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Cannabinoids for the Treatment of Chronic Pruritus: A Review
Christina Avila, MPH, Susan Massick, MD, Benjamin H. Kaffenberger, MD, Shawn G.
Kwatra, MD, Mark Bechtel, MD
PII:
S0190-9622(20)30120-1
DOI:
https://doi.org/10.1016/j.jaad.2020.01.036
Reference:
YMJD 14169
To appear in:
Journal of the American Academy of Dermatology
Received Date: 10 April 2019
Revised Date:
15 January 2020
Accepted Date: 18 January 2020
Please cite this article as: Avila C, Massick S, Kaffenberger BH, Kwatra SG, Bechtel M, Cannabinoids
for the Treatment of Chronic Pruritus: A Review, Journal of the American Academy of Dermatology
(2020), doi: https://doi.org/10.1016/j.jaad.2020.01.036.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
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© 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
Capsule Summary
•
The endocannabinoid system plays an active role in the skin and cannabinoid products
are an emerging consideration for skin therapy, particularly for itch.
•
Physicians should be knowledgeable about the mechanistic justification on the use of
cannabinoids for refractory pruritus that fails standard therapies when it is a legal option.
1
Cannabinoids for the Treatment of Chronic Pruritus: A Review
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Christina Avila, MPH1, Susan Massick, MD2, Benjamin H. Kaffenberger, MD2, Shawn G
Kwatra, MD3, Mark Bechtel, MD2
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The Ohio State University College of Medicine, Columbus, OH, 43202
Division of Dermatology, Ohio State University Wexner Medical Center Columbus, OH, 43221
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Division of Dermatology, Johns Hopkins University School of Medicine, Baltimore MD 21205
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Corresponding Author:
Mark Bechtel, MD
OSU Dermatology
2012 Kenny Road. 2nd Floor
Columbus, OH, 43221
[email protected]
Word Count: Abstract (197) Main text (1997) Capsule summary (50)
Number of References: 68
Number of Figures: 1
Number of Tables: 2
Funding sources: None
Conflict of Interest: None declared
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Abstract: Medical marijuana is becoming widely available to patients in the U.S. and with
36
recreational marijuana now legalized in many states, patient interest is on the rise. The
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endocannabinoid system plays an important role in skin homeostasis in addition to broader
38
effects on neurogenic responses such as pruritus and nociception, inflammation, and immune
39
reactions. There are numerous studies of in vitro and animal models that provide insight into the
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possible mechanisms of cannabinoid modulation on pruritus, with the most evidence behind
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neuronal modulation of both peripheral itch fibers and centrally-acting cannabinoid receptors. In
42
addition, human studies, while limited due to differences in cannabinoids used, disease models,
43
and delivery method, have consistently shown significant reductions in both scratching and
44
symptomatology in chronic pruritus. Clinical studies that have shown reduction in pruritus in
45
several dermatologic (atopic dermatitis, psoriasis, asteatotic eczema, prurigo nodularis, allergic
46
contact dermatitis) and systemic (uremic pruritus, cholestatic pruritus) diseases. These
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preliminary human studies warrant controlled trials to confirm the benefit of cannabinoids for
48
treatment of pruritus and to standardize treatment regimens and indications. In patients who have
49
refractory chronic pruritus after standard therapies, cannabinoid formulations may be considered
50
as an adjuvant therapy where it is legal.
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Introduction: Pruritus is one of the most common complaints from patients who come to the
58
dermatologist. Chronic pruritus, defined as pruritus greater than 6 weeks, reduces quality-of-life
59
and can be as debilitating as chronic pain1. Pruritus has been reported in 30.9-36.2% of
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dermatology patients and 16.8% of the general population reports chronic pruritus at some point
61
in their lives2–4. Current treatment options include a combination of emollients, topical
62
anesthetics, menthol, oral and topical glucocorticoids, oral antihistamines and neuroactive
63
medications, however none can claim consistent or complete efficacy5-6. Cannabinoids, which
64
modulate the endogenous endocannabinoid system (ECS), have shown promise for treatment of
65
itch in the clinical literature to date, which encompasses clinical studies in multiple diseases
66
including for the management of refractory pruritus7–10.
