Benzodiazepine‐induced photosensitivity reactions: A compilation of cases from literature review with Naranjo causality assessment

1 BACKGROUND

Benzodiazepines, commonly used for treatment of anxiety and sleep disorders, are prescribed frequently. Approximately 1 in 20 adults in the United States filled a benzodiazepine prescription during the course of a year.1 Despite its frequent use, benzodiazepines may not be a well-known cause of photosensitivity due to its low incidence (<1%) and tertiary resources do not consistently list benzodiazepines as a potential cause of photosensitivity.2, 3

Cutaneous photosensitivity reactions occur when drugs, taken systemically or applied topically, increase sensitivity to ultraviolet (UV) rays from the sun and other light sources.4 Usually, the reaction is initiated by biochemical changes in the patient's tissue subsequent to an exogenous substance absorbing sunlight.4 These exogenous substances absorb photons and move from the ground state to the reactive state leading to either phototoxicity or photoallergic reactions.4, 5

Phototoxicity and photoallergy are two distinct types of photosensitivity reactions. Phototoxic reactions occur when a compound is activated by light and causes damage to cell membranes and, in some cases, DNA.6 Additionally, phototoxic reactions appear as exaggerated sunburn on the exposed area.7 On the other hand, photoallergic reactions are a type IV immune-mediated response and occur after previous drug sensitization.8 Photoallergic reactions resemble allergic contact dermatitis, as the reaction is not only limited to sun-exposed areas of the body and may spread outside exposed areas.7

Although phototoxic and photoallergic reactions have different mechanisms, they are diagnosed with the same photosensitivity tests. A diagnosis can be made with detailed patient history and a proper physical examination; however, conducting the diagnostic testing can be beneficial in determining a drug-induced photosensitivity reaction, especially for medications that lack literature.9 Two common diagnostic tests used are photopatch and oral photoprovocation tests (also referred to as an oral photochallenge).9

During a photopatch test, the medication is mixed with either petrolatum or alcohol, applied on the patient's skin in two different sets, and both sets are occluded.9 After the medication has been applied for 24 or 48 hours, the patch and covering are removed, and one set is irradiated (commonly with UVA light) while the other set remains unexposed to radiation. At periodic intervals over the next week, the irradiation sites are compared to unexposed areas. The practitioner examines the sites for erythema, edema, and vesiculation. The photopatch test is considered positive if (1) the reaction occurs only on the irradiated set or (2) if the reaction is greater on the irradiated set than the unexposed set.9

However, when photosensitivity occurs with systemic agents, diagnostic photopatch is frequently falsely negative.9, 10 When photopatch tests are negative, clinicians may test whether the reaction occurs after the oral intake of the drug. In oral photoprovocation testing, clinicians administer the offending drug orally, then expose a patch of skin to UVA or UVB radiation and observe at periodic intervals for erythemic skin reactions.9

In another variation of diagnostic testing, the administration of the drug with drug provocation testing (DPT) may diagnose drug hypersensitivity..11 DPT testing involves oral readministration of the drug and observation of a reaction; however, this may not be preferred due to the severe reaction the drug could induce.11

In most tertiary references discussing photosensitivity, benzodiazepines are not listed as a potential cause.4 In those references that list benzodiazepines as a causative factor, many commonly cite two case reports of alprazolam and chlordiazepoxide, which resulted in a photosensitivity reaction.9 Chlordiazepoxide has also been found to cause phototoxic reactions in mice.12 Considering the common use of benzodiazepines and the limited literature on benzodiazepine-induced photosensitivity available to date, we sought to review the literature to identify all cases of benzodiazepine-induced photosensitivity. We analyzed the clinical presentation and diagnosis of these photosensitivity reactions and applied a standardized causality assessment to all cases.

2 METHODS

A search for benzodiazepine-induced photosensitivity case reports was conducted to establish past incidence reports from various patients around the world. The search was initiated by utilizing PubMed's “MeSH” search feature and CINAHL, in which the major terms, “Benzodiazepine/Photosensitivity” and “Photosensitivity disorders/chemically induced” were searched from 1964 to 2019. In addition, we further conducted a search on Micromedex, individually searching all the benzodiazepines available. We looked under in-depth adverse effects for each benzodiazepine to identify any photosensitivity case reports which were available. Furthermore, a search was also performed on Google Scholar to identify additional cases.

