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11 Articles in Volume 13, Issue #8
Ask the Expert: Intranasal Ketamine for Migraine Therapy
Assessment and Treatment of Neuropathic Pain
Diabetes & PAD: Diagnosis, Prevention, and Treatment Paradigms
Editor's Memo: Chronic Low Back Pain: Bringing Back A Forgotten Treatment
Evaluation and Treatment of Chemo- or Radiation-Induced Painful Complications
Guide to Implantable Devices for Intrathecal Therapy
Is Buprenorphine a ‘Partial Agonist’? Preclinical and Clinical Evidence
Letters to the Editor: Hormones and Genetic Testing
Pain Management in Kenya: A Team Experience
PROP versus PROMPT: FDA Speaks
Use of Ultrasound in Detection Of Rotator Cuff Tears

Evaluation and Treatment of Chemo- or Radiation-Induced Painful Complications

With cancer treatment success comes a downside—more disability and pain. Part 4 of this four-part series on cancer pain will discuss painful complications of chemotherapy and/or radiation therapy.

Chemotherapy (CT), radiation therapy (RT), and their combination are commonly prescribed for patients with cancer. These life-saving treatments, however, often cause systemic side effects including bone marrow suppression, immunosupression, nausea, vomiting, diarrhea, fever, anorexia, asthenia, cachexia, cardiovascular, renal and hepatic toxicity, alopecia, sloughing of skin and mucosal membranes (related to its effects on rapidly mitotic cellular function), as well as central and peripheral neuropathic toxicities.

Mucositis and peripheral polyneuropathy are amongst the most common painful side effects from these treatments, and will be the focus of this article. Painful mucositis can be disabling and affect the future course of CT and/or RT. Painful peripheral polyneuropathy may occur as delayed sequelae of effective treatment. To follow are some strategies to minimize side effects and morbidity, as well as effective analgesics to control symptoms.

(Editor's Note: Links to Part 1, Part 2, and Part 3)

Mucositis

Mucositis and xerostomia (stomatitis) are common side effects following CT and/or RT. Mucositis affects 400,000 cancer patients annually, is associated with infection in 80% of patients, and has a mortality rate of 10% due to sepsis.1 There is a significantly increased cost of care for patients who develop mucositis, including hospitalizations requiring parenteral or gastric feedings, and higher utilization of opioids.2

Mucositis and xerostomia occur most commonly following the treatment of blood dyscrasias (hematologic cancers) or transplantation, followed by colorectal cancer treatment (if CT is used only). In head and neck cancers, mucositis has a prevalence of up to 80%, and occurs more commonly following combined CT and RT, especially if patients receive more than 5,000 cGy of radiation.

Mucositis may occur anywhere in the GI tract including the esophagus, small and large intestine, but is more commonly symptomatic in the oral mucosa. The ulcers may occur on the lip, buccal mucosa, palate, or tongue.3 The pathophysiology of mucositis includes initial inflammation with disruption of the epithelial cells followed by damage to the subepithelial layers of mucosa caused by free radicals released by cytokines. This is followed by ulceration and secondary infection. Secondary infections with leukoplakia include bacterial and yeast (thrush) infections, as well as viral infection, particularly recrudescent herpes simplex virus (HSV). A pseudomembrane formation is initiated by fibroblasts, and then subsequent healing occurs.1

Initial symptoms include xerostomia with highly viscous saliva, followed by very painful oral mucosal ulcers with surrounding inflammation (erythema) of the mucosal membranes with odynophagia, dysphagia, and dysgeusia (alteration in taste perception), dysarthria, and insomnia (due to pain). The loss of salivary gland secretion may occur as a result of dehydration, anticholinergic medications, CT (usually occurs after 4-10 days, lasting 7-14 days), and RT (usually occurs after 3 to 4 weeks).1 Xerostomia also carries an increased incidence of dental caries.

