Rebound vs Allergic Reaction

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In a significant number of cases rosacea patients have been suffering damage caused by what is termed 'rebound' or an 'allergic reaction.' This post is to help you understand the difference.

Rebound

rebound (verb) [ no obj. ] (rebound on/upon) (of an event or situation) have an unexpected adverse consequence for (someone, esp. the person responsible for it): Nicholas's tricks are rebounding on him.
rebound (noun) • [ usu. as modifier ] the recurrence of a medical condition, esp. after withdrawal of medication: rebound hypertension.
(obviously there are more definitions for rebound but I picked the pertinent ones) 
Found this medical dictionary that said: 
rebound : a spontaneous reaction; especially: a return to a previous state or condition following removal of a stimulus or cessation of treatment --withdrawal of antihypertensive medication may lead to a rebound hypertensive crisis—<Emergency Medicine>

Rebound Effect

"The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re-emergence, the severity of the symptoms is often worse than pretreatment levels." Wikipedia

"Many antidepressants, including SSRIs, can cause rebound depression, panic attacks, anxiety, and insomnia when discontinued." Wikipedia

There is a report that there may be rebound blood clotting when aspirin is stopped suddenly when taken over a long period. 

In rosacea, it is not uncommon for those who have been on long term antibiotic treatment for rosacea, i.e., doxycycline, who stop the treatment experience rebound, or a worsening of the rosacea.

"Pimecrolimus and tacrolimus could be effective for rosacea. However, both of them could also induce rosacea." [13] Is this a rebound effect from the treatment, an allergic reaction to the treatment or what exactly is such a reaction called?

Rosacea Rebound with Brimonidine
There is one case of brimonidine rebound after two years of using it, which is the generally accepted use of the term ‘rebound.’ In another paper on this subject it is called "brimonidine rebound/contact dermatitis".

“Some subjects in the clinical trials discontinued use of Mirvaso topical gel because of erythema. Some subjects in the clinical trials reported a rebound phenomenon, where erythema was reported to return worse compared to the severity at baseline” [1]

"An observation noted during the clinical trials and subsequently after this agent reached the United States marketplace is that a subset of individuals (10–20%) have experienced worsening of facial erythema during the course of rosacea therapy with topical brimonidine." [1]

"It has been noted over time that 10 to 20 percent of patients treated with brimonidine 0.33% gel experience reversible worsening of facial erythema, usually presenting as either paradoxical erythema shortly after application or rebound erythema after eventual loss of pharmacologic effect or drug discontinuation." [1]

One paper suggests naming "dermatitis medicamentosa" for this phenomenon and reports, "Rebound erythema secondary to use of topical brimonidine in the setting of rosacea is an important, possibly significantly distressing potential side effect that may be under-reported; there is little photo-documentation in the literature to date. " [2]

"For example, real-world use has shown that a percentage of patients (in our experience, approximately 10 to 20%) treated with brimonidine experience a worsening of erythema that has been called "rebound." Our routine use of this agent for >1 year has yielded strategies to set patient expectations, optimize treatment initiation, and minimize potential problems; this article details those strategies. Because we believe that the term "rebound" has been used to describe several physiologically distinct events, we have also proposed more specific terminology for such events." [7]

"We report a case of facial erythema of rosacea that responded well to this medication, however, rebounded with significantly greater erythema than baseline for the patient." [8]

"Rebound reactions have previously been reported with alpha adrenergic receptor agonists administered nasally and ophthalmically. Rebound is medically defined as a reversed response occurring upon withdrawal of a stimulus." [9]

"We propose that this reaction constitutes rebound dilation of the capillaries caused by down-regulation of alpha-2 adrenergic receptors following use of BT. This may be similar to rhinitis medicamentosa, observed with overuse of alpha-adrenergic agonist nasal sprays (eg, oxymetazoline and xylometazoline).4 This reaction directly opposes the goal of therapy." [10]

"Exaggerated rebound erythema ~12 hours after application of brimonidine topical gel has also been reported. The erythema may be worse than baseline but typically resolves within 6–12 hours." [11]

