Neuropathy is an irritation or damage to nerves, which causes poor “communication” between nerves; it can affect motor, sensory and/or autonomic nerves. Certain chemotherapy agents can cause this damage, creating a challenge for both patients and practitioners in balancing the goal of cure with a patient’s quality of life.
The incidence of CIPN can vary greatly among patients being treated with chemotherapy. Wolf, Barton, Kottschade, Grothey and Loprinzi (2008) report that 30-40% of cancer patients receiving chemotherapy will develop CIPN during their treatments. With an incidence this notable, there is a significant importance for practitioners to have an appropriate understanding of pathophysiology, risk factors, presenting symptoms and symptom management related to CIPN.
Among the many challenges that a patient with cancer faces, perhaps one of the most poorly understood, yet most life-changing, is CIPN. It can greatly affect the quality of life for patients already facing many other difficulties arising from a cancer diagnosis. The pain and dysfunction associated with CIPN can impact a patient’s life in many ways, from “simple” things such as buttoning a shirt or opening a jar, to pain that affects nearly every daily activity and interferes with sleep. It is essential for nurses to know the presenting symptoms, risk factors associated with and evidence-based management of CIPN. The goal of treatment is for the patient to receive the full recommended dose of chemotherapy for their specific disease, but this goal can cause practitioners to “push” the limits of certain side effects Therefore, nurses must be vigilant in identifying and monitoring CIPN, to advocate for necessary dose reductions before CIPN becomes severe and/or irreversible.
The successful treatment of patients with CIPN includes managing pain, preventing progression of this side effect and assuring patient safety while treating the cancer with optimal chemotherapy doses This should be kept in mind and changes to regimen and dosing continually assessed It is the responsibility of the oncology nurse to develop a plan of care to manage the symptoms of CIPN, keep the patient safe and allow them to continue cancer treatment The use of both pharmacological and alternative treatments, can greatly improve the chances of successful chemotherapy treatment and CIPN management.
CIPN has been a complication with oncology patients undergoing chemotherapy treatment since the use of chemotherapeutics became widespread. This has continued in recent years due to the continued lack of understanding of the pathophysiology of CIPN and the introduction of new agents that can cause CIPN. The actual mechanism of action for CIPN is unknown, but several theories are currently under consideration (Vanotti, 2007). One such idea is nerve cell damage and death through a mechanism known as excitotoxicity (Yarbro, Frogge & Goodman 2004). Within the central nervous system, neurons receive abnormal pain signals from peripheral nerves, causing them to produce increased pain signals throughout the body, resulting in increased release of glutamate. The excess glutamate forces N-methyl D-aspartate (NMDA) receptors to remain open, allowing increased calcium flux into neurons, resulting in overexcitation and eventually neuronal rupture (Armstrong, Almidrones & Gilbert 2005). The end result of this process is pain without a painful stimulus, also known as neuropathic pain. Another theory behind the pathophysiological development of CIPN is that of axonal nerve degeneration or a “dying back” of nerves (Ocean & Vahdat 2004). As axonal degeneration progresses, it usually occurs symmetrically in a distal to proximal fashion, exhibiting the “dying back” phenomenon. As these neurons die, incomplete ion channel closure causes non-stimulus induced pain signals to emanate throughout the affected areas.
CIPN in some cases is reversible, while in other cases it is partially or completely irreversible, despite the removal of the presumed cause. The need for better understanding of the pathophysiology becomes increasingly more apparent when discussing the limited preventive and treatment options for CIPN. This lack of knowledge related to CIPN pathophysiology greatly hinders the development of successful treatments.
