England Journal of Medicine.

pharmacokinetic drug-drug interactions. The American Journal of Managed Care. 2011;**17**(Suppl

**118**

treatment-related and complex cancer pain: A perspective from the British pain society endorsed by the UK Association of Palliative Medicine and the Royal College of General Practitioners. Pain Medicine. 2010;**11**:872-896

**121**

treatment.

**Chapter 8**

**Abstract**

*Xue-Bin Yan*

**1. Introduction**

opment of this work in clinical treatment.

**2. The definition of breakthrough cancer pain**

Breakthrough Cancer Pain

Breakthrough cancer pain has attracted more and more attentions recently because it has become the biggest obstacle to control cancer pain. Pain can occur at any stage of cancer. Despite the aggressive treatment, some patients still experience high-intensity pain in the short term, which is commonly referred to as breakthrough pain. Typical breakthrough pain has clinical features such as rapid onset and short duration, and it has uncontrollable and unpredictable characteristics, which impact the overall life quality of patients and the therapeutic effect of cancer pain. It has always been a puzzle and difficult in clinical treatment of breakthrough cancer pain. This paper aims to provide a more detailed review of the definition, assessment tools, classification and characteristics, epidemiology, and mechanism and treatment of breakthrough cancer pain, in order to facilitate the future devel-

**Keywords:** breakthrough cancer pain, characteristics, mechanisms, therapy

Pain is one of the most common clinical symptoms associated with malignant tumors. Thirty to forty percent of patients suffer from pain at the beginning of diagnosis [1]. In actively treated patients, this proportion is higher, accounting for 50%, and in advanced cancer, even up to 90% [2]. Although it can effectively control the background pain of most cancer patients according to the WHO threestep analgesic principle, it still suffers from cancer pain. Cancer patients, indeed, may suffer from intense pain spikes that break through the control of chronic pain. Uncontrollable and unpredictable characteristics of a complex manifestation of cancer pain, termed as breakthrough cancer pain (BTP), have always baffled the treatment and the adverse effects including diet, sleep, daily activities, relationships with others, aggravating depression and anxiety and will impact patients' quality of life. Therefore, the control of breakthrough cancer pain is still a very difficult problem for clinicians. In view of the current lack of research data on outbreak pain in China, this paper aims to provide a more detailed review of the breakthrough cancer pain, in order to facilitate the future development of this work in clinical

Background pain in cancer patients manifests as a persistent state of pain (most commonly 12 hours or longer), usually controlled by long-term administration. According to the WHO three-step analgesia program, general background cancer

## **Chapter 8** Breakthrough Cancer Pain

*Xue-Bin Yan*

### **Abstract**

Breakthrough cancer pain has attracted more and more attentions recently because it has become the biggest obstacle to control cancer pain. Pain can occur at any stage of cancer. Despite the aggressive treatment, some patients still experience high-intensity pain in the short term, which is commonly referred to as breakthrough pain. Typical breakthrough pain has clinical features such as rapid onset and short duration, and it has uncontrollable and unpredictable characteristics, which impact the overall life quality of patients and the therapeutic effect of cancer pain. It has always been a puzzle and difficult in clinical treatment of breakthrough cancer pain. This paper aims to provide a more detailed review of the definition, assessment tools, classification and characteristics, epidemiology, and mechanism and treatment of breakthrough cancer pain, in order to facilitate the future development of this work in clinical treatment.

**Keywords:** breakthrough cancer pain, characteristics, mechanisms, therapy

### **1. Introduction**

Pain is one of the most common clinical symptoms associated with malignant tumors. Thirty to forty percent of patients suffer from pain at the beginning of diagnosis [1]. In actively treated patients, this proportion is higher, accounting for 50%, and in advanced cancer, even up to 90% [2]. Although it can effectively control the background pain of most cancer patients according to the WHO threestep analgesic principle, it still suffers from cancer pain. Cancer patients, indeed, may suffer from intense pain spikes that break through the control of chronic pain. Uncontrollable and unpredictable characteristics of a complex manifestation of cancer pain, termed as breakthrough cancer pain (BTP), have always baffled the treatment and the adverse effects including diet, sleep, daily activities, relationships with others, aggravating depression and anxiety and will impact patients' quality of life. Therefore, the control of breakthrough cancer pain is still a very difficult problem for clinicians. In view of the current lack of research data on outbreak pain in China, this paper aims to provide a more detailed review of the breakthrough cancer pain, in order to facilitate the future development of this work in clinical treatment.

### **2. The definition of breakthrough cancer pain**

Background pain in cancer patients manifests as a persistent state of pain (most commonly 12 hours or longer), usually controlled by long-term administration. According to the WHO three-step analgesia program, general background cancer

pain can be adequately controlled in 70–90% of patients [3]. Despite good control of baseline pain, some patients have short-term, short-lived, intense pain episodes. This is called breakthrough cancer pain (BTP) [4].

The first definition of cancer pain is proposed by Portenoy and Hagen in 1989 as the following: BTP is a transient increase in pain, greater than moderate intensity, occurring on moderate- or lower-intensity baseline pain [5]. In the third edition of Oxford palliative medicine textbook, BTP is defined as a transient deterioration of pain experienced by patients with relatively stable and well-controlled baseline pain [6]. In 2009, the UK and Ireland Conservative Treatment Collaborative Committee (APM) put forward the following views on outbreak pain and concluded that as long as the following three conditions are met at the same time, it can be diagnosed as an BTP: (1) having background cancer pain, (2) the background cancer pain adequately controlled in the last week (NRS score ≤ 3 points), and (3) the pain temporarily acutely aggravated [7].

#### **3. Evaluation tools for breakthrough cancer pain**

For cancer patients, the intensity of pain should be assessed at each visit. The most common is the numerical score (NRS). The pain intensity level from 0 to 10 is evaluated as 0 indicating lack of pain (no pain) and 10 indicating the most extreme pain (the most imaginable pain). Visual analog scale (VAS) is also frequently used; patients use a 100 mm length digital scale to describe pain intensity (0, no pain; 100, the most powerful pain imaginable). The descriptive Likert scale (painless, mild pain, moderate pain, strong pain, severe pain) is the least accurate but is usually the most understandable for the patient.

But general tools may not be sufficient to adequately cover the complexity of BTP. Several specific features of BTP are reflected in background pain, treatmentrelated factors (including trigger events and predictability), and time factors. Key factors include relationship to background pain, time to last BTP, frequency, peak pain intensity, position, time from onset to maximum intensity, duration, cause, predictability, general remission, BTP relief, pain satisfaction with relief, the onset of pain relief, and satisfaction with the onset of pain relief. Other items completed by professionals include the etiology of BTP and the pathophysiology of BTP [8]. Understanding these factors is critical to being able to construct an effective analgesic strategy, which is the primary purpose of any pain assessment. The lack of BTP assessment tools may be related to the fact that some authors advocate the use of general pain tools without the need for a separate BTP assessment tool [9, 10]. Recently, a new evaluation tool was developed and validated for BTP (Webber's BAT tool). The assessment tool provides information about BTP and how the efficacy and toxicity of BTP drugs interfere with everyday life, and the reliability and effectiveness of testing in a group of patients is quite good [11].

