**4. Nociceptive pain**

**•** diagnostic or therapeutic procedures (bone marrow aspiration or biopsy, lumbar puncture) that may result in acute somatic pain, and may require specific premedication protocols as

**•** acute postoperative pain or postsurgical syndromes (i.e., following tumor debulking or radical neck dissection) need to be treated with patient-controlled analgesics in selected patients. Such drugs may include cyclooxygenase-2 inhibitors, selective non-steroidal antiinflammatory drugs (NSAIDs), calcium ligand-gated ion channel anticonvulsants, in

**•** direct tumor involvement may cause a painful experience which is often described as constant, aching, gnawing, and well localized (as a result of vascular obstruction or invasion,

Bone metastases are another common responsible of cancer-related physical impairment. Such causes of cancer pain may lead to nociceptive (somatic and visceral), neuropathic, or mixed pain; they may occur in combination with acute or active disease, subacute disease, or chronic disease undergoing palliative care-as well as disease in complete remission with residual

Other sources of pain may include pathologic or osteoporotic stress fractures, and osteonec‐ rosis (following steroids or Radiotherapy). Chemotherapy (CT) side effects may include mucositis, while Radiotherapy (RT) side effects may present as odontophagia, mucositis, or

Lymphedema resulting from RT or surgical excision may result in painful swelling surround‐ ing the affected region or the extremities, eventually leading to painful cellulitis or skin ulceration. A painful scar or keloid may occur following wound healing, carrying an increased

A controversial aspect related to iatrogenic pain is the phenomenon of hyperalgesia observed during chronic treatment with opioids; although the exact mechanism underlying this phenomenon is still unknown, it seems to be related to tolerance to opioid drugs administered chronically, repetitive stimulation of spinal NMDA receptors, dynorphin activity at the spinal level, specific abnormalities of central processes regulating the neural transmission to the nerve, and a possible action of cholecystokinin at the central nervous system level. [14]

Onset and assistance of pain during the clinical course of cancer may stem from direct mass effect, relationship between tumor and host, iatrogenic damage; from a physiopathological

well as analgesic treatments for several days following the mentioned procedures.

addition to pre-procedural local anesthetic nerve blocks.

or mucous membranes ulceration).

risk of wound-site neoplasms.

**3. Cancer pain: Pathogenetic classification**

standpoint, cancer pain may be classified as follows: [15]

**• Nociceptive pain** due to invasion/ulceration of surrounding tissues;

**• Inflammatory pain** through the classical cascade of acute inflammation;

effects.

64 Updates on Cancer Treatment

burns.

Nociceptive pain stems from an acute or persistent injury to somatic or visceral tissues. Somatic nociceptive pain is described by patients as "aching", "stabbing", or "throbbing", and arises from injury to bones, joints or muscles. Visceral nociceptive pain results from injury to viscera. It is poorly localized and is reported as "cramping" or "gnawing", especially when it involves a hollow viscus (e.g. bowel obstruction). Conversely, visceral nociceptive pain may be described as "aching", "stabbing", "sharp", and it is similar to somatic nociceptive pain, whenever it involves other visceral structures (e.g. organ capsules, myocardium). Visceral pain is often referred to somatic sites due to the convergence on somatic afferents within the dorsal root ganglia and dorsal horns. [18]

Stimuli from tissue injury activate primary afferent neurons called nociceptors, located in the skin, muscles, joints, and visceral organs. Nociceptors are high-threshold receptors, i.e. they are silent unless significantly stimulated. [19]

Most nociceptors are polymodal, responding to thermal, physical, and chemical stimuli. Neuron cell bodies are located within the superficial laminae of the dorsal root ganglia and trigeminal ganglia. Once depolarization occurs, transmission advances proximally via thin myelinated A-δ fibers (fast) or reduce unmyelinated C fibers (slow). Interneurons within laminae I and II of the dorsal horn amplify or neurotransmission. Afferent axons end in lamina I or II, and second-order afferent neurons cross the midline and ascend to the brainstem and thalamus through the anterolateral quadrant of the controlateral half of the spinal cord. Together with axons from second-order lamina I neurons, these fibers form the spino-thalamic tract, which is the major ascending pathway with regard to information about pain and temperature. Sensory fibers, associated with affective responses, also ascend in the controlateral dorsolateral spinal cord to the medial thalamus or brainstem and, then, to the cingulated cortex and limbic lobe. Downward modulation occurs through the periaqueductal gray (PAG) and rostral ventral medulla (RVM) with axons that run across the dorsal lateral funiculus. The axons just mentioned, modulate pain directly through connections to secondary afferent neurons in the dorsal horn or via connections with interneurons in laminae I and II.

