Anesth Analg 2001;93:192-196
© 2001 International Anesthesia Research Society
REGIONAL ANESTHESIA
Amantadine, a N-Methyl-D-Aspartate Receptor Antagonist, Does Not Enhance Postoperative Analgesia in Women Undergoing Abdominal Hysterectomy
André Gottschalk, MD*,
Frank Schroeder, MD*,
Mike Ufer, MD*,
Ali Oncü, MS*,
Hartmut Buerkle, MD , and
Thomas Standl, MD*
*Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; and Department of Anesthesiology, Westfälische Wilhelms-Universität, Münster, Germany
Address correspondence and reprint requests to André Gottschalk, MD, Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Address e-mail to andregottschalk{at}hotmail.com
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Abstract
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N-methyl-D-aspartate (NMDA) antagonists administered before surgery will improve postoperative analgesia, presumably by inhibiting spinal sensitization processes. However, current clinical formulations of NMDA antagonists either enable only an oral application (i.e., dextromethorphan) or are associated with psychotropic side effects, as with the IV delivery of ketamine. Because of its noncompetitive NMDA receptor antagonist characteristics, amantadine may improve postoperative analgesia when administered before surgically induced trauma. In this prospective, randomized clinical study, we examined whether female patients undergoing elective abdominal hysterectomy experienced less postoperative pain when IV amantadine was applied in comparison with placebo before the start of surgery. Thirty patients were randomly assigned to receive 500 mL saline IV before the induction of standardized general anesthesia in Group 1 (Control group) or, in a double-blinded manner, 200 mg amantadine IV in 500 mL saline in Group 2 (Treatment group). Postoperative pain control was provided via IV patient-controlled analgesia with piritramide. During the first 48 h after tracheal extubation, pain perception was assessed by visual analog scales, and all analgesic requirements were documented. There were no significant differences between the two groups with respect to pain scores, postoperative analgesic requirements, and the incidence of side effects. Because of no differences in postoperative pain or opioid consumption, we conclude that a preoperative dose of 200 mg amantadine IV fails to enhance postoperative analgesia in patients undergoing elective abdominal hysterectomy.
Implications: Because of no differences in postoperative pain or opioid consumption, weconclude that a preoperative dose of 200 mg amantadine IV fails to enhancepostoperative analgesia in patients undergoing elective abdominalhysterectomy.
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Introduction
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Modern concepts of postoperative pain therapy aim to influence specific pain receptors via a multimodal pharmacologic intervention by receptor modulation before the pain stimulus arises. Central sensitization may be caused by the activation of N-methyl-D-aspartic acid (NMDA) receptors, which may contribute to the postoperative pain (1–5). The excitatory amino acid glutamate binds to the NMDA receptor localized in the dorsal horn of the spinal cord after presynaptic liberation from afferent nerve fibers. If this binding is suppressed or inhibited, neuropathic pain, inflammation pain, and surgically induced pain may be reduced (1,6). However, most of the clinically available NMDA antagonists are available only for oral administration, such as dextromethorphan, or they display serious psychotropic side effects, as with ketamine. Amantadine, another noncompetitive NMDA receptor antagonist, has been used in the therapy of Parkinson’s disease, dementia, and spasticity. Its formulation permits either an oral route of drug delivery or, more appealing in the perioperative setting, an IV route of administration. For all routes, the side effect profile of amantadine in appropriate dosages seems to be nonharmful. In two clinical reports, IV administration of amantadine resulted in decreased neuropathic pain in cancer patients and showed less chronic neuropathic pain up to 5 mo after the administration of amantadine, in contrast to the Control group (7,8). This study examines whether the advantages of NMDA receptor inhibition described for neuropathic pain can be transferred to surgical patients. After a randomized, double-blinded, placebo-controlled protocol, 30 female patients received either 200 mg amantadine or saline IV before they underwent abdominal hysterectomy using general anesthesia.
