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From the Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Yahatanishiku, Kitakyushu, Japan.
Address correspondence to: Dr. Kouichiro Minami, Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan. Phone: +81-93-691-7265; Fax: +81-93-601-2910; E-mail: kminami{at}med.uoeh-u.ac.jp
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Abstract |
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Methods: ASA physical status I or II adult patients (n = 30) presenting for major elective orthopedic surgery of the upper extremities or mastectomy were enrolled. Patients were randomly assigned to receive treatment with tramadol (n = 10), famotidine (n = 10), or saline (n = 10). General anesthesia was then induced using propofol, vecuronium bromide, and fentanyl. After inducing anesthesia, the gastric pH was measured using pH test paper and, then, 100 mg tramadol, 20 mg famotidine, or saline were injected into the deltoid muscle. Three hours after starting the operation, gastric juice was again aspirated and its gastric pH measured.
Results: There were no differences in the pH before anesthesia between the three groups. By contrast, gastric pH was increased in the tramadol group by the same amount as it was in the famotidine group three hours after administering the drugs. Gastric pH of the saline, famotidine, and tramadol groups was 2.6 ± 2.5, 6.3 ± 2.0, and 6.4 ± 0.8, respectively.
Conclusion: These results suggest that tramadol inhibits the secretion of gastric acid.
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Introduction |
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). Tramadol binds to µ-opioid receptors with approximately 100 times less affinity than morphine1 and tramadol causes much less respiratory depression than equianalgesic doses of morphine.2 This suggests that the antinociceptive action of tramadol is not due to opioid receptor binding, but may occur via a different mechanism that is not yet understood. Recently, we reported its inhibitory effects on cholinergic receptors.3,4 Sagata et al. reported that atropine displaces (14C)-tramadol binding to adrenal medullary cells.3 Shiraishi et al. showed that tramadol at clinically relevant concentrations inhibits muscarinic receptor function. More recently, it was also reported that tramadol inhibits type-3 muscarinic receptor (M3) function at clinically relevant concentrations.4 In a clinical setting, tramadol sometimes causes a dry mouth and constipation.1 Our previous findings may explain the modulation of the anticholinergic effects of tramadol.
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We investigated the effects of tramadol on the pH of gastric juice during anesthesia to determine whether tramadol inhibits secretion from the gastric glands.
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Methods |
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General anesthesia was induced using propofol 1.5 mg•kg–1, vecuronium bromide 0.1 mg•kg–1, and fen-tanyl 1.2 µg•kg–1. An orogastric tube (15-Fr; JF-C15120C, JMS, Hiroshima, Japan) was inserted by the same anesthesia resident in all patients, who aspirated the gastric juice and measured gastric pH using pH test paper (pH-Fix 0-14 and pH-Fix 4.5-10, Macherey-Nagel GmbH, Drüen, Germany). The resident was blinded to group assignment. A patient was eliminated from the study if more than two attempts were required to pass the gastric tube. After induction, 100 mg tra-madol, 20 mg famotidine, or saline in an equal volume (2 mL) were injected into the deltoid muscle. Ventilation was adjusted to maintain the PaCO2 at 35 to 40 mmHg. Anesthesia was maintained with 1.0 to 1.5% isoflurane in combination with 67% nitrous oxide in oxygen. Three hours after starting the operation, a new orogastric tube (15-Fr) was inserted and gastric juice was aspirated and the pH measured again.
The results are presented as the mean ± SD. The data were analyzed using analysis of variance, and a post hoc test (Scheffe test). A P value < 0.05 was accepted as statistically significant.
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Results |
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). No patient was eliminated from the study because of difficulty with the insertion of the oro-gastric tube. There was no difference in the pH before anesthesia among the three groups (P = 0.8282, power 0.08; Table II). The pH of the gastric juice did not change in the control group three hours after administering saline (P = 0.77, power 0.06). By contrast, gastric pH was elevated in the tramadol (P = 0.0002, power 0.98) and famotidine (P < 0.0001, power 0.999) groups. There were no significant differences among the groups in postoperative outcomes.
