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PAIN MEDICINE

Perioperative Nimodipine and Postoperative Analgesia

Gerri Casey, SRN^*, Sally-Ann Nortcliffe, FRCA^*, Paul Sharpe, FRCA^*, and D. J. Buggy, MD, MSc, DME, FRCPI, FCA(Irel), FRCA

*Departments of Anaesthesia, Critical Care and Pain Management, University Hospitals of Leicester, Leicester General Hospital, Leicester LE5 4PW, UK and Mater Misericordiae University Hospital, Dublin 7, Ireland and Outcomes Research^TM Institute, Louisville, Kentucky

Address correspondence to Donal Buggy, MD, Department of Anaesthesia, Mater Misericordiae University Hospital, Dublin 7, Ireland. Address e-mail to donal.buggy{at}nbsp.ie. Reprints will not be available from the author.

	Abstract

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There is experimental evidence that nimodipine, an L-type dihydropiridine calcium channel blocker with relatively high blood-brain barrier penetration, enhances the antinociceptive properties of morphine. We tested the hypothesis that oral nimodipine taken preoperatively and 6 hourly for 48 h postoperatively would reduce visual analog scale pain scores and morphine consumption in morphine-naive patients with acute postoperative pain. Forty patients undergoing total knee replacement surgery (age 70 ± 7 yr, 28 male) were randomized by computer-generated numbers to receive capsules containing either nimodipine 30 mg or placebo in a double-blind study design. All patients received 3 capsules (nimodipine 90 mg or placebo) 1–2 h before induction of anesthesia followed by oral nimodipine 30 mg or placebo 6 hourly for 48 hours postoperatively. Spinal anesthesia was induced with hyperbaric bupivacaine 0.5% (2.4–3.0 mL) and fluids and ephedrine were given at the discretion of the anesthesiologist. Morphine patient-controlled analgesia (PCA, bolus 1 mg, lockout 5 min) was given for postoperative analgesia. Primary outcome measures were visual analog pain scores at rest and on moving (sitting forward) and PCA morphine consumption. Morphine consumption was significantly larger in nimodipine patients at 12 h (39 ± 18 versus 29 ± 15; P = 0.04), 24 h (62 ± 23 versus 45 ± 24; P = 0.02), and 48 h (88 ± 34 versus 61 ± 27; P = 0.01). There were no significant differences in pain scores at rest or moving or in time to first use of morphine analgesia. This study has demonstrated increased morphine consumption after 12 h in postoperative patients receiving nimodipine, suggesting that, in patients undergoing knee replacement surgery, it has no adjunctive analgesic effect and may actually inhibit the analgesic effect of morphine.

	Introduction

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Opioids are the mainstay of treating acute postoperative pain. However, they are associated with a number of adverse events, including nausea and vomiting, respiratory depression, mood alteration, and pruritus. Treatment with adjunctive analgesic drugs can have a morphine-sparing effect, thereby reducing these side effects. This has been demonstrated with nonsteroidal antiinflammatory drugs, such as diclofenac (1), but these drugs are associated with their own adverse event profile, including gastrointestinal hemorrhage and renal impairment.

There is growing evidence suggesting that voltage-gated calcium channels have an important role in the transmission of nociceptive impulses. Subtypes of voltage-gated calcium channels include L-, N-, and T- Ca²⁺ calcium channels. Calcium influx and efflux from sensory neurons appears to facilitate nociceptive neurotransmitter release in the spinal cord (2). Acute opioid exposure decreases intracellular calcium levels and Ca²⁺ binding to synaptic membranes (3). Conversely, increases in intracellular Ca²⁺ are associated with development of central sensitization after a noxious insult (4). L-type voltage-gated Ca²⁺ channels have been shown to have a functional role in morphine antinociception in a diabetic rat model (5).

It seems logical to hypothesize, therefore, that inhibition of Ca²⁺ into sensory neurons using calcium antagonists might reduce pain and requirement for morphine in clinical situations. Nimodipine is a dihydropiridine calcium channel antagonist, which binds to the L-type voltage gated calcium channel. It crosses the blood-brain barrier and is demonstrably effective in the prevention of secondary ischemic neurological damage after subarachnoid hemorrhage (6). There are case reports of its efficacy when administered epidurally in reducing pain and opioid requirement in patients receiving palliative analgesic therapy (7). However, a placebo-controlled cross-over study in cancer patients failed to demonstrate any analgesic benefit of oral nimodipine (8).

We tested the hypothesis in a randomized, double-blind, placebo-controlled clinical trial that perioperative nimodipine commenced preoperatively and continued for 48 h postoperatively would reduce pain and morphine requirements.

	Methods

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After obtaining Hospital Ethics Committee approval and written informed patient consent, 52 ASA I–III patients aged 40–80 yr were enrolled. All patients were scheduled for unilateral total knee arthroplasty. All surgery was performed by fully trained staff surgeons, assisted by trainee surgeons.

