This phase III trial tests if gabapentin can prevent the need for opiate pain medication for mouth sores (oral mucositis) in patients undergoing treatment with chemotherapy and radiation for squamous cell carcinoma of the head and neck region. Oral mucositis is a common side effect of radiation treatment and can cause severe pain, dysphagia, and weight loss resulting in feeding tube placement, worse health-related quality of life, treatment interruptions, unplanned hospitalizations, and significant financial burden. Mucositis pain is often treated with opioid pain medications which do provide pain relief but have many known side effects not limited to mental clouding, constipation, fatigue, endocrinopathy, neurotoxicity, sleep-disordered breathing, and most distressingly persistent opioid use. Gabapentin may help relieve pain from oral mucositis caused by radiation while also reducing the need for opiate pain medications for patients receiving chemotherapy and radiation for squamous cell carcinoma of the head and neck region

PRIMARY OBJECTIVE: I. To determine whether prophylactic high dose gabapentin, titrated to a dose of 3600 mg (1200 mg three times per day \[TID\]), is superior to placebo in increasing the proportion of patients not needing opiates while undergoing chemoradiation therapy. SECONDARY OBJECTIVES: I. To determine whether prophylactic high dose gabapentin is superior to placebo in prolonging the time to first opioid use while undergoing chemoradiation therapy. II. To determine whether prophylactic high dose gabapentin is superior to placebo in improving patient reported pain scores using the 0-10 numerical rating scale (NRS) from baseline to 4 weeks after the end of chemoradiation therapy. EXPLORATORY OBJECTIVES: I. To explore the duration of opioid use from the time of initiation to cessation by arm as well as describe the proportion of patients remaining on opioids at 3 months, 6 months, and 1 year by arm. II. To explore the trajectory of patient reported symptom and quality of life outcomes using the Oral Mucositis Weekly Questionnaire (OMWQ) by arm. III. To explore the trajectory of patient reported symptom and quality of life outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-30) by arm. IV. To explore the trajectory of patient reported symptom and quality of life outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck-43 (EORTC QLQ-H\&N43) by arm. V. To evaluate the adverse event profiles of prophylactic high dose gabapentin versus placebo. VI. To assess the tolerance of high dose gabapentin. VII. To explore the trajectory of patient health using patient body mass index (BMI) and creatinine, absolute neutrophil count (ANC) as routinely obtained by arm. VIII. To describe the incidence of feeding tube requirement during and after chemoradiation therapy by arm. IX. To describe the dose of prescribed opioids standardized using the Morphine Milligram Equivalent calculator by arm. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Starting by radiation treatment 8, patients receive placebo orally (PO) once daily (QD) on day 1, twice daily (BID) on day 2, then three times daily (TID) starting day 3 onward. Patients also receive standard of care radiation, chemotherapy and pain medications. Treatment with placebo continues in the absence of disease progression or unacceptable toxicity, until the symptoms of oral mucositis and other treatment effects begin to resolve and other pain medications has been stopped. Patients then continue to receive placebo TID for 9 additional days, at sequentially smaller doses, then BID for 1 day and QD for one day before stopping. Patients undergo blood sample collection throughout the study. ARM II: Starting by radiation treatment 8, patients receive gabapentin PO QD on day 1, BID on day 2, then TID starting day 3 onward. Patients also receive standard of care radiation, chemotherapy and pain medications. Treatment with gabapentin continues in the absence of disease progression or unacceptable toxicity, until the symptoms of oral mucositis and other treatment effects begin to resolve and other pain medications has been stopped. Patients then continue to receive gabapentin TID for 9 additional days, at sequentially smaller doses, then BID for 1 day and QD for one day before stopping. Patients undergo blood sample collection throughout the study. After completion of study treatment, patients are followed up at 4 weeks, 3 months and 6 months after the last dose of chemoradiation therapy.