Early signal of diverted use of tropicamide eye drops in France

Abstract

Aims

Tropicamide is a mydriatic drug used as eye‐drops for diagnostic or therapeutic purposes. From 2013, a diverted use by intravenous route has been suspected in Eastern Europe in opioids users. To date, no signal of misuse has been identified in France. The aims of this study were to investigate any early signals of a diverted use of tropicamide eye drops and to collect information regarding motives for the misuse and tropicamide‐induced effects.

Methods

Information was obtained at three levels: (1) at regional level (Midi‐Pyrénées area), from reimbursement data and pharmacists’ reports on suspicious requests; (2) at national level: from reimbursement data and prescriptions suggesting possible abuse from the OSIAP (Ordonnances Suspectes, Indicateur d'Abus Possible) survey; and (3) at international level: from VigiBase^® reports and Web sources. Beta‐blocker eye‐drops were used as comparators.

Results

In France, in 2014–2015, 17 (0.91%, 95% CI [0.53–1.46%]) falsified prescriptions involving tropicamide were identified in the OSIAP survey (compared with 0%, 95% CI [0–0.19%] for beta‐blockers). Moreover, 37 other suspicious prescriptions were presented in 2015 (notified in 2016). In Midi‐Pyrénées, seven patients aged 35–49 were reimbursed for 19–45 vials of 10 ml, in a year. Since September 2014, the regional Addictovigilance Centre has received 91 notifications of suspicious requests to obtain tropicamide. In VigiBase^®, two cases were identified but none in France. An increased interest in tropicamide‐related Internet searches was observed from Russia and Ukraine.

Conclusions

These results represent the first early warnings of a tropicamide diverted use in France. Tropicamide abusers would seek euphoria or hallucinations. The high doses involved in intravenous administration could lead to serious complications.

What is Already Known about this Subject

• Tropicamide may cause euphoria, confusional state, delusions or visual hallucinations at high doses.

• The potential exists for misuse and abuse of atropinic drugs, in patients with psychiatric comorbidities notably.

• An early signal of intravenous administration of tropicamide has been identified in Europe (but not in France) in opioids users.

What this Study Adds

• A first signal of a diverted use of tropicamide eye drops was identified in several areas in France.

• Euphoria and hallucinations are sought by users as well as a decrease in opioid consumption.

• The easy access and the low cost of tropicamide eye drops are factors contributing to their potential misuse.

Tables of Links

TARGETS
GPCRs 2
Muscarinic

LIGANDS
Cyclopentolate
Trihexyphenidyl
Tropicamide

These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2.

Introduction

The misuse of atropinic drugs has been documented in particular in severe mental illness subjects and seems to occur frequently with trihexyphenidyl ‘to get high’ 3, 4. Other drugs such as diphenhydramine and dimenhydrinate, which also have antihistaminic properties, are available without a prescription and used by teenagers, young adults and patients with psychotic disorders for recreational purposes 5, 6. Indeed, users seek effects like hallucinations, euphoria (i.e., general well‐being or relaxation), an alleviation of anxiety or depressive symptoms or a stimulating effect that receptor‐M1 blocking agents can induce 3, 7. Among atropinic drugs, tropicamide is an ophthalmic solution indicated for therapeutic or diagnostic procedures, used for a very short‐term exposure period at starting doses of one drop (150 μg of tropicamide) and not exceeding 3 ml of the solution. When it reaches blood circulation, atropine‐like effects including confusional state, delirium, acute psychosis, visual hallucinations, hyperexcitability or drowsiness may appear especially at high dosages, in children or elderly people 8, 9.

From 2013 in Italy, a diverted use of tropicamide has been suspected by some pharmacists, who have observed an abnormal increase in eye drop sales 10. In its annual report for 2014, the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has identified intravenous tropicamide administration as a new practice in opioid abusers 11. Recently, in France, the first report of several falsified prescriptions involving tropicamide eye drops has been notified by some community pharmacists in the Midi‐Pyrénées area (Southwest France).

The present paper aimed to investigate an early signal of a diverted use of tropicamide eye drops. We also intended to provide clues to determine reasons for misusing this drug and describe tropicamide‐induced effects.

Methods

We designed a multisource investigation reviewing data reported to the French Addictovigilance Network as well as published data and informal information.

