ORIGINAL ARTICLE - Safety of Tramadol as a Pre-Induction Agent

Tariq Hayat Khan, MCPS, FCPS*

*Consultant Anesthesiologist & Pain Management Specialist, KRL General Hospital, Islamabad (Pakistan).

Correspondence: Dr. Tariq Hayat Khan, Consultant Anesthesiologist & Pain Management Specialist, KRL General Hospital, G-9/1, Mauve Area, Islamabad (Pakistan); Cell: +92 321 5149709; e-mail: tariqhayatkhan@hotmail.com.

ABSTRACT

Objective: To study the safety profile of intravenous use of tramadol immediately before induction of general anesthesia.

Design: Prospective, observational study.

Study Period: January 2005 to October 2007.

Setting: Combined MilitaryHospitalMultan, MilitaryHospitalRawalpindi and RailwayHospitalRawalpindi.

Patients & Methods: 600 patients of ASA-I to ASA-III, aged 10-50 years, undergoing elective surgery were selected for the study under convenient sampling. Children less than 10 years were excluded. Morbidly obese and patients with history of syncope, convulsive syncope, panic attacks and other convulsive events were excluded. Ladies undergoing caesarian section were also excluded from the study. The patients were injected 1.5mg/kg body weight, but not exceeding 100mg of tramadol (100mg of the drug diluted to 10 ml) intravenously, slowly over a period of two minutes as a part of pre-induction regimen. Patients were monitored for any untoward signs and symptoms for 10 min and all observations were recorded.

Results: The main complications / side-effects observed were nausea / vomiting, sweating, heart sinking and seizures in that order. Out of 600 patients, 47 (7.83 %) patients complained of nausea alone and 9(1.5%) patients had a bout of vomiting, 23 (3.88%) patients were observed to have sweating, 31 (5.17%) female patients complained of heart sinking and 2(0.33%) patients had had seizure activity.

Conclusion: We conclude that although the use of IV tramadol as a pre-induction agent is associated with a low risk of side effects, but due to its potential to cause seizure activity, it is best avoided in the environments where adequate resuscitative measures are not available.

Keywords: Pre-induction, Tramadol, Safety, Seizure activity.

Citation: Khan TH. Safety of tramadol as a pre-induction agent. Anaesth Pain & Intensive Care 2009;13(2):57-60.

INTRODUCTION

Tramadol is a cyclohexanol derivative with µ-agonist activity. It has been used as an analgesic for postoperative or chronic pain or as a part of balanced anesthesia since the late 1970s, and became one of the most popular analgesics of its class in many countries including Pakistan. International interest has been renewed during the past few years, when it was discovered that tramadol not only acts on opioid receptors, but also inhibits serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake. Parenteral or oral tramadol has proved to be an effective and well-tolerated analgesic agent in the perioperative setting. Adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Some reports suggested that the drug may cause seizures especially in the presence of concomitant treatment with antidepressant agents.1 Studies suggested that the incidence of drug-induced seizures is rare, especially in the therapeutic dosage range. This study was designed to observe any untoward side-effect of tramadol injected intravenously for pre-induction before induction of general anaesthesia.

PATIENTS & METHODS

A prospective, observational study was conducted consecutively at three hospitals at Multan and Rawalpindi, from January 2005 to October 2007. 600 patients of ASA-I to ASA-III, aged 10-50 years, undergoing elective surgery were included. Children less than 10 years were excluded as they were often given less than the projected dose of the tramadol, and for most of them it was hard to wait on the operating table for the observation period. On the other hand, patients over 50 years receive morphine as a preferred narcotic analgesic at the former two hospitals, hence were excluded. Patients with history of syncope, convulsive syncope, panic attacks and other convulsive events were excluded. Morbidly obese patients were also excluded, as were patients with full stomach. The selected patients were to undergo all types of surgeries under general anaesthesia, less obstetric patients scheduled to undergo Caesarian section. The demographic data is given in Table 1.

Table 1: Demographic Data
Total No. of Patients 600
Male/Female ratio 475/12519:5
Age (Mean±SD) 34±14.7 years
Bodyweight (Mean±SD) 67.3±17.51 Kg
Dose of Tramadol 1.5 mg/kgMax: 100 mg
ASA status I-III
Types of Surgery: N(%)
General Surgery 371(61.83%)
Gynae/Obs 67(11.17%)
Orthopaedic Surgery 134(22.33%)
ENT Surgery 28(4.67%)
 

 

 

 

 

 

 

 

The patients were injected 1.5mg/kg body weight of tramadol (100mg of the drug diluted to 10 ml) intravenously, slowly over a period of two minutes as a part of pre-induction. Total dose was not exceeded to 100 mg regardless of the weight of the patient. The induction was carried out after a lapse of 10 minutes. Patients who could not wait for the stipulated time even after intravenous administration of the drug, due to any reason were excluded. During this period patients were observed for any untoward signs. They were frequently questioned to about any unpleasant feeling. Blood pressure, ECG, SpO2 and pulse rate were monitored with multi-parameter monitors. The observations were carefully recorded.

