Study Design and Ethics
This was a phase 3, multicenter, randomized, double-blind, three-arm study to evaluate the safety, tolerability, and efficacy of IV tramadol (tramadol hydrochloride) versus placebo and IV morphine (morphine sulfate) in the management of postoperative pain following abdominoplasty, a soft-tissue surgical model involving skin, muscle, and adipose tissue. All three study sites were located in the US. Patients were randomized in a 3:3:2 ratio to IV tramadol 50 mg, placebo, or IV morphine 4 mg. Study drugs were administered at baseline, hour 2, hour 4, and every 4 h thereafter through to hour 44.
Potentially equipotent doses of IV tramadol and IV morphine were chosen based on published data that support a 10:1 to 15:1 tramadol/morphine efficacy ratio [10,11,12,13,14,15,16,17]. The total amount of IV morphine administered was 28 mg on day 1 and 24 mg on day 2, similar to doses utilized in other comparable studies [18, 19].
In order to maintain the blind for study purposes, patients received both an IV infusion and an IV push at each dosing time point, with IV tramadol administered as a 15-min infusion and IV morphine 4 mg administered as an IV push, per usual clinical practice. Placebo IV infusion and IV push were also used to maintain the blind.
The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonization (ICH)/Good Clinical Practice (GCP) guidelines, applicable regulatory requirements, and the sponsor or its delegate’s policy on bioethics. Aspire institutional review board (Santee, CA) reviewed the study protocol and informed consent forms. The study was registered at ClinicalTrials.gov (December 13, 2018; trial number NCT03774836), with the first patient enrolled on December 14, 2018 and the last patient completing the study on May 6, 2019.
The primary endpoint was the sum of pain intensity differences over 24 h (SPID24), and the key secondary outcomes were Patient Global Assessment (PGA) at 24 h, SPID48, and total rescue medication used through 24 h. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital signs, and electrocardiograms (ECGs).
Study Treatment and Eligibility
Male and female subjects between the ages of 18 and 75 years with an American Society of Anesthesiologists (ASA) classification of I or II undergoing abdominoplasty were enrolled. The surgical protocol consisted of a low transverse abdominal incision, infra-umbilical fascial plication, and unilateral or bilateral drain placement. Each site followed a study-specific surgical and anesthetic protocol to reduce variability. Patients were housed in a healthcare facility and were to receive parenteral analgesia for at least 48 h after surgery. Patients with clinically significant disease or conditions that might have created an unacceptable risk were excluded. Other exclusion criteria included known physical dependence on opioids and the use of any opioids (including tramadol) within the past 30 days prior to surgery. Post-surgical eligibility required patients report a score of moderate or severe on a 4-point categorical rating scale (with categories of none, mild, moderate, and severe) and have a Numerical Pain Rating Scale (NPRS) pain score of ≥ 5 (on a scale from 0 to 10, where higher scores indicate worse pain) within 3 h after the end of surgery and an NPRS score of ≥ 5 at baseline (T0). Each patient underwent screening, a pre-operative assessment within 24 h prior to surgery, the surgical/treatment visit, assessment through to hour 48, and assessment at the follow-up visit (day 7).
Pain intensity assessments were recorded immediately prior to the first dose (baseline, T0) and at frequent intervals through to 48 h after the first treatment. PGA was assessed by asking “How would you rate the study medication in terms of its effectiveness in controlling your pain?” (0 = poor; 1 = fair; 2 = good; 3 = very good; 4 = excellent).
Statistical Methods
A sample size of 360 patients (135 each in the tramadol and placebo groups and 90 in the morphine group) was planned, to provide over 90% power to detect an SPID24 difference of 15 between placebo and tramadol, assuming a common SPID24 standard deviation (SD) of 38 (40% effect size) and an alpha of 0.05 using a two-sided analysis of covariance (ANCOVA) testing mean differences. Ninety patients in the morphine group allowed for at least 80% power to detect a 20% absolute difference between tramadol and morphine in the incidence of each individual preferred term of opioid-related adverse events (ORAEs).
