Analgesic and antacid properties of i.m. tramadol given before Caesarean section under general anaesthesia

M. Elhakim*, W. Abd El-Megid, A. Metry, A. El-hennawy and K. El-Queseny

Department of Anaesthesia, Faculty of Medicine, Ain-Sham University, Cairo, Egypt

* Corresponding author. E-mail: mokhtar.elhakim{at}gmail.com

Accepted for publication September 22, 2005.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Intramuscular (i.m.) tramadol increases gastric pH during anaesthesia similar to famotidine. We investigated the antacid analgesic value of a single dose of i.m. tramadol given 1 h before elective Caesarean section performed under general anaesthesia.

Methods. Sixty ASA I parturients undergoing elective Caesarean section were included in a randomized double-blind study. The patients were randomly allocated to receive i.m. tramadol 100 mg (n=30) or famotidine 20 mg (n=30) 1 h before general anaesthesia.

Results. At the beginning and the end of anaesthesia, patients receiving tramadol had a median gastric fluid pH of 6.4, which was not significantly different from those treated with famotidine (median 6.3). The infant well-being, as judged by Apgar score, cord blood gas analysis, and neurobehavioural assessment showed no significant difference between the two groups. Nalbuphine consumption in the first 24 h after operation was reduced by 35% in the tramadol group. Pain intensity score on sitting and sedation were significantly greater in famotidine group up to 24 h after surgery. There was no significant difference in incidence and severity of nausea and vomiting between the two groups.

Conclusion. A single i.m. dose of tramadol is useful pre-treatment to minimize the risk of acid aspiration during operation, and in improving pain relief during 24 h after surgery.

Keywords: anaesthesia, obstetric ; analgesics opioid, tramadol ; antacid, famotidine


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for µ opioid receptor. It inhibits serotonin and norepinephrine neuronal reuptake.1 Tramadol is less likely to cause neonatal respiratory depression and hence it has been recommended for analgesia in parturients undergoing vaginal delivery.2

Tramadol also inhibits type-3 muscarinic receptor (M3); which primarily mediates gastric gland secretion and smooth muscle contraction.3 Approximately 30% of women undergoing elective Caesarean section have a significant amount of acidic contents in their stomach unless they receive antacid within 1 h before surgery.4 The aim of this study was to assess the antacid and analgesic value of single dose of i.m. tramadol given 1 h before elective Caesarean section performed under general anaesthesia.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We studied 60 ASA I women undergoing elective Caesarean section. The study was approved by the hospital Ethics Committee and all participants gave informed consent to this double-blind study. Patients with a history of gastritis, gastric or duodenal ulcers were excluded from study.

The patients fasted from midnight (8 h fast). They were randomly allocated (using a computer generated random number) to receive either tramadol 100 mg or famotidine 20 mg i.m. 1 h before induction of anaesthesia. The medication was given by the ward nurse. The patients were transported to the operating theatre in the lateral position and 15° left lateral tilt was maintained on the operating table. An 18-gauge i.v. cannula was inserted into forearm, and ECG, pulse oximeter and indirect arterial pressure monitor (Dinamap) attached.

After 3 min of pre-oxygenation, general anaesthesia was induced with propofol 2 mg kg–1 followed rapidly by succinylcholine 1 mg kg–1. Cricoid pressure was applied after loss of consciousness and maintained until airway was secured using a tracheal tube. After tracheal intubation, a 16-French gauge multi-orifice, vented Salem nasogastric tube was inserted and its correct position was confirmed by epigastric auscultation of injected air. Gastric content measurement (volume and pH) was made twice: after induction of anaesthesia and at the end of anesthesia. The pH was measured using a pH meter.

Anaesthesia was maintained with a mixture of nitrous oxide 50% and halothane 0.5% in oxygen. After recovery from succinylcholine, muscle relaxation was maintained with vecuronium 0.1 mg kg–1. Lungs were mechanically ventilated and normocapnia (end-tidal carbon dioxide) was maintained. Systolic, mean, and diastolic arterial pressures and heart rate were recorded every 2 min for the first 20 min. An infusion of compound lactate solution 500 ml was given over the first 10 min. The times from induction of anaesthesia until delivery of the newborn (I–D time) and from the uterine incision to the delivery (U–D time) were recorded. Also, maternal oxygen saturation and end-tidal carbon dioxide concentration at the time of delivery were recorded.

