Enhancement of the epidural morphine-induced analgesia by systemic nifedipine

Pain, 53 (1993) 341-355 0 1993 Elsevier Science

341 Publishers

B.V. All rights reserved

0304-3959/93/$06.00

PAIN 02303

Enhancement

of the epidural morphine-induced by systemic nifedipine

Ivan T. Pereira

a, Wiliam A. Prado

b, and Marlene

analgesia

P. DOS Reis a

Departments of ’ Surgery, Orthopedics and Traumatology, Discipline of Anesthesiology, and b Pharmacology, Faculty of Medicine of Ribeiriio Preto, Ribeinio (Brazil) (Received

27 July 1992, revision

received

16 December

1992, accepted

21 January

1993)

We evaluated postoperative pain relief and incidence of side effects of the combination of epidural Summary morphine (0.5 mg) and sublingual nifedipine (10 mg). Thirty-six patients were submitted to elective operations and divided into 4 groups receiving placebo (groups A and B) or morphine (groups C and D) by the epidural route, followed by sublingual placebo (groups A and C) or nifedipine (groups B and D) administered in a double-blind fashion. The mean ( f S.E.M.) periods of analgesia were 16.6 f 1.6 (A), 15 (B) 105 f 77.0 (0, and 428.8 + 72.0 (D) min. No patient had pruritus, excessive sedation or respiratory depression. Episodes of nausea and/or vomiting requiring no specific therapy were observed in groups A, B and D. Nifedipine-treated groups also had a significant fall in blood pressure which was controlled by rehydration. These results indicate that epidural morphine-induced postoperative pain relief may be enhanced by systemic administration of nifedipine, with easily controlled side effects. Key words:

Epidural morphine; Nifedipine; Postoperative

Introduction

Epidural administration of opioids has been widely shown to provide strong and long-lasting relief of experimental, postoperative, and chronic pain (Cousins and Mather 19841, accompanied by minimal changes in sympathetic, sensory or motor functions (Cousins et al. 1979; Wang et al. 1979; Bromage et al. 1980b). However, a number of side effects such as pruritus, nausea and vomiting, urinary retention, hypotension, and lifethreatening respiratory depression have also been reported to be associated with the clinical use of epidural opioid analgesia (Bromage et al. 1982; Lanz et al. 1982). The usual doses of morphine for epidural analgesia range from 2 to 10 mg (Cousins and Mather 19841, the larger doses being associated with a higher incidence of Correspondence to: Dr. W.A. Prado, Department of Pharmacology, Faculty of Medicine of RibeirCo Preto, 14049-900 Ribeirlo Preto, SP, Brazil. Tel.: (016) 633-3035, ext. 246; FAX: (016) 633-1586.

pain; Calcium-channel

blocker

side effects. Thus, alternatives which result in minimal concentrations of opioids within the cerebrospinal fluid with maximum analgesic effects may be useful for the clinical management of pain (El-Baz et al. 1984; Tamsen and Gordh 1984; Hjorts et al. 1985). Several groups of investigators have shown that calcium channel blockers such as verapamil, nimodipine, nifedipine, and cinnarizine may potentiate opioid antinociception in rodents (Benedek and Sziksay 1984; Del Pozo et al. 1987; Contreras et al. 1988). Fentanyl analgesia is also potentiated in patients by simultaneous intravenous administration of nimodipine (Van Borman et al. 1985). More recently, it was shown that intrathecal administration of cinnarizine produces antinociception and enhances opioid antinociception in rats (Rego et al. 1990). This evidence prompted us to study the effects of systemic administration of nidefipine on epidural morphine-induced relief of postoperative pain following a variety of surgical procedures in patients admitted to the gynecology department of a large teaching hospital.