Peripheral neuropathy can present differently depending on a number of factors. These can include aspects such as the patient’s medical and surgical history and risk factors, renal and hepatic function, age, current medications or supplements and the type and dosage of chemotherapy they are receiving. It is important to be aware of certain medical histories that may predispose one to CIPN, including diabetes mellitus, hypothyroidism, alcoholism, rheumatoid arthritis, systemic lupus erythematosus, AIDS, vitamin deficiency, renal failure and others (Wickham, 2004). A common pattern among these disease processes is their interaction within the nervous system, predisposing a patient to further nerve damage manifesting in CIPN. Medications and/or supplements that may increase the risk for developing CIPN include hydralazine, metronidazole, lithium, dapsone, phenytoin, cimetadine, amiodarone and amitriptyline (Wickham, 2004).
After assessing a patient’s risk factors through a complete health history, it is important to take into consideration the type and dosage of chemotherapy the patient will be receiving to identify the treatment-associated risk of developing CIPN. The most common chemotherapeutic classes associated with the development of CIPN include vinca alkaloids, taxanes and platinum-based drugs (Wickham, 2004) The vinca alkaloids consist of vinblastine, vinorelbine, and vincristine, which have been shown to cause the most cases of CIPN. Vincristine treatment at doses greater than 5mg leads to sensory symptoms, where motor symptoms begin to appear at cumulative doses of 30-40mg (Ocean & Vahdat 2004). In the taxane family, paclitaxel, docetaxel and Abraxane (paclitaxel bound to albumin), have all been shown to lead to CIPN (Hausheer, Schilsky, Bain, Berghorn & Lieberman 2006). Doses of paclitaxel that place a patient at risk for CIPN are 250mg/m2 as single dose and 1000mg/m2 as a cumulative dose (Ocean & Vahdat 2004). Cisplatin and oxaliplatin are the platinum-based drugs with the highest prevalence of CIPN development. Patients who have received a cumulative dose of 400mg/m2 of cisplatin are most likely to exhibit sensory neuropathies (Ocean & Vahdat 2004) Newer agents that may cause CIPN include bortezomib (Velcade), thalidomide and epothilones At high doses, cytarabine and etoposide may cause CIPN and, in rare cases, ifosfamide (Stubblefield & O’Dell, 2009).
The symptoms exhibited by patients who present with CIPN can include both sensory, motor and autonomic dysfunction. Sensory symptoms can include paresthesia, hyperesthesia, hypoesthesia (including temperature decreased or mis-perception), dysesthesia, pain, numbness and tingling and hyporeflexia (Vishovsky, Collins, Abbott, Aschenbrenner & Hart 2007). Diminshed or absent proprioception, vibratory sensation, cutaneous sensation and sense of discrimination may also be exhibited in these patients (Vishovsky, et al. 2007). Clinically, patients may have cool, hairless, dry and/or thin skin in the effected extremities Motor presenting symptoms can include weakness, gait or balance disturbances and difficulty with fine motor skills (Vishovsky, et al. 2007). A complete neurological examination is imperative for proper diagnosis of these patients. Sensory and motor symptoms typically present in a glove-stocking pattern, most notably not traveling above the ankle or wrist, with varying degrees of severity.
Some patients will experience autonomic neuropathy, which occurs when autonomic nerves, both sympathetic and parasympathetic, are damaged Symptoms can include bowel obstruction, severe constipation, postural hypotension and cardiac dysfunction (heart rate variability, tachycardia). Of note, autonomic neuropathy can also develop as a late effect of chemotherapy (Hansen, 1990).
Prior to starting therapy with a neurotoxic agent a baseline assessment should be performed, including asking about risk factors, medications, previous chemotherapy and any existing symptoms of peripheral neuropathy. A thorough neurologic exam should be performed to identify any preexisting deficits Testing should include muscle strength, sensory ability (pain and temperature), reflexes and, if relevant, autonomic nerve function. Documentation of this history and exam will be helpful if symptoms arise during treatment.
After a complete history and physical examination is completed, it is important to consider differential diagnoses for the presenting symptoms. The most common symptoms of CIPN include numbness and tingling in hands and feet. Possible differential diagnoses of parasthesias include peripheral neuropathy related to diabetes mellitus, Raynaud’s phenomenon, multiple sclerosis, hypothyroidism, stroke, brain tumor and spinal injury, including cord compression In the case of CIPN, the offending agent should be identified.