"Case reports have been included to highlight several instances of contact dermatitis and rebound erythema in patients who used topical brimonidine gel, in contrast to the relatively low incidence of these adverse events in early studies." [11] (bold added)

Rebound is a Possible Multifactorial Effect
The two top reasons for a Mirvaso-induced rebound affect are:
1. The stimulation of Hypoxia-Inducible Factors from adjacent skin cells and from within the vascular smooth cell layer of the blood vessels - these are potent dilators that measure oxygen saturation in and around cells to ensure adequate oxygen delivery. Over constriction or hours of constriction can greatly deplete oxygen saturation and inadvertently stimulate very potent dilators.
2. Over time, alpha-1 and alpha-2 adrenoceptor stimulation increases the production of inducible nitric oxide, which is the primary inflammatory form of nitric oxide -- we see this a lot in Vascular Micro-Physiology and Pharmacology.
The other problem that patients will note over time is a decreased constrictor response (different from rebound dilation):
1. This is because overstimulation of alpha adrenoceptors results in downregulation of receptors (ie. they decrease in number on the vessel surface and internalize)
2. G-Proteins uncouple from active alpha adrenoceptors which blocks the signal cascade transduction -- which in turn -- blocks the ability of vessels to constrict
This is an oversimplification of a complex physiological process, but that is why it is always better to block a potent dilator than add an active constrictor.

Galderma acknowledges the rebound effect with Mirvaso.

"Phase III trials (Fowler et al. 2013) – 2 patients (1.6%) discontinued the study because of adverse events (severe skin irritation in one subject and “intermittent rebound erythema” in the other subject)." [12]

"During clinical trials, some subjects discontinued use of brimonidine topical gel because of erythema or flushing. Onset of flushing ranged from 30 minutes to several hours after application and disappeared after discontinuation of brimonidine tartrate. For some subjects the new onset erythema was worse compared to the severity at baseline. Intermittent flushing occurred in some subjects treated with brimonidine tartrate topical gel." [12]

Allergic Reaction to Medicine

Any prescription or nonprescription medicine can cause an allergic reaction. Allergic reactions are common and unpredictable. The seriousness of the allergic reaction caused by a certain medicine will vary.

Allergic Reaction to a Medicine - WebMD

So one of my questions is how does one differentiate an allergic reaction from rebound? Isn't it possible that what everyone is calling a rebound could be an allergic reaction to a medicine? It seems logical to me that in some cases what is called a ‘rebound’ could be an allergic reaction to brimonidine since the reaction happens rather quickly. A significant number of the reports of brimonidine treatment for rosacea indicate this happens within the first few days of initial treatment.

All the examples of rebound I found listed for medical rebound above involve using a drug for a long period and then stopping the drug and a rebound happens, for example, rebound headaches. 

Take for example those who have an allergy to penicillin. If given penicillin they react quickly with rashes, hives, itchy eyes, swollen tongue, and in severe cases anaphylactic reaction. Usually one finds out rather quickly if one has an allergy to penicillin.

"Topical calcineurin inhibitors, pimecrolimus and tacrolimus, can be used to treat rosacea. However, they can also induce rosacea-like eruptions." [13] Are the 'rosacea-like eruptions' an allergic reaction or a rebound effect? 

It seems logical that some of the 242 anecdotal reports using brimonidine may indicate that what everyone is calling 'rebound' might instead be an allergic reaction. 

Allergic Reaction to Brimonidine
"MIRVASO topical gel is contratindicated in patients who have experienced a hypersensitivity reaction to any component. Reactions have included angioedema, urticaria, and contact dermatitis"

"Allergic contact dermatitis was reported in the clinical trials for MIRVASO topical gel"

"Events reported post marketing with the use of MIRVASO topical gel include angioedema, throat tightening, tongue swelling, and urticaria,"

"Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists"

"Local Vasomotor Adverse Reactions"

The above quotes are taken from Hypersensitivity and Adverse Reactions from the Mirvaso Package Insert

"Allergic contact dermatitis, although reported on occasion, appears to be a relatively uncommon adverse event associated with use of brimonidine 0.33% gel for rosacea." [1]

