Remifentanil in real clinical conditions: strange case of Dr. Jekyll and Mr. Hyde?

It appears that, like Dr. Jekyll and Mr. Hyde in the famous story by Robert Louis Stevenson¹, remifentanil in real clinical settings has two faces. While it is undoubtedly a potent and well controllable μ-opioid agonist with unique pharmacokinetics and wide clinical application, on the other hand, perhaps no other opioid is as much associated with opioid-induced hyperalgesia (OIH)², that is, initial analgesic effects that are followed by increased sensitivity to pain/reduced pain thresholds³.

Remifentanil is a synthetic 4-anilide-piperidine, side-chain linked by an ester bond, which is responsible for its rapid inactivation by non-specific hydrolysis of plasma and tissue esterases⁴. The onset time is on average 1.3 min and the context-sensitive half-time 3 min, regardless of infusion duration⁵. Remifentanil is a selective μ-opioid agonist and has almost the same adverse effects as other opioids which include hyperalgesia. Despite the short context-sensitive half-time number of animal studies has shown the potential for remifentanil abuse too⁶. But requirement for self-administration of the IV form of the drug makes this route impractical. Only one report of remifentanil abuse has been published so far⁷.

Remifentanil is very convenient for outpatient use, where the expected postoperative pain is mild or moderate⁸. Its context-sensitive half-life time also makes it suitable for awake anesthesiological techniques in a broad range of neurosurgical procedures with craniectomy and craniotomy⁹ and for spinal procedures that require neurophysiological monitoring¹⁰.

A very hot topic in the anesthesiological community is the use of remifentanil for pain relief during labor. It is an effective analgesic with a high degree of mother satisfaction¹¹. Widely discussed, in this context, is its safety, especially for the mother. However, the current report of the Swiss remifentanil register declares it to be safe¹².

Rapid Sequence Induction to general anesthesia is typically described without opioid administration¹³. Especially in Cesarean delivery, there is a fear of transplacental transfer of opioid and effects on the postnatal adaptation of the newborn. On the other hand, especially in high-risk women in labor where there is a concern about sympathoadrenergic reaction, the administration of the opioid is warranted. Remifentanil prior to the start of Rapid Sequence Induction is suitable for this indication. Recent studies also confirm the stabilization of hemodynamics during induction of anesthesia with minimal impact on postnatal adaptation of the newborn^14,15. For perioperative pain management, remifentanil can be used in patient-controlled analgesia (PCA) with background infusion. If this option is missing, it is necessary to provide analgesia with either a combination of medium or long-acting non-opioid or opioid analgesics.

However, the evidence for remifentanil OIH in clinical practice is not clearcut. One systematic review of the literature on OIH in surgical settings showed that 16 supported OIH with remifentanil and 6 refuted it¹⁶. On the other hand, given the multitude of methodological issues detected by other reviewers, no valid conclusions can be drawn. It is untrue to say there is no evidence to confirm OIH if valid comparison of studies cannot be made. As an illustration in this issue, Ohnesorge et al.¹⁷ compared intraoperative high-dose remifentanil, which is suspected of causing OIH, with low-dose sufentanil. They compared somatosensory thresholds prior to and 20 hours after surgery and found no significant differences. On the other hand a recent Japanese study confirmed increased need for local anesthesia using high-dose remifentanil intraoperatively¹⁸ and an Italian study described more frequent reporting of pain-related complaints using the patient-related outcomes questionnaire (PRO)¹⁹.

Given the methodological variability of published studies, there is a need for more research including the contribution of remifentanil induced hyperalgesia to chronic pain and the role of pharmacological modulation to reverse this process. But the real clinically preferred examples of remifentanil use imply that the adverse effects can be maintained under control and therefore remifentanil does not have to follow the tragic fate of Stevenson’s story in the future.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

P.S. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.

The CMRO peer reviewer on this manuscript has no relevant financial or other relationships to disclose.

Acknowledgement

Many thanks to Tamara Skrisovska and Alena Stouracova for review of the article and Alexander Oulton for important advices and proof reading.