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STUDY OBJECTIVE: We compare paracetamol with a combination of paracetamol, ibuprofen, and codeine for pain relief in acute minor musculoskeletal injuries.
METHODS: This was a prospective, double-blind, randomized, active-controlled, parallel-arm study at an urban tertiary hospital emergency department. Participants were aged 18 to 65 years and had acute (<48 hours) closed limb or trunk injuries with moderate pain (greater than 3/10). A single dose of 1 g of paracetamol, 400 mg of ibuprofen, and 60 mg of codeine was compared with a single dose of 1 g of paracetamol, placebo ibuprofen, and placebo codeine. The minimum detectable difference in pain was taken as 1.3.
RESULTS: Baseline characteristics and pain were similar. There were clinically detectable reductions in pain at rest at 60 minutes for paracetamol: -1.6; 95% confidence interval (CI) -2.2 to -1.1); n=59 and the combination -2.0; 95% CI -2.5 to -1; n=59; difference -0.4; 95% CI -1.1 to 0.29; P=.26. At 120 minutes, the reduction in pain was -2.4; 95% CI -3.2 to -1.6 for paracetamol (n=30) and -2.9; 95% CI -3.7 to -2.2 for the combination (n=35); difference -0.5; 95% CI -1.6 to 0.5; P=.32. Rescue analgesia was required by 4 of 59 patients in the paracetamol group and 5 of 60 in the combination group (P>.99). More participants in the combination group had adverse events: 14 of 60 versus 5 of 59 in the paracetamol group, relative risk 2.8; 95% CI 1.1 to 7.2. No adverse events were serious.
CONCLUSION: Combining oral paracetamol, ibuprofen, and codeine as the initial treatment for pain associated with acute musculoskeletal injuries was not superior to paracetamol alone for pain reduction at 60 minutes or need for rescue analgesia, with more adverse events in the combination group.
|Family Medicine (FM)/General Practice (GP)|
|General Internal Medicine-Primary Care(US)|
|Special Interest - Pain -- Physician|
This is intriguing because much has been written about combination OTC and mild opioid analgesia. I think this calls for a systematic review of acetaminophen or equivalents against other comparisons. Too early to close the door on this given the small study sample.
As an emergency physician and anaesthesiologist, I would suspect that the study size and population studied were contributing factors to not finding a difference here as the trends showed the combination therapy (Paracetamol 1 gm Ibuprofen 400mg and codeine 60 mg was trending better (though only slightly) than the Paracetamol 1 gm alone at 60 minutes. Longer assessment interval at 120 min with the whole population even if assessed by phone (as they used a verbal rating scale) may have shown a difference. My personal practice is to often use acetaminophen (North American equivalent of paracetamol) and ibuprofen in combination with good effect after 1-2 hrs in similar patients (mostly upper/lower extremity sprains).
A combination of paracetamol (APAP), ibuprofen and codeine did not have a clinically relevant improvement in pain control in the emergency department versus paracetamol alone. That said, when telling a patient that you are giving them an analgesic that they could have received from their own house (as opposed to a "chance" at getting a study drug that includes codeine), they frequently experience less pain relief - at least in the unblinded setting of clinical care. Also, by probability theory, it is practically guaranteed that providing 3 drugs concurrently will increase the chance of adverse effects (versus one). It would have been interesting if the other combinations were tried (ibu + APAP, ibu + cod, APA + cod) as it is possible that ibu + APAP could have been better since patients would have felt less of the effects of the cod, which is likely to cause the most AE.
Very limited conclusions can be drawn from this small study of acute pain treatment for only the first two hours after treatment was begun. The question is important but needs further research.
We need more comparative studies of analgesics. Fascinating result that 1 gm plain acetaminophen/paracetamol is as effective as 1 gm acetaminophen plus 400 mg ibuprofen plus codeine. We have been sold a bill of goods on NSAIDS ("anti-inflammatory") and narcotics for years.
I find the premise of this study troubling. In my practice I do not use codeine, so I found the combination arm undoable, at least for me. Also, a lot of patients I care for have contraindications to NSAIDs. What I took away from this study is that for MSK injuries, Tylenol works just as well as a somewhat problematic combination of medications.
Interesting study that I would like to see replicated in other emergency rooms.
Highly germane in today's debates on appropriate agents for pain control.
The trial of acetaminophen and ibuprofen version of oxycodone in the ER for acute muscular pain definitely gave the nod to the former, so it is interesting that the codeine in this trial (added to the same meds) was likewise not superior. We need to change the mindset that pain meds are the be-all and end-all. They have side effects as well as non-superiority.
Ask any street-drug purchaser, codeine is a sucky narcotic: little if any analgesia or euphoria, bad side-effects. Not surprised this did not have an additional effect, or that the additional effect was canceled by the negative side effects. There is at least some evidence that paracetamol/acetaminophen + an NSAID is superior to either. In mice: Miranda, H. F., et al. (2006). "Synergism between paracetamol an nonsteroidal anti-inflammatory drugs in experimental acute pain." Pain 121(1-2): 22-28. In humans, if you believe the drug company: Merry, A. F., et al. (2010). "Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial." Br J Anaesth 104(1): 80-88. And a review supports the idea: Ong, C. K., et al. (2010). "Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain." Anesth Analg 110(4): 1170- 1179. But this article adds just a bit to the countervailing hypothesis, as found in: Bondarsky, E. E., et al. (2013). "Ibuprofen vs acetaminophen vs their combination in the relief of musculoskeletal pain in the ED: a randomized, controlled trial." Am J Emerg Med 31(9): 1357-1360., and Dahl, V., et al. (2004). "Ibuprofen vs. acetaminophen vs. ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction." Eur J Anaesthesiol 21(6): 471-475.