Pain Management
REVIEW For reprint orders, please contact: [email protected]
Neuropathic pain in cancer survivors
Rakesh Garg1 & Sushma Bhatnagar*,1 Practice points ●●
The occurrence of pain in cancer survivors may be debilitating.
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Pain or pain syndromes may be primarily a sequel of cancer per se or side effects of
treatment received by the patients, including surgical interventions, chemotherapy and radiotherapy. ●●
There is a lack of research for chronic cancer pain management in cancer survivors.
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For pain assessment in cancer survivors, comprehensive information regarding onset and duration, severity and characteristics of neuropathic pain has to be collected.
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Neuropathic pain in cancer survivors is unique and needs a holistic and personalized management.
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The multidisciplinary and multimodal management is essential for such neuralgic
pain in cancer survivors. This may require a balanced combination of pharmacological and nonpharmacological techniques, including psychological support.
SUMMARY The occurrence of pain in cancer survivors may be debilitating. These pain syndromes may be of different types, including neuropathic pain. The research related to cancer management has been done extensively in certain areas, but such research in cancer survivors is still lacking. The chronic pain in cancer survivors is not only under-reported but also under-treated. The assessment of pain in cancer survivors is multifaceted because of many domains like physical, social and psychological. Usually, the pain management may be considered similar to that for chronic noncancer pain, but with a caveat that such pain may at times be indicative of cancer recurrence. The multidisciplinary and multimodal management is essential for such neuralgic pain in cancer survivors. This may require a balanced combination of pharmacological and nonpharmacological techniques, including psychological support. The overall goal that remains in such patients for pain management is to improve the quality of life. Here we review certain pertinent aspects of neuropathic pain in cancer survivors.
KEYWORDS
• cancer • cancer survivor • mechanism • neuropathic • pain • pain management
The advancement in medical sciences has improved the outcome of cancer and thus increased the number of cancer survivors. The ‘cancer survivors’ have been variously defined. It may be any person who has been diagnosed with cancer, from the time of diagnosis through the balance of life [1] . It, thus, may be phased into three time periods as diagnosis to treatment, from treatment to extended survival and finally long-term survival [2] . Others define it as ‘someone who has completed Department of Anaesthesiology, Pain & Palliative Care, Dr B.R. Ambedkar Institute Rotary Cancer Hospital, AIIMS, New Delhi, India *Author for correspondence: [email protected] 1
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Review Garg & Bhatnagar initial treatment and has no apparent evidence of active disease, is living with progressive disease and may be receiving treatment, but is not in the terminal phase of illness, or someone who has had cancer in the past’ [3] . The more precise definition has also been proposed, which states ‘those who have completed the active antineoplastic phase of their treatment, have no evidence of disease, are under cancer surveillance and those whose cancer pain syndrome is not related to active disease progression’ [4,5] . The cancer survivors have some peculiar concerns, though they are declared to be disease free, that is, cancer free [6] . These include various adverse effects relating to the treatment received by them for cancer, and psychological concerns as well [1] . These cancer survivors also have to face certain medical issues, which at times, may be related to age and comorbidities, and social issues like socioeconomic status and family/support group [1,6] . The cancer survivors may have to bear the various pain syndromes related to treatment therapy or in other terms sequel of cancer and its treatment. Adjusting to these difficult symptoms appears to be quite challenging for the cancer survivors and may significantly affect the quality of life. The occurrence of pain in cancer survivors may be debilitating. This pain or pain syndromes may be primarily a sequel of cancer per se or side effects of treatment received by them, including surgical interventions, chemotherapy and radiotherapy. These pain syndromes may be of different types, including neuropathic pain. The neuropathic pain has been defined as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’ or more recently as ‘Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’ [6–8] . The research related to cancer management has been done extensively in certain areas, but such research in cancer survivors is still lacking. The chronic pain in cancer survivors is not only under-reported but also under-treated [9,10] . The assessment of pain in cancer survivors is multifaceted because of many domains like physical, social and psychological. Usually, the pain management may be considered similar to that for chronic noncancer pain, but with a caveat that such pain may at times be indicative of cancer recurrence [9,10] . The overall goal that remains in such patients for pain management is to improve the quality of life [6] .
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Methods We have performed a PubMed search using search terms such as ‘cancer survivor,’ ‘pain,’ ‘neuropathic pain/pain mechanism/pain management’ and ‘analgesia.’ All papers (original trials, reviews, retrospective studies, case reports, commentaries, editorials) in English language that specifically discussed the relevant issues are included. ●●Incidence
The survival rate has improved over last few decades and it exceeds over 80% for some cancers with around 68% 5-year survival rate overall [6,10,11] . Pain has been reported by 33% of patients cured for cancer, while other authors report that persistent pain is seen in 50% of cancer patients treated with chemotherapy, surgery and radiotherapy [12–15] . This is much higher than the pain seen in patients without history of cancer (18%) [16] . As survival rates improve, pain physicians will have to manage an increased number of patients for persistent pain syndromes [9] . In spite of available treatment options, undertreatment of pain may be seen in up to 40% of patients as per WHO reports [10] . The three most common sites for those living with a history of cancer in men include prostate cancer (43%), colorectal cancer (9%) and melanoma (7%) and in women include breast (41%), uterine (8%) and colorectal (8%) cancer [3,8,9] . Pain is more commoner in patients of post-thoracotomy (80%), postamputation/phantom limb (50–80%), postneck dissection (52%) and breast cancer (63%) [9] . These types of pain are usually the result of cancer treatment rather than the sequel of cancer per se [9] . The etiology of neuropathic pain has been related to 75.7% for cancer, 11.4% for treatment, 4.9% for associated, 5.9% for unrelated and 2.1% for unknown cause [17] . ●●Importance of attending pain in cancer
survivor
The occurrence of pain resulting from chemotherapy, radiotherapy, surgery or interventional procedures in cancer survivors may debilitate the quality of life significantly [3,18] . Thus, chronic pain in cancer survivors may have impact on physical, psychological and social functioning and cancer survivor may have anxiety and depression [3,18] . These may also have impact on functional abilities and sleep, and as a consequence, may lead to daytime fatigue and mood
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Neuropathic pain in cancer survivors disturbances [3] . For a noncancer pain, a conservative approach may be accepted, but for a cancer survivor, emergence of new pain needs to be assessed on urgent basis and comprehensively to rule out cancer recurrence or metastasis [19] . The various risk factors responsible for chronic pain in cancer survivors include the anatomical site, stage and histology of the disease; treatments received, the treatment regimens, duration and dosages; length of time that has elapsed since treatment; and underlying risk factors independent of the cancer or its treatment, for example, associated comorbidities [3] . In spite of available treatment to a large extent, cancer pain remains under-treated in almost half of the patients, especially in cancer survivors. The reasons for such under-managed cases have been attributed to geographical areas, which include Europe, Asia and low-income countries and absence of expertise/centers for managing such cancer pains [10] . These parameters need to be accounted for setting up infrastructure in such areas to provide better pain management to cancer survivors to improve their quality of life. ●●Pathogenesis
& etiological causes
Chronic pain has been observed more often in cancer survivors treated for breast, prostate, lung, thoracic, head and neck or colorectal cancers. Certain cancers, like breast cancer, have been studied and reported for chronic neuropathic pain. The three main types of cancer pain observed in cancer survivors include neuropathic (abnormal nerve impulses, commonly from chemotherapy), nociceptive/somatic (involving muscles, bone, connective tissue) and nociceptive/visceral (involving organs, such as liver or pancreas) [9,20] . The various types of neuropathic pain seen in cancer survivors include postmastectomy, postthoracotomy, postradical neck, postamputation pain syndromes, and brachial or lumbosacral plexopathy [9,21] . The neuropathophysiological pathway for the cancer neuropathic pain remains the same as for noncancer pain, though the etiology differs. The pain in cancer survivors may be related not only to primary disease pathology, but also to treatment like surgical intervention, chemotherapy or radiotherapy, by general debility or even any concurrent disorder. These interventions cause ‘disturbance of function or pathological change in a nerve(s)’ and, thus, are the cause of neuropathic pain [6] .