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68
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The Endocannabinoid System Cannabinoids represent a broad class of endogenous and
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exogenous arachidonic acid-derivative compounds with activity at the cannabinoid receptors,
71
CB1 and CB2. These exist as phytocannabinoids derived from the Cannabis sativa plant (e.g.
72
∆(9)-tetrahydrocannabinol [THC], cannabidiol [CBD]), endogenous endocannabinoids (e.g.
73
anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), and synthetic cannabinoids11-12. The
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ECS refers to the lipid-signaling system that includes the endocannabinoids, their receptors, and
75
degradative or inactivating enzymes and is involved in physiologic and pathologic mechanisms
76
throughout the human body, such as cognition, nociception, and inflammation13-14. The ECS
77
plays an important role in skin health. The ECS maintains epidermal homeostasis, regulates hair
78
follicles and sebaceous glands, and plays a role in nociception and inflammation and
79
dysregulation has been linked to several skin diseases, atopic dermatitis, psoriasis, scleroderma,
3
80
and skin cancer15–17. Cannabinoids are ligands to the canonical cannabinoid receptors CB1 and
81
CB2 and the transient receptor potential (TRP) ion channels with individual differences in
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affinity and activity (Table 1)18–21. These receptors have near ubiquitous expression in the skin,
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and are present on terminal nerve endings of cutaneous fibers that extend to the dermis and
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epidermis22
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The Role of Cannabinoids for Pruritus The evidence in the literature suggests the anti-pruritic
87
effects of cannabinoids are due to a combination of effects on neuronal activation, transmission
88
along the afferent pathway, and local modulation of keratinocyte and mast cells (Figure 1). The
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anti-pruritic effect of cannabinoid receptor ligation on peripheral and central nervous tissue may
90
be a result of actions at multiple receptors, as experiments in various models of skin diseases
91
show individual CB1, CB2, or TRP channel modulation exhibit reduced pruritus18,23–25.
92
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Similar to the role of cannabinoids in pain, increased activity at both CB1 and CB2 have been
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shown to alleviate pruritus26–29. These analgesic and anti-pruritic effects occur at the central and
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peripheral level. In the CNS, the analgesic and anti-pruritic effects are predominately mediated
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through CB1 receptors, congruent with their activity as the main centrally-acting cannabinoid
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receptor26,28–30. In the periphery, activity at both CB1 and CB2 are thought to induce
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analgesia28,29. These effects have been shown in both inflammatory and neurogenic pain and itch
99
and are due to activity on both local inflammation and neuronal activation. Increased
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endocannabinoids in neural tissue specifically decreases histaminergic itch and direct effects of
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cannabinoids on neuronal receptors increase the nociceptive threshold10,31-32. Alterations of CB1
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and CB2 expression occur in states of chronic pain and it is thought that this modulation of
4
103
activity at these receptors is responsible for the effects of cannabinoids on sensation33. Together
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this suggests that the ECS regulates neuronal transmission in the itch sensory pathway through
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direct binding of receptors on the nerves. Topical cannabinoid agonists can also decrease mast
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cell recruitment to the skin, however the anti-pruritic effect can be independent of local
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histamine release19.
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The transient receptor potential ion channels are a group of membrane proteins widely expressed
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in the skin and nervous system which mediate sensory responses such as nociception and
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pruritus34. These channels play a critical role in cutaneous nerve fiber activation and respond to
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various stimuli such as inflammatory mediators, temperature, pH, and mechanical stimuli35. Six
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TRP channels from three subfamilies (TRP vanilloid [TRPV1, TRPV2, TRPV3, TRPV4], TRP
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ankyrin [TRPA1], and TRP melastatin [TRPM1]), all of which play roles in itch sensation, have
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been reported to interact with endogenous and exogenous cannabinoids35-36. TRPV1, widely
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known as the capsaicin receptor, has been the most studied TRP channel with regards to
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cannabinoid-mediated modulation of pruritus34,37. TRPV1 and TRPA1 have been shown
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separately to play key roles in itch pathways with blockade or absence showing consistent
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reductions in itch24,38–42. TRPV1 has a paradoxical effect upon activation because it is rapidly
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desensitized which leaves it refractory to additional stimulation36. In the case of TRPV1,
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cannabinoids disrupt neurogenic inflammation through antagonism or stabilization of the ion
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channel in the closed confirmation, which prevents neuronal activation by pruritic mediators36.
