Background: Oral mucositis is a dreaded complication of cancer treatment for many common cancers (head and neck cancer (HNC), esophageal cancer, even hematologic cancers), The pain is often severe and can even compel patients to halt potentially curative cancer treatment (1,2). Fast Fact #121 describes the assessment of cancer-related oral mucositis. The location, severity, and duration of tissue injury along with the elevated risk for opioid misuse found in patients with HNCs for example, (3-5) create unique analgesic and safety considerations. This Fast Fact assimilates the published evidence to offer multimodal analgesic strategies for oral mucositis pain from cancer treatment.
Importance of early patient education about the pain trajectory: The rapid rate of mitosis in mucosal tissue makes it prone to injury from chemotherapy and radiation. Oral mucositis pain from radiation therapy typically begins after 1-2 weeks then peaks near the third week (1,2). Chemotherapy regimens, especially those containing fluorouracil, methotrexate, or etoposide, can worsen mucositis injury within 3-14 days of administration (6). Patients should be counseled about this pain trajectory prior to and during cancer treatment, as they may need extra encouragement. They should be made aware that opioid therapy in the short term is often needed. For those undergoing treatment with curative intent (e.g., localized HNCs), they should be informed that 1-2 months after radiation treatment ends, tissue healing usually occurs and hence around this time opioids are commonly tapered.
Preventative interventions: See Fast Fact #130 for a discussion on oral care recommendations, mouth washes, and other preventative interventions. Glutamine is a non-essential amino acid that acts as a key substrate in the proliferation of epithelial cells lining the oral mucosa. It is commonly obtained as an over-the-counter dietary supplement, though prescribed formulations are also available. Randomized control trials suggest 5-15 grams of oral glutamine up to 2-3 times a day decreases the incidence of severe oral mucositis and may decrease the need for opioids when initiated at the beginning of a radiation course (7). Major oncologic organizations recommend it to prevent severe mucositis pain in patients with HNC, though it is recommended against use in hematopoietic stem cell transplant patients (8).
Opioid therapy: Short-acting (SA), full agonist opioids such as morphine, hydromorphone, and oxycodone are common initial agents (9). For patients exhibiting persistent pain despite regular doses of SA opioids, round-the-clock use of long-acting (LA) opioids should be considered (9). Difficulties with swallowing intact pills make LA formulations of oxycodone or morphine problematic. Therefore, LA opioids which can be given as a transdermal patch (e.g., fentanyl, buprenorphine) or as a crushed pill or solution (e.g., methadone) are often prescribed (3). For those exhibiting unsafe opioid use behaviors with SA opioids (self-titration, misuse, unaccounted/lost pills, etc.), LA opioid monotherapy (no co-prescription of a SA opioid) can be considered as a harm reduction approach if paired with other standard safety practices (e.g., frequent pill/patch counts, urine drug screening, naloxone co-prescription) (10).
- Fentanyl patch: likely the most used LA opioid in this patient population. See Fast Fact #2.
- Methadone: a LA opioid used for cancer pain, OUD, and chronic pain (11). See Fast Facts #75, 86, and 171. One controlled study showed at least non-inferiority to fentanyl patches for nociceptive mucositis pain (12). Two controlled studies showed improved quality of life and pain scores plus less frequent breakthrough opioid use compared with other LA opioid regimens (13,14).
- Buprenorphine: a partial opioid agonist/antagonist used to treat cancer and chronic pain and OUD (15). See Fast Facts #221, 268, and 441. Sublingual (SL), transmucosal (TM), and transdermal buprenorphine (TDB) formulations are available. Though SL and TM options have quick onset, their use is limited for oral mucositis pain because of an association with dental caries, infection, and teeth loss (16). The limited available evidence for the TDB patch suggests variable efficacy for cancer-related mucositis pain (17-20). Since the maximum available TDB dose in the U.S. is only 20 mcg/hr, it is limited to patients with low opioid requirements.
Gabapentin: Retrospective studies suggest improved pain control when used as an adjuvant analgesic (21-24), however, randomized controlled studies show mixed results (25). Questions remain regarding the optimal dosing for cancer-related mucositis pain, with one randomized pilot study suggesting relatively high-doses (2700 mg daily) are more effective and potentially opioid-sparing (13).
