The incidence of a cancer diagnosis within the UK is rising, with an estimated increase of 40% by 2035 (Cancer Research, 2019). However, as treatment modalities and screening become more sophisticated there are more individuals living longer with and as a result of a cancer diagnosis (Cancer Research, 2019).
As the incidence of cancer increases, so does the incidence of individuals living with pain as a direct result of cancer treatment. It is estimated that 66% of individuals with advanced disease and 39% who have completed curative treatment will report pain (Van den Beuken-van Everdingen et al, 2016). Persistent cancer pain is complex and multifactorial, and can have a detrimental impact on patients' quality of life, as it affects not only physical domains but also has a significant impact on psychosocial domains (Sun et al, 2008). Despite the complex nature of persistent cancer pain, it remains poorly understood and managed (Sun et al, 2008).
There has been heightened awareness of analgesic prescribing for chronic pain, although the focus has largely been on chronic-non-cancer pain. There is little guidance in the management of chronic cancer pain and a better understanding is needed of the role of long-term analgesic use in this population (Reyes-Gibby et al, 2016; Sun et al, 2008).
Background
The use of systemic chemotherapy as a treatment modality for cancer is widely used, with around one-third of all individuals receiving chemotherapy as part of their treatment (National Cancer Registration & Analysis Service and Cancer Research UK, 2017). Given the high use of chemotherapy agents during treatment, it is not surprising that chemotherapy-induced peripheral neuropathy (CIPN) is arguably one of the most common and debilitating symptoms following cancer treatment (Beijers et al, 2014; Lee et al, 2019). With the increased use of chemotherapy and decrease in mortality rates the incidence of CIPN is rapidly becoming a major issue faced within those living with and beyond cancer (Zajaczkowska et al, 2019). The exact incidence of CIPN is unknown, due to multiple lines of treatment being used and poor reporting. However, it is estimated that up to 50% of individuals will report chronic CIPN, depending on the type of agent being used (Lee et al, 2019; Brown et al, 2014). Agents commonly associated with the development of CIPN include:
- Platinums (Oxaloplatin, Cisplatin)
- Taxanes (Paclitaxel)
- Vinca Alkaloids (Vincristine)
- Thalidomide's (Brown et al, 2014).
Physiology of chemotherapy-induced peripheral neuropathy
CIPN is the result of damage from exposure to chemotherapy agents, which alter the ability of neurons to maintain normal metabolic function (Binner et al, 2011). The full extent of the physiology driving CIPN is complex and still not fully understood, as the treatment being administered will determine the mechanism of action that results in nerve damage. However, it is thought that common factors are due to structural changes in the mitochondria within the cells, changes to the pain mediators with the nervous system, and abnormal transmission of pain signals (Flatters and Bennett, 2006; Cavaletti et al, 2002; Xiao and Bennett, 2008).
In the majority of instances, symptoms improve once treatment has completed or been stopped. However, in 40% of individuals, symptoms will persist and develop into a chronic pain state. The development into a chronic pain state is thought to be linked to central sensitisation of the peripheral and central nervous systems (Lee et al, 2019). Central sensitisation occurs when the pain system enters a state of heightened awareness of pain transmission and results in a lowering of pain thresholds. This heightened state continues well beyond normal tissue healing and results in the manifestation of chronic pain (Latremoliere et al, 2009)
Symptoms of CIPN are variable and will depend on the chemotherapy agent being used, as it will have a unique toxicity profile, depending on its site of action. The symptoms can be broken down into three main groups see Table 1. It is important to note that the variation and incidence of these symptoms is personal to the individual and they may report one or all of these symptoms.
Table 1. CIPN presenting symptoms
| Site of Action | Symptom | Common Agent |
|---|---|---|
| Sensory |
|
|
| Motor |
|
|
| Autonomic |
|
|
Assessment methods
The cornerstone of any good pain management plan must start with a robust pain assessment, which is essential to establish the nature of the pain and any influencing factors. Before embarking on pain assessment, it is important to consider the biopsychosocial model for pain. This model acknowledges that the experience of pain is generated from not only the biological cause (site of tissue or nerve damage) but also psychosocial factors, such as feelings of helplessness and loss of hope regarding pain management (Gatchel et al, 2007).