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Many of the clinical trials performed on cannabinoids for treatment of pruritus have used
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palmitoylethanolamine (PEA), which is a ligand at TRPV1 channels and has no direct interaction
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with CB1 and CB243-44. Capsaicin cream, a current option for refractory neuropathic pain, works
5
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in part through activation/desensitization of the TRPV1 channels45. The anti-pruritic effects of
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cannabinoids through the TRPV1 ion channel would support the use of CBD, which has a similar
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effect on TRPV1 and no direct activity at the canonical CB1/CB2 receptors.
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Inflammation in the skin is a major contributor to the pathogenesis of pruritus with local
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inflammatory factors such as histamine, cytokines, and neuropeptides serving as pruritogens.
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CB2 is widely expressed in peripheral immune cells and in most studies CB2 binding decreases
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inflammation including in models of dermatitis46. CB1 activation may have anti-inflammatory
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properties in skin diseases as well, CB1 binding in a murine model of atopic dermatitis (AD)
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decreased Th2 cytokine production18. Mast cells, which co-express CB1 and CB2, have inhibited
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activation, proliferation, and degranulation by CB1 binding and tonic suppression of mast cell
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function is thought to occur specifically through CB1 agonism19,47-48.
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Clinical Trials of Cannabinoids For Pruritic Diseases Topical application and oral
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administration of cannabinoids have shown promise for treatment of itch specifically in several
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diseases which includes pruriceptive itch such as dermatitis, neurogenic itch in metabolic
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derangements, and chronic intractable itch in prurigo (Table 2)8–10,47,49–51. AD is one of the most
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common forms of chronic itch and has been one of the most studied pruritic conditions in pre-
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clinical and clinical studies for cannabinoids44. Topical treatments of PEA and adelmidrol (a
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PEA analogue) significantly reduced inflammation and pruritus in a large-observational study
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and small open-label study after application of the cannabinoid-containing cream for 4 weeks to
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patients with AD 51,52. Topical cannabinoids have also shown promise for treatment in asteatotic
6
149
eczema (AE), however differences between the vehicles in this specific study confound the
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study findings8. Although most itch can be attributed to etiologies in the skin, pruritus can be a
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herald of underlying systemic diseases and metabolic abnormalities. One of the most common
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causes of systemic causes of itch is uremic pruritus which affects over half of patients on chronic
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dialysis53. Topical application of a derma-membrane system (DMS)-based lotion in combination
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with the AEA and PEA for three weeks decreased pruritus in patients on hemodialysis and by the
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end of the study nearly half of the patients had complete elimination of their itch7,49. Cholestatic
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disease causes pruritus in a large number of patients with primary biliary cirrhosis or hepatitis C
157
infections, and Dronabinol, a synthetic THC, was incidentally reported to provide short-term
158
relief in three patients with intractable pruritus secondary to chronic liver disease50,54.
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Randomized controlled trials on cannabinoids for treatment of itch with PEA-containing topicals
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have been reported in recent years in AE (N=60) and chronic pruritus (N=100) specifically, and
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while both showed reduction of itch, the difference was only significant in the case of AE7-8.
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This in combination with the fact that the majority of reported studies have been open-label or
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observational show the need for additional controlled trials to delineate whether there is a true
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benefit to cannabinoid-containing topicals.