Regional data

Data derived from sentinel community pharmacies

In connection with the Regional Health Authority, the Toulouse Addictovigilance Centre centralizes observations derived from the regional network of community pharmacists related to abuse, dependence or misuse of drugs. These sentinel community pharmacies are distributed across the Midi‐Pyrénées and Limousin areas (Southwest France). Data were collected up to 5 July 2016.

Data related to tropicamide reimbursement

Data concerning tropicamide dispensing in the Midi‐Pyrénées and Limousin areas were obtained from the local healthcare insurance office for 2014 as well as the 10 ml vial containing tropicamide (not the single‐dose containers). The information included the number of reimbursed tropicamide boxes for a given patient (with an anonymous identifier). Elderly patients over 65 years old were excluded from the analysis.

National data

Data related to suspicious requests from the OSIAP survey

OSIAP (Ordonnances Suspectes, Indicateur d'Abus Possible) is a French survey performed by the French Addictovigilance Network among community pharmacists. This study aims to collect forged and falsified prescriptions to identify drugs liable to be diverted from their medical use or at risk of abuse or dependence 12, 13. Prescriptions recorded from 2001 to 2015 were analysed. Beta‐blocker eye drops (except those in combination) were used as comparators (Table 1) and 95% confidence intervals (CI) were estimated using a Poisson approximation for rare events.

Table 1.

Beta‐blocking agents used as comparators

ATC classification	ATC code	Name of the drug
S01ED Ophthalmological drugs – Antiglaucoma preparations and miotics – Beta blocking agents	S01ED01	timolol
	S01ED02	betaxolol
	S01ED03	levobunolol
	S01ED04	metipranolol
	S01ED05	carteolol
	S01ED06	befunolol

Data related to tropicamide reimbursement

Open Medic is a public platform providing aggregate data on reimbursed drugs delivered in French community pharmacies 14. We collected information for the 10 ml tropicamide package in the 20–59 age group. Data were extracted for 2014 and 2015.

International data

Data related to pharmacovigilance reporting within VigiBase^®

In the World Health Organisation database, called VigiBase^®, the MedDRA terms described in Table 2 were selected for tropicamide and the six beta‐blocker comparators (Table 1). Each case was reviewed in order to discern dependence or abuse‐related effects from effects related to medical use. Patients aged under 20 or over 64 years of age were excluded from the analysis. Data were exported on 30 June 2016.

Table 2.

MedDRA terms used for the research in the database VigiBase^®

HLT	Drug and chemical abuse
PT	Dependence; intentional product misuse; drug abuse; drug dependence; drug diversion; euphoric mood; substance abuse; substance dependence
LLT	Drug use via unapproved administration route; dysthymic disorder

HLT, high‐level terms; LLT, low‐level terms; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred terms

Data related to public's and drug users’ motivations from unofficial Web sources

Google Trends^®

Google has created its publicly available database that evaluates the frequency a term is typed into the Google search engine. Even though this tool has some limitations such as reproducibility of the results, it can be used to access the interest and behaviour of a large population 15. The search term selected was ‘Tropicamide‐chemical element’. The Web query applied to all countries from January 2004 to 4 July 2016 for the subcategory ‘health’.

Media and Internet forums

Random online searches were performed to evaluate the information disclosed to the general public and between drug users. The following specific websites were visited on 4 and 5 July 2016: bluelight.org, psychoactif.org, psychonaut.com, erowid.org, drugs‐forum.com, asud.org, drogues‐info‐service.fr, drogues.blog.lemonde.fr, using keywords in French or in English: ‘tropicamide’, ‘mydriaticum’, ‘visumidriatic’, ‘mydriatics’, ‘eye drops’, ‘legal high’, ‘new substances’ and followed related discussions.

Results

Regional and national data

Reimbursement data

In France in 2014, 126 129 patients in the 20–59 age group have been reimbursed for 161 388 bottles of 10 ml containing tropicamide. Four areas have an average consumption level above 1.3 packs per patient. These are located in Southwest of France (Auvergne‐Rhône‐Alpes and Languedoc‐Roussillon‐Midi‐Pyrénées areas) and North of France (Nord‐Pas‐de‐Calais‐Picardie and Normandy). The same trend was observed for 2015 with 123 701 patients concerned and 159 081 vials reimbursed. The local Midi‐Pyrénées and Limousin data revealed that 6405 subjects under 65 years of age had at least one 10 ml vial reimbursement, and 10 had more than 10 boxes in the year. Among these 10 patients, a woman and five men aged between 35 and 49 obtained between 19 and 28 vials during 2014 and one man was reimbursed for 45 vials in 1 month.