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Chemotherapy has been implicated as a commoner reason for neuropathic pain in cancer survivors. The peripheral neuropathy is the most common form of neurotoxicity with chemotherapy, with an variable incidence of about 30–40% [9] . The pathophysiological mechanisms include the distal axon (axonopathy) and/or the neurons of the dorsal root ganglia (neuronopathy) [6,8] . These can be differentiated by history and clinical examination in context with exposure of chemotherapy and are important for prognostication. The neuronopathy is usually complete and nonreversible, while axonopathy has fluctuating symptoms in terms of frequency and severity [22] . The neuropathic toxicity due to chemotherapy is related to factors like patient’s age, single-dose intensity, cumulative dose, combinations of neurotoxic agents, coexisting neuropathies, genetic susceptibility, alcohol abuse, impaired drug metabolism and excretion of active metabolites [23–25] . The occurrence of chemotherapy-induced neuropathic pain increases from 3–7% with single drug to as high as 38% with multiple agents of chemotherapy [3] . The chemotherapeutic agents like plant alkaloids (vincristine and vinblastine); taxanes (paclitaxel); the platinumbased compounds (cisplatin, carboplatin and oxaliplatin); and the antimitotics (methotrexate, cytosine arabinoside and fluorouracil) have been studied and found to have increased the incidence of neuropathic pain [6] . The newer ‘biologics’ also have higher risk for neuropathic pain [8] . The chemotherapeutic drugs usually affect sensory nerves, but motor and autonomic nerves may also be affected [3] . The chemotherapy-induced neuropathy presents with a characteristic involvement of longer nerves and with bilateral, symmetrical ‘stocking and glove’ phenomenon of the distal extremities and with paresthesia or dysesthesia along with numbness or tingling [3,6,11] . At times, in addition to sensory symptoms, muscle weakness may also be present [11] . The timing of presentation of symptoms after chemotherapy is quite variable. The agents like cisplatin manifest signs of neuropathy, which occur about 1 month after the therapy, while oxaliplatin may produce symptoms within 30–60 min after the infusion [26,27] . The symptoms including paresthesia, dysesthesia, pain, or sensory and motor impairment may even persist years after treatment is discontinued [28,29] . The resolution of pain is also variable in these patients.
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Review Garg & Bhatnagar Radiation therapy has been associated with neuralgic pain. The neuropathic pain severity is related to radiation exposure, the dose of radiation and vicinity to major nerves or nerve plexus [3,6] . The advancement and refinements in radiation oncology have decreased the insult to nerve and plexuses and, thus, the incidence of radiation induces neuralgic pain [30] . The pathophysiology of radiation-induced neuropathies is not well known, but possible etiology includes radiationinduced fibrosis and associated factors such as ischemia, oxidative stress and inflammation [31] . The presentation is quite variable and may present from 6 months to 20 years after receiving treatment [3,6] . The clinical presentation is shooting, burning, pins and needles, numbness and tightness pain [3] . Surgical intervention may also insult the neural structures directly or indirectly, leading to neuralgic pain. Surgery has long been documented to lead to persistent pain, including phantom sensations after limb amputation and chronic syndromes such as the post-thoracotomy or postmastectomy syndrome [9] . Breast cancer has been reported to have good outcome with a 5-year survival over 80% as a result of earlier diagnosis and improved management [6] . Almost 50% of breast cancer survivors have a concern of pain [6] . The concurrent radiotherapy, chemotherapy, hormonal therapy and reconstructive surgery further increase the occurrence of pain, which has been clubbed as postmastectomy pain syndrome and characterized by burning, shooting and electric shock-like sensations in the skin around the surgical sites [6,32,33] . The pathogenesis of pain is multifactorial and the pain may be nociceptive (damage to muscles and ligaments) or neuropathic (damaged nerves or dysfunction of the nervous system) [6,34] . It may involve peripheral as well as spinal and supraspinal structure effects [33] . The neuropathic pain in breast cancer survivors is phantom breast pain, intercostobrachial neuralgia, pain secondary to the presence of a neuroma and pain due to damage to other nerves (medial pectoral, lateral pectoral, thoracodorsal and long thoracic nerves) [33,35] . The persistent pain in cancer survivors who have undergone thoracotomy has been reported to be as high as 80% [6] . The pain is usually neuropathic and may be related to the intercostal nerve injury during surgical intervention [6] . Such pain has been reduced due to better surgical procedures like minimally invasive procedure, such as video-assisted thoracotomy and managing the
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perioperative pain with multimodal approach [6] . The incidence of neuropathic pain for head and neck surgery varies around 30–50% and also this is further increased with concurrent radio and chemotherapy. The pain after amputation may be in the amputated area or a phantom pain and is usually neuropathic pain and may occur in any body parts, including limbs, breast ad so on [3,6] . ●●Neuropathic pain types/syndromes
The various neuropathic pain types in cancer patients include plexopathies, peripheral mononeuropathies, paraneoplastic sensory neuropathy, leptomeningeal metastasis, cranial neuralgias like glossopharyngeal neuralgia, trigeminal neuralgia and malignant painful radiculopathy [11] . ●●Management
The primary goal of management of neuropathic pain in cancer patients is to improve the quality of life. The management of neuropathic pain in cancer survivors is quite challenging and requires multidisciplinary and multimodal approach. It includes pharmacologic, interventional, nonpharmacologic strategies and supportive therapy. In the absence of concrete evidence for neuropathic pain management in cancer survivors, the management is extrapolated from evidence of other noncancer neuropathic pain management. Once the cancer survivor is evaluated for not representing a recurrent disease, a holistic approach of pain management needs to be developed [9] . Analgesics should be titrated based on the patient’s goals, their pain intensity and the severity of undesirable or adverse drug effects. If feasible, the underlying cause of neuropathic pain needs also to be managed like relieving nerve compression using steroid [11] . However, the treatment for neuropathic pain remains symptomatic. The chemotherapy-induced neuropathic pain may be improved by carefully choosing the chemotherapy regime. Research for various therapies for prevention and management of chemotherapy-induced neuropathic pain has been done, but no concrete recommendations could be made [11] . Certain preventive measures like amifostine, glutathione, N-acetyl carnitine, N-acetyl cysteine, glutamine/glutamate and vitamin E have been reported to reduce the chemotherapy-induced neural symptoms. Other agents with good response to chemotherapyinduced neuropathic pain include topical agents like baclofen/amitriptyline/ketamine gel, and
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Neuropathic pain in cancer survivors serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine [36] . The nutritional supplements such as evening primrose oil, α-lipoic acid and capsaicin have been reported to be effective in diabetic peripheral neuropathy, but their role in cancer survivors is not concrete [29] . The surgical interventioninduced neuropathic pain needs to be modified by improving and improvising the surgical skills in addition to good perioperative pain control. The radiation-induced neuropathic pain has been much improved with better and modified radiation therapy. Pharmacologic therapy
Anticonvulsants, tricyclic antidepressants and opioids can be effective for alleviating neuropathic pain [6,37,38] . While opioids are mainstay of management in cancer patients, it alone may not be optimal for neuropathic pain in cancer survivors. The various drug options include a balanced combination of antidepressants, anti epileptic drugs and topical agents in addition to nonsteroidal anti-inflammatory agents [7,39] . Gabapentin and pregabalin have recently been emerged as main line of management for neuropathic pain [11,40] . These drugs may be associated with side effects like somnolence, dizziness, edema, weight gain, nausea, vertigo, asthenia, dry mouth and ataxia [11] . These side effects spontaneously resolve with time. However, if persistent or distressing, the dose may be reduced to balance the side effects with regard to clinical benefits or these drugs may be mutually changed [11] . These drugs also have anxiolytic action and may be beneficial in cancer survivors who may present with anxiety due to presence of disease. The carbamazepine and its analog oxcarbazepine have been reported to be first-line management for certain neuropathic pain like trigeminal neuralgia [41] . However, it has not been proven to be first-line treatment for neuropathic pain in cancer survivors [11] . Also, other anticonvulsants like lamotrigine and valproate are reported to have conflicting reports in neuropathic pain and no data are available with regard to neuropathic pain in cancer survivors. Presently, these drugs may not be recommended for management of neuropathic pain in cancer survivors. Drugs belonging to antidepressant group have been found to have good response in patients with neuropathic pain by reducing pain and need of other analgesic agent. The drugs from this group include tricyclic antidepressants
