Effect of continuous low-dose intravenous diltiazem on epidural fentanyl analgesia after lower abdominal surgery

K. Nitahara1, M. Matsunaga1, K. Katori1, H. Yotsui1, H. Higuchi1,2 and K. Higa1

1 Department of Anesthesiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. 2 Department of Anesthesiology, National Defense Medical College, Saitama, Japan

Corresponding author. E-mail: nitahara@fukuoka-u.ac.jp

Accepted for publication: December 2, 2002


    Abstract
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Background. The postoperative opioid-sparing effects of systemic L-type calcium channel blockers are controversial. We investigated whether the postoperative analgesic effect of epidural fentanyl was enhanced by i.v. infusion of diltiazem at a rate that would minimize any cardiovascular depressant effect.

Methods. After elective lower abdominal gynaecological surgery, 30 patients were randomized to receive continuous i.v. diltiazem 1 µg kg–1 min–1 (diltiazem group) or the same volume of saline (control group) for 24 h. Cumulative postoperative epidural fentanyl consumption, visual analogue scale (VAS) scores and verbal rating scores (VRS) at rest and during mobilization, sedation scores, incidence of side-effects and overall patient satisfaction were assessed.

Results. There was no significant difference in cumulative epidural fentanyl consumption between the groups at any period. Although there were no statistically significant differences in VAS scores, VRS, sedation scores, incidence of side-effects and overall patient satisfaction, there was a trend to an increased incidence of nausea in the diltiazem group.

Conclusions. Continuous i.v. infusion of diltiazem did not reduce epidural fentanyl consumption when administered at dosages having minimal haemodynamic depressant effects.

Br J Anaesth 2003; 90: 507–9

Keywords: analgesic techniques, epidural; analgesics opioid, fentanyl; heart, antiarrhythmics, diltiazem; heart block, calcium channel blockers; pain, postoperative


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Opioids inhibit voltage-gated calcium channel conductance and L-type calcium channel blockers potentiate the analgesic effects of opioids in humans.1 The analgesic effect of morphine by L-type calcium channel blockers occurs at a spinal cord level2 and epidural fentanyl analgesia occurs primarily through a spinal mechanism.3 We found no studies that tested the effect of continuous infusion of L-type calcium channel blockers on epidural fentanyl analgesia. In this study, we investigated whether analgesia from epidural fentanyl was enhanced by systemic L-type calcium channel blocker administration at a dosage that would have minimum cardiovascular depressant effects.


    Methods and results
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Thirty-two ASA I or II female patients who were scheduled for lower abdominal gynaecological surgery were enrolled. Institutionally approved written informed consent was obtained from each patient. Based on previous observations, the standard deviation of cumulative epidural fentanyl consumption was assumed to be approximately 16%.4 This means that a sample size of 12 patients per group was needed to detect a 20% reduction in epidural fentanyl consumption at a two-sided 5% significance level with a power of 80%.

Patients were premedicated with oral diazepam 10 mg. An epidural catheter was inserted at the T12–L2 interspace. Epidural anaesthesia to achieve T4–6 sensory block (to cold) was established by injecting mepivacaine 2% via the catheter. General anaesthesia was induced and maintained with propofol.

In the postanaesthesia care unit (PACU), patients were randomized to receive continuous i.v. diltiazem 1 µg kg–1 min–1 (diltiazem group) or the same volume of saline (control group) for 24 h. At the same time, each patient received fentanyl 50 µg plus mepivacaine 0.25% 5 ml epidurally. The patient-controlled analgesia pump was set to deliver an epidural background infusion of fentanyl solution 3 µg ml–1 at 4 ml h–1 and a 4 ml bolus of the same solution on demand with a lockout time of 10 min and a maximum dose of 20 ml h–1.

Data were collected from the PACU 3 and 6 h after surgery and then three times a day between 8:00 and 10:00 a.m., 0:00 and 2:00 p.m., and 6:00 and 8:00 p.m. until the morning of the second day after surgery. Data collection included visual analogue scale (VAS) scores for pain at rest and during mobilization (0=no pain, 100=worst imaginable pain), verbal rating scores (VRS) for pain at rest and during mobilization (0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain), and sedation scores (0=alert, 1=drowsy, 2=sleeping but easily arousable by calling, 3=awakened only by shaking, 4=unarousable). Overall satisfaction was assessed at the discontinuation of treatment (0=no satisfaction, 3=best satisfaction). Consumption of patient-controlled epidural fentanyl was recorded 3, 6, 12, 24, 36 and 48 h after operation.

Differences between the groups were analysed using the unpaired t-test, the Mann–Whitney U-test and the {chi}2-test. P<0.05 was considered statistically significant.

Epidural analgesia was not established sufficiently in two patients and data from these patients were not included in the analysis. There were no statistically significant differences between the groups with respect to patient characteristics, duration of surgery and anaesthetic requirements.

