Peripheral morphine reduces acute pain in inflamed tissue after third molar extraction: A double-blind, randomized, active-controlled clinical trial.

Background: The clinical use of peripheral analgesic effects of opioids has been investigated in numerous controlled clinical trials. The majorities of these have tested the local, intra-articular administration of morphine in knee surgery and have demonstrated marginal postoperative analgesia.

Objective: We examined direct morphine infiltration of the surgical site in a clinical model of tooth pain under two different conditions. Eighty-eight patients undergoing surgical tooth removal entered into the two prospective, parallel, randomized, double-blind studies.

Methods: Patients undergoing surgical tooth removal received a standard local anaesthetic solution (articaine plus epinephrine) before surgery. Patients were assigned to an injection of peripheral 2mg morphine either into non-inflamed (Trial I) or inflamed (Trial II) submucous tissue before the surgery. Patients who received an intramuscular morphine in the upper arm were concomitantly given 1ml isotonic saline (NaCl) as a submucous injection. Patients who received a submucous injection of morphine peripherally were concomitantly given an intramuscular injection (IM) of 1ml of NaCl in the upper arm. Postoperative pain intensity was assessed by the numeric rating scale every 30min for the first 2h and then every hour for the next 8h after surgery. In addition, patients recorded the occurrence of side effects and the supplemental consumption of ibuprophen and codeine+paracetamol combination tablets.

Results: Of the eighty-eight original participants, nine patients (4 patients in Trial I and 5 patients in Trial II) were withdrawn for protocol noncompliance and loss at follow-up. Thirty-one patients in trial I and forty-eight patients in trial II were analyzed. Patients receiving 2mg morphine into non-inflamed tissue did not show any further reduction in pain scores and pain medication consumption compared to IM morphine group (Trial I). In patients receiving 2mg morphine into inflamed tissue, pain scores at rest were reduced to a similar extent in both groups at all measurement times up to 10h in the follow-up (Trial II). At the same time, in the area under the curves pain scores on swallowing between 2 and 6h in the peripheral morphine group (5.2±5.6) were significantly lower than in the IM morphine group (9.3±7.3, p=0.03), demonstrating the marginal analgesic efficacy of additional morphine. Sedation scores were significantly higher in the peripheral morphine group only 1h after surgery in Trial I (p=0.008). The time to first analgesic intake was similar between groups. No serious side effects were reported.

Conclusions: Our results showed in patients undergoing surgical tooth removal that injection of 2mg of morphine into inflamed tissue results in significantly lower pain scores on swallowing in the early postoperative state while administration into non-inflamed tissue is not effective.

Implications: Our studies indicate that the peripheral administration of opioids, at the doses and conditions set out for these two studies, produces significant analgesia by a pharmacologically specific mechanism that is active in chronically, but not acutely, inflamed tissue. Thus, consistent with preclinical experimental studies, the requirement of an inflammatory process for the occurrence of the peripheral opioid effects is also found in the clinical setting.