Mohta and colleagues [1] rightly emphasize that adverse drug reactions must be taken into account when considering the use of any drug to prevent the occurrence of postoperative shivering. They then present a convincing argument that tramadol is a useful drug for this purpose but did not, in our opinion, adequately put this in the context of some adverse effects of the drug.

Tramadol is contraindicated in patients with uncontrolled epilepsy and porphyria. [2]

It has also been suggested that tramadol, which is a serotonin reuptake inhibitor, may contribute to the serotonin syndrome, a hyper-excitatory condition arising as a result of an excess of 5-HT in the central nervous system [3]. Other drugs which in overdose or combination may precipitate serotonin syndrome include all classes of antidepressants, pethidine and sumatriptan. [3] Patients with a previous history of seizures or porphyria and those taking antidepressants were excluded from this study. Mohta and colleagues did not emphasize that these contraindications and cautions were the reason for the exclusions in their discussion which may have clarified the study.

It has become apparent that spinal 5-HT₃ receptors may be involved in the analgesic action of tramadol. It appears that the use of 5-HT₃ receptor antagonists (ondansetron etc) may decrease the analgesic efficacy of tramadol. [4,5] Conversely, tramadol is emetogenic and it has been suggested that these effects may be mediated by inhibition of serotonin reuptake at 5-HT₃ receptors. [6] Mohta et al state that no differences in rates of nausea and vomiting were noted. Had they instead used ondansetron or a higher dose of metoclopramide (at which the drug is more effective [7] and also has increased action at 5-HT₃ receptors ,[8]), their findings may have been different. Their data do show non-significant increased relative risks of nausea and vomiting between the lowest and highest doses of tramadol of 60% and 50%. Alternatively it may be that this study of 165 subjects was underpowered in this respect.

Mohta’s study failed to demonstrate significant differences in nausea and vomiting between pethidine and any of the tramadol doses.  The study data suggests that the risk of vomiting between 0.5 mg/kg pethidine and tramadol 3 mg/kg was doubled and the risk of nausea elevated 4 fold. The lack of significance again may reflect the power of the study. Direct comparison with an emetic drug such as pethidine may not highlight the observed emetogenic effect of tramadol. In patients with a particularly high risk of PONV, neither pethidine (proemetic) or tramadol (interaction with 5HT₃ antagonists) would be first line analgesic choices. With the ubiquity of 5HT₃ antagonist use, we suggest that routine use of tramadol against shivering may be at the expense of increased nausea and vomiting.

Kevin D Johnston

Simon JM Raby

Specialist Registrars

Department of Anaesthesia, Wycombe General Hospital, Alexandra Road, High Wycombe, Buckinghamshire HP11 2TT

References

1 Mohta M, Kumari N, Tyagi A, Sethi AK, Agarwal D, Singh M. Tramadol for prevention of postanaesthetic shivering: a randomized double-blind comparison with pethidine. Anaesthesia 2009;64:141-6

2 British National Formulary Number 56 September 2008

3 Jones D, Story DA. Serotonin syndrome and the anaesthetist. Anaes and Intensive care 2005;33:181-7

4 De Witte JL, Schoenmaekers B, Sessler DI, Deloof T. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg 2001;92:1319-21

5 Arcioni R, della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A. Ondansetron inhibits the analgesic effects of tramadol: A possible 5-HT₃ spinal receptor involvement in acute pain in humans. Anesth Analg 2002;94:1553-57

6 Barann M, Urban B, Stamer U, Dorner Z, Bonisch H, Bruss M. Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT₃A receptors: a possible mechanism for tramadol-induced early emesis. Eur J Pharmacol 2006;531:54-8

7 Wallenborn J, Gelbrich G, Bulst D, Behrends K, Wallenborn H, Rohrbach A, Krause U, Kuhnast T, Wiegel M, Olthoff D. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomized double blind multicentre trial. BMJ 2006;333:324-7

8 Gullickson GW, Loeffler RF, Virina MA. Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs. J Pharmacol Exp Ther 1991;258:103-10