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Methods
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After approval of the local ethics committee, 30 adult female patients, ASA physical status I–III, who were undergoing elective abdominal hysterectomy were enrolled in this randomized, double-blinded, placebo-controlled study. After written informed consent was obtained, patients were assigned to one of the two study groups according to a computer-generated random list. Exclusion criteria consisted of preoperative opioid use or dependency, renal dysfunction, medication with psychopharmaceuticals or nonsteroidal antiinflammatories, obstructive glaucoma, chronic obstructive lung disease, and allergy to amantadine. All patients underwent this operation because of uterine myoma.
Patients received 0.1 mg/kg midazolam orally 45 min before they were transferred to the anesthesia room. Thirty minutes before the induction of general anesthesia, patients of Group 1 (Placebo group) received 500 mL saline IV, whereas those in Group 2 received 200 mg amantadine in 500 mL saline IV (Treatment group) within 30 min. The IV route of amantadine was chosen because oral intake of this drug is not absolutely reliable before abdominal surgery, and peak concentrations can be reached only within 1 to 3 h. The respective infusion was given by an anesthesiologist who was not otherwise involved in the study. Patients and investigators were blinded to the protocol. On the day before surgery, patients were asked about preexisting pain by use of a 100-mm visual analog scale (VAS) (0= no pain, 100= unbearable pain).
General anesthesia was induced with remifentanil via perfusor with an initial dose of 0.3 µg · kg-1 · min-1 IV and propofol 2 mg/kg IV. Tracheal intubation was facilitated with cisatracurium 0.1 mg/kg IV. Anesthesia was maintained with IV remifentanil 0.2–0.3 µg · kg-1 · min-1 and propofol 6–8 mg · kg-1 · h-1. Patients were ventilated with a fraction of inspired oxygen of 0.3, and a PETCO2 of 32–36 mm Hg was maintained. Infusions of remifentanil and propofol were stopped at the end of operation (skin closure).
Immediately after tracheal extubation, patient-controlled anesthesia was initiated for postoperative pain management in both study groups. Patients were allowed to administer 3.5 mg piritramide IV per application with a 5-min lockout and a 4-h maximum of 45 mg. Ten milligrams of piritramide is equivalent to 7.5 mg morphine (9). Piritramide consumption was registered continuously over 48 h by the pump.
Patients were monitored during the first four (minimum) to six (maximum) postoperative hours in the recovery room. After that period, they were transferred to the ward without additional monitoring.
Immediately after admission to the recovery room (Hour 0) and 1, 2, 4, and 6 h later, patients were evaluated with respect to the level of consciousness (1 = fully awake; 2 = sleepy, easy to wake; 3 = sleepy, difficult to wake; 4 = unconscious), incidence of nausea, allergic reactions, pruritus, shivering, and intensity of pain by an blinded observer with a standardized questionnaire. Patients evaluated the intensity of pain at rest and with cough by use of the VAS. Noninvasive arterial blood pressure, heart rate, body temperature (tympanion), respiratory rate, and episodes of vomiting were recorded. Twenty-four and 48 h after the operation, evaluations were performed on the ward.
Continuous variables between groups were tested for statistical significance by using unpaired Student’s t-tests. Nonparametric data were tested with the  2 test. P < 0.05 was considered to be statistically significant.
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Results
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Patients did not differ with respect to demographic data or time of surgery and anesthesia (Table 1). ASA status was evenly spread between groups. Comparison of the vital variables (systolic and diastolic blood pressures, heart rate, respiratory rate, and tympanic temperature) also did not reveal significant differences between groups during the study period. The infusion of amantadine was well tolerated by each patient, and no remarkable side effects were observed after a dose of 200 mg IV.
