Cancer is a major health concern and a leading cause of mortality worldwide (Abuderman, 2018). The prevalence of cancer is increasing globally, with an estimated 26 million new cases by 2030 (Thun et al., 2010). The Saudi Cancer Registry has reported 14,336 registered cases of cancer in 2012 (Bazarbashi et al., 2017). Notably, the cancer survival rate has increased over the past decade. The United States National Cancer Institute reported more than 14 million cases with a five-year survival rate in 2014 and it has been estimated an increase in survival rate to 19 million survivors by 2024. The increase in survival rate is largely due to anti-cancer treatments including chemotherapy, radiation therapy, surgery, immunotherapy, stem cell transplant and hormone therapy (Salas-Vega et al., 2016). Data in 2011 from the American National Cancer Database indicates that most of cancer cases are treated with chemotherapy alone or combined with other cancer therapies (Miller et al., 2016). Chemotherapy is used as an initial treatment for cancer, or with other cancer treatments or as a palliative to extend the survival of cancer patients when all other therapies fail (Lundqvist et al., 2015).
Chemotherapy causes toxicity because it is most effective in proliferating tumor cells during their active dividing phase. So, it is non-selective and targets non-cancerous normal host cells including those in the bones, gastrointestinal cells lining, hair follicles and neurons (DeVita et al., 2015). This produces side effects such as nausea, vomiting, loss of appetite, loss of hair, pain and numbness. These side effects can be debilitating, affecting daily living activities which might lead to discontinuation or a reduction in the chemotherapy schedule. Hence, mitigating the side effects of chemotherapy is important for optimizing chemotherapy regimens and improving the quality of life of cancer patients and survivors. (Lundqvist et al., 2015). Chemotherapeutic agents cause severe toxic damage to the peripheral nervous system accompanied by chronic peripheral neuropathic pain. Chemotherapy-induced neuropathic pain (CINP) affects most patients undergoing chemotherapy. The pathophysiology of CINP is not fully understood, however, neurotoxicity is a dose dependent and varies between chemotherapeutic agents (Argyriou et al., 2012;Ness et al., 2013).
2. Neuropathic Pain
The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG; 2009), defined peripheral neuropathic pain as "pain arising as direct consequence of a lesion or disease affecting the somatosensory system" (Finnerup et al., 2016). A nociceptor is a sensory receptor for pain in the peripheral neuron that induces a noxious (painful) stimuli. Sensitization is the reduction in pain threshold, or stated differently, an increase in pain sensation at the nociceptors which may also induce spontaneous (without noxious stimulus) painful discharge in the peripheral nervous system. This is known as peripheral sensitization. Central sensitization is an increased sensitization of the central nervous system in response to afferent peripheral neurons (Ashmawi and Freire, 2016;Woolf, 2011). Hyperalgesia is defined as an increased sensation of pain. Sensitization and allodynia are types of hyperalgesia. Allodynia occurs when a normal tactile sensation stimulates pain.
The nociceptors are stimulated by peptides such as bradykinin that are released due to tissue damage. These peptides stimulate the nociceptors to release glutamate and peptides such as substance P. Also, a chemical stimulus might cause a release of neurotransmitters such as substance P from nociceptors, inducing vasodilation and the recruitment of inflammatory mediators in a process called neurogenic inflammation. This inflammation induces pain in order to protect the damaged tissue leading to a recruitment of additional inflammatory mediators which stimulates nociceptors and pain pathways (Dubin and Patapoutian, 2010). This process involves multiple molecular changes in the dorsal root ganglia (DRG).
The dorsal root ganglia are clusters of neuron cell bodies that reside outside the spinal cord where cell bodies of the sensory peripheral nervous system originate. It detects various types of pain (touch, mechanical and temperature) based on the type of nerve fiber that is stimulated (C, Aδ, Aβ) (Purves, 2012 ;Le Pichon and Chesler, 2014). C fibers are the most abundant, smallest in diameter and unmyelinated (slow) neurons that transmit the sensation of pain. It has a partially selective receptors that respond easily to different stimulants such as cytokines and toxins. Aδ fibers are medium size myelinated (fast) fibers that transmit pain and temperature sensations that are stimulated by nerve injury and inflammation. Aβ are the largest nerve fiber in the DRG and are stimulated by low mechanical threshold (Le Pichon and Chesler, 2014). The DRG lacks a surrounding capsular membrane and a blood barrier which makes it more vulnerable to toxins and inflammation than the central nervous system which sensitize nociceptors and enhance pain leading to peripheral neuropathy (Sapunar et al., 2012).
Peripheral neuropathy includes both a dysfunction or a lesion in the peripheral nervous system in the sensory and/or motor pathways (Finnerup et al., 2010). Peripheral neuropathic disorders can be classified into mononeuropathy or polyneuropathy. Mononeuropathy is a lesion or disorder in a single peripheral nerve as seen in carpal tunnel syndrome (inflammation of the median nerve causing a tingling sensation and numbness of the hand) and sciatica (inflammation or injury to the sciatic nerve causing a shooting /electrical pain coursing along the nerve in the affected leg). Polyneuropathy is a malfunction of multiple neurons such as neuropathy caused by diabetes mellitus which represents 18-49% of polyneuropathy cases reported in hospitals. Other causes of polyneuropathies include chemotherapeutic drugs and immune related causes (Hanewinckel et al., 2016;Watson and Dyck, 2015).