"However, there have been reports of cutaneous adverse reactions at the site of brimonidine application. These include flushing, worsening erythema, burning sensation, and contact dermatitis, most of which present immediately or early in the course of therapy." [3]

"Topical application causes vasoconstriction of superficial vessels at the site of application, allowing for the reduction of erythema. We hypothesize that the reaction seen in our patient represents a compensatory vasodilation of vessels in the surrounding skin due to chronic vasoconstriction at the site of long-term brimonidine use. Findings from history, physical examination, laboratory testing, and histopathologic examination ruled out several other etiologies, including photosensitivity and autoimmune conditions. We therefore conclude that this is a probable adverse drug reaction to brimonidine." [3]

The authors of this paper avoid the term rebound and refer to a patient who "after 7 months of brimonidine treatment, showing compensatory vasodilatation and flushing in untreated areas of right lateral cheek, neck, and chest."  "Physical examination revealed marked bright erythema diffusely covering areas of the lateral cheeks, neck, and upper chest. Interestingly, there was clear sparing of the sites of brimonidine application on the central face." The authors describe this event as "a probable adverse drug reaction to brimonidine." [3]

Cookson et al describes an allergic contact dermatitis caused by Mirvaso. [4] Bangsgaard et al describe two cases of "Sensitization to and allergic contact dermatitis caused by Mirvaso." [5] In a letter to the editor, Ashray Rajagopalan and Bishakha Rajagopalan describe "Allergic contact dermatitis to topical brimonidine." [6]

"Early studies reported low incidence of contact dermatitis and rebound erythema with topical brimonidine tartrate, but recent case studies suggest that these are potentially significant reactions. Contact dermatitis to either vehicle ingredients or brimonidine occurred in multiple patients." [11]

"Case reports have been included to highlight several instances of contact dermatitis and rebound erythema in patients who used topical brimonidine gel, in contrast to the relatively low incidence of these adverse events in early studies." [11] (bold added)

"Allergic Contact Dermatitis – occurred in about 1% of subjects across clinical trials. Patch testing of 2 subjects revealed sensitivity to brimonidine tartrate in one subject and sensitivity to the preservative phenoxyethanol in the other subject." [12]

RRDi MAC Members Comments
Note: I sent emails to all the MAC members about this question and a few responded by email to me the following - note Post #7 by Dr. Anna Holmes😞  The source for all these replies below can be found here (scroll through all the posts in the thread all the way down). The replies are listed below for your convenience:

Reply from Raymond Peat, Ph.D.

"I don't think either allergy or rebound would be the best description for the direct promotion of the secretion of inflammatory cytokines by a vasoconstrictor drug or its excipients. Since nitric oxide, prostaglandins, and inflammatory cytokines probably contribute to the problem, non-toxic inhibitors of those, such as vitamins A, E, and K, aspirin, and caffeine might be helpful for the basic problem."

Dr. Peat gave the following references: 

J Neurosci Res. 2002 Jan 15;67(2):264-74.
Tumor necrosis factor expressed by primary hippocampal neurons and SH-SY5Y cells 
is regulated by alpha(2)-adrenergic receptor activation.
Renauld AE, Spengler RN.
Department of Pathology, School of Medicine and Biomedical Sciences, Buffalo, New
York, USA.
Neuron expression of the cytokine tumor necrosis factor-alpha (TNF), and the regulation of the levels of TNF by alpha(2)-adrenergic receptor activation were investigated. Adult rat hippocampal neurons and phorbol ester (PMA) differentiated SH-SY5Y cells were examined. Intracellular levels of TNFmRNA accumulation, as well as TNF protein and that released into the supernatant were quantified by in situ hybridization, immunocytochemistry and bioanalysis, respectively. Both neuron cultures demonstrated constitutive production of TNF. Activation of the alpha(2)-adrenergic receptor increased intracellular levels of TNF mRNA and protein in SH-SY5Y cells after addition of graded concentrations of the selective agonist, Brimonidine (UK-14304) to parallel cultures. Intracellular levels of mRNA were increased in a concentration-dependent fashion within 15 min of UK-14304 addition and were sustained during 24 hr of receptor activation. In addition, the levels of TNF in the supernatant were increased in both types of neuron cultures within 15 min of alpha(2)-adrenergic receptor activation. Furthermore, levels of TNF significantly increased in the supernatants of both neuron cultures after potassium-induced depolarization. A reduction in this depolarization-induced release occurred in hippocampal neuron cultures after exposure to the sympathomimetic tyramine with media replacement to deplete endogenous catecholamines. This finding reveals a role for endogenous catecholamines in the regulation of TNF production. Potassium-induced depolarization resulted in the release of TNF in hippocampal neuron cultures within 15 min but not until 24 hr in SH-SY5Y cultures demonstrating a temporally mediated event dependent upon cell type. Neuron expression of TNF, regulated by alpha(2)-adrenergic receptor activation demonstrates not only how a neuron controls its own production of this pleiotropic cytokine, but also displays a normal role for neurons in directing the many functions of TNF.
Copyright 2002 Wiley-Liss, Inc.

