Inclusion Criteria:
* 18 years of age or older. Because no dosing or adverse event data are currently available on the use of methylnaltrexone in participants \<18 years of age, children are excluded from this study.
* Histologically-confirmed oral cavity squamous cell carcinoma \[(T1-T4, N (any)\] that is amenable to curative-intent surgery
* Able to receive the study drug for at least two weeks preoperatively
* Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
* The effects of methylnaltrexone on the developing human fetus are unknown. For this reason and because methylnaltrexone agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. This includes all female participants, between the onset of menses (as early as 8 years of age) and 55 years unless the participants presents with an applicable exclusionary factor which may be one of the following:
* Postmenopausal (no menses in greater than or equal to 12 consecutive months).
* History of hysterectomy or bilateral salpingo-oophorectomy.
* Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
* History of bilateral tubal ligation or another surgical sterilization procedure.
* Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while her partner participates in this study, she should inform her treating physician immediately.
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Participants who are receiving any other investigational agents.
* Non-English/Non-Spanish speaking participants.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to methylnaltrexone or other agents used in the study.
* Participants with uncontrolled intercurrent illness, including chronic kidney disease defined as a eGRF \<60 ml/mim, and liver disease defined as transaminitis \> 2 folds from normal levels, cirrhosis and hyperbilirubinemia \> 2 folds from normal levels
* Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* Participants with psychiatric illness/social situations that would limit compliance with study requirements.
* Urgent or emergency surgery
* Participants with known distant metastatic disease
* Participants with primary brain tumors or brain metastases. Methylnaltrexone has poor penetration of the blood brain barrier and there is limited available data regarding the safety of the drug in participants with central nervous system tumors.
* Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with methylnaltrexone, breastfeeding should be discontinued if the mother is treated with methylnaltrexone. These potential risks may also apply to other agents used in this study.
* Peptic ulcer or intestinal perforation or colitis or other intestinal disorders such as Crohn's disease, diverticulitis, or Ogilvie's syndrome, intestinal obstruction or severe diarrhea because of risk of intestinal perforation.
* Use of other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.