Portenoy et al. used the Beck Depression Scale (BDI) questionnaire, the beck anxiety scale (BAI) questionnaire, and the baseline pain intensity measurement based on the VAS scale to assess the impact of BTP on quality of life. In 178 patients with well-controlled baseline pain, both groups were extracted and evaluated based on whether they had BTP. In 65% of patients, BTP is caused by cancer, and in other cases it is related to the treatment used. Baseline pain is more severe in patients with BTP. In addition, how pain affects mood, work, sleep, mobility, social relationships, and life satisfaction is also assessed. Each aspect is evaluated over a range of values from 0 to 10 (0, no effect; 10, overall impact). In the case of the BDI and BAI scales, the patient responded to 21 questions, ranging from 0 to 3 (0 for asymptomatic and 3 for highest symptom intensity) [12].

**123**

changes in mood and sleep problems [18].

**5. Epidemiology of breakthrough cancer pain**

*Breakthrough Cancer Pain*

*DOI: http://dx.doi.org/10.5772/intechopen.84581*

(tailored) treatment, and adequate reassessment.

It is worth noting that BTP may have a negative impact on prognosis [13] and may also have an adverse effect on the duration of cancer treatment [14]. Accurate diagnosis of pain types and early introduction of appropriate treatments should be sought. Moreover, in the lack of exhaustive tools, successful BTP diagnosis (and management) is the result of the combination of adequate assessment, appropriate

**4. Classification and characteristics of breakthrough cancer pain**

insufficient control of the underlying cancer pain and that it is not a BTP [7].

BTP is characterized by a rapid onset, usually occurring in a matter of minutes or even seconds (average about 3 minutes), stronger than baseline pain, up to 7 points (NRS score), and very short duration (average 30 minutes) [1]. In a large study of 1412 patients, 80.6% of patients reported a significant negative impact of BTP on daily life. The average number of episodes was 2.4 per day with an average intensity of 7.4/10. In patients reporting a rapid onset of BTP, this is predictable in approximately half of the cases, while BTP with a gradual onset (>10 minutes) is less predictable. The average duration of an untreated episode of BTP was approximately 30 minutes [10]. These characteristics may change during the course of the disease. For example, patients who are receiving palliative care are older, have lower levels of Karnofsky, have fewer BTP episodes per day, and have slower BTP episodes than those assessed in the pain clinic or oncology ward. BTP is less predictable [18]. Davies et al. published the results of a multicenter clinical trial involving 1000 patients treated in 28 professional palliative care units in 13 European countries from 2008 to 2011. Patients were classified as eligible for trial according to a questionnaire on five questions. Forty-four percent of patients were induced by specific factors, 41.5% were idiopathic, and 14.5% were mixed. The results showed that specific factors caused by BTP patients' activity problems and basic daily activities were more frequent, while those with idiopathic pain were more common with

There are wide variations in the estimates of incidence reported in the literature, possibly due to the different backgrounds and implications of the definition

Breakthrough cancer pain can be divided into sporadic pain (incidental pain), spontaneous or idiopathic pain, and discontinuation of drug withdrawal (end of dose). Mixing BTP can also be included as the fourth subtype [15]. Sporadic pain is a common type of BTP, with a shorter peak intensity and a shorter duration, more predictable, often caused directly after muscle or bone activity, such as getting up, turning over, going to toilets, coughs, etc. It can also be associated with contraction or spasm of visceral smooth muscle, such as bowel or bladder spasm, so patients are more willing to limit their activity to avoid triggering BTP, although the duration of pain is unpredictable even after cessation of activity. There is no obvious cause of selfexplosive pain, and the duration of pain is more than 30 minutes. It is generally not directly related to regular analgesic treatment and has no significant correlation with physical activity [16]. In general, when there is sufficient analgesia for most of the day, three to four episodes per day are considered acceptable [17]. Insufficient analgesic drugs are relatively rare. It often occurs at the next point in the continuous analgesic treatment phase for 1–2 hours, and acute pain occurs on the basis of continuous pain treatment. APM believes that the analgesic drug dose-deficient outbreak is caused by

#### *Breakthrough Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84581*

*From Conventional to Innovative Approaches for Pain Treatment*

This is called breakthrough cancer pain (BTP) [4].

**3. Evaluation tools for breakthrough cancer pain**

effectiveness of testing in a group of patients is quite good [11].

ally the most understandable for the patient.

3 for highest symptom intensity) [12].

temporarily acutely aggravated [7].

pain can be adequately controlled in 70–90% of patients [3]. Despite good control of baseline pain, some patients have short-term, short-lived, intense pain episodes.

The first definition of cancer pain is proposed by Portenoy and Hagen in 1989 as the following: BTP is a transient increase in pain, greater than moderate intensity, occurring on moderate- or lower-intensity baseline pain [5]. In the third edition of Oxford palliative medicine textbook, BTP is defined as a transient deterioration of pain experienced by patients with relatively stable and well-controlled baseline pain [6]. In 2009, the UK and Ireland Conservative Treatment Collaborative Committee (APM) put forward the following views on outbreak pain and concluded that as long as the following three conditions are met at the same time, it can be diagnosed as an BTP: (1) having background cancer pain, (2) the background cancer pain adequately controlled in the last week (NRS score ≤ 3 points), and (3) the pain

For cancer patients, the intensity of pain should be assessed at each visit. The most common is the numerical score (NRS). The pain intensity level from 0 to 10 is evaluated as 0 indicating lack of pain (no pain) and 10 indicating the most extreme pain (the most imaginable pain). Visual analog scale (VAS) is also frequently used; patients use a 100 mm length digital scale to describe pain intensity (0, no pain; 100, the most powerful pain imaginable). The descriptive Likert scale (painless, mild pain, moderate pain, strong pain, severe pain) is the least accurate but is usu-

But general tools may not be sufficient to adequately cover the complexity of BTP. Several specific features of BTP are reflected in background pain, treatmentrelated factors (including trigger events and predictability), and time factors. Key factors include relationship to background pain, time to last BTP, frequency, peak pain intensity, position, time from onset to maximum intensity, duration, cause, predictability, general remission, BTP relief, pain satisfaction with relief, the onset of pain relief, and satisfaction with the onset of pain relief. Other items completed by professionals include the etiology of BTP and the pathophysiology of BTP [8]. Understanding these factors is critical to being able to construct an effective analgesic strategy, which is the primary purpose of any pain assessment. The lack of BTP assessment tools may be related to the fact that some authors advocate the use of general pain tools without the need for a separate BTP assessment tool [9, 10]. Recently, a new evaluation tool was developed and validated for BTP (Webber's BAT tool). The assessment tool provides information about BTP and how the efficacy and toxicity of BTP drugs interfere with everyday life, and the reliability and

Portenoy et al. used the Beck Depression Scale (BDI) questionnaire, the beck anxiety scale (BAI) questionnaire, and the baseline pain intensity measurement based on the VAS scale to assess the impact of BTP on quality of life. In 178 patients with well-controlled baseline pain, both groups were extracted and evaluated based on whether they had BTP. In 65% of patients, BTP is caused by cancer, and in other cases it is related to the treatment used. Baseline pain is more severe in patients with BTP. In addition, how pain affects mood, work, sleep, mobility, social relationships, and life satisfaction is also assessed. Each aspect is evaluated over a range of values from 0 to 10 (0, no effect; 10, overall impact). In the case of the BDI and BAI scales, the patient responded to 21 questions, ranging from 0 to 3 (0 for asymptomatic and

**122**

It is worth noting that BTP may have a negative impact on prognosis [13] and may also have an adverse effect on the duration of cancer treatment [14]. Accurate diagnosis of pain types and early introduction of appropriate treatments should be sought. Moreover, in the lack of exhaustive tools, successful BTP diagnosis (and management) is the result of the combination of adequate assessment, appropriate (tailored) treatment, and adequate reassessment.