Br J Ophthalmol. 2007 Jan;91(1):29-32. 
Measurement of inflammatory cytokines by multicytokine assay in tears of patients
with glaucoma topically treated with chronic drugs.
Malvitte L, Montange T, Vejux A, Baudouin C, Bron AM, Creuzot-Garcher C, Lizard G.
CHU Dijon, Service d'Ophtalmologie, 3 rue du Faubourg Raines, 21000 Dijon,
France. laure.malvitte@wanadoo.fr
AIM: To investigate the ocular surface inflammatory response to chronic topical treatments in patients with glaucoma by measuring the cytokine level in tears using multiplex bead analysis.
METHODS: Tear samples were collected from 21 patients with glaucoma and 12 healthy volunteers. Tears were analysed for the presence of 17 cytokines: interleukin (IL)1beta, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL17, granulocyte colony stimulating factor, granulocyte-macrophage stimulating factor, interferon (INF)gamma, monocyte chemotactic protein (MCP)1, macrophage inflammatory protein 1beta and tumour necrosis factor (TNF)alpha. The cytokines in each sample of tears were measured using multiplex bead analysis with microspheres as solid support for immunoassays.
RESULTS: In the tears of treated patients, proinflammatory cytokines (IL1beta, IL6, IL12, TNFalpha) were significantly increased compared with controls. T helper (Th)1 (INFgamma, IL2) and Th2 (IL5, IL10, IL4) type cytokines were also significantly higher (p<0.05); however, the most marked increase was observed with Th1 cytokines. The expression of chemokine IL8 and MCP1 was also increased in the treated group.
CONCLUSION: This study shows that pro-inflammatory cytokine secretion by conjunctival cells is increased in response to topical treatments for glaucoma. The characterisation of cytokines in tears was previously limited by the small volume attainable, a limitation that has been overcome by multiplex analysis.

Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H231-8. 
Brimonidine evokes heterogeneous vasomotor response of retinal arterioles:
diminished nitric oxide-mediated vasodilation when size goes small.
Rosa RH Jr, Hein TW, Yuan Z, Xu W, Pechal MI, Geraets RL, Newman JM, Kuo L.
Department of Opthamology and Surgery, Scott and White Eye Institute, Texas A & M
University System Health Science Center, Temple, TX 76508, USA.
rrosa@swmail.sw.org