VAS scores were similar, being <40 at rest and <50 at mobilization in both groups at any time. VRS were also similar and <2 in both groups at any period. VAS scores and VRS in the PACU were <10 and <0.5 in the two groups respectively. There was no significant difference in cumulative epidural fentanyl consumption between the groups at any time (Fig. 1). There were no significant differences between the groups in sedation scores and in the incidence of side-effects, including pruritus, nausea, vomiting, headache and dizziness. However, there was a trend towards an increase in the incidence of nausea in diltiazem group. Nausea occurred in 40% of the diltiazem group (6 of 15) and 13% of the control group (2 of 15) (P=0.09) and was observed only within the first 24 h. Overall patient satisfaction was also similar between the groups.



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Fig 1 Cumulative patient-controlled epidural fentanyl consumption (mean and SD) for the two groups 2, 6, 12, 36 and 48 h after operation. There was no significant difference between the groups at any period.

 

    Comment
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
The most common side-effects of systemic L-type calcium-channel blockers are attributable to excessive vasodilatation. Diltiazem and verapamil are less potent vasodilators than other L-type calcium channel blockers, e.g. the dihydropyridines. Diltiazem has a less negative inotropic effect than verapamil. For these reasons, we investigated diltiazem as an adjunct to epidural fentanyl in this study.

The vasodilating effects of diltiazem are present at plasma concentrations above 100 ng ml–1.5 The plasma diltiazem concentrations associated with a 20% prolongation of atrioventricular conduction time range from 65 to 250 ng ml–1.6 We gave diltiazem at an infusion rate of 1 µg kg–1 min–1. Katori and colleagues7 showed that diltiazem 1 µg kg–1 min–1 stabilizes the plasma concentration at 40–60 ng ml–1 2–4 h after the start of the infusion. Although we did not measure the plasma diltiazem concentration, no patient developed clinically significant hypotension or bradycardia during the study.

Naito and colleagues8 showed in rabbits that diltiazem penetrated rapidly into the cerebrospinal fluid (CSF) through the blood–brain barrier after i.v. administration, and the concentration in CSF reached a peak 5 min after the injection.8 The CSF/plasma ratio of diltiazem was 0.05–0.2, which is similar to that of nimodipine.9

It is probable that L-type calcium-channel blockers act more effectively by the epidural route. However, Koh and Cotman10 showed that verapamil and diltiazem 3 µM produced an increase in lactate dehydrogenase, released by damaged or destroyed cells. The migration of epidural catheters into the subarachnoid space is a well-documented complication. Although the toxicity of L-type calcium-channel blockers in the spinal cord is not clear, we selected the systemic route for the use of diltiazem.

In conclusion, low-dose diltiazem administered as an adjunct to epidural fentanyl offered no advantages in either pain relief or epidural fentanyl consumption after lower abdominal gynaecological surgery.


    References
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
1 Santillan R, Maestre JM, Hurle MA, Florez J. Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report. Pain 1994; 58: 129–32[CrossRef][ISI][Medline]

2 Omote K, Sonoda H, Kawamata M, Iwasaki H, Namiki A. Potentiation of antinociceptive effects of morphine by calcium-channel blockers at the level of the spinal cord. Anesthesiology 1993; 79: 746–52[ISI][Medline]

3 Cohen S, Pantuck CB, Amar D, Burley E, Pantuck EJ. The primary action of epidural fentanyl after Cesarean delivery is via a spinal mechanism. Anesth Analg 2002; 94: 674–9[Abstract/Free Full Text]

4 Cohen S, Lowenwirt I, Pantuck CB, Amar D, Pantuck EJ. Bupivacaine 0.01% and/or epinephrine 0.5 µg/ml improve epidural fentanyl analgesia after Cesarean section. Anesthesiology 1998; 89: 1354–61[CrossRef][ISI][Medline]

5 Joyal M, Pieper J, Cremer K, et al. Pharmacodynamic aspects of intravenous diltiazem infusion. Am Heart J 1986; 111: 54–61[CrossRef][ISI][Medline]

6 Fukuhara S, Echizen H, Naito M, et al. An interindividual variability in the sensitivity of atrioventricular node to diltiazem in patients with paroxysmal supraventricular tachycardia. J Clin Pharmacol 1989; 29: 102–6[Abstract/Free Full Text]

7 Katori K, Dan K, Horie T, Kubo N, Ohara G. The effect of prophylactic intravenous diltiazem drip infusion on myocardial ischemia during noncardiac surgery. Masui 1997; 46: 835–41[Medline]

8 Naito K, Nagao M, Otsuka S, Harigaya S, Nakajima H. Penetration into and elimination from the cerebrospinal fluid of diltiazem, a calcium antagonist, in anesthetized rabbits. Arzneim Forsch 1986; 36: 25–8[Medline]

9 Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm—a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 1983; 308:24.

10 Koh JY, Cotman CW. Programmed cell death: its possible contribution to neurotoxicity mediated by calcium channel antagonists. Brain Res 1992; 587: 233–40[CrossRef][ISI][Medline]





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