#### **4. Classification and characteristics of breakthrough cancer pain**

Breakthrough cancer pain can be divided into sporadic pain (incidental pain), spontaneous or idiopathic pain, and discontinuation of drug withdrawal (end of dose). Mixing BTP can also be included as the fourth subtype [15]. Sporadic pain is a common type of BTP, with a shorter peak intensity and a shorter duration, more predictable, often caused directly after muscle or bone activity, such as getting up, turning over, going to toilets, coughs, etc. It can also be associated with contraction or spasm of visceral smooth muscle, such as bowel or bladder spasm, so patients are more willing to limit their activity to avoid triggering BTP, although the duration of pain is unpredictable even after cessation of activity. There is no obvious cause of selfexplosive pain, and the duration of pain is more than 30 minutes. It is generally not directly related to regular analgesic treatment and has no significant correlation with physical activity [16]. In general, when there is sufficient analgesia for most of the day, three to four episodes per day are considered acceptable [17]. Insufficient analgesic drugs are relatively rare. It often occurs at the next point in the continuous analgesic treatment phase for 1–2 hours, and acute pain occurs on the basis of continuous pain treatment. APM believes that the analgesic drug dose-deficient outbreak is caused by insufficient control of the underlying cancer pain and that it is not a BTP [7].

BTP is characterized by a rapid onset, usually occurring in a matter of minutes or even seconds (average about 3 minutes), stronger than baseline pain, up to 7 points (NRS score), and very short duration (average 30 minutes) [1]. In a large study of 1412 patients, 80.6% of patients reported a significant negative impact of BTP on daily life. The average number of episodes was 2.4 per day with an average intensity of 7.4/10. In patients reporting a rapid onset of BTP, this is predictable in approximately half of the cases, while BTP with a gradual onset (>10 minutes) is less predictable. The average duration of an untreated episode of BTP was approximately 30 minutes [10]. These characteristics may change during the course of the disease. For example, patients who are receiving palliative care are older, have lower levels of Karnofsky, have fewer BTP episodes per day, and have slower BTP episodes than those assessed in the pain clinic or oncology ward. BTP is less predictable [18].

Davies et al. published the results of a multicenter clinical trial involving 1000 patients treated in 28 professional palliative care units in 13 European countries from 2008 to 2011. Patients were classified as eligible for trial according to a questionnaire on five questions. Forty-four percent of patients were induced by specific factors, 41.5% were idiopathic, and 14.5% were mixed. The results showed that specific factors caused by BTP patients' activity problems and basic daily activities were more frequent, while those with idiopathic pain were more common with changes in mood and sleep problems [18].

#### **5. Epidemiology of breakthrough cancer pain**

There are wide variations in the estimates of incidence reported in the literature, possibly due to the different backgrounds and implications of the definition of BTP. A multicenter study in the four Nordic countries in 201,135 surveyed the incidence of BTP in 320 patients with cancer pain by issuing questionnaires, all from palliative care centers or pain treatment centers. Of these, 83% had breakthrough cancer pain, in which 44% had sporadic outbreaks, 39% had spontaneous outbreaks, and 17% had both types of pain. On average, there were three outbreaks of pain every 24 hours. The longest interval was 2 times/week, and the shortest interval was 24 times a day. According to the degree of pain, 3% of patients were mild, 37% were moderate, and 60% were severe [8].

In some epidemiological studies, although not verified, the patient's background pain may be uncontrolled or not receiving opioids. For example, in more than half of patients with severe background pain, a different phenomenon than other patients was observed, and patients without BTP had higher background pain intensity. In other studies, most patients had uncontrolled background pain, who received nonopioid analgesics or weak opioids or were dissatisfied with pain management.

#### **6. Mechanisms of breakthrough cancer pain**

The pathogenesis of cancer pain is very complicated. The most common causes are malignant tumor compression and infiltration of pain-sensitive organ structures such as bones, muscle soft tissue, peripheral nerves, internal organs, and the others. There is also atrophy and cancer cachexia, or it may be the result of aggressive anticancer treatment, but the real cause in some patients is unclear [19].

The most common nociceptors associated with cancer pain are afferent nerves, which can transmit various noxious stimuli to the central nervous system through the periphery. Nociceptors mainly have two major functions: transduction of pain signals and transmission of pain signals. Various noxious stimuli can directly activate the nociceptors, transmitting the electrochemical nerve impulse signals generated by the afferent nerves to the central nervous system of the patient, and the patient has a feeling of pain. Cancer and immune cells in the tumor mass region release several neuroimmune mediators that interact with multiple receptors on peripheral nociceptive nerve terminals to promote abnormal discharge and hyperexcitability. In addition, tumors that grow near the peripheral nerve can impair the integrity of the nerve and induce neurological conditions associated with persistent pain, hyperalgesia, or allodynia. Both of these effects of the tumor on the peripheral nerves can lead to central sensitization, which further enhances the efficacy of nociceptive transmission through the spinal dorsal horn and the perception of BTP [20].

During the operation, tissue damage associated with damage to the surrounding small nerves can be caused. After tissue damage, inflammatory mediators and other substances (e.g., histamine, serotonin, nerve growth factor, bradykinin, leukotrienes, prostaglandins, norepinephrine, cytokines, etc.) are damaged at the wound site tissue and inflammatory cells, and sympathetic nerve endings are released. The released material can alter the excitability of nociceptors by phosphorylating and upregulating the cell membrane or upregulating ion channels in the nerve. This peripheral sensitization can explain the increased sensitivity of early postoperative clinical manifestations to mechanical stimulation of the wound site. However, postoperative pain cannot be explained only by peripheral mechanisms. Repetitive, detrimental input from sensitized C fibers causes activation of the signal cascade within the dorsal horn cells, thereby facilitating the response. Central sensitization may explain the increased sensitivity of noninvasive tissue around the wound to mechanical stimulation. Under these conditions, mechanical stimulation caused by exercise and cough may cause BTP [21].

**125**

*Breakthrough Cancer Pain*

analgesic treatment [22].

sensitization [23].

role in cancerous outbreaks [24].

**7. Treatment of breakthrough cancer pain**

fentanyl transdermal patches or MS contin) up to 150 mg/d.