Topical agents: Topical opioids present a potentially safer analgesic approach, given their limited risk of systemic absorption (26,27). Fast Fact #185 explores this in more detail, including reliability challenges since they usually require a compounding pharmacy. Fast Fact #130 provides a discussion on the role of topical lidocaine and magic mouthwashes. Topical dexamethasone (e.g., 2.5 mg) and even honey may also have a role in prevention and treatment of mucositis per small, controlled studies (28,29).
Doxepin is a tricyclic antidepressant that, when used as a mouthwash or oral rinse, has been shown to decrease mucositis pain compared to placebo. However, it is not clear how clinically significant this result is. Patients should be counseled on adverse effects including drowsiness and stinging/burning with intake (9,30). Cost may be prohibitive due to the compounding of liquid formulations.
NSAIDs or acetaminophen are adjuvant analgesic options for mucositis pain if there are no contraindications. While commonly prescribed, there is no clear evidence that they are significantly opioid-sparing, and they are not included in current organizational recommendations (8).
Low-energy laser therapy: Recent MASCC/ISOO guides support using low-energy laser therapy, or photobiomodulation, in preventing oral mucositis from stem cell transplantation and radiation for HNC treatment (8). See Fast Fact #130 for more details.
- Blakaj A, Bonomi M, Gamez ME, Blakaj DM. Oral mucositis in head and neck cancer: Evidence-based management and review of clinical trial data. Oral Oncol. 2019;95:29-34.
- Ling IS, Larsson B. Individualized pharmacological treatment of oral mucositis pain in patients with head and neck cancer receiving radiotherapy. Support Care Cancer. Sep 2011;19(9):1343-50.
- Hashibe M, Brennan P, Chuang S-c, et al. Interaction between Tobacco and Alcohol Use and the Risk of Head and Neck Cancer: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev. 2009;18(2):541-550.
- Neilson K, Pollard A, Boonzaier A, et al. A longitudinal study of distress (depression and anxiety) up to 18 months after radiotherapy for head and neck cancer. Psychooncology. 2013;22(8):1843-1848.
- Webster LR. Risk Factors for Opioid-Use Disorder and Overdose. Anesth Analg. 2017;125(5):1741-1748.
- Lalla RV, Bowen J, Barasch A. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 2014; 120:1453-1461.)
- Alsubaie HM, Alsini AY, Alsubaie KM, et al. Glutamine for prevention and alleviation of radiation-induced oral mucositis in patients with head and neck squamous cell cancer: Systematic review and meta-analysis of controlled trials. Head Neck. 2021;43(10):3199-3213.
- Elad S, Cheng KKF, Lalla RV, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2020;126(19):4423-4431.
- Brown TJ, Gupta A. Management of cancer therapy-associated oral mucositis. JCO Oncology Practice 2020; 16(3):103-110.
- Lowry S. When management of cancer-related pain is complicated by coexisting opioid use disorder: a case review. Journal of Hospice and Palliative Nursing 2022; 24(2):112-118.
- Mercadante S, Bruera E. Methadone as a First-Line Opioid in Cancer Pain Management: A Systematic Review. J Pain Symptom Manage. 2018;55(3):998-1003.
- Haumann J, van Kuijk SMJ, Geurts JW, et al. Methadone versus Fentanyl in Patients with Radiation-Induced Nociceptive Pain with Head and Neck Cancer: A Randomized Controlled Noninferiority Trial. Pain practice : the official journal of World Institute of Pain.
- Hermann GM, Iovoli AJ, Platek AJ, et al. A single-institution, randomized, pilot study evaluating the efficacy of gabapentin and methadone for patients undergoing chemoradiation for head and neck squamous cell cancer. Cancer. 2020;126(7):1480-1491.
- Haumann J, Geurts JW, van Kuijk SM, Kremer B, Joosten EA, van den Beuken-van Everdingen MH. Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer. Eur J Cancer. 2016;65:121-129.
