In this study, we demonstrated that pretreatment with remifentanil at a small dose of 0.3 μg/kg reduced the incidence and severity of sufentanil-induced cough without influencing the hemodynamics during anesthetic induction. The incidence of cough was 31% in patients in group C and decreased to 4.8% in patients in Group R.
Coughing following the administration of opioid drugs during general anesthesia induction is often reported. In this study, the incidence of cough induced by sufentanil was 31%. In an study by Agarwal et al. (2) sufentanil 0.3μg/kg injected over 5 seconds elicited cough in 15.8% of patients, while in another study by Li et al. (14) the incidence of cough was 37% after the injection of sufentanil 0.5μg/kg within 3 seconds. With a high dose of sufentanil (1μg/kg), the incidence of sufentanil-induced cough could be up to 45.8%(1). The various incidence among different studies might be due to the different doses of sufentanil used and the differences in concentrations, administration rate,race and age(1, 15).
Various mechanisms have been proposed to explain opioid-induced cough. A plumonary chemoreflex mediated by either vagal C-fiber receptors close to pulmonary vessels or irritant receptors may play a role in opioid-induced cough (16). Opioid-induced histamine release(17) and muscle rigidity leading to sudden closure of the vocal cords or supraglottic obstruction by soft tissue(18) may be another possible casual factor for cough. In addition, in several studies, it was demonstrated that opioid receptor dualism might be an important mechanism of opioid-induced cough (3, 8, 19) .
Various pretreatments with drugs, such as lidocaine, terbutaline, dezocine, dexmedetomidine, and magnesium sulfate have been reported to reduce the incidence of opioid-induced cough (1, 5, 6, 8, 20), however these drugs might add side effects and potential risks. In a study by He et al. (5), an injection with dexmedetomidine 0.5 μg/kg or 1.0 μg/kg over 10 minutes inhibited cough induced by the subsequent fentanyl (4 μg/kg) intravenous injection. However, this dose of dexmedetomidine has the potential to cause bradycardia and hypotension, therefore an injection that is too slow may cause an issue. In another study (1), 30 or 50 mg/kg of MgSO4 inhibited cough induced by a subsequent injection with 1.0 μg/kg sufentanil, however several patients dropped out of the study due to an obvious burning sensation during the injection of MgSO4. In addition, the injection of MgSO4 could increase plasma levels of magnesium. Furthermore, inhalation of terbutaline (5 mg in 2 ml NS; via a jet nebulizer) fifteen minutes before bolus fentanyl (5 μg/kg, iv) has been reported to inhibit cough (6), however the inaccessibility of terbutaline, long operating time, and complicated operations are some limitations of this approach. The injection of lidocaine 0.5 mg/kg has been proven effective to suppress fentanyl-induced cough (20) , however the inhibition of cardiac function may be a potential risk. Dezocine 0.1 mg/kg 2 minutes prior to the administration of intravenous sufentanil (0.5 µg/kg) can also effectively suppress fentanyl-induced cough (8), however in short surgeries, the excessive sedation time of this dose of dezocine may be a problem.
In several other studies, a pre-emptive small dose of the opioids was used to inhibit opioid-induced cough, which could avoid the additional side effects or potential risks of other types of drugs. Hung et al. (4) reported that a pre-emptive small dose of fentanyl (25 μg) significantly reduced cough induced by a subsequent injection of 125 μg fentanyl, and Phua et al.(3) showed that intramuscular morphine pretreatment 1 hour before general anesthesia induction could also decrease the incidence of fentanyl-induced cough. However, either fentanyl or morphine has limitations because of long onset or long duration time.
In the current study, we found that remifentanil, an opioid that is readily available, with both short onset and duration time, could decrease the incidence and severity of sufentanil-induced cough during anesthetic induction.
It is not yet clear how small doses of opioids inhibit the cough caused by opioids themselves. In a study by Hung et al. (4), a pre-emptive small dose of fentanyl (25 μg) significantly reduced cough induced by a subsequent injection with 125 μg fentanyl, and this phenomenon was thought to be associated with the lower plasma concentration fluctuation of fentanyl.
However, in the current study, we found that a pre-emptive small dose of 0.3 μg/kg remifentanil reduced cough induced by a subsequent injection with 0.5 μg/kg sufentanil. However, what was used as a pretreatment was another opioid, remifentanil, not sufentanil itself. Hence, the theory of fluctuations in the sufentanil plasma concentration mentioned above seems unlikely.
We hypothesized that opioid receptor dualism may be a possible mechanism to partly explain this phenomenon. One of the common and useful side-effects of opioid analgesics is suppression of the cough reflex, which is the basis of their use in oral cough suppressants (3). Sufentanil, fentanyl, and remifentanil infusion before recovery from general anesthesia have previously been reported to suppress coughing during extubation (9, 21, 22). Opioids may inhibit the cough reflex by a direct effect on the cough center in the medulla, at doses lower than those required for analgesia (3). Therefore, we suggested that the anti-tussive effect of pre-emptive remifentanil in the present study might be related to a centrally-acting effect. The low priming dose of remifentanil might initially exert a central anti-tussive effect and then inhibit the cough-inducing effect of a subsequent large dose of sufentanil. This hypothesis was partly supported by the study of Phua et al.(3) in which the incidence of fentanyl-induced cough was reduced by intramuscular morphine pretreatment 1 hour before general anesthesia induction . However, this speculation lacks definitive evidence, and therefore additional studies are warranted to verify this hypothesis, and to reveal the underlying mechanism of action.
Given that remifentanil has a respiratory depressive effect, possible apnea-related absence of cough after remifentanil administration must be considered. It is also possible that the dose of remifentanil caused a transient apnea that resulted in an absence of coughing. For example, Remifentanil took 50-60 seconds to reach the effect point, and the apnea took 40-50 seconds, which partially or even completely covered the observation time after sufentanil administration.
Remifentanil may induce muscle rigidity and blood pressure and HR decline (15). In a study performed by Shen et al (15), three patients in the rernifenranil group showed muscle rigidity. and one patient had significant bradycardia that required treatment with atropine. However, in our study, none of the patients showed such adverse reactions, which might be due to the very low dose of remifentanil that was used.
Our study has several limitations. Few studies have shown the number doses of remifentanil that are used to suppress cough caused by opioids, therefore, we used a dose of remifentanil that was close to the dose of fentanyl used in the study of Hung et al. (4) in which a pre-emptive small dose of fentanyl (25 μg) was used to reduce cough induced by a subsequent injection with125 μg fentanyl. Thus, we used a single dose of remifentanil, and therefore do not know whether different doses, such as 0.1 μg/kg, 0.2 μg/kg, 0.4 μg/kg would be effective in suppressing the sufentanil-induced cough reflex. Additional studies will need to be performed to explore the relationship between dose and the cough suppressing effect of remifentanil.