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Combined THC and CBD to treat pain in epidermolysis bullosa: a report of three cases



Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care‐based interventions. Opioid‐based therapies underpin pain‐care in EB however are unable to provide adequate analgesia in a significant proportion of patients. Cannabinoid‐based medicines (CBMs) have been increasingly studied for pain conditions of various etiologies and pose as a novel dimension for pain‐care in EB. We present three cases of EB who were prescribed pharmaceutical‐grade sublingually administered CBMs comprising tetrahydrocannabinol (THC) and cannabidiol (CBD). All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake. This article is protected by copyright. All rights reserved.
British Journal of Dermatology
Combined tetrahydrocannabinol and cannabidiol to treat
pain in epidermolysis bullosa: a report of three cases
N.H.B. Schr
ader iD,
J.C. Duipmans,
B. Molenbuur,
A.P. Wolff
and M.F. Jonkman iD
Departments of
Anaesthesiology and
Anaesthesiology Pain Center; University of Groningen, University Medical Center Groningen, Groningen,
the Netherlands
Nicholas H.B. Schrader.
Accepted for publication
16 October 2018
Funding sources
None provided.
Conflicts of interest
None declared.
DOI 10.1111/bjd.17341
Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by
intense pain related to disease pathology and care-based interventions. Opioid-
based therapies underpin pain care in EB; however, they are unable to provide
adequate analgesia in a significant proportion of patients. Cannabinoid-based
medicines (CBMs) have been studied increasingly for pain conditions of various
aetiologies and pose as a novel dimension for pain care in EB. We present three
patients with EB who were prescribed pharmaceutical-grade sublingually admin-
istered CBMs comprising tetrahydrocannabinol and cannabidiol. All three patients
reported improved pain scores, reduced pruritus and reduction in overall
analgesic drug intake.
What’s already known about this topic?
Pain is the most burdening symptom for patients suffering from severe epidermol-
ysis bullosa (EB). Patients are exposed to numerous drug interventions, including
high-dose strong opioids, which often do not provide adequate analgesia and may
induce adverse effects.
Cannabinoid-based medicines (CBMs) have been investigated for pain of various
aetiologies and show promise through their interaction with the endocannabinoid
system localized to central pain circuits.
Cannabidiol has been reported to reduce wound pain in children with EB.
What does this study add?
The prescription of sublingually administered pharmaceutical-grade CBMs may add
additional value to pain-care in EB and should be further investigated.
Pain is the most debilitating symptom in adults with epider-
molysis bullosa (EB), caused by mucocutaneous blistering,
wound care and medical interventions, and in the long term
is exacerbated by psychological and central sensitization. The
prevalence of pain in EB is 5993% across subtypes,
leads to significant distress and poor quality of life.
The chal-
lenging management of pain in EB is characterized by a note-
worthy consumption of pain medication. Opioids underpin EB
pain care starting as early as infancy; however, they are con-
sidered problematic due to developing tolerance, dependence,
opioid-induced hyperalgesia, hormonal changes and obstipa-
tion. This concerns both patients with EB and caregivers, and
urges a pursuit for alternative treatments.
In the Netherlands, the prescription of pharmaceutical-grade
cannabinoid-based medicines (CBMs) containing tetrahydro-
cannabinol (THC) and cannabidiol (CBD) for pain has continu-
ally increased since becoming medically available in 2003.
use of CBMs for pain in EB is discussed increasingly,
remains unexplored territory. Here we report anecdotal outcomes
of three patients with EB suffering from refractory pain who
were prescribed CBMs.
Case report
Case 1
A 64-year-old woman (EB012-01) diagnosed with junctional EB
generalized intermediate (JEB-gen intermed) suffered from
refractory pain for over 20 years, reporting 9/10 for pain on the
visual analogue scale (VAS). Her daily pain therapy included 3 9
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published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
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1000 mg paracetamol, 2 910 mg oxycodone extended release
(ER), 1 910 mg codeine-phosphate, 2 925 mg amitriptyline
and 1 95mgg
topical morphine (applied to the painful right
heel). However, this regimen could not provide satisfactory
analgesia. Ten years prior, she attempted treatment with an
inhaled CBM; however, she experienced only short-lived analge-
sia (<45 min), and the presence of euphoria and dizziness. Sub-
sequently an orally administered CBM tea was prescribed with
no adequate pain relief.