RESULTS

The main complications / side-effects observed were nausea / vomiting, sweating, heart sinking and seizures in that order. Out of 600 patients, 23 (3.88%) patients were observed to have sweating, 47 (7.83 %) patients complained of nausea alone and 9(1.5%) patients had a bout of vomiting. Out of 47 patients who felt nauseated, 36(6%) were females and the rest 11(1.83%) were males. 31 (5.17%) female patients complained of heart sinking, which was relieved by inj. midazolam 1-3 mg IV. One patient, a 25 years old male, developed frank seizures after about half the calculated dose had been injected. He was immediately injected pentothal, followed by suxamethonium and was intubated. Another male patient, aged 34 years, developed seizures immediately after the full dose of the tramadol had been injected. He, too, was induced rapidly and intubated. Thus 2(0.33%) patients had had seizure activity. The seizures were tonic-clonic in nature, started from the muscles of the face, were fine to start with, but rapidly developed into moderate intensity. There was no warning sign such as visual or auditory aura. Soon, whole body was in rapid jerky motion till it was terminated by injection of pentothal. Both of these patients had no history of convulsive disorders, and none of them was on any medication before the surgery. None of the patients complained of urticaria. The cut point for blood pressure change was set to be a 10% increase or decrease in the mean blood pressure from the baseline. Although slight decrease was noted, the effect on mean blood pressure or pulse rate was not significant. The summary of the observed untoward side effects is given as Table 2.

Table 2: Incidence of complications

Complication

Incidence N(%)

M:F
Sweating

23 (3.88%)

17:6    (3.58:4.8%)
Nausea

47 (7.83 %)

11:36  (5.47:16.8%)
Vomiting

09 (1.5%)

1:2    (1.3:2.4%)
Heart sinking

31 (5.17%)

0:31  (0:6.4%)
Seizures

02 (0.33%)

2:0    (0.42:0%)
 

 

 

 

 

DISCUSSION

Tramadol is a synthetic analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for µ-receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation2.  International interest has been renewed during the past few years, when it was discovered that tramadol not only acts on opioid receptors, but also inhibits serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake. Tramadol has been used intraoperatively as part of balanced anaesthesia. Such use is under discussion, however, as it was associated with a high incidence of intraoperative recall and dreaming, and postoperative respiratory depression has been described after intraoperative administration of high doses.

Although many studies have been conducted regarding safety and usefulness of peri-operative tramadol in children3-5, we have noticed a general tendency among our anaesthetists to use tramadol in comparatively lower doses than were used for age group in our study.

Nausea and vomiting are the most frequently reported adverse effects. In controlled studies, haemodynamic and respiratory parameters were only minimally impaired. The risk of severe respiratory depression in typical dosages is negligible in comparison with other opioids used for postoperative pain management. 6-7
Scott and Perry reported an incidence of 1.6 to 6.1% of nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. They showed no clinically relevant effects on respiratory or cardiovascular parameters at recommended doses in adults or children8. In our patients the incidence of these side effects was 1.5 to 7.83%, the most frequent being mild to moderate nausea (7.83%) and the least common being frank vomiting (1.5%). An interesting finding was the complaint of heart sinking (5.17%), which was readily controllable with small doses of IV midazolam. No patient complained of dizziness or drowsiness.

Tramadol has been associated with seizure activity, perhaps due to itsmonoamine uptake inhibition and serotonergic modulating properties. A large number of studies have been conducted to study this activity during the last decade or so. Previous US studies suggest a relatively low risk of seizures with tramadol, unless it is taken by people with epilepsy or taken with other drugs that reduce the seizure threshold. 9-10 Analysis of administrative data from a large U.S. managed care population, a cohort of 9218 adult tramadol users and 37,232 concurrent nonusers showed fewer than 1% of users had a presumed incident seizure claim after the first tramadol prescription. Risk of seizure claim was increased 2- to 6-fold among users adjusted for selected comorbidities and concomitant drugs. Risk was highest among those aged 25-54 years, those with more than four tramadol prescriptions, and those with history of alcohol abuse, stroke, or head injury11.

Labate and Newton mentioned in their study, that the seizures were generalized tonic–clonic, without auras or focal features. In their study no patient had a prior history of seizures, and none had a recurrence since they had ceased taking tramadol12. This was consistent with our study. Both patients in our study developed seizures of generalized tonic-clonic type, and had no previous history of seizures and no previous exposure to the drug.