Risk factors of neuropathic pain include, female gender, older age, manual work and diabetes which affect patient’s quality of life (Smith and Torrance, 2012). Several studies have attempted to determine the prevalence of neuropathic pain. A population-based study estimated that neuropathic pain affects 10% of the general population in the USA (DiBonaventura et al., 2017). A systemic review study also reported that 6.9% to 10% of the studied population had neuropathic pain (van Hecke et al., 2014). Neuropathic pain causes a hyperactivity or hyperexcitability of nociceptors which is clinically characterized by pain hyperalgesia or spontaneous ongoing pain (Watson and Dyck, 2015). Also, neuropathic pain induces allodynia which is characterized by a burning, shooting, tingling or electrical sensation (Savage et al., 2014).
Knowledge of the anatomy, cellular and molecular mechanism of neuropathic pain contributes to an understanding of the pathophysiology of neuropathic pain and aid to find an effective treatment (Colloca et al., 2017).
3. Mechanisms of Peripheral Neuropathic Pain
3.1. Mitochondrial Dysfunction in Neuropathic Pain
One of the possible mechanisms of neuropathic pain is mitochondrial dysfunction in sensory neurons. The mitochondria are responsible for supplying energy for cell bodies through oxidative phosphorylation and they control the cell cycle, apoptosis and calcium homeostasis. Hence mitochondria are the regulators of cell aging and cell death. Mitochondrial dysfunction leads to a release of reactive oxygen species (ROS). High levels of ROS damages the cell membrane causing a mutation in mitochondrial DNA. The mutation leads to failure of energy production and further production of ROS in a vicious cycle leading to cell aging and cell death. Neurological disorders including Parkinson’s disease and peripheral neuropathy are related to mitochondrial dysfunction (Ino and Iino, 2016;Finsterer, 2017). Patients with peripheral neuropathies have more mitochondrial DNA mutations compared to patients without neuropathic pain with greater prominence in distal neurons compared to DRG neurons (Lehmann et al., 2011). Studies of animal models of neuropathic pain show that mitochondrial dysfunction induces neuropathic degeneration in sensory neurons (Persson et al., 2013;Summers et al., 2014). Accumulation of mitochondria in the distal sensory neurons affects calcium homeostasis leading to abnormal action potential dynamics. Mitochondrial dysfunction also leads to an energy deficit which causes spontaneous nerve impulses in distal axons (Bennett et al., 2014). Chemotherapy causes mitochondrial abnormalities. Duggett et al. (2016) reported an increased production of ROS in paclitaxel-treated rats which is an indicator of mitochondrial dysfunction (Duggett et al., 2016). This mitochondrial toxicity is present only in sensory neurons (Xiao et al., 2011). Drugs that inhibit mitochondrial function increased symptoms of cold and pain hypersensitivity in chemotherapy (paclitaxel, oxaliplatin, cisplatin) treated rats suggesting that mitochondrial dysfunction plays an important role in exacerbating symptoms of CINP (Xiao and Bennett, 2012;Zheng et al., 2012;Zheng et al., 2011). Drugs that improve mitochondrial function such as α-lipoic acid and acetyl-l-carnitine reduced pain symptoms in both chemotherapy-treated rats and diabetic neuropathic pain rat models (Zheng et al., 2011;Xiao et al., 2012;Janes et al., 2013).
3.2. Ion Channels in Neuropathic Pain
Regardless of the etiology of the peripheral neuropathic pain, once damage occurs in the peripheral neurons, ion receptors in the afferent neurons are upregulated depending on the type of stimulus. Peripheral sensitization occurs in neuropathic disorders such as diabetic neuropathic pain and CINP. Nociceptors express ion channels and inflammatory receptors that are either coupled together to generate action potentials or as mediators for transduction of an action potential. These inflammatory mediators activate nociceptors within minutes and are maintained throughout the duration of inflammation. The chemo-sensitivity of nociceptors are either stimulated by inflammatory mediators that directly stimulate nociceptors (such as bradykinin) or by cytokines that have a pro-nociceptive action. This inflammation leads to an increase in neurotransmitters in the spinal cord such as substance P and glutamate causing an excitatory reaction that travels to the thalamus. This excitatory reaction is processed by the thalamus to generate an inhibitory pain mechanism. In neuropathic pain, this inhibitory mechanism might be dysfunctional which might also cause allodynia (Gwak and Hulsebosch, 2011;Dubin and Patapoutian, 2010).
Ion channels modulates the resting membrane potentials in the DRG and generate action potentials that produces pain (Le Pichon and Chesler, 2014). These ion channels include: transient receptor potential cation channel subfamily V member 1 (TRPV1) that mostly detect heat stimuli, transient receptor potential cation channel subfamily M member 8 (TRPM8) which detects cold sensation (Salat and Filipek, 2015), C fibers low threshold mechanical stimuli (C-LTMRs) (Li et al., 2011), channelrhodopsin-2 (ChR2) mechanoreceptors for light touch (Ji et al., 2012), sodium voltage gated channels (Nav) for nerve injury (Theile and Cummins, 2011), and hyperpolarization-activated current (HCN 1-4) for cold allodynia and mechanical pain in neuropathic pain and inflammatory pain (Cordeiro Matos et al., 2015) (Figure 1.1).