After the umbilical cord was clamped, an infusion of oxytocin 20 units in 500 ml of 5% glucose was started, nalbuphine 0.25 mg kg–1 was given i.v. and nitrous oxide was increased to 67%. Halothane was discontinued at the start of skin suture and nitrous oxide was stopped 2 min later. Residual neuromuscular block was antagonized with a mixture of neostigmine 0.05 mg kg–1 and atropine 0.02 mg kg–1.

The surgeon graded uterine relaxation on an unmarked 10-cm visual analogue scale; 0 indicated none and 10 severe relaxations. In combination with the need for supplementary doses of oxytocin, this gave a clinical indication of the degree of uterine relaxation. The mother's haemoglobin concentration and packed cell volume (PCV) were recorded before and after (24 h) operation. All mothers were questioned during the first postoperative day about intra-operative dreaming or awareness.

All neonates were assessed each time by the same paediatrician who was unaware of the treatment group. Apgar scores were recorded at 1 and 5 min. Umbilical venous and arterial blood gas analysis were performed at delivery. After 24 h the neurobehavioural responses of the neonates were evaluated.

For postoperative analgesia, patients received nalbuphine by PCA, delivering i.v. nalbuphine 0.05 mg kg–1 with lockout time of 20 min. For escape analgesia, patients were given a bolus of i.v. nalbuphine 10 mg. An anaesthetist, blinded to the treatment groups, visited the patients at 6, 12, 18, and 24 h after surgery. The patients were asked to record the intensity of abdominal pain at rest, on deep inspiration, and on sitting up, on a 10-cm analogue scale ranging from 0 for no pain to 10 for the worst pain imaginable. The cumulative nalbuphine consumption was recorded. A four-point verbal rating score (awake, drowsy, rousable, or deep sleep) was used to assess sedation. The frequency and severity of nausea and vomiting were also assessed as follows: (0) no nausea, (1) mild-moderate nausea, (2) mild vomiting (once per observation period) with severe nausea, (3) moderate vomiting (twice per observation period), (4) severe vomiting (3–4 times per observation period), (5) persistent vomiting that needed treatment with antiemetic agent.

Power analysis revealed a sample size of 30 patients per group was sufficient to achieve a power of 80% and an {alpha} of 0.05 to detect a mean difference of 0.5–0.7 in pH and volume variables or 30% reduction in total opioid consumption. Statistical analysis was performed using Student's t test, {chi}2 test and ANOVA as appropriate. Proportion of patient for risk of aspiration (pH<2.5 and volume >0.4 ml kg–1) were compared using the {chi}2 test with Yate's correction when necessary. A value of P<0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There were no differences in patient characteristics between the groups (Table 1). There were no differences in mean baseline values of systolic arterial pressure or heart rate between the two groups. The values of these variables increased after tracheal intubation in both groups (P<0.01) and returned to baseline level by 4–6 min in the tramadol group and 7–10 min in the famotidine group.


View this table:
[in this window]
[in a new window]
 
Table 1 Patient characteristics and data collected during surgery. Values are mean (range or SD). I–D, induction delivery time; U–D, uterine delivery time; , oxygen saturation; , end-tidal CO2 concentration at time of delivery. No significant differences were found between the two groups

 
The total dose of nalbuphine was significantly greater at 24 h in the famotidine group [mean (SD) 46.5 (1.7) mg] than in the tramadol group [30.3 (7.5)] (P<0.05). Analysis of nalbuphine used in 6-hourly epochs revealed a significantly greater use in the famotidine group at 6–12 (P<0.05) and 18–24 h (P<0.01) after operation compared with the tramadol group (Fig. 1). The median time to first request for analgesia was increased from 21 to 46 min in the tramadol group. Pain intensity scores on sitting were significantly lower in tramadol group at 6–12 (P<0.05) and 18–24 h (P<0.01) after operation than in famotidine group (Fig. 2). The scores for sedation were significantly lower in tramadol group at all time intervals (P<0.05) (Table 2). There was no significant difference between the two groups in pain intensity score at rest or on deep respiration, incidence and severity of nausea and vomiting, or rescue antiemetic consumption over 24 h after surgery (Table 3).



