Schmerzmedizin (D) – Intravenous diclofenac-orphenadrine in the treatment of postoperative pain after remifentanil-based total intravenous anesthesia for elective cruciate ligament surgery.

Objective:

Even though evidence for intravenous diclofenac as a treatment for postoperative pain is low [1] diclofenac-orphenadrine has been shown to reduce PCA analgesic requirement in unilateral total hip arthroplasty [2]. This may be caused by the NMDA receptor antagonistic effect of orphenadrine [3] which may prevent opioid induced hyperalgesia. The objective of this study was to investigate the opioid sparing effect of diclofenac-orphenadrine (Neodolpasse®) in comparison to diclofenac alone.

Methods:

We performed a double-blind, randomized, placebo-controlled, parallel-group, single-center exploratory clinical study. Included were patients receiving elective cruciate ligament surgery. 72 patients were included and randomly assigned to 3 treatment groups. All patients in each group received two infusions: the first after fixation of the graft replacement and the second 8 hours later. Anesthesia was performed as a total intravenous anesthesia using propofol, remifentanil for induction and maintenance and, if necessary, rocuronium for endotracheal intubation. No other narcotics, analgesics, or sedatives were used.

As soon as the patient was awake PCA was established for 48 hours, delivering 0.2 mg Hydromorphone in 0.5 ml with each bolus. Lock-out period of the PCA system was fixed to 5 min. Pain was assessed by measuring the PCA-demand for Hydromorphone after 24 hours and 48 hours postoperatively. In addition, VAS score for pain was ascertained within the first 120 minutes postoperatively, and after 24 hours 48 hours. Furthermore the local and systemic tolerability and safety of the clinical study medications was assessed.

Additionally, study patients were assessed using the Delirium Detection Score two and 24 hours after the first infusion. Overall safety of the infusion solutions was assessed by laboratory safety values, vital signs and by the adverse event profile until 48 hours post-surgery.

Results and discussion:

There was no significant difference in total dose of PCA analgesics required over 24 hours or 48 hours post-surgery between all groups. The mean rate of bolus after 48 hours was 28.04 (SD ± 18.56) in the diclofenac-orphenadrine group, 40.81 (SD ± 35.42) in the Diclofenac group, and 38.29 (SD ± 22.93) in the placebo group. Moreover, there was no significant difference in VAS score for pain at 30 minutes (p = 0.288), 120 minutes (p = 0.942), 24 hours (p = 0.83.5) and 48 hours (p = 0.055) postoperatively. As for safety parameters none of the patients tested positive for delirium using the Delirium Detection Score, neither two hours after the operation nor the day after. Nausea was comparably low in all three groups with an incidence of 30% in the diclofenac-orphenadrine group, 19% in the diclofenac group and 33% in the placebo group (p = 0.548).

Conclusion:

This study does not support previous findings of a reduction in postoperative pain when administering diclofenac-orphenadrine compared to Diclofenac alone or a placebo. Nevertheless, we did not find any differences regarding safety between the placebo, diclofenac and diclofenac-orphenadrine groups.

References:

[1] McNicol ED et al. Cochrane Database of Systematic Reviews 2018, Issue 8. Art. No: CD012498.

[2] Gombotz H et al. Wien Med Wochenschr. 2010 Nov;160(19 – 20):526 – 34

[3] Kornhuber J et al. J Neural Transm Gen Sect. 1995;102(3):237 – 46.