In this search, we did identify photosensitivity reports with the thienobenzodiazepine, olanzapine. However, as thienobenzodiazepine are characterized as multi-receptor targeted agents, we narrowed our search to strictly benzodiazepines.13 With this search, we identified 10 case reports; 2 case reports were excluded as they did not describe a photosensitivity reaction. We included one case of photo-oncholysis, as it occurred after intense sun exposure. We retrieved the data from the case reports, including age, gender, benzodiazepine dose/frequency, reaction, and rechallenge results. For time to reaction, we considered the benzodiazepine start date as the index date. For time to positive/negative diagnostic tests, we considered the day of patch application or oral drug administration to be the index date. Results were analyzed using JMP® 14.3.0. Continuous variables were tested for normality using the Shapiro-Wilk W test. Continuous data were determined to be parametric and reported as mean and standard deviation. Nonparametric data were reported as median and interquartile range.

Causality was assigned with the Naranjo Scale. One pharmacist and three pharmacy interns reviewed all cases independently and evaluated the Naranjo scale independently. Afterward, the four reviewers met as a group to achieve consensus. A score of 0 indicated “doubtful” probability, a score of 1 to 4 indicated “possible” probability, scores of 5 to 8 indicated “probable” probability, and scores greater than 9 showed a “definite” probability.14

3 RESULTS 3.1 Baseline characteristics

Among the eight patient cases, the mean (±SD) age was 46.3 ± 17.4 years (Table 1). Out of the eight case reports, half were females. Three patient cases were identified in Spain; the other cases occurred in India, Italy, Japan, South Korea, and the United States.

TABLE 1. Baseline characteristics n = 8 Agea—years 46.3 ± 17.4 Gender Female 4 (50.0%) Male 3 (37.5%) Unknown 1 (12.5%) Countries with reported cases Spain 3 (37.5%) India 1 (12.5%) Italy 1 (12.5%) Japan 1 (12.5%) South Korea 1 (12.5%) USA 1 (12.5%) Benzodiazepine (BZD) Alprazolam 3 (37.5%) Tetrazepam 2 (25.0%) Chlordiazepoxide 1 (12.5%) Clobazam 1 (12.5%) Clorazepate dipotassium 1 (12.5%) a Reported as Mean ± SD. 3.2 Implicated benzodiazepines

In our case series, the most common benzodiazepines involved in photosensitivity reactions were alprazolam (n = 3) followed by tetrazepam (n = 2). Other benzodiazepines implicated in photosensitivity include chlordiazepoxide, clorazepate, and clobazam (Table 1).

3.3 Time to onset and resolution

In two patients, photosensitivity reactions developed after a single dose of medication.15, 16 In eight cases, the onset of the photosensitivity reaction occurred within 1-3 days (37.5%) and occurred after 7 days in the remaining cases (Table 2). Finally, in one case, the onset of the reaction was not reported.17

TABLE 2. Benzodiazepine photosensitivity results Time to photosensitivity reaction 1-3 days 3 (37.5%) 3-7 days 0 (0.0%) 7-14 days 2 (25.0%) >14 days 2 (25.0%) Unknown 1 (12.5%) Time to photosensitivity resolutiona – days (n = 6) 7 (2-37.5) Time to photosensitivity resolution <1 week 3 (37.5%) 1-2 weeks 2 (25.0%) 3 months 1 (12.5%) Unknown 2 (25.0%) Rechallenge test Positive 6 (75.0%) Negative 1 (12.5%) Unknown 1 (12.5%) Note Classified by available data from articles. a Reported as median (IQR).

The time to resolution after benzodiazepine discontinuation was reported in 6 cases (Table 2). In 62.5% of patients, lesions resolved within 2 weeks. The exception was the one patient with onycholysis, whose time to resolution was 4 months.18 Time to onset and resolution for each patient can be found in the appendix.

3.4 Type of photosensitivity reaction

The location and severity of the symptoms varied in each case report (Table S1). Most reactions occurred in sun-exposed areas of the body, including arms, legs, and face. Usually, the symptoms were not life-threatening; however, Case 7 presented with toxic epidermal necrolysis, the most severe reaction found, which required hospitalization for 20 days.19

The majority of cases presented reactions would be best classified as phototoxic, with the exception of one case. Case 5, which involved chlordiazepoxide, was classified as photoallergic due to symptoms spreading to areas that were not exposed to the sun.20