Before the induction of anesthesia, patients showed smaller VAS values in the Control group compared with the Treatment group (0.3 ± 1.3 vs 1.9 ± 4.5 at rest, P < 0.05; and 0.3 ± 1.3 vs 2.6 ± 6.2 on coughing, P < 0.05). In addition, patients receiving amantadine showed a significantly larger subjective pain perception at rest on extubation than did patients in the Control group (P < 0.05) (Fig. 1, A and B). No significant differences of VAS between groups were observed. No additional significant differences between groups were found with respect to piritramide consumption within the first 48 postoperative hours (Fig. 2). Levels of consciousness were similar in both groups (Table 2).
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Figure 1. (a) Comparison of pain perception (VAS 0–100) by patients at rest. (b) Comparison of pain perception (VAS 0–100) by patients on coughing. Data are mean ± SD. *P < 0.05 versus Control group. 0 = immediately after extubation. VAS = visual analog scale.
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The incidence of side effects was also comparable between groups. In each group there was one patient with preexisting nausea before the induction of anesthesia. Incidences of nausea and vomiting and antiemetic requirements (5-hydroxytryptamine-3 antagonists) are shown in Table 3. One patient of each group suffered from shivering in the first hour after extubation. Pruritus or allergic reactions were not seen during the whole study period in any patient.
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Discussion
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This placebo-controlled study failed to show improved analgesia when the NMDA-receptor antagonist amantadine was administered before surgery in patients undergoing abdominal hysterectomy. Although there are several studies suggesting analgesic effects of amantadine in neuropathic pain states, acute postoperative pain might differ from other pain states, such as inflammatory pain or neuropathic pain. Our results are in accordance with data obtained by other investigators, who also could not find improved postoperative analgesia by the preadministration of noncompetitive NMDA antagonists, such as dextromethorphan or ketamine (10–12). Although there was no difference in the required intraoperative opioid dosages, the preexisting more intense pain level in the Amantadine group might have affected the postoperative outcome measures. Because the significantly higher VAS values were measured only before the application of amantadine and immediately after extubation, a carryover effect of the enhanced preoperative VAS assessment might be a possible explanation for this observation in the treatment group. Because amantadine has an elimination half-life of 10 to 14 hours, one could argue that amantadine has a certain analgesic effect, because the VAS assessments that were higher in the amantadine group before and immediately after surgery were comparable between groups after two hours, indicating a reduction in VAS in the Amantadine group. However, in the setting of this study, differences in VAS before surgery and immediately after extubation seem clinically irrelevant, although Aida et al. (13) found that preexisting pain may affect the success of preemptive analgesic interventions. In addition, the same group has suggested that visceral pain might not be responsive to the concept of early (i.e., before tissue injury) NMDA-receptor inhibition (14). However, these latter suggestions are in contrast to studies revealing a preemptive analgesic effect of the noncompetitive antagonist dextromethorphan in patients undergoing tonsillectomy (1). In this study we were using amantadine, because one of the major advantages of amantadine over dextromethorphan is its IV mode of delivery, thereby enhancing its availability. In comparison with ketamine, amantadine is well tolerated and has a low side effect profile (mainly sedation, dry mouth, and dizziness).
The results of previous studies investigating the analgesic effects of NMDA receptor blockade in the context of abdominal hysterectomy are contradictory. Henderson et al. (15) observed a significantly reduced consumption of analgesics after abdominal hysterectomy with the preoperative administration of dextromethorphan, whereas McConaghy et al. (12) found no improved postoperative analgesic effects in a comparable setting. The same results were obtained by Dahl et al. (16), who could not show a preemptive analgesic effect with ketamine. However, postoperative pain perception in these studies is probably influenced by various factors, such as the intraoperative administration of morphine and diclofenac and wound infiltration with bupivacaine, which outlasted the end of surgery. To avoid a continuing effect of the intraoperatively-administered analgesics, we used remifentanil for intraoperative analgesia because of its excellent pharmacokinetic and pharmacodynamic characteristics, which allow immediate assessment of pain after termination of the infusion.