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(amitriptyline, imipramine) and the selective serotonin norepinephrine reuptake inhibitors (like duloxetine, venlafaxine) [42] . The analgesic effect is independent of its antidepressant effect and thus also the doses. The side effects with these drugs are primarily due to their anticholinergic effects and include dry mouth, constipation, urinary retention, sweating and blurred vision. Other issues include the possibility of orthostatic hypotension, and somnolence specially in elderly [11] . These drugs need to be avoided in patients of epilepsy, heart failure and heart blocks. Duloxetine has been reported to be effective in chemotherapy-induced peripheral neuropathy. Application of topical lidocaine has been found to be effective in neuropathic pain, specially in mixed peripheral focal neuropathy with allodynia, chemotherapy-induced peripheral neuropathy and postbreast surgery pain syndromes [43,44] . It is available as 5% lidocaine patch and maximum three patches may be applied over 12 h in a day [11] . Capsaicin patch application reduces substance P from nociceptors and, thus, provides analgesic action in neuropathic pain [34,45] . Application of this agent may itself be painful and thus requires adjunctive local anesthetic agent as well for optimal effect [11] . It may be considered as having minimal side effect and found to be safe for long-term use [11] . The cancer pain is usually mixed and thus requires a multimodality management. The neuropathic pain due to cancer mass may also require opioids because of associated somatic or visceral component and these have been reported to be beneficial in neuropathic pain. The opioid agents include pure μ-agonists like morphine, hydromorphone, fentanyl and oxycodone. Morphine remains the most commonly used drug [46] . The dose needs to be titrated as per response and side effect profile of the patient. Patients on opioids need to be assessed periodically for tolerance and any aberrant use to mitigate potential misuse. Cannabinoids have also been tried with positive results in cancer patients with neuropathic pain [11] . N-methyl d-aspartate antagonists like ketamine have been found to be effective in selective group of patients having refractory neuropathic pain [11] . These drugs have been found to be effective with possible etiology of central wind-up and with neuropathic, inflammatory or ischemic pain [11] . The use of gabapentin and pregabalin is well established for neuropathic pain and level A
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Review Garg & Bhatnagar evidence exists for these drugs [40,47] . The level B evidence is reported in literature for tricyclic antidepressants and tramadol, while valproate has been found to be inefficacious. So, the tricyclic antidepressants (25–150 mg/day), gabapentin (1200–3600 mg/day) and pregabalin (150–600 mg/day) have been reported to be firstline therapy for neuropathic pain [40,48] . Second line of management includes the use of tramadol in a dose of 200–400 mg/day. The strong opioids may be considered as second/third-line therapy for neuropathic pain [49] . The combined use of more than one drug is usually required and a combination therapy (level A for gabapentin combined with opioids or TCA) has been used for patients having suboptimal response to individual drugs [40] . The pharmacologic therapy should be cautiously balanced keeping in mind the comorbidities, contraindications and concomitant treatments [40] . During combination therapy, drugs need to be sequentially started and titrated and modified according to the patient’s response and the side effects. Interventions
Patients with neuropathic pain may benefit from interventional procedures like nerve blocks, trigger point injections, spinal cord stimulators or implanted intrathecal pumps [50] . However, these patients need to be selected after thorough examination for the beneficial outcome with regard to pain relief. Those patients who show inadequate pain relief with conventional but comprehensive pharmacological management even on administering maximal acceptable doses or have adverse effect, may be considered for interventions. Also, refractory or intractable neuropathic pain may require interventional modalities like use of spinal cord stimulation and peripheral nerve stimulation devices [51] . Supportive therapy
Survivors with chronic pain are encouraged to actively participate in their pain management plan of care and utilize a broad range of therapies [46] . These methods include a multimodal approach to pain with an emphasis on self-activation and nonpharmacologic therapies. Strategies include regular aerobic activity, thermal therapy, and home physical therapy stretching and strengthening exercises [9] . Counseling to address anxiety, depression, coping, and complementary therapies, such as acupuncture, massage and yoga are additional supportive approaches.
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Newer approaches: scrambler therapy
Apart from various classical interventions, certain therapy like scrambler therapy, a patient-specific electrocutaneous nerve stimulation device, has been proven of some benefit in neuropathic pain in cancer patients. Scrambler therapy works on the approach of stimualting the nerves and thus providing nonpain stimulus to block the pain sensation from the affected area [52] . It has been reported to relive the chronic neuropathic pain better than conventional drug-based management [53] . It is provided with repeated sessions with one session per day over 1–2 weeks [53,54] . ●●Psychological support in cancer survivors
The neuropathic pain in cancer survivors has associated psychological distress as well [6] . This psychological aspect further aggravates the pain and makes the management more complex. The pain may be reported exaggerated due to emotional distress, depression, anxiety and fear [50] . The various physical aspects like mobility, physical functioning, sleep and concentration are disturbed by the neuropathic pain [46,52] . The untreated or undertreated pain may lead to extremes of depressive episodes, making the necessity of effective pain management. It needs to be emphasized that the psychological factors may not be responsible for direct cause of pain, but may affect the perception of pain, thus affecting the response to pain and making the management more difficult [46] . Various psychological interventions are aimed at personal beliefs and appraisals, emotional reactions, coping behaviors and social contextual factors [46] . These patients need a good amount of reassurance, but after thorough evaluation for disease recurrence. The need of regular exercise and relaxation techniques like imagery, relaxation and breathing practices will ease them of their suffering and apprehensions [9] . Future perspective The chronic pain management in cancer survivors is an emerging field [6] . Presently, evidence is scarce with relation to its overall management. At present, most data are extrapolated from those for neuropathic pain of noncancer patients. A lot of research is required in this field with regard to its occurrence, relation to its etiological factors, prevention and management. The comprehensive information needs to be collected with regard to the onset and duration, severity and characteristics of neuropathic pain in cancer
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Neuropathic pain in cancer survivors survivors. The role of various pharmacological and nonpharmacological interventions and its impact on quality of life in cancer survivors need to be evaluated independently. The evidence is also required for correlating the effect on quality of life and responses to interventions in cancer survivors with neuropathic pain [6] . Conclusion Neuropathic pain in cancer survivors is unique and needs a holistic and personalized management. The multidisciplinary and multimodal management is essential for such neuralgic pain in cancer survivors. This may require a balanced combination of pharmacological References Papers of special note have been highlighted as: • of interest •• of considerable interest 1
2
3
Siegel R, DeSantis C, Virgo K et al. Cancer treatment and survivorship statistics. CA Cancer J. Clin. 62, 220–241 (2012). Mullan F. Seasons of survival: reflections of a physician with cancer. N. Engl. J. Med. 313, 270–273 (1985). Chapman S. Chronic pain syndromes in cancer survivors. Nurs. Stand. 25, 35–41 (2011).
• Focuses on chronic pain syndromes that can occur following cancer treatment, examining the effect of pain on patients’ quality of life. 4
Feuerstein M. Defining cancer survivorship. J. Cancer Surviv. 1, 5–7 (2007).
5
Harrington CB, Hansen JA, Moskowitz M, Todd BL, Feuerstein M. It’s not over when it’s over: long-term symptoms in cancer survivors – a systematic review. Int. J. Psychiatry Med. 40, 163–181 (2010).
6
7
8
9
Polomano RC, Farrar JT. Pain and neuropathy in cancer survivors. AJN 106 , 39–47 (2006). Treede RD, Jensen TS, Campbell JN et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology70, 1630–1635 (2008). Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer related neuropathic pain: the intersection of cancer pain and neuropathic pain. Oncologist 15, 3–8 (2010). Davies PS. Chronic pain management in cancer survivors. Nurse Pract. 38, 28–38 (2013).
