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Respiratory depression following oral tramadol in a patient with impaired renal function
Pain 71 (1997) 111–112
Respiratory depression following oral tramadol in a patient with impaired renal function S.K. Barnung*, M. Treschow, F.M. Borgbjerg Department of Anaesthesiology, University of Copenhagen, Bispebjerg Hospital, DK 2400 Copenhagen, Denmark Received 2 September 1996; revised version received 14 December 1996; accepted 6 January 1997
Keywords: Tramadol; Renal function; Respiratory depression
1. Introduction Tramadol, a centrally acting analgesic, has been available in several countries since the late 1970s. In patients with impaired renal function the elimination half-life of tramadol is 1.5–2 times longer than in healthy persons (Lee et al., 1993). Only two cases of respiratory depression following tramadol have been described; both cases were in small children (Lee et al., 1993). The present case describes respiratory depression in an adult male with impaired renal function.
2. Case The patient was a 75-year-old male (113 kg, approximately 175 cm) with a long history of non-insulin dependent diabetes, atherosclerosis and ischaemic heart disease, complicated with myocardial infarction in 1994 leading to cardiac incompensation. Furthermore, the patient suffered from chronic renal failure with the following laboratory values within the last 6 months: creatinine 183–317 mmol/ l (normal range: 60–130) and urea 28–37 mmol/l (normal range: 2.5–7.5). Creatinine clearance was not calculated. On admission the patient complained of angina pectoris and leg cramps and was treated with diuretics, calciumantagonists, nitroglycerine, oral hypoglycaemic drugs and 5 mg of morphine intravenously, resulting in drowsiness but no signs of respiratory depression. The following day * Corresponding author. Bengtasvej 12, DK 2900 Hellerup, Denmark. Tel.: +45 39401982; fax: +45 39401982; e-mail: [email protected]
analgesic treatment with tramadol (Nobligan) was instituted (50 mg three times daily). The dose was increased 2 days later to 100 mg three times daily and 12 days later increased to 100 mg, four times daily. Three days after the last increase, the patient was found stuporous and neurologic examination including a CAT scan of the brain revealed no focal abnormalities. The pupils were small but not pin-point, respiratory insufficiency developed with a respiratory rate of 5/min, and arterial blood gases were abnormal despite oxygen (5 l O2/min) administration (pH: 7.10; PCO2: 9.1 kPa; PO2: 12.5 kPa and standard base excess: −8.3.) A dosage of naloxone 0.4 mg was injected intravenously and within minutes the patient regained consciousness, and respiration normalised. Ten minutes later the patient lost consciousness again, respiration became shallow, and he was admitted to the intensive care unit. Repeated bolus doses and infusion of naloxone to a total of 6 mg were necessary. The patient remained conscious without pain until discharge from the intensive care unit the next day.
3. Discussion Tramadol exerts its analgesic effect through two mechanisms: a weak opioid activity and modulation of monoaminergic pathways by reuptake inhibition (Dayer et al., 1994). The potency of tramadol is approximately 1:10 compared to morphine (Hennies et al., 1988). Eighty-five per cent of an oral dose of tramadol is metabolised in the liver to one active metabolite, O-demethyl tramadol (M1), and 90% is excreted by the kidneys. The elimination kinetics of tramadol are described by a two compartment model, with an
0304-3959/97/$17.00 1997 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S0304-3959 (97 )0 3350-2
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elimination half-life of (t1/2b) 5.1 h (SD 0.8 h) after an oral dose and a t1/2b of the active metabolite M1 of 9 h (Lee et al., 1993). The M1 metabolite shows a higher affinity for opioid receptors than tramadol (Lee et al., 1993), but the clinical significance of M1 is not fully recognised (Eggers and Power, 1995). In patients with impaired hepatic or renal function the elimination half-life is increased approximately twofold (Lee et al., 1993). Consequently, in patients with renal or hepatic failure, multiple administration of tramadol requires increased dosage interval (Lee et al., 1993). Generally, tramadol is considered to possess a low risk of respiratory depression (Eggers and Power, 1995). The present patient had a verified chronic renal impairment and it is of interest that the patient tolerated a dose of tramadol 100 mg orally three times a day for 14 days without complications, whereas approximately 72 h after an increase in dosage to 100 mg four times daily he experienced symptoms of an opioid overdosage. The patient received no other respiratory depressant drugs and the symptoms of respiratory depression disappeared following naloxone treatment and reappeared when the effect of naloxone treatment decreased. These facts strongly indicate that the opioid effect of tramadol was responsible for the symptoms.
In conclusion, tramadol may result in respiratory depression in patients with renal failure. Dose titration should be performed with specific attention to the level of consciousness, to minimise the occurrence of respiratory depression.
Acknowledgements We thank Dr. Michael Crawford for his assistance and for helpful comments on the manuscript.
References Eggers, K.A. and Power, I., Editorial, Br. J. Anaesth., 74 (1995) 3. Dayer P., Collart, L. and Desmeules, J., The pharmacology of tramadol, Drugs, 47 (Suppl. 1) (1994) 3–7. Hennies, H.H., Friderichs, E. and Schneider, J., Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids, Arzneimittelforschung, 38 (1988) 877–880. Lee, C.R., McTavish, D. and Sorkin, E.M., Tramadol, Drugs, 46 (1993) 313–340.
