Remifentanil as a Soft Drug Prototype 

A “soft drug” is an active compound that can easily be transformed into an inactive metabolite in the body [1]. Anesthesiology requires careful consideration of three axes: safety, effectiveness, and efficiency [2]. In medical practice, the third axis (efficiency) is often less prioritized; however, anesthesia must be readily produced and reversed on demand [3]. “Soft drugs” are metabolically fragile and designed to be deactivated in a predictable and controllable way after achieving their therapeutic role; thus, soft drug anesthetics are ideal anesthetic agents and a focus of research efforts [3,4]. One drug that aligns with the soft drug concept is remifentanil. 

Although the soft drug concept would not be put forward until much later, in the 1950s, succinylcholine was introduced into the anesthesia formulary. Its utility centered around its short duration of action, classifying it as a ‘soft drug’; however, its adverse effects of bradycardia, malignant hyperthermia, and hyperkalemia in at-risk patients have decreased its use [5].  

In terms of structure, ester moieties are critical to soft drug development. The typical metabolic pathway of esters is enzymatic hydrolysis to a carboxylic acid metabolite. For the soft drug paradigm to be fully realized, this metabolite must have little pharmacological activity and the ester moiety should be available to the enzyme, ensuring rapid metabolism [6].  

Remifentanil is a μ-receptor opioid agonist and a member of the 4-anilidopiperidine class, which includes fentanyl and fentanyl-related synthetic opioids [7,8]. Pharmacodynamically, remifentanil presents similarly to other fentanyl-related compounds; for example, it produces physiological changes similar to ʏ-receptor agonists, such as sedation [7]. Like other drugs of this class, remifentanil’s adverse effects include nausea, vomiting, bradycardia, and respiratory depression. Because it does not release histamine, the drug has much fewer adverse hemodynamic effects, in contrast to morphine, although remifentanil is about 200 times more potent [7,9]. 

Remifentanil is a modern prototype of the soft drug concept, with a rapid onset and offset of action, translating to quick regaining of consciousness and more efficient operating use [2,9]. Among all clinically available opioids, only remifentanil is resistant to accumulation after prolonged intravenous infusion, allowing for the rapid modulation of anesthesia depth and making the drug best suited for procedures of short duration (i.e. “day surgery”) [9,10]. The ester structure of remifentanil makes it vulnerable to hydrolysis by blood-nonspecific esterases; the ensuing rapid metabolism makes the drug a useful adjunct to anesthesia regimens for awake craniotomy [11]. Intensely stimulating procedures such as laryngoscopy may also benefit from remifentanil primarily because of the drug’s high lipid solubility which allows it to reach peak efficacy within 1-2 minutes of bolus administration [12]. Prior work by Minto et al. demonstrate elderly patients may require less remifentanil as a direct result of different pharmacodynamics; lean body mass was also found to have a significant effect [13]. For patients from ages 20-85, researchers observed a ~50% reduction in the drug’s EC50; similar results were derived in a separate study by another research team [12,14]. Remifentanil has also proved to be particularly useful in cardiac surgery, as it offers stable operating times and facilitates tracheal extubation [9]. For neurosurgical removal of supratentorial lesions, patients receiving remifentanil had faster recovery and less of a need for intravenous propofol than patients receiving fentanyl [9]. 

The soft drug strategy is a promising new approach in anesthesiology [2]. Succinylcholine was the first unofficial soft drug while remifentanil is now being considered a modern-day prototype. Large-scale randomized trials could improve our current understanding of remifentanil and its benefits to anesthesiology.  


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