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and nonpharmacological techniques, including psychological support. This will help in improving the quality of life of cancer survivors. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
10 Deandrea S, Montanari M, Moja L, Apolone
G. Prevalance of undertreatment in cancer pain. A review of published literature. Ann. Oncol.19, 1985–1991 (2008). 11 Fallon MT. Neuropathic pain in cancer. Br.
J. Anaesth. 111, 105–111 (2013). •• Authors describe the neuropathic pain in cancer patients with an additional issue in cancer survivors. 12 Everdingen MH, deRijke JM, Kessels AG,
Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann. Oncol. 18, 1437–1449 (2007). 13 Kanner RM, Martini N, Foley KM.
Epidural spinal cord compression (ESCC) in pancoast (superior pulmonary sulcus) tumor: clinical presentation and outcome. Trans. Am. Neurol. Assoc. 106, 75–77 (1981). 14 Jaeckle KA, Young DF, Foley KM. The
natural history of lumbosacral plexopathy in cancer. Neurology 35, 8–15 (1985). 15 Foley KM. The treatment of cancer pain. N.
Engl. J. Med. 313, 84–95 (1985). 16 Mao JJ, Armstrong K, Bowman MA, Xie
SX, Kadakia R, Farrar JT. Symptom burden among cancer survivors: impact of age and comorbidity. J. Am. Board Fam. Med. 20, 434–443 (2007). 17 Grond S, Zech D, Diefenbach C, Radbruch
L, Lehmann KA. Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred to a pain service. Pain 64, 107–114 (1996). 18 Sun V, Borneman T, Piper B, Koczywas M,
Ferrell B. Barriers to pain assessment and management in cancer survivorship. J. Cancer Surviv. 2, 65–71 (2008).
19 Gee RE, Finns JJ. Barriers to pain and
symptom management, opioids, health policy and drug benefits. J. Pain Symptom Manage. 25, 101–103 (2003). 20 Wickham R. Chemotherapy-induced
peripheral neuropathy: a review and implications for oncology nursing practice. Clin. J. Oncol. Nurs. 11, 361–376 (2007). 21 Burton AW, Fanciullo GJ, Beasley RD,
Fisch MJ. Chronic pain in the cancer survivor: a new frontier. Pain Med. 8, 189–198 (2007). 22 Hausheer FH, Schilsky RL, Bain S et al.
Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin. Oncol. 33, 15–49 (2006). •• Authors have comprehensively discussed the issue of chemotherapy-induced neuropathic pain. 23 Visovsky C. Chemotherapy-induced
peripheral neuropathy. Cancer Invest. 21, 439–451 (2003). 24 Dropcho EJ. Neurotoxicity of cancer
chemotherapy. Semin. Neurol. 24, 419–426 (2004). 25 Stubblefield MD. Cancer rehabilitation.
Semin. Oncol. 38, 386–393 (2011). 26 LoMonaco M. Cisplatin neuropathy:
clinical course and neurophysiological findings. J. Neurol. 239, 199–204 (1992). 27 Verstappen CC. Neurotoxic complications
of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 63, 1549–1563 (2003). 28 Fossa SD. Long-term sequelae after cancer
therapy – survivorship after treatment for testicular cancer. Acta Oncol. 43, 134–141 (2004).
www.futuremedicine.com
315
Review Garg & Bhatnagar 29 Rock E, DeMichele A. Nutritional
39 Burton AW, Fanciullo GJ, Beasley RD, Fisch
approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors. J. Nutr. 133, 3785S–3793S (2003). 30 Bucci MK. Advances in radiation therapy:
conventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J. Clin. 55, 117–134 (2005). 31 Dropcho EJ. Neurotoxicity of radiation
therapy. Neurol. Clin. 28, 217–234 (2010). 32 Wickham R. Chemotherapy-induced
peripheral neuropathy: a review and implications for oncology nursing practice. Clin. J. Oncol. Nurs. 11, 361–376 (2007). 33 Smith SH, Wu SX. Persistent pain after breast
cancer treatment. Ann. Palliat. Med. 1, 182–194 (2012). 34 Poleshuck EL, Katz J, Andrus CH et al. Risk
factors for chronic pain following breast cancer surgery: a prospective study. J. Pain 7, 626–634 (2006). 35 Jung BF, Ahrendt GM, Oaklander AL et al.
Neuropathic pain following breast cancer surgery: proposed classification and research update. Pain 104, 1–13 (2003). 36 Pachman DR, Barton DL, Watson JC,
Loprinzi CL. Chemotherapy induced peripheral neuropathy: prevention and treatment. Clin. Pharamacol. Therap.90, 377–387 (2011). • Authors have comprehensively discussed the issue of chemotherapy-induced neuropathic pain. 37 Cavaletti G, Zanna C. Current status and
future prospects for the treatment of chemotherapy-induced peripheral neurotoxicity. Eur. J. Cancer 38, 1832–1837 (2002). 38 Kuroi K, Shimozuma K, Ohashi Y et al. A
questionnaire survey of physicians’ perspectives regarding the assessment of chemotherapy-induced peripheral neuropathy in patients with breast cancer. Jpn J. Clin. Oncol. 38, 748–754 (2008).
316
MJ. Chronic pain in the cancer survivor: a new frontier. Pain Med. 8, 189–198 (2007). 40 Attal N, Cruccu G, Baron R et al. EFNS
guidelines on the pharamacological treatment of neuropathic pain: 2010 version. Eur. J. Neurol. 17, 1113–1123 (2010). 41 Zakrzewska JM, McMillan R. Trigeminal
neuralgia: the diagnosis and management of this excruciating and poorly understood facial pain. Postgrad. Med. J. 87, 410–416 (2011). 42 Sindrup SH, Otto M, Finnerup NB, Jensen
TS. Antidepressants in the treatment of neuropathic pain. Basic Clin. Pharmacol. Toxicol. 96, 399–409 (2005). 43 Meier T, Wasner G, Faust M et al. Efficacy
of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106, 151–158 (2003). 44 Rowbotham MC, Davies PS, Verkempinck
C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 65, 39–44 (1996). 45 Finnerup NB, Sindrup SH, Jensen TS. The
evidence for pharmacological treatment of neuropathic pain. Pain 150, 573–581 (2010). • Authors have described various aspects of drug management for neuropathic pain. 46 Pachman DR, Barton DL, Swetz KM,
Loprinzi CL. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J. Clin. Oncol.30, 3687–3696 (2012). 47 Arbaiza D, Vidal O. Tramadol in the
treatment of neuropathic cancer pain: a double-blind, placebo-controlled study. Clin. Drug Investig. 27, 75–83 (2007).
gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 374, 1252–1261 (2009). 49 Eisenberg E, McNicol ED, Carr DB.
Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 293, 3043–3052 (2005). 50 Gronseth G, Cruccu G, Alksne J et al.
Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology 71, 1183–1190 (2008). 51 de Leon-Casasola OA. Spinal cord and
peripheral nerve stimulation for neuropathic pain. J. Pain Symptom Manage. 38, 28–38 (2009). 52 Marineo G, Iorno V, Gandini C, Moschini
V, Smith TJ. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial. J. Pain Symptom Manage. 43, 87–95 (2012). •• Authors describe the role of this newer therapy of management of neuropathic pain. 53 Coyne PJ, Wan W, Dodson P, Swainey C,
Smith TJ. A trial of scrambler therapy in the treatment of cancer pain syndromes and chronic chemotherapy-induced peripheral neuropathy. J. Pain Palliat. Care Pharmacother. 27, 359–364 (2013). 54 Sabato AF, Marineo G, Gatti A. Scrambler
therapy. Minerva Anesthesiol. 71, 479–482 (2005).
48 Gilron I, Baley JM, Tu D, Holdern DR,
Jackson AC, Houlden RL. Nortriptyline and
Pain Manage. (2014) 4(4)
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REVIEW For reprint orders, please contact: [email protected]
Neuropathic pain in cancer survivors
Rakesh Garg1 & Sushma Bhatnagar*,1 Practice points ●●
The occurrence of pain in cancer survivors may be debilitating.
