ABSTRACT
Title
Tramadol-associated Psychiatric Adverse Events: A Signal from the pharmacovigilance data of Italian Medicines Agency (AIFA)
Authors
L.Sottosanti1, F.Ferrazin1, A.Capuano2, F.Rossi2, S. Potenza1
1 Italian Medicines Agency, Pharmacovigilance Office, Rome, Italy
2 Clinical Pharmacology Unit and Pharmacovigilance Centre of Campania Region, University of Naples, Napoli, Italy;
1 Italian Medicines Agency, Pharmacovigilance Office, Rome, Italy
2 Clinical Pharmacology Unit and Pharmacovigilance Centre of Campania Region, University of Naples, Napoli, Italy;
Abstract
Suicidal behavior (SB) represents a major public health issue.1 Each year in Europe over than 100,000 men and women commit suicide2 and most often SB is caused by simultaneous ingestion of 2 or more central nervous system-acting drugs, which may be associated with therapeutic error, idiopathic response, or intentional overdose. On April 2005 the Committee for medicinal products for human use (CHMP) of the European Medicines Agency (EMA) warned thatall SSRI and SNRI antidepressants were associated with increased suicide-related behavior and hostilityin young people. This warning was added to the labels of all SSRI and SNRI containing products3.
Recently the Italian Medicines Agency has identified a new signal of SB associated with tramadol containing products.
Tramadol is an analgesic indicated for the treatment of moderate to severe chronic pain with a significant effect in the pain relief by weak opioid receptor agonism and inhibition of serotonin and noradrenaline reuptake. It is also recommended for pain in patients with underlying depressive symptoms although these patients are already at increased risk of suicidal. In fact, the principal risk factor for suicide is depression.
From a review of safety data (literature and post marketing cases) of a generic product containing tramadol it was noted several cases regarded overdose were occurred as a consequence of a tramadol intoxication alone or in combination with other drugs. In several cases the event was precipitated by a drug interaction between tramadol and central nervous system (CNS) depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. In other cases tramadol was the only substance present in toxic concentrations. Some cases occurred in drug abuser and the blood drug concentrations in almost all deaths exceeded the therapeutic serum range of 0.1-0.3 mg/L.
This signal was supported by the decision of the US Food and Drug Administration (FDA), that on May 2010, had included a warning on risk of suicide in the tramadol containing products4. The association between depression and risk of suicidal thoughts is supported by scientific evidence5. Moreover if in all SmPC of SSRI and SNRI a warning on the risk of suicidal thoughts and suicidal behaviours was added it was considered appropriate to add a warning on suicidal risk also in the product information of tramadol because it is a centrally acting opioid analgesic that exerts its effect also through the inhibition of norepinephrine and serotonin reuptake.
This analysis provide an update on recent data and regulatory action regarding the risk of suicide in association with the use of tramadol containing products. Based on this review all italian marketing authorization holders (MAHs) were required to update their SmPC/labelling of tramadol containing products through a variation in order to include changes relating to CNS safety. The warning information emphasizes the risk of suicide for patients who are addiction-prone, taking tranquilizers or antidepressant drugs and the risk of overdosage.
It is important that physicians and patients are aware of the possibility of risk of suicide specially in those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS depressant drugs.
Bertolote JMF, et. al (2005) Am J Med Genet C Semin Med Genet;133:8-12
World Health Organization. (2004) WHO, European health for all database (HFA-DB)
Avaible from URL
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SSRI_31/WC500013082.pdf
Avaible from URL
http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM213265.pdf
Tjäderborn M. et. al (2007) Forensic Sci Int.20;107-11.
Recently the Italian Medicines Agency has identified a new signal of SB associated with tramadol containing products.
Tramadol is an analgesic indicated for the treatment of moderate to severe chronic pain with a significant effect in the pain relief by weak opioid receptor agonism and inhibition of serotonin and noradrenaline reuptake. It is also recommended for pain in patients with underlying depressive symptoms although these patients are already at increased risk of suicidal. In fact, the principal risk factor for suicide is depression.
From a review of safety data (literature and post marketing cases) of a generic product containing tramadol it was noted several cases regarded overdose were occurred as a consequence of a tramadol intoxication alone or in combination with other drugs. In several cases the event was precipitated by a drug interaction between tramadol and central nervous system (CNS) depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. In other cases tramadol was the only substance present in toxic concentrations. Some cases occurred in drug abuser and the blood drug concentrations in almost all deaths exceeded the therapeutic serum range of 0.1-0.3 mg/L.
This signal was supported by the decision of the US Food and Drug Administration (FDA), that on May 2010, had included a warning on risk of suicide in the tramadol containing products4. The association between depression and risk of suicidal thoughts is supported by scientific evidence5. Moreover if in all SmPC of SSRI and SNRI a warning on the risk of suicidal thoughts and suicidal behaviours was added it was considered appropriate to add a warning on suicidal risk also in the product information of tramadol because it is a centrally acting opioid analgesic that exerts its effect also through the inhibition of norepinephrine and serotonin reuptake.
This analysis provide an update on recent data and regulatory action regarding the risk of suicide in association with the use of tramadol containing products. Based on this review all italian marketing authorization holders (MAHs) were required to update their SmPC/labelling of tramadol containing products through a variation in order to include changes relating to CNS safety. The warning information emphasizes the risk of suicide for patients who are addiction-prone, taking tranquilizers or antidepressant drugs and the risk of overdosage.
It is important that physicians and patients are aware of the possibility of risk of suicide specially in those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS depressant drugs.
Bertolote JMF, et. al (2005) Am J Med Genet C Semin Med Genet;133:8-12
World Health Organization. (2004) WHO, European health for all database (HFA-DB)
Avaible from URL
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/SSRI_31/WC500013082.pdf
Avaible from URL
http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM213265.pdf
Tjäderborn M. et. al (2007) Forensic Sci Int.20;107-11.