Treating neuropathic pain in cancer

Neuropathic pain occurs in a significant portion of patients with cancer. Although as much as 9% of cancer patients have solely neuropathic pain, many patients have a mixed pain syndrome, which often can be challenging to treat. Neuropathic pain is caused by abnormal or injured peripheral nerves or by abnormal pain circuits in the central nervous system causing a pain response.

On a mechanistic level in the periphery, neuropathic pain occurs due to “peripheral sensitization” via upregulation of specific sodium channels on C fibers and in sensory A fibers simultaneously causing a lower threshold for nerve firing (“burning” pain) and spontaneous nerve firing (paresthesias). In the CNS, sensitization to firing from C pain fibers and disinhibition can occur at the spinal cord level resulting in allodynia and hyperalgesia, which are abnormal pain responses to mild or non-noxious stimuli. Calcium channels mediate a lower threshold for firing, and NMDA (N-methyl D-aspartate) receptors are upregulated in the spinal cord, making both the calcium channels and NMDA receptors prime pharmacologic targets.

Stephanie Harman

Patients with neuropathic pain report symptoms of paresthesias and dysesthesias as well as allodynia, hyperalgesia and hyperpathia. Although most symptoms of neuropathic pain are sensory, there can be signs of muscle wasting and weakness in some patients with nerve damage.

There are multiple neuropathic cancer pain syndromes caused by direct infiltration of the tumor including cranial nerve neuralgias, mononeuropathies, radiculopathies, plexopathies (cervical, brachial and lumbosacral), as well as central pain from spinal cord compression.

Paraneoplastic syndromes, although not through direct mechanical infiltration, also can cause peripheral neuropathies via autoimmune mechanisms.

In treatment-associated neuropathic pain, multiple chemotherapeutic agents can cause both neuropathic pain and nueropathies. The main classes of chemotherapies include the platinum agents, the taxanes, the vinca alkaloids and thalidomide. Less commonly, some of the antimetabolites like 5-FU can also cause neuropathy. Unfortunately, studies on neuroprotective agents have been disappointing; there are no clear guidelines for preventing chemotherapy-associated neuropathies.

Certain cancer-related surgeries can cause neuropathic pain as well, including mastectomy, neck dissections, and thoracotomy. For patients who undergo amputation, phantom limb pain and stump pain are other neuropathic pain syndromes that may occur.

Management

Nonpharmacologic management of neuropathic pain includes radiation therapy, ie, in the case of nerve compression, and surgical decompression in certain cases of spinal cord compromise. There have been no studies for the use of alternative therapies for neuropathic pain specifically in cancer, though there has been some evidence for the use of acupuncture in diabetic neuropathy.

Anticonvulsants

With regards to pharmacologic management, there is a growing evidence base for the use of gabapentin in cancer-related neuropathic pain. Much of the prior research has been in diabetic neuropathy and post-herpetic neuralgia. Gabapentin is now one of the major treatments recommended by both the WHO and the NIH consensus guidelines for neuropathic pain.

Alongside gabapentin, pregabalin (gabapentin analog) is also being used to treat neuropathic pain; these gabapentinoids are thought to bind to the calcium channels on nociceptive neurons. Gabapentinoids, compared to other anticonvulsants, tend to not have as many drug interactions or adverse effects. Because they are excreted renally they require careful dosing in patients with renal dysfunction.

Other anticonvulsants have been used in the treatment of neuropathic pain, including carbamazepine (particularly for trigeminal neuralgia), lamotrigine, topiramate and oxcarbazepine.

Antidepressants

Antidepressants have also been studied in the treatment of neuropathic pain, but not specifically cancer-related neuropathic pain. There is strong evidence for the use of tricyclic antidepressants such as nortryptiline and amitriptyline, though the anticholinergic adverse effects can limit their use. Nontricyclic antidepressants are also increasingly used, particularly venlafaxine and duloxetine, which are both serotonin norepinephrine reuptake inhibitors — or SNRIs — that have shown to be of some benefit in studies of patients with diabetic neuropathy.

Opioids

Opioids are considered a primary treatment of neuropathic pain though sometimes they are assumed to be ineffective. Multiple studies have suggested overall improvement in pain with use of opioid therapy, regardless of the type (nociceptive vs. neuropathic). Gilron et al in 2005 demonstrated that between gabapentin, morphine, and gabapentin plus morphine for neuropathic pain, the gabapentin/morphine combination achieved the best analgesic response; both medications were at lower doses than when used exclusively.

Local anesthetics

Local anesthetics are another class of medication for neuropathic pain, often primarily used by pain specialists. This includes transdermal lidocaine, widely used in the treatment of postherpetic pain as well as other neuropathic pain conditions.

Intravenous lidocaine has also been used for severe neuropathic pain. Mexiletine is an oral sodium channel blocker and antiarrhythmic that has been used more recently in neuropathic pain. Notably, capsaicin cream is also considered a topical anesthetic that depletes substance P (pain neurotransmitter).

Other adjuvants

For syndromes of neuropathic pain that are not responsive to standard therapies, there are multiple adjuvant therapies. Corticosteroids are often used in cord compression and plexopathies, but are limited by adverse effects for chronic use. Alpha-adrenergic agonists like clonidine have been effective adjuncts, often alongside opioid therapy; clonidine has also demonstrated benefit in the treatment of sympathetically maintained pain.

Ketamine, an NMDA antagonist and anesthetic, has been shown in multiple studies to improve pain control as an adjunct, but can be limited due to the dissociative side effects. Interventional therapies for neuropathic pain are helpful, particularly when pain is not controlled by the above therapies. This can take on the form of a neural blockade or intrathecal administration of medications.

Although neuropathic pain remains a challenging cancer-related pain syndrome, there are multiple treatment strategies and modalities available, and neuropathic pain continues to be a prominent area of pain research.

Stephanie Harman, MD, is a Palliative Care Physician at Stanford University Medical Center and Director of the Inpatient Palliative Care service.

For more information:

• Blumenthal DT. Cur Pain Headache Rep. 2009;13:282-287.
• Chang. J Pall Med. 2006;9:1414-1434.
• Hawley P. Fast Fact and Concept #187. Non-tricyclic Antidepressants for Neuropathic Pain. September 2007. End-of-Life/Palliative Education Resource Center www.eperc.mcw.edu.
• Abrahm, JL. A Physician’s Guide to Pain and Symptom Management in Cancer Patients. 2nd ed. Baltimore, MD: The Johns Hopkins University Press; 2005:200-210.
• Pappagallo M. Difficult pain syndromes: bone pain, visceral pain, neuropathic pain. In: Berger AM, Shuster JL, Von Roenn JH, eds. Principles and Practice of Palliative Care and Supportive Oncology. 3rd ed. Philadelphia, PA: Lippincott Williams&Wilkins;2007: 27-36.