Laryngoscopy and subsequent endotracheal intubation (L&I) result in activation of the sympathetic nervous system due to stimulation of somatic and visceral nociceptive afferents of the epiglottis, hypopharynx, peritracheal area and vocal cords. The net effect of such nociceptive input is that of cardiovascular stimulation, which results in an increase in blood pressure (BP) and heart rate (HR)  and electroencephalogram (EEG) arousal . These excitatory effects may result in significant haemodynamic changes especially in coronary heart disease patients with ensuing undesirable cardiac ischaemia, dysrhythmias or even left heart failure. Opioids have been shown to blunt these stimulatory effects on the cardiovascular system. This beneficial effect has been demonstrated separately for fentanyl [3,4], alfentanil  and sufentanil [4,6] in patients without pre-existing cardiac disease. It however remains open whether opioid potencies are related to the blockade of sympathetic discharge and the ensuing haemodynamic consequences. Since opioids such as fentanyl or remifentanil used for induction may cause respiratory depression and/or muscular rigidity [7-9], we studied the effects of the κ-agonist nalbuphine [10,11] and the partial agonist meptazinol , both of which have been shown to result in no respiratory depression [13,14] when used in clinically equieffective doses.
Using opioids with different potency it was possible to answer the question as to whether efficacy or other opioid-related effects account for a sufficient suppression of cardiovascular effects induced by L&I and which agent shows preferable characteristics for the induction period. We also studied possible EEG arousal responses accompanying L&I.
Materials and methods
After Ethics Committee approval and informed written patient consent, 75 unpremedicated (ASA status 1–2), patients (age 18–55 yr) scheduled for elective plastic surgery (face lifting/brightening, liposuction, breast augmentation, reconstruction surgery) were included in this prospective study. The patients were prospectively randomized to anaesthetic induction with the partial agonist meptazinol (2.5 mg kg−1), the mixed agonist/antagonist nalbuphine (0.3 mg kg−1) or the pure agonist fentanyl (5 μg kg−1) followed by thiopentone and vecuronium. Aside from cardiovascular parameters, determined via an oscillometric, non-invasive BP measurement system (Hewlett Packard Medical Systems, Böblingen, Germany), a fronto-temporal three-lead bispectral index (BIS) disposable electrode assembly (BIS Sensor; Aspect Medical Systems, Natick, MA, USA) was used to measure depth of anaesthesia (BIS-XP®; Aspect Medical Systems, Natick, MA, USA). During the control measurement of BIS, patients were asked to relax and to keep their eyes closed in order to minimize muscle artifact electrode impedance was kept below 3 kΩ, while baseline HR and BP values were taken.
Following intravenous (i.v.) bolus of the opioid by the anaesthesiologist unaware of the agent used, pre-oxygenation by mask with 100% oxygen was initiated for 3 min. Anaesthesia was induced by an i.v. bolus of thiopentone 4 mg kg−1, followed by 0.2 mg kg−1 of vecuronium, both of which were given over 20 s. Simultaneously, sevoflurane 1% in oxygen was continuously applied via face mask and ventilation assisted or controlled as necessary to keep end-tidal CO2 between 4.0 and 5.0 kPa throughout the study. Exactly 3 min after the start of anaesthesia induction, laryngoscopy and intubation, always done by the same anaesthesiologist, was performed over less than 25 s. Thereafter sevoflurane (1.0–2.5%) and nitrous oxide (FiO2 0.5) were administered for maintenance of anaesthesia. Patients were systematically asked about awareness or other anaesthetic problems at the post-anaesthetic visit.
Before anaesthesia, 1 min after induction and 1 min after L&I, HR, systolic BP and BIS were measured. End-tidal CO2, FiO2 and oxygen saturation were recorded at 1 min intervals.
Before starting the prospective open label study, a priori power analysis was performed. Based on a previous study in patients undergoing L&I for open heart surgery , to detect a difference of maximal power values by 50%, an effect level of 1.0, with an a error of 5% and a power of 80%, at least 20 patients were calculated as necessary.
An observer unaware of the induction agent used analysed all data collected. Statistical analysis was performed using the Graph Pad Prism® Statistical software package (Statistics for Mac, version 4.0c 2005; Intuitive Software, San Diego, CA, USA). Patient characteristics and haemodynamic data were expressed as mean ± standard deviation. Between-group differences for patient characteristics and haemodynamic data were analysed using an unpaired t-test, and within-group haemodynamic differences for control vs. 1 min after intubation were tested by paired two-tailed t-test. For calculation of statistical difference among the three groups, the Kruskal–Wallis test was used, while Newman–Keuls multiple comparison test was used for computation of the degree of statistical difference among the groups. A value of P < 0.05 was considered statistically significant.