View larger version (14K):
[in this window]
[in a new window]
 
Fig 1 Mean (SD) hourly consumption of nalbuphine in the tramadol (T) and famotidine (F) groups. *P<0.05, **P<0.01.

 


View larger version (9K):
[in this window]
[in a new window]
 
Fig 2 Mean (SD) pain scores on sitting, for patients in the tramadol (T) and famotidine (F) groups. *P<0.05, **P<0.01.

 

View this table:
[in this window]
[in a new window]
 
Table 2 Verbal rating score (VRS) for sedation in tramadol (T) and famotidine (F) groups. The results are presented as number of patients.

 

View this table:
[in this window]
[in a new window]
 
Table 3 Number of patients with different grades of nausea and vomiting during the first 24 h after operation in the tramadol (T) and famotidine (F) groups

 
There was no significant difference between the two groups in surgeon's assessment of relaxation, requirement of additional oxytocin, the haemoglobin concentration and PCV values before and after operation. Umbilical blood gas analysis and neonatal Apgar scores were satisfactory and similar between groups (Table 4). The neurobehavioural assessment of the neonates, 24 h after delivery, did not show any difference between the two groups. None of the mothers complained of intra-operative dreams or awareness.


View this table:
[in this window]
[in a new window]
 
Table 4 Median (range) Apgar scores at 1 and 5 min, and mean (SD) umbilical arterial and venous blood gas analysis at delivery in the tramadol (T) and famotidine (F) groups. There were no differences between the groups

 
Gastric pH and volume at the beginning and end of anaesthesia and the number of patients at risk for aspiration did not differ significantly between the two groups (Table 5).


View this table:
[in this window]
[in a new window]
 
Table 5 Median (range) pH and volume of gastric contents, and percentage of patients with pH less than 2.5 and volume more than 0.4 ml kg–1. No significant differences were seen between the tramadol (T) and femotidine (F) groups

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We have found that administration of single dose i.m. tramadol 1 h before Caesarean section increased gastric pH during operation similar to famotidine, and reduced nalbuphine consumption and pain intensity on sitting during first postoperative day with less sedation. It has been suggested that giving tramadol before the start of surgery may minimize the initiation of pain in the tissues and enhance their effectiveness as analgesia.5 This may explain relative haemodynamic stability during induction–delivery time, reduction in opioid consumption and better pain relief on sitting after operation in the tramadol group in present study. Tramadol and its metabolite noncompetitively inhibit the NMDA receptors, which may contribute to its analgesic effects.6 As we reported previously, pre-medication with a NMDA-receptor antagonist reduced pain provoked by movement, enhanced postoperative analgesia and reduced postoperative analgesic requirements.7

The combination of tramadol with morphine in the postoperative period of painful surgery was found to be infra-additive.8 A weak opioid agonist tramadol may potentially inhibit the analgesia provided by full agonist morphine, compete for the same effector µ receptor. Webb and colleagues9 found that patients receiving intra-operative tramadol had significantly better opinions of their pain relief and used significantly less postoperative morphine with no increase in side-effects. Further, in the present study patients receiving tramadol 1 h before operation had significantly lower pain scores and used less postoperative nalbuphine. Pain mechanisms are subject to alterations with time and that these alterations involve transition from NMDA to non-NMDA receptor-mediated transmission in central pain pathways.10 Preoperative blockade of NMDA receptors by tramadol enhances and prolongs the duration of the antinociceptive activity of nalbuphine. Also, combination of non-opioid analgesic action of tramadol with opioid nalbuphine analgesia was found to be co-additive as part of multi-modal approach in pain relief.11

