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Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ®)

  • Last Modified: 04/23/2014

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Orofacial Pain in Cancer Patients

Orofacial Pain due to Cancer
Orofacial Pain due to Cancer Management
Treatment of Pain in Cancer Patients
        Management of pain due to oral mucositis
        Topical approaches for mucosal pain relief
        Systemic medications
        Nonpharmacologic pain management strategies
Orofacial Pain Summary

Pain in cancer patients may arise from onset of the disease through survivorship and may be:[1]

  • Caused by the malignant disease.
  • Caused by acute or chronic complications of cancer therapy.
  • Coincidental and unrelated to the cancer.

Cancer pain causes increased morbidity, reduced performance status, increased anxiety and depression, and diminished quality of life (QOL). Dimensions of acute and chronic pain include the following:

  • Sensory
  • Physiologic
  • Affective
  • Cognitive
  • Behavioral
  • Sociocultural

Management of head and neck pain and oral pain may be particularly challenging because eating, speech, swallowing, and other motor functions of the head and neck and oropharynx are constant pain triggers.

Orofacial Pain due to Cancer

Acute and chronic pain in cancer can result from several factors, including the following:

  • Pain due to malignant disease:
    • Local/regional cancer.
    • Oral involvement in systemic/hematopoietic cancer.
    • Metastatic disease.

  • Pain due to treatment:
    • Surgery.
    • Radiation.
    • Chemotherapy.

  • Pain unrelated to malignancy.

Pain at diagnosis is often low intensity but typically becomes more frequent and severe with advancing disease. Cancer pain may be caused by local and distant tumor effects. Direct invasion by cancer may cause pain and may result from inflammatory and neuropathic mechanisms. Effective prevention and management of pain in cancer requires knowledge of the factors and mechanisms involved.

It is estimated that 45% to 80% of all cancer patients have inadequate pain management. Seventy-five percent to 90% of patients with terminal or advanced cancer may have pain. Pain may be present in up to 85% of patients with head and neck cancers (HNCs) at diagnosis.

Orofacial pain associated with cancer management is a well-recognized adverse effect of treatment. Pain due to oral mucositis is the most frequently reported patient-related complaint during cancer therapy. Severe and painful mucositis is associated with additional hospital admissions and prolonged periods in hospital, leading to delayed, interrupted, or altered cancer therapy protocols that may affect prognosis, QOL, and cost of care. Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT), occurring in 25% to 70% of patients; oral lesions are often painful.

In addition to HNCs, oral manifestations of leukemia and lymphoma may cause pain and loss of function. Lymphomas and leukemias may induce pain by infiltration of pain-sensitive structures and if secondary oral infection occurs. Multiple myeloma frequently presents with pain and, when associated with teeth, presents a diagnostic challenge. Intracranial malignancies may give rise to orofacial pain and headache. Even in diagnosed cancer patients, the prediction of intracranial metastases with new or changed headache is difficult.

Pain may present similarly to classical trigeminal neuralgia. Jaw pain may be caused by metastatic cancer, and tumors arising from the breast, prostate, thyroid, lung, and kidney have a propensity to spread to bone in the head and neck, most commonly seen in the posterior mandible. Metastasis in the oral region may be the first indication of a distant undiscovered malignancy in up to 60% of patients. Patients with nasopharyngeal cancer report pain that may be referred to the temporomandibular joint region and masquerade as temporomandibular disorder. Orofacial pain has been reported in patients with a distant nonmetastasized cancer, most commonly in the lungs.

The mechanism of pain is thought to be involvement of the vagus or phrenic nerve. Paraneoplastic processes may present with peripheral neuropathies, particularly in patients with lung cancer and lymphoma. Neuropathies are commonly reported in patients with malignancy (1.7%–5.5%) because of the direct effects of the tumor, paraneoplastic syndromes, and treatment-related toxicities.

