POST-OPERATIVE PAIN · White paper
Post-Operative Pain Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About post-operative pain — and why its trials are hard
Post-operative pain (POP) affects nearly all surgical patients, typically peaking in the first 24-48 hours and, if poorly controlled, progressing to chronic post-surgical pain (CPSP). In the U.S. roughly 80% of patients report some post-operative pain and 30-50% experience moderate-to-severe pain early after surgery. Management has shifted from opioid-centric regimens toward multimodal analgesia and Enhanced Recovery After Surgery (ERAS) protocols that combine opioids, NSAIDs, acetaminophen, local/regional anesthesia and adjuncts to spare opioids. This shift is driven by the opioid crisis: landmark work by Brummett and colleagues (JAMA Surgery, 2017) showed roughly 6% of opioid-naive patients develop persistent opioid use after even minor surgery. The approved armamentarium spans opioids (oxycodone, morphine, fentanyl), NSAIDs (ketorolac, ibuprofen, celecoxib), acetaminophen, long-acting local anesthetics such as liposomal bupivacaine (Exparel), and the first-in-class non-opioid NaV1.8 inhibitor suzetrigine (Journavx). Trials are complicated by high placebo response, subjective pain scales, and poor generalizability across surgical models, making SPID-type pain-intensity endpoints and opioid-consumption measures central to registration.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Liposomal bupivacaine (Exparel) | 2011 | Single-dose local infiltration for post-surgical analgesia | Bunionectomy and hemorrhoidectomy pivotal studies; EXCLAIM | AUC of NRS pain intensity through 72 h; opioid consumption | Significant pain reduction vs placebo; ~28% of patients opioid-free post-op vs ~10% placebo |
| Suzetrigine (Journavx) | 2025 | Moderate-to-severe acute pain (non-opioid, selective NaV1.8 inhibitor) | Phase 3 abdominoplasty and bunionectomy studies | SPID48 (sum of pain intensity difference over 48 h) | Statistically superior to placebo on SPID48; not superior to hydrocodone/acetaminophen |
| Acetaminophen (Ofirmev / Tylenol) | 1955 | Mild-to-moderate pain; multimodal component | Hip/knee replacement and laparoscopic surgery pain studies | Pain intensity vs placebo; opioid consumption | Statistically significant greater pain reduction vs placebo; documented opioid-sparing |
| Ketorolac (Toradol) | 1989 | Short-term moderate-to-severe pain (NSAID) | Registration analgesia studies | Pain intensity difference / rescue analgesia | Potent short-term NSAID analgesia; opioid-sparing (exact placebo-corrected value unverified) |
| Oxycodone (controlled-release) (OxyContin) | 1995 | Moderate-to-severe post-surgical pain (opioid) | NCT00271973 and registration studies | Pain reduction vs placebo | 20 mg significantly superior to placebo; 10 mg not significant; later REMS added for abuse risk |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in post-operative pain development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| VX-128 (NaV1.8 inhibitor) — Phase 1 (Vertex) | Development discontinued in 2018 after underwhelming efficacy/clinical outcomes | Insufficient effect; program redirected to VX-548 (suzetrigine) |
| Remoxy (extended-release oxycodone) — Multiple FDA submissions | Rejected repeatedly; program abandoned | Manufacturing issues, unproven abuse-deterrent effectiveness and safety concerns |
| Gabapentin (pre-emptive, single dose) — NCT02359110 (gynecologic laparoscopy) | Single pre-operative dose did not significantly reduce post-operative pain | Inconsistent opioid-sparing; not FDA-approved for POP, used off-label in multimodal regimens |
Choosing the right endpoint
Primary endpoints that matter in post-operative pain trials
- SPID (Sum of Pain Intensity Differences) — Primary efficacy anchor over a defined window (often 0-48 h); depends on subjective VAS/NRS scales, mitigated with validated instruments
- Total opioid consumption — Objective co-primary/key secondary endpoint reflecting opioid-sparing; confounded by variable metabolism and rescue protocols
- Time to first rescue analgesia — Indicates durability of the primary analgesic; requires strict, pre-specified rescue criteria to reduce variability
- Rescue analgesia requirement — Fewer rescue doses signal effective primary control; interpretation improved by stratifying patients by baseline pain
- Incidence of adverse events (e.g. respiratory depression) — Safety endpoint central to non-opioid value propositions; needs standardized AE classification and reporting
How iNGENū runs post-operative pain trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
The full white paper: approved-product analyses, pivotal endpoints and trial-design strategy. Open-access · no sign-in.
Frequently asked questions
Post-Operative Pain clinical trials — FAQs
What is the primary efficacy endpoint in post-operative pain trials?
Is there a new non-opioid option for acute surgical pain?
Why do so many post-operative pain drugs fail in trials?
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