Pain syndromes that develop in oncological diseases

Introduction

Pain is a complex physiological mechanism that has a huge impact on all areas of life - daily activities, psychological and emotional state, physical health. Pain is one of the main symptoms of oncological disease - as many as 38% of patients experience moderate to severe pain. Oncological pain has many manifestations, ranging from mild to very severe, and can occur during treatment, with terminal illness, or persist after successful treatment of the oncological disease. Often, the nature of pain and accompanying symptoms related to oncological disease can help identify a specific pain syndrome caused by the oncological process. Identifying the pain syndrome is important because it can help determine the etiology of pain, facilitate the diagnostic process of the disease, and predict the prognosis of pain or even the disease itself. Pain syndromes caused by oncological diseases are classified as acute and chronic. Acute pain syndromes are usually related to tumor changes (e.g., necrosis, bleeding, bone fractures, organ obstruction), treatment, and interventional diagnostics, while chronic pain is directly related to the neoplastic process or antineoplastic therapy.

Acute Pain Syndromes

Iatrogenic and Disease-Related Acute Pain

The most common acute pain syndromes are iatrogenic or directly related to oncological disease. The latter require urgent medical interventions and treatment. The main syndromes include bleeding, pathological fractures, and organ obstruction.

Bleeding

Bleeding occurs in an average of 6-10% of patients with advanced cancer. This complication of oncological disease can be caused by many factors, such as local vascular damage, changes in platelet function and count, or systemic processes (e.g., disseminated intravascular coagulation). It can manifest as either sudden episodic life-threatening bleeding or occult minor bleeding. Bleeding from a tumor is a life-threatening complication, often accompanied by pain, which can help diagnose this pathology. For example, bleeding in hepatocellular carcinoma can occur in up to 26% of cases, often accompanied by severe pain in the right upper abdominal quadrant. In all cases of bleeding, it is important to identify the cause of bleeding and pain, provide appropriate treatment - both local (hemostatic agents and dressings, radiotherapy, endoscopic ligation and coagulation, transcutaneous arterial embolization) and systemic (vitamin K, vasopressin, antifibrinolytic therapy, blood components). In some cases, surgical treatment may be necessary.

Pathological Fractures

A pathological bone fracture occurs in a bone affected by a pathological process, without trauma. Bones can fracture due to either a primary tumor or metastases. The most common sites of metastasis to bones are breast, lung, kidney, prostate, and thyroid tumors, which account for up to 80% of all bone metastases. Metastases are usually multifocal, occurring in the axial skeleton, proximal femur, and humerus. Patients with metastatic bone disease usually complain of intense pain that worsens at night and does not improve with narcotic and non-narcotic analgesics, and neurological symptoms (e.g., radiculopathies). Long bone fractures are usually treated surgically, while vertebral fractures can be treated conservatively or surgically, especially if spinal canal decompression and mechanical stabilization are needed. All patients need to consider radiotherapy after surgery.

Organ Spindle Obstruction or Perforation

These complications manifest with severe pain and acute abdominal symptoms. Pain is usually initially localized, visceral, and becomes diffuse, very intense, and can lead to peritonitis. Surgical treatment can reduce pain - stenting, decompression, surgical treatment.

Acute Pain Syndromes Caused by Antineoplastic Treatment

Oral Mucositis

It is an erythematous and ulcerative lesion of the oral mucosa that develops in patients undergoing chemotherapy or radiotherapy. Chemotherapy can cause mucositis throughout the entire gastrointestinal tract, but it most commonly affects the mouth. Its incidence ranges from 51% to 100% in patients treated for head and neck cancer. Oral mucositis presents with severe pain, significantly disrupts nutritional function, and promotes the development of secondary infections. When treating oral mucositis, it is important to focus on pain control, ensuring adequate nutrition, oral decontamination and prevention of dry mouth, and treatment of bleeding.

Chemotherapy-Induced Neuropathy

This is a common unwanted side effect of chemotherapy, dependent on dose, progressing during treatment, and persisting even after treatment. Chemotherapy-induced neuropathy occurs in 68% of cases in the first month of treatment and persists in 30% of patients after 6 months of treatment. Neuropathy presents with sensory symptoms - burning pain, tingling, increased sensitivity to cold or touch, decreased proprioceptive sensations. This complication can be caused by many drugs used in chemotherapy - platinum, taxanes, thalidomide, bortezomib, vinca alkaloids.

Radiation-Induced Plexopathy

Shoulder plexopathy can develop with radiotherapy for intrathoracic, breast, lung, or lymph node neoplasms. It manifests with paresthesia, numbness, hyperesthesia, or pain in the neck, shoulder, or lateral chest wall, later followed by weakness, leading to amyotrophy in the shoulder abductors and chest flexor muscle groups. New radiotherapy techniques could help prevent plexopathies.