Orofacial Pain due to Cancer Management

The most common acute oral side effect of radiation therapy and/or cancer chemotherapy is oral mucositis. Oral mucositis and associated pain are the most distressing symptoms reported by patients receiving head and neck radiation therapy and aggressive neutropenia-inducing chemotherapy regimens. Combined chemotherapy and radiation therapy results in increased frequency, severity, and duration of mucositis. (Refer to the Oral Mucositis section of this summary for more information.)

Mucositis pain may interfere with daily activities in approximately one-third of patients, interfering with social activities and mood in more than half. Mucosal pain may persist long after the mucositis resolves. Reports of mucosal sensitivity at 1-year follow-up are common, suggesting that chronic symptoms may be related to tissue change, including epithelial atrophy and/or neuropathy.

Orofacial pain after HNC therapy can be caused by musculoskeletal syndromes, including temporomandibular disorders associated with muscular fibrosis, scar formation, and discontinuity of the jaw. Ablative surgery may lead to tissue defects that may cause significant loss of orofacial function. Resection of the maxilla and mandible leads to sensory impairment, and more than half of patients experience regional hyperalgesia or allodynia. Pain scores after surgery for HNCs are highest for oral cavity cancers, followed by cancers of the larynx and oropharynx.

At more than 6 months postsurgery, impairment due to moderate to severe pain may be seen in approximately one-third of patients. Analgesics and physiotherapy are commonly used in pain management in these patients. Long-term HNC survivors (>3 years) continue to suffer from more pain and functional problems. Surgery-related pain involves inflammatory and neuropathic pain mechanisms.

Postradiation osteonecrosis and bisphosphonate-associated osteonecrosis are recognized oral complications that may cause pain; clinical presentation may include pain, swelling, and bone exposure. Oral GVHD represents a local manifestation of a systemic disease post-HCT that may result in mucosal and arthritic pain. Viral reactivation of herpes viruses may cause pain. Postherpetic neuralgia may result in chronic pain causing painful dysesthesias in the affected area that may persist for years.

Treatment of Pain in Cancer Patients

Pain management should be directed at the diagnoses of etiologic factors, pain mechanisms involved, and pain severity. (Refer to the PDQ summary on Pain for more information.) Pain mechanisms in cancer include the following:

  • Inflammation.
    • Malignant disease.
    • Complications of treatment.
    • Infection.
  • Tumor invasion, pressure on structures, or ulceration of mucosal surface.
  • Nociceptive pain.
  • Neuropathic pain.
Management of pain due to oral mucositis

Oral mucositis pain is associated with release of proinflammatory cytokines and neurotransmitters that activate nociceptors at the site of injury and may be increased by secondary mucosal infection. Pain experience is influenced by anxiety, depression, sociocultural variation, and quality and quantity of sleep.

Topical approaches for mucosal pain relief

Topical anesthetics have a limited duration of effect in mucositis pain (15–30 minutes), may sting with application on damaged mucosa, and affect taste and the gag reflex. Some patients will apply local anesthetics directly to specific sites of ulceration, but no controlled studies have been reported.

Topical anesthetics are often mixed with coating and antimicrobial agents such as milk of magnesia, diphenhydramine, or nystatin but have not been subjected to controlled studies. However, these mixtures result in dilution of each component, which may limit the therapeutic effect. In addition, various agents in the mix may interact, reducing the effect of the components.

Topical benzydamine (not available in the United States), an anti-inflammatory and analgesic/anesthetic agent, has been shown in randomized controlled studies to reduce pain in oral mucositis and reduce the need for systemic analgesics.[2] Other topical approaches include the following:

  • A single application of topical doxepin, a tricyclic antidepressant, in cancer patients produces analgesia for 4 hours or longer.[1] Besides producing an extended period of pain relief, application of topical doxepin to damaged mucosa is not accompanied by burning.

  • Topical morphine has been shown to be effective for relieving pain,[1] but there is concern about dispensing large volumes of the medication.

  • Topical fentanyl prepared as lozenges administered in a randomized placebo-controlled study showed relief of oral mucositis pain.