We chose spinal anesthesia for this study because we felt that patients would be more likely to be able to tolerate orally administered nimodipine in the immediate postoperative period. Therefore, any patient for whom spinal anesthesia was contraindicated, or who refused spinal anesthesia, was excluded. Other exclusion criteria were uncontrolled hypertension (because of the potential vasoactive properties of nimodipine) patients on concurrent medication for coronary artery disease, congestive cardiac failure, those taking calcium channel blockers already, and known allergy to calcium antagonists. The trial medication was withheld and the patient was withdrawn from the study, if the patient had a systolic blood pressure less than 100 mm Hg at the time the drug was due for administration.

After enrollment, patients were randomly allocated to one of two groups: the nimodipine group received a preoperative oral initial dose of nimodipine 90 mg 1 h before surgery, followed by oral nimodipine 30 mg 6 hourly for 48 h postoperatively.

The control group received identical placebo tablets at the same time intervals, which was performed in a double-blind fashion. This was achieved with assistance from our pharmacy department, who prepared identical capsules containing nimodipine and placebo and organized each patient’s supply of medication into a code-labeled tablet container.

At preoperative assessment, patients were informed about standard 100 mm visual analog scales (VAS) for pain measurement and the use of morphine patient-controlled analgesia (PCA), bolus 1 mg, lockout time 5 min. All patients had a standardized spinal anesthetic. Sedation with 1–3 mg of IV midazolam was permitted during the operation.

Patients were administered with 500 mL of compound sodium lactate solution before commencement of subarachnoid blockade. Hyperbaric bupivacaine 0.5%, 2.5–3.0 mL was administered via a 25-gauge pencil-point spinal needle. The precise volume varied depending on the physical size of the patient and was left to the clinical judgment of the anesthesiologist.

Dermatomal sensory level of block was recorded at 15 min before commencement of surgery. Any episodes of hypotension, defined as a reduction in baseline systolic blood pressure of more than 30%, or systolic arterial blood pressure <90 mm Hg, were treated with incremental doses of IV ephedrine.

After surgery, patients were attached to the PCA administration system. This was set to administer 1 mg bolus doses with a 5-min lockout. Before leaving the postanesthesia care unit, patients received a bolus dose of 0.05 mg/kg, as an initial dose for when the subarachnoid block regressed.

VAS scores for pain were recorded, at rest and on attempted knee flexion, at 2, 4, 6, 8, 12, 24 and 48 h postoperatively. Patients reporting VAS >50 mm received a further morphine 0.05 mg/kg bolus dose from the PCA; otherwise, patients were advised to use the PCA as required. Time to first use of PCA was recorded, as was morphine consumption at 2, 4, 6, 8, 12, 24 and 48 h after the study. Arterial blood pressure, respiratory rate, and sedation were also assessed at these intervals. Sedation was assessed by the following scale: 3 = rousable by physical stimuli, 2 = rousable by verbal command; 1 = drowsy, eyes closed occasionally, 0 = fully awake.

Data were collected and analyzed on SPSS v.10 for Windows (SPSS, Chicago, IL). Having confirmed that the data were normally distributed using the Kolmogorov-Smirnov test, Student’s independent samples, 2-sided, t-test was used for comparison of patient characteristics, morphine consumption, time to first rescue analgesia, VAS scores, sedation, and arterial blood pressure data. Bonferroni correction was used to correct for repeated comparisons. Chi-squared test was used for comparison of dichotomous variables.

The power of the study was calculated on the basis of VAS scores. Previous studies of knee replacement surgery patients indicated a standard deviation in VAS on moving of 20 mm. We decided that a VAS reduction of 20 mm was the minimum reduction in pain we wished to detect. Therefore, n = 21 patients in each group would be required if the risk of a Type I error was 5% and the risk of a Type II error 10%, giving the study a 90% power of detecting this difference in VAS. Permission to enroll 52 patients was sought to allow for withdrawals and protocol violations.

	Results

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We recruited 52 patients into the study. A total of 12 patients, 6 in each group, were withdrawn from the analysis. The most common reason was failure to establish spinal blockade. No patient failed to tolerate oral nimodipine. The study profile is outlined in Figure 1.

View larger version (26K): [in this window] [in a new window]   Figure 1. Study profile. GA, general anesthesia.

Both groups were well matched in terms of age, gender, and weight. Oral nimodipine therapy had no effect on the dermatomal distribution of block created by intrathecal bupivacaine or on rescue ephedrine requirement (Table 1).

Figures 2 and 3 show VAS scores at rest and on movement, respectively. There were no statistically significant differences between the two groups at any time period.

View larger version (23K): [in this window] [in a new window]   Figure 2. Visual analog scale (VAS) scores for pain at rest. Data shown are mean ±sd. There were no significant differences between the groups.

View larger version (24K): [in this window] [in a new window]   Figure 3. Visual analog scale (VAS) scores for pain moving. Data shown are mean ± sd. There were no significant differences between the groups.