The full analysis set (FAS) population was defined as all randomized patients who received at least one dose of study medication. Patients were analyzed according to the treatment group they were randomized to. The safety population was defined as all patients who received study medication. Patients were analyzed according to the actual treatment they received. There was one patient randomized to placebo who received a single dose of IV tramadol 50 mg and thus was included in the tramadol 50 mg arm for the purposes of the safety assessment.
Assessment of Efficacy
All SPID calculations were performed using the standard trapezoidal rule:
$${\text{SPID}} = \mathop \sum \limits_{i = 0}^{x} \left( {\frac{{{\text{PID}}_{i} + {\text{PID}}_{i + 1} }}{2}} \right)* \left( {T_{i + 1} - T_{i} } \right)$$
where PIDi = the pain intensity difference (PID) at time i, and (Ti+1 − Ti) is the time difference in hours between time i and time i + 1. Multiple imputation (Rubin 1976) [30] was used to impute for missing pain scores. Specifically, for the primary endpoint (SPID24), 100 imputed datasets were created, with data imputation for missing values due to missingness at random as well as due to discontinuation due to adverse events (AEs) or lack of efficacy (missing, not at random) and to account for use of rescue medication (the last NPRS score prior to the use of any rescue medication was used to impute subsequent NPRS scores for the subsequent protocol-specified time points for measurement of pain intensity through to 4 h after the dosing of the rescue medication). The 100 imputed datasets were analyzed using an ANCOVA model with treatment as the main effect and study center, baseline body mass index (BMI) (< 30 kg/m2 vs ≥ 30 kg/m2), and baseline NPRS score as covariates (these covariates were prespecified for the model to account for any possible end-of-study imbalances among the treatment groups).
The PGA at hour 24 and hour 48 was assessed for treatment-group differences using an ANCOVA with pooled study center, BMI, and the baseline pain score as covariates. Total consumption of rescue medication (Advil 400 mg) was calculated as the total amount of rescue analgesia (milligrams) captured in the Rescue Medications electronic case report form (eCRF) and recorded as given to the patient between the first dose of study medication through to 24 h after the first dose. The total consumption of rescue analgesia was analyzed using the nonparametric Wilcoxon rank sum test to test each active versus placebo comparison separately.
Alpha Control
All inferential assessments were two-sided tests performed at the 0.05 alpha level unadjusted for multiple comparisons. A hierarchical alpha testing strategy was utilized to control for the overall experiment-wise alpha for the tramadol versus placebo comparison (the comparisons to morphine were exploratory only, and thus no adjustments were made for those comparisons). As there were multiple tests being performed (the single primary efficacy variable pairwise test and the three key secondary efficacy tests), the following strategy was applied. If the primary efficacy endpoint, SPID24, was significant for the tramadol versus placebo comparison (in favor of the tramadol arm), then statistical testing was to proceed to the tramadol key secondary endpoints, to be tested in the following order:
If the statistical test was a significant comparison at the nominal 0.05 level and two-sided (in favor of the tramadol arm) for the first endpoint, then testing was to proceed to the next endpoint in the list, and so on. Once a non-significant test occurred, endpoints lower in the list were to be considered not statistically significant. All analyses were performed using the SAS System® version 9.4.
Assessment of Safety
The incidence of TEAEs was summarized for each treatment group by Medical Dictionary for Regulatory Authorities (MedDRA) system organ class (SOC) and preferred term.
This study was designed to carefully assess the relative safety and tolerability of IV tramadol versus morphine, with specific pre-defined safety outcomes for ORAEs (bradypnea, constipation, dizziness, dizziness postural, hypoxia, respiratory disorder, nausea, somnolence, sedation, vomiting, pruritus, and pruritus generalized), TEAEs potentially related to substance abuse (defined as indicated in the FDA guidance “Assessment of Abuse Potential of Drugs Guidance for Industry: January 2017”), gastrointestinal TEAEs (that are often associated with opioid treatment, including nausea, grade 2 nausea, vomiting, and use of antiemetics for nausea). Local tolerability of the infusion site was also assessed. Respiratory impairment (RI) was defined as a clinically relevant worsening of respiratory status—taking into account selected safety parameters such as respiratory rate, oxygen saturation, and somnolence/sedation.