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

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Abstract

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.
CASE REPORT: THERAPY BJD
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,
1
J.C. Duipmans,
1
B. Molenbuur,
2
A.P. Wolff
3
and M.F. Jonkman iD
1
Departments of
1
Dermatology,
2
Anaesthesiology and
3
Anaesthesiology Pain Center; University of Groningen, University Medical Center Groningen, Groningen,
the Netherlands
Correspondence
Nicholas H.B. Schrader.
E-mail: n.h.b.schrader@umcg.nl
Accepted for publication
16 October 2018
Funding sources
None provided.
Conflicts of interest
None declared.
DOI 10.1111/bjd.17341
Summary
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,
1
and
leads to significant distress and poor quality of life.
2
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.
3
The
use of CBMs for pain in EB is discussed increasingly,
4
yet
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
©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) 1
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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
1
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
1
CBD, 13 mg mL
1
THC)
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
1
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
1
CBD, 13 mg mL
1
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
resolved.
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
1
CBD, 13 mg mL
1
THC)
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.
Discussion
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 effec-
tive 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 tech-
niques, and does not respond adequately to targeted thera-
pies.
9
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.
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 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.
12
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.
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 bur-
den for children with EB,
2
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.
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 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.
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 concur-
rently 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 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.
References
1 Fine JD, Johnson LB, Weiner M, Suchindran C. Assessment of
mobility, activities and pain in different subtypes of epidermolysis
bullosa. Clin Exp Dermatol 2004; 29:1227.
2 Goldschneider KR, Good J, Harrop E et al. Pain care for patients
with epidermolysis bullosa: best care practice guidelines. BMC Med
2014; 12:178.
3 de Hoop B, Heerdink ER, Hazekamp A. Medicinal cannabis on
prescription in the Netherlands: statistics for 20032016. Cannabis
Cannabinoid Res 2018; 3:545.
4 Chelliah MP, Zinn Z, Khuu P, Teng JMC. Self-initiated use of topi-
cal cannabidiol oil for epidermolysis bullosa. Pediatr Dermatol 2018;
35:e2247.
5 Yuen WY, Frew JW, Veerman K et al. Health-related quality of life
in epidermolysis bullosa: validation of the Dutch QOLEB question-
naire and assessment in the Dutch population. Acta Derm Venereol
2014; 94:4427.
6 Von Bischhoffshausen S, Ivulic D, Alvarez P et al. Recessive dys-
trophic epidermolysis bullosa results in painful small fibre neu-
ropathy. Brain 2017; 140:123851.
7 Schrader N, Yuen W, Jonkman M. Pain quality assessment scale
for epidermolysis bullosa. Acta Derm Venereol 2017; 98:3469.
8 Finnerup NB, Attal N, Haroutounian S et al. Pharmacotherapy for
neuropathic pain in adults: a systematic review and meta-analysis.
Lancet Neurol 2015; 14:16273.
9 Woolf CJ. Central sensitization: implications for the diagnosis and
treatment of pain. Pain 2011; 152 (Suppl. 3):S215.
10 Whiting PF, Wolff RF, Deshpande S et al. Cannabinoids for medical
use a systematic review and meta-analysis. JAMA 2015; 313:245673.
11 Thomas BF, Pollard GT. Preparation and distribution of cannabis
and cannabis-derived dosage formulations for investigational and
therapeutic use in the United States. Front Pharmacol 2016; 7:285.
12 Castillo PE, Younts TJ, Chavez AE et al. Endocannabinoid signaling
and synaptic function. Neuron 2012; 76:7081.
13 Russo EB. Cannabinoids in the management of difficult to treat
pain. Ther Clin Risk Manag 2008; 4:24559.
14 Mounessa JS, Siegel JA, Dunnick CA, Dellavalle RP. The role of
cannabinoids in dermatology. JAmAcadDermatology2017; 77:18890.
15 Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three
plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and
delta9-tetrahydrocannabivarin. Br J Pharmacol 2008; 153:199215.
©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. ...
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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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