342

Methods Thirty-six women aged 23-65 years and weighing 45-78 kg, who underwent elective gynecological operations (hysterectomy and colpoperineoplasty, with or without tubal ligature) were studied. The study was approved by the Ethics Committee of the University Hospital of the Faculty of Medicine of Ribeirlo Preto, and informed consent was obtained from all patients. None of the selected patients had received opioid for at least 30 days before surgery. On the day before surgery, body weight, initial arterial pressure, and initial heart rate were recorded. The patients were also informed to request an analgesic if pain of any intensity occurred during the post-surgical period. Premeditation consisted of 0.1-0.2 mg/kg diazepam (Valium; Roche) (maximum dose: 10 mg), administered intravenously 30 min before surgery. The lumbar epidural space was then identified using a Touhy 18-ga epidural needle and the ‘loss of resistance’ technique. An epidural catheter was threaded into the space via the needle to protrude 5 cm beyond the needle tip. Intravascular and intrathecal placements were excluded by the absence of changes in both pressure and heart rate recorded 2 min after a test dose of local anesthetic (3 ml of a solution containing 2% lidocaine with adrenaline 1: 200000) given through the catheter. Anesthesia was then induced with thiopentone sodium (Thionembutal; Abbott) at a dose of 5-7 mg/kg, and endotracheal intubation was facilitated by intravenous injections of succinylcholine (Quelicin; Abbott) at a dose of 1.0-2.0 mg/kg (maximum dose: 100 mg). Anesthesia was mantained with nitrous oxide (50%) in oxygen (50%), and enflurane (Etrane; Abbott) at 1.5-2.5% inspired concentration. Muscle relaxation was provided by intravenous injection of 0.1 mg/kg pancuronium (Pavulon; Organon). Inhalation anesthesia was discontinued at the time of wound closure. Residual neuromuscular blockade was antagonized 10 min later with 2 mg neostigmine (Prostigmine; Roche) and 1 mg atropine sulfate. The patients were then randomly assigned to 4 groups. Patients in groups A and B received a bolus epidural injection of 10 ml drug-free saline as placebo. Patients in groups C and D received a bolus epidural injection of 0.5 mg morphine sulfate (Dimorf; Cristalia) diluted to a volume of 10 ml with preservative-free saline. The patients were then extubated, the epidural catheter was withdrawn, and final arterial pressure and final heart rate were recorded 3 min later. After these procedures a capsule containing 10 mg nifedipine (Adalat; Bayer) was perforated and its content dropped under the tongue of each patient in groups B and D. Patients in group A and C received 0.5 ml of drug-free saline as placebo by the same route. All drugs and placebos were administered in a double-blind fashion. Drug and placebo were transferred to droppers and given by one experimenter (I.T.P.) who was unaware of the contents of epidural and sublingual administrations. The same observer also carried out data recordings throughout the experiment. A maximum period of 15

TABLE PATIENT

Results

The 4 groups were similar with regard to age, body weight, and duration of operation (Table 11). No patient reported the occurrence of pruritus, nor was excessive sedation or respiratory depression noticed in any case. None of the patients had a respiratory frequency of less than 10 breaths per min. Three patients in groups D (33%) and 1 in group A (12%) had an episode of nausea and vomiting. Two patients in group B had nausea (22%). These side effects occurred within 1 h of sublingual administration, were of mild intensity, and did not require specific treatment. No patient in group C had nausea or vomiting. The groups were different with regard to the mean period of analgesia (x2 = 24.9, P < 0.01; values correct for ties, Kruskall-Wallis test) (Fig. 1). One patient in

I DATA

Mean (+ S.E.M.) values. Group

min elapsed between the discontinuation of anesthesia and the sublingual administration of nifedipine, which was taken as t = 0 min. Arterial pressure and heart rate were recorded at t = 60, 120, 180, and 240 min. Drug-free saline was infused intravenously for correction of any fall in arterial pressure. The occurrence of respiratory depression, nausea, vomiting, pruritus, or excessive sedation was recorded and treated when necessary. Urinary retention could not be assessed since all patients had a urinary catheter in place. All patients were monitored for 12 h following sublingual nifedipine or placebo administration. A routine parenteral analgesic (3 ml of a solution containing demerol, dipirone, and prometazine at concentrations of 50, 500, and 50 mg/ml, respectively) was provided if the patient complained of pain of any intensity during the 12-h period of monitoring. After this period, a nurse-administered p.r.n. system was established. The time between t = 0 and the moment at which the patient complained of pain was considered to be period of analgesia. One observer (I.T.P.) determined when the patient would receive routine analgesic medication and provided it. Demographic data were analysed using Student’s t-test for unpaired data. Differences in the periods of analgesia among the 4 groups were compared using the Kruskall-Wallis test followed by the Mann-Whitney CJ test. Data on cardiovascular parameters were submitted to MANOVA analysis of variance (multiple range test) followed by a Duncan test. P < 0.05 was regarded as significant in all cases.