The complex nature of CIPN can make assessment more challenging due to a variety of factors that not only relate to the symptom itself but also views from individuals and healthcare professionals. Research suggests that healthcare professionals lack knowledge and confidence when assessing CIPN, impacting their ability to manage CIPN effectively (Binner et al, 2011; Smith et al, 2014). This issue has been seen in patient reports of care perspective as Tanay and Armes (2019) found that although patients reported symptoms of CIPN at the time of treatment they felt that the symptom was ignored and they were left to manage on their own. These feelings of patients being left on their own contribute to the biopsychosocial idea of pain experience and potentially contribute to the severity of pain experienced. There is a need to demystify the assessment process for healthcare professionals and empower them to feel confident in their assessment skills.
There are a number of options for detailed assessment methods, such as skin biopsies and quantitative sensory testing. These methods require specialist input and are difficult to perform at the bedside (Lee et al, 2019). There are a wide range of assessment tools available for use, however, there is no gold standard tool that is universally used across practice Molassiotis et al (2019). There is a great deal of debate around the choice of assessment tool, with some tools resulting in an overestimation of symptoms, which impacts on reliability of the diagnosis (Molassiotis et al, 2019). This compounds the problem faced by both healthcare professionals and patients when assessing the impact and severity of symptoms. A recent systematic review of the available assessment tools was completed by Haryani et al (2017), based on a review of 20 tools in 19 studies. They recommended the use of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx) and Total Neuropathy Score (TNS).
FACT/GOG-Ntx was originally designed and validated for use in women being treated with taxanes and platinum-based treatments for the management of gynaecological cancers (Calhoun et al, 2003). The tool consists of 11 questions that assess the impact of sensory and motor symptoms on daily activities, such as dexterity when using buttons (Curcio, 2016). This tool encompasses patient-reported symptoms only and does not require a physical examination, which is often been the cause of a lack of confidence when assessing CIPN (Binner et al, 2011). In comparison, the Total Neuropathy Score (TNS) was initially developed for use in diabetic neuropathy and consisted of a detailed physical examination and individuals reports of sensory and motor symptoms. Although this version had proven its reliability, and validity it is not feasible to use in everyday practice due to time constraints and reduced access to nerve conduction studies within a cancer setting. A shortened form was developed, which excluded the physical examinations and only focused on sensory and motor symptoms (Cavaletti et al, 2006). Although there are a wide variety of tools, it is important to use these as a guide to aid the assessment process and ensure that you and the patient are able to use the tool effectively to generate a reliable interpretation of the results.
Management
The pharmacological treatment of CIPN is challenging and the evidence base around the analgesics use of is limited. When considering treatment options for CIPN, it is important to first consider if chemotherapy treatment is ongoing, as if the symptoms are severe this may require a dose reductiom or be stopped. However, this should be a discussion with the oncology team and the individual receiving treatment, as this will impact on overall treatment plans. There are no national guidelines relating to the specific management of CIPN, however, there are National Institute for Health and Care Excellence (NICE) guidelines regarding the management of neuropathic pain within a non-specialist setting (NICE, 2013). The NICE guidance does make reference to CIPN as a cause for pain and suggests first-line treatment should be offered either Amitriptyline, Duloxetine, Gabapentin or Pregabalin. If first-line treatment is not effective, then this should be rotated to one of the other options.
