Combined Tetrahydrocannabinol and Cannabidiol to Treat Pain in Epidermolysis Bullosa

A Report of Three Cases

N.H.B. Schräder; J.C. Duipmans; B. Molenbuur; A.P. Wolff; M.F. Jonkman


The British Journal of Dermatology. 2019;180(4):922-924. 

In This Article


Pain in EB significantly impacts quality of life and day-to-day functioning.[1,5] In addition to nociceptive pain associated with blistering and wounds, peripheral nerve damage objectified in RDEB,[6] and postulated in JEB, adds plausibility to reported high pain scores in these EB types.[7] Neuropathies limit the central role of opioids for EB pain as they may be less effective for this type of pain according to systematic analysis.[8]

The persistent inflammatory condition in RDEB skin may also contribute to central sensitization to painful stimuli,[6] which is challenging to objectify through diagnostic techniques, and does not respond adequately to targeted therapies.[9] The different aetiologies of pain in EB require tailored interventions and therefore pain care is optimized through combined drug treatments and psychological interventions. However, the limited effectiveness of conventional analgesics stresses the fact that the gold standard for pain care in EB has yet to be established, hence motivating clinicians to consider alternative treatments for EB pain from various aetiologies.

All three patients were prescribed CBMs, comprising THC and CBD, by way of sublingual administration, with good effects. However, two patients had used at least one other administration form of which one patient had administered self-acquired CBMs. Studies on CBM treatments show varying levels of success with moderate-quality evidence supporting CBM efficacy for chronic pain.[10] In general, the difficulty of measuring clinical outcomes of CBM treatments is characterized by numerous administration forms and cannabinoid compositions. This has led to a call for the production and distribution of standardized, pharmaceutical-grade, CBM compositions and administration forms which can increase the predictability of dosing and effects as well as reducing the hazards of over- and underdosing, in the clinical setting.[11]

Cannabinoids mimic the actions of endocannabinoids, endogenous ligands, which play a key role in synaptic transmission. Pain modulation has been a central point of discussion, explained, among other reaons, by the actions of cannabinoids on neuronal circuits through cannabinoid-binding receptor (CB) dependent and independent pathways.[12]

CB1 and CB2 are expressed on presynaptic terminals of primary afferent pain circuits, brain areas processing nociception, including the central–medial thalamic nuclei, periaqueductal grey and raphe nuclei, and are colocalized with μ-opioid receptors in the spinal cord junction for peripheral nociceptive neurons. The role of CB2 antinocinception has also been implied in inflammatory and neuropathic pain models, likely due to the interaction of the endocannabinoid system with endorphin/enkephalin, vanilloid/transient receptor potential and inflammatory systems.[13] CB1/2 have been localized in human skin, and CB2 activation on keratinocytes is described to produce antinociception through the peripheral release of endogenous opioids.[13]

Pruritus entails the largest physical and psychological burden for children with EB,[2] and the reported diminished frequency and intensities of pruritus in these cases is notable as the antipruritic effects of CBMs have been postulated in several dermatological conditions.[14]

In these cases, patients were prescribed a combination of THC and CBD, which are the most studied plant-based cannabinoids (phytocannabinoids). THC, like the endocannabinoids 2-arachyldonylglycerol and anandamide, is a partial agonist of CB1/2 and has been shown to stimulate β-endorphin production, allowing for opioid sparing in clinical practice.[15] CBD, in contrast to THC, has a low affinity for CB1/2, and at high doses does not produce psychotropic effects.[13] Interestingly, CBD is able to antagonize undesired effects of THC such as sedation and intoxication while concurrently improving desirable effects like analgesia.[13]

Although the therapeutic potential of CBMs in pain control in EB is interesting, one cannot exclude the effect of placebo on patient-reported changes. In addition to this, core aspects of CBM therapeutics include the sufficient expression of CB1/2, which in EB is unknown. These limitations warrant further investigations of CBMs in controlled study settings in order to objectify the reported pain changes observed in these cases, and close the gap between current treatment standards and patient needs.