'opioid-unrelated' originates from modern English as a compound of 'opioid' and 'unrelated'. 'Opioid' ultimately derives from Greek 'opion' via Latin 'opium' plus the suffix '-oid' meaning 'resembling', while 'unrelated' is formed from the prefix 'un-' meaning 'not' and 'related' (the past participle/adjective from 'relate').

'Opioid' was coined in the late 19th century from 'opium' + '-oid' and came into common medical use to denote substances acting like or on opium/opioid receptors; 'related' comes from Latin 'relatus' (past participle of 'referre') through Old French and Middle English, and 'unrelated' is the Modern English negative formation. The compound 'opioid-unrelated' is a recent, technical formation used in 20th–21st century medical and research writing.

Initially, 'opioid' meant 'like opium' in a morphological sense, but it evolved to denote substances that act on opioid receptors or have opiate-like effects; 'unrelated' historically meant 'not connected', and that core sense remains, so the compound's current meaning is 'not connected with or caused by opioids' used as a clinical descriptor.