Brimonidine, an alpha2-adrenergic receptor (AR) agonist, has been employed in the treatment of glaucoma due to its beneficial effects on intraocular pressure reduction and neuroprotection. In addition, some studies have implicated that brimonidine might influence ocular blood flow; however, its effect on the retinal microcirculation has not been documented. Herein, we examined the vasomotor action of brimonidine on different branching orders of retinal arterioles in vitro and determined the contribution of the alpha2-AR subtype and the role of endothelium-derived nitric oxide (NO) in this vasomotor response. First- and second-order retinal arterioles of pigs were isolated, cannulated, and pressurized for functional studies. Videomicroscopic techniques were employed to record diameter changes in response to brimonidine. RT-PCR was performed for detection of alpha-AR and endothelial NO synthase (eNOS) mRNA in retinal arterioles. All first-order arterioles (82 +/- 2 microm ID) dilated dose dependently to brimonidine (0.1 nM to 10 microM) with 10% dilation at the highest concentration. Second-order arterioles (50 +/- 1 microm ID) responded heterogeneously with either dilation or constriction. The incidence and magnitude of vasoconstriction were increased with increasing brimonidine concentration. Administration of the NO synthase inhibitor NG-nitro-L-arginine methyl ester abolished the brimonidine-induced vasodilation in first- and second-order arterioles. Regardless of vessel size, vasomotor responses (i.e., vasodilation and vasoconstriction) of retinal arterioles were sensitive to the alpha2-AR antagonist rauwolscine. Consistent with the functional data, alpha2A-AR and eNOS mRNAs were detected in retinal arterioles. Collectively, our data demonstrate that brimonidine at clinical doses evokes a consistent NO-dependent vasodilation in first-order retinal arterioles but a heterogeneous response in second-order arterioles. These vasomotor responses are mediated by the activation of alpha2-AR. It appears that brimonidine, depending on the concentration and vessel size, may alter local retinal blood flow.

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Reply from Anna Holmes, PhD
Allergic sensitization was measured by patch testing patients across the Mirvaso clinical development program with suspected allergic contact dermatitis. The overall incidence of confirmed sensitization was less than 1%. Sensitization can occur, but the incidence is low.

Reply from Robert Latkany, M.D.
"Mirvaso is 0.33% brimonidine gel. Brimonidine has been used to lower intraocular pressure on the eyes for glaucoma for years. It typically is not a first line agent and has had several modifications over the years. The most recent formulation is Alphagan P 0.1% by Allergan. This concentration appears to cause less redness and irritation than the higher concentration bottles. In fact, I often use this drop to decrease the redness in some patients with fairly prominent vessels that are disfiguring. I am pretty sure there is an ophthalmologist seeking a patent on the use of brimonidine to address "red eyes". So all that said, there is probably a role here for facial erythema. But further studies will need to be done on what concentration is most appropriate and what frequency is needed. My guess is it should be given in 4 week cycles in a diluted concentration but a study should easily determine the most successful approach."

Reply from Husein Husein El-Ahmed, MD
Allergic reaction is a immune-mediated process which requires a previous contact of antigen presenting cells to the drug. This first contact shows no symptoms in the person, and it is known as sensibilization. Once one person is sensibilized, the second contact to the drug leads to a rapid reaction including rash, itchy eyes, swollen tongue, and even, anaphylactic reaction.

Rebound is a NON-immune-mediated process in which the symptoms are caused for the effect or the lack of effect (discontinuation) of a drug. This reaction is rather quickly, but no immune cells are implicated, in overall terms.

Since Mirvaso was lanched in my country (Spain), I have observed poor impact on my clinical practice: This drug is targeted to reduce erythema on rosácea (Flushing) with many researches supporting its efectivity. However, most of my patients suffering from rosacea do not complain on flushing, but permanent redness for which brimonidine gel is not indicated. This reduces dramatically the prescription of this drug on my daily clinical practice.
I have discussed this matter with my local colleages and they have found the same limitation in this way.

Reply from Joseph Fowler, MD
In the clinical trials that I am aware of, there were few if any reports of this "rebound" phenomenon occurring. Also, in the many patients that I have prescribed the drug for, I have had a few who felt Mirvaso did not work as well as they wished. But I have had only 1 patient have worsening of redness as the drug effect wears off. So while I'm sure there are some patients who don't like Mirvaso, the majority in my experience have had beneficial effects.

As I am sure you are aware, it is much more likely for someone to send in negative comments than to report in when they are satisfied with a product. Perhaps those who are experiencing unwanted effects haven't been initially counseled by the prescribing doc about appropriate usage and application techniques? perhaps other diagnoses instead of or in addition to rosacea are in the mix? Perhaps there are other reasons for less than optimal success being reported. At any rate, since the effect of topical brimo is very transient, I can't imagine any serious adverse effects and any "reaction" lasting more than a few days probably suggests something else is going on in the patient's skin. It is unfortunate that not all patients respond perfectly to this or any other drug, but from what I have seen it is a very valuable agent to combat erythema of rosacea.

