Nicholas Schrader

Background and Aims Epidermolysis bullosa (EB) is a rare, inherited skin fragility disorder characterised by blistering, chronic wounds, and lifelong multisystem complications. Pain is consistently ranked as the most debilitating burden of the disease. It is not a single phenomenon: it arises from tissue damage and wound care (nociceptive pain), from dysfunctional or damaged neurons (neuropathic pain), and, as this thesis argues, from central amplification mechanisms that sustain pain beyond what tissue pathology alone can explain (nociplastic pain). Despite this burden, evidence-based analgesic strategies remain inadequate. Cannabinoid-based medicines (CBMs) represent a biologically plausible treatment candidate, given that the endocannabinoid system modulates pain, inflammation, and itch at multiple levels of the nervous system. This thesis characterises EB pain with greater precision and constructs a stepwise evidence base for CBM efficacy and tolerability, centred on the affective dimension of pain as a primary therapeutic target. Chapter 2 - What EB Patients Need Most A systematic needs assessment using the Patient Benefit Index for Skin diseases (PBI-S) was conducted in 68 patients with EB. The four highest-ranking unmet treatment needs were: to get better skin quickly, to be healed of all skin alterations, to be free of itching, and to be free of pain. Pain correlated positively with all 25 assessed patient needs across the questionnaire, demonstrating its pervasive impact on every domain of wellbeing and providing the empirical justification for positioning pain as the primary therapeutic target throughout the thesis. Chapter 3 - The Character of EB Pain The Pain Quality Assessment Scale (PQAS) was administered to 43 patients with EB. Ninety-one percent reported pain, with neuropathic features, including burning, stabbing, and electric shock sensations, especially prominent in RDEB and JEB. Notably, pain unpleasantness was consistently the highest-rated pain quality across most subtypes, often exceeding intensity scores. This matters: unpleasantness captures the affective, suffering dimension of pain, and its prominence suggests that central processing mechanisms play a key role in EB pain, pointing toward a mechanistic picture that goes beyond nociception alone. Chapter 4 - First Clinical Signals Three patients with different EB subtypes, each with their own complex and individually tailored analgesic regimen, were treated with sublingual THC/CBD oil (Transvamix) in a supervised, physician-led clinical setting with careful dose titration. Despite differences in diagnosis and prior medication history, all three experienced substantial and sustained improvements in pain, reductions in pruritus, and a marked analgesic-sparing effect including weaning from opioid medications. The treatment was well tolerated in all cases. These observed outcomes under medical supervision provided a credible rationale to pursue further investigation of this treatment modality. Chapter 5 - Real-World Evidence An international online survey was completed by 71 EB patients or their caregivers from five continents. The breadth of reported benefit from CBM-use is striking: 95% reported improvement in overall EB symptoms, 94% in pain, 91% in pruritus, and 81% in wound healing, spanning the exact domains patients had identified as their most important needs in Chapter 2. Seventy-nine percent had reduced or discontinued conventional analgesic medications. Only 24% of CBM-use was prescribed by doctors. Self-reported side-effects were minimal; the most common was dry mouth (44%), and no serious adverse events from CBM-use were reported by respondents. Chapter 6 - Designing a Rigorous Trial in a Rare Disease The protocol for the C4EB randomised controlled trial is described. The trial was designed as a double-blind, placebo-controlled crossover study evaluating sublingual Transvamix (10% THC, 5% CBD) in adult patients with EB, with functional MRI (fMRI) incorporated as an exploratory outcome to assess CBM effects on central pain processing networks. The protocol addresses the specific methodological challenges of conducting rigorous interventional research in a rare and heterogeneous patient population. Chapters 7 & 8 - The C4EB Study: Results Eight adult patients with EB completed the trial. The primary outcome, a statistically significant improvement in the pain affect domain of the short-form McGill Pain Questionnaire (SF-MPQ2), was not achieved, and pain unpleasantness did not significantly decrease versus placebo. This must be understood in context: the sample was small, the crossover period short, and nociplastic pain mechanisms likely require longer treatment windows to engage. Clinically meaningful signals nonetheless emerged: 75% of participants achieved a ≥30% reduction in overall pain with CBMs versus 50% with placebo. Half of all analgesics were discontinued during the CBM phase; all were continued during placebo, a striking analgesic-sparing effect. The fMRI sub-study was feasible and well tolerated, providing preliminary evidence of heterogeneous changes in central pain network connectivity after CBM administration. The adverse event profile was favourable throughout. Chapter 9 - Synthesis and Implications The Discussion integrates the thesis findings into a mechanistic account of EB pain as nociceptive, neuropathic, and likely nociplastic in nature, arguing that repeated tissue injury, chronic inflammation, and the psychological burden together drive a pain experience that nociceptive-directed treatments cannot adequately address. Across the case series, and international cross-sectional survey, patients consistently reported benefits from CBMs on multiple domains known to affect quality of life in EB. Drawing on the broader CBM literature, it is proposed that cannabinoids may preferentially modulate affective pain pathways, offering a mechanistic explanation for the clinically meaningful signals observed, despite the primary endpoint not being met in the C4EB study. Importantly, the C4EB study is framed as informative rather than merely negative: it provides proof of concept for a controlled design in EB, generates the first controlled safety data for sublingual CBMs in this population, and demonstrates for the first time that patients with EB can safely undergo resting-state fMRI in a trial setting. Timely nociceptive pain control may also help prevent nociplastic transition, positioning effective analgesia early on as a potentially disease-modifying strategy. CONCLUSION Pain in EB is severe, multidimensional, and undertreated. This thesis maps the breadth of its burden and homes in on affective and nociplastic dimensions that nociception-focused treatments cannot fully address. Although the C4EB study did not meet its primary endpoint, cannabinoid-based medicines demonstrated consistent signals across analgesic sparing, global pain reduction, and patient-reported benefit, with a tolerability profile that supports continued clinical consideration. What is now needed are trials that are mechanistically precise, adapted to rare disease constraints, and anchored in outcomes that patients experience as meaningful.