The three groups were demographically comparable (Table 1) and although mean age and mean weight in the fentanyl group was high when compared to the two other groups, this was not statistically significant. No problems arose with the induction scheme used, no patient had an oxygen saturation of below 97% at any time and no patient moved, coughed or caused artifacts. Also, post-anaesthetic questioning did not reveal any episodes of awareness.
Table 2 shows the intergroup differences in haemodynamic parameters for control vs. 1 min after L&I. From these data it can be seen that compared to control, the meptazinol group demonstrated no increase in systolic BP and only a minor but non-significant decrease in HR (Table 2). This is in contrast to the nalbuphine group, where there was a highly significant (P < 0.001) increase of systolic BP and also a highly significant (P < 0.001) increase in HR (Table 2). In addition, 3 patients of this group developed an increase in systolic BP of up to 200 mmHg following tracheal intubation, while no patient in the two other groups showed such haemodynamic responses. Patients in the fentanyl group also demonstrated some effect on haemodynamics. There was a non-significant increase in systolic BP, and a significant (P < 0.05) increase in HR (Table 2).
Intergroup statistical comparison of systolic BP changes demonstrated an overall highly significant difference (P < 0.0047, Fig. 1). The increase was significant between the meptazinol and the nalbuphine groups (P < 0.01), and between the nalbuphine and the fentanyl group (P < 0.05) but not between the meptazinol and the fentanyl groups (P > 0.05).
There was a significant difference in HR among the three groups (P < 0.0001; Fig. 2). Intergroup significance between meptazinol and nalbuphine was P < 0.001; there was no intergroup significance between the meptazinol and the fentanyl groups (P > 0.05); there was a highly significant difference between the nalbuphine and the fentanyl groups (P < 0.01).
L&I also produced an increase in BIS. In this context the BIS-values 1 min after induction were compared with values 1 min after intubation within each group. There was a 19% decrease in the meptazinol group, an 18% increase in the nalbuphine group and an 8% decrease in the fentanyl group (Table 2). Among the three groups, BIS-values after intubation were highest in the nalbuphine, lowest in the meptazinol, with an in-between value in the fentanyl group (Fig. 3). There was a significant difference between the meptazinol and the nalbuphine groups (P < 0.001), no significant difference between the meptazinol and the fentanyl groups (P > 0.05) but a highly significant difference between the nalbuphine and the fentanyl groups (P < 0.001).
The increase in BP and HR with L&I during induction is well established in the literature [16,17]. Also, studies in patients being induced with varying doses of thiopentone, fentanyl, lidocaine, droperidol and succinylcholine, have demonstrated a significant correlation between presystolic BP and its response to L&I . In addition, when using fentanyl or sufentanil for induction in cardiac patients, a significant increase in mean arterial pressure and HR with fentanyl was demonstrated . The present results suggest that meptazinol has advantages over nalbuphine or even fentanyl for the induction of anaesthesia as the noxious stimulation of laryngoscopy and tracheal intubation was accompanied by no cardiovascular stimulation and no increase in BIS. This is in spite of the fact that meptazinol has only an analgesic potency comparable to pethidine [19,12], with a 7-fold and a 2000-fold lesser potency than nalbuphine and fentanyl, respectively . The reason for its superiority in reflex blockade very likely is due to a supraspinal and a spinal mechanism . The additional spinal mechanism is of cholinergic activity , which may account for an improved antinociception and blockade of subsequent cardiovascular stimulation. Besides the intrinsic binding to the specific opioid receptor, cholinergic activity of an opioid is another mechanism of nociceptive blockade, as demonstrated by others. Thus, opioid analgesia could be enhanced by addition of the cholinesterase inhibitor neostigmine [23-25]. In addition, potentiation of opioid-induced antinociception by cholinergic agents also has been corroborated by animal , and human studies with physostigmine , which supports the notion that descending cholinergic pathways in systemic opioid analgesia are major contributors for pain reduction. Since it has been demonstrated that meptazinol, aside from its opioid activity, also activates the descending pathways  and affects acetylcholine binding sites in the spinal cord  the present results are probably mainly related to its additional activation of cholinergic pathways.
Meptazinol therefore has a unique opioid analgesic pharmacology, which may account for the observed differences among the three tested opioids. In addition, binding studies suggest a relative selectivity for the opioid μ-1 receptor-site, as opposed to the other opioid receptor binding sites such as the μ-2, the δ- or the κ-receptor site . Such binding selectivity is consistent with meptazinol's supraspinal site of action and its sensitivity to the μ-1 receptor-selective opiate antagonist naloxonazine resulting in a lesser degree of respiratory depression than with morphine or fentanyl .