 
 
3.2.1. Sodium Channels
Voltage gated sodium channels are large transmembrane ion channels which are the main mediators for membrane excitability and action potential (Theile and Cummins, 2011). These channels are crucial to normal cell excitability thus playing a key role in pain. Injured nerves induce abnormal neural excitability which leads to abnormal sensation such as hypersensitivity and allodynia (Theile and Cummins, 2011). There are thirteen subtypes of voltage gated sodium channels (Nav) but mainly Nav1.7, Nav1.8 and Nav1.9 are expressed in the peripheral nervous system. Sodium channels are upregulated in the DRG in neuropathic pain and CINP animal models which is characterized by symptoms of mechanical allodynia (Chen et al., 2011b) Modulation of sodium ion channels attenuates nociceptive hyper-excitability in neuropathic pain and inflammatory pain animal models (Hildebrand et al., 2011;Gudes et al., 2015). Hence blocking these sodium ion channels may be a neuroprotective strategy for chemotherapy patients (Sittl et al., 2012).
3.2.2. TRPV Ion Channels
Transient receptor potential cation channel subfamily V member 1 (TRPV-1) ion channel has been extensively studied in pain mechanisms. TRPV1 is highly expressed in neuropathic pain models (Salat and Filipek, 2015). Paclitaxel- treated rats with pain behavior expressed TRPV in their DRG (Hara et al., 2013). A study by Li et al. (2015) showed that pain symptoms in these rats are caused by upregulation of TRPV through Toll-like receptors 4 (TLR4) and blocking TLR4 in paclitaxel- treated rats increased pain threshold in these rats (Li et al., 2015).
3.2.3. TRPM8 Ion Channels
Transient receptor potential cation channel subfamily M member 8 (TRPM-8) are ligand gated non-selective ion channels that are expressed in DRG and respond to cold sensation (25-28 oC). These ion channels are found to be upregulated in spinal nerve injury rat models with cold allodynia symptoms (Su et al., 2011). Additionally, these ion channels were upregulated in CINP with cold hypersensitivity behavior (Descoeur et al., 2011;Salat and Filipek, 2015).
3.2.4. Hyperpolarization-Activated and Cyclic Nucleotide-Gated Ion Channels
HCN are ion channels that generate an inward current in a cardiac pacemaker (Gao et al., 2012). They are cation channels that are activated when the membrane potential is hyperpolarized (Kase and Imoto, 2012). There are four subtypes including, HCN1, HCN2, HCN3, HCN4. These channels are permeable to potassium and sodium ions, thus contributing to the action potential and resting membrane potential of neurons (Emery et al., 2011). Immunohistochemistry studies found that HCN ion channels are expressed in the heart, brain, pancreas and DRG (Kase and Imoto, 2012). HCN ion channels have an excitatory, modulatory and inhibitory effect on neurons which allows these channels to contribute to the control of the resting membrane potential (directly at the synapses or indirectly through resting membrane potential created by sodium or potassium ion channels). HCN ion channels also controls the selectivity of action potentials and filtration of unwanted action potentials (Kase and Imoto, 2012). In the DRG, HCN ion channels contribute with neuronal action potentials (Smith et al., 2015). Each isoform of HCN ion channels are excited differently based on the duration and frequency of activation (Herrmann et al., 2015). HCN1 ion channels are a fast acting ion channels that are expressed in large diameter neurons of the DRG more than in medium and small neurons. Deletion of the HCN1 ion channels affects the action potential of the large neurons in the DRG. HCN3 channels are expressed in DRG neurons but have slower activation than the HCN1 and HCN2 ion channels (Romanelli et al., 2016).
The most abundant isoforms found in the DRG neurons are HCN1 and HCN2 (Acosta et al., 2012). Models of neuropathic pain have reported an upregulation in HCN1, HCN2 and HCN3 ion channels in DRG neurons. Blocking HCN ion channel decreased neural excitation and attenuated pain behavior indicating that HCN ion channels are involved in the firing of the action potential in these animals (Weng et al., 2012;Smith et al., 2015). Animal models of CINP also showed an upregulation of the expression of HCN1 ion channel (Zhang and Dougherty, 2011) Also, symptoms of CINP were reduced by blocking HCN receptor in these animal models (Descoeur et al., 2011). In the neuropathic pain animal model, HCN4 expression in neurons was uncertain (Liu et al., 2017). Previous studies also reported that HCN4 is poorly expressed in the DRG (Kouranova et al., 2008;Wang et al., 2012).
4. Chemotherapeutic Drugs
The most neurotoxic chemotherapeutic drugs are vinca alkaloids, cisplatin, and taxanes (Miltenburg and Boogerd, 2014). Depending on the chemotherapeutic agent, CINP causes sensory neuropathy, sensorimotor neuropathy, with or without autonomic nervous system neuropathy (Park, 2014). Chemotherapeutic agents such as taxanes and vinca alkaloids do not cross the blood-brain barrier. This might explain that neuropathy is reported in the peripheral nervous system which is not protected like the central nervous system by the brain-blood barrier (Poupon et al., 2015). The severity of CINP depends on the drug, dose, treatment schedule, and the presence of other disorders such as diabetes mellitus (Hershman et al., 2013).
