This time last year, the pharmaceutical industry (especially the analgesic business) worked itself into a tizzy when synthetic tramadol and its mammalian metabolites were isolated from the roots of the African pin cushion tree (Nauclea Latifolia) in Northern Cameroon. Not just that, it was also found that the roots had clinically viable concentrations. The natives have for long used it to treat pain, epilepsy, malaria and a host of other medical conditions. The scientists now found that the concentrations were high enough that the natives could simply grow, harvest and extract it without ever needing a prescription. The best thing to have come out of Cameroon, after Samuel Eto’o, one would have thought. The joy, however, was short lived when another group of scientists who were digging around found that it was just the northern trees which had them. They didn’t find tramadol in the roots of the pin cushion trees growing in Southern Cameroon. Published recently, their paper proved that it was all down to ‘anthropogenic contamination.’ In other words, the off-label administration of tramadol to cattle in the northern region had lead to cross-contamination of the soil and water through feces and urine containing tramadol as well as its metabolites. These compounds were then absorbed by the plants. All a bit of an anticlimax, one would say, mirroring Eto’o’s career – ending up playing for Everton after having played for Barcelona.
Close on its heels comes another disconcerting paper on tramadol. Fournier and colleagues analysed data from the United Kingdom Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics (HES) database to determine whether use of tramadol, when compared with use of codeine, another weak opioid not previously associated with hypoglycemia, is associated with an increased risk of hospitalization for hypoglycemia in individuals with noncancer pain. In this rather large epidemiological study involving 334 034 patients (28 110 – tramadol and 305 924 – codeine), they found that patients commencing treatment with tramadol were 3 times more likely to be hospitalized with hypoglycemia in the subsequent 30 days than those who commenced treatment with codeine. The randomized controlled trials which were designed to detect analgesic effects previously did not pick up hypoglycemia, as they were grossly under-powered to pick up this rare side-effect (7/10000/year). The true rate, however, might be much higher as it may not be reported in diabetics, may not be recognised in non-diabetics, and may not have resulted in hospital admissions. Mechanistically too it is possible, as serotonin induces hypoglycemia in diabetic rats and mice, and use of anti-depressants acting on serotonin and noradrenaline pathways have been associated with hypoglycemia. Moreover, tramadol-mediated stimulation of μ receptors appeared to increase insulin signaling, thereby increasing hepatic sensitivity to insulin. Furthermore, these effects were blocked by naloxone.
There are several other challenges with tramadol. It is metabolized by the cytochrome P 450 superfamily of membrane associated proteins (CYP enzymes). The enzyme CYP2D6, which metabolizes codeine to morphine, also metabolizes tramadol to its active metabolite M1 (which binds to the μ opioid receptors). The expression of CYP2D6 is extremely variable resulting in dramatic variability in M1 synthesis. Humans could be ‘poor metabolizers’ or ‘ultrarapid metabolizers.’ Codeine is ineffective at typical doses in up to 10% of Caucasians carrying two non-functional CYP2D6 alleles. On the other hand, when the alleles are over expressed, as in 10% of Italians, Greeks and Arabs, more M1 is synthesized increasing the risk of adverse drug effects. In addition, CYP2D6 could be inhibited by the selective serotonin reuptake inhibitors (SSRI’s) such as paroxetine and fluoxetine, and by certain other antihistamines (diphenhydramine) and antidepressants (bupropion). The ultrarapid metabolizers, when on these medications, could be rendered ‘functional poor metabolizers’. CYP2D6 could, in addition, be induced by rifampicin and dexamethasone, making the same patients even more prone to adverse effects. Nelson and Juurlink in the editorial accompanying the paper on hypoglycemia have observed that, ‘Giving a known dose of tramadol is tantamount to giving an unknown dose of opioid. This is of direct relevance to the drug’s safety and effectiveness.’
Similar to opioids, tramadol has issues such as dependence, tolerance and addiction, and could be abused. In England and Wales, tramadol-related deaths have tripled from 2009-2013. The United States, Australia and England have all restricted the use of the drug by rescheduling it. India too has recently categorised tramadol under Schedule H1. Furthermore, Serotonin syndrome – a predictable consequence of excess serotonin in the central or peripheral nervous system – resulting in hyperthermia and multi-organ damage, is a consequence of using tramadol in combination with SSRI’s. In addition, tramadol reduces the seizure threshold at therapeutic doses. Put together, the adverse effects of tramadol are dangerous. Hypoglycemia, the newest on the block, could be life threatening. All this when the analgesic effects are at best moderate. We might have thrown caution to the wind in planting African pin cushion trees in our back yard, but we will have to be cautious in prescribing tramadol for diabetics on hypoglycemics.