- Pergolizzi J, Aloisi AM, Dahan A, et al. Current Knowledge of Buprenorphine and Its Unique Pharmacological Profile. Pain Practice. 2010;10(5):428-450.
- FDA warns about dental problems with buprenorphine medicines dissolved … U.S. Food and Drug Administration. https://www.fda.gov/media/155352/download. Published January 12, 2022. Accessed June 8, 2022.
- Huscher A, De Stefani A, Smussi I, et al. Transdermal Buprenorphine for Oropharyngeal Mucositis-Associated Pain in Patients Treated with Radiotherapy for Head and Neck Cancer. J Palliat Med. 2010;13(4):357-358
- Menten J, Carpentier I, Deschutter H, Nuyts S, Van Beek K. The Use of Transdermal Buprenorphine to Relieve Radiotherapy-Related Pain in Head and Neck Cancer Patients. Cancer Invest. 2013;31(6):412-420.
- Vokurka S, Skardova J, Karas M, et al. Oropharyngeal Mucositis Pain Treatment with Transdermal Buprenorphine in Patients After Allogeneic Stem Cell Transplantation. J Pain Symptom Manage. 2010;39(6):e4-e6.
- Russo L, Meliambro N, Ipek S, et al. Prophylaxis of severe oral mucositis with tramadole and buprenorphine in patients with lymphoproliferative diseases undergoing high-dose chemotherapy with autologous haematopoietic progenitor cells rescue: a single centre experience. Bone Marrow Transplant. 2009;43:S358.
- Smith DK, Cmelak A, Niermann K, et al. Preventive use of gabapentin to decrease pain and systemic symptoms in patients with head and neck cancer undergoing chemoradiation. Head Neck. 2020;42(12):3497-3505.
- Bar Ad V, Weinstein G, Dutta PR, Chalian A, Both S, Quon H. Gabapentin for the treatment of pain related to radiation-induced mucositis in patients with head and neck tumors treated with intensity-modulated radiation therapy. Head Neck. 2010;32(2):173-177.
- Starmer HM, Yang W, Raval R, et al. Effect of Gabapentin on Swallowing During and After Chemoradiation for Oropharyngeal Squamous Cell Cancer. Dysphagia. 2014;29(3):396-402.
- Raval R, Richardson M, Kumar R, Mills N, Katulis L, Quon H. Gabapentin Therapy for Prevention and Management of the Pain Syndrome in Oropharyngeal Carcinoma Patients Treated With Radiation: A Retrospective Study. Int J Radiat Oncol Biol Phys.
- Cook A, Modh A, Ali H, et al. Randomized Phase 3, Double-Blind, Placebo-Controlled Study of Prophylactic Gabapentin for the Reduction of Oral Mucositis Pain During the Treatment of Oropharyngeal Squamous Cell Carcinoma. International Journal of Radiation Oncology*Biology*Physics. 2022;112(4):926-937.
- Cerchietti LC, Navigante AH, Körte MW, et al. Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study. Pain. 2003;105(1-2):265-273.
- Saunders DP, Rouleau T, Cheng K, et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer. 2020;28(5):2473-2484.
- Kawashita Y, Koyama Y, et al. Effectiveness of a comprehensive oral management protocol for the prevention of severe oral mucositis in patients receiving radiotherapy with or without chemotherapy for oral cancer: a multicentre phase II, randomized controlled trial. International Journal of Oral and Maxillofacial Surgery 2019; 48(7):857-864.
- Noce CW, Gomes A, et al. Randomized double-blind clinical trial comparing clobetasol and dexamethasone for the topical treatment of symptomatic oral chronic graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20:1163-8.
- Sio TT, Le-Rademacher JG, Leenstra JL, et al. Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial. JAMA. 2019;321(15):1481-1490.
Authors’ Affiliations: 1University of Texas Southwestern Medical Center, Dallas, TX; 2Medical College of Wisconsin, Milwaukee, WI
Conflicts of Interest: The authors have no conflicts of interest to report.
Version History: first electronically published in September 2022
Fast Facts and Concepts are edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin (PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’s content. The full set of Fast Facts are available at Palliative Care Network of Wisconsin with contact information, and how to reference Fast Facts.
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