PANSAID – Acetaminophen and Ibuprofen post THA
Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty: The PANSAID Randomized Clinical Trial.
Thybo KH, Hägi-Pedersen D, Dahl JB, et al.
JAMA. 2019 Feb 12;321(6):562-571. [Full Text]
Multimodal or combination pain management is generally thought to be more effective than single agent and is potentially opioid sparring. However, commonly available over the counter agents such as acetaminophen (also known as paracetamol) or NSAIDs are often not utilized in settings where their analgesic effect is perceived to be insufficient or because of concerns for side effects. NSAIDs specifically have cardiovascular and renal toxicities, and are perceived to increase bleeding risk or affect wound healing. In the case of fractures, NSAIDs are specifically associated with non-union with prolonged use [1].
The PANSAID trial was a small study designed to assess acetaminophen and ibuprofen use post-operatively (post-op) to determine if either or the combination could be opioid sparring or if there were any associated increased side effects with their use. While the scope of PANSAID was limited to post-op total hip arthroplasty (THA), it represents a body of literature growing in the wake of the opioid crisis exploring non-opioid analgesia.
Patient Population and Design
Patients aged > 18 that were scheduled for unilateral, primary THA were recruited from 6 hospitals in Denmark. They had to been functionally ASA class 1-3 and have a BMI < 40. Patient on daily opioids (not tramadol and codeine) or that had previous ulcer, heart failure, liver failure, or renal failure, or known thrombocytopenia were excluded.
Patients were randomized 1:1:1:1 into 4 groups of medication combination and dose as shown below. Trial medications were given starting 1 hour before surgery and then every 6 hours for 24hours for a total of 4 doses.
- Full dose acetaminophen + ibuprofen (1000 mg + 400 mg)
- Acetaminophen (1000 mg) + placebo
- Ibuprofen (400mg) + placebo
- Half dose acetaminophen + ibuprofen (500 mg + 200 mg)
All participants had PCA morphine (no basal, bolus 2 mg, lock-out Q10 min). No pain medication (including peripheral regional anesthesia) other than the trial medication and the PCA morphine was allowed.
Outcomes and Safety Measures
The trial had 2 co–primary outcomes: total morphine consumption for the first 24 hours post-op and proportion of patients with 1 or more adverse events (AEs) from the surgery out to 90 days post-op. Particular attention to ibuprofen AEs was taken and the three groups that received some ibuprofen was compared to the acetaminophen only group. The AEs at 90 days were obtained via phone interviews and patient self report. A secondary outcome was pain scored on a visual analog scale from 0 (no pain) to 100 during 30° flexion of the hip and at rest at 6 and 24 hours.
Results
A total of 559 patients was enrolled with 136, 142, 141, and 140 patients per groups 1-4, respectively. The groups were similar at baseline.
Median 24-hour morphine consumption for the four groups was: (1) 20 mg, (2) 36 mg, (3) 26 mg, and (4) 28 mg. The 16 mg difference of morphine within 24 hours between the full dose acetaminophen + ibuprofen (#1) and the acetaminophen only group (#2), was the only significant difference that the authors thought was clinically meaningful, P < .001. The other differences of 10 mg and 8 mg were not thought to be as clinically meaningful.
The overall proportion of patients with 1 or more AE by 90 days post-op was 14% and these were not significantly different between those that received any ibuprofen to any acetaminophen. At 24 hours, the acetaminophen plus ibuprofen group had lower pain scores than all other groups.
Discussion
In the first 24 hours after THA, the PANSAID study suggests the combination of acetaminophen and ibuprofen is opioid sparring (by 16 mg morphine equivalents) relative to using acetaminophen alone. The 10 mg morphine equivalents difference between the ibuprofen alone and acetaminophen alone group was not thought to be clinically significant, even though it was statistically significant.
Perhaps there is less hesitancy to add acetaminophen to pain regimens than there is for NSAIDs. But at the same time the effectiveness of acetaminophen in pain management is also supported by mixed evidence. For example, in chronic hip and knee osteoarthritis, the effect on pain and function seems to be minimal [2].
In contrast, NSAIDs may be considered more effective but typically concern for AEs are the limiting factor. Yet these risk of adverse effects may be lower than perceived, especially over short periods. In a retrospective of high risk outpatients (HTN, CHF, CKD), the use of NSAIDs was not associated with adverse outcomes [3]. In the case of post operative fracture pain management, NSAIDs were not associated with non-union as long as use is limited to < 3 weeks [1]. And in PANSAID, no significant AEs were noted at 90 days post-op. Again, while there results cannot be extrapolated to all situations and conditions, perhaps providers should give a little more consideration to utilizing short courses of NSAIDS (after carefully considering risk factors and with good monitoring) for acute pain management.
| F: Follow up | 24 hours post-op then 90 day phone follow-up |
| R: Randomization | Yes |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | DASAIM, Sophus Johansens Fond, Region Zealand Health Scientific Research Foundation, the local research foundation at Næstved-Slagelse-Ringsted Hospitals, the A.P. Møller Foundation for the Advancement of Medical Science, Aase og Ejnar Danielsens Fond, and the Grosserer Christian Andersen og Hustru Ingeborg Andersen, f. Schmidts legat (fund) |
- Kim H, Kim DH, Kim DM, et al. Do Nonsteroidal Anti-Inflammatory or COX-2 Inhibitor Drugs Increase the Nonunion or Delayed Union Rates After Fracture Surgery?: A Propensity-Score-Matched Study. J Bone Joint Surg Am. 2021 Aug 4;103(15):1402-1410.
- Leopoldino AO, Machado GC, Ferreira PH, Pinheiro MB, Day R, McLachlan AJ, Hunter DJ, Ferreira ML. Paracetamol versus placebo for knee and hip osteoarthritis. Cochrane Database Syst Rev. 2019 Feb 25;2(2):CD013273.
- Bouck Z, Mecredy GC, Ivers NM, et al. Frequency and Associations of Prescription Nonsteroidal Anti-inflammatory Drug Use Among Patients With a Musculoskeletal Disorder and Hypertension, Heart Failure, or Chronic Kidney Disease. JAMA Intern Med. 2018 Nov 1;178(11):1516-1525.
