|Year : 2015 | Volume
| Issue : 3 | Page : 425-428
Neuropathic pain in cancer patients: A brief review
V Loomba1, H Kaveeshvar2, A Upadhyay1, N Sibai1
1 Department of Anesthesiology and Pain Medicine, Henry Ford Hospital, Detroit, USA
2 Department of Neurology, Henry Ford Hospital, Detroit, USA
|Date of Web Publication||18-Feb-2016|
Department of Anesthesiology and Pain Medicine, Henry Ford Hospital, Detroit
Source of Support: None, Conflict of Interest: None
Neuropathic pain (NP) is initiated or caused by a primary lesion or dysfunction in the nervous system. The NP in cancer patients is typically due to a combination of inflammatory, neuropathic, ischemic, infiltrative, and compression mechanisms that involve one or more anatomic sites. These patients will often have various types of co-existing pain syndromes and co-morbidities. Thus, any treatment plan needs to be individualized. After a thorough clinical assessment and evaluation, a combination therapy including anticonvulsants, antidepressants, N-methyl-D-aspartate antagonists, opiates, topical agents, and interventional procedures should be considered in these patients.
Keywords: Cancer, neuropathic pain, pain
|How to cite this article:|
Loomba V, Kaveeshvar H, Upadhyay A, Sibai N. Neuropathic pain in cancer patients: A brief review. Indian J Cancer 2015;52:425-8
| » Introduction|| |
Many patients with cancer complain of pain syndromes at various sites with a wide variety of descriptors. As many as 48% of patients with early stage cancer and 64–75% of patients with advanced stage cancer have pain., It has been estimated 20% of pain described in cancer patients is of neuropathic origin, and approximately 40% of cancer patients have neuropathic pain (NP), which is often difficult to control. Complicating the matter, patients will often complain of pain from cancer treatment that affects therapy of the cancer itself. A great barrier to controlling pain is inadequate classification of pain and identification of underlying pain mechanisms, which is important in regards to NP as co-analgesic drugs are beneficial when used in conjunction with opioids for pain management.,
Cancer patients are also surviving longer than ever making pain control for quality of life management more important than ever. 5-year survival rates for many types of cancer have improved over the last 40 years, exceeding 80% for some malignancies. In addition, Up to 40% of 5-year cancer survivors report pain., At the moment, there is no prospective population data to estimate the probability that a given cancer patient will develop pain as a consequence of treatment or the natural history of the disease.
There is an important distinction between neuropathic cancer pain (NCP) (i.e., NP directly cause by cancer) and NP in a cancer patient, which may be caused by cancer treatment or comorbid disease. This is particularly important given that a higher proportion of NP in cancer patients is caused by treatment or comorbid disease when compared with the etiology of all cancer pain.
Before reviewing the different treatment modalities for optimal treatment of NP in cancer patients, it would be beneficial to identify the characteristics and potential etiology of NP.
| » Etiology of Neuropathic Pain in Cancer Patients|| |
The definition of NP is “pain initiated or caused by a primary lesion or dysfunction in the nervous system.” Patients will often describe the pain as shooting, lancinating, or burning. In cancer, NP is typically due to a combination of inflammatory, neuropathic, ischemic, infiltrative, and compression mechanisms that involve one or more anatomic sites., NP in cancer is often a chronic condition involving acute exacerbations. They can be either spontaneous or triggered. These patients will typically complain of pain which significantly affects their quality of life, sleep and the general sense of well-being. Spontaneous pain is typically described as constant or fluctuating with intermittent episodes of pain free or less intense intervals. Other associated symptoms can also include parasthesia and dysasthesia. The NP is typically due to nerve compression, deafferentation nerve injury, or sympathetically induced pain. Tumor infiltration of nerves can often cause perineural inflammation and disrupt neuronal transmission. Deafferentation nerve pain can often be caused by prolonged tumor infiltration. This is typically manifested as loss of sensation in an area innervated by a peripheral nerve, plexus, or nerve root. Sympathetic pain, associated with vasodilation, increased skin temp, abnormal pattern of sweating, trophic changes, and allodynia, can often be due to cancers directly or indirectly involving the sympathetic chain. Common cancer specific NP syndromes are listed in [Table 1].