Conclusion
It is very clear from the package insert that comes with each prescription for Mirvaso that an allergic reaction was found in the clinical trials in some cases and that happens post marketing. It is also conclusive that Galderma acknowledges the rebound issue with Mirvaso. Whether you experience an allergic reaction or rebound depends on who describes the event and the history.

Reply to this Topic
There is a reply to this topic button somewhere on the device you are reading this post. 

End Notes

[1] J Clin Aesthet Dermatol. 2017 Jul; 10(7): 28–32.
Topical a-Agonist Therapy for Persistent Facial Erythema of Rosacea and the Addition of Oxmetazoline to the Treatment Armamentarium: Where Are We Now?
James Q. Del Rosso, DO, FAOCD, FAAD

[2] Dermatol Online J. 2015 Jan 1;21(3). pii: 13030/qt93n0n7pp.
Dermatitis medicamentosa: severe rebound erythema secondary to topical brimonidine in rosacea.
Werner K, Kobayashi TT.

[3] JAMA Dermatol. 2015 Oct;151(10):1136-7. doi: 10.1001/jamadermatol.2015.1252. Full Text
Erythema in Skin Adjacent to Area of Long-term Brimonidine Treatment for Rosacea: A Novel Adverse Reaction.
Gillihan R, Nguyen T, Fischer R, Rajpara A, Aires D.

[4] Contact Dermatitis. 2015 Dec;73(6):366-7. doi: 10.1111/cod.12476.
Allergic contact dermatitis caused by Mirvaso®, brimonidine tartrate gel 0.33%, a new topical treatment for rosaceal erythema.
Cookson H, McFadden J, White J, White IR.

[5] Contact Dermatitis. 2016 Jun;74(6):378-9. doi: 10.1111/cod.12547.
Sensitization to and allergic contact dermatitis caused by Mirvaso(®) (brimonidine tartrate) for treatment of rosacea - 2 cases.
Bangsgaard N, Fischer LA, Zachariae C.

[6] Australasian Journal of Dermatology, LETTER TO THE EDITOR, https://doi.org/10.1111/ajd.12299
Allergic contact dermatitis to topical brimonidine
Ashray Rajagopalan, Bishakha Rajagopalan

[7] J Drugs Dermatol. 2015 Jan;14(1):33-40.
Optimizing the use of topical brimonidine in rosacea management: panel recommendations.
Tanghetti EA, Jackson JM, Belasco KT, Friedrichs A, Hougier F, Johnson SM, Kerdel FA, Palceski D, Hong HC, Hinek A, Cadena MJ.

[8] J Am Acad Dermatol. 2014 May;70(5):e109-10. doi: 10.1016/j.jaad.2014.01.853. Full Text
Brimonidine effective but may lead to significant rebound erythema.
Ilkovitch D, Pomerantz RG.

[9] J Clin Aesthet Dermatol. 2015 Aug;8(8):29-35.
Dermatological Adverse Events Associated with Topical Brimonidine Gel 0.33% in Subjects with Erythema of Rosacea: A Retrospective Review of Clinical Studies.
Holmes AD, Waite KA, Chen MC, Palaniswamy K, Wiser TH, Draelos ZD, Rafal ES, Werschler WP, Harvey AE.

[10] J Am Acad Dermatol. 2014 Feb;70(2):e37-8. doi: 10.1016/j.jaad.2013.10.054. Full Text
Rebound erythema and burning sensation from a new topical brimonidine tartrate gel 0.33%.
Routt ET, Levitt JO.

[11] Patient Prefer Adherence. 2017; 11: 1143–1150.
Spotlight on brimonidine topical gel 0.33% for facial erythema of rosacea: safety, efficacy, and patient acceptability
Michael S Anderson, Anish Nadkarni, Leah A Cardwell, Hossein Alinia, and Steven R Feldman

[12] National Drug Monograph, March 2015
Brimonidine Topical Gel (MIRVASO)
VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives

[13] Topical calcineurin inhibitors as a double-edged sword in rosacea: a systematic review