Severity of Mucositis

The severity of oral mucositis can be graded from 0-4 based on the World Health Organization oral toxicity scale. National Cancer Institute Common Toxicity Criteria (NCI CTC) is another scale based solely on functional deficits (Table 1). Alternative nutritional support should be considered if malnutrition results in >5% weight loss.

Mucositis is commonly caused by CT agents including melphalan (Alkeran), fluorouracil (5-FU, Efudex), doxorubicin (Doxil), cisplatin, paclitaxel, bleomycin, rapalogs (rapamycin derivatives), and cytarabine. These agents generally result in the highest frequency of side effects, particularly if combined with RT. Methotrexate and etoposide (Etopophos) are secreted into the saliva, with direct toxic effects on the mucosa (Table 2).4

Prevention of Mucositis

Risk factors for the development of mucositis include poor oral hygiene, dental caries, periodontal disease, high titers of HSV, and positive cultures for Candida.4 A dental assessment including regular inspection of the oral cavity is recommended. Patients are told to avoid smoking, alcohol, and spices. Proper nutrition, including a high protein diet for wound healing and hydration to prevent dehydration, also are recommended.

For the prevention of mucositis, oral hygiene protocols include brushing with toothpaste and warm water using a soft toothbrush or foam swab, use of Biotène products, use of non-alcoholic mouthwashes and rinses, baking soda, and flossing. Mucositis is commonly pretreated with cryotherapy (ice chips), which causes local vasoconstriction, thus decreasing the delivery of CT to the oral mucosa. It may be given prophylactically, 5 minutes prior to the administration of CT.

To prevent mucositis following RT, there is an innovative surgery that transposes the submandibular salivary gland out of the field of radiation, thus preserving most salivary function.5 Most recently, intensity-modulated RT has been developed that more specifically targets the cancer, without affecting the adjacent salivary glands.6

Treatment of Mucositis And Xerostomia

There are a number of agents available to treat or reduce painful mucositis. One area of research has been the development of agents that go to the core of CT or RT-induced mucositis—inflammation. Glutamine supplementation in the form of AES-15 (Saforis) has recently shown promise by improving amino acid replacement in the damaged epithelium.7 Palifermin (Kepivance), a keratinocyte growth factor preparation, has been approved by the FDA for use with high-dose CT regimens associated with high rates of mucositis.8 Clinical studies of the agent found that it improved mucositis scores by approximately 33%, as well as reduced the need for opioids.9,10 The side effects include local mucosal toxicity, rash, and hypotension. Velafermin (rhFGF-20) is a recombinant fibroblast growth factor under investigation for the treatment of mucositis.11

Oral Barriers

MuGard is FDA-approved for the management of mucositis and stomatitis.12 When swirled around the mouth, the mucoadhesive protectant forms a hydrogel coating over the oral mucosa. Episil is another mucoadhesive protectant that creates a lipid membrane that bonds to the mucosa for pain relief of oral mucositis and stomatitis.13 Other oral protectants include Gelclair, another mucoadhesive thin gel, with a soothing effect.14 NeutrSal is an FDA-approved calcium phosphate mouth rinse for the management of mucositis.1 The agent is started at the beginning of CT or RT and is designed to replace the normal ionic and pH balance in mouth.

Other Rinses

Caphosol (may be combined with fluoride rinses) is a mouth rinse that has been shown to prevent and treat oral mucositis caused by radiation and high dose CT.15 Tricyclic antidepressants, especially doxepin mouth rinse, have been found to be effective at reducing pain associated with mucositis, but may cause a dry mouth and drowsiness.16

The antiseptic chlorhexidine (Peridex, Periogard) has been extensively studied in multiple randomized trials with mixed results. Other topical rinses include diphenhydramine, viscous lidocaine, benzocaine gel, normal saline, benzydamine hydrochloride (a nonsteroidal anti-inflammatory agent), nystatin, corticosteroids, sucralfate suspension, sodium-sucrose octasulfate oral rinse, aloe vera, 2% silver nitrate solution, capsaicin lozenges, anti-pyrosis (magnesium hydroxide/aluminum hydroxide), and anti-dia­rrheal (kaolin-pectin solution) agents.17 Honey, with or without a combination of olive oil, propolis and beeswax, has been tried with some success.18