The neurochemistry of these processes involves multiple neurotransmitters including endor‐ phins, prostaglandins, gamma-amino-butyric acid (GABA), cannabinoids, and many others molecules, that are all targets for analgesic medications.[20]

The spine is the most common target of bone metastases, with affected patients experiencing back pain. Direct extension of a vertebral tumor may lead to spinal cord or nerve roots damage, thereby producing substantial neurological compromise. Back pain deriving from vertebral metastases is, therefore, a marker of an increased risk of epidural spinal cord or cauda equina compression.

**Figure 2.** Detection by sensory neurons of noxious stimuli produced by tumours. Figure from Molecular mechanisms of cancer pain. Mantyh PW, Clohisy DR, Koltzenburg M, Steve P. Hunt. Nature reviews | Cancer Volume 2 | March 2002

## **5. Inflammatory pain**

Any given neoplasm harbors several non-cancerous cell types, including immune-system cells such as macrophages, neutrophils, and T cells. These cells may secrete various sensitizing factors, or excite directly primary afferent neurons, such as prostaglandins [21, 22], tumor necrosis factor-α (TNF-α) [23, 24], endothelins [25], interleukin-1 and interleukin-6 [26, 28], epidermal growth factor [29], transforming growth factor-β [30], and platelet derived growth factor. [31, 33] Indeed, specific receptors for these factors are by expressed primary afferent neurons.

Intra- and extracellular pH of solid tumors is lower than that of the surrounding normal tissues. [34]

Local acidosis — secondary to the accumulation of acid metabolites — is a hallmark of tissue injury. [35]

The finding that sensory neurons can be directly excited by protons or acidic compounds has generated sizable interest among basic and clinical researchers. [36]

Studies have shown that several subsets of sensory neurons express different acid-sensing ion channels [37]. The two main classes of acid-sensing ion channels, expressed by nociceptors, are Vanilloid receptor subunit (VR1) [38, 40] and the acid-sensing ion channel-3 receptors (ASIC3). [41]

thereby producing substantial neurological compromise. Back pain deriving from vertebral metastases is, therefore, a marker of an increased risk of epidural spinal cord or cauda equina

**Figure 2.** Detection by sensory neurons of noxious stimuli produced by tumours. Figure from Molecular mechanisms of cancer pain. Mantyh PW, Clohisy DR, Koltzenburg M, Steve P. Hunt. Nature reviews | Cancer Volume 2 | March 2002

Any given neoplasm harbors several non-cancerous cell types, including immune-system cells such as macrophages, neutrophils, and T cells. These cells may secrete various sensitizing factors, or excite directly primary afferent neurons, such as prostaglandins [21, 22], tumor necrosis factor-α (TNF-α) [23, 24], endothelins [25], interleukin-1 and interleukin-6 [26, 28], epidermal growth factor [29], transforming growth factor-β [30], and platelet derived growth factor. [31, 33] Indeed, specific receptors for these factors are by expressed primary afferent

Intra- and extracellular pH of solid tumors is lower than that of the surrounding normal

Local acidosis — secondary to the accumulation of acid metabolites — is a hallmark of tissue

The finding that sensory neurons can be directly excited by protons or acidic compounds has

generated sizable interest among basic and clinical researchers. [36]

compression.

66 Updates on Cancer Treatment

**5. Inflammatory pain**

neurons.

tissues. [34]

injury. [35]

Both these types of channels are sensitized and excited by a decrease in pH. More specifically, VR1 is activated when the pH falls below the value of 6.0, whereas the pHinduced activation of ASIC3 seems to depend on the co-expression of other ASIC chan‐ nels by the same nociceptor. [42]

There are several mechanisms by which tumors may induce a decrease in pH. As inflammatory cells invade the neoplastic tissue, they release protons generating local acidosis. The increased frequency of the apoptotic phenomenon within the neoplastic microenvironment contributes to acidosis, as apoptotic cells release intracellular ions in order to create a more acidic pH, thus activating the specific signaling by acid-sensing channels that are expressed by nociceptors. Tumor-induced release of protons and acidosis are thought to be particularly important in the generation of bone cancer pain. Both osteolytic (bone-destroying) and osteoblastic (boneforming) metastases are characterized by osteoclast proliferation and hypertrophy [43, 45]

**Figure 3.** The tumor–nociceptor interface. Figure modified from: Farmaci e Dolore. Di Iorio P. In Saggini R, Buoso S, Pestelli G. (ed) Dolore e Riabilitazione. Minerva Medica 2014. p61