Respiratory depression following oral tramadol in a patient with impaired renal function S.K. Barnung*, M. Treschow, F.M. Borgbjerg Department of Anaesthesiology, University of Copenhagen, Bispebjerg Hospital, DK 2400 Copenhagen, Denmark Received 2 September 1996; revised version received 14 December 1996; accepted 6 January 1997
Keywords: Tramadol; Renal function; Respiratory depression
1. Introduction Tramadol, a centrally acting analgesic, has been available in several countries since the late 1970s. In patients with impaired renal function the elimination half-life of tramadol is 1.5–2 times longer than in healthy persons (Lee et al., 1993). Only two cases of respiratory depression following tramadol have been described; both cases were in small children (Lee et al., 1993). The present case describes respiratory depression in an adult male with impaired renal function.
2. Case The patient was a 75-year-old male (113 kg, approximately 175 cm) with a long history of non-insulin dependent diabetes, atherosclerosis and ischaemic heart disease, complicated with myocardial infarction in 1994 leading to cardiac incompensation. Furthermore, the patient suffered from chronic renal failure with the following laboratory values within the last 6 months: creatinine 183–317 mmol/ l (normal range: 60–130) and urea 28–37 mmol/l (normal range: 2.5–7.5). Creatinine clearance was not calculated. On admission the patient complained of angina pectoris and leg cramps and was treated with diuretics, calciumantagonists, nitroglycerine, oral hypoglycaemic drugs and 5 mg of morphine intravenously, resulting in drowsiness but no signs of respiratory depression. The following day * Corresponding author. Bengtasvej 12, DK 2900 Hellerup, Denmark. Tel.: +45 39401982; fax: +45 39401982; e-mail: [email protected]
analgesic treatment with tramadol (Nobligan) was instituted (50 mg three times daily). The dose was increased 2 days later to 100 mg three times daily and 12 days later increased to 100 mg, four times daily. Three days after the last increase, the patient was found stuporous and neurologic examination including a CAT scan of the brain revealed no focal abnormalities. The pupils were small but not pin-point, respiratory insufficiency developed with a respiratory rate of 5/min, and arterial blood gases were abnormal despite oxygen (5 l O2/min) administration (pH: 7.10; PCO2: 9.1 kPa; PO2: 12.5 kPa and standard base excess: −8.3.) A dosage of naloxone 0.4 mg was injected intravenously and within minutes the patient regained consciousness, and respiration normalised. Ten minutes later the patient lost consciousness again, respiration became shallow, and he was admitted to the intensive care unit. Repeated bolus doses and infusion of naloxone to a total of 6 mg were necessary. The patient remained conscious without pain until discharge from the intensive care unit the next day.
3. Discussion Tramadol exerts its analgesic effect through two mechanisms: a weak opioid activity and modulation of monoaminergic pathways by reuptake inhibition (Dayer et al., 1994). The potency of tramadol is approximately 1:10 compared to morphine (Hennies et al., 1988). Eighty-five per cent of an oral dose of tramadol is metabolised in the liver to one active metabolite, O-demethyl tramadol (M1), and 90% is excreted by the kidneys. The elimination kinetics of tramadol are described by a two compartment model, with an
0304-3959/97/$17.00 1997 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S0304-3959 (97 )0 3350-2
112
S.K. Barnung et al. / Pain 71 (1997) 111–112
elimination half-life of (t1/2b) 5.1 h (SD 0.8 h) after an oral dose and a t1/2b of the active metabolite M1 of 9 h (Lee et al., 1993). The M1 metabolite shows a higher affinity for opioid receptors than tramadol (Lee et al., 1993), but the clinical significance of M1 is not fully recognised (Eggers and Power, 1995). In patients with impaired hepatic or renal function the elimination half-life is increased approximately twofold (Lee et al., 1993). Consequently, in patients with renal or hepatic failure, multiple administration of tramadol requires increased dosage interval (Lee et al., 1993). Generally, tramadol is considered to possess a low risk of respiratory depression (Eggers and Power, 1995). The present patient had a verified chronic renal impairment and it is of interest that the patient tolerated a dose of tramadol 100 mg orally three times a day for 14 days without complications, whereas approximately 72 h after an increase in dosage to 100 mg four times daily he experienced symptoms of an opioid overdosage. The patient received no other respiratory depressant drugs and the symptoms of respiratory depression disappeared following naloxone treatment and reappeared when the effect of naloxone treatment decreased. These facts strongly indicate that the opioid effect of tramadol was responsible for the symptoms.
In conclusion, tramadol may result in respiratory depression in patients with renal failure. Dose titration should be performed with specific attention to the level of consciousness, to minimise the occurrence of respiratory depression.
Acknowledgements We thank Dr. Michael Crawford for his assistance and for helpful comments on the manuscript.
References Eggers, K.A. and Power, I., Editorial, Br. J. Anaesth., 74 (1995) 3. Dayer P., Collart, L. and Desmeules, J., The pharmacology of tramadol, Drugs, 47 (Suppl. 1) (1994) 3–7. Hennies, H.H., Friderichs, E. and Schneider, J., Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids, Arzneimittelforschung, 38 (1988) 877–880. Lee, C.R., McTavish, D. and Sorkin, E.M., Tramadol, Drugs, 46 (1993) 313–340.