Time to first use of PCA was 65 ± 54 min in nimodipine patients compared with 77 ± 51 min in placebo (P = 0.55). Time to rescue analgesia (bolus of morphine) was (mean ± sd) 255 ± 110 min in the nimodipine group compared with 203 ± 93 min in the placebo group (P = 0.24). There were no significant differences between the groups either in terms of arterial blood pressure and incidence of postoperative nausea or vomiting. Lowest systolic arterial blood pressure was 114 ± 21 in the nimodipine group compared with 115 ± 13 in the placebo group. Seven nimodipine patients (35%) compared with 8 placebo patients (40%) experienced nausea or vomiting postoperatively.

	Discussion

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We have shown that perioperative oral nimodipine therapy had no statistically significant effect on postoperative static or dynamic pain scores after knee replacement surgery. Surprisingly, we found that nimodipine resulted in increased postoperative morphine consumption at 12, 24, and 48 hours.

These are the first data to suggest an antianalgesic action of nimodipine, which contrasts with the findings of a clinical study comparing the analgesic efficacy of IV nimodipine infusion for 20 hours postoperatively, nifedipine 60 mg orally, and magnesium infusion after postoperative pain in a randomized, placebo-controlled study. Patients receiving nifedipine had higher resting pain scores and morphine consumption at 24–48 hours compared with the other groups. Nimodipine had no effect on pain or morphine consumption (9). As in our study, there is no clear explanation for this observation. Previous trials of L-type calcium channel antagonists in acute postoperative pain and cancer pain have produced conflicting results (8,10–12).

There are a number of reasons why we may have observed this unexpected increase in morphine consumption at 12–24 hours in patients receiving nimodipine. In contrast to Zarauza et al. (9), we gave intermittent doses of oral nimodipine, rather than a continuous infusion. It is possible that the dose we chose to administer, or the route of administration, was inadequate. Zarauza et al. used a continuous infusion, 30 µg · kg^–1 · h^–1 for 20 hours, in their study. However, the total dose of nimodipine given in this way would be approximately 40 mg in the average patient: our patients received 30 mg 6-hourly for 2 days. More recent data suggest that up to 3 times larger doses of nimodipine may be used safely, if given in divided aliquots up to 6 times daily (13). We have no reason to believe that absorption was less in patients receiving nimodipine compared with those receiving placebo: the incidence of intraoperative or postoperative nausea and vomiting was 15% and 10%, respectively. Perhaps larger doses over longer time periods might have yielded greater efficacy at L- or N-type calcium channels, leading to analgesia. However, our chosen dose of nimodipine has been shown to be clinically active in the treatment of subarachnoid hemorrhage (3) and produces effective serum and cerebrospinal fluid levels of the drug. It is also possible that administration of the Ca²⁺ antagonist closer to the spinal cord (i.e., via the spinal or epidural route) produces optimum efficacy.

The terminal half-life of nimodipine is only about 3 hours. Even if it is accepted that nimodipine in adequate concentration does enhance opioid analgesia, it is plausible that PCA opioid requirements might increase to compensate for decreased nimodipine levels more than 3 h after nimodipine administration.

N-methyl-d-aspartate (NMDA) calcium channels may be more important than Ca²⁺ channels in the establishment of central sensitization (5). This is supported by clinical evidence showing that the NMDA antagonist, ketamine, is more effective than calcium antagonists in postoperative pain (14). Furthermore, it is conceivable that L-type calcium channels may be less important than N- or T-type calcium channels in mediating an antinociceptive effect. An N-type Ca²⁺ antagonist prevented the inhibitory effect of free intracellular Ca²⁺ on morphine analgesia, an effect that was not seen with nimodipine, an L-type Ca²⁺ antagonist (15).

Perhaps most importantly, L-type calcium channels may have their primary role in mediating chronic, rather than acute, pain because they have a role in opioid tolerance (16). This may explain the discrepancy in results between trials of patients with acute and chronic cancer pain. However, our finding of a persistent antianalgesic effect of nimodipine from 12–48 hours remains puzzling and may be attributable to a Type I error. Detailed checks were made for errors in the study drug coding system, but it was proven to be correct.

In conclusion, in this randomized, double-blind, placebo-controlled, clinical trial, we found that perioperative oral nimodipine, continued for 48 hours after knee replacement surgery, was actually associated with larger morphine consumption than placebo. There were no differences in pain scores at rest or moving. These data do not support the use of nimodipine to reduce pain in the acute postoperative setting. If licensed N-type calcium channel antagonists emerge, their possible role in postoperative analgesia may warrant investigation.

We thank Ally Dulloo for his assistance with data collection, Ms. Gillian Hartley, Pharmacist, for coding the study medication and randomizing the patients and our surgical and nursing colleagues for their cooperation.

	Footnotes

 
Supported by University Hospitals of Leicester, Leicester General Hospital and The Mater College for Educational Research.

Accepted for publication September 19, 2005.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Casey, G. Articles by Buggy, D. J. Search for Related Content PubMed PubMed Citation Articles by Casey, G. Articles by Buggy, D. J.