  • Topical capsaicin has been studied for the control of oral mucositis pain [3] but is poorly tolerated by patients. Pretreatment initiation of capsaicin may represent an approach to desensitize patients before the onset of mucositis.

Topical coating agents may reduce pain in mucositis. Coating agents such as sucralfate may have a role to play in mucosal pain management but not in reducing tissue damage.

Systemic medications

Pain management strategies directed at diagnoses and pain mechanisms include the following:

  • Topical anesthetics/analgesics.
    • Topical before systemic therapies; if topicals are effective, continue while adding systemic analgesics.

  • Systemic analgesics.

  • Adjuvant medications (muscle relaxants, anti-inflammatories, antianxiety medications, antidepressants, anticonvulsants).

  • Adjuvant therapies (physiotherapy, relaxation, cognitive-behavioral therapies, counseling).

  • Palliative radiation therapy.

Additional and nonpharmacologic pain management techniques in oncology include the following:

  • Transcutaneous electrical nerve stimulation.
  • Cold/moist heat applications.
  • Hypnosis.
  • Acupuncture.
  • Psychological approaches:
    • Distraction.
    • Relaxation/imagery.
    • Cognitive/behavioral therapy.
    • Music therapy, drama therapy.
    • Counseling.

Suggestions for the use of opioids in cancer pain include the following:

  • Use the lowest effective dose.

  • Base time-contingent prescription on drug characteristics.

  • Provide analgesics for breakthrough pain.

  • Combine with nonopioid analgesics.

  • Provide prophylaxis/treatment for constipation.

  • Conduct regular pain assessment and modify management, depending on pain control.

  • Follow steps in World Health Organization (WHO) analgesic ladder.

The WHO analgesic ladder is a three-step strategy for managing pain in cancer patients.[4] Pain management must be directed at the severity of pain; the lowest dose of strong opioids (step 3 in the WHO ladder) may be chosen instead of weak opioids for better pain control.[5,6]

Analgesics should be provided on a time-contingent basis to provide a steady state of analgesia; when needed, medication should be available to manage breakthrough pain. Adjuvant medications such as tricyclic antidepressants, gabapentin, and other centrally acting pain medications should be considered, particularly in light of the developing understanding of the common neuropathic mechanisms involved in cancer pain (see list of pain mechanisms).[6-8] Regular assessment of pain and modification of pain medications are necessary.

Transdermal fentanyl is widely used for extended duration therapy in the management of pain in the outpatient setting. Cyclooxygenase-2 (COX-2) is upregulated in mucositis; therefore, COX-2 inhibitors represent potential agents that may affect pain and evolution of mucositis.

Adjuvant medications should be used in addition to analgesics. Patients who experienced neuropathic cancer pain and received amitriptyline in addition to morphine were studied in a randomized controlled trial.[9][Level of evidence: I] Limited additional analgesic effect and increased drowsiness, confusion, and dry mouth were observed; however, the central actions of amitriptyline may improve sleep.

Gabapentin is a voltage-sensitive sodium and calcium channel blocker that is used for management of a variety of pain conditions and may improve pain control when used in addition to morphine in cancer patients. Drugs that affect the N-methyl-D-aspartate receptor may affect neuropathic pain; gabapentin is one of these and is well tolerated. Other agents that may be used in pain management include the following:

  • Cannabinoids.
  • Alpha-2 adrenergic receptor agonists.
  • Nicotine.
  • Lidocaine.
  • Ketamine.

Addiction in opioid therapy is not generally a concern for cancer patients; the focus should be on escalating to stronger opioids as needed (based on assessment) and using adjuvant approaches to provide adequate pain relief. However, the clinician always should be cognizant of potential drug-seeking behavior by the patient.

Tolerance and physical side effects such as constipation, nausea, vomiting, and mental clouding occur with opioids and should be managed prophylactically, if possible. Stool softeners and other approaches to bowel management should be initiated along with the initial opioid prescription. Adequacy of the approach should be assessed regularly.