Systemic Therapy

The systemic therapy of mucositis with opioids has been well established and recommended; although a topical morphine rinse may be considered for more localized effects, with reduced side effects.19 Transmucosal immediate-release fentanyl (TIRF) products, which are FDA-approved for breakthrough cancer pain, also hold promise for adult opioid-tolerant patients. These agents, which come in different formulations (buccal or sublingual), must be used with caution with mucositis Grades 3 or 4, avoiding the administration at the site of mouth ulcerations. There is an intranasal TIRF preparation (Lazanda) that may be considered in patients who cannot tolerate an oral sublingual or buccal formulation (Table 3).

Others

Newer studies have suggested low-energy helium-neon laser appears to be effective for mucositis.1 Topical thrombin packs and topical antifibrin-olytic agents, such as tranexamic acid, may control the bleeding from mouth ulcers, particularly in patients with CT-induced thrombocytopenia. It is recommended that antibiotics, antiviral, and/or antifungal agents be restricted to patients who display evidence of infection.17

Xerostomia may be treated with radioactive cyclopentanone thione,20 pilocarpine (cholinergic agonist), amifostine or N-acetylcysteine (anti-oxidants), sodium hyaluronate, artificial saliva (Mouthkote, Xerolube, Moistir, Salivert, Sage), and glycerol swabs.7

Chemotherapy-induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-dependent side effect of many CT agents. CIPN can result in severe pain and other complications, including neuropathic ulcers. The neurotoxic CT agents, including the vinca alkaloids (eg, vinblastine, vincristine, vinorelbine), etoposide, platinum-based salts (cisplatin, carboplatin, and oxaliplatin), and taxanes (paclitaxel, docetaxel, and cabazitaxel), have a 67% prevalence for CIPN. Other neurotoxic CT agents, including epothilones, ixabepilone (Ixempra), thalidomides (lenalidomide and pomalidomide), bortezomib (Velcade), carfilzomib (Kyprolis), and eribulin (Halaven), have lower neurotoxicity rates, with a 30% prevalence of CIPN.21 Other risk factors for CIPN include genetic host susceptibility, older age, comorbid conditions including diabetes, drug interactions, and metabolic pathways.22

CT neurologic toxicity is believed to affect the mitochondrial sodium-potassium pump of the peripheral nerve axons and the dorsal root ganglion (DRG), resulting in reduced pain threshold and ectopic spontaneous firing of nocioceptors. CIPN can be a serious adverse event requiring dose reductions, increased infusion duration or discontinuation of CT regimen, which may adversely affect prognosis. In the majority of the patients, CIPN is potentially reversible if recognized early and effective strategies are employed. However, the patient’s recovery may take months or even years.

Chronic CIPN symptoms significantly reduce physical functioning and quality of life of cancer patients.23 Optimization of the nutritional and hydration status, including nutritional supplements, can reduce morbidities.21

Preventing CIPN

Currently there are no specific or approved treatments for prophylaxis from CT side effects.24 However, investigational studies suggest that intravenous calcium and magnesium infusions are most promising. The treatments are thought to exert an effect by interfering with oxalate metabolism, which in turn reduces neuronal hyperexcitability.25 Another antioxidant agent, glutathione, which has a high affinity for heavy metals and in animal models, has also been promising in decreasing the accumulation of platinum from cisplatinum in the DRG.23 Amifostine, an organic thiophosphate, protects normal cells from the radical oxygen effects of radiation and as a neuroprotectant with paclitaxel therapy (which can result in an very acute painful syndrome). ORG 2766, an analog of corticotropin, promotes neurite outgrowth, and has been reported to protect against cisplatin neuropathy, preventing the loss of peripheral motor function.4 Acetyl-l-carnitine is an antioxidant that affects the axonal mitochondria to stabilize nerve membranes, has been reported to lessen neuropathic painful symptoms in patients receiving paclitaxel or cisplatin.