4.1. Taxanes
Taxanes are chemotherapeutic agents that includes paclitaxel (taxol) and docetaxel (Miltenburg and Boogerd, 2014). Taxanes are used to treat tumors of the ovary, breast, lungs, head and neck (Weaver, 2014). Taxanes inhibit microtubule dynamics which interfere with the normal microtubule functions during cell division (Wozniak et al., 2013). Microtubules are motor cytoskeletons composed of α-tubulin and β-tubulin that mediate many intracellular functions in neurons such as maintaining cell shape, controlling cell division, modulating ion channel distribution, and provide trafficking for growth factors and neurotransmitters. Microtubules are fundamental to maintaining neural polarization. Polarization is essential in neuron development and maintenance of function (Xiao et al., 2016). Transport of growth factors is important for axonal and dendritic growth. Because of the elongated architecture of neurons, microtubules are essential for transferring survival factors to the cell body and removal of components of toxin from axon terminals (LaPointe et al., 2013). An alteration in axonal transport contributes to neural pathology (Fournier et al., 2015). Taxanes are microtubule-stabilizing agents that block mitosis and cell division causing cell death leading to inhibition in axonal transport which is a proposed mechanism in CINP in paclitaxel-treated cancer patients (Kent and Lele, 2016). Also, Paclitaxel therapy affects the microtubules of host neural cells, leading to peripheral neuropathy (Miltenburg and Boogerd, 2014).
Common paclitaxel toxicities include, neutropenia, peripheral neuropathy, nausea and vomiting (Llombart-Cussac et al., 2016). Paclitaxel treatment causes pain that develops within 24-48 hours after treatment and lasts for 5 to 7 days (Fernandes et al., 2016;Loprinzi et al., 2011). The incidence of paclitaxel-induced neuropathic pain is 86% (Fernandes et al., 2016) and it is referred as paclitaxel acute pain syndrome (P-APS). This pain mostly affects the sensory nerves and it is extremely deliberating which might lead to discontinuation of a potentially curative drug depending on the dose and duration of treatment (Loprinzi et al., 2011;Ferrier et al., 2013).
4.2. Vinca alkaloids
Vinca alkaloids include, vinblastine, vinorelbine and vincristine. These chemotherapeutic agents are microtubules destabilizing agents that bind to tubulin and prevent cell mitosis leading to cell death depending on the dose and duration of treatment. This inhibits the proliferation of malignant cells. Similar to taxol, vinca alkaloids cause a loss of axonal microtubules, affecting their arrangement, orientation and length leading to axonal degeneration (Miltenburg and Boogerd, 2014). Vinca alkaloids are used to treat breast cancer and lung cancer. Side effects of vinca alkaloids include nausea, vomiting, dyspnea and fever. Neuropathic pain is a common side effect of vinca alkaloids affecting sensory-motor-autonomic polyneuropathy which leads to discontinuation of treatment (Moudi et al., 2013).
4.3. Platinum derivatives
Platinum containing anti-cancer drugs include cisplatin, carboplatin, and oxiplatin. These drugs inhibit DNA synthesis by binding to the DNA, forming DNA adducts and preventing its replication and transcription (Argyriou et al., 2012;Zhao et al., 2016). They are used to treat ovarian, cervical, lung, head and neck cancer. The most common dose limiting side effects are nausea, vomiting and peripheral neuropathy (numbness, paresthesia and sensory ataxia). Accumulation of platinum compounds in the DRG has been reported, leading to gangliopathy which decreases cellular metabolism and neural transportation (Miltenburg and Boogerd, 2014;Argyriou et al., 2012).
4.4. Bortezomib
Bortezomib are proteasome inhibitors that are used to treat malignant cancer. It upregulates pro-apoptotic proteins resulting in apoptosis of malignant cells. It also suppresses the pathways that downregulate anti-apoptotic genes leading to cell death (Chen et al., 2011a). The most common dose-limiting side effect is peripheral neuropathy (Argyriou et al., 2012).
 
 
5. Chemotherapy- Induced Neuropathic Pain (CINP)
5.1. Symptoms of CINP
CINP results in sensory neuropathy more than motor and autonomic neuropathy. These symptoms are presented in a stocking and gloves pattern and are reported in more than 50-96% of cancer patients undergoing paclitaxel treatment which affect their daily quality of life and may lead to discontinuation of treatment (Reeves et al., 2012;Golan-Vered and Pud, 2013;Han and Smith, 2013). Wolf et al. (2012) reported that symptoms of numbness (57%), tingling (63%) and shooting pain (18%) were present in the hands and foots of the majority of the studied population of chemotherapy-treated patients who received taxanes, oxaliplatin, carboplatin/cisplatin, vinca alkaloids and thalidomide (Wolf et al., 2012).
Paclitaxel-induced neuropathic pain was also reported in animal studies. Symptoms in these animals were characterized by mechanical hypersensitivity, heat hypersensitivity and cold hypersensitivity symptoms (Hama and Takamatsu, 2016).
Electrophysiological studies have reported reduced pain thresholds among neuropathic pain patients and an ectopic action potential has been recorded from mechanoreceptors that cause allodynia and spontaneous pain in patients with neuropathic pain (Sonohata et al., 2013;Spaic et al., 2010) and in CINP animal models (Boehmerle et al., 2014).
