Combining Morphine With Acetaminophen for Postsurgical Pain

Alex Macario, MD, MBA


January 14, 2014

Median Effective Dose (ED50) of Paracetamol and Morphine for Postoperative Pain: A Study of Interaction

Zeidan A, Mazoit JX, Ali Abdullah M, Maaliki H, Ghattas T, Saifan A
Br J Anaesth. 2014;112:118-123

Study Summary

Anesthesia practice today has largely eliminated serious adverse events in healthy patients who are having routine surgery. As a result, current practice and clinical quality improvement are increasingly focused on reducing more common postoperative outcomes, such as pain and nausea.

In fact, among the cardinal principles that we teach to trainees is that multimodal analgesia -- the practice of administering multiple agents to reduce pain -- is preferable to using a single analgesic at higher doses in the postoperative setting. The underlying theory is that combining lower doses of analgesic drugs that target different mechanisms or receptors increases efficacy and minimizes overall adverse effects.

In this clinical trial of 90 healthy patients (American Society of Anesthesiologists physical status score 1 or 2) undergoing inguinal hernia repair, appendectomy, varicocelectomy, anal fistulotomy, breast lump resection, or a minor orthopedic surgical procedure, pain levels were assessed in the recovery room with a numerical rating scale from 0 (no pain) to 10 (worst imaginable pain). As soon as the patient reported a pain score higher than 3 out of 10, the patient was randomly assigned to 1 of 3 groups:

  • The acetaminophen (paracetamol) group received an initial dose of 1.5 g acetaminophen intravenously, with subsequent dose adjustments in 0.5 g increments;

  • The morphine group received 5 mg intravenously, with dose adjustments of 1 mg; and

  • The acetaminophen/morphine combination group received initial intravenous doses of 1.5 g acetaminophen and 3 mg morphine, with dose-adjustment increments of 0.25 g for acetaminophen and 0.5 mg for morphine.

The investigators calculated the effective dose in 50% of patients (ED50) for analgesic efficacy (defined as achieving a pain score ≤ 3 on a scale of 0 to 10) for acetaminophen only, morphine only, and the combination of acetaminophen and morphine. Clinically, a pain score of 3 or less after surgery is considered to reflect adequate analgesia.

The ED50 was determined using the Dixon and Mood up-and-down technique. With this technique, a first dose is given to the first patient. and the second dose is given according to the following rule: If the patient responds positively (pain score ≤ 3), the dose is reduced by 1 step for the next patient. Conversely, if the patient responds negatively (pain score > 3), the dose is increased by 1 step.

Zeidan and colleagues concluded that the median ED50 is 2.1 g for acetaminophen alone and 5 mg for morphine alone. Then, using a graphical method called "isobolographic analysis," they determined that the combination of the 2 drugs produced an additive analgesic effect. The median ED50 of the combination was lower than that of each drug given alone: 1.3 g for acetaminophen and 2.7 mg for morphine.


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