Chemotherapy induced pain is becoming increasingly common. Symptoms are typically dose dependent. Common oncology drugs are known to cause NP include: Oxaliplatin, carboplatin, cisplatin, paclitaxel, docetaxel, bortezomib, lenalidomide, thalidomide, eopthilone, and vinca alkaloids. Oxaliplatin is well known to induce neuropathy consisting of an acute allodynia and dysesthesia in a stocking and glove distribution, as well as, a pharyngolaryngeal dysesthesia manifesting as shortness of breath or dysphagia induced by cold drinks. Other treatment modalities such as radiation can also often cause plexopathy. NP secondary to procedures due to nerve injury is common, especially after nephrectomy, mastectomy, and thoracotomy.
| » Initial Approach Toward Patients|| |
It is important to obtain a good pain history and to be able to consider potential mechanisms of NP (i.e., compression, medication side-effect, etc.). In assessing etiology of NP in cancer, imaging studies such as computed tomography scan and/or magnetic resonance imaging can help identify bone metastatic lesions and spinal pathology, respectively. Electromyography can help demonstrate nerve pathology and nerve conduction studies can help detect the neuropathy, specifically. Selective sympathetic blocks can be helpful in both diagnosis and therapy of sympathetic pain. There should also be a comprehensive psychiatric evaluation when evaluating a patient as the diagnosis of cancer often coincides with significant negative expectations, which can contribute to pain and suffering.
| » Therapeutic Options|| |
Anticonvulsants are long time mainstay medications that are especially useful in treating NP primarily described as electrical or lancinating pain, as well as pain that does not respond well to antidepressants. One of the most often prescribed anticonvulsants for NP is gabapentin and pregabalin. Neurontin modulates function of α2-δ subunit of voltage gated calcium channels in the dorsal horn of the spinal cord, which decreases the release of substance P and glutamate. Pregabalin works similarly to gabapentin; however, it also has additional anxiolytic activity. Both medications are generally well-tolerated with the most common side-effects being somnolence and dizziness, weight gain, nausea, vertigo, dry mouth, and ataxia. Both medications are extracted renally and require renal adjustment dosing for patients with renal impairment. Both medications have been proven to be highly efficacious in nonmalignant NP.
Carbamezapine is also a common anticonvulsant used for the treatment of NP. Carbamazepine and its analog oxcarbazepine work by blocking sodium dependent action potentials. Oxcarbazepine, however, does not induce hepatic enzymes and overall has fewer drug-drug interactions than carbamazepine. Trials comparing the two typically report similar analgesic effect, however oxcarbazepine is reported to have less side effects.
Anticonvulsants such as valproate acid and lamotrigine have a limited role in NP. There are some studies that suggest valproate may provide relief for patients with postherpetic neuralgia and diabetic neuropathy. Lamotrigine stabilizes neural membranes via blockage of voltage gated sodium channels and inhibiting the release of glutamate. While open studies suggest, lamotrigine is helpful in NP thus far controlled studies found no efficacy. Thus, lamotrigine continues to have a limited role in the treatment of NP.,
Anti-Depressants seem to be effective for various NP states as well independent of their psychiatric effect. Tricyclic antidepressants (TCA), such as amitriptyline and nortriptyline, act as serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, anticholinergic-anti muscarinic drugs, alpha-1 adrenergic antagonists, and antihistamines. While TCA's are known to be effective for nonmalignant NP, there has been recent evidence TCA's are effective for NP related to cancer specifically. Typical side-effects include constipation, dry mouth, ocular changes and urinary hesitancy due to muscarinic receptor antagonism, as well as sedation due to antihistamine effect as well as orthostatic hypotension due to the peripheral alpha adrenoreceptor blockade. Other side-effects include conduction abnormalities and prolong intraventricular conduction and, therefore, should be used with caution in patients with extensive cardiac history. In general, TCAs are initiated slowly with initial dosing beginning at 10–25 mg daily titrating up to 50–150 mg daily.