Compared to nalbuphine, such an additive/synergistic action of meptazinol is also expressed in a lack of EEG arousal reaction. In the group with nalbuphine, the thiopentone-induced decline in BIS was disrupted by desynchronization resulting in an increase in BIS-value. Although nalbuphine has the advantage of a respiratory depressant ceiling-effect , and compared to fentanyl or morphine, exhibits lesser spasm of the sphincter of Oddi [31,32], in the present study it demonstrates the least potential to block unwanted afferents induced by L&I. This smaller amount of blocking capabilities might be due to its low analgesic potency, which is only 0.7 × that of morphine and 0.004 × that of fentanyl . Being a ligand at the κ-opioid receptor  one may argue that this receptor is not involved in the laryngeal or pharyngeal reflex arch. Contrary, the μ-opioid receptor may play a more important role in depressing the laryngeal reflex, since both meptazinol  as well as fentanyl  mainly interact with the opioid μ-site. This assumption is underlined by the ability of fentanyl to reduce the increase in vigilance (BIS-increase) and hypertension, usually seen with thiopental sodium in the absence of opioid. In spite of its 200-fold higher analgesic potency when compared to meptazinol, the μ-ligand however, was less able to depress reflex tachycardia. Such data support the notion, that aside from the opioid μ-receptor, descending cholinergic inhibitory pathways in the spinal cord play a significant role in the transmission of laryngeal/tracheal afferents.
While thiopentone was used in a dose usually administered for the induction of anaesthesia , clinically equipotent doses of meptazinol , nalbuphine  and fentanyl [15,38] were given for bolus induction. This is confirmed by the similar baseline BIS-values in the three groups. In addition, to reliably ensure clinically and ethically acceptable induction conditions, we had the choice between using nitrous oxide and sevoflurane supplementation with thiopentone. We decided on sevoflurane supplementation with the concentration chosen because it was closer to clinical practice and is associated with a fast onset of action . While the results reflect the interaction between the induction agent and sevoflurane, the differences between the groups can be considered to reflect differences between three opioid agents as the three groups received identical concentrations of sevoflurane under identical conditions. One may argue, that use of higher dosage of nalbuphine might have successfully depressed the haemodynamic and arousal reaction following L&I. However, doses higher than the therapeutic margin of 200 mg/70 kg will result in an analgesic ceiling , which is not seen with fentanyl as it preferentially binds to the opioid μ-receptor .
Changes in the EEG and its univariate derivative, the BIS can be used to determine arousal [42,43]. Measuring the BIS in the context of an opioid-thiopentone induction, such passive EEG methods only determine cortical depression or hypnotic potency, being unable to assess the dynamic phenomenon of antinociceptive potency . Our observations suggest not only better initial subcortical antinociception in the meptazinol group, but also better subsequent damping of cortical reactions following nociceptive activation of the cortex. The latter conclusion is supported by the significantly lesser increase in BIS-value following visceral nociception of intubation and stimulation of the vocal cords. This goes well with the high density of μ-opioid receptors in subcortical regions associated with nociceptive processing and the generation of arousal (e.g. thalamus, reticular formation). Blockade of these regions would be expected to shield the cortex from nervous nociceptive impulses causing arousal and subsequent desynchronization , which results in an increase in BIS . In this regard, the higher affinity for and greater intrinsic activity at the μ-receptors of fentanyl than nalbuphine seems to produce better block of the aforementioned subcortical structures than nalbuphine . On the other hand meptazinol shows selectivity for the μ-1-opioid receptor, which when taken together with its cholinergic activity  also results in a superior blockade.
By using the BIS criteria for degree of cortical depression, our data has shown similarly deep anaesthesia just prior to laryngoscopy an intubation. This illustrates the difficulties of predicting the response to nociception from the degree of cortical depression prior to the stimulus, particularly between different drugs.
In conclusion, during anaesthesia induction, L&I induced a nociceptive stimulus involving superficial structures, which are associated with an excitatory EEG arousal reaction and an increase in HR and systolic BP. EEG arousal and haemodynamic reaction are significantly better controlled by meptazinol or fentanyl than with nalbuphine. Nalbuphine, meptazinol and fentanyl, when combined with thiopentone and sevoflurane have similar depressant effects on cortical function in the absence of nociceptive stimulation. However, meptazinol provides better blockade of subcortical nociceptive processing than either nalbuphine or fentanyl.
1. Stoelting R. Circulatory changes during direct laryngoscopy
and tracheal intubation. Anesthesiology
1977; 47: 381–383.