A further explanation for the ineffectiveness of the amantadine treatment in this study might be explained by the fact that the prevention and therapy of acute and intense perioperative pain requires more NMDA receptor blockade than treatment of chronic pain states. The relatively decreased potency of amantadine in blocking the NMDA receptor, in comparison with other NMDA receptor antagonists such as memantine or ketamine, suggests that a larger dose of amantadine would have probably been required to obtain significant effects.
Thus, further studies are needed with NMDA-receptor antagonists with a more intense affinity for the specific receptor or a larger dose or earlier application of the respective drug. Whether, in the clinical setting of fast-tracking general anesthesia, NMDA receptor antagonists with few side effects, such as amantadine, might be important in reducing postoperative pain intensity and analgesic requirements has still to be elucidated.
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References
|
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-
Kawamata T, Omote K, Kawamata M, Namiki A. Premedication with oral dextromethorphan reduces postoperative pain after tonsillectomy. Anesth Analg 1998; 86: 594–7.[Abstract]
-
Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 1987; 26: 1235–8.[Web of Science][Medline]
-
Dickenson AH. Plasticity: implications for opioid and other pharmacological interventions in specific pain states. Behav Brain Sci 1997; 20: 392–403.[Web of Science][Medline]
-
Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293–9.[Web of Science][Medline]
-
Xu XJ, Zhang X, Hokfelt T, Wiesenfeld-Hallin Z. Plasticity in spinal nociception after peripheral nerve section: reduced effectiveness of the NMDA receptor antagonist MK-801 in blocking wind-up and central sensitization of the flexor reflex. Brain Res 1995; 670: 342–6.[Web of Science][Medline]
-
Baron R. Neuropathic pain: Pathophysiological concepts, predictors and new therapies. Aktuelle Neurologie 1997; 24: 94–102.
-
Pud D, Eisenberg E, Spitzer A, Adler R, et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain 1998; 75: 349–54.[Web of Science][Medline]
-
Eisenberg E, Kleiser A, Dortort A, et al. The NMDA (N-methyl-D-aspartate) receptor antagonist memantine in the treatment of postherpetic neuralgia: a double-blind, placebo-controlled study. Eur J Pain 1998; 2: 321–7.[Web of Science][Medline]
-
Kay B. A clinical investigation of piritramide in the treatment of postoperative pain. Br J Anaesth 1971; 43: 1167–71.[Abstract/Free Full Text]
-
Rose JB, Cuy R, Cohen DE, Schreiner MS. Preoperative oral dextromethorphan does not reduce pain or analgesic consumption in children after adenotonsillectomy. Anesth Analg 1999; 88: 749–53.[Abstract/Free Full Text]
-
Grace RF, Power I, Umedaly H, et al. Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparotomy. Anesth Analg 1998; 87: 1135–8.[Abstract/Free Full Text]
-
McConaghy PM, McSorley P, McCaughey W, Campbell WI. Dextromethorphan and pain after total abdominal hysterectomy. Br J Anaesth 1998; 81: 731–6.[Abstract/Free Full Text]
-
Aida S, Fujihara H, Taga K, et al. Involvement of presurgical pain in preemptive analgesia for orthopedic surgery: a randomized double blind study. Pain 2000; 84: 169–73.[Web of Science][Medline]
-
Aida S, Baba H, Yamakura T, et al. The effectiveness of preemptive analgesia varies according to the type of surgery: a randomized, double-blind study. Anesth Analg 1999; 89: 711–6.[Abstract/Free Full Text]
-
Henderson DJ, Withington BS, Wilson JA, Morrison LM. Perioperative dextromethorphan reduces postoperative pain after hysterectomy. Anesth Analg 1999; 89: 399–402.[Abstract/Free Full Text]
-
Dahl V, Ernoe PE, Steen T, et al. Does ketamine have preemptive effects in women undergoing abdominal hysterectomy procedures? Anesth Analg 2000; 90: 1419–22.[Abstract/Free Full Text]
Accepted for publication February 14, 2001.
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Abstract
Introduction