Sublingual CBM oil (20 mg mL
CBD, 13 mg mL
was started at 05 mg CBD and 0325 mg THC, 4 9daily and
increased stepwise up to 25 mg CBD and 1625 mg THC, 4 9
daily. She reported VAS scores ranging between 1/10 and 4/10.
At 3 months, she was weaned off oxycodone-ER and at 6
months, oxycodone immediate-release (IR) was used for dress-
ing changes only. During the following 2 years, treatment with
topical morphine was replaced with 1 mg CBD and 065 mg
THC CBM oil, applied daily to her painful heel; she was also
weaned off amitriptyline. Notably, she also reported a moderate
reduction of pruritus expressed by a lower pruritus frequency
and reduced urges to scratch. An increased appetite was the only
side-effect reported from the CBM, and she currently maintains
that this treatment provides adequate pain relief.
Case 2
A 41-year-old man (EB132-01) diagnosed with JEB-gen inter-
med was treated for pain, for over 10 years, with 1000 mg
paracetamol, 4 9200 mg ibuprofen, 20 mg oxycodone-IR
and 5 mg g
topical morphine, daily. He reported a VAS for
pain of 9/10 and sought alternative analgesic modalities. He
was therefore started on treatment with a sublingual CBM (20
mg mL
CBD, 13 mg mL
THC). At 1 month he reached a
dose of 3 mg CBD and 195 mg THC, 4 9daily and reported
a VAS for pain of 3/10. He was weaned off oxycodone-IR
and topical morphine was stopped. Additionally, after com-
mencing the CBM treatment, he reported a reduction in the
frequency and intensity of his pruritus, as well as a reduced
urge to scratch. At 6 months, due to an increase of wound
pain, supplementary treatment was started with 5 mg oxy-
codone-IR 3 9daily, subsequently inducing a self-reported
distorted sense of time and delayed reaction time. On the
grounds of a drugdrug interaction, the CBM was reduced to
nocturnal doses only, which alleviated these symptoms and
his pain relief was maintained. He stopped CBM treatment 2
months later as his health insurance withdrew reimbursement
of the sublingual CBM oil, which he could not afford (200
per month). He was admitted to hospital after a subsequent
exacerbation of skin ulcerations and pain, whereby his clinical
team resorted to treatment with prednisolone 15 mg daily for
2 weeks, which provided only moderate analgesia. His pain
treatment remains unresolved.
Case 3
A 36-year-old man (EB015-01) diagnosed with recessive dys-
trophic EB generalized severe (RDEB-gen sev), had a history
of complications including chronic pain, pruritus, obstipation,
pseudosyndactyly, squamous cell carcinoma (SCC) of his
hands, and multiple amputations. His pain treatment consisted
of topical morphine, oxycodone-ER, oxycodone-IR, amitripty-
line, paracetamol, etoricoxib and locally injected dexametha-
sone. He experienced sedative side-effects from amitriptyline,
delayed wound healing by topical morphine, and obstipation
due to oxycodone-ER, oxycodone-IR and etoricoxib. Unable
to tolerate these side-effects, he experimented with CBM-flos
(the dried flower of the female cannabis plant) by way of
combustion and inhalation. During routine clinical follow-up
he reported an improvement of pain treated with paracetamol
and inhaled CBM-flos and his opioid-induced obstipation
After 6 months, worsening tumour pain in both hands
required supplementary analgesia. As EB pain recommenda-
tions indicated the use of strong opioids, which were con-
traindicated due to his susceptibility to side-effects, a
sublingual CBM oil (20 mg mL
CBD, 13 mg mL
was started. At 1 week he reported a 40% reduction in pain
intensity. Both the sublingual CBM and intrapulmonary CBM
were continued for 2 years. The combination of intrapul-
monary and sublingual CBMs surpassed previous pain treat-
ments, and additionally reduced the severity of pruritus and
his urge to scratch.
Later, he entered terminal care as a sequela of metastasized
cutaneous SCC and persisted to continue both intrapulmonary
and sublingual CBM administration, combined with 10 mg
amitriptyline and 10 mg prednisolone, daily. He died at 38
years of age.
Pain in EB significantly impacts quality of life and day-to-day
In addition to nociceptive pain associated with
blistering and wounds, peripheral nerve damage objectified in
and postulated in JEB, adds plausibility to reported
high pain scores in these EB types.
Neuropathies limit the
central role of opioids for EB pain as they may be less effec-
tive for this type of pain according to systematic analysis.