Serotonin norepinephrine reuptake inhibitors
Serotonin Norepinephrine reuptake inhibitors (SNRIs) have been shown to be useful medications in the treatment of diabetic NP. Common SNRI's prescribed include venlafaxine and duloxetine. The advantage of venlafaxine and duloxetine application in NCP treatment is that, apart from pain relief, they can serve a useful therapeutic role for clinical depression. Specifically, venlafaxine may be more effective in ameliorating neuropathies in cancer patients., However, a relatively recent randomized control trial demonstrates duloxetine has shown efficacy in chemotherapy induced peripheral neuropathy. Another advantage of SNRI's, as opposed to other antidepressants in the treatment of NP, is that SNRI's are typically tolerated well and with continued treatment, the side-effects tend to decrease. Most common side-effects include Nausea, fatigue, dizziness, constipation, anorexia, dry mouth and sexual dysfunction. Duloxetine should be avoided in patients with hepatic insufficiency. Venlafaxine should be prescribed with dose adjustment in patients with renal or hepatic insufficiency.
In regards to opiates, it is now well documented that NP responds to opioids with a similar effect size to antidepressants and gabapentin and pregabalin.,, It must be taken into consideration, however, that studies drawing the aforementioned conclusion did not include cancer patients. Cancer patients typically have more than just NP, which does not occur in isolation and thus opioids, may be considered with these types of patients.
N-methyl-D-aspartate receptor antagonists
N-methyl-D-aspartate (NMDA) receptors within the spinal cord play a significant role in the pathophysiology of chronic NP. It is believed NMDA receptors play an especially significant role in pain wind-up, which is the perceived increase in pain intensity when a painful stimulus is repeatedly administered above a critical rate. Therefore, NMDA receptor antagonists have been used in an attempt to abolish wind-up at the spinal cord level. NMDA receptor antagonists ketamine and dextromethorphan have been studied for use in relieving NP. Ketamine is a potent NMDA receptor antagonist when taken at the sub anesthetic doses by decreasing hypersensitivity in the dorsal horn. It has been suggested to have the ability to reduce opioid resistant NP in cancer patients. However, ketamine often produces adverse side effects such as hallucinations and dissociative reactions limiting the practical use of the medication clinically.
Topical agents: Lidocaine and capsaicin
Topical agents such as lidocaine and capsaicin are relatively inexpensive options with few systemic side-effects and may be reasonable adjuvant options. Lidocaine is an amide local anesthetic agent, which blocks fast voltage gated sodium channels in the cell membrane of postsynaptic neurons, preventing depolarization and inhibiting the generation and propagation of nerve impulses. The main mechanism through which topical lidocaine is said to act is by inhibition of ectopic discharge in sensitized and hyperactive cutaneous nociceptors. There is evidence for the efficacy of the lidocaine patch 5% in patients with postherpetic neuralgia and mixed peripheral focal neuropathy with allodynia., It is typically tolerated well with the most common side effect being skin irritation. Systemic absorption is minimal. However, its use is still contraindicated in patients taking class I antiarrhythmic medications.
Capsaicin is responsible for the spice in chili pepper and works by depleting substancePfrom the terminals of afferent C fibers leading to a decreased pain perception. Studies have suggested a modest reduction in polyneuropathic and postherpetic neuralgia pain after single high-concentration capsaicin patch. It is a relatively inexpensive option with few systemic side-effects and thus may be a reasonable adjuvant option.
With cancer pain being difficult to control, some practitioners may choose to provide adjuvant therapy with cannaboids. It has been suggested that cannabinoids suppress the hyperalgesia and allodyniua associated with NP via CB1 and CB2 receptor specific mechanisms. Clinical studies largely affirm that cannabinoids are efficacious in suppressing NP in humans. Cannabinoids have significant antiemetic effects and increase appetite. Therefore, cannabinoids may prove to be useful in NP associated with nausea and decreased appetite. A systematic review of the adverse effects of medical cannabinoids revealed most (96.6%) of the adverse effects from cannibanoids were “not serious”, and of the most serious side effects, the most common were relapse in MS, vomiting, and urinary tract infections. While there is some evidence to support the potential for cannabinoids to be helpful for diverse NP states, there are concerns associated with legal and addiction issues.
Due to the difficult to control nature of NP, some practitioners have turned to interventional procedures for the management of NP. In 2013, the International Congress on Neuropathic Pain (NeuPSIG) published recommendations for the interventional management of NP. Specifically, data were presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with various nonmalignant peripheral and central NP conditions. There were weak recommendations made for epidural steroid injections, SCS, and there were conclusive recommendations made against the use of radiofrequency ablation as well as sympathetic blocks. However, it was noted that it is difficult to make conclusive recommendations due to poor quality of available data and it was suggested that interventional procedures should be part of more future randomized clinical trials, long-term studies, and head to head comparisons between interventional and noninterventional treatments.