5.2. Assessment of CINP
Tools for assessment of neuropathic pain are either objectively by clinical examination or subjectively by patients report of pain. Clinical examination such as pin-prick test and tendon reflexes are valid tests for neurological neuropathy. Electrophysiological tests such as nerve conduction velocity are less sensitive than clinical examination (Miltenburg and Boogerd, 2014). Subjective report of pain includes the following: Common Toxicity Criteria and Common Terminology Criteria for Adverse Events consists of a set of standardized classification of side effects of chemotherapy drugs and it is a common assessment tool for assessing CINP that classifies the severity of the adverse effects of chemotherapy to the nervous system including pain (grade 1 as mild to grade 3 as a severe) which affects daily living and may necessitate hospitalization. Total Neuropathy Score is another tool for assessing CINP which is an evaluation of motor, sensory and autonomic nervous system for signs of neuropathy (Cavaletti et al., 2013). However, some investigators reported a low reliability and validity of the Total Neuropathy Score for assessing CINP (Smith et al., 2010). Quantitative Sensory Testing is a psychophysical assessment tool that evaluates vibration, thermal and painful stimuli and it is used for assessing CINP (Velasco et al., 2015). A 0-10-point numerical rating scale (NRS) and visual analog scale were also reported as valid tools for evaluating neuropathic pain. These scales present an estimated number for the degree of pain that is subjectively reported by the patient (Cleeland et al., 2010;Golan-Vered and Pud, 2013;Hershman et al., 2014). The Patient Global Impression of Change is a 7-grade assessment tool that measures subjective pain and the progression of pain (Mankowski et al., 2017). The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) is most recommended scale for neuropathic pain and is used to quantify neuropathic and nociceptive pain which includes two parts of assessing self-reported patient, assessment of neuropathic pain and clinical testing by a physician for hyperalgesia and allodynia (Erbas et al., 2011;Kelle et al., 2016).
In animals, CINP is assessed by evaluating mechanical, heat and cold hypersensitivity symptoms. A mechanical force against the paws is used to assess mechanical pain and a hot /cold plate is used to assess thermal pain (Rigo et al., 2013;Hwang et al., 2012;Burgos et al., 2012;Pascual et al., 2010).
5.3. Prevention and Treatment
Currently, no known prevention or treatments are available for CINP except for dose reduction or changing to a less effective chemotherapeutic agent. Treatment of neuropathic pain represents a major economic burden on health care (Dworkin et al., 2011).
CINP is currently treated with analgesics, antidepressants, and antiepileptic drugs which induce unwanted side effects such as nausea, vomiting, dizziness and cognitive impairment (Hershman et al., 2014). To increase the efficacy of chemotherapy, neuroprotective agents were tested for the prevention or mitigation of adverse effects. Ideally, neuroprotective agents should be effective, well tolerated and not compromise the effects of chemotherapeutic drugs. Although numerous neuroprotective drugs are currently used, their efficacy for treating and /or preventing CINP remains unproven (Sisignano et al., 2014). The following are some examples of commonly used drugs:
5.3.1. Amifostine
Amifostine acts as a potent nonspecific cytoprotective drug against free radicals produced by radiation and chemical drugs. It reduces the toxic effect of cancer drugs on normal cells, thereby optimizing the effects of radiotherapy and chemotherapy on cancer cells. Amifostine is a prodrug that is converted into an active thiol metabolite by alkaline phosphate. The selectivity of the cytoprotection of amifostine is due to alkaline phosphate, which is essential for transformation into its active form. Alkaline phosphate is produced in normal cells but not in tumor cells resulting in the cytoprotection of normal cells (Kuntic et al., 2013). Studies have reported that amifostine has a neuroprotective effect in chemotherapy patients. However, other studies reported its insignificant against neurotoxicity induced by chemotherapy or survival rate (Albers et al., 2014). Side effects of amifostine include nausea, vomiting, and light-headedness (Hershman et al., 2014). The neuroprotective effect and side effects of amifostine depends on the chemotherapeutic agent being used and on the dose of amifostine and chemotherapeutic agent (Sisignano et al., 2014).
5.3.2. Acetyl-L-Carnitine
Acetyl-L-carnitine is a naturally occurring compound which is essential for fatty acid metabolism in mitochondria and plays a key role in mitochondrial energy production. Normally, carnitine and all its derivatives are reabsorbed by the kidneys. However, chemotherapeutic drugs increase the excretion of acetyl-L-carnitine from the kidneys. Acetyl-L-carnitine has been used as a neuroprotective drug against nephrotoxicity, cardiotoxicity and neurotoxicity due to chemotherapy (Sayed-Ahmed, 2010). It has been suggested that acetyl-L-carnitine has a protective effect on the mitochondria of neurons which may mitigate CINP (Xiao et al., 2012). Sun et al. (2016) reported that acetyl-L-carnitine reduced CINP (Sun et al., 2016). Other clinical study reported that acetyl-L-carnitine is ineffective in reducing CINP (Hershman et al., 2013). Although animal studies showed a significant improvement in CINP, human studies are inconclusive (van Dam et al., 2016). Further clinical studies are required to confirm the efficacy of acetyl-L-carnitine as a neuroprotective agent (Kraft et al., 2012).
5.3.3. Glutathione
Glutathione is the most abundant tripeptide thiol in humans. It is biologically important in the synthesis of proteins, DNA, enzyme activities and cell protection especially in neurons and astrocytes. There are evidences of the neuroprotective effect of glutathione against oxidants (Traverso et al., 2013). Small clinical and experimental trials have reported a significant improvements in neurotoxicity symptoms in cancer patients receiving chemotherapy (Hershman et al., 2014), but larger clinical studies reported that it is ineffective as a neuroprotective agent for chemotherapy patients (Leal et al., 2014;Pachman et al., 2014).