Vitamin E has been used as an antioxidant, which binds free oxygen radicals in the lipid metabolism of axons. Carbamezine and oxycarbamezine affect sodium channels of the sensory neurons and DRG, and can prevent CIPN in animal models. Oral glutamine, an amino acid neurotransmitter that can bind to presynaptic terminals, has been found to be helpful in studies following paclitaxel CT. Melatonin, a pineal hormone and antioxidant, has been shown to reduce CT-induced neurotoxicity,23 and if used topically, can prevent radiation burns.26 Alpha-lipoic acid, a broad-spectrum antioxidant may protect sensory neurons, reportedly may help ameliorate symptoms from diabetic, docetaxel and cisplatin, or oxaliplatin neuropathy. Erythropoietin, 3,5 tetrahydroprogesterone, nimodipine, diethyldithiocarbamate, valproate, and interleukin-6 have also been studied for their neuroprotective potential.23

For oxaliplatin toxicity, calcium gluconate, gabapentin, carbamazepine, intravenous (IV) amifostine, and glutathione have been tried to minimize polyneuropathy symptoms.4 Isaxinone enhances peripheral nerve regeneration and protects against vincristine-induced neuropathy, but is hepatotoxic. To prevent tissue necrosis or RT-induced neuropathies, pentofylline, an antifibrinogen, may be helpful in treating fibrosis and improving circulation from ischemic tissue damage. Hyperbaric oxygen therapy increases oxygenation of irradiated tissue, promoting angiogenesis and enhancing osteoblast repopulation and fibroblast function for RT-induced osteonecrosis and persisting wounds.4 Metanx is a medical food containing B vitamins (B12, B6, and folate) that can improve endothelial function and promote vasodilation. Metanx has been FDA-approved for the treatment of painful diabetic neuropathy.27,28

No single agent has an FDA indication for CIPN. Symptomatic treatments include oral serotonin/norepinephrine reuptake inhibitors (duloxetine [Cymbalta] and venlafaxine), tricyclic antidepressants (amitriptyline), antiepileptics (lamotrigine, gabapentin and pregabalin [Lyrica]), and opioids (Table 4).22

The increasingly popular use of topical formulations may include selective combinations of ketamine, amitriptyline, baclofen,29 gabapentin, diclofenac, ketoprofen, fluroprofen, doxepin, pentofylline, lidocaine, bupivacaine, mexilitene, cyclobenzaprine, clonidine, capcaisin, morphine, tramadol, melatonin, anabolic steroids, corticosteroids and amlodipine, antimicrobials (especially antivirals), and menthol. Many of these can be custom formulated by a compounding pharmacy using lipoderm, anhydrous gel, or dimethyl sulfoxide (DMSO) solvent.

Topical anesthetic (lidocaine [Lidoderm]) and antiinflammatory (diclofenac [Flector]) patches have also been used. These topical formulations must be applied to intact skin for symptomatic relief of painful peripheral neuropathy, keloids, scars, and localized pain in the soft tissue, joint, or bone. There is approximately 5% to 10% systemic absorption.

Transcutaneous electrical nerve stimulation (TENS) applied to the lower extremities appears to be potentially effective in the treatment of CIPN.30

Summary

The use of these adjuvant analgesics in cancer patients to prevent or treat painful mucositis or peripheral neuropathy is still often guided solely by anecdotal experience. Future studies focused on the cancer population are needed to expand and improve the use of these treatments. Some of the potential options discussed here may be applied to other etiologies of peripheral neuropathic pain.

Last updated on: October 28, 2014
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