2. Wilder-Smith OHG, Hagon A, Tassonyi E. EEG arousal during laryngoscopy
and intubation: comparison of thiopentone or propofol supplemented with nitrous oxide. Br J Anaesth
1995; 75: 441–446.
3. Tolksdorf W, Schäfer E, Pfeiffer J, von Mittelstaedt G. Adrenalin-, Noradrenalin-, Blutdruck- und Herzfreqenzverhalten während der Intubation in Abhängigkeit unterschiedlicher Fentanyl-Dosen. Anästh Intensivther Notfallmed
1987; 22: 171–176.
4. Bowdle TA, Ward RJ. Induction of anesthesia with small doses of sufentanil or fentanyl: dose versus EEG response, speed of onset, and thiopental requirement. Anesthesiology
1989; 70: 26–30.
5. Tolksdorf W, Kollmann C, Simon H-B, Schulz U. Der Einfluß unterschiedlicher Alfentanildosen auf Blutdruck, Herzfrequenz und Plasmakatecholaminspiegel bei der endotrachealen Intubation. Anästh Intensivther Notfallmed
1990; 25: 198–202.
6. Kay B, Nolan D, Mayall R, Healy TE. The effect of sufentanil on the cardiovascular responses to tracheal intubation. Anaesthesia
1987; 42: 382–386.
7. Splinter W, Cervenko F. Hemodynamic responses to larangoscopy and tracheal intubation in geriatric patients: effects of fentanyl, lidocaine, and thiopentone. Can J Anaesth
1989; 36: 370–378.
8. Iyer V, Russell W. Induction using fentanyl to suppress the intubation response in the cardiac patient: what is the optimal dose? Anaesth Intens Care
1988; 16: 411–417.
9. Randel GI, Fragen RJ, Liboro ES, Jamerson BD, Gupta S. Remifentanil blood concentration effect relationship at intubation and skin incision in surgical patients compared to alfentanil. Anesthesiology
1994; 81: A375.
10. Schmidt WK, Tam SW, Shotzberger GS, Smith DH, Clark R, Vernier VG. Nalbuphine. Drug Alcohol Depen
1985; 14: 339–362.
11. Dumas PA. MAC reduction of enflurane and isoflurane and postoperative findings with nalbuphine HCl and fentanyl: a retrospective study. In: Gomez QJ ed., VII World Congress of Anaesthesiologists
, Manila, Philippines. Amsterdam: Exerpta Medica, 1984: 43–53.
12. Holmes B, Ward A Meptazinol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs
1985; 30: 285–312.
13. Jordan C. A comparison of the respiratory effects of meptazinol, pentazocine and morphine. Br J Anaesth
1979; 51: 497–501.
14. Gal TJ, Di Fazo CA, Moscicki J. Analgesic and respiratory depressant activity of nalbuphine: a comparison with morphine. Anesthesiology
1982; 57: 367–374.
15. Freye E, Dehnen-Seipel H, Latasch L, Behler M, Wilder-Smith OHG. Slow EEG-power spectra correlate with hemodynamic changes during laryngoscopy
and intubation following induction with fentanyl and sufentanil. Acta Anaesth Belg
1999; 50: 71–76.
16. Harris CE, Murray AM, Anderson JM, Grounds RM, Morgan M. Effects of thiopentone, etomidate and propofol on the hemodynamic response to tracheal intubation. Anaesthesia
1988; 43: 32–36.
17. Lindgren L, Yli-Hankala A, Randell T, Kirvela M, Scheirin M, Neuvonen PJ. Haemodynamic and catecholamine responses to induction of anaesthesia and tracheal intubation: comparison between propofol and thiopentone. Br J Anaesth
1988; 70: 306–310.
18. Rampil IJ, Matteo RS. Changes in EEG spectral edge frequency correlate with the hemodynamic response to laryngoscopy
and intubation. Anesthesiology
1987; 67: 139–142.
19. Robson PJ. Clinical review of parenteral meptazinol. Postgrad Med J
1983; 59: 85–92.
20. Freye E. Opioide in Der Medizin.
Berlin, Heidelberg, New York: Springer, 2004.
21. Dray A, Nunan L, Wire W. Meptazinol: unusual opioid receptor activity at supraspinal and spinal sites. Neuropharmacology
1986; 25: 343–349.
22. Bill DJ, Hartley JE, Stephens RJ, Thompson AM. The antinociceptive activity of meptazinol depends on both opiate and cholinergic mechanisms. Br J Pharmacol
1983; 79: 191–199.
23. Hood HD, Mallak KA, James RL, Tuttle R, Eisenach JC. Enhancement of analgesia from systemic opioid in humans by spinal cholinesterase inhibition. J Pharmacol Expt Ther
1997; 282: 86–92.