5.3.4. Calcium /magnesium infusion
Calcium /magnesium infusion is used for neuroprotection in oxaliplatin chemotherapy. The calcium ions bind to oxaliplatin metabolites and oxalate to prevent neurotoxicity. Some studies have reported a significant protective effect of calcium/magnesium infusion in reducing oxaliplatin-induced neurotoxicity (Ao et al., 2012). However, larger studies reported calcium /magnesium infusion was ineffective for neuroprotection in oxaliplatin-treated cancer patients and these studies did not recommend its use because it might interfere with the efficacy of these chemotherapeutic agents (Loprinzi et al., 2014;Pachman et al., 2014). Larger studies are warranted to investigate its protective effects on normal cells during chemotherapy (Kurniali et al., 2010).
5.3.5. Vitamin E
Vitamin E is a fat-soluble vitamin with an antioxidant, antiangiogenic, pro-apoptotic and anti-inflammatory activity. Its apoptotic effect on tumors has been reported in some studies (Aggarwal et al., 2010). Pace et al. (2010) reported that vitamin E relieved symptoms of neurotoxicity induced by different chemotherapeutic agents (Pace et al., 2010). On the contrary, a larger study showed no significant change in chemotherapy-induced neurotoxicity when using vitamin E as a neuroprotective agent (Kottschade et al., 2011;Pachman et al., 2014).
5.3.6. Antiepileptic (anticonvulsants) drugs
Anticonvulsants drugs can be sodium and calcium channel blockers and stimulators of GABA pathway (Chong and Bazil, 2010;Chong and Lerman, 2016). Many anticonvulsants are used to prevent CINP (Sisignano et al., 2014). The beneficial effects of these drugs for reducing CINP has been previously reported (Hershman et al., 2014). Anticonvulsants may interfere with anti-cancer treatment. Also, anticonvulsants have many side effects such as psychological, vision abnormalities and bone density loss (Chong and Lerman, 2016). A larger clinical trial using anticonvulsants as a pain-relieving treatment did not report its efficacious in reducing CINP symptoms (Shinde et al., 2016).
5.3.7. Antidepressant drugs
Antidepressants are used for the prevention and treatment of neuropathic pain including CINP (Sisignano et al., 2014;Mehta et al., 2015;Gallagher et al., 2015). The three types of antidepressants with analgesic effects in neuropathic pain are tricyclic antidepressant, serotonin and noradrenaline reuptake inhibitors (Mehta et al., 2015). The prevention of neuropathic pain due to antidepressants has been previously reported (Smith et al., 2013). Others reported that antidepressants were ineffective in preventing or treating CINP (Baltenberger et al., 2015). Many side effects are associated with antidepressants including, nausea, insomnia, diarrhea, dry mouth and dizziness. These side effects depend on the class of drugs being used (Chong and Lerman, 2016).
5.3.8. Analgesics
Analgesics are frequently used to manage neuropathic pain such as nerve injury and diabetic neuropathic pain (Finnerup et al., 2010;Majithia et al., 2016). The available analgesic drugs do not effectively reduce neuropathic pain. More studies are required to evaluate the effectiveness of analgesics in CINP and to determine the appropriate dose for optimal pain control while minimizing side effects (Brzeziński and Chwedorowicz, 2011;Sisignano et al., 2014).
5.3.9. Other preventive and treatment strategies for CINP
Topical application of a mixture of amitriptyline and ketamine gel reduced CINP but results were inconclusive (Barton et al., 2011;Gewandter et al., 2014). Other treatment strategies to reduce CINP include exercise (Courneya et al., 2014), frozen gloves (Eckhoff et al., 2013), acupuncture (Franconi et al., 2013), and electrical stimulation (Pachman et al., 2015). The most effective strategy is dose reduction of the chemotherapeutic agent (Argyriou et al., 2012;Loprinzi et al., 2011;Hershman et al., 2014) which may reduce the effectiveness of chemotherapy.
6. Cytokines in CINP
Cytokines are small non-structural proteins that include a large, diverse group of peptide molecules. They have an important function in intercellular communication and interaction between the immune system and the nervous system (Ren and Dubner, 2010). Cytokines regulate inflammation and immunity. They are categorized based on their cellular source into lymphocytes (lymphokines), cytokines with chemotactic activities (chemokines), monocytes (monokines) and leukocytes acting on other leukocytes (interleukins) (Austin and Moalem-Taylor, 2010).
Inflammatory cytokines and chemokines may play a critical role in clinical symptoms of CINP caused by paclitaxel and various classes of chemotherapeutic agents. Cytokines and chemokines are correlated to neuropathic pain (Luchting et al., 2015;Ren and Dubner, 2010). Experimental studies reported that treating rats with certain cytokine antagonists reduces the symptoms of neuropathic pain (Kim et al., 2016;Llorian-Salvador et al., 2016). The levels of certain cytokines are elevated in cancer patients treated with chemotherapy (Cheung et al., 2015;Vendrell et al., 2015). A study of prostate cancer patients reported elevated cytokines level after one cycle of taxol treatment compared pre-treatment levels (Mahon et al., 2015). Elevated levels of certain cytokines after chemotherapy were correlated with chemotherapy related symptoms such as cognitive functions (Cheung et al., 2015;Cheung et al., 2013), fatigue (Sha et al., 2015) and pain (Wang and Lehky, 2012). Cytokines can be grouped as pro-inflammatory and anti-inflammatory cytokines (Austin and Moalem-Taylor, 2010).
