Tramadol—A True Natural Product?

Abstract

We have independently investigated the source of tramadol, a synthetic analgesic largely used for treating moderate to severe pain in humans, recently found in the roots of the Cameroonian medicinal plant, Nauclea latifolia. We found tramadol and its three major mammalian metabolites (O‐desmethyltramadol, N‐desmethyltramadol, and 4‐hydroxycyclohexyltramadol) in the roots of N. latifolia and five other plant species, and also in soil and local water bodies only in the Far North region of Cameroon. The off‐label administration of tramadol to cattle in this region leads to cross‐contamination of the soil and water through feces and urine containing parent tramadol as well as tramadol metabolites produced in the animals. These compounds can then be absorbed by the plant roots and also leached into the local water supplies. The presence of tramadol in roots is, thus, due to an anthropogenic contamination with the synthetic compound.

Nauclea latifolia: biological activity and alkaloid phytochemistry of a West African tree

“…72 More recently, it was reported that aqueous extracts of N. latifolia roots exhibited an antinociceptive effect in the murine model. 12 This variability was backed-up by another study that used an induced writhing movement test on mice: heterogeneous results were obtained from samples harvested in various locations with different climatic characteristics. This evaluation led to the identication of a very active analgesic alkaloidal fraction.…”

“…2) led inevitably to some controversy. 12 This suggestion was based primarily on negative evidence: the absence or presence of only trace amounts of tramadol (<0.0002% w/w) in some samples of N. latifolia. 12 This suggestion was based primarily on negative evidence: the absence or presence of only trace amounts of tramadol (<0.0002% w/w) in some samples of N. latifolia.…”

“…12 This suggestion was based primarily on negative evidence: the absence or presence of only trace amounts of tramadol (<0.0002% w/w) in some samples of N. latifolia. 12 More recently, the same group provided additional data pertinent to the origin of tramadol, using isotopic 14 C analyses. 13 These data validate their proposal that tramadol is widely abused in ethnoveterinary use, but do not invalidate the claim that the tramadol isolated from N. latifolia is of natural origin.…”

“…The ethnomedical applications cover a large range of diseases, including pain-management, diabetes, infections, and malaria. 12,13 Additional experiments are required to categorically provide a clear-cut answer to this. [4][5][6][7] Recently, N. latifolia was brought under the spotlight aer the publication of the occurrence of racemic (1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol in its roots at a high concentration.…”

Myth debunked: Keratinous pangolin scales do not contain the analgesic tramadol

“…Nauclea latifolia) that is commonly used in African populations as a treatment for pain (Boumendjel et al, 2013). This was later confirmed to be the result of anthropogenic contamination through overuse of synthetic tramadol in humans and livestock, rather than synthesized by the plant itself (Kusari et al, 2014;Kusari, Tatsimo, Zühlke, & Spiteller, 2016). Thus, there is so far no substantiated evidence that tramadol is synthesized in biological systems.…”