320 Chapter 10 hypocretin production (leading to narcolepsy symptom improvement). This gene expression theory has only recently been first proposed and is still being heavily debated. As opioids were usually initiated for indications other than narcolepsy type 1 (apart from one respondent), the possible interaction between pain relief and narcolepsy symptom improvement cannot be fully ruled out in this observational study. To minimise the influence of this unwanted effect we asked respondents to compose a timeline of possible narcolepsy symptom severity changes and compare possible changes in their narcolepsy symptoms to times when they were not yet experiencing the indication for which the opioid was later prescribed. Respondents were also explicitly asked to consider possible changes when taking opioids separate from long-standing effects of their regular narcolepsy medication. Possible recall bias was minimised by including only opioid use in the past three years and the opioid details were verified through correspondence with the prescribing physician or pharmacist. In our study we included a relatively small well-defined sample of 100 people with narcolepsy type 1 through our tertiary sleep-wake clinic. Within the Netherlands most people with narcolepsy are treated in specialized tertiary clinics, but this could hinder the generalizability of our results. There was a proportion of eligible subjects that was informed about the study which did not complete the questionnaire (21/121). We have methodologically tried to minimise the possible effect of selection bias by the non-responders by motivating all approached subjects to participate irrespective of recent opioid use or not. The limited sample size could have also affected the robustness of our results, which is emphasized by the relatively large spread of the 95% CIs. Future research should target a larger general population of people with narcolepsy type 1, and also use other inclusion sources such as patient organizations and self-help groups. The results of our small study indicate the need for a randomized controlled trial to confirm our results. Those treated outside tertiary clinics should also be included in this trial to better represent all people with narcolepsy type 1. Our systematic literature review could also be subject to publication bias of positive results. Grey literature searches in multiple trial registries and Google Scholar yielded no results for trials on opioid use in narcolepsy making the presence of unpublished negative trials less probable. Conclusions The combination of our systematic literature review and cross-sectional questionnaire study provides new insights into the nature and extent of
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