6.1. Pro-inflammatory cytokines
Pro-inflammatory cytokines upregulate inflammation. It includes interleukins such as IL-1, IL-2, IL-6, IL-12 and other cytokines such as IFNᵧ and TNFα (Ramesh et al., 2013;Ren and Dubner, 2010). They are produced by different cells in response to a wide variety of stimuli which are recognized by specific cells to produce a cytokine-mediated response. These newly produced cytokines are recognized by other cells to initiate a response cascade based on the type of cytokine produced. Each cytokine has a different activation pathway and their response is either local on the cell itself (autocrine) or on adjacent cells (paracrine). The key regulators of pro-inflammatory cytokines are IL-1, IL-6 and TNFα (Turner et al., 2014).
6.1.1. Interleukin -1
The interleukin-1 (IL-1) family consist of 11 members including, IL-1α, IL-1β, IL-1Ra [receptor antagonist], IL-18, IL-33, IL-36α, IL-36β, IL-36ᵧ, IL-36Ra, IL-37, ILHy2 (Turner et al., 2014;de Oliveira et al., 2011). The IL-1α and IL-1β precursors are produced by macrophages, monocytes, neutrophil, dendritic cells and lymphocyte through the activation of pattern recognition receptors (PRR) which includes Toll-like receptors (TLR) and NOD-like receptors (NLR) followed by the activation of nuclear factor-κB (NF-κB) during cellular damage, infection, and inflammation (Ren and Dubner, 2010;Turner et al., 2014;de Oliveira et al., 2011). IL-1α and IL-1β precursors are converted to their active form by interlukin-1 converting enzyme or caspase-1. IL-1α and IL-1β act on the IL-1RI receptors (active receptor) which activates intracellular signal transduction and IL-1RII (decoy receptor) which does not activate intracellular signal transduction. The IL-1Ra also acts on IL-1R1 without inducing signal transduction but it simply blocks the receptor thus preventing IL-1α and IL-1β to act on it (de Oliveira et al., 2011;Turner et al., 2014). Both IL-1α and IL-1β have a biological (such as cell proliferation and apoptosis), a physiological (such as in fever) effects and are overexpressed in some disorders such as rheumatoid arthritis and neuropathic pain (Ren and Dubner, 2010;de Oliveira et al., 2011). An increased expression of IL-1 was observed in the DRG of animal models of disc herniation (Choi et al., 2015). Blocking IL-1 reduced hypersensitivity in pain animal models (Gabay et al., 2011). Also, paclitaxel-treated rats that received an IL-1 blocker decreased their symptoms of CINP (Kim et al., 2016)
6.1.2. Tumour Necrosis Factor- α
Tumour Necrosis Factor- α (TNF-α) is a pro-inflammatory cytokine that is mainly produced by macrophages. It induces apoptosis by activating the TNFR1 and TNFR2 receptors. These receptors induce the nuclear factor-κB (NF-κB) signaling pathway. TNF-α induces expression of cell adhesion molecules and chemokines, thus, recruiting leukocytes to the site of injury (Aggarwal et al., 2012). It sets a positive feed-back loop for greater production of TNF-α and other cytokines such as IL-1 (Lees et al., 2013;Gane et al., 2016). TNF-α is not normally expressed in the nervous system, hence its physiological functions in the nervous system cannot be determined. During disease, TNF-α is produced by microglial cells and has a destructive effect in many neurological diseases such as Alzheimer’s disease and neuropathic pain (Rubio-Perez and Morillas-Ruiz, 2012). Burgos et al. (2012) reported elevated levels of TNF-α in paclitaxel-treated animals showing symptoms of CINP (Burgos et al., 2012). Treating animal models of pain with TNF-α blocker reversed symptoms of pain hypersensitivity (Iwatsuki et al., 2013).
6.1.3. Interleukin -6
Interleukin -6 (IL-6) is a member of the neuropoietins family that share structural properties with other cytokines such as IL-11 and IL-33 (Erta et al., 2012). It plays an important role in inflammatory response and host defense mechanisms. It is a pro-inflammatory cytokine that causes fever and it is a marker of tissue damage (de Oliveira et al., 2011). Physiologically, it is involved in the neurogenesis of neurons (Rubio-Perez and Morillas-Ruiz, 2012;Erta et al., 2012) and it regulates neuropeptide expression after neural tissue damage (de Oliveira et al., 2011). IL-6 is expressed by various cells including, fibroblasts, endothelial cells and astrocytes (Turner et al., 2014). It acts on its receptor (IL-6R) which activates JAK-STAT signaling leading to STAT3 phosphorylation and IL-6 expression (Turner et al., 2014;Erta et al., 2012). IL-6 is expressed in both the peripheral and central nervous system. It is upregulated by other cytokines such as TNF-α, IL-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-ᵧ) and interlukin-17 (IL-17) (de Oliveira et al., 2011;Erta et al., 2012). A study of prostate cancer patients found an increased serum levels of IL-6 after chemotherapy and pain was one of the reported symptoms by these patients (Dorff et al., 2010). It was also found to be upregulated in pain animal models and in neuropathic pain patients and treating these animals or humans with IL-6 antagonist attenuated neuropathic pain symptoms (Moini-Zanjani et al., 2016;Ohtori et al., 2012;Vendrell et al., 2015).