I thank Johnston and Raby for showing interest in our article. They have shown their concern regarding increased nausea and vomiting if tramadol is routinely used to prevent shivering. However, they failed to acknowledge the main aim of our study that was to explore the potential of a routinely used post-operative analgesic to provide an additional advantage of anti-shivering effect [1]. Tramadol provides good postoperative analgesia and is a widely prescribed analgesic marketed in over 90 countries [2]. Tramadol has the advantages of lesser degree of sedation and minimal respiratory depression over other opioids [3]. It is associated with a low incidence of cardiac depression and significantly less dizziness and drowsiness than morphine [4]. It also produces less constipation, urinary retention and dependence than equianalgesic doses of strong opioids [5, 6]. In comparison with NSAIDs, it is more effective as an analgesic [4, 7]. It is also safer as it does not provoke bronchospasm, gastro-intestinal mucosal damage or renal impairment. The main problem with tramadol is increased nausea and vomiting, but the incidence and severity can often be reduced by intra-operative administration in the surgical patient and by administration of a prophylactic anti-emetic such as metoclopramide [4, 5].

Concerns are being raised against about the use of ondansetron along with tramadol [8, 9] as ondansetron can antagonise analgesia produced by tramadol. On the other hand, this theory has been refuted by some other workers [10] and these drugs are still being used together [11]. Taking in view these controversies, we suggest it is advisable to use metoclopramide for anti-emesis along with tramadol until the time a meta-analysis clarifies the effect of ondansetron on tramadol analgesia. Metoclopramide is quite effective in a dose of 10 mg in our patient population and we have been using it successfully for a long time to prevent and control nausea and vomiting.

Johnston and Raby have rightly emphasised that tramadol is contra-indicated in certain situations. However, tramadol is not a new drug and has been in use for many decades [12]. The contra-indications and cautions of this drug are well known and that is why these comprised the exclusion criteria of our study.

Thus, use of tramadol in the post-operative period, keeping in mind the contra-indications and cautions, is undoubtedly justified. It is reiterated that tramadol 2 mg.kg along with metoclopramide 10 mg is a good option to be administered at the time of wound closure to have an additional advantage of preventing postanaesthetic shivering, in addition to its good analgesia with minimal side-effects.

M. Mohta

References

1.      Mohta M, Kumari N, Tyagi A, Sethi AK, Agarwal D, Singh M. Tramadol for prevention of postanaesthetic shivering: a randomized double-blind comparison with pethidine. Anaesthesia 2009; 64: 141-6.

2.      Bamigbade TA, Langford RM. Tramadol hydrochloride: An overview of current use. Hospital Medicine 1998, 59: 373-6.

3.      Shipton EA. The future. In: Shipton EA. Pain – acute and chronic. London: Arnold, 1999: 344-6.

4.      Lehmann KA. Tramadol in acute pain. Drugs 1997; 53 (Suppl 2): 25-33.

5.      Bamigbade TA, Langford RM. The clinical use of tramadol hydrochloride. Pain Reviews 1998; 5: 155-82.

6.    Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clinical Pharmacokinetics 2004; 43: 879-923.

7.    Shipton EA. Tramadol - present and future. Anaesthesia and Intensive Care 2000; 28: 363-74.

8.   De Witte JL, Schoenmaekers B, Sessler DI, Deloof T. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesthesia and Analgesia 2001; 92: 1319-21.

9.   Arcioni R, della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A. Ondansetron inhibits the analgesic effects of tramadol: A possible 5-HT₃ spinal receptor involvement in acute pain in humans. Anesthesia and Analgesia 2002; 94: 1553-57.

10.  Erhan E, Onal A, Kocabas S, Parlar A, Yegul I, Kosay S. Ondansetron does not block tramadol-induced analgesia in mice. Methods and Findings in Experimental and Clinical Pharmacology. 2005; 27: 629-32.

11. Cattabriga I, Pacini D, Lamazza G, Talarico F, Di Bartolomeo R, Grillone G, Bacchi-Reggiani L. Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial. European Journal of Cardiothoracic Surgery 2007; 32: 527-31.

12.  Reeves RR, Burke RS. Tramadol: basic pharmacology and emerging concepts. Drugs Today 2008; 44: 827-36.