Much of the toxicity in tramadol overdose appears to be attributable to the monoamine uptake inhibition rather than its opioid effects. Agitation, tachycardia, confusion and hypertension suggest a possible mild serotonin syndrome. The serotonergic modulating properties of tramadol mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with reuptake inhibitors (e.g. selective serotonin reuptake inhibitor-SSRIs), agents that potentiate the effect of 5-HT (e.g., monoamine oxidase inhibitor-MAOIs) or 5-HT agonists13.

There is still controversial data about pro- or anti-convulsant effect of tramadol in vitro, some researches demonstrated that tramadol has anticonvulsant effect in mice but there are many reports of tramadol-induced seizures in humans 14. Seizures have been reported in patients receiving the drug in overdose and, rarely, at the recommended dose unless it is taken by people with epilepsy or taken with other drugs that reduce the seizure threshold 15.

The smallest amount of tramadol associated with seizure was 200 mg, and 84.6% of seizures occurred within 6 hours administration. In a general population, there is association between seizures and tramadol use in males, long-term therapy, suicide attempts, intentional abuse or misuse, and tachycardia 16. Most of these studies were conducted with long-term use of the drug via oral route. We have not seen a study in which adverse effects and especially seizure activity was noted after single parentral administration.

Out of 600 patients in our study, only two patients (0.33%) developed seizures, both with no previous history of convulsive episodes. It was also noted that the seizure activity occurred within therapeutic range on first exposure. In our set-up, we had full means of resuscitative measures within reach, and the patients were scheduled to undergo general anaesthesia, which was readily induced and the seizure activity was immediately controlled. But although the incidence of this activity is low, the clinicians must be cautious while injecting tramadol intravenously in outdoor settings or where resuscitative measures are not readily available.

CONCLUSION

The use of IV tramadol as a pre-induction agent in balanced anaesthesia technique is safe and associated with a low risk of side effects, but the IV use of drug can produce tonic-clonic seizures in a very small population of patients and hence, probably best avoided in the environments where adequate resuscitative measures are not available.

REFERENCES

  1. Gardner JS, Blough D, Drinkard CR, et al. Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy 2000; 20: 1423-1431.
  2. Dayer P, Desmeules J, Collart L, Pharmacology of tramadol: Drugs 1997; 53 Suppl 2:18-24
  3. Prakash S, Tyagi R, Gogia AR, Singh R, Prakash S. Efficacy of three doses of tramadol with bupivacaine for caudal analgesia in paediatric inguinal herniotomy. Br J Anaesth. 2006;97(3):385-8. Epub 2006 Jun 23.
  4. Chu YC, Lin SM, Hsieh YC, Chan KH, Tsou MY. Intraoperative administration of tramadol for postoperative nurse-controlled analgesia resulted in earlier awakening and less sedation than morphine in children after cardiac surgery. Anesth Analg. 2006 Jun;102(6):1668-73.
  5. Gunduz M, Ozalevli M, Ozbek H, Ozcengiz D. Comparison of caudal ketamine with lidocaine or tramadol administration for postoperative analgesia of hypospadias surgery in children. Paediatr Anaesth. 2006 Feb;16(2):158-63.
  6. Radbruch L, Grond S, Lehmann KA. A risk-benefit assessment of tramadol
  7. Khosravi MB, Khezri S, Azemati S. Tramadol for pain relief in children undergoing herniotomy: a comparison with ilioinguinal and iliohypogastric blocks. Paediatr Anaesth. 2006 Jan;16(1):54-8
  8. Khosravi MB, Khezri S, Azemati S. Tramadol for pain relief in children undergoing herniotomy: a comparison with ilioinguinal and iliohypogastric blocks. Paediatr Anaesth. 2006 Jan;16(1):54-8
  9. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain,  Drugs 2000 Jul;60(1):139-76
  10. Gasse C, Derby L, Vasilakis-Scaramozza C, Jick H. Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy 2000;20:629-634.
  11. Jick H, Derby LE, Vasilakis C, Fife D. The risk of seizures associated with tramadol. Pharmacotherapy 1998;18:607-611.
  12. Mehrpour M. Intravenous Tramadol-Induced Seizure: Two Case Reports. IJPT 2005;4:146-147
  13. Angelo Labate, Mark R Newton. Tramadol and new-onset seizures. Med J Aust 2005;182(1):42-3.
  14. Spiller HA, Gorman SE, Villalobos D, Benson BE, Ruskosky DR, Stancavage MM, Anderson DL. Prospective multi-center evaluation of tramadol exposure. J Toxicol Clin Toxicol. 1997;35(4):361-4.
  15. Manocha A, Sharma KK, Mediratta PK. On the mechanism of anticonvulsant effect of tramadol in mice. Pharmacol Biochem Behav 2005;82(1):74-81.
  16. Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with tramadol. JAMA 1997;278:1661.
  17.  Marquardt KA, Alsop JA, Albertson TE. Tramadol exposures reported to statewide poison control system. Ann Pharmacother 2005;39(6):1039-44.