There is currently no gold standard practice for the treatment of CIPN This fact arises from the incomplete understanding of the development of the disease, which can vary greatly even among patients receiving similar chemotherapy regimens Since there is no treatment that targets the cause of neuropathy, patients with CIPN are treated to alleviate their symptoms using both pharmacological and non-pharmacological interventions Some patients may prefer non-pharmacological treatments if they are available and offer similar pain relief to medications.
There are a wide range of pharmacological agents that are used to treat CIPN with varying degrees of effectiveness (Kaley & Deangelis 2009). Infusions of calcium and magnesium have been trialed to help improve some of the painful symptoms in patients with CIPN. It is thought that by increasing the concentration of these ions outside of peripheral neurons, the frequency of sodium channel openings will decrease. Unlimited channel opening (or channel hyperexcitability) is thought to be one of the inducers of pain due to CIPN. The therapy was first tested in patients receiving oxaliplatin with CIPN and showed marginal improvement in their symptoms (Gamelin, et al 2004). Administration of calcium and magnesium also showed a preventative benefit in patients receiving oxaliplatin who had yet to develop CIPN, with a smaller number of patients developing CIPN while receiving the infusions than those who did not Randomized controlled studies have not been performed, and the effectiveness of calcium and magnesium infusions in treating CIPN induced by non-oxaliplatin therapies needs to be investigated, but it appears that these infusions may be helpful in preventing and treating some of the symptoms of CIPN
Amitriptyline has been tested in a double-blind controlled study for the treatment of CIPN. This tricyclic antidepressant and its active metabolite, noretriptyline, inhibit the re-uptake of norepinepherine and serotonin, which are both thought to decrease nerve excitability (Wolf & Sagar 2008). These molecules have shown promise in the treatment of diabetes induced peripheral neuropathy, but further characterization and study is required to better understand their role in treating patients with CIPN. Studies have not conclusively supported tricyclic antidepressants efficacy for the treatment of CIPN. A study performed in Finland in 2008 begun by treating patients with low levels (10mg/day) of amitriptyline, then increasing the dose weekly by 10mg/day, up to 50mg/day, where it was maintained for a total of eight weeks. The study tested the effects on 33 patients undergoing a wide range of chemotherapy regimens who displayed some symptoms of CIPN. The results of this study found no statistically significant decrease in symptoms of the patients receiving amitriptyline as compared to the placebo control group (Kautio, Haanpaa, Saarto & Kalso 2008). A similar study was performed with noretriptyline in 51 patients receiving cisplatin-based chemotherapies, increasing the noretriptyline dose over a four week period (Hammack, et al 2002) The study was not able to make any decisive findings due to the small number of patients enrolled, which is problematic of many of the trials using pharmacological interventions.
Glutamine has also been used to treat CIPN by exhibiting neuroprotection through some undefined mechanism. A study investigating oral glutamine used a dose of 15mg twice daily, with one group of patients who had colorectal cancer and were receiving oxaliplatin and a second group with breast cancer receiving paclitaxel (Wang, et al. 2007). The design of this study had similar problems as described above, including sample sizes too small to establish statistical significance. However, the patients receiving the glutamine therapy did not have to decrease their chemotherapy dose due to CIPN as often as those receiving chemotherapy alone, which is an encouraging finding for future investigation. In another study looking at patients with breast cancer receiving paclitaxel, those who were administered glutamine exhibited fewer neurological symptoms associated with CIPN such as weakness, vibratory sensation loss, and toe numbness (Stubblefield, et al 2005).