The persistent inflammatory condition in RDEB skin may
also contribute to central sensitization to painful stimuli,
which is challenging to objectify through diagnostic tech-
niques, and does not respond adequately to targeted thera-
The different aetiologies of pain in EB require
tailored interventions and therefore pain care is optimized
through combined drug treatments and psychological inter-
ventions. 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 clini-
cians 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
©2018 The Authors. British Journal of Dermatology
published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
British Journal of Dermatology (2018)
2Combined THC and CBD to treat pain in EB, Schr
ader et al.
self-acquired CBMs. Studies on CBM treatments show vary-
ing levels of success with moderate-quality evidence sup-
porting CBM efficacy for chronic pain.
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.
Cannabinoids mimic the actions of endocannabinoids,
endogenous ligands, which play a key role in synaptic trans-
mission. Pain modulation has been a central point of discus-
sion, explained, among other reaons, by the actions of
cannabinoids on neuronal circuits through cannabinoid-bind-
ing receptor (CB) dependent and independent pathways.
CB1 and CB2 are expressed on presynaptic terminals of pri-
mary afferent pain circuits, brain areas processing nociception,
including the centralmedial thalamic nuclei, periaqueductal
grey and raphe nuclei, and are colocalized with l-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.
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.
Pruritus entails the largest physical and psychological bur-
den for children with EB,
and the reported diminished fre-
quency and intensities of pruritus in these cases is notable as
the antipruritic effects of CBMs have been postulated in several
dermatological conditions.
In these cases, patients were prescribed a combination of
THC and CBD, which are the most studied plant-based
cannabinoids (phytocannabinoids). THC, like the endo-
cannabinoids 2-arachyldonylglycerol and anandamide, is a
partial agonist of CB1/2 and has been shown to stimulate
b-endorphin production, allowing for opioid sparing in clini-
cal practice.
CBD, in contrast to THC, has a low affinity for
CB1/2, and at high doses does not produce psychotropic
Interestingly, CBD is able to antagonize undesired
effects of THC such as sedation and intoxication while concur-
rently improving desirable effects like analgesia.
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 thera-
peutics 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.
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©2018 The Authors. British Journal of Dermatology
published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
British Journal of Dermatology (2018)
Combined THC and CBD to treat pain in EB, Schr
ader et al.3
... EB patients and clinicians continually seek out novel treatments to improve symptomatic care and quality of life. Two recent case series have brought to light the use of cannabinoidbased medicines (CBMs) in the EB-care setting [7][8][9]. However, the therapeutic potential and risks of such drugs have yet to be delineated in the context of EB care. ...
... The cross-sectional online survey obtained selfreported data on demographics, disease characteristics, CBM characteristics, effects of CBMs on EB symptoms, side effects, and changes in concomitant medication use (Additional file 1: Appendix 1). Survey questions were developed based on previously reported effects of CBMs on EB and other conditions, as well as input from EB patients and expert physicians [7,8]. As this was an internationally disseminated survey, given the potential illegality of CBMs, it was designed to uphold participant anonymity. ...
... The literature assessing CBM treatments in EB is non-existent. To date only two small (n = 6 total) retrospective case-series have been published, which highlighted various cannabinoid compositions of CBMs, administered topically or sublingually [7,8]. The reported effects here were strikingly similar, characterized by reductions in pain, pruritus, and in the use of other systemic medications, such as opioids. ...
Full-text available
Background Epidermolysis bullosa (EB) patient anecdotes and case reports indicate that cannabinoid-based medicines (CBMs) may alleviate pain and pruritus and improve wound healing. CBM use has not been characterized in the EB patient population. Objectives To evaluate CBM use among EB patients, including CBM types, effects on symptoms (e.g., pain and pruritus), disease process (e.g., blistering, wounds, and inflammation), well-being (e.g., sleep, appetite) and concomitant medications. Methods English-speaking EB patients or caregivers completed an online international, anonymous, cross-sectional survey regarding CBM use. Respondents reported the types of CBMs, subsequent effects including perceived EB symptom alteration, changes in medication use, and side effects. Results Seventy-one EB patients from five continents reported using or having used CBMs to treat their EB. Missing question responses ranged between 0 (0%) and 33 (46%). Most used more than one CBM preparation (mean: 2.4 ± 1.5) and route of administration (mean: 2.1 ± 1.1). Topical and ingested were the most common routes. Pain and pruritus were reported retrospectively to decrease by 3 points (scale: 0–10; p < 0.001 for both) after CBM use. Most reported that CBM use improved their overall EB symptoms (95%), pain (94%), pruritus (91%) and wound healing (81%). Most participants (79%) reported decreased use of pain medications. The most common side-effect was dry mouth (44%). Conclusions CBMs improve the perception of pain, pruritus, wound healing, and well-being in EB patients and reduced concomitant medication use. Nevertheless, a direct relation between the use of CBMs and reduction of the above-mentioned symptoms cannot be proven by these data. Therefore, future controlled studies using pharmaceutically standardised CBM preparations in EB are warranted to delineate the risks and benefits of CBMs.
