With the increasing appearance of transdermal fentanyl generics since 2004 when patent protection of the reference Duragesic expired, opportunities to switch between different generics have arisen. Transdermal fentanyl is subject to bioequivalence regulation because only approximately 92% of the dose is absorbed as a result of the need to maintain a diffusion gradient from plaster to skin. Considering the high potency of fentanyl and the potential dangerous adverse effects of full mu opioid receptor agonists, we assessed evidence suggesting a revision of the confidence limits of bioequivalence of 80-125%. A few cases have been reported where a prescribed ascension in transdermal fentanyl dosing triggered respiratory depression. Values of concentration that produce a 50% effective response for decreasing the ventilatory volume lie within the plasma concentration range of 1.4-2.5 ng/mL during transdermal fentanyl analgesia. However, an exchange of the reference with a generic with higher bioavailability would trigger respiratory depression only in extreme situations and is clinically supported by only a single case report. Experimental or clinical evidence is required to provide the necessary database for final judgement of bioequivalent limits of fentanyl generics. At present, the evidence is not sufficient to advise other bioequivalence criteria than those previously applied to transdermal fentanyl.