Nonpharmacologic pain management strategies

In randomized trials, hypnosis has been shown to be a useful pain management strategy for cancer patients. Additional psychological techniques such as counseling, distraction, relaxation techniques, and other cognitive and behavioral training programs have been described (see list of psychological approaches to pain management techniques).

Physical management of orofacial pain includes the use of ice chips for oral cooling, cold compresses, and physical therapy. Acupuncture (refer to the PDQ summary on Acupuncture for more information), transcutaneous nerve stimulation, group therapy, self-hypnosis, relaxation, imagery, cognitive behavioral training, and massage therapy have been considered to alleviate pain in cancer patients. Relaxation and imagery may alleviate pain due to oral mucositis.[1,3];[10][Level of evidence: I][11]

Orofacial Pain Summary

Orofacial pain is common in cancer patients and may be caused by the cancer or its treatment. Orofacial pain is frequently associated with locoregional cancer, but it can also be a sign of systemic and distant cancer.

Pain management requires diagnosis of the various causes and mechanisms of pain in cancer patients. Practitioners must obtain regular pain ratings during the treatment of patients with cancer-related pain. Because pain is frequently multifactorial, addressing each of the dimensions of a patient’s pain can improve pain control. Attention should be paid to the patient’s overall medical status and oral status.

It is important to recognize and manage the side effects of analgesic therapy, especially those induced by opioids and adjuvant medications. Use of effective topical pain therapy with the initial mucosal injury may allow for reduced duration or reduced doses of systemic medications. Awareness of adjuvant approaches to management is essential; both medications and complementary management with evidence of effect should be considered.

References
  1. Epstein JB, Elad S, Eliav E, et al.: Orofacial pain in cancer: part II--clinical perspectives and management. J Dent Res 86 (6): 506-18, 2007.  [PUBMED Abstract]

  2. Kazemian A, Kamian S, Aghili M, et al.: Benzydamine for prophylaxis of radiation-induced oral mucositis in head and neck cancers: a double-blind placebo-controlled randomized clinical trial. Eur J Cancer Care (Engl) 18 (2): 174-8, 2009.  [PUBMED Abstract]

  3. Berger A, Henderson M, Nadoolman W, et al.: Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J Pain Symptom Manage 10 (3): 243-8, 1995.  [PUBMED Abstract]

  4. Meuser T, Pietruck C, Radbruch L, et al.: Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93 (3): 247-57, 2001.  [PUBMED Abstract]

  5. Eisenberg E, Marinangeli F, Birkhahn J, et al.: Time to modify the WHO analgesic ladder? Pain: Clinical Updates 13 (5): 1-4, 2005. Also available online. Last accessed April 17, 2014. 

  6. Benedetti C, Brock C, Cleeland C, et al.: NCCN Practice Guidelines for Cancer Pain. Oncology (Williston Park) 14 (11A): 135-50, 2000.  [PUBMED Abstract]

  7. Ripamonti C, Dickerson ED: Strategies for the treatment of cancer pain in the new millennium. Drugs 61 (7): 955-77, 2001.  [PUBMED Abstract]

  8. Rankin KV, Jones DL, Redding SW, eds.: Oral Health in Cancer Therapy: A Guide for Health Care Professionals. 3rd ed. Austin, Tex: Dental Oncology Education Program, 2008. Also available online. Last accessed April 17, 2014. 

  9. Mercadante S, Arcuri E, Tirelli W, et al.: Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study. Tumori 88 (3): 239-42, 2002 May-Jun.  [PUBMED Abstract]

  10. Mercadante S, Fulfaro F, Casuccio A: A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis. Eur J Cancer 38 (10): 1358-63, 2002.  [PUBMED Abstract]

  11. Epstein JB, Hong C, Logan RM, et al.: A systematic review of orofacial pain in patients receiving cancer therapy. Support Care Cancer 18 (8): 1023-31, 2010.  [PUBMED Abstract]