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The darker side of tramadol

The dangers of addiction to the opioid, which were not anticipated at the drug’s launch, serve as a reminder that clinicians always have more to learn.

Tramadol abuse

Source: Callie Jones

Tramadol is one of the few drugs to achieve the ignominious fate of increased regulation. The drug was classified as a schedule 3 controlled drug in June 2014 following its increased use as a drug of abuse.

This would have been hard to envisage at its UK launch 20 years ago. Developed synthetically by Grünenthal, tramadol has a unique dual action – it acts as a weak opioid receptor agonist and inhibits the reuptake of serotonin and noradrenaline. This weak action meant it was considered a safer alternative to opiates. Since the British National Formulary (BNF) first included tramadol in September 1994, it has stated the drug has “less addiction potential” than other opioids, and one 1997 study advised it was “highly unlikely to lead to dependence”.

We now know tramadol’s dual action means the risk of adverse effects in overdose is much higher: although respiratory depression is less common than with other opioids, patients are more likely to experience seizures and its serotonergic effects can cause severe serotonin syndrome. The dangers are compounded by the fact that naloxone only reverses tramadol’s opioid effects.

As our knowledge and clinical understanding develops, we refine a medicine’s use and reassess its place in therapy

Concerns about addiction were raised almost as soon as the drug launched. Between June 1994 and October 1996, the UK Committee on Safety of Medicines received five reports of drug dependence and withdrawal symptoms. It was only as the use of tramadol rose, largely following the withdrawal of co-proxamol in 2005, that the extent of the potential harms became apparent. In 2006, tramadol was implicated in 81 deaths in England and Wales; in 2011, it was 154. The drug had been obtained illegally in the majority of cases.

This should not be viewed as a failure or oversight. As our knowledge and clinical understanding of a medicine develops, we refine its use and reassess its place in therapy. Sildenafil was famously trialled as a treatment for angina before the real benefits of phosphodiesterase type 5 inhibitors became apparent. Gabapentin was initially marketed solely for epilepsy before claiming its place in treating neuropathic pain. And the cardiac risks of domperidone, which resulted in new restrictions from the Medicines and Healthcare products Regulatory Agency (MHRA) in May 2014, only came to light fully after decades of use by millions of patients.

Today we know far more about tramadol than we could have predicted in 1994. It is not even truly synthetic: in 2013, researchers discovered it occurs naturally in Nauclea latifolia, an African shrub used in herbal medicine. Tramadol is another reminder that our knowledge is never complete, and proof that pharmacovigilance should never stop.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.20066098

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