*DOI: http://dx.doi.org/10.5772/intechopen.84581*

Recent studies have found that specific nuclei located in the posterior thalamus

Visceral pain may be located in the visceral or distant body parts. Two types of nociceptors dominate the internal organs: high threshold receptors and intensityencoded mechanoreceptors. In addition, the presence of "silent" nociceptors has been found. "Silent" nociceptors are activated in the event of tissue damage or inflammation and may contribute to the signaling of chronic visceral pain. High threshold nociceptors may be activated in acute pain states. For example, prolonged

stimulation of the internal organs, such as inflammation, may sensitize high threshold nociceptors and activate "silent" nociceptors. Sensitized nociceptors may now also respond to harmless stimuli. Increased peripheral neuronal activity results in increased excitability in the visceral-somatic neurons in the spinal cord (central sensitization). For example, BTP caused by food intake can be explained by sensitization of visceral mechanoreceptors, and the increase in pain area is due to central

Our team found that the activation of astrocytes in the dorsal horn of spinal cord and connexin 43 (Cx43) protein is involved in the process of bone pain in bone metastases in mice. The total amount of Cx43 protein and phosphorylation may be important factors affecting cancer outbreak pain factor. Gap 26 blocks the gap junction channel of the spinal dorsal horn, which can improve the pain behavior index of mice with cancerous outbreak pain and downregulate the expression of Cx43 protein, which can regulate the pain of cancerous outbreak. The spinal dorsal horn EAAT1 protein is involved in the pathogenesis of mouse basic cancer pain, and EAAT2 protein has an effect on the occurrence and maintenance of bone metastases. Activation of EAAT2 by Cef improves its pain behavioral metrics and regulates burst pain. Cx43 can affect the protein expression of EAATs but EAAT2 does not affect the expression of Cx43 protein. Spinal dorsal horn Cx43-EAATs may play a

Treatment with BTP includes medication, nerve block, nerve damage, TNES, palliative exposure to bone lesions, the use of bisphosphonates, and identification and prevention of factors that induce BTP (e.g., excessive physical labor, persistent cough, constipation). The NCCN guidelines for adult cancer pain [25] recommends the use of 10–15% of immediate-release opioids in total daily analgesics to treat BTP. If the number of outbreaks of pain per day exceeds 4 times, the amount of the basic analgesic drug is raised. Opioid analgesics have no ceiling effect. For severe refractory pain, high-dose opioid controlled-release preparations are often needed for analgesic treatment. Large doses are defined as daily doses of oxycodone sustained-release tablets (or equivalent doses of other opioid analgesics such as

are associated with pain-related networks. Related studies have found that the most effective inhibitors of noxious stimuli are β-endorphin, enkephalin, and dynorphin. The most common precursor of β-endorphin is proopiomelanocortin; the precursor of enkephalin and leucine enkephalin is mainly proenkephalin-A (pro-ENK); the precursor of dynorphin is enkephalin original B. Β-Endorphin mainly binds to opioid receptors, and enkephalin mainly binds to opioid receptors, and dynorphin mainly binds to opioid κ receptors. The commonly used opioids, oxycodone and morphine sustained-release tablets, are combined with receptors and/or K receptors to mimic the action of endogenous opioid peptides to achieve

#### *Breakthrough Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84581*

*From Conventional to Innovative Approaches for Pain Treatment*

mild, 37% were moderate, and 60% were severe [8].

**6. Mechanisms of breakthrough cancer pain**

of BTP. A multicenter study in the four Nordic countries in 201,135 surveyed the incidence of BTP in 320 patients with cancer pain by issuing questionnaires, all from palliative care centers or pain treatment centers. Of these, 83% had breakthrough cancer pain, in which 44% had sporadic outbreaks, 39% had spontaneous outbreaks, and 17% had both types of pain. On average, there were three outbreaks of pain every 24 hours. The longest interval was 2 times/week, and the shortest interval was 24 times a day. According to the degree of pain, 3% of patients were

In some epidemiological studies, although not verified, the patient's background pain may be uncontrolled or not receiving opioids. For example, in more than half of patients with severe background pain, a different phenomenon than other patients was observed, and patients without BTP had higher background pain intensity. In other studies, most patients had uncontrolled background pain, who received nonopioid analgesics or weak opioids or were dissatisfied with pain management.

The pathogenesis of cancer pain is very complicated. The most common causes are malignant tumor compression and infiltration of pain-sensitive organ structures such as bones, muscle soft tissue, peripheral nerves, internal organs, and the others. There is also atrophy and cancer cachexia, or it may be the result of aggressive anticancer treatment, but the real cause in some patients is unclear [19].

The most common nociceptors associated with cancer pain are afferent nerves, which can transmit various noxious stimuli to the central nervous system through the periphery. Nociceptors mainly have two major functions: transduction of pain signals and transmission of pain signals. Various noxious stimuli can directly activate the nociceptors, transmitting the electrochemical nerve impulse signals generated by the afferent nerves to the central nervous system of the patient, and the patient has a feeling of pain. Cancer and immune cells in the tumor mass region release several neuroimmune mediators that interact with multiple receptors on peripheral nociceptive nerve terminals to promote abnormal discharge and hyperexcitability. In addition, tumors that grow near the peripheral nerve can impair the integrity of the nerve and induce neurological conditions associated with persistent pain, hyperalgesia, or allodynia. Both of these effects of the tumor on the peripheral nerves can lead to central sensitization, which further enhances the efficacy of nociceptive transmission through the spinal dorsal horn and the perception of BTP [20]. During the operation, tissue damage associated with damage to the surrounding small nerves can be caused. After tissue damage, inflammatory mediators and other substances (e.g., histamine, serotonin, nerve growth factor, bradykinin, leukotrienes, prostaglandins, norepinephrine, cytokines, etc.) are damaged at the wound site tissue and inflammatory cells, and sympathetic nerve endings are released. The released material can alter the excitability of nociceptors by phosphorylating and upregulating the cell membrane or upregulating ion channels in the nerve. This peripheral sensitization can explain the increased sensitivity of early postoperative clinical manifestations to mechanical stimulation of the wound site. However, postoperative pain cannot be explained only by peripheral mechanisms. Repetitive, detrimental input from sensitized C fibers causes activation of the signal cascade within the dorsal horn cells, thereby facilitating the response. Central sensitization may explain the increased sensitivity of noninvasive tissue around the wound to mechanical stimulation. Under these conditions, mechanical stimulation caused by

**124**

exercise and cough may cause BTP [21].

Recent studies have found that specific nuclei located in the posterior thalamus are associated with pain-related networks. Related studies have found that the most effective inhibitors of noxious stimuli are β-endorphin, enkephalin, and dynorphin. The most common precursor of β-endorphin is proopiomelanocortin; the precursor of enkephalin and leucine enkephalin is mainly proenkephalin-A (pro-ENK); the precursor of dynorphin is enkephalin original B. Β-Endorphin mainly binds to opioid receptors, and enkephalin mainly binds to opioid receptors, and dynorphin mainly binds to opioid κ receptors. The commonly used opioids, oxycodone and morphine sustained-release tablets, are combined with receptors and/or K receptors to mimic the action of endogenous opioid peptides to achieve analgesic treatment [22].