... Phytocannabinoids (THC, CBD) were explored as a therapeutic option among three EB patients (36 to 61years of age) (Schräder et al., 2019). Sublingual delivery of THC (13 mg/ml) and CBD (20 mg/ml) was provided to all participants. ...
... following one week of sublingual CBD-THC combination oil, the patient reported a 40% reduction in pain (Schräder et al., 2019). ...
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In recent years, cannabinoid products have gained popularity among the general public. The anti-inflammatory properties of cannabinoids have piqued the interest of researchers and clinicians, as they represent promising avenues for the treatment of autoimmune and inflammatory skin disorders that may be refractory to conventional therapy. The objective of this study was to review the existing literature regarding cannabinoids for dermatologic conditions. A primary literature search was conducted in October 2020, using the PubMed and Embase databases, for all articles published from 1965 to October 2020. Review articles, studies using animal models, non-dermatologic, and pharmacologic studies were excluded. From 248 non-duplicated studies, 26 articles were included. There were 13 articles on systemic cannabinoids and 14 reports on topical cannabinoids. Selective cannabinoid receptor type 2 (CB2) agonists were found to be effective in treating diffuse cutaneous systemic sclerosis (dcSSc) and dermatomyositis (DM). Dronabinol demonstrated efficacy for trichotillomania. Sublingual cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (THC) were successful at treating pain associated with epidermolysis bullosa (EB). Available evidence suggests cannabinoids may be effective for the treatment of various inflammatory skin disorders. While promising, additional research is necessary to further evaluate efficacy, and to determine dosing, safety, and long-term treatment guidelines.
... The effects might have been due to the anti-inflammatory activity of CBD and might have beneficially modulated keratin expression [96,97]. Likewise, in another small pilot study, three EB patients, who were prescribed pharmaceutical-grade sublingually administered cannabinoid-based medicine (CBM) comprising THC and CBD, reported improved pain scores, reduced pruritus, and decreased overall analgesic drug intake [98]. The effects of cannabinoids are tested, and still are today, in acne, a skin disease triggered by various processes such as seborrhoea, hormonal imbalances, immune reactions, and infectious and environmental factors [99]. ...
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Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... The use of cannabinoid-based substances outside the controlled clinical setting outweighed prescribed CBMs in this cohort, which is likely due to the lack of cost reimbursement in the Netherlands. CBMs are gaining traction as potential therapies in EB; two case-series, as well as a recent international survey, highlight a plethora of patient-reported benefits from CBMs [39][40][41][42]. It is therefore imperative that new, high-quality research should ascertain the potential risks and benefits of CBMs in EB care. ...
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Epidermolysis bullosa (EB) is a genetic blistering skin condition for which no cure exists. Symptom alleviation and quality of life are therefore central to EB care. This study aimed to gain insight into EB patient needs and benefits from current clinical care. Two questionnaires were administered cross-sectionally to adult EB patients at the Dutch expertise centre for blistering diseases. Patient needs and benefits were analyzed using the patient benefit index survey (PBI-S). Ancillary data were compiled pertaining to self-reported EB severity, pain and pruritus, as well as current and previous treatments. In total, 104 participants were included (response rate 69.8%). Sixty-eight participants comprised the analyzed cohort (n = 36 omitted from analysis). The needs given the highest importance were to get better skin quickly (64.7%) and to be healed of all skin alterations (61.8%). A positive correlation between pain and EB severity and the importance of most needs was observed. Minimal clinically important differences within the PBI-S, relating to reported benefits from clinical care, were reported by 60.3% of the cohort. This study highlights a discrepancy between patient needs and feasible treatment outcomes. Utilizing the PBI-S in conjunction with well-established multidisciplinary care may catalyze the process of tailoring treatments to the needs of individual patients.