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Formulations The delivery method of cannabinoids, which are highly lipophilic, determines
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efficacy due to different bioavailability and distribution dependent on the route of
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administration55. While the most common method of recreational marijuana use is inhalation,
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oral-ingestion and topical-transdermal hold promise for treatment of skin diseases with regards to
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efficacy and safety profile, and most studies to date utilize these delivery methods. Oral delivery
7
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of cannabinoids has the advantage of standard concentrations and doses, however there are
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individual differences in bioavailability due to absorption and first-pass metabolism in the
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liver55. The onset of action and maximal plasma concentrations occur 1-2 hours after ingestion
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(up to 6 hours) with effects reported for up to 20 hours increasing the risk of overdose when
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individuals self-administer oral cannabinoids55. Due to the studies that show that cannabinoid
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agonists anti-pruritic effect is in part due to cannabinoid receptors in the CNS, systemic
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cannabinoids may be optimal for severe itch where topicals would only address peripheral
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mechanisms. There have been no reports on the effects of inhaled marijuana on chronic itch;
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however, smoked marijuana has been shown effective for management of neuropathic pain,
181
which suggests it has promise for treating pruritus56. In addition to smoking plant product,
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marijuana can be inhaled through aerosolization (vaping) which has risen in popularity due to the
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false perceptions about its safety. In truth both methods pose significant health risks to the user,
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with vaping specifically linked to recent cases of acute severe pulmonary disease - likely due to
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the numerous chemicals in the products57,58.
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Topical cannabinoids are of particular interest in skin disease because of the high safety profile
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and direct, local application to involved areas and recent years have brought an assortment of
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cannabinoid-containing topicals such as oils, lotions, emollients, creams, and patches specifically
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advertised for use on the skin. Cannabinoids are lipophilic and are readily absorbed through the
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skin, with only aqueous layers of the skin to limit diffusion. To date, systemic effects have not
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been reported after topical application of cannabinoids and furthermore many of the anti-pruritic
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effects of cannabinoids were shown utilizing non-THC cannabinoids (CBD, PEA), eliminating
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the concern for undesired psychoactive effects. Furthermore, while most studies showed
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reductions in pruritus, increased pruritus was reported as a side effect in a small number of
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patients51. Allergic reactions to cannabis are rare but possible and range from life-threatening to
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more mild reactions. Direct contact with plants reported to cause urticaria and contact dermatitis
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in a small number of patients59.
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Limitations Given the complexity of the ECS and the heterogeneity of cannabinoid structure
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and function, cannabinoids may have different effects depending on the origin of the pruritus,
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and future research will hopefully provide more mechanistic precision60. Pre-clinical studies
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have shown that cannabinoids alleviate itch after both topical and systemic administration and
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shed light on the possible underlying mechanism. Interpretation of clinical studies, however, is
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limited by the lack of double-blinded controlled clinical trials and by the variation in cannabinoid
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product, delivery method, and formulation.
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Conclusion An estimated 1% of individuals who live in states with medical marijuana programs
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use physician-recommended cannabis, and while pruritus is not a qualified condition for
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recommendation, topical cannabinoids are sold by dispensaries and advertised as anti-pruritic,
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analgesic, and anti-inflammatory61-62. Despite the limited number of published studies, trials
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done at present have shown consistent improvement in pruritus in the setting of multiple
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diseases. In the future, patient interest and use of cannabinoid-products, either the botanical
214
product, derivative, or targeted compound, will continue to rise. The literature warrants further
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investigation as an anti-pruritic agent and physicians should be knowledgeable to use of
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cannabinoids for chronic pruritus that fails standard therapies in states where it is a legal option.
