|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.
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