There is some evidence that combination therapy for NP in cancer patients may be more efficacious than monotherapy. For example, a combination of gabapentin and imipramine has been shown to provide greater pain control rather than either drug alone. It must be taken into account however that combination therapy may result in more adverse side effects.
| » Conclusion|| |
Overall, there are many good potential therapies for NP in cancer patients. Generally cancer patients have various types of co-existing pain syndromes and co-morbidities, thus any treatment plan needs to be individualized. Therefore, a predictable and easy to use treatment algorithm would be difficult to create and follow. There is no strong evidence for choosing one particular therapy over another. Most of the evidence in regards to NP therapy study patients with diabetic polyneuropathy and postherpetic neuralgia and it is unclear if the results of these studies will necessarily translate to other conditions such as NP associated with cancer.
| » References|| |
van den Beuken-van Everdingen MH, de Rijke 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 2007;18:1437-49.
Julie H, Irene H. Cancer pain epidemiology: A systematic review. In: Bruera E, Portenoy R, editors. Cancer Pain: Assessment and Management. London: Cambridge University Press; 2003. p. 19-37.
Bennett MI, Rayment C, Hjermstad M, Aass N, Caraceni A, Kaasa S. Prevalence and aetiology of neuropathic pain in cancer patients: A systematic review. Pain 2012;153:359-65.
Oldenmenger WH, Sillevis Smitt PA, van Dooren S, Stoter G, van der Rijt CC. A systematic review on barriers hindering adequate cancer pain management and interventions to reduce them: A critical appraisal. Eur J Cancer 2009;45:1370-80.
Bennett MI. Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: Systematic review. Palliat Med 2011;25:553-9.
Anderson KO, Richman SP, Hurley J, Palos G, Valero V, Mendoza TR, et al.
Cancer pain management among underserved minority outpatients: Perceived needs and barriers to optimal control. Cancer 2002;94:2295-304.
Nelson JE, Meier DE, Oei EJ, Nierman DM, Senzel RS, Manfredi PL, et al.
Self-reported symptom experience of critically ill cancer patients receiving intensive care. Crit Care Med 2001;29:277-82.
Lema MJ, Foley KM, Hausheer FH. Types and epidemiology of cancer-related neuropathic pain: The intersection of cancer pain and neuropathic pain. Oncologist 2010;15 Suppl 2:3-8.
Merskey H, Bogduk N. Classification of Chronic Pain. Seattle, WA: International Association for the Study of Pain (IASP) Press; 1994. p. 1-240.
Woolf CJ, Mannion RJ. Neuropathic pain: Aetiology, symptoms, mechanisms, and management. Lancet 1999;353:1959-64.
Swarm R, Paice J, Anghelscu D, Benedetti C, Cleeland C, deLeon-Casasola O,et al
. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain2014. Available from: http://oralcancerfoundation.org/treatment/pdf/pain.pdf
. Urch CE, Dickenson AH. Neuropathic pain in cancer. Eur J Cancer 2008;44:1091-6.
Urch CE, Dickenson AH. Neuropathic pain in cancer. Eur J Cancer 2008;44:1091-6.
Fallon MT. Neuropathic pain in cancer. Br J Anaesth 2013;111:105-11.
England JD, Happel LT, Kline DG, Gamboni F, Thouron CL, Liu ZP, et al.
Sodium channel accumulation in humans with painful neuromas. Neurology 1996;47:272-6.
Churcher M. Sympathetic dependent pain states. Pain 1989;39:366.
Forman AD. Peripheral neuropathy and cancer. Curr Oncol Rep 2004;6:20-5.
Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 2006;33:15-49.
Attal N, Bouhassira D, Gautron M, Vaillant JN, Mitry E, Lepère C, et al.
Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: A prospective quantified sensory assessment study. Pain 2009;144:245-52.
Straube S, Derry S, McQuay HJ, Moore RA. Enriched enrolment: Definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. Br J Clin Pharmacol 2008;66:266-75.
Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150:573-81.
Kochar DK, Garg P, Bumb RA, Kochar SK, Mehta RD, Beniwal R, et al.
Divalproex sodium in the management of post-herpetic neuralgia: A randomized double-blind placebo-controlled study. QJM 2005;98:29-34.
Breuer B, Pappagallo M, Knotkova H, Guleyupoglu N, Wallenstein S, Portenoy RK. A randomized, double-blind, placebo-controlled, two-period, crossover, pilot trial of lamotrigine in patients with central pain due to multiple sclerosis. Clin Ther 2007;29:2022-30.
Rao RD, Flynn PJ, Sloan JA, Wong GY, Novotny P, Johnson DB, et al.
Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: A phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer 2008;112:2802-8.
Mishra S, Bhatnagar S, Goyal GN, Rana SP, Upadhya SP. A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: A prospective randomized double-blind placebo-controlled study. Am J Hosp Palliat Care 2012;29:177-82.
Alvarez W Jr, Pickworth KK. Safety of antidepressant drugs in the patient with cardiac disease: A review of the literature. Pharmacotherapy 2003;23:754-71.
Ashburn MA, Lipman AG. Management of pain in the cancer patient. Anesth Analg 1993;76:402-16.
Tasmuth T, Härtel B, Kalso E. Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain 2002;6:17-24.
Durand JP, Goldwasser F. Dramatic recovery of paclitaxel-disabling neurosensory toxicity following treatment with venlafaxine. Anticancer Drugs 2002;13:777-80.
Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, et al.
Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA 2013;309:1359-67.
Stahl SM, Grady MM, Moret C, Briley M. SNRIs: Their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr 2005;10:732-47.
Arbaiza D, Vidal O. Tramadol in the treatment of neuropathic cancer pain: A double-blind, placebo-controlled study. Clin Drug Investig 2007;27:75-83.
Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, et al.
Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology 2002;59:1015-21.
Vadalouca A, Raptis E, Moka E, Zis P, Sykioti P, Siafaka I. Pharmacological treatment of neuropathic cancer pain: A comprehensive review of the current literature. Pain Pract 2012;12:219-51.
Javery KB, Ussery TW, Steger HG, Colclough GW. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth 1996;43:212-5.
Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F, Hueppe 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 2003;106:151-8.
Hashmi JA, Baliki MN, Huang L, Parks EL, Chanda ML, Schnitzer T, et al.
Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study. Mol Pain 2012;8:29.
Wallace M, Pappagallo M. Qutenza®: A capsaicin 8% patch for the management of postherpetic neuralgia. Expert Rev Neurother 2011;11:15-27.
Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: From the bench to the bedside. Neurotherapeutics 2009;6:713-37.
Hall W, Christie M, Currow D. Cannabinoids and cancer: Causation, remediation, and palliation. Lancet Oncol 2005;6:35-42.
Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: A systematic review. CMAJ 2008;178:1669-78.
Dworkin RH, O'Connor AB, Kent J, Mackey SC, Raja SN, Stacey BR, et al.
Interventional management of neuropathic pain: NeuPSIG recommendations. Pain 2013;154:2249-61.
Arai YC, Matsubara T, Shimo K, Suetomi K, Nishihara M, Ushida T, et al.
Low-dose gabapentin as useful adjuvant to opioids for neuropathic cancer pain when combined with low-dose imipramine. J Anesth 2010;24:407-10.
|This article has been cited by|
||The use of antineuropathic medications for the treatment of chronic pain
| ||Ivan Urits, Nathan Li, Kevin Berardino, Kimberly Aleen Artounian, Prudhvi Bandi, Jai Won Jung, Rachel J. Kaye, Laxmaiah Manchikanti, Adam M. Kaye, Thomas Simopoulos, Alan D. Kaye, Monica Torres, Omar Viswanath |
| ||Best Practice & Research Clinical Anaesthesiology. 2020; 34(3): 493 |
|[Pubmed] | [DOI]|
||Home care with acupuncture increased the quality of life in a patient with advanced cancer with neuropathic pain induced by bone metastasis: a case report
| ||Ching-Feng Su |
| ||Journal of Integrative Medicine. 2018; 16(3): 208 |
|[Pubmed] | [DOI]|