●●
Pain or pain syndromes may be primarily a sequel of cancer per se or side effects of
treatment received by the patients, including surgical interventions, chemotherapy and radiotherapy. ●●
There is a lack of research for chronic cancer pain management in cancer survivors.
●●
For pain assessment in cancer survivors, comprehensive information regarding onset and duration, severity and characteristics of neuropathic pain has to be collected.
●●
Neuropathic pain in cancer survivors is unique and needs a holistic and personalized management.
●●
The multidisciplinary and multimodal management is essential for such neuralgic
pain in cancer survivors. This may require a balanced combination of pharmacological and nonpharmacological techniques, including psychological support.
SUMMARY The occurrence of pain in cancer survivors may be debilitating. These pain syndromes may be of different types, including neuropathic pain. The research related to cancer management has been done extensively in certain areas, but such research in cancer survivors is still lacking. The chronic pain in cancer survivors is not only under-reported but also under-treated. The assessment of pain in cancer survivors is multifaceted because of many domains like physical, social and psychological. Usually, the pain management may be considered similar to that for chronic noncancer pain, but with a caveat that such pain may at times be indicative of cancer recurrence. The multidisciplinary and multimodal management is essential for such neuralgic pain in cancer survivors. This may require a balanced combination of pharmacological and nonpharmacological techniques, including psychological support. The overall goal that remains in such patients for pain management is to improve the quality of life. Here we review certain pertinent aspects of neuropathic pain in cancer survivors.
KEYWORDS
• cancer • cancer survivor • mechanism • neuropathic • pain • pain management
The advancement in medical sciences has improved the outcome of cancer and thus increased the number of cancer survivors. The ‘cancer survivors’ have been variously defined. It may be any person who has been diagnosed with cancer, from the time of diagnosis through the balance of life [1] . It, thus, may be phased into three time periods as diagnosis to treatment, from treatment to extended survival and finally long-term survival [2] . Others define it as ‘someone who has completed Department of Anaesthesiology, Pain & Palliative Care, Dr B.R. Ambedkar Institute Rotary Cancer Hospital, AIIMS, New Delhi, India *Author for correspondence: [email protected] 1
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Review Garg & Bhatnagar initial treatment and has no apparent evidence of active disease, is living with progressive disease and may be receiving treatment, but is not in the terminal phase of illness, or someone who has had cancer in the past’ [3] . The more precise definition has also been proposed, which states ‘those who have completed the active antineoplastic phase of their treatment, have no evidence of disease, are under cancer surveillance and those whose cancer pain syndrome is not related to active disease progression’ [4,5] . The cancer survivors have some peculiar concerns, though they are declared to be disease free, that is, cancer free [6] . These include various adverse effects relating to the treatment received by them for cancer, and psychological concerns as well [1] . These cancer survivors also have to face certain medical issues, which at times, may be related to age and comorbidities, and social issues like socioeconomic status and family/support group [1,6] . The cancer survivors may have to bear the various pain syndromes related to treatment therapy or in other terms sequel of cancer and its treatment. Adjusting to these difficult symptoms appears to be quite challenging for the cancer survivors and may significantly affect the quality of life. The occurrence of pain in cancer survivors may be debilitating. This pain or pain syndromes may be primarily a sequel of cancer per se or side effects of treatment received by them, including surgical interventions, chemotherapy and radiotherapy. These pain syndromes may be of different types, including neuropathic pain. The neuropathic pain has been defined as ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’ or more recently as ‘Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’ [6–8] . The research related to cancer management has been done extensively in certain areas, but such research in cancer survivors is still lacking. The chronic pain in cancer survivors is not only under-reported but also under-treated [9,10] . The assessment of pain in cancer survivors is multifaceted because of many domains like physical, social and psychological. Usually, the pain management may be considered similar to that for chronic noncancer pain, but with a caveat that such pain may at times be indicative of cancer recurrence [9,10] . The overall goal that remains in such patients for pain management is to improve the quality of life [6] .
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Methods We have performed a PubMed search using search terms such as ‘cancer survivor,’ ‘pain,’ ‘neuropathic pain/pain mechanism/pain management’ and ‘analgesia.’ All papers (original trials, reviews, retrospective studies, case reports, commentaries, editorials) in English language that specifically discussed the relevant issues are included. ●●Incidence
The survival rate has improved over last few decades and it exceeds over 80% for some cancers with around 68% 5-year survival rate overall [6,10,11] . Pain has been reported by 33% of patients cured for cancer, while other authors report that persistent pain is seen in 50% of cancer patients treated with chemotherapy, surgery and radiotherapy [12–15] . This is much higher than the pain seen in patients without history of cancer (18%) [16] . As survival rates improve, pain physicians will have to manage an increased number of patients for persistent pain syndromes [9] . In spite of available treatment options, undertreatment of pain may be seen in up to 40% of patients as per WHO reports [10] . The three most common sites for those living with a history of cancer in men include prostate cancer (43%), colorectal cancer (9%) and melanoma (7%) and in women include breast (41%), uterine (8%) and colorectal (8%) cancer [3,8,9] . Pain is more commoner in patients of post-thoracotomy (80%), postamputation/phantom limb (50–80%), postneck dissection (52%) and breast cancer (63%) [9] . These types of pain are usually the result of cancer treatment rather than the sequel of cancer per se [9] . The etiology of neuropathic pain has been related to 75.7% for cancer, 11.4% for treatment, 4.9% for associated, 5.9% for unrelated and 2.1% for unknown cause [17] . ●●Importance of attending pain in cancer
survivor
The occurrence of pain resulting from chemotherapy, radiotherapy, surgery or interventional procedures in cancer survivors may debilitate the quality of life significantly [3,18] . Thus, chronic pain in cancer survivors may have impact on physical, psychological and social functioning and cancer survivor may have anxiety and depression [3,18] . These may also have impact on functional abilities and sleep, and as a consequence, may lead to daytime fatigue and mood
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Neuropathic pain in cancer survivors disturbances [3] . For a noncancer pain, a conservative approach may be accepted, but for a cancer survivor, emergence of new pain needs to be assessed on urgent basis and comprehensively to rule out cancer recurrence or metastasis [19] . The various risk factors responsible for chronic pain in cancer survivors include the anatomical site, stage and histology of the disease; treatments received, the treatment regimens, duration and dosages; length of time that has elapsed since treatment; and underlying risk factors independent of the cancer or its treatment, for example, associated comorbidities [3] . In spite of available treatment to a large extent, cancer pain remains under-treated in almost half of the patients, especially in cancer survivors. The reasons for such under-managed cases have been attributed to geographical areas, which include Europe, Asia and low-income countries and absence of expertise/centers for managing such cancer pains [10] . These parameters need to be accounted for setting up infrastructure in such areas to provide better pain management to cancer survivors to improve their quality of life. ●●Pathogenesis
& etiological causes
Chronic pain has been observed more often in cancer survivors treated for breast, prostate, lung, thoracic, head and neck or colorectal cancers. Certain cancers, like breast cancer, have been studied and reported for chronic neuropathic pain. The three main types of cancer pain observed in cancer survivors include neuropathic (abnormal nerve impulses, commonly from chemotherapy), nociceptive/somatic (involving muscles, bone, connective tissue) and nociceptive/visceral (involving organs, such as liver or pancreas) [9,20] . The various types of neuropathic pain seen in cancer survivors include postmastectomy, postthoracotomy, postradical neck, postamputation pain syndromes, and brachial or lumbosacral plexopathy [9,21] . The neuropathophysiological pathway for the cancer neuropathic pain remains the same as for noncancer pain, though the etiology differs. The pain in cancer survivors may be related not only to primary disease pathology, but also to treatment like surgical intervention, chemotherapy or radiotherapy, by general debility or even any concurrent disorder. These interventions cause ‘disturbance of function or pathological change in a nerve(s)’ and, thus, are the cause of neuropathic pain [6] .