Radiation-Induced Enteritis and Proctitis

Enteritis can present with pain, acute or chronic small bowel obstruction, nausea, anorexia, weight loss, meteorism, diarrhea, steatorrhea, and malabsorption. These symptoms can be caused by damage to the small bowel or secondary disorders (e.g., bile salt malabsorption, bacterial overgrowth syndrome, lactose intolerance). Acute enteritis usually resolves within 3 months, requiring supportive treatment. Chronic enteritis can occur from 18 months to 2 years after radiation and significantly impacts patients' quality of life. Radiation proctitis is caused by pelvic tumors treated with radiotherapy. Acute proctitis develops immediately or within 3 months after starting radiotherapy and presents with diarrhea, nausea, tenesmus, mucus discharge, and minor bleeding, while chronic proctitis develops in 2–20% of patients on average 8–12 months after the end of radiotherapy. Proctitis can manifest with acute proctitis symptoms along with severe bleeding, strictures, perforations, fistulas, and bowel obstruction in chronic cases.

Chronic Pain Syndromes

Nociceptive or neuropathic chronic pain is experienced by 15–75% of patients with cancer. Pain can be directly related to the tumor or the treatment of the oncological disease.

Tumor-Induced Chronic Pain Syndromes

Tumor-related pain can be somatic, affecting bones, joints, muscles, and soft tissues, or visceral, arising from organ compression, perforation, or painful visceral structure damage, such as visceral pleura, liver capsule, or peritoneum. Patients may suffer from chronic neuropathic pain, pain caused by leptomeningeal metastases, radiculopathies, plexopathies, and paraneoplastic syndromes.

Chronic Somatic Pain

Bone metastases and primary bone tumors are the most common causes of chronic pain. The exact factors leading to the development of multi-focal bone pain due to metastases are unknown. It is believed that this may be due to direct activation of nociceptive receptors by the tumor, mechanical deformations from microfractures, local release of growth factors and chemical mediators. Other causes of multi-focal bone pain can be malignant hematologic diseases causing pain due to bone marrow expansion, and a rare form of paraneoplastic syndrome characterized by renal phosphate loss, known as oncogenic osteomalacia. It is important to mention that the most common sites of bone metastases are the vertebrae. When back pain is present, a common oncological complication to suspect is neoplastic epidural spinal cord compression. This complication can lead to irreversible loss of neurological functions and usually starts with back or neck pain, followed by neurological symptoms. Another cause of chronic somatic pain is muscle damage due to sarcomas, muscle metastases, or muscle spasms resulting from radiculopathies, plexopathies, or electrolyte imbalances due to paraneoplastic syndromes.

Chronic Visceral Pain

Visceral pain syndromes are common among patients with gastrointestinal or gynecological malignancies. Pain in the liver area occurs in primary liver tumors or liver metastases due to stretching of the liver capsule. It is usually dull, felt on the right side below the rib cage, and can radiate to the ipsilateral shoulder if the malignant process affects the upper part of the capsule. Epigastric pain arises from the midline retroperitoneal syndrome, which can be caused by pancreatic tumors, retroperitoneal sarcomas, or invasion of the abdominal wall. Diffuse abdominal pain is caused by chronic bowel obstruction due to ovarian and colorectal cancer. Another cause of chronic visceral pain is peritoneal carcinomatosis. This complication presents with nonspecific symptoms – abdominal discomfort, nausea, weight loss, cachexia, and fatigue, later developing signs of bowel obstruction and increasing ascites. Visceral pain can be caused by adrenal pain syndrome. It develops due to adrenal metastases in non-small cell lung cancer, manifesting as unilateral flank pain spreading to the ipsilateral upper and lower abdominal quadrants. Severe acute pain can occur due to bleeding from the adrenals. A significant cause of visceral pain is ureteral obstruction, usually caused by gastrointestinal, genitourinary, and gynecological tumors. Obstruction can be acute or chronic, characterized by intermittent flank pain radiating to the inguinal region.

Paraneoplastic Syndromes

Paraneoplastic syndromes arise due to hormones, peptides, and cytokines secreted by the tumor and most commonly affect the endocrine, neurological, hematological, rheumatological, and skin systems. The clinical presentation of these syndromes can be diverse, often characterized by chronic pain. The most painful paraneoplastic syndromes are typically described by subacute sensory neuronopathy and hypertrophic osteoarthropathy. Subacute sensory neuronopathy manifests early with ataxia, loss of deep tendon reflexes, hypoesthesia, painful paresthesias in the upper limbs and perioral area. This paraneoplastic syndrome most commonly occurs in patients with small cell lung carcinoma, breast, gynecological tumors, and lymphomas. Symptoms usually appear weeks to months after diagnosis and lead to the patient's disability. Immunomodulatory treatment with glucocorticosteroids, plasmapheresis, and intravenous immunoglobulin is usually unsuccessful, and only the primary oncological treatment can halt the progression of subacute sensory neuronopathy. Another paraneoplastic syndrome causing pain is hypertrophic osteoarthropathy. It manifests as abnormal proliferation of skin and peri-auricular tissues in the limbs and has three main clinical symptoms: clubbing of the fingertips, periostosis of long bones, and synovial fluid effusion. The most common tumors causing this complication are lung (e.g., bronchogenic carcinoma and metastases), pleural and mediastinal (e.g., mesothelioma, thymoma, Hodgkin's lymphoma), gastrointestinal, cardiovascular (e.g., atrial myxoma), among others. Patients complain of burning bone pain felt in the fingers, eventually leading to their clubbing.