3.5 Photosensitivity diagnosis

For cases with photosensitivity diagnostic testing conducted, all patients had positive results except one (Table 3). In most cases, a combination of patch test and photopatch test were used to diagnose photosensitivity reactions induced by benzodiazepines. Among three cases in which photopatch and oral photoprovocation testing was performed, 2 of 3 cases showed negative photopatch results, while the oral photoprovocation test was positive for all three patients.15, 17, 21 In two cases, readministration of the drug resulted in a likely photosensitivity reaction; however, exposure to UV light in a controlled environment was not performed.16, 22 Finally, in one case, the diagnosis was based on characteristics of lesions and clinical history alone.18

TABLE 3. Results of skin testing performed & Naranjo assessment for each case Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Photopatch – – NA + NA Unknown – NA Oral photoprovocation + + NA + + Unknown NA NA Drug provocation Test (DPT) NA NA ?a NA NA Unknown NA + Naranjo Scale Definite Definite Probable Definite Definite Possible Probable Definite Abbreviations: −, Negative response; +, Positive response; NA, not available. a Reaction recurred while taking both fluoxetine 25 mg and alprazolam 0.25 mg. Alprazolam was not tested alone.

In the four cases with oral photoprovocation tests, patients tested positive as early as day 3 and as late as day 14 (Table 2). In one case, photosensitivity reactions examined 2 hours after oral administration of medication were negative, and follow-up was not reported until patients noticed pruritic erythema 14 days after taking the medication; three days later UVA irradiation showed positive reactions at 24 hours (Table S1).21 Thus, time to photosensitivity reaction with oral photoprovocation testing is quite varied from patient to patient.

Among four cases with photopatch tests, follow-up results were not consistent (Table S1). In two cases, the authors did not mention whether the reactions were followed up in the next several days after the test was performed.17, 21 In one of the remaining cases, the results were only read at 48 and 72 hours, and they were negative.19 In the final case, the photopatch test was positive on day 4.15

3.6 Naranjo scale

We applied the Naranjo scale, an adverse drug event probability scale, to identify the causality of each case of photosensitivity. According to the Naranjo scale, 5 cases were classified as definite, 2 case was probable and 1 case was possible benzodiazepine-induced photosensitivity (Table 3).14

3.7 Treatment of photosensitivity

Treatment of photosensitivity reactions included discontinuing the offending agent for all cases. Additional adjunct therapy varied from case to case. In one case, topical corticosteroids were used.16 In another case, additional therapies included applying cool tap water, administration of oral diphenhydramine hydrochloride (Benadryl), and topical hydrophilic ointment on the skin lesions, to relieve the burning and itching of the lesions.20 Finally, one case required the use of systemic antihistamines and corticosteroids for complete resolution of the lesions.15 For benzodiazepine-induced photosensitivity reactions, discontinuing the causative agent alone was sufficient to resolve lesions in most cases.

4 DISCUSSION

Benzodiazepines are commonly prescribed; however, there is limited evidence on photosensitivity reactions caused due to benzodiazepines. We found three cases with alprazolam, two cases with tetrazepam, one case with clorazepate, one case with chlordiazepoxide, and one case with clobazam. These drugs are currently available on the market besides tetrazepam, which is unavailable in the United States. As benzodiazepines have been used for a long period of time with some adverse reactions reported, providers may be less likely to report adverse reactions.4

Drugs causing photosensitivity are lipophilic, allowing the drug to accumulate in the skin and absorb ultraviolet (UV) or visible radiation. Photosensitizing drugs usually have a low molecular weight (200 to 500 Daltons) and photosensitizing structures consisting of planar polyaromatic or polycyclic configurations with heteroatoms.4 These criteria are consistent with benzodiazepines drugs in this case series, which made these benzodiazepines more susceptible to photosensitivity reactions.

In addition, many drugs implicated in photosensitivity reactions have a chlorinated aromatic moiety.4 Photosensitivity reactions can occur due to the dissociation of the chlorine atom from the aromatic structure via UV radiation leading to the formation of free radicals that react with lipids, proteins, and DNA.4 Interestingly, all benzodiazepines implicated in photosensitivity from these case reports have a chlorinated aromatic moiety.