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Chemotherapy has been implicated as a commoner reason for neuropathic pain in cancer survivors. The peripheral neuropathy is the most common form of neurotoxicity with chemotherapy, with an variable incidence of about 30–40% [9] . The pathophysiological mechanisms include the distal axon (axonopathy) and/or the neurons of the dorsal root ganglia (neuronopathy) [6,8] . These can be differentiated by history and clinical examination in context with exposure of chemotherapy and are important for prognostication. The neuronopathy is usually complete and nonreversible, while axonopathy has fluctuating symptoms in terms of frequency and severity [22] . The neuropathic toxicity due to chemotherapy is related to factors like patient’s age, single-dose intensity, cumulative dose, combinations of neurotoxic agents, coexisting neuropathies, genetic susceptibility, alcohol abuse, impaired drug metabolism and excretion of active metabolites [23–25] . The occurrence of chemotherapy-induced neuropathic pain increases from 3–7% with single drug to as high as 38% with multiple agents of chemotherapy [3] . The chemotherapeutic agents like plant alkaloids (vincristine and vinblastine); taxanes (paclitaxel); the platinumbased compounds (cisplatin, carboplatin and oxaliplatin); and the antimitotics (methotrexate, cytosine arabinoside and fluorouracil) have been studied and found to have increased the incidence of neuropathic pain [6] . The newer ‘biologics’ also have higher risk for neuropathic pain [8] . The chemotherapeutic drugs usually affect sensory nerves, but motor and autonomic nerves may also be affected [3] . The chemotherapy-induced neuropathy presents with a characteristic involvement of longer nerves and with bilateral, symmetrical ‘stocking and glove’ phenomenon of the distal extremities and with paresthesia or dysesthesia along with numbness or tingling [3,6,11] . At times, in addition to sensory symptoms, muscle weakness may also be present [11] . The timing of presentation of symptoms after chemotherapy is quite variable. The agents like cisplatin manifest signs of neuropathy, which occur about 1 month after the therapy, while oxaliplatin may produce symptoms within 30–60 min after the infusion [26,27] . The symptoms including paresthesia, dysesthesia, pain, or sensory and motor impairment may even persist years after treatment is discontinued [28,29] . The resolution of pain is also variable in these patients.
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Review Garg & Bhatnagar Radiation therapy has been associated with neuralgic pain. The neuropathic pain severity is related to radiation exposure, the dose of radiation and vicinity to major nerves or nerve plexus [3,6] . The advancement and refinements in radiation oncology have decreased the insult to nerve and plexuses and, thus, the incidence of radiation induces neuralgic pain [30] . The pathophysiology of radiation-induced neuropathies is not well known, but possible etiology includes radiationinduced fibrosis and associated factors such as ischemia, oxidative stress and inflammation [31] . The presentation is quite variable and may present from 6 months to 20 years after receiving treatment [3,6] . The clinical presentation is shooting, burning, pins and needles, numbness and tightness pain [3] . Surgical intervention may also insult the neural structures directly or indirectly, leading to neuralgic pain. Surgery has long been documented to lead to persistent pain, including phantom sensations after limb amputation and chronic syndromes such as the post-thoracotomy or postmastectomy syndrome [9] . Breast cancer has been reported to have good outcome with a 5-year survival over 80% as a result of earlier diagnosis and improved management [6] . Almost 50% of breast cancer survivors have a concern of pain [6] . The concurrent radiotherapy, chemotherapy, hormonal therapy and reconstructive surgery further increase the occurrence of pain, which has been clubbed as postmastectomy pain syndrome and characterized by burning, shooting and electric shock-like sensations in the skin around the surgical sites [6,32,33] . The pathogenesis of pain is multifactorial and the pain may be nociceptive (damage to muscles and ligaments) or neuropathic (damaged nerves or dysfunction of the nervous system) [6,34] . It may involve peripheral as well as spinal and supraspinal structure effects [33] . The neuropathic pain in breast cancer survivors is phantom breast pain, intercostobrachial neuralgia, pain secondary to the presence of a neuroma and pain due to damage to other nerves (medial pectoral, lateral pectoral, thoracodorsal and long thoracic nerves) [33,35] . The persistent pain in cancer survivors who have undergone thoracotomy has been reported to be as high as 80% [6] . The pain is usually neuropathic and may be related to the intercostal nerve injury during surgical intervention [6] . Such pain has been reduced due to better surgical procedures like minimally invasive procedure, such as video-assisted thoracotomy and managing the
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perioperative pain with multimodal approach [6] . The incidence of neuropathic pain for head and neck surgery varies around 30–50% and also this is further increased with concurrent radio and chemotherapy. The pain after amputation may be in the amputated area or a phantom pain and is usually neuropathic pain and may occur in any body parts, including limbs, breast ad so on [3,6] . ●●Neuropathic pain types/syndromes
The various neuropathic pain types in cancer patients include plexopathies, peripheral mononeuropathies, paraneoplastic sensory neuropathy, leptomeningeal metastasis, cranial neuralgias like glossopharyngeal neuralgia, trigeminal neuralgia and malignant painful radiculopathy [11] . ●●Management
The primary goal of management of neuropathic pain in cancer patients is to improve the quality of life. The management of neuropathic pain in cancer survivors is quite challenging and requires multidisciplinary and multimodal approach. It includes pharmacologic, interventional, nonpharmacologic strategies and supportive therapy. In the absence of concrete evidence for neuropathic pain management in cancer survivors, the management is extrapolated from evidence of other noncancer neuropathic pain management. Once the cancer survivor is evaluated for not representing a recurrent disease, a holistic approach of pain management needs to be developed [9] . Analgesics should be titrated based on the patient’s goals, their pain intensity and the severity of undesirable or adverse drug effects. If feasible, the underlying cause of neuropathic pain needs also to be managed like relieving nerve compression using steroid [11] . However, the treatment for neuropathic pain remains symptomatic. The chemotherapy-induced neuropathic pain may be improved by carefully choosing the chemotherapy regime. Research for various therapies for prevention and management of chemotherapy-induced neuropathic pain has been done, but no concrete recommendations could be made [11] . Certain preventive measures like amifostine, glutathione, N-acetyl carnitine, N-acetyl cysteine, glutamine/glutamate and vitamin E have been reported to reduce the chemotherapy-induced neural symptoms. Other agents with good response to chemotherapyinduced neuropathic pain include topical agents like baclofen/amitriptyline/ketamine gel, and
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Neuropathic pain in cancer survivors serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine [36] . The nutritional supplements such as evening primrose oil, α-lipoic acid and capsaicin have been reported to be effective in diabetic peripheral neuropathy, but their role in cancer survivors is not concrete [29] . The surgical interventioninduced neuropathic pain needs to be modified by improving and improvising the surgical skills in addition to good perioperative pain control. The radiation-induced neuropathic pain has been much improved with better and modified radiation therapy. Pharmacologic therapy
Anticonvulsants, tricyclic antidepressants and opioids can be effective for alleviating neuropathic pain [6,37,38] . While opioids are mainstay of management in cancer patients, it alone may not be optimal for neuropathic pain in cancer survivors. The various drug options include a balanced combination of antidepressants, anti epileptic drugs and topical agents in addition to nonsteroidal anti-inflammatory agents [7,39] . Gabapentin and pregabalin have recently been emerged as main line of management for neuropathic pain [11,40] . These drugs may be associated with side effects like somnolence, dizziness, edema, weight gain, nausea, vertigo, asthenia, dry mouth and ataxia [11] . These side effects spontaneously resolve with time. However, if persistent or distressing, the dose may be reduced to balance the side effects with regard to clinical benefits or these drugs may be mutually changed [11] . These drugs also have anxiolytic action and may be beneficial in cancer survivors who may present with anxiety due to presence of disease. The carbamazepine and its analog oxcarbazepine have been reported to be first-line management for certain neuropathic pain like trigeminal neuralgia [41] . However, it has not been proven to be first-line treatment for neuropathic pain in cancer survivors [11] . Also, other anticonvulsants like lamotrigine and valproate are reported to have conflicting reports in neuropathic pain and no data are available with regard to neuropathic pain in cancer survivors. Presently, these drugs may not be recommended for management of neuropathic pain in cancer survivors. Drugs belonging to antidepressant group have been found to have good response in patients with neuropathic pain by reducing pain and need of other analgesic agent. The drugs from this group include tricyclic antidepressants
