Propofol and opioids such as remifentanil demonstrate intense synergism. The interaction can be quantified using a hypnotic-analgesic endpoint such as ablating response to laryngoscopy. For example, remifenanil concentration of 4ng/ml may reduce propofol concentration associated with loss of response to laryngoscopy by two-thirds (Bouillon 2004). Probability to tolerate laryngoscopy (PTOL) and its derivative, the noxious stimulation response index (NSRI), have been proposed as measures of potency of propofol-remifentanil drug combination (Hannivoort 2016).

Using different combinations of CE-propofol and CE-remifentanil (effect-site concentrations of propofol and remifentanil respectively), all yielding the same predicted response (90% probability to tolerate laryngoscopy, PTOL90), a line (isobole) is drawn connecting all the possible combinations of CE-propofol/CE-remifentanil to achieve the same identical effect (van den Berg 2021). In our simulation programme, the same method is repeated for PTOL80, PTOL70... PTOL10 to generate a total of 9 isoboles on the 2-dimensional chart. The contour of the isoboles is typical of synergism, or supradditive interaction.

Using PTOL90 isobole as an example, the combinations of CE-propofol and CE-remifentanil yielding the identical effect are: {8.6mcg/ml, 1ng/ml}, {5.9mcg/ml, 2ng/ml}, {3.6mcg/ml, 4ng/ml}, {2mcg/ml, 8ng/ml} according to the Bouillon interaction model (van den Berg 2021). Following this, the clinician may decide on using PTOL as a guidance to control different CE of propofol/remifentanil based on haemodynamic, hypnotic, or other consequences while maintaining the same level of pharmacodynamic endpoint.