Anticonvulsant drugs, specifically carbamazepine, have also been used to treat CIPN. These drugs decrease the rate of sodium channel openings, which in turn decreases the number of neurons that fire and send pain signals to the brain. Unfortunately, these have not been shown to effectively decrease the symptoms of CIPN. Two newer anticonvulstant drugs, gabapentin and pregabalin, are also being used as treatments for CIPN (Tsavaris, 2008). The exact method of action is still unknown, but they are thought to operate on the voltage-gated calcium channels in the central nervous system, decreasing the pain signals from the peripheral nerves. There are conflicting results from different studies investigating the effectiveness of gabapentin in treating CIPN symptoms. One open-label study used patients with both treatment (including chemotherapy and surgery) and tumor induced neuropathies and found that pain scores were lower in the group receiving gabapentin (300-1800mg/day) than those who were not treated (Ross, et al 2005). However, a double-blind placebo controlled trial in patients who had exhibited CIPN symptoms for over a month found that gabapentin at a target dose of 2700mg/day did not significantly improve pain scores compared to the placebo group (Rao, et al 2007). The next generation of gabapentin, pregabalin, is currently being used to treat neuropathic pain in diabetic peripheral neuropathy with success. It is now being used in patients with CIPN while studies attempt to determine its effectiveness are ongoing (Arezzo, Rosenstock, Lamoreaux & Pauer 2008).
The combination of gabapentin with opioids for pain management has also been studied in patients with CIPN (Keskinbora, Pekel & Aydinli 2007). Multimodal therapy is important in neuropathic conditions, and the findings of the study suggest that combining opioids with other treatments for CIPN can greatly diminish the symptoms and increase the patient’s quality of life.
Several non-pharmacological interventions are also being used to treat patients with CIPN. As with the pharmacological treatments, the goal of the therapies is to diminish the pain of CIPN, not necessarily treat the underlying pathophysiology. Among the interventions used are acupuncture, physical activity, and capsaicin ointment (Visovsky et al. 2007). Physical exercise is an important component of healthy living, and patients with CIPN are encouraged to be active as tolerated using any combination of resistance and aerobic activities Wong and Sagar (2006) published a case series on the effect of acupuncture on five patients with CIPN. They found that the patients responded favorably to treatment, but the small sample size has limited the conclusive power of the study. Capsaicin is a popular treatment that patients often suggest due to its ease of administration and targeted relief There have been no studies in patients with CIPN, but capsaicin cream was shown to improve the symptoms of patients with diabetic neuropathy in their feet (Visovsky et al, 2007). Capsaicin can be used as an adjunct with other treatments for peripheral neuropathy.
Patient education is essential to the management of CIPN. Nurses are the front line in supporting and guiding patients experiencing CIPN. Education for patients receiving potentially neuropathic agents should include signs and symptoms they may experience and when to inform their health practitioner. These include numbness and/or tingling in fingers or toes, weakness in extremities, difficulty opening jars or buttoning clothes or disturbances with gait and balance. According to an article in the Clinical Journal of Oncology Nursing by Wickham in 2007, safety in the home environment is very important and includes the following reminders for patients and their families: ensuring rooms have good lighting and using flashlights and nightlights at night to avoid stumbling and falling are simple fixes that can significantly decrease the risk of serious injury arising from CIPN Other effective home controls include installing handrail where possible, including the bathroom and shower area, avoiding loose rugs and clutter on floor in highly traveled areas and ensuring safety when dealing with extreme temperatures when bathing, cooking or being outdoors in the winter Patients should be instructed to check their feet daily, as they may not detect injury in areas that have a sensory deficit. Patients should be told that CIPN symptoms often improve 6-12 months after treatment, but can become chronic for some. Patients who develop severe or irreversible CIPN may benefit from physical and/or occupational therapy and a home visit to ensure safety in their home environment
In conclusion, it is important for the practitioner to have an understanding of the theories of pathophysiology related to CIPN, assess a patient’s known risk factors and presenting symptoms of CIPN and have knowledge of both pharmacological and non-pharmacological treatments for CIPN. A successful treatment of CIPN is characterized by maintaining the recommended course of chemotherapy treatment while maintaining a high quality of life and level of comfort for the patient Further research is necessary to improve the intervention strategies for patients experiencing CIPN.
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