6.1.4. Interukin-2
Interleukin-2 (IL-2) is a pro-inflammatory cytokine that is mainly produced by T lymphocytes and acts through its receptors IL-2Rα, IL-2Rβ and IL-2R. It induces signaling by JAK /STAT to promote maturation and proliferation of immune cells (T lymphocytes, B cells, monocytes, neutrophils and natural killer cells) and other cytokines such as TNF-α and IFN-ᵧ (de Oliveira et al., 2011). Although IL-2 is a pro-inflammatory cytokine, studies have shown that it is inversely related to pain score reported by neuropathic pain patients (Uceyler et al., 2010;Allison et al., 2016)
6.1.5. Interleukin – 12
Interleukin-12 (IL-12) is a pro-inflammatory cytokine that is produced by T lymphocytes, monocytes, neutrophils and dendritic cells. Its main function is to produce IFN-ᵧ and natural killer cells (Turner et al., 2014). IL-12 is composed of two subunits and has two receptors, IL-12β1 and IL-12β2, that induce signaling through JAK /STAT pathway. It set a positive feedback loop for its own production, however, certain cytokines such as, IL-10, IL-23, IL-4 and IFN-ᵧ decreases its expression (Vignali and Kuchroo, 2012). There are evidence of reduced levels of IL-12 in patients complaining of pain (Panis and Pavanelli, 2015). Chen et al. (2013) reported a decreased mechanical hyperalgesia in rats injected with IL-12 (Chen et al., 2013).
6.1.6. Interferon gamma
Interferon gamma (IFN-ᵧ) is a pro-inflammatory cytokine that is produced by T lymphocytes and natural killer cells. It is stimulated by inflammatory and immune reaction and act on IFN-ᵧR1 and IFN-ᵧR2 receptors to induce signaling through the JAK /STAT pathway (Turner et al., 2014). IFN-ᵧ has an antiproliferative effects on tumor cells and it regulates the production of other cytokines such as IL-12 and TNFα.(Bekisz et al., 2010). IFN-ᵧ are expressed by DRG and microglia in peripheral neurons (Allison et al., 2016). Studies showed that IFN-ᵧ in normal neurons stimulates painful allodynia in patients and in animal models of neuropathic pain indicating the correlation of IFN-ᵧ in the pathophysiology of neuropathic pain (Austin and Moalem-Taylor, 2010;Sonekatsu et al., 2016).
6.2. Anti-inflammatory cytokines
Anti-inflammatory cytokines are a group of cytokines that suppress the effects of pro-inflammatory cytokines (Rubio-Perez and Morillas-Ruiz, 2012). The most potent anti-inflammatory cytokine is interleukin 10 (IL-10) which affects macrophage production of IL-1, IL-6 and TNFα. Other anti-inflammatory cytokines are TGFβ, PDGF, IL-4, IL-13, IL-11 and IL-1Ra. Interleukins such as IL-6 and IL-27 are considered both pro-inflammatory and anti-inflammatory cytokines depending on their site of production (Arango Duque and Descoteaux, 2014). Also, interleukins such as IL-13 and IL-4 are anti-inflammatory cytokines that reduces the effects of some pro-inflammatory cytokines (de Oliveira et al., 2011). IL-11 is another anti-inflammatory cytokine that is expressed in neural tissue of the brain and spinal cord. A study reported an increased expression of IL-11 after spinal cord injury (Cho et al., 2012). Another anti-inflammatory cytokine is platelet-derived growth factor (PDGF) that is increased significantly after spinal cord injury causing hyperalgesia and allodynia in a rat model of neuropathic pain (Donica et al., 2014).
6.2.1. Interleukin 10
Interleukin-10 (IL-10) is the most potent anti-inflammatory cytokine. It is produced by various cells including immune cells (T cells, B cells) macrophage and dendritic cells (de Oliveira et al., 2011). It has a key role in immune regulation during infection. It acts on its receptors IL-10R1 and IL-10R2 through the JAK /STAT pathway halting macrophage and monocyte activation which inhibits the action of many proinflammatory cytokines, chemokines and IL-10 itself (Turner et al., 2014;de Oliveira et al., 2011). In neuropathic pain animal model, IL-10 suppressed symptoms of mechanical allodynia which indicates a promising role of IL-10 in reducing neuropathic pain (Khan et al., 2015).
6.2.2. Interleukin -4
Interleukin-4 (IL-4) is an anti-inflammatory cytokine that is produced by T lymphocytes, eosinophils and basophils. It is expressed by various cells such as T and B lymphocytes and natural killer cells. It reduces the effects of macrophage, IL-1, TNFα and IL-8 (de Oliveira et al., 2011). In the nervous system, IL-4 is produced by macrophage, microglia and astrocytes. It is expressed by T cells and oligodendrocytes through the IL-4R receptor which induces the JAK /STAT signaling pathway (de Oliveira et al., 2011). Lower levels of IL-4 was reported by patients with chronic pain indicating its possible analgesic effect (Busch-Dienstfertig and González-RodrÃguez, 2013;Uceyler et al., 2011). It was also found to be decreased in neuropathic pain animal models (Bobinski et al., 2017).