Visceral pain may be located in the visceral or distant body parts. Two types of nociceptors dominate the internal organs: high threshold receptors and intensityencoded mechanoreceptors. In addition, the presence of "silent" nociceptors has been found. "Silent" nociceptors are activated in the event of tissue damage or inflammation and may contribute to the signaling of chronic visceral pain. High threshold nociceptors may be activated in acute pain states. For example, prolonged stimulation of the internal organs, such as inflammation, may sensitize high threshold nociceptors and activate "silent" nociceptors. Sensitized nociceptors may now also respond to harmless stimuli. Increased peripheral neuronal activity results in increased excitability in the visceral-somatic neurons in the spinal cord (central sensitization). For example, BTP caused by food intake can be explained by sensitization of visceral mechanoreceptors, and the increase in pain area is due to central sensitization [23].

Our team found that the activation of astrocytes in the dorsal horn of spinal cord and connexin 43 (Cx43) protein is involved in the process of bone pain in bone metastases in mice. The total amount of Cx43 protein and phosphorylation may be important factors affecting cancer outbreak pain factor. Gap 26 blocks the gap junction channel of the spinal dorsal horn, which can improve the pain behavior index of mice with cancerous outbreak pain and downregulate the expression of Cx43 protein, which can regulate the pain of cancerous outbreak. The spinal dorsal horn EAAT1 protein is involved in the pathogenesis of mouse basic cancer pain, and EAAT2 protein has an effect on the occurrence and maintenance of bone metastases. Activation of EAAT2 by Cef improves its pain behavioral metrics and regulates burst pain. Cx43 can affect the protein expression of EAATs but EAAT2 does not affect the expression of Cx43 protein. Spinal dorsal horn Cx43-EAATs may play a role in cancerous outbreaks [24].

#### **7. Treatment of breakthrough cancer pain**

Treatment with BTP includes medication, nerve block, nerve damage, TNES, palliative exposure to bone lesions, the use of bisphosphonates, and identification and prevention of factors that induce BTP (e.g., excessive physical labor, persistent cough, constipation). The NCCN guidelines for adult cancer pain [25] recommends the use of 10–15% of immediate-release opioids in total daily analgesics to treat BTP. If the number of outbreaks of pain per day exceeds 4 times, the amount of the basic analgesic drug is raised. Opioid analgesics have no ceiling effect. For severe refractory pain, high-dose opioid controlled-release preparations are often needed for analgesic treatment. Large doses are defined as daily doses of oxycodone sustained-release tablets (or equivalent doses of other opioid analgesics such as fentanyl transdermal patches or MS contin) up to 150 mg/d.

#### **7.1 Drugs**

Opioids are still the most important and effective drugs for the treatment of breakthrough cancer pain [26]. The main opioids currently used to treat BTP are morphine immediate-release tablets, oxycodone sustained-release tablets, fentanyl sublingual tablets (SLF), morphine sustained-release tablets and controlled-release tablets, fentanyl nasal spray (INFS), fentanyl transmucosal citrate (OTFC), morphine sulfate (injection), sufentanil injection (injection), and so on. The above various types of morphine agonists work in combination with secretory opioid receptors, which produce analgesic effects after agonizing the receptor.

Oral administration is the most common route of administration for cancerous outbreaks and is the recommended route of administration by the WHO. The NICE guidelines recommend immediate-release of morphine for BTP first-line first-aid drugs and do not provide fentanyl as a first-line rescue drug but morphine. The onset and duration of immediate-release tablets may not be suitable for the treatment of many BTP events [27]. Oxycodone sustained-release tablets can be used as a two-step drug or as a three-step analgesic drug, which can simultaneously agonize both receptors and K receptor opioid receptors, with high bioavailability and clinical good analgesic effect and less drug-related adverse reactions [22]; the analgesic intensity is about twice that of morphine immediate-release tablets. After oral administration, there will be two release phases, which provide early onset of rapid analgesia. The fast release phase and the subsequent sustained-release phase, through the rapid release phase to achieve the purpose of treating burst pain, do not require conversion of the dosage form; clinical application of oxycodone controlledrelease tablets is more and more extensive.

In order to evaluate the efficacy of oral morphine and oral transmucosal fentanyl preparations to provide further insight into their relative merits as treatments for BTP, we conducted an analysis to compare the effects of fentanyl, morphine, and placebo on BTP indirectly (**Table 1**, **Figures 1**–**6**). The therapeutic effect was evaluated by the difference in pain intensity difference (PID) score. We found that all opioids provided better analgesic effects during the first hour after dosing, whereas fentanyl may provide a higher level of pain relief than oral morphine. Participants administered a transmucosal fentanyl showed lower pain intensity and higher pain relief at all time points than placebo or oral morphine, and the fentanyl achieved significant pain relief faster. But there is no significant difference between the various transmucosal fentanyl preparations. From the PID score, the analgesic effect of fentanyl is stronger than oral morphine. And improvements in pain relief were apparent within 30 minutes of treatment, with the PID being larger for the fentanyl preparations than for MSIR during this period. This is of potential importance because most BTP episodes occur within 30 minutes. However, there are few existing studies, especially regarding the comparison of fentanyl with oral morphine, which is a limitation of this mixed treatment. Moreover, the possibility of systematic differences between undetected data sources for heterogeneity analysis cannot be ruled out. In conclusion, although oral morphine is still an appropriate treatment option for BTP, oral transmucosal fentanyl may be more clinically advantageous in some patients.

The recently published guidelines support this approach and recommend the use of fast- or short-acting opioids to treat BTP, whose pharmacodynamics reflect the rapid onset and short duration of pain [28]. The Cochrane review reported the utility of seven different transmucosal fentanyl compared to oral opioids. Oral and nasal transmucosal fentanyls are an effective treatment for BTP [29]. The drugs such as fentanyl oral effervescent tablets and fentanyl sublingual tablets have also

**127**

**Fentanyl (F) and placebo/morphine PID (C)**

**Study**

**5 minutes**

> **F**

N

N

2.58

1.22

N

N

N

N

N

N

4.57

2.46

INFS vs. placebo

(HANS2009 [33])

INFS vs. placebo

0.59

0.49

1.32

0.93

1.96

1.33

2.69

1.73

3.19

2.08

3.57

2.21

(RUSSELL2010 [34])

INFS vs. placebo

N

N

2.4

1.5

N

N

N

N

N

N

N

N

(MORTEN2015 [35])

INFS vs. IRMS

1

1

2.02

1.8

3.22

2.68

4.38

3.64

4.95

4.47

5.58

5

(FALLON2011 [36])

SFT vs. placebo

N

N

N

N

2.43

2.06

4.11

3.39

N

N

5.58

4.52

(NAOHITO2015 [37])

SFT vs. placebo

N

N

1.2

0.92

2.04

1.51

2.94

2.1

N

N

3.45

2.51

(RANCK2009 [38])

SFT vs. placebo

0.7

0.5

1.6

1.1

2.6

1.8

3.5

2.5

N

N

3.9

2.7

(NOVOTNA2014 [39])

SFT vs. placebo

N

N

N

N

N

N

3.18

2.7

N

N

N

N

(NAOHITO2015 [40])

OTFC vs. placebo

0.3

0.3

0.8

0.7

1.4

1.2

2.5

1.9

3

2.3

3.3

2.4

(RAUCK2009 [41])

OTFC vs. IRMS

N

N

N

N

1.86

1.46

2.88

2.4

3.55

3.03

4.03

3.57

(PAUL2001 [42])

**Table 1.** *META analysis data*

**C**

**F**

**C**

**F**

**C**

**F**

**C**

**F**

**C**

**F**

**C**

**10 minutes**

**15 minutes**

**30 minutes**

**45 minutes**

**60 minutes**

*Breakthrough Cancer Pain*

*DOI: http://dx.doi.org/10.5772/intechopen.84581*


#### *Breakthrough Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84581*

*From Conventional to Innovative Approaches for Pain Treatment*

release tablets is more and more extensive.

