This study will compare the effects of oral pregabalin with placebo on postoperative pain and morphine usage after mastectomy.

Pregabalin is an anticonvulsant agent approved by the United States Food and Drug Administration (FDA) for the treatment of neuropathic pain associated with post-herpetic neuralgia and diabetic neuropathy.

Women 18-70 years of age, undergoing unilateral modified mastectomy or lumpectomy with axillary node dissection will be recruited to participate in the study. Patients unable to cooperative, those that have known allergy to pregabalin or morphine and a history of drug or alcohol abuse, chronic pain, history of daily intake of analgesics or steroids, or impaired kidney function will all be excluded from the study. A pregnancy test will also be performed to exclude pregnant women from the study.

Oral pregabalin 300 mg (or placebo) will be administered to patients 1-2 hours before surgery followed by 150 mg 12 hours later. Thereafter, 150 mg of oral pregabalin (or placebo) will be administered twice daily until day 14. Whether a patient receives pregabalin or placebo will be decided based on a process similar to tossing a coin.

Patients will receive a standard general anesthetic for their operation and will receive intravenous patient-controlled analgesia (PCA) morphine for pain in the immediate postoperative period. Oral opioids will be administered after discontinuation of the PCA.

Subjects will be visited after the operation while in the hospital and intermittently for three months at the outpatient clinic after discharge from the hospital. Subjects will be asked to return remaining study drug/empty container when they are at the hospital for their 2 week follow up visit.

Potential adverse effects of pregabalin include dizziness, somnolence, peripheral edema, weight gain, headache, dry mouth, blurry vision, and ataxia. The incidence of these side effects occurring ranges variously between 1 and 25%. Investigators will closely monitor all patients for the occurrence of these side effects.

TITLE: The Effects of Oral Pregabalin versus Placebo on Postoperative Pain and Morphine Consumption after Mastectomy

INVESTIGATOR: Babatunde O. Ogunnaike, MD. Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Texas

RATIONALE: In recent years, persistent pain after surgical procedures has been recognized as a major factor delaying recovery and return to normal daily living. Long-lasting pain has been reported after numerous surgical procedures including mastectomy. The prevalence of persistent post-mastectomy pain has been quoted to be anywhere from 40% to 80% and may substantially impact the life of patients treated for cancer (Smith et al. Pain 1999; 83: 91-5). Peripheral and central sensitization after tissue and nerve injury have been implicated in the development of more intractable pain that potentially can become chronic (Joshi & Ogunnaike, Anesthesiology Clin N Am 2005; 23: 21-36) Gabapentin, an anticonvulsant widely used for the treatment of chronic pain, has been shown to decrease neuropathic pain (Rice & Maton, Pain 2001; 94: 215-24) Dirks et al. (Anesthesiology 2002; 97: 560) reported that gabapentin 1200 mg prior to surgery reduced postoperative morphine requirements and movement-related pain after radical mastectomy. However, the immediate as well as long-term benefits of the drug were not evaluated in their study. Fassoulaki et al. (Anesth Analg 2002; 95: 985-91) also observed that pain at rest and movement pain were both reduced by gabapentin in the early postoperative period. Pregabalin is a new anticonvulsant agent recently approved by the FDA for the treatment of neuropathic pain associated with post-herpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN) [Gajraj NM. Pain Practice 2005; 5: 95-102]. This study is designed to evaluate the analgesic efficacy of pregabalin after mastectomy.

OBJECTIVES:

Primary: To evaluate the effects of pregabalin on postoperative opioid requirements and opioid-related side effects Secondary: To evaluate the effects of pregabalin on pain scores at 3 months after mastectomy.

INCLUSION CRITERIA:

1. Women 18-70 years of age
2. American Society of Anesthesiologists (ASA) physical status I to III
3. Undergoing unilateral modified radical mastectomy or lumpectomy with axillary node dissection

EXCLUSION CRITERIA:

1. Patients unable to cooperate
2. Allergy to pregabalin or morphine
3. History of drug or alcohol abuse
4. Chronic pain
5. Daily intake of analgesics or steroids
6. Impaired kidney function

OTHER THERAPY: IV-PCA morphine for rescue pain management in the immediate postoperative period and oral opioids after discontinuation of IV-PCA. Patients will be started on morphine PCA at a dose of 1 mg every 10 minutes for a maximum possible total dose of 6 mg per hour. This dose of morphine can be increased at the discretion of the treating physician. Transition to oral opioid hydrocodone/acetaminophen (5 mg/500 mg) will begin at 8 am on postoperative day 1 at a dose of 1 tablet every 4 hours as needed for pain. Total dose of morphine and the total number of tablets of hydrocodone/acetaminophen will be recorded immediately prior to discharge.

STUDY DESIGN: Phase III, randomized, double-blind, placebo-controlled study.

STUDY DRUG REGIMENS: Oral pregabalin 300mg (or placebo) will be administered to patients 1-2 hours before surgery followed by 150mg 12 hours later. Thereafter, 150mg of oral pregabalin (or placebo) will be administered twice daily until day 14.

