This is a single-center, randomized, open-label, Phase 4 clinical trial investigating the efficacy of multiple-dose administrations of Pregabalin or Gabapentin in combination with traditional opioid pain medications to decrease the amount of opioid pain medication usage in single-system orthopedic trauma patients.

Patients included in this trial were admitted under the care of the Trauma Nurse Practitioners (TNPs) who lead management of these patients. The TNP service is a 24/7 model where TNPs admit and manage patients under the trauma attending doctors from patient arrival in the emergency department until discharge, unless a higher level of care is indicated. The TNP patient census was monitored to identify new admissions who met the study criteria. Eligibility for participation was determined based on pre-established inclusion and exclusion criteria . Over the course of the trial, three changes were made to the eligibility criteria. To increase enrollment, the inclusion age range was revised from 18-70 years to 18 years and older. Additionally, the enrollment window was adjusted from 24 hours to 36 hours to facilitate the inclusion of patients admitted over the weekend. Receipt of a peripheral nerve block was also added to the exclusion criteria due to its potential to influence reported pain levels.

Patients included in the study were divided into 3 groups: pregabalin, gabapentin, and a control group receiving neither treatment. An SPSS algorithm using simple randomization was employed to generate a randomization list and assign patients to one of three groups. A sample size of 70 patients per study group (total of 210 patients) including 10% attrition was targeted. The sample size was determined based on Cohen's d formula using a power of 80%, a medium effect size indicating a 69% difference between groups. Effect sizes were calculated for planned comparisons (pregabalin vs. gabapentin, pregabalin vs. neither pregabalin nor gabapentin, gabapentin vs. neither pregabalin nor gabapentin) using t-statistics. An interim analysis was conducted after enrollment reached approximately 25% of the projected sample size to evaluate the study progress.

Enrollment and consenting of participants were performed by the research coordinators. Upon obtaining informed consent, participants were randomized sequentially to one of the three study arms by the coordinators, using the pre-generated randomization list. Enrolled patients were informed of their study arm and the TNP's initiated study drugs accordingly. Participants were followed throughout their hospital stay and remained in the study for a duration of seven days or until discharge, whichever occurred first. Patients underwent no additional cost for participating in the study as both pregabalin and gabapentin were frequently used as adjunct analgesia in this patient population at the study institution. Standard of care remained the same regardless of study participation. Patients were removed from the study if they were transferred to a higher level of care requiring a different service line.

For dosing purposes, patients with creatinine clearance (CrCl) greater than 60 ml/min received 50 mg of pregabalin every 8 hours in the pregabalin group or 300 mg of gabapentin every 8 hours in the gabapentin group. Those with CrCl less than or equal to 60ml/min received the same dose given every 12 hours, and the regimen was changed to every 8 hours if their CrCl increased above 60ml/min while enrolled. Creatine clearance was monitored daily during hospital course with dosage adjustments as necessary.

For this study, pain scores documented by nursing staff when patients requested additional pain medications were included. Pain scores were based upon a standard Numeric Rating Scale (0 = "no pain", 10 = "worst pain imaginable"). Patients who were already using prescription narcotics were eligible to participate and were continued on their home regimens as deemed necessary by providers. Adjunct non-opioid analgesia was administered at the discretion of the managing service. In-hospital narcotic exposure was ascertained by examining total amount of narotics administered in oral Morphine Milligram Equivalents (MME).

Data were collected via patient chart review and from the institution's trauma registry. Baseline patient characteristics extracted included age, gender, body mass index (BMI), days of enrollment, time from enrollment to first study drug administration, presence of rib fracture, timestamp of surgical intervention if applicable, prescription narcotics upon admission and comorbidities. Primary outcome measures included daily opioid intake during enrollment. Secondary outcomes included daily non-opioid analgesic intake, documented pain scores, post-enrollment complications (unplanned ICU admission or intubation), and daily incentive spirometry values for those with rib fractures. Additionally, adverse events such as somnolence, dizziness, fatigue, ataxia, tremor, amnesia, etc. were also monitored.

Inclusion Criteria:

1. Nurse Practitioner service admissions
2. 18 years of age or older
3. Patients enrolled within 36 hours of admission
4. Anticipated duration of hospitalization > 24 hours from time of consent
5. Active order(s) for opioids in place at the time of enrollment

Exclusion Criteria:

1. Clinician discretion based on patient care management
2. Intubated patients
3. Patients with epidural
4. Patients with pregabalin/gabapentin as home medications
5. Patients receiving pregabalin/gabapentin upon admission
6. Traumatic brain injury patients
7. CrCl<30ml/min or on HD
8. Unable to take enteral medications
9. On Patient Controlled Analgesia (PCA)
10. Patients with complicated wound closure
11. History of epilepsy
12. Documented history of substance use disorder

Up to 7 days or discharge, whichever occurred first

Study coordinators monitored charts for any adverse events post enrollment for 7 days or until discharge, whichever occurred first. These were reported to the PI and classified as serious or not, and reported to the IRB accordingly. Most were felt to be unrelated to study drugs. Only those reported as dizziness, somnolence or confusion were felt to possibly be related and study medications were stopped. All adverse events resolved prior to discharge.

The estimated sample size was not attained due to organizational implementations of specified multi-modal regimens. The limited sample size may have rendered the study underpowered to detect significant effects and constrained the generalizability of the study findings. Inconsistences existed in gabapentinoids being initiated perioperative versus post-operatively. Pain scores were only collected at time of opioid medication requests not comprehensively.