Chronic Pain Syndromes Induced by Antineoplastic Treatment

Pain Caused by Chemotherapy

Chemotherapy often induces neuropathies classified as acute or time-limited. For some patients, neuropathy-induced pain persists even after treatment. Chronic impairments affect sensory, motor, and autonomic functions, with patients complaining of paresthesias, dysesthesias, painful hyperalgesia, and allodynia. All these symptoms cause pain, may persist even after successful oncological treatment, and significantly impact patients' quality of life.

Complications Caused by Glucocorticoids

Glucocorticosteroids commonly used to treat neoplastic diseases can lead to many painful and disabling complications. One of the most severe, affecting 9% to 40% of patients, is avascular necrosis of the femoral head, causing severe pain and arthropathy. Glucocorticoids are the most common cause of secondary osteoporosis, which can lead to spontaneous vertebral fractures, chronic neck or back pain development.

Pain After Surgical Interventions

Chronic pain after surgeries is neuropathic and usually develops by damaging nerves during surgical treatment. Pain syndrome after mastectomy occurs in 25–60% of cases due to axillary nerve and peripheral nerve damage in the chest wall when removing axillary lymph nodes. The treatment of this syndrome is complex, but according to the latest data, antidepressants such as amitriptyline and venlafaxine, local capsaicin creams, and autologous fat grafting can significantly reduce pain. Another cause of chronic pain is post-thoracotomy pain syndrome. It occurs in 50% of cases after thoracotomy and persists in 30% of patients even 4–5 years after surgery. Although the exact cause of this pain is unknown, it is believed to be caused by intercostal nerve damage during surgery, leading to neuropathic and myofascial pain. Adequate preoperative analgesia is thought to reduce the risk of developing this syndrome. Chronic pelvic pain arises after pelvic surgeries, developing into postoperative pelvic pain syndrome. Pain is caused by spasms of the pelvic floor muscles, pudendal nerve neuralgia, and secondary infection.

Phantom Pain After Amputation

After limb amputation, both stump and phantom chronic pain can develop. Phantom pain of the amputated limb can occur in 42–78% of patients. Stump pain usually develops due to neuroma formation at the amputation site, but other factors such as poorly fitted prostheses, recurrent tumors, infection, or ischemia are also important. Phantom pain is explained by many theories, starting from changes in the spinal cord and cerebral cortex (cortical somatosensory reorganization) and ending with mirror neurons. This pain is considered neuropathic, so various neuropathic pain-reducing drugs, surgical interventions, mirror neuron applications, ultrasound, cognitive-behavioral therapies, etc., are used for treatment. Despite a better understanding of phantom pain and the availability of various treatment methods, managing this syndrome remains complex.

Chronic Pain Syndromes Caused by Radiotherapy

Radiation therapy is widely used in treating oncological diseases, but it can cause both acute and chronic pain syndromes. Chronic pain usually arises due to radiation-induced plexopathies, myelopathies, gastrointestinal tract damage, lymphedema, and osteonecrosis. Radiation-induced plexopathies most commonly affect the cervical, brachial, or lumbosacral plexus months or even years after radiation therapy. Although pain is common, it is not usually severe. Radiation-induced myelopathy is a rare but severe complication when the white matter of the spinal cord is affected. The clinical presentation varies, most commonly presenting as slowly progressive ascending sensory-motor plegia, acute paraplegia or tetraplegia, and damage to the bowel and bladder sphincters. Gastrointestinal tract damage can manifest as radiation-induced enteritis or proctitis, bowel obstruction, fistulas, and stricture formation. Lymphedema usually develops due to radiation in the breast, shoulder, or pelvic areas. Patients complain of pain, pressure, impaired motor function, and have an increased risk of secondary bacterial or fungal infections. The pathophysiological mechanism of pain is musculoskeletal, but some patients may develop neuropathic pain due to plexus damage or nerve compression syndrome. Radiation therapy for treating head and neck tumors can lead to osteonecrosis of the lower jaw, resulting from impaired intracranial blood flow and secondary post-traumatic or odontogenic infections due to weakened immune function.

Summary

Impact on Quality of Life

Pain occurring in patients with oncological diseases is a common phenomenon that has a huge impact on the quality of life of patients. Often, pain syndromes can persist even after successful treatment of the disease.

Complications

Most of the resulting complications, in addition to pain syndromes, also cause other symptoms that can lead to disability and are difficult to treat. Pain can be acute due to iatrogenic causes or directly due to tumor-related phenomena, such as bleeding, pathological bone fractures, or compression of organs.

Chronic Pain

Chronic pain develops directly due to the oncological disease or may be caused by treatment. In each case, it is necessary to carefully assess the nature of the pain, as it often arises before other complications develop.

The Challenge of Treating Oncological Pain

Despite the rapid advancement of new treatment technologies, the issue of treating oncological pain remains very relevant.