DURATION OF STUDY: Patients will be followed for 3 months (90 days)

VISIT FREQUENCY: Patients will be visited daily while in hospital and followed daily postoperatively via telephone for 1 week and thereafter on postoperative days 14, 30, and 90 approximately. After discharge home, patients will be contacted by telephone to record pain assessments. The patient will be asked to return remaining study/drug empty container at the hospital when she comes in for her 2 week follow up visit with the surgery oncology clinic.

SAMPLE SIZE: Based on previous studies, a 30% reduction in opioid use is considered to be clinically relevant, with a type 1 error of 5% and a power of 90%, 40 patients will be required in each study group.

EFFICACY MEASURES:

1. Pain scores (VAS) and categorical
2. Morphine consumption (IV-PCA and oral opioid dosage)
3. Side effects rated using the symptom distress questionnaire, which includes measure of frequency, intensity, and bothersomeness evaluated on a four-point verbal scale (none, mild, moderate, severe).
4. Modified Brief Pain Inventory - short form (mBPI - sf)

PATIENT SAFETY PROCESS AND MONITORING:

Safety assessments would include monitoring of adverse events, the occurrence, nature, intensity, and relationship to the study drug. Clinical experience with a group-related drug (gabapentin) and results from clinical trials with pregabalin supports the notion that pregabalin is very well tolerated with minimal side effects including, headache, dizziness, somnolence, blurring of vision, weight gain, and peripheral edema. Patients would be specifically questioned about these side effects and any other unanticipated occurrences during clinic visits and over the telephone. Patients would be advised to avoid consumption of alcohol which may potentiate the sedative effects of pregabalin. Patients that may be on central nervous system depressants such as opiates or benzodiazepines would be informed that they may experience additive central nervous system (CNS) effects such as somnolence. Patient who may become pregnant will be advised to notify the investigators so that they may be removed from the study.

REPORTING ADVERSE EVENTS Definition An adverse event is any condition, which appears or worsens after participation in the study. All adverse events will be noted on the Adverse Reaction Case Report Form, whether or not it is felt to be related to the trial activities.

Severity

Whenever possible adverse events will be graded by a numerical score according to the defined Toxicity Grading Scale (NCI's Common Toxicity Criteria). Adverse events not included in the defined toxicity Grading Scale will be scored on the Adverse Reaction CRF according to their impact on the subject's ability to perform daily activities as follows:

Mild (causing no limitation of usual activities) Grade 1 Moderate (causing limitation of usual activities) Grade 2 Severe (causing inability to carry out usual activities) Grade 3

Serious Adverse Events

International Conference on Harmonisation (ICH) Guideline E6 defines a serious adverse event as those events which meet any of the following criteria:

• Fatal
• Immediately life-threatening
• Results in inpatient hospitalization or prolongation of existing hospitalization
• Results in persistent or significant disability/incapacity
• Results in a congenital anomaly/birth defect

Follow-up All adverse events will be followed up according to good medical practices.

Adverse Event Reporting All adverse experiences occurring during participation in the trial will be reported on the Adverse Reaction form in the subject's Clinical Research File (CRF) binder. The nature of each adverse event, date and time of onset, outcome, intensity and action taken will be established. Details of any corrective treatment will be recorded on the appropriate pages of the CRF binder.

Any adverse event that is serious and unexpected will be reported within two days to the Simmons Comprehensive Cancer Center Data and Safety Monitoring Committee, the UT Southwestern Institutional Review Board, the UTSW Medical Risk Management Office, and the Study Sponsor (DoD).

Institutional Review Board: 214-648-3060 UT Southwestern Medical Risk Management Office: 214-648-6905 SCCC DSMC: 214-648-1906

Data and Safety Monitoring Plan

This protocol falls under the purview of The Simmons Comprehensive Cancer Center (SCCC) Data and Safety Monitoring Committee (DSMC). Data and safety monitoring will be conducted as described in the SCCC Operations Manual which is available on request. Briefly, The data and safety monitoring plan at the University of Texas Southwestern Medical Center (UTSW) Simmons Comprehensive Cancer Center is designed to ensure that the safety and data quality for clinical trials involving patients with cancer or trials for cancer control, screening or prevention, meet the requirements of UTSW, the SCCC, the UTSW Institutional Review Board (IRB), the National Cancer Institute (NCI) as well as local, state and federal regulations. The Data and Safety Monitoring Committee (DSMC) is an independent committee appointed by the Director of the Cancer Center and is responsible for carrying out the data and safety monitoring plan. The plan mandates daily monitoring of all Severe Adverse Events (SAE) reported in conjunction with trials conducted through the SCCC Clinical Research Office. Accrual and adverse events (not serious) are reviewed quarterly. The DSMC has the authority to recommend suspension of closure of a trial for safety or performance issues.

Inclusion Criteria:

1. Women, 18-70 years of age
2. ASA physical status I to III
3. Undergoing unilateral modified radical mastectomy or lumpectomy with axillary node dissection

Exclusion Criteria:

1. Patients unable to cooperate
2. Have known allergy to pregabalin or morphine
3. A history of drug or alcohol abuse
4. History of chronic pain
5. Daily intake of analgesics or steroids
6. Impaired kidney function

90 days after mastectomy