Abstracts

Rationale: A nocebo effect, a negative response due solely to expectation, has been largely overlooked by researchers and clinicians, but has accounted for considerable discontinuation rates in medical trials. We report a case of the nocebo phenomenon leading to withdrawal from a controlled epilepsy study in a patient who was generic-brittle with a history of worsened seizures with generic lamotrigine (LTG) switching. Bioequivalence in Epilepsy Patients (BEEP) is an outpatient bioequivalence study of the brand name Lamictal versus the leading generic LTG product. The study design is double blinded and fully replicated. Epilepsy subjects are dosed two periods with Lamictal and two with generic product, totaling four randomized periods. Methods: Subject 009 was enrolled into BEEP and randomized to a sequence and blinded to LTG manufacturer (brand or generic) by tablet overencapsulation. Methods included scheduled contacts, diaries and pill counting for dosing adherence and adverse event reporting. Subject 009 completed the first three periods (2 weeks per period) and less than four days of the final period.Results: Results indicate a case of a nocebo effect under controlled clinical trial conditions. The subject dropped out of this study in the final arm due to self-identified adverse mood effects and increased seizures. Prior to enrolling, the subject believed that generic LTG product from Cadista was effective, while that from Northstar caused increased seizures. Throughout the study, the subject exhibited an active awareness to switching between brand and generic, albeit not an accurate one. Drug doses were missed or delayed on only two occasions. Within a few days after starting period 1, involving Lamictal, subject 009 reported an exacerbation of seizures. On day 7 of period 2, which involved generic product, the subject wrote No episodes. Now, I think this is the name brand. The last half of period 1 (brand) and all of periods 2 (generic) and 3 (brand) were unremarkable. When just switched to period 4 (generic), adverse events were almost immediate. We suspect the subject recalled a long period of successful outcomes, and therefore expected and perceived adverse effects with the last switch. On day 2 of period 4, the subject described feeling fearful, depressed, and paranoid, and experienced two seizures. Subsequent seizures on days 3 and 4 ( this last switch was causing seizures ) led to termination on day 5 from the study. On day 6, subject was seizure-free and reported feeling 90% better and predicted will be 100 % tomorrow . Thereafter, subject was at baseline and seizure-free.Conclusions: Our epilepsy subject appears to have experienced a nocebo effect of sufficient severity to warrant withdrawal from a blinded bioequivalence study of brand versus generic lamotrigine. That the nocebo effect may, similarly, account for reported sensitivity to product switching in other vulnerable patients should be considered in future studies of generic equivalence.