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Genodermatoses are rare inherited skin diseases that frequently affect other organs. They often have marked effects on wellbeing and may cause early death. Progress in molecular genetics and translational research has unravelled many underlying pathological mechanisms, and in several disorders with high unmet need, has opened the way for the introduction of innovative treatments. One approach is to intervene where cell-signaling pathways are dysregulated, in the case of overactive pathways by the use of selective inhibitors, or when the activity of an essential factor is decreased by augmenting a molecular component to correct disequilibrium in the pathway. Where inflammatory reactions have been induced by a genetically altered protein, another possible approach is to suppress the inflammation directly. Depending on the nature of the genodermatosis, the implicated protein or even on the particular mutation, to correct the consequences or the genetic defect, may require a highly personalised stratagem. Repurposed drugs, can be used to bring about a “read through” strategy especially where the genetic defect induces premature termination codons. Sometimes the defective protein can be replaced by a normal functioning one. Cell therapies with allogeneic normal keratinocytes or fibroblasts may restore the integrity of diseased skin and allogeneic bone marrow or mesenchymal cells may additionally rescue other affected organs. Genetic engineering is expanding rapidly. The insertion of a normal functioning gene into cells of the recipient is since long explored. More recently, genome editing, allows reframing, insertion or deletion of exons or disruption of aberrantly functioning genes. There are now several examples where these stratagems are being explored in the (pre)clinical phase of therapeutic trial programmes. Another stratagem, designed to reduce the severity of a given disease involves the use of RNAi to attenuate expression of a harmful protein by decreasing abundance of the cognate transcript. Most of these strategies are short-lasting and will thus require intermittent life-long administration. In contrast, insertion of healthy copies of the relevant gene or editing the disease locus in the genome to correct harmful mutations in stem cells is more likely to induce a permanent cure. Here we discuss the potential advantages and drawbacks of applying these technologies in patients with these genetic conditions. Given the severity of many genodermatoses, prevention of transmission to future generations remains an important goal including offering reproductive choices, such as preimplantation genetic testing, which can allow selection of an unaffected embryo for transfer to the uterus.
Background: Since its legalization in Canada, cannabis use has expanded to include commercially available topical formations. Several scientifically unsupported claims regarding the therapeutic efficacy of topical cannabis are also being made. Developing an understanding of the consumer uses of topical cannabis is important for clinicians to provide appropriate counseling and inform potential areas of therapeutic development. We are examining the prevalence, purpose of use, and sources of information regarding topical cannabis in the Canadian population, with a focus on dermatologic uses. Method: A cross-sectional, anonymous electronic, voluntary survey was developed to assess the use of topical cannabis amongst adults in Canada. Results: Cannabis was used topically at least once by 24.3% of respondents who started the survey. The commonest form of topical cannabis were creams (26.2%). The most common dermatologic conditions being treated with topical cannabis included atopic dermatitis (25%), acne (19%), and anti-aging (16%); for non-dermatologic conditions, common uses were for joint stiffness or tendonitis (30%) and headaches and migraines (27%). Topical cannabis was reported to be most effective for joint stiffness and tendonitis, general muscular soreness, headaches, eczema, pruritus, acne, and psoriasis. Most respondents obtained and received information about topical cannabis from dispensaries. Conclusion: Canadians use topical cannabis for a broad range of systemic and dermatologic purposes, most of which have limited evidence. Future clinical studies are required to elucidate the therapeutic efficacy and safety of topical cannabis. Dermatologists should screen their patients for topical cannabis use and be aware of the limited evidence of therapeutic potential.
Inherited epidermolysis bullosa (EB) comprises rare disorders that manifest with fragility and blistering of the skin and mucous membranes, with variable clinical severity. Management of EB is challenging due to disease rarity and complexity, the wide range of extracutaneous manifestations and a profound impact on daily life for the patient and family members. Although reference centres providing multidisciplinary care for EB exist in each European country, it is common for healthcare professionals that are not specialized in this rare disorder to treat EB patients. Here, experts of the European Reference Network for Rare and Undiagnosed Skin Diseases (ERN‐Skin, https://ern‐ propose practical recommendations for the diagnosis and management of the commonest clinical issues, skin blisters and wounds, oral manifestations, pain and itch.
Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited blistering skin disorders characterized by skin fragility following minor trauma, usually present since birth. EB can be categorized into four classical subtypes, EB simplex, junctional EB, dystrophic EB and Kindler EB, distinguished on clinical features, plane of blister formation in the skin, and molecular pathology. Treatment for EB is mostly supportive, focusing on wound care and patient symptoms such as itch or pain. However, therapeutic advances have also been made in targeting the primary genetic abnormalities as well as the secondary inflammatory footprint of EB. Pre-clinical or clinical testing of gene therapies (gene replacement, gene editing, RNA-based therapy, natural gene therapy), cell-based therapies (fibroblasts, bone marrow transplantation, mesenchymal stromal cells, induced pluripotential stem cells), recombinant protein therapies, and small molecule and drug repurposing approaches, have generated new hope for better patient care. In this article, we review advances in translational research that are impacting on the quality of life for people living with different forms of EB and which offer hope for improved clinical management.
University of Conneticut School of Medicine The public and health care providers are increasingly curious about the potential medical benefits of Cannabis. In vitro and in vivo studies of Cannabis have suggested it has favorable effects on regulating pain, pruritus, and inflammation, making it a potentially attractive therapeutic agent for many dermatologic conditions. The body of literature reporting on the role of cannabinoids in dermatology is in its infancy but growing. We review the current research, possible cutaneous adverse effects, and future directions for cannabinoids and their use in skin cancer, acne, psoriasis, pruritus, dermatitis, scleroderma, dermatomyositis, cutaneous lupus erythematous, epidermolysis bullosa, pain, and wound healing.
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Pain is one of the most debilitating B symptoms in epidermolysis bullosa (EB) leading to reduced quality of life. Pain in EB comprises both neuropathic and non-neuropathic qualities. An assessment of pain qualities has not formerly been completed in EB. The Pain Quality Assessment Scale (PQAS) is an adjusted version of the validated Neuropathic Pain Scale and includes 20 pain qualities and descriptors. Patients with EB (n = 43) rated the pain qualities in the PQAS on 20 numerical scales and 1 multiple choice question. Pain was experienced by 39 patients (91%). In general, patients with EB experience intense and unpleasant pain on the surface of the skin; the hands and feet are most commonly affected. The subtypes, recessive dystrophic EB and junctional EB reported pain qualities pathognomonic of neuropathic pain. The PQAS adds value to the current practice of global pain intensity scoring in EB.
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Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.
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This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing canna- binoids in pain treatment. Tetrahydrocannabinol (THC, Marinol ® ) and nabilone (Cesamet ® ) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC (partial CB 1 receptor agonist ) and can- nabidiol (CBD, a non-euphoriant, anti-infl ammatory analgesic with CB 1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numer- ous randomized clinical trials have demonstrated safety and effi cacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profi les. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
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Cannabis is classified as a schedule I controlled substance by the US Drug Enforcement Agency, meaning that it has no medicinal value. Production is legally restricted to a single supplier at the University of Mississippi, and distribution to researchers is tightly controlled. However, a majority of the population is estimated to believe that cannabis has legitimate medical or recreational value, numerous states have legalized or decriminalized possession to some degree, and the federal government does not strictly enforce its law and is considering rescheduling. The explosive increase in open sale and use of herbal cannabis and its products has occurred with widely variable and in many cases grossly inadequate quality control at all levels—growing, processing, storage, distribution, and use. This paper discusses elements of the analytical and regulatory system that need to be put in place to ensure standardization for the researcher and to reduce the hazards of contamination, overdosing, and underdosing for the end-user.
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Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. Twenty-eight databases from inception to April 2015. Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.
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Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effects and patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial. Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care for these patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge and practice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB. The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International (DEBRA International), an organization dedicated to improvement of care, research and dissemination of knowledge for EB patients worldwide. An international panel of experts in pain and palliative care who have extensive experience caring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of care without direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted. The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as well as the panel of clinical experts. During development, EB family input was obtained and the document was reviewed by a wide variety of experts representing several disciplines related to the care of patients with EB. The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinically relevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care of patients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs between adults and children, it will be so noted. Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease is often times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guideline development process also highlighted areas for research in order to improve further the evidence base for future care.
Epidermolysis bullosa is a rare blistering skin disorder that is challenging to manage because skin fragility and repeated wound healing cause itching, pain, limited mobility, and recurrent infections. Cannabidiol, an active cannabinoid found in cannabis, is postulated to have antiinflammatory and analgesic effects. We report 3 cases of self‐initiated topical cannabidiol use in patients with epidermolysis bullosa in an observational study. One patient was weaned completely off oral opioid analgesics. All 3 reported faster wound healing, less blistering, and amelioration of pain with cannabidiol use. Although these results demonstrate promise, further randomized, double‐blind clinical trials are necessary to provide scientific evidence of our observed benefits of cannabidiol for the treatment of epidermolysis bullosa.