However, the chlorinated aromatic fragment may not completely explain the mechanism of benzodiazepine photosensitivity. Diazepam and tetrazepam have fairly similar chemical structures, and both drugs contain a chlorinated aromatic moiety. In one of the cases, the patient was taking diazepam and tetrazepam. Despite chemical similarities between tetrazepam and diazepam, the patient experienced photosensitivity only to tetrazepam.15 This may have been due to the higher lipophilic character of tetrazepam. Higher Log P values indicate that the drug is more lipophilic. Tetrazepam has a higher Log P value at 3.2, as opposed to diazepam's Log P value of 2.82. As a result, tetrazepam is more lipophilic, resulting in a higher concentration under the skin where it can be exposed to UV radiation, thus causing photosensitivity reactions.4

There are several reasons why benzodiazepine-induced phototoxicity may be under-recognized and under-reported. Benzodiazepines are usually taken as needed, which may decrease drug levels leading to fewer reactions.23 Furthermore, as discontinuation resolves photosensitivity reaction, testing may not be commonly done in clinical practice—leading to under-reporting of photosensitivity. Photopatch testing combines the techniques of two subspecialties in dermatology, allergy dermatitis (patch testing) and photodermatology (phototesting).24 As these two different specialties use specialized equipment, it is fairly uncommon to have both technologies together. Photoallergic reactions may resemble drug eruptions; thus, a patch test and oral photoprovocation test may be necessary to distinguish between a drug eruption and a photosensitivity reaction.23 There are case reports of patients having skin eruptions likely due to benzodiazepines; however, two patients had negative patch tests and no follow-up photopatch or oral photoprovocation testing.25, 26 Lack of photosensitivity testing may lead to misclassification of photosensitivity as allergic skin reaction. Oral photoprovocation testing is superior to photopatch in diagnosing photosensitivity reactions. Patch testing with benzodiazepines has shown that higher concentrations may be required to demonstrate a response; thus, the accuracy of photopatch testing may be limited by the concentration used.27 When a patient has a photosensitivity reaction to an oral drug, photopatch testing may result in false negatives for systemic photosensitizing drugs.10 Oral re-exposure is generally not recommended if the patient has a history of life-threatening reactions, such as toxic epidermal necrolysis (TEN).28 For example, one patient in this case series had photo-induced TEN.19 As several alternatives to benzodiazepines exist in clinical practice, oral re-exposure to benzodiazepines may have an unacceptable risk-benefit ratio.

As photosensitivity reactions may take days to occur, false negatives may be reported if the observation period for diagnostic testing is just a few days. Current photopatch recommendations include observing skin reactions every other day for at least 2-3 days.23 However, observing the photopatch for up to a week may catch delayed photoallergic reactions.24 In our case reports, only one case observed the reactions after the photopatch test every other day and noted positive reactions on day 4.15 In the other three cases, two cases did not mention follow-up observation, and one case stopped follow-up after reading were negative at 48 and 72 hours.17, 19, 21 Similarly, a skin reaction from oral photoprovocation testing may take several days to develop, as lipophilic drugs taken orally may take time to build up drug levels in the skin. In one case, a negative result recorded 2 hours after oral photoprovocation; however, the patient presented 14 days later with lesions.21 This indicates that follow-up with a photo-induced method should be done days later due to lipophilic characteristics of the medication.

While photosensitivity may be under-reported for benzodiazepines as these drugs have been used in practice for a long time, there are serious implications for providers and patients. As benzodiazepines are not always listed as photosensitizers, practitioners may overlook benzodiazepines as a cause of photosensitivity. Pharmacists should consider counseling patients about the risk of photosensitivity and the need to avoid excessive sun exposure—even in darker-skinned patients as photosensitivity reactions may lead to hospitalization and temporarily decrease their quality of life.19

Our case series included a diverse population and obtained results from clinical practice leading to high external validity. As this is a case series, there was no control group. However, many of these patients served as their own control for testing—as phototesting was done with and without drug presence. The biggest limitation was the lack of detail in many of these case reports limiting our efforts to determine the type of testing completed, frequency of follow-up during testing, and missing patient demographic data. Furthermore, not all photosensitivity reactions were routinely monitored with the appropriate photopatch/phototesting/oral photoprovocation testing, leading to uncertain conclusions regarding the offending drug. Lastly, as this is an older drug, providers may not be publishing benzodiazepine-induced photosensitivity reactions leading to bias in our data set.4

For medications that have been in the market for a long time, it is important to encourage voluntary reporting of rare adverse effects into pharmacovigilance databases. Side effects associated with older medications are less commonly reported to pharmacovigilance databases than side effects of newer medications.4 Benzodiazepines have been in the market for a long time and are commonly used; however, only 8 cases related to photosensitivity reactions have been published, all of which occurred before 2000. Further studies into benzodiazepine-induced photosensitivity should include identifying cases from the FDA Adverse Event Reporting System (FAERS) and other reporting databases. Ideally, clinicians should report all testing that was done to diagnose the photosensitivity reaction. However, photosensitivity may continue to remain underdiagnosed as photopatch and oral photoprovocation testing require specialized equipment.