Opioids are still the most important and effective drugs for the treatment of breakthrough cancer pain [26]. The main opioids currently used to treat BTP are morphine immediate-release tablets, oxycodone sustained-release tablets, fentanyl sublingual tablets (SLF), morphine sustained-release tablets and controlled-release tablets, fentanyl nasal spray (INFS), fentanyl transmucosal citrate (OTFC), morphine sulfate (injection), sufentanil injection (injection), and so on. The above various types of morphine agonists work in combination with secretory opioid receptors, which produce analgesic effects after agonizing

Oral administration is the most common route of administration for cancerous outbreaks and is the recommended route of administration by the WHO. The NICE guidelines recommend immediate-release of morphine for BTP first-line first-aid drugs and do not provide fentanyl as a first-line rescue drug but morphine. The onset and duration of immediate-release tablets may not be suitable for the treatment of many BTP events [27]. Oxycodone sustained-release tablets can be used as a two-step drug or as a three-step analgesic drug, which can simultaneously agonize both receptors and K receptor opioid receptors, with high bioavailability and clinical good analgesic effect and less drug-related adverse reactions [22]; the analgesic intensity is about twice that of morphine immediate-release tablets. After oral administration, there will be two release phases, which provide early onset of rapid analgesia. The fast release phase and the subsequent sustained-release phase, through the rapid release phase to achieve the purpose of treating burst pain, do not require conversion of the dosage form; clinical application of oxycodone controlled-

In order to evaluate the efficacy of oral morphine and oral transmucosal fentanyl preparations to provide further insight into their relative merits as treatments for BTP, we conducted an analysis to compare the effects of fentanyl, morphine, and placebo on BTP indirectly (**Table 1**, **Figures 1**–**6**). The therapeutic effect was evaluated by the difference in pain intensity difference (PID) score. We found that all opioids provided better analgesic effects during the first hour after dosing, whereas fentanyl may provide a higher level of pain relief than oral morphine. Participants administered a transmucosal fentanyl showed lower pain intensity and higher pain relief at all time points than placebo or oral morphine, and the fentanyl achieved significant pain relief faster. But there is no significant difference between the various transmucosal fentanyl preparations. From the PID score, the analgesic effect of fentanyl is stronger than oral morphine. And improvements in pain relief were apparent within 30 minutes of treatment, with the PID being larger for the fentanyl preparations than for MSIR during this period. This is of potential importance because most BTP episodes occur within 30 minutes. However, there are few existing studies, especially regarding the comparison of fentanyl with oral morphine, which is a limitation of this mixed treatment. Moreover, the possibility of systematic differences between undetected data sources for heterogeneity analysis cannot be ruled out. In conclusion, although oral morphine is still an appropriate treatment option for BTP, oral transmucosal fentanyl may be more clinically advantageous in

The recently published guidelines support this approach and recommend the use of fast- or short-acting opioids to treat BTP, whose pharmacodynamics reflect the rapid onset and short duration of pain [28]. The Cochrane review reported the utility of seven different transmucosal fentanyl compared to oral opioids. Oral and nasal transmucosal fentanyls are an effective treatment for BTP [29]. The drugs such as fentanyl oral effervescent tablets and fentanyl sublingual tablets have also

**7.1 Drugs**

the receptor.

**126**

some patients.

**Table 1.** *META analysis data*


#### **Figure 1.**

*Fentanyl versus placebo/morphine PID 5 minutes.*


#### **Figure 2.**

*Fentanyl versus placebo/morphine PID 10 minutes.*


#### **Figure 3.**

*Fentanyl versus placebo/morphine PID 15 minutes.*


#### **Figure 4.**

*Fentanyl versus placebo/morphine PID 30 minutes.*


**129**

*Breakthrough Cancer Pain*

**Figure 6.**

to other treatments [30].

**7.2 Cell therapy**

**7.3 Gene therapy**

peutic purposes.

an opiate rescuer naloxone is prepared at the bedside.

(PCIA), epidural (PCEA), and subcutaneous (PCPA).

cells, sympathetic ganglion cells, and some neurotumor cells.

*DOI: http://dx.doi.org/10.5772/intechopen.84581*

*Fentanyl versus placebo/morphine PID 60 minutes.*

been approved for use in European and American countries. However, the state of oral mucosa, drug distribution, and oral infections will affect the absorption of drugs, thus affecting the analgesic effect of drugs. Fentanyl nasal spray (INFS) has been approved by the European Commission in 2009 and has been officially used in the clinic. It has been marketed globally and is mainly used for outbreak pain in cancer patients who maintain analgesic treatment with drugs such as oral opioids. Treatment: nasal mucosal sprays are suitable for those with oral mucosal damage or saliva dysfunction, but those with nasal mucosal bleeding or ulcers need to switch

Both morphine sulfate injection and sufentanil citrate injection can be administered intravenously. Intravenous use of opioids has a fast onset and a positive effect [31, 32]. However, it is necessary to evaluate the pain every 15 minutes, and should be alert to the acute side effects of drugs such as respiratory depression [32], vomiting, dizziness, acute urinary retention, etc., especially acute respiratory depression, severe cases can be directly life-threatening, so opioid veins The application should be performed in a ward with emergency conditions or in an emergency ward, and

Individualized doses and modes of administration can also be tailored to the condition, and stable morphine is delivered to the human body via intravenous

Cell treatment is to return autologous cells cultured in vitro to patients. Through

Gene therapy refers to a method of achieving analgesic effects by altering gene expression in a patient. It can be divided into in vivo pathways and in vitro pathways. In vitro route refers to the removal of target cells from the body or the adoption of cell lines and the in vitro introduction of therapeutic genes into the body for therapeutic purposes. In vivo route refers to the direct introduction of therapeutic genes into the body. In pain research, there are two main aspects of gene therapy, namely, by upregulating anti-pain gene expression and downregulating pain gene expression, specifically interfering with the biological behavior of pain for thera-

these cells with biological micro-pump function, they can continue to secrete analgesic substances to relieve pain or improve pain thresholds, such as serotonin, norepinephrine, dynorphin, enkephalin, neurotrophic factor, etc., to achieve the purpose of relieving cancer pain or improving the pain threshold of patients. The most extensive and intensive research is the analgesic effect of adrenal chromaffin

#### **Figure 5.**

*Fentanyl versus placebo/morphine PID 45 minutes.*

#### *Breakthrough Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84581*

#### **Figure 6.**

*From Conventional to Innovative Approaches for Pain Treatment*

**128**

**Figure 5.**

**Figure 3.**

**Figure 1.**

**Figure 2.**

**Figure 4.**

*Fentanyl versus placebo/morphine PID 15 minutes.*

*Fentanyl versus placebo/morphine PID 10 minutes.*

*Fentanyl versus placebo/morphine PID 5 minutes.*

*Fentanyl versus placebo/morphine PID 30 minutes.*

*Fentanyl versus placebo/morphine PID 45 minutes.*

*Fentanyl versus placebo/morphine PID 60 minutes.*

been approved for use in European and American countries. However, the state of oral mucosa, drug distribution, and oral infections will affect the absorption of drugs, thus affecting the analgesic effect of drugs. Fentanyl nasal spray (INFS) has been approved by the European Commission in 2009 and has been officially used in the clinic. It has been marketed globally and is mainly used for outbreak pain in cancer patients who maintain analgesic treatment with drugs such as oral opioids. Treatment: nasal mucosal sprays are suitable for those with oral mucosal damage or saliva dysfunction, but those with nasal mucosal bleeding or ulcers need to switch to other treatments [30].