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Abbreviations and acronyms:
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222
2-AG = 2-arachidonoylglycerol
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AD = atopic dermatitis
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AE = asteatotic eczema
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AEA = anandamide
226
CB1 = cannabinoid receptor 1
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CB2 = cannabinoid receptor 2
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CBD = cannabidiol
229
DMS = derma-membrane system
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ECS = endocannabinoid system
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GPCR = G-protein-coupled receptor
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THC = ∆(9)-tetrahydrocannabinol
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TRP = transient receptor potential
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TRPA1 = TRP ankyrin 1
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TRPM1 = TRP melastatin 1
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TRPV1 = TRP vanilloid 1
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TRPV2 = TRP vanilloid 2
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TRPV3 = TRP vanilloid 3
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TRPV4 = TRP vanilloid 4
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PEA = palmitoylethanolamine
241
10
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19
446
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448
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Table 1. Select cannabinoids and their receptors. The cannabinoids have different affinities
452
for both cannabinoid-specific and non-specific receptors. In general, increased activity at the
453
CB1 and CB2 receptors has been reported to alleviate pruritus while decreased activity of the
454
TRPV1 ion channels alleviates pruritus. *Both CBD and PEA may have indirect effects on CB-
455
specific receptors as both have been shown to increase AEA levels.22-24,26,27-28,31,63-64
456
[Abbreviations: 2-AG = 2-arachidonoylglycerol, AEA = anandamide, CB1 = cannabinoid
457
receptor 1, CB2 = cannabinoid receptor 2, CBD = cannabidiol, GPCR = G-protein-coupled
458
receptor, THC = ∆(9)-tetrahydrocannabinol, TRPV1 = TRP vanilloid 1, PEA =
459
palmitoylethanolamine]
460
461
462
463
464
465
20
466
467
468
469
470
471
Figure 1. The Itch Pathway and Intersection with the Endocannabinoid System.
472
Cannabinoids as a class are an enticing treatment option for neurogenic diseases because of the
473
ability to modulate the ECS in the central and peripheral nervous systems. This level of
474
modulation is responsible for the efficacy of cannabinoids found for treatment of chronic pain,
475
neuropathic pain, spasticity due to multiple sclerosis, and refractory pediatric seizures65,66. The
476
anti-pruritic effect of treatment with topical or systemic cannabinoids is most likely due to a
477
similar mechanism of action. Most itch occurs in response to local inflammation and skin
478
disease. Unmyelinated C-fibers that extend to the epidermis and dermis detect pruritogens from
479
exogenous (e.g. mechanical stimulation) and endogenous sources such as histamine, and secreted
480
products from nearby keratinocytes and mast cells. Activation of pruritogenic receptors, usually
481
a G protein-coupled receptor, initiates a cascade of intracellular signaling processes and
482
ultimately neuronal stimulation67. Following the interaction with local pruritogens, the impulse
483
passes the dorsal root ganglion to synapse in the dorsal horn of the spinal cord before ascension
484
up the contralateral spinothalamic tract to the thalamus and ultimately the cortex to process the
485
information68. Pruritus can occur due to pathology at any point along this pathway, from
486
peripheral skin diseases and distal neuropathies to central causes such as an underlying
487
psychological condition. Both the canonical cannabinoid receptors CB1 and CB2 and the non21
488
specific TRP channels are present on cutaneous nerve fibers and agonism and
489
antagonism/desensitization respectively have reported anti-pruritic effects. [Abbreviations: CB1
490
= cannabinoid receptor 1, CB2 = cannabinoid receptor 2, CBD = cannabidiol, TRPA1 = TRP
491
ankyrin 1, TRPV1 = TRP vanilloid 1]
492
493
494
495
Table 2. Changes in Pruritus Following Modulation of the ECS in Human Studies. The
496
studies listed in the table include human and clinical studies to date that used pruritus as a
497
measurement after treatment with a cannabinoid-containing compound. There were documented
498
anti-pruritic effects in both studies that utilized compounds that favored CB1 and CB2 (AEA,
499
Dronabinol) and those that favored the non-specific TRP channels (PEA). [Abbreviations: AEA
500
= anandamide, PEA = palmitoylethanolamine]
501
502
503
504
505
506
507
508
509
22
510
23
*Both CBD and PEA may have indirect effects on CB-specific receptors as both have been shown to
increase AEA Levels. (Abbreviations: 2-AG = arachidonoylglycerol; AEA = anadamide; CB2 = cannabinoid
receptor 1; CB2 = cannabinoid receptor 2; CBD = cannabidiol; GPCR = G-protein-coupled receptor; THC =
Δ(9)-tetrahydrocannabinol; TRPV1 = TRP vanilloid 1; PEA = palmitoyethanolamine
Abbrevations: AEA = anadamide; PEA = palmitoylethanolamine