Ranges

are indicated

between

Treatments Epidural

Sublingual

A

placebo

placebo

B

placebo

nifedipine

C

morphine

placebo

D

morphine

nifedipine

brackets. Age (year)

Weight (kg)

Duration of surgery (min)

43 & 3 (29-60) 44 + 3 (32-59) 40 * 4 (23-65) 40 * 2 (30-50)

58.5 + 2.1 (54-70) 59.6 & 2.9 (48-74) 59.7 * 1.9 (53-71) 60.4 + 3.4 (45-78)

126+ 8 (85-180) 182f9 (150-225) 173 * 12 (120-240) 191 f 15 (120-290)

343 0

0

0 0 0

1 00 00 0

b w

p

sl

P

P N

M P

M N

Fig, 1. Individuals (0) and mean (0) periods of analgesia in patients receiving epidural (ep) morphine (M = 0.5 mg) or placebo (PI followed by sublingual (sl) placebo or nifedipine (N = 10 mg). Vertical bars = S.E.M.

group A had a 30-min period of analgesia. The remaining patients in group A and all patients in group B requested additional analgesia within 15 min following sublingual administration. Six patients in group C had pain within 15 min following sublingual placebo, 1

cmtig 13 -

requested no additional analgesic, and 2 patients had periods of analgesia lasting not longer than 100 min. No patient in group D had analgesia for periods shorter than 220 min, and only 1 was pain free throughout the experiment. All patients in this study, except for two cases who had a 12-h period of analgesia (Fig. 11, required routine analgesic. No patient, however, required more than one dose of routine analgesic for complete pain relief throughout the remaining period of monitoring. The mean periods of analgesia (It S.E.M) were 16.0 5 1.6 min in group A, 15 (B), 105.0 -t_77.0 (0, and 428.0 f 72.0 (D). The Mann-Whitney U test revealed that the mean values of groups B and C (U = 30) were not significantly different and did not differ significantly from the mean value of group A (U = 40 and 33, respectively). Ln contrast, the mean period of analgesia in group D was significantly longer than in group A fU = 0; P < 0.00, B (U = 0; P < 0.011, and C (U = 8.5; P < 0.01). The experimental groups did not differ significantly with regard to the mean heart rate (not shown) and mean systolic and diastolic pressures (Fig. 2) recorded before or immediately after the surgical procedures. The heart rate also did not change significantly in any group up to 4 h following sublingual administration of placebo or nifedipine (not shown). The data in Fig. 2 also show that systolic and diastolic pressures did not vary significantly with time in groups A, B, and C, whereas a significant fall in both pressures was observed in group D. This fall in blood pressure, however, was easily controlled in all patients by intravenous infusion of drug-free saline. Analysis of variance of the data as a whole indicates that the groups had different changes in systolic pres-

cmHg L “Jl

I2

-1 P 7-

12

10 -

i

f

1 time

2 (h)

3

4

I

f

1 time

2 (h1

3

4

Fig. 2. Changes in the systolic (left) and diastolic (right) arterial pressures induced by postoperative epidural injections of morphine (M = 0.5 mg) or placebo (P) followed by sublingual administration of placebo or nifedipine (N = 10 mg). Recordings were made on the day before surgery(i), 3 min after discontinuation of anesthesia (f), and 1, 2, 3, and 4 h after sublingual administration. (01 group A (P + PI, (*I group B (M + P), (D I group C (P + NJ, and (~1 group D (M + N). Points are the mean f i S.E.M.) of 9 patients per group. (1) Significantly different from any other group; (2) Signi~cantly different from groups A and B, (3) Signific~tly different from group B; f8 Signi~cant~y different from groups B and C (P < 0.05, Duncan’s test).

344

sure with the time after sublingual administration (F3,32 = 7.44; P < 0.01). A non-significant difference between groups was found with regard to variations in diastolic pressure with the time (F3,s2 = 2.01; P = 0.13). Duncan’s test revealed significant differences in the systolic pressures at 1 h (F = 10.91, 2 h (9.63), 3 h (7.41, and 4 h (7.26), and diastolic pressures at time 1 h (5.03) and 2 h (4.09). The F value for diastolic pressure at 3 h (2.35) was not significant (P = 0.09) but group D was significantIy different from groups B and C. No difference among groups was found for diastolic pressures recorded at 4 h (F = 1.45; P = 0.24).