The onset of action of tramadol after parenteral administration is in the range of 15–30 min, and duration of its effects is 3–6 h. The improvement in pain scores and analgesic consumption over 24 h after surgery was much longer than expected and cannot be explained by systemic effects of a single dose of tramadol. We share the view of others12 that the preventive treatment of postoperative pain may substantially reduce the analgesic requirement after surgery. Another possible explanation would be the potent analgesic effects of the metabolite of tramadol, O-desmethyl tramadol; with elimination half-life of 9 h.13 Also, this may explain the best analgesic efficacy and high significant nalbuphine sparing effects during 18–24 h postoperatively.

Intra-operative use of tramadol may cause awareness and dose-dependent EEG activation, increased arterial pressure, insufficient sedative activity, and increased incidence of postoperative nausea.14 The EEG activation changes were reported to be minor and lasting for 20 min.15 This activation has been shown to be followed by EEG depression, at the time of maximum serum tramadol concentration, exhibiting a biphasic response as most hypnotics.16 Also after tramadol injection, systolic arterial pressure has been shown to increase by 14–16 mm Hg and diastolic arterial pressure by 10–12 mm Hg for 4–6 min, and returning to baseline within 15 min.17 Tramadol did not antagonize the hypnotic effects of volatile anaesthesia as evidenced by p-deletion test.18 The initial dose of tramadol, if administered postoperatively, can be associated with an increased incidence of nausea.19 In the present study, these previously reported adverse effects were avoided effectively by administering tramadol 1 h before the patient was anaesthetized. Furthermore, we found a more rapid rate of recovery of psychomotor function in patients after tramadol, leading to a greater sense of well-being, and lesser postoperative sedation.

Tramadol did not increase the extent of uterine relaxation or bleeding. Neonatal Apgar score, umbilical blood gas analysis, and neuro-behavioural responses did not suggest any impairment of placental perfusion or fetal circulation in the tramadol group. Baraka and colleagues20 demonstrated that supplementation of general anaesthesia with i.v. tramadol in parturients undergoing elective Caesarean delivery can result in lower umbilical vein and higher than the corresponding values with i.v. fentanyl. However, the Apgar scores and neurobehavioural responses in their study were within normal limits. Tramadol blocks the reuptake of serotonin and norepinephrine at the nerve terminals and can produce uterine vasoconstriction with possible fetal asphyxia. The difference in umbilical blood gas analysis between the present study and the study by Baraka and colleagues could be attributed to the difference in bioavailability of tramadol after two different modes of administration. The maximum plasma concentrations after i.m. tramadol would be expected to be 166 ng ml–1 0.75 h after injection, the corresponding value for i.v. tramadol would be 293 ng ml–1 0.5 h after injection.21 In addition, the use of fentanyl in the control group of the study by Baraka and colleagues could have induced a relative dilatation in the maternal uterine blood vessels, with possible changes in referred maternal and fetal . Also with an i.v. fluid load given over the first 10 min of anaesthesia in the present study, placental blood flow may have been better preserved during delivery. This may explain the lack of difference in the blood gas data between the two groups in the present study.

As reported previously, we found that both famotidine and tramadol produced a similar level of gastric content pH (approximately 6.00) at the beginning and end of anaesthesia.22 The inhibitory effects of tramadol on muscarinic receptor (M3) function explain our present results. Tramadol, in common with all opioids, delays gastric emptying and this is confirmed in this study where 16.6% of the tramadol patients had gastric volume more than 0.4 ml kg–1. This incidence was higher in comparison with famotidine group but the difference was not statistically significant. The clinical effects of tramadol on gastric emptying may be determined by its weak action on µ opioid receptor and relative inhibitory effects on serotonin and norepinephrine neuronal reuptake.23 In our study, the volume aspirated using blind technique may have underestimated true gastric volume, but it is an easy method which has been commonly used in similar studies. Gastric fluid volume and pH are but two of several risk factors for aspiration. We used the volume more than 0.4 ml kg–1 and pH less than 2.5 criteria to describe risk for aspiration.24 We share the widespread scepticism on the usefulness of these figures.25 26 Because other studies of aspiration risk reported their data with respect to these criteria, we did so as well to facilitate comparison.