Both morphine sulfate injection and sufentanil citrate injection can be administered intravenously. Intravenous use of opioids has a fast onset and a positive effect [31, 32]. However, it is necessary to evaluate the pain every 15 minutes, and should be alert to the acute side effects of drugs such as respiratory depression [32], vomiting, dizziness, acute urinary retention, etc., especially acute respiratory depression, severe cases can be directly life-threatening, so opioid veins The application should be performed in a ward with emergency conditions or in an emergency ward, and an opiate rescuer naloxone is prepared at the bedside.

Individualized doses and modes of administration can also be tailored to the condition, and stable morphine is delivered to the human body via intravenous (PCIA), epidural (PCEA), and subcutaneous (PCPA).

#### **7.2 Cell therapy**

Cell treatment is to return autologous cells cultured in vitro to patients. Through these cells with biological micro-pump function, they can continue to secrete analgesic substances to relieve pain or improve pain thresholds, such as serotonin, norepinephrine, dynorphin, enkephalin, neurotrophic factor, etc., to achieve the purpose of relieving cancer pain or improving the pain threshold of patients. The most extensive and intensive research is the analgesic effect of adrenal chromaffin cells, sympathetic ganglion cells, and some neurotumor cells.

#### **7.3 Gene therapy**

Gene therapy refers to a method of achieving analgesic effects by altering gene expression in a patient. It can be divided into in vivo pathways and in vitro pathways. In vitro route refers to the removal of target cells from the body or the adoption of cell lines and the in vitro introduction of therapeutic genes into the body for therapeutic purposes. In vivo route refers to the direct introduction of therapeutic genes into the body. In pain research, there are two main aspects of gene therapy, namely, by upregulating anti-pain gene expression and downregulating pain gene expression, specifically interfering with the biological behavior of pain for therapeutic purposes.

#### **7.4 Interventional neuroradiologic therapy**

Nerve block and nerve damage are one of the main treatments for cancer pain by blocking the pain transmission pathway. The current clinical damage treatment is damage to peripheral nerves, nerve roots, celiac plexus, subarachnoid space, and pituitary gland. Before the operation, physical examination and imaging methods were used to fully determine the pain range of the patient, and the nerves to be controlled were determined. Under the guidance of CT, the target nerve was destroyed by means of anhydrous alcohol, chemotherapy drugs such as doxorubicin, or physical ablation. Analgesic effect, with positive effect, fast onset, and little effect on other organ functions, has unique advantages for outbreak pain and intractable cancer pain that are ineffective for medical treatment. Currently, nerve blockers or lesions often have anesthesiologists, or the implementation of pain specialists in specialist hospitals has extremely high requirements for the operation of doctors in the positioning of nerves and imaging; otherwise it is likely to cause serious consequences.

#### **8. Summary**

Breakthrough cancer pain is a type of problem that clinicians urgently need to solve. There is currently no recognized definition and classification system for cancer BTP, and there are no well-proven BTP assessment tools that pose significant challenges to clinical management. Although breakthrough cancer pain has common clinical features, there are significant differences between individuals, which require clinicians to emphasize the importance of individualized, multidisciplinary analgesic programs on the basis of comprehensive treatment. In short, the current overall treatment effect of breakthrough cancer pain is not good; it is worthy of our attention.

#### **Author details**

Xue-Bin Yan The Third Xiang-Ya Hospital of Central South University, Changsha, China

\*Address all correspondence to: yanxb999@126.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**131**

*Breakthrough Cancer Pain*

2002;**24**(1):45-52

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.84581*

[1] Xavier GB, Federico M, Francisco M,

[9] Andrew ND. Cancer-related breakthrough pain. British Journal of Hospital Medicine. 2006;**67**(8):414-416

2007;**8**(suppl 1):S3-S7

2014;**48**(4):619-631

Pain. 1999;**81**(1-2):129-134

Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain.

2003;**101**(1-2):55-64

2003;**20**(2):140-148

2010;**4**(3):181-185

2015;**28**(5):559-564

[10] Payne R. Recognition and diagnosis of breakthrough pain. Pain Medicine.

[11] Webber K, Davies AN, Zeppetella G, et al. Development and validation of the breakthrough pain assessment tool (BAT) in cancer patients. Journal of Pain and Symptom Management.

[12] Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: Characteristics and impact in patients with cancer pain.

[13] Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assessment of the Edmonton staging system for cancer pain. Journal of Pain and Symptom Management. 1995;**10**(5):348-355

[14] Hwang SS, Chang VT, Kasimis B.

[15] Gutgsell T, Walsh D, Zhukovsky DS,

[16] Porta-Sales J. Breakthrough cancer pain and current treatment options. European Journal of Pain Supplements.

[17] Mercadante S. Breakthrough pain in cancer patients: Prevalence, mechanisms and treatment options. Current Opinion in Anaesthesiology.

et al. A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. American Journal of Hospice & Palliative Medicine.

et al. Breakthrough cancer pain: Prevalence and characteristics in patients in Catalonia, Spain. Journal of Pain and Symptom Management.

[2] Lesage P, Portenoy RK. Trends in cancer pain management. Cancer

[3] World Health Organization. Cancer Pain Relief: With a Guide to Opioid Availability. 2nd ed. Geneva: World Health Organization; 1996. http://www. who.int/iris/handle/10665/37896

Control. 1999;**6**(2):136-145

[4] Portenoy RK, Hagen NA. Breakthrough pain: Definition, prevalence and characteristics. Pain.

[5] Portenoy RK, Hagen NA. Breakthrough pain: Definition and management. Oncology. 1989;**3**(8

[6] Portenoy R, Forbes K, Lussier D, et al. Difficult pain problems: An integrated approach. In: Oxford Textbook of Palliative Medicine. Vol. 3. Oxford University Press (OUP); 2004. pp. 438-458. ISBN: 978-0-199-65609-7

[7] Davies AN, Dickman A, Reid C, et al. The management of cancer-related breakthrough pain: Recommendations

[8] Mercadante S, Marchetti P, Cuomo A, et al. Breakthrough pain and its treatment: Critical review and recommendations of IOPS (Italian oncologic pain survey) expert group. Supportive Care in Cancer.

of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. European Journal of Pain.