Discussion The present study shows that a single dose of sublingual nifedipine significantly enhances and prolongs the postoperatory pain relief induced by epidural morphine. Epidural morphine at doses equal to or higher than 2 mg has been reported to be necessary for an effective relief of postoperative pain (Crawford et al. 1981; Rawal et al. 1981; Hughes et al. 1982; Martin et al. 1982), the frequency of successful analgesia being higher for the 5-mg dose (McClure et al. 1980). In this study we deliberately chose a smaller morphine dose (0.5 mg) which alone should not produce effective pain relief. In fact, patients receiving epidural morphine followed by sublingual placebo (group Cl had a very short mean period of analgesia (15 min) which was not significantly different from control patients (group A). However, 1 patient in group C was pain-free throughout the experiment. We could not determine whether this patient had a particularIy high pain threshold or high sensitivity to the analgesic effect of morphine. The majority of our control patients complained of pain within 30 min following sublingual administration of placebo. All patients receiving sublingual nifedipine following epidural placebo (group B) complained of pain within 15 min. The systemic effects of nifedipine is known to begin within 2-3 min after sublingual administration, but its peak plasma concentration is reached within about 60 min (Patzschke et al. 1975; Ramsch 1981). The additional routine analgesic used here does not permit us to exclude a late analgesic effect of nifedipine, but it is clear that nifedipine had no early analgesic effect at the dose used here. Nifedipine also exhibits no analgesic property following systemic (Ramaswamy et al. 1986; Contreras et al. 1988) or intrathecal administration to rodents (Rego et al. 1990). The mean period of analgesia in patients receiving epidural morphine and sublingual nifedipine (group DI was about 4 times longer than in patients of group C. Since different degrees of pain were not evaluated,

these results do not allow us to distin~ish pain from anxiety, fright or general discomfort. It is possible, therefore, that the degree of the nifedipine-induced potentiation of opiate antinociception was underestimated. Postoperative analgesia provided by epidural opiates is accepted to be the result of a selective blockade of opiate nociceptors in dorsal horn cells (Bromage et al 1980a). This effect has been attributed to a decreased synaptosomal calcium concentration (Guerrero-Mu~oz et al. 1979; Ross and Cardenas 1979; Kamikubo et al. 19831, probably due to an opiate-induced reduction in the voltage-dependent calcium entry into neurons (North and Williams 1983; Duggan and North 1984). It is tempting, therefore, to speculate about an additive interaction of nifedipine and morphine at the level of transmembrane calcium currents on dorsal horn cells. None of our patients had pruritus, excessive sedation, or respiratory depression. These side effects are frequently observed in patients receiving doses of epidural morphine higher than 0.5 mg (Cousins and Mather 1984). Patients receiving epidural morphine and sublingual placebo had no episodes of nausea or vomiting. Nausea and vomiting may frequently occur a few hours after epidural injection of higher doses of morphine (Bromage et al. 1982). In contrast, 22% of the patients treated with epidural placebo and sublingual nifedipine had nausea, and 33% of patients receiving the combination of morphine and nifedipine had an episode of nausea and vomiting. These effects were of mild intensity, occurred shortly after sublingual nifedipine, and required no anti-emetic therapy. These characteristics resemble those observed in non-operated patients treated with sublin~al nifedipine only (Ebner and Diinschede 1976). Therefore, the episodes of nausea and vomiting occurring in our patients were probably due to nifedipine and not to an additive interaction of nifedipine and morphine. Neither experimental group showed significant changes in mean heart rate throughout the experiments. The mean systolic and diastolic pressures also did not change significantly in patients receiving epidural morphine and sublingual placebo. In contrast, a significant fall in both systolic and diastolic pressures was observed in all patients treated with sublingual nifedipine, The recordings made 10 min after nifedipine in patients of groups B and D were not significantly different. However, a longer period elapsed for a full return to the control level in patients treated with epidural morphine and sublingual nifedipine. Hypotension is not a common side effect of epidural morphine administration (Bromage et al. 1980a) since it depends on systemic circulation of the opioid to produce histamine release and attenuation of the sympathetic stimulation-induced vasoconstriction (SzCkely 1982). Nifedipine impairs the transmembrane calcium

345

flow in vascular smooth cells, a property which confers to this drug a strong and abrupt vasodilatory action (Greenberg 1987). An additive interaction of nifedipine and mo~hine, therefore, is unlikely to determine the early fall in both systolic and diastolic pressure. However, the present results do not allow us to exclude that such interaction may be the reason for the longer period of hypotension observed in group D. Whatever the cause, the hypotension was easily controIled by hydric replenishment. In summary, this study shows that postoperative pain relief produced by epidural administration of morphine may be enhanced and prolonged by sublingual administration of nifedipine with minimal and easily controlled side effects.

Acknowledgement

We thank manuscript.

Mrs.

F.H.F.

Petean

for

typing

the

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