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(amitriptyline, imipramine) and the selective serotonin norepinephrine reuptake inhibitors (like duloxetine, venlafaxine) [42] . The analgesic effect is independent of its antidepressant effect and thus also the doses. The side effects with these drugs are primarily due to their anticholinergic effects and include dry mouth, constipation, urinary retention, sweating and blurred vision. Other issues include the possibility of orthostatic hypotension, and somnolence specially in elderly [11] . These drugs need to be avoided in patients of epilepsy, heart failure and heart blocks. Duloxetine has been reported to be effective in chemotherapy-induced peripheral neuropathy. Application of topical lidocaine has been found to be effective in neuropathic pain, specially in mixed peripheral focal neuropathy with allodynia, chemotherapy-induced peripheral neuropathy and postbreast surgery pain syndromes [43,44] . It is available as 5% lidocaine patch and maximum three patches may be applied over 12 h in a day [11] . Capsaicin patch application reduces substance P from nociceptors and, thus, provides analgesic action in neuropathic pain [34,45] . Application of this agent may itself be painful and thus requires adjunctive local anesthetic agent as well for optimal effect [11] . It may be considered as having minimal side effect and found to be safe for long-term use [11] . The cancer pain is usually mixed and thus requires a multimodality management. The neuropathic pain due to cancer mass may also require opioids because of associated somatic or visceral component and these have been reported to be beneficial in neuropathic pain. The opioid agents include pure μ-agonists like morphine, hydromorphone, fentanyl and oxycodone. Morphine remains the most commonly used drug [46] . The dose needs to be titrated as per response and side effect profile of the patient. Patients on opioids need to be assessed periodically for tolerance and any aberrant use to mitigate potential misuse. Cannabinoids have also been tried with positive results in cancer patients with neuropathic pain [11] . N-methyl d-aspartate antagonists like ketamine have been found to be effective in selective group of patients having refractory neuropathic pain [11] . These drugs have been found to be effective with possible etiology of central wind-up and with neuropathic, inflammatory or ischemic pain [11] . The use of gabapentin and pregabalin is well established for neuropathic pain and level A
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Review Garg & Bhatnagar evidence exists for these drugs [40,47] . The level B evidence is reported in literature for tricyclic antidepressants and tramadol, while valproate has been found to be inefficacious. So, the tricyclic antidepressants (25–150 mg/day), gabapentin (1200–3600 mg/day) and pregabalin (150–600 mg/day) have been reported to be firstline therapy for neuropathic pain [40,48] . Second line of management includes the use of tramadol in a dose of 200–400 mg/day. The strong opioids may be considered as second/third-line therapy for neuropathic pain [49] . The combined use of more than one drug is usually required and a combination therapy (level A for gabapentin combined with opioids or TCA) has been used for patients having suboptimal response to individual drugs [40] . The pharmacologic therapy should be cautiously balanced keeping in mind the comorbidities, contraindications and concomitant treatments [40] . During combination therapy, drugs need to be sequentially started and titrated and modified according to the patient’s response and the side effects. Interventions
Patients with neuropathic pain may benefit from interventional procedures like nerve blocks, trigger point injections, spinal cord stimulators or implanted intrathecal pumps [50] . However, these patients need to be selected after thorough examination for the beneficial outcome with regard to pain relief. Those patients who show inadequate pain relief with conventional but comprehensive pharmacological management even on administering maximal acceptable doses or have adverse effect, may be considered for interventions. Also, refractory or intractable neuropathic pain may require interventional modalities like use of spinal cord stimulation and peripheral nerve stimulation devices [51] . Supportive therapy
Survivors with chronic pain are encouraged to actively participate in their pain management plan of care and utilize a broad range of therapies [46] . These methods include a multimodal approach to pain with an emphasis on self-activation and nonpharmacologic therapies. Strategies include regular aerobic activity, thermal therapy, and home physical therapy stretching and strengthening exercises [9] . Counseling to address anxiety, depression, coping, and complementary therapies, such as acupuncture, massage and yoga are additional supportive approaches.
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Newer approaches: scrambler therapy
Apart from various classical interventions, certain therapy like scrambler therapy, a patient-specific electrocutaneous nerve stimulation device, has been proven of some benefit in neuropathic pain in cancer patients. Scrambler therapy works on the approach of stimualting the nerves and thus providing nonpain stimulus to block the pain sensation from the affected area [52] . It has been reported to relive the chronic neuropathic pain better than conventional drug-based management [53] . It is provided with repeated sessions with one session per day over 1–2 weeks [53,54] . ●●Psychological support in cancer survivors
The neuropathic pain in cancer survivors has associated psychological distress as well [6] . This psychological aspect further aggravates the pain and makes the management more complex. The pain may be reported exaggerated due to emotional distress, depression, anxiety and fear [50] . The various physical aspects like mobility, physical functioning, sleep and concentration are disturbed by the neuropathic pain [46,52] . The untreated or undertreated pain may lead to extremes of depressive episodes, making the necessity of effective pain management. It needs to be emphasized that the psychological factors may not be responsible for direct cause of pain, but may affect the perception of pain, thus affecting the response to pain and making the management more difficult [46] . Various psychological interventions are aimed at personal beliefs and appraisals, emotional reactions, coping behaviors and social contextual factors [46] . These patients need a good amount of reassurance, but after thorough evaluation for disease recurrence. The need of regular exercise and relaxation techniques like imagery, relaxation and breathing practices will ease them of their suffering and apprehensions [9] . Future perspective The chronic pain management in cancer survivors is an emerging field [6] . Presently, evidence is scarce with relation to its overall management. At present, most data are extrapolated from those for neuropathic pain of noncancer patients. A lot of research is required in this field with regard to its occurrence, relation to its etiological factors, prevention and management. The comprehensive information needs to be collected with regard to the onset and duration, severity and characteristics of neuropathic pain in cancer
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Neuropathic pain in cancer survivors survivors. The role of various pharmacological and nonpharmacological interventions and its impact on quality of life in cancer survivors need to be evaluated independently. The evidence is also required for correlating the effect on quality of life and responses to interventions in cancer survivors with neuropathic pain [6] . Conclusion Neuropathic pain in cancer survivors is unique and needs a holistic and personalized management. The multidisciplinary and multimodal management is essential for such neuralgic pain in cancer survivors. This may require a balanced combination of pharmacological References Papers of special note have been highlighted as: • of interest •• of considerable interest 1
2
3
Siegel R, DeSantis C, Virgo K et al. Cancer treatment and survivorship statistics. CA Cancer J. Clin. 62, 220–241 (2012). Mullan F. Seasons of survival: reflections of a physician with cancer. N. Engl. J. Med. 313, 270–273 (1985). Chapman S. Chronic pain syndromes in cancer survivors. Nurs. Stand. 25, 35–41 (2011).
• Focuses on chronic pain syndromes that can occur following cancer treatment, examining the effect of pain on patients’ quality of life. 4
Feuerstein M. Defining cancer survivorship. J. Cancer Surviv. 1, 5–7 (2007).
5
Harrington CB, Hansen JA, Moskowitz M, Todd BL, Feuerstein M. It’s not over when it’s over: long-term symptoms in cancer survivors – a systematic review. Int. J. Psychiatry Med. 40, 163–181 (2010).
6
7
8
9
Polomano RC, Farrar JT. Pain and neuropathy in cancer survivors. AJN 106 , 39–47 (2006). Treede RD, Jensen TS, Campbell JN et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology70, 1630–1635 (2008). Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer related neuropathic pain: the intersection of cancer pain and neuropathic pain. Oncologist 15, 3–8 (2010). Davies PS. Chronic pain management in cancer survivors. Nurse Pract. 38, 28–38 (2013).