A main criticism of this study may relate to the unlicensed use of tramadol during pregnancy and lactation in some countries. Our present knowledge about the risk of administering medications during pregnancy is incomplete, and the practitioner is left to weigh the risks against the benefits of instituting pharmacological therapy for each individual.27 28 In the present study, tramadol was administered in a single i.m. dose near term and not in early pregnancy.

In summary, our study shows that single dose i.m. tramadol 1 h before elective Caesarean delivery is effective in lowering the risk of acid aspiration during operation and improving pain relief during 24 h after surgery. We could not attribute any problem to tramadol in our patients, although no conclusion can be drawn about safety from the number of patients used in this study.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Vickers MD, O'Flaherty D, Szekely SM, Read M, Yoshiznmi J. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia 1992; 47: 291–6[ISI][Medline]

2 Viegas OA, Khaw B, Ratnam SS. Tramadol in labour pain in primiparous patients. A prospective comparative clinical trial. Eur J Obstet Gynecol Reprod Biol 1993; 49: 131–5[CrossRef][ISI][Medline]

3 Shiga T, Minami K, Shiraisbi M, et al. The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M3 receptors. Anesth Analg 2002; 95: 1269–63[Abstract/Free Full Text]

4 Roberts RB, Shirly MA. The obstetrician's role in reducing the risk of aspiration pneumonitis with particular reference to the use of oral antacids. Am J Obstet Gynecol 1976; 124: 611–17[ISI][Medline]

5 Chiaertti A, Viola L, Pietrini D, et al. Preemptive analgesia with tramadol and fentanyl in pediatric neurosurgery. Child Nerv Syst 2000; 16: 93–9[CrossRef][ISI][Medline]

6 Hara K, Minami K, Sata T. The effects of tramadol and its metabolite on glycine, {gamma}-aminobutyric acidA, and n-methyl-d-aspartate receptors expressed in xenopus oocytes. Anesth Analg 2005; 100: 1400–5[Abstract/Free Full Text]

7 Elhakim M, Khalafallah Z, El-Fattah H A, Farouk S, Khattab A. Ketamine reduces swallowing-evoked pain after paediatric tonsillectomy. Acta Anaesthesiol Scand 2003; 47: 604–9[CrossRef][ISI][Medline]

8 Marcou TA, Marque S, Mazoit J-X, Benhamou D. The median effective dose of tramadol and morphine for postoperative patients: A study of interactions. Anesth Analg 2005; 100: 469–74[Abstract/Free Full Text]

9 Webb SR, Leong S, Myles PS, Burn SJ. The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo controlled randomized trial. Anesth Analg 2002; 95: 1713–8[Abstract/Free Full Text]

10 Rabben T, Oye I. Interindividual differences in the analgesic response to ketamine in chronic orofacial pain. Eur J Pain 2001; 5: 233–40[CrossRef][Medline]

11 Kehlet H, Dahl JB. The value of multimodal or balanced analgesia in postoperative pain treatment. Anesth Analg 1993; 77: 1048–56[ISI][Medline]

12 Wall PD. The prevention of postoperative pain. Pain 1988; 33: 289–90[CrossRef][ISI][Medline]

13 Dayer P, Desmeules J, Collart L. The pharmacology of tramadol. Drugs 1997; 53: 18–24[ISI][Medline]

14 Eggers KA, Power I. Editorial: Tramadol. Br J Anaesth 1995; 74: 247–9[CrossRef][ISI][Medline]

15 Coetzee JF, Martiz JS, du Toit C. Effect of tramadol on depth of anaesthesia. Br J Anaesth 1966; 76: 415–18

16 Veselis RA, Reinsel R, Alagesan R, Heino R, Bedford RF. The EEG as a monitor of midazolam amnesia: changes in power and topography as a function of amnesic state. Anesthesiology 1991; 74: 866–74[ISI][Medline]