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Discussion |
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Lintz et al. reported that the minimal effective serum concentration was reached within a few minutes.7 The maximum plasma concentration peaked at 193 µg•mL–1 0.75 hr after 50 mg tramadol im and terminal elimination half-life was 5.5 hr in 12 healthy male subjects.7 Noguchi et al., previously reported that the effect of im famotidine reached a peak 120 min after injection.8 Therefore, we measured the gastric pH three hours after administration. It has also been reported that tramadol concentrations are considerably higher in saliva and urine than in serum and that minimal effective serum concentrations are maintained for nine to ten hours on average.7 The concentration/time relationship of tramadol in the gastric mucosa remains unknown.
In recent studies, we suggested that tramadol inhibits muscarinic receptor function.3,4 Sagata et al. reported that (14C)-tramadol bound to adrenal medullary cells is replaced by atropine, indicating that tramadol competitively affects muscarinic receptors.3 Shiraishi et al. reported that tramadol at clinically relevant concentrations inhibits M1 receptor function via quinuclidinyl benzilate (QNB)-binding sites.9 In addition, tramadol inhibits M3 receptor function via QNB-binding sites at clinically relevant concentrations.4 These findings suggest that tramadol has anticholiner-gic effects. The inhibitory effects of tramadol on muscarinic receptor function explain our present results. Both gastrin and histamine strongly stimulate the secretion of acid by parietal cells.10 In our study, the pH in the tramadol group was similar to that in the famotidine group. It would be relevant to study the effects of tramadol on histamine- and gastrin-induced secretion of acid.
Common non-steroidal anti-inflammatory drug (NSAID) analgesics are used widely. However, they often cause ulcers, possibly via the inhibition of prostaglandin synthesis in the stomach. Patients with underlying gastric ulcer are at particular risk of NSAID-induced gastric ulcer.11 Our results suggest that tramadol might be a suitable analgesic for such patients.
In conclusion, gastric pH was higher in the tra-madol group than in the control group, which suggests that tramadol inhibits the secretion of gastric acid. Recently, several groups reported that tramadol has less effects on gastric emptying than morphine.12,13 The significance of this finding with regard to clinical outcomes remains to be determined.
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Footnotes |
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References |
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2 Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol 1997; 43: 71–5.[Medline]
3 Sagata K, Minami K, Yanagihara N, et al. Tramadol inhibits norepinephrine transporter function at desipramine-binding sites in cultured bovine adrenal medullary cells. Anesth Analg 2002; 94: 901–6.
4 Shiga Y, Minami K, Shiraishi M, et al. The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M3 receptors. Anesth Analg 2002; 95: 1269–73.
5 Lefkowitz RJ, Hoffman BB, Taylor P. Neurohumoral transmission: the autonomic and somatic motor nervous systems. In: Gilman AG, Rall TW, Nies AS, Taylor P (Eds). Goodman and Gilman’s The pharmacological basis of Therapeutics, 8th ed. New York: Pergamon Press; 1990: 84–121.
6 Pfeiffer A, Kromer W, Friemann J, et al. Muscarinic receptors in gastric mucosa are increased in peptic ulcer disease. Gut 1995; 36: 813–8.
7 Lintz W, Beier H, Gerloff J. Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion. Int J Clin Pharmacol Ther 1999; 37: 175–83.[Medline]
8 Noguchi J, Yamamura H, Inada Y, et al. A double-blind evaluation of famotidine for pre-anesthetic intramuscular administration – its effects on volume and pH of gastric juice (Japanese). Masui 1987; 36: 592–603.[Medline]
9 Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A. Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors. J Pharmacol Exp Ther 2001; 299: 255–60.
10 Guyton AC. Secretory functions of the alimentary tract. In: Guyton AC (Ed.). Textbook of Medical Physiology, 8th ed. Philadelphia: W.B. Saunders; 1991: 709–25.
11 Zeidler H. Epidemiology of NSAID-induced gastropa-thy. Clin Rheumatol 1991; 10: 369–73.[Medline]
12 Wilder-Smith CH, Hill L, Wilkins J, Denny L. Effects of morphine and tramadol on somatic and visceral sensory function and gastrointestinal motility after abdominal surgery. Anesthesiology 1999; 91: 639–47.[Medline]
13 Crighton IM, Martin PH, Hobbs GJ, Cobby TF, Fletcher AJ, Stewart PG. A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesth Analg 1998; 87: 445–9.
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