Patients with the genetic blistering skin condition, epidermolysis bullosa (EB), report a significant impact on quality of life compared to other skin conditions [1]. EB is considered a rare disease with an incidence and point-prevalence in the Netherlands of 41.3 per million live births and 22.4 per million population, respectively [2]. Amongst adults with EB, pain is the most debilitating symptom initially caused by blistering, chronic wounds, skin contractures and neuropathies [3]. Persistent pain in EB becomes a complex multidimensional experience due to psychosocial, and emotional components [3–6]. Due to this complex nature of pain in EB, adequate analgesia is difficult to achieve, leading to chronic refractory pain. In a recent cross-sectional study on EB in the Netherlands, patients with all EB-types rated “unpleasant” pain quality as the highest score of 20 qualities of pain [7]. This is interesting as research has shown that pain affect, located in the limbic system, which can be reported as the pain quality “unpleasantness”, is functionally distinct from sensory discriminative pain processing pathways [8]. One method to assess pain affect is by using functional magnetic resonance imaging (fMRI) techniques to measure brain connectivity in known and suspected neuroanatomical areas processing pain affect [8–10]. Research groups applying this technique have identified the amygdala and anterior cingulate cortex (ACC) as central brain areas with altered connectivity during chronic pain. Furthermore, independent of the aetiology of chronic pain, all chronic pain states (measured by fMRI) show similarities in altered brain connectivity, sometimes referred to as neuronal reorganization, which can be subsequently reversed with effective treatments [9].

Endogenously produced cannabinoids (endocannabinoids) play a key role in the modulation of pain signals by binding endocannabinoid receptors 1 and 2 (CB1/2) [11, 12]. CB1/2 are ubiquitous in the human body, however CB1 is most prevalently found in the central nervous system with the exception of lower brain-stem regions for cardiovascular and respiratory functions—explaining the unattainable lethal doses and complete absence of mortality from exogenous plant-derived cannabinoid (phytocannabinoid) administration [13–15]. As CB1/2 are densely populated in the frontal-limbic areas of the brain, their role in modulating pain affect has been proposed [16]. Like these endocannabinoids, exogenous cannabinoids, namely delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), also target these receptors, modulating neurotransmitter release in the CNS. Specifically, the amygdala and ACC are shown to have altered functional connectivity to brain cortices through CB1/2 agonism [16]. This change in connectivity significantly correlates with a decrease in pain, and more specifically, a decrease in the pain quality “unpleasantness” from noxious stimuli after systemic administration of phytocannabinoids [16–18]. In recent years, clinical studies on various painful diseases have shown the superiority of combining multiple cannabinoids compared to single-cannabinoid extracts, with specific regard to the combination of THC and CBD [19–21]. This is likely attributed to an improved tolerance of THC-based interventions, by way of paradoxical CBD CB1/2 receptor antagonism [20, 21].

It is important to note that the use of cannabinoid-based medicines (CBM) for pain, often as self-medication, have preceded clinical studies and sufficient clinical evidence. Given the limited effectiveness of conventional treatments in EB, it is well-known that these patients have used CBMs for symptom alleviation and have subsequently reported promising anecdotes. A recent study collected data on 71 EB patients around the world using CBMs. Although the cohort mainly comprised patients with a more severe EB, all EB-types described symptomatic improvements. A considerable obstacle to interpreting these experiences is the significant variability in administration forms, cannabinoid compositions, and doses used by patients. Additionally, these products are often not regulated as pharmaceutical products and therefore lack pharmaceutical-grade standardisation and quality control. However, seventeen of the participants administered CBMs sublingually and retrospectively reported mean NRS (0–10) pain reductions of 3.58 (±1.8) after administering CBMs [22].

In the Netherlands, CBMs are produced and compounded by companies overseen by the Dutch government and have been available on prescription since 2003. From 2015 CBM oils comprising THC and CBD in varying ratios have been empirically prescribed to several Dutch patients with EB [23]. Good quality evidence on CBM effectiveness in EB, and mechanisms of action, remain elusive. Nevertheless, clinical studies on heterogenous chronic pain conditions show moderate evidence for the efficacy of CBMs (comprising THC and CBD) versus placebo [24, 25].

To date, it has also been shown that neither the dose administered nor detected plasma levels of cannabinoids are good predictors of pain alleviation when treated with CBMs. The high inter-individual variability (CV%) is likely due to patient variations in BMI, enterohepatic circulation, degradation in the gut, previous cannabinoid exposure, the endogenous cannabinoid system (endocannabinoid system) compositions and differences in administration technique [26, 27].

Therefore, the current best-practice is for patients administering CBMs to undergo dose-escalation titration following a premeditated dosage build-up scheme (e.g., administration 4x daily). In order to achieve an effective dose, patients continue titration until side-effects are reached, then reduce their dose by one step in the titration scheme, and subsequently maintain the achieved dose [28]. Methods for dose-escalation vary significantly between patients in clinical practice, which is why a fixed titration scheme should be employed for research studies. This feasibly standardizes the dose-escalation for all participants in clinical studies, individualizing the dose-required but standardizing the method to achieve this. Controlled studies in rare diseases, like EB, encounter several hurdles including small population sizes, high participation burden and ethical dilemmas related to placebo administration. To address these, the proposed study allows for participation with unchanged medication regimens already in place and employs a crossover methodology where participants will receive both placebo and the chemically active intervention for a short period of time.

Taken together, the unmet treatment needs for pain in EB and moderate quality evidence for the use of CBMs to treat pain and modulate pain affect, open grounds for further clinical investigation. To substantiate this research avenue, CBM interventions in EB, the proposed explorative study will gain insight into effects of Transvamix^®, a sublingually administered and standardized CBM, on pain, brain connectivity, doses achieved through titration and adverse events. New fMRI techniques to assess brain connectivity enhance the assessment of both baseline connectivity characteristics in EB patients with pain, as well as connectivity changes in areas processing pain affect. In the clinical research setting it is therefore imperative to standardize dose-escalation schemes, administer standardized pharmaceutical grade CBMs, apply validated patient reported outcomes, and employ sufficient sample sizes and rigorous statistical analyses. We hypothesize a novel avenue of pain intervention for EB by modulating pain affect–objectified by fMRI.