17 Duthie DJR. Remifentanil and tramadol. Br J Anaesth 1998; 81: 51–7[Abstract/Free Full Text]

18 Coetzee JF, van Loggerenberg H. Tramadol or morphine administered during operation: a study of immediate postoperative effects after abdominal hysterectomy. Br J Anaesth 1998; 81: 737–41[Abstract/Free Full Text]

19 Rang W-W, Mok MS, Huang S, Hung CP, Huang MH. Intraoperative loading attenuates nausea and vomiting of tramadol patient-controlled analgesia. Can J Anesth 2000; 47: 968–73[Abstract]

20 Baraka A, Siddik S, Assaf B. Supplementation of general anesthesia with tramadol or fentanyl in parturients undergoing elective caesarean section. Can J Anaesth 1998; 45: 631–4[Abstract]

21 Lintz W, Beier H, Gertoff J. Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion. Int J Clin Pharmacol Ther 1999; 37: 175–83[ISI][Medline]

22 Minami K, Ogata J, Horishita T, et al. Intramuscular tramadol increases gastric pH during anesthesia. Can J Anesth 2004; 51: 545–8[Abstract/Free Full Text]

23 Crighton IM, Martin PH, Hobbs GJ, Cobby TF, Fletcher AJP, Stewart PD. A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesth Analg 1998; 87: 445–9[Abstract]

24 Roberts R, Shirley M. Reducing the risk of acid aspiration during cesarean section. Anesth Analg 1974; 53: 859–68[ISI][Medline]

25 Schreiner MS. Gastric fluid volume: is it really a risk factor for pulmonary aspiration? Anesth Analg 1998; 87: 754–6[CrossRef][ISI][Medline]

26 Hardy J-F, Lepage Y, Bonneville-Chouinard N. Occurrence of gastroesphageal reflux on induction of anaesthesia does not correlate with the volume of gastric contents. Can J Anaesth 1990; 37: 502–8[Abstract]

27 Rathmell JP, Viscomi CM, Ashburn MA. Management of non-obstetric pain during pregnancy and lactation. Anesth Analg 1997; 85: 1074–87[CrossRef][ISI][Medline]

28 Lagoy CT, Joshi N, Cragan JD, Rasmussen SA. Medication use during pregnancy and lactation: an urgent call for public health action. J Women's Health 2005; 14: 104–9[CrossRef][ISI]




E-letters:

Read all E-letters

Antacid properties of preoperative i.m. tramadol
kingsley Barasua Pepple
British Journal of Anaesthesia, 3 Jan 2006 [Full text]
Tramadol in Pregnancy
RACHNA SHANKAR
British Journal of Anaesthesia, 5 Jan 2006 [Full text]
Additional use of Tramadol in Parturients
Dr Snehal Ramnath Kumbhare
British Journal of Anaesthesia, 9 Jan 2006 [Full text]
Tramadol in caesarean section under general anesthesia
rajesh mahajan, et al.
British Journal of Anaesthesia, 13 Feb 2006 [Full text]
Reply
M Elhakim
British Journal of Anaesthesia, 15 Feb 2006 [Full text]
Re: Additional use of Tramadol in Parturients
Mokhtar Elhakim, et al.
British Journal of Anaesthesia, 21 Feb 2006 [Full text]
Re: Tramadol in Pregnancy
mokhtar Elhakim, et al.
British Journal of Anaesthesia, 21 Feb 2006 [Full text]
Re: Antacid properties of preoperative i.m. tramadol
mokhtar Elhakim, et al.
British Journal of Anaesthesia, 21 Feb 2006 [Full text]

This Article
Abstract
Full Text (PDF)
All Versions of this Article:
95/6/811    most recent
aei260v1
E-Letters: Submit a response to the article
E-letters: View responses
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Elhakim, M.
Articles by El-Queseny, K.
PubMed
PubMed Citation
Articles by Elhakim, M.
Articles by El-Queseny, K.