5 CONCLUSION

Photosensitivity reactions with benzodiazepines may be under-reported as (1) these drugs are typically used as needed and not scheduled for daily use, (2) testing for photosensitivity is not easily feasible, leading to (3) potential misclassification of photosensitivity as allergic skin reactions.

CONFLICTS OF INTEREST

None.

The data that supports the findings of this study are available in the supplementary material of this article

Filename Description phpp12691-sup-0001-TableS1.docxWord document, 22.6 KB Table S1

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

REFERENCES

1Olfson M, King M, Schoenbaum M. Benzodiazepine use in the United States. JAMA Psychiatry. 2015; 72(2): 136- 142. 2Escalante J, Ortiz-Nava C, Flores P, Priego JM, Garcia-Martinez C. Synthesis, NMR and crystallographic studies of 2-substituted dihydroquinazolinones derived from (S)-phenylethylamine. Molecules. 2007; 12(2): 173- 182. 3Selvaag E. Clinical drug photosensitivity. A retrospective analysis of reports to the Norwegian Adverse Drug Reactions Committee from the years 1970–1994. Photodermatol Photoimmunol Photomed. 1997; 13(1–2): 21- 23. 4Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf. 2002; 25(5): 345- 372. 5Monteiro AF, Rato M, Martins C. Drug-induced photosensitivity: photoallergic and phototoxic reactions. Clin Dermatol. 2016; 34(5): 571- 581. 6Kim K, Park H, Lim KM. Phototoxicity: its mechanism and animal alternative test methods. Toxicol Res. 2015; 31(2): 97- 104. 7Lugovic L, Situm M, Ozanic-Bulic S, Sjerobabski-Masnec I. Phototoxic and photoallergic skin reactions. Coll Antropol. 2007; 31(Suppl 1): 63- 67. 8Mokos ZB, Lipozencic J. Photoallergic drug reactions. Acta Med Croatica. 2011; 65(2): 107- 110. 9Blakely KM, Drucker AM, Rosen CF. Drug-induced photosensitivity-an update: culprit drugs, prevention and management. Drug Saf. 2019; 42(7): 827- 847. 10Khandpur S, Porter RM, Boulton SJ, Anstey A. Drug-induced photosensitivity: new insights into pathomechanisms and clinical variation through basic and applied science. Br J Dermatol. 2017; 176(4): 902- 909. 11Aberer W, Kranke B. Provocation tests in drug hypersensitivity. Immunol Allergy Clin North Am. 2009; 29(3): 567- 584. 12Ison AE, Davis CM. Phototoxicity of quinoline methanols and other drugs in mice and yeast. J Invest Dermatol. 1969; 52(2): 193- 198. 13Mendonca Junior FJ, Scotti L, Ishiki H, Botelho SP, Da Silva MS, Scotti MT. Benzo- and thienobenzo- diazepines: multi-target drugs for CNS disorders. Mini Rev Med Chem. 2015; 15(8): 630- 647. 14 Adverse Drug Reaction Probability Scale (Naranjo) in Drug Induced Liver Injury. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD) 2012. 15Quinones D, Sanchez I, Alonso S, et al. Photodermatitis from tetrazepam. Contact Dermatitis. 1998; 39(2): 84. 16Kanwar AJ, Gupta R, Das Mehta S, Kaur S. Photosensitivity due to alprazolam. Dermatologica. 1990; 181(1): 75. 17Schwedler S, Mempel M, Schmidt T, Abeck D, Ring J. Phototoxicity to tetrazepam – a new adverse reaction. Dermatology. 1998; 197(2): 193- 194. 18Torras H, Manuel Mascaro J Jr, Mascaró JM. Photo-onycholysis caused by clorazepate dipotassium. J Am Acad Dermatol. 1989; 21(6): 1304- 1305. 19Redondo P, Vicente J, Espana A, Subira ML, De Felipe I, Quintanilla E. Photo-induced toxic epidermal necrolysis caused by clobazam. Br J Dermatol. 1996; 135(6): 999- 1002. 20Luton EF, Finchum RN. Photosensitivity reaction to chlordiazepoxide. Arch Dermatol. 1965; 91(4): 362- 363. 21Watanabe Y, Kawada A, Ohnishi Y, Tajima S

留言 (0)

沒有登入
gif