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and nonpharmacological techniques, including psychological support. This will help in improving the quality of life of cancer survivors. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
10 Deandrea S, Montanari M, Moja L, Apolone
G. Prevalance of undertreatment in cancer pain. A review of published literature. Ann. Oncol.19, 1985–1991 (2008). 11 Fallon MT. Neuropathic pain in cancer. Br.
J. Anaesth. 111, 105–111 (2013). •• Authors describe the neuropathic pain in cancer patients with an additional issue in cancer survivors. 12 Everdingen MH, deRijke JM, Kessels AG,
Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann. Oncol. 18, 1437–1449 (2007). 13 Kanner RM, Martini N, Foley KM.
Epidural spinal cord compression (ESCC) in pancoast (superior pulmonary sulcus) tumor: clinical presentation and outcome. Trans. Am. Neurol. Assoc. 106, 75–77 (1981). 14 Jaeckle KA, Young DF, Foley KM. The
natural history of lumbosacral plexopathy in cancer. Neurology 35, 8–15 (1985). 15 Foley KM. The treatment of cancer pain. N.
Engl. J. Med. 313, 84–95 (1985). 16 Mao JJ, Armstrong K, Bowman MA, Xie
SX, Kadakia R, Farrar JT. Symptom burden among cancer survivors: impact of age and comorbidity. J. Am. Board Fam. Med. 20, 434–443 (2007). 17 Grond S, Zech D, Diefenbach C, Radbruch
L, Lehmann KA. Assessment of cancer pain: a prospective evaluation in 2266 cancer patients referred to a pain service. Pain 64, 107–114 (1996). 18 Sun V, Borneman T, Piper B, Koczywas M,
Ferrell B. Barriers to pain assessment and management in cancer survivorship. J. Cancer Surviv. 2, 65–71 (2008).
19 Gee RE, Finns JJ. Barriers to pain and
symptom management, opioids, health policy and drug benefits. J. Pain Symptom Manage. 25, 101–103 (2003). 20 Wickham R. Chemotherapy-induced
peripheral neuropathy: a review and implications for oncology nursing practice. Clin. J. Oncol. Nurs. 11, 361–376 (2007). 21 Burton AW, Fanciullo GJ, Beasley RD,
Fisch MJ. Chronic pain in the cancer survivor: a new frontier. Pain Med. 8, 189–198 (2007). 22 Hausheer FH, Schilsky RL, Bain S et al.
Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin. Oncol. 33, 15–49 (2006). •• Authors have comprehensively discussed the issue of chemotherapy-induced neuropathic pain. 23 Visovsky C. Chemotherapy-induced
peripheral neuropathy. Cancer Invest. 21, 439–451 (2003). 24 Dropcho EJ. Neurotoxicity of cancer
chemotherapy. Semin. Neurol. 24, 419–426 (2004). 25 Stubblefield MD. Cancer rehabilitation.
Semin. Oncol. 38, 386–393 (2011). 26 LoMonaco M. Cisplatin neuropathy:
clinical course and neurophysiological findings. J. Neurol. 239, 199–204 (1992). 27 Verstappen CC. Neurotoxic complications
of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 63, 1549–1563 (2003). 28 Fossa SD. Long-term sequelae after cancer
therapy – survivorship after treatment for testicular cancer. Acta Oncol. 43, 134–141 (2004).
www.futuremedicine.com
315
Review Garg & Bhatnagar 29 Rock E, DeMichele A. Nutritional
39 Burton AW, Fanciullo GJ, Beasley RD, Fisch
approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors. J. Nutr. 133, 3785S–3793S (2003). 30 Bucci MK. Advances in radiation therapy:
conventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J. Clin. 55, 117–134 (2005). 31 Dropcho EJ. Neurotoxicity of radiation
therapy. Neurol. Clin. 28, 217–234 (2010). 32 Wickham R. Chemotherapy-induced
peripheral neuropathy: a review and implications for oncology nursing practice. Clin. J. Oncol. Nurs. 11, 361–376 (2007). 33 Smith SH, Wu SX. Persistent pain after breast
cancer treatment. Ann. Palliat. Med. 1, 182–194 (2012). 34 Poleshuck EL, Katz J, Andrus CH et al. Risk
factors for chronic pain following breast cancer surgery: a prospective study. J. Pain 7, 626–634 (2006). 35 Jung BF, Ahrendt GM, Oaklander AL et al.
Neuropathic pain following breast cancer surgery: proposed classification and research update. Pain 104, 1–13 (2003). 36 Pachman DR, Barton DL, Watson JC,
Loprinzi CL. Chemotherapy induced peripheral neuropathy: prevention and treatment. Clin. Pharamacol. Therap.90, 377–387 (2011). • Authors have comprehensively discussed the issue of chemotherapy-induced neuropathic pain. 37 Cavaletti G, Zanna C. Current status and
future prospects for the treatment of chemotherapy-induced peripheral neurotoxicity. Eur. J. Cancer 38, 1832–1837 (2002). 38 Kuroi K, Shimozuma K, Ohashi Y et al. A
questionnaire survey of physicians’ perspectives regarding the assessment of chemotherapy-induced peripheral neuropathy in patients with breast cancer. Jpn J. Clin. Oncol. 38, 748–754 (2008).
316
MJ. Chronic pain in the cancer survivor: a new frontier. Pain Med. 8, 189–198 (2007). 40 Attal N, Cruccu G, Baron R et al. EFNS
guidelines on the pharamacological treatment of neuropathic pain: 2010 version. Eur. J. Neurol. 17, 1113–1123 (2010). 41 Zakrzewska JM, McMillan R. Trigeminal
neuralgia: the diagnosis and management of this excruciating and poorly understood facial pain. Postgrad. Med. J. 87, 410–416 (2011). 42 Sindrup SH, Otto M, Finnerup NB, Jensen
TS. Antidepressants in the treatment of neuropathic pain. Basic Clin. Pharmacol. Toxicol. 96, 399–409 (2005). 43 Meier T, Wasner G, Faust M et al. Efficacy
of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106, 151–158 (2003). 44 Rowbotham MC, Davies PS, Verkempinck
C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 65, 39–44 (1996). 45 Finnerup NB, Sindrup SH, Jensen TS. The
evidence for pharmacological treatment of neuropathic pain. Pain 150, 573–581 (2010). • Authors have described various aspects of drug management for neuropathic pain. 46 Pachman DR, Barton DL, Swetz KM,
Loprinzi CL. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J. Clin. Oncol.30, 3687–3696 (2012). 47 Arbaiza D, Vidal O. Tramadol in the
treatment of neuropathic cancer pain: a double-blind, placebo-controlled study. Clin. Drug Investig. 27, 75–83 (2007).
gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 374, 1252–1261 (2009). 49 Eisenberg E, McNicol ED, Carr DB.
Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA 293, 3043–3052 (2005). 50 Gronseth G, Cruccu G, Alksne J et al.
Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology 71, 1183–1190 (2008). 51 de Leon-Casasola OA. Spinal cord and
peripheral nerve stimulation for neuropathic pain. J. Pain Symptom Manage. 38, 28–38 (2009). 52 Marineo G, Iorno V, Gandini C, Moschini
V, Smith TJ. Scrambler therapy may relieve chronic neuropathic pain more effectively than guideline-based drug management: results of a pilot, randomized, controlled trial. J. Pain Symptom Manage. 43, 87–95 (2012). •• Authors describe the role of this newer therapy of management of neuropathic pain. 53 Coyne PJ, Wan W, Dodson P, Swainey C,
Smith TJ. A trial of scrambler therapy in the treatment of cancer pain syndromes and chronic chemotherapy-induced peripheral neuropathy. J. Pain Palliat. Care Pharmacother. 27, 359–364 (2013). 54 Sabato AF, Marineo G, Gatti A. Scrambler
therapy. Minerva Anesthesiol. 71, 479–482 (2005).
48 Gilron I, Baley JM, Tu D, Holdern DR,
Jackson AC, Houlden RL. Nortriptyline and
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