2009;**13**(4):331-338

2016;**24**(2):961-968

1990;**41**(3):273-281

Suppl):25-29

*Breakthrough Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84581*

#### **References**

*From Conventional to Innovative Approaches for Pain Treatment*

Nerve block and nerve damage are one of the main treatments for cancer pain by blocking the pain transmission pathway. The current clinical damage treatment is damage to peripheral nerves, nerve roots, celiac plexus, subarachnoid space, and pituitary gland. Before the operation, physical examination and imaging methods were used to fully determine the pain range of the patient, and the nerves to be controlled were determined. Under the guidance of CT, the target nerve was destroyed by means of anhydrous alcohol, chemotherapy drugs such as doxorubicin, or physical ablation. Analgesic effect, with positive effect, fast onset, and little effect on other organ functions, has unique advantages for outbreak pain and intractable cancer pain that are ineffective for medical treatment. Currently, nerve blockers or lesions often have anesthesiologists, or the implementation of pain specialists in specialist hospitals has extremely high requirements for the operation of doctors in the positioning of nerves and imaging; otherwise it is likely to cause serious

Breakthrough cancer pain is a type of problem that clinicians urgently need to solve. There is currently no recognized definition and classification system for cancer BTP, and there are no well-proven BTP assessment tools that pose significant challenges to clinical management. Although breakthrough cancer pain has common clinical features, there are significant differences between individuals, which require clinicians to emphasize the importance of individualized, multidisciplinary analgesic programs on the basis of comprehensive treatment. In short, the current overall treatment effect of breakthrough cancer pain is not good; it is worthy of our

**7.4 Interventional neuroradiologic therapy**

**130**

**Author details**

consequences.

**8. Summary**

attention.

Xue-Bin Yan

provided the original work is properly cited.

\*Address all correspondence to: yanxb999@126.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

The Third Xiang-Ya Hospital of Central South University, Changsha, China

[1] Xavier GB, Federico M, Francisco M, et al. Breakthrough cancer pain: Prevalence and characteristics in patients in Catalonia, Spain. Journal of Pain and Symptom Management. 2002;**24**(1):45-52

[2] Lesage P, Portenoy RK. Trends in cancer pain management. Cancer Control. 1999;**6**(2):136-145

[3] World Health Organization. Cancer Pain Relief: With a Guide to Opioid Availability. 2nd ed. Geneva: World Health Organization; 1996. http://www. who.int/iris/handle/10665/37896

[4] Portenoy RK, Hagen NA. Breakthrough pain: Definition, prevalence and characteristics. Pain. 1990;**41**(3):273-281

[5] Portenoy RK, Hagen NA. Breakthrough pain: Definition and management. Oncology. 1989;**3**(8 Suppl):25-29

[6] Portenoy R, Forbes K, Lussier D, et al. Difficult pain problems: An integrated approach. In: Oxford Textbook of Palliative Medicine. Vol. 3. Oxford University Press (OUP); 2004. pp. 438-458. ISBN: 978-0-199-65609-7

[7] Davies AN, Dickman A, Reid C, et al. The management of cancer-related breakthrough pain: Recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. European Journal of Pain. 2009;**13**(4):331-338

[8] Mercadante S, Marchetti P, Cuomo A, et al. Breakthrough pain and its treatment: Critical review and recommendations of IOPS (Italian oncologic pain survey) expert group. Supportive Care in Cancer. 2016;**24**(2):961-968

[9] Andrew ND. Cancer-related breakthrough pain. British Journal of Hospital Medicine. 2006;**67**(8):414-416

[10] Payne R. Recognition and diagnosis of breakthrough pain. Pain Medicine. 2007;**8**(suppl 1):S3-S7

[11] Webber K, Davies AN, Zeppetella G, et al. Development and validation of the breakthrough pain assessment tool (BAT) in cancer patients. Journal of Pain and Symptom Management. 2014;**48**(4):619-631

[12] Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: Characteristics and impact in patients with cancer pain. Pain. 1999;**81**(1-2):129-134

[13] Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assessment of the Edmonton staging system for cancer pain. Journal of Pain and Symptom Management. 1995;**10**(5):348-355

[14] Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain characteristics and responses to treatment at a VA medical center. Pain. 2003;**101**(1-2):55-64

[15] Gutgsell T, Walsh D, Zhukovsky DS, et al. A prospective study of the pathophysiology and clinical characteristics of pain in a palliative medicine population. American Journal of Hospice & Palliative Medicine. 2003;**20**(2):140-148

[16] Porta-Sales J. Breakthrough cancer pain and current treatment options. European Journal of Pain Supplements. 2010;**4**(3):181-185

[17] Mercadante S. Breakthrough pain in cancer patients: Prevalence, mechanisms and treatment options. Current Opinion in Anaesthesiology. 2015;**28**(5):559-564

[18] Davies A, Buchanan A, Zeppetella G, et al. Breakthrough cancer pain: An observational study of 1000 European oncology patients. Journal of Pain and Symptom Management. 2013;**46**(5):619-628

[19] Svendsen KB, Andersen S, Arnason S, et al. Breakthrough pain in malignant and non-malignant diseases: A review of prevalence, characteristics and mechanisms. European Journal of Pain. 2005;**9**(2):195-206

[20] Schmidt BL, Hamamoto DT, Simone DA, et al. Mechanism of cancer pain. Molecular Interventions. 2010;**10**(3):164

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[22] Cheng Y, Yu S-y. Mechanism of cancer pain and the analgesia mechanism of common opiate drugs. Drug Evaluation. 2012;**3**:6-9

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[32] Elsner F, Sabatowski R, Radbruch L. Emergency pain treatment-ambulatory intravenous morphine titration in a patient with cancer pain. Anästhesiologie Intensivmedizin Notfallmedizin Schmerztherapie. 2000;**35**(7):462-464

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[34] Portenoy RK, Burton AW, Gabrail N, et al. A multicenter, placebocontrolled, double-blind, multiplecrossover study of fentanyl pectin nasal spray (FPNS) in the treatment of breakthrough cancer pain. Pain.

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[36] Fallon M, Reale C, Davies A, et al. Efficacy and safety of fentanyl pectin nasal spray compared with immediaterelease morphine sulfate tablets in the treatment of breakthrough cancer pain: A multicenter, randomized, controlled, double-blind, double-dummy multiple-

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[38] Rauck RL, Tark M, Reyes E, et al. Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain. Current Medical Research and Opinion. 2009;**25**(12):2877-2885

[39] Novotna S, Valentova K, Fricova J, et al. A randomized, placebo-controlled study of a new sublingual formulation of fentanyl citrate (fentanyl ethypharm)

[40] Naohito S, Ikuo G, Osamu T, et al. Efficacy and safety of sublingual fentanyl orally disintegrating tablet at

for breakthrough pain in opioidtreated patients with cancer. Clinical Therapeutics. 2014;**36**(3):357-367

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[37] Shimoyama N, Gomyo I, Katakami

sublingual fentanyl orally disintegrating tablet at doses determined by titration for the treatment of breakthrough pain in Japanese cancer patients: A multicenter, randomized, placebocontrolled, double-blind phase III trial. International Journal of Clinical

#### *Breakthrough Cancer Pain DOI: http://dx.doi.org/10.5772/intechopen.84581*

*From Conventional to Innovative Approaches for Pain Treatment*

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Section 4

Non-Pharmacological

Approaches

Section 4