Unfortunately, the evidence base for the use of these medications in CIPN is poor, with little high-quality evidence clearly demonstrating the benefits. A recent systematic review by Hou et al (2018) found low-quality evidence that supports the use of Duloxetine in the management of CIPN. However, although the studies included did show a reduction in pain scores, the sample sizes were small. Hou et al (2018) reported that the evidence base surrounding the use of Pregabalin, Gabapentin and Amitriptyline was not sufficient to generate a recommendation and more research is needed regarding the role of these medications in this population. Although NICE (2013) also recommends the use of Tramadol to manage breakthrough pain, caution must be used when introducing this into the management plan, as there is an increased risk of developing serontonergic syndrome when prescribed alongside SSRIs such as those recommended for first-line use (Fallon, 2013). There is limited evidence on the use of opioids in the CIPN population (Hou et al, 2018). Guidance should be sought from specialist pain services before initiating opioids for chronic pain states, to ensure that appropriate follow-up and monitoring occurs (Brown and Farquahr-Smith, 2017).
Given that the evidence base for the use of pharmacological management is limited there is a need to consider a multimodal treatment plan to ensure optimal management of CIPN symptoms. There are numerous topical and non-pharmacological approaches that can be used. However, the evidence base for these is limited. It is worthwhile considering a trial of these as an alternative to medications that can have a significant side effect profile.
There is emerging evidence for the use of topical treatments such as topical menthol cream. The cooling effect of the menthol results in activation of TRPM8 sensory nerve, which is found throughout the peripheries, and this activation results in an analgesic effect (Proudfoot et al, 2006). Early studies demonstrated a reduction in pain scores by 82% and an improvement in sensation, quality of life and mobility (Fallon et al, 2015). Topical capsaicin can also be used as a method of managing chronic neuropathic pain similar to CIPN. This is available in two strengths as either high-dose single-patch treatment 8% or low-dose topical total dissolved solids treatment 0.075%. The mechanism of action is based on desensitisation of the painful area through depletion of substance P, which is an essential component in pain transmission (Tofthagen et al, 2013). Use of a high-strength patch has demonstrated an 84% reduction in pain scores at 12 weeks (Filipczak-Bryniarska et al, 2017) and a recent Cochrane review has demonstrated its role in reducing pain scores within chronic neuropathic pain states (Derry et al, 2013). Other topical treatments that may have a role include Lidocaine plasters; however, there is limited evidence to support the use of this practice. A recent Cochrane review found no high-quality evidence to support the use of Lidocaine plasters in the management of neuropathic pain, but they did acknowledge that clinical experience supports the use of this as a management option (Derry et al, 2013). In some cases, Lidocaine plasters can be just as effective as conventional drug-based therapy but with considerably less side effects (Brown and Farquahr-Smith, 2017). Although these are not recommend for routine prescribing by NICE, the Neuropathic Pain Special Interest Group guidelines do recommend the use of Lidocaine plasters for localised neuropathic pain (Dworkin et al, 2010). Although the evidence base for their use in CIPN is limited, it can have a role as part of a wider management plan and should be considered as an alternative to conventional analgesics (Fallon, 2013).
When formulating a management plan, it is important to consider non-pharmacological strategies that can enrich and provide additional support to individuals living with this debilitating symptom. In individuals whose symptoms are negatively impacting on quality of life, it is essential to consider early interventions from physiotherapy and occupation therapy to improve function and quality of life (Tofthagen et al, 2013). Other interventions such as acupuncture and massage may also have a role. However, the evidence base is weak and more research is needed to show efficacy of these interventions (Oh and Kim, 2018).
When prescribing in this situation is it is challenging and will ultimately need to be a joint decision between the prescriber and the individual. Although the NICE (2013) guidelines suggest a choice for first-line treatment it is important to consider local prescribing practices as these will often outline hierarchy for use of these analgesics. Given the poor level of evidence regarding the use of these medications, it is important to continually review the efficacy and side effect burden of these medications, and if there is no noticeable benefit, then these should be stopped.
Conclusion
CIPN is becoming more common in individuals living with cancer and post treatment. Its exact mechanism of action is complex and, as a result, is adding to the complexity in its management. Early assessment and identification of these symptoms is essential when formulating a management plan. More support is needed to improve healthcare professional's knowledge and confidence in managing this population. Although the evidence base and guidance is limited, the final prescribing decision should be based on a joint consultation between the prescriber and the patient to encourage a holistic and multimodal approach to managing this complex symptom.