24. Omais M, Lauretti GR, Paccola CAJ. Epidural morphine and neostigmine for postoperative analgesia after orthopedic surgery. Anesth Analg
2002; 95: 1698–1701.
25. Lauretti GR, Lima ICPR. The effects of intrathecal neostigmine on somatic and visceral pain: improvement by association with a peripheral anticholinergic. Anesth Analg
1996; 82: 617–620.
26. Chiang C-Y, Zhuo M. Evidence for the involvement of a descending cholinergic pathway in systemic morphine analgesia. Brain Res
1989; 478: 293–300.
27. Beilin B, Bessler H, Papismedov L, Weinstock M, Shavit Y. Continuous physostigmine combined with morphine-based patient-controlled analgesia in the postoperative period. Acta Anaesthesiol Scand
2005; 49: 78–84.
28. Gillberg PG, d'Argy R, Aquilonius SM. Autoradiographic distribution of [3H]acetylcholine binding sites in the cervical spinal cord of man and some other species. Neurosci Lett
1988; 90: 197–202.
29. Pasternak GW, Adler BA, Rodriguez J. Characterization of the opioid receptor binding and animal pharmacology of meptazinol. Postgrad Med J
1985; 61: 5–12.
30. Romagnoli A, Keats AS. Ceiling effect for respiratory depression by nalbuphine. Clin Pharmacol Ther
1980; 27: 478–485.
31. Vatahasky E, Haskel Y. The effect of nalbuphine (Nubain®
) compared to morphine and fentanyl on common bile duct pressure. Curr Ther Res
1985; 37: 95–102.
32. McCammon RL, Stoelting RK, Madura JA. Effects of butorphanol, nalbuphine, and fentanyl on intrabiliary tract dynamics. Anesth Analg
1984; 63: 139–142.
33. Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG. Goodman & Gilman's the Pharmacological Basis of Therapeutics.
New York: The McGraw-Hill Companies Inc, 1996.
34. Spiegel K, Pasternack GW. Meptazinol: a novel mu-1 selective opioid analgesic. J Pharmacol Expt Ther
1984; 228: 414–419.
35. Corbett D, Paterson SJ, Kosterlitz HW. Selectivity of ligands for opioid receptors. In: Herz A ed., Opioids I. Handbook of Experimental Pharmacology.
Berlin, Heidelberg, New York: Springer, 1993: 645–680.
36. Hargreaves J, Kay B, Healy TE. Meptazinol as an analgesic adjunct to total intravenous anaesthesia in cystoscopy patients. Anaesthesia
1985; 40: 490–493.
37. Borgeat A, Fuchs T, Wilder-Smith O, Tassonyi E. The effect of nalbuphine and droperidol on spontaneous movements during induction of anesthesia with propofol in children. J Clin Anesth
1993; 5: 12–14.
38. Cork RC, Weiss J, Hameroff SR, Bentley JB. Pre-treatment with low-dose fentane for rapid-sequence intubation. Anesthesiology
1983; 59: A334.
39. Lu CC, Tsai CS, Ho ST et al
. Pharmacokinetics of sevoflurane uptake into the brain and body. Anaesthesia
2003; 58: 951–956.
40. Freye E, Buhl R, Ciaramelli F. Somatosensory-evoked potentials as predictors of the analgesic efficacy of nalbuphine, a mixed narcotic analgesic. Pain Clin
1987; 1: 225–231.
41. Freye E, Buhl R. Somatosensory-evoked potentials for the evaluation of analgesic properties of nalbuphine in man. Anesth Analg
1986; 65: 551.
42. Levy WJ. Intraoperative EEG patterns: implications for EEG monitoring. Anesthesiology
1984; 60: 430–434.
43. Shah NK, Spydell J, Desidero D, Bedford D. Processed EEG monitoring for preventing awareness during light isoflurane/fentanyl anaesthesia. In: Bonke B, Fitch W, Millar K eds., Memory and Awareness in Anaesthesia.
Amsterdam: Swets & Zeitlinger, 1990: 378–381.
44. Gurses E, Sungurtekin H, Tomatir E, Dogan H. Assessing propofol induction of anesthesia dose using bispectral index analysis. Anesth Analg
2004; 98: 128–131.
45. Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroenceph Clin Neurophysiol
1949; 1: 455–473.
46. De Souza EB, Schmidt WK, Kuhar MJ. Nalbuphine: an autoradiographic opioid receptor binding profile in the central nervous system on an agonist/antagonist analgesic. J Pharmacol Expt Ther
1987; 244: 391–402.