Suspicious requests and falsified prescriptions

The first suspicious requests were notified to the Toulouse Addictovigilance Centre on September 2014 by community pharmacists located in and around Toulouse. Since then and until 5 July 2016, 65 pharmacies (including several on‐duty pharmacies) have reported 91 suspicious attempts to obtain tropicamide eye drops (Figure 1). Initially located in Toulouse city and close surroundings, requests spread throughout other Midi‐Pyrénées departments (Figure 2). Among the 91 reports, 59 (64.8%) involved a prescription form including photocopies of six different prescriptions identified in 46 (78%) cases. One of these prescriptions was written in Russian and presented in four pharmacies. Concerning spontaneous requests, a repetitive pattern was identified by pharmacists: individuals, men exclusively, in their 40s, native Eastern Europe, ask for tropicamide eye drops to send to a family member back home, due to a stock shortage in their countries, etc. Some pharmacists have reported insistent even aggressive behaviours when faced with professional refusal to comply. According to data from the national OSIAP survey, in 2006, one suspicious prescription involved tropicamide along with tobramycin/dexamethasone eye drops and buprenorphine. No other suspicious prescription mentioning tropicamide was recorded until 2014, whereas there were 17 (0.91%, 95% CI [0.53–1.46%]) in 2014–2015. In 2014, tropicamide was involved in 0.89% (eight prescriptions among 900 collected) of suspicious prescriptions and 0.94% (nine prescriptions among 961) in 2015. In 2016, the French Addictovigilance Network was informed that 37 other suspicious prescriptions of tropicamide were presented in pharmacies in 2015 (that could not be integrated into the 2015 OSIAP survey due to a lack of information regarding dates of presentation in pharmacies). Overall, for 2015, 46 suspicious prescriptions were aggregated. Among the 54 prescriptions collected between 2014 and 2015, tropicamide was the only drug mentioned in 43 (79.6%) cases and associated with pregabalin in nine (16.7%) cases. One prescription involved three other drugs (atorvastatin, lysine acetylsalicylate, and zopiclone) and another involved prednisolone. All prescriptions mentioned 10 ml bottles exclusively, for one to six vials. Criteria of suspicion were mainly falsified criteria such as computer generated forms and copies. Apart from the Midi‐Pyrénées area, suspicious requests were reported in other French areas: Essonne and Eure (North France), Lot‐et‐Garonne (Southwest France), Drôme, Loire and Rhône (East France) (Figure 3). One subject purchased a kit containing syringes (sterile kit available in pharmacies for intravenous drug users) while presenting a prescription of tropicamide eye drops.

Figure 1.

Accumulated number of reports of suspicious requests to obtain tropicamide eye drops from community pharmacists between September 2014 and 5 July 2016

Figure 2.

Evolution of geographical location of notifications of suspicious attempts to obtain tropicamide eye drops from community pharmacists as function of time (Midi‐Pyrénées area, to 5 July 2016)

Figure 3.

Reports of suspicious attempts to obtain tropicamide eye drops (France, to 5 July 2016)

Considering the period from 2001 to 2015, seven suspicious prescriptions (among 8807 or 0.08%, 95% CI [0.04–0.18%]) mentioning at least one of the six beta‐blockers used as comparators were recorded in OSIAP survey: four cases with timolol (one in 2002 also mentioning clonazepam, two in 2005 and one in 2013) and three cases with carteolol (one in 2005, one in 2010 and one in 2012). No prescription with the beta‐blockers was recorded in 2014 and 2015.

International data

VigiBase^®

Among the 73 658 notifications recorded in VigiBase^® with the selected MedDRA terms (Table 2), we have identified two cases of abuse/dependence with tropicamide, reported in two men (age unknown) in 2016 in Germany and Egypt with a diverted intravenous route in one case. Regarding the comparators, five cases of abuse/dependence were identified (three with timolol in 1996, one with betaxolol in 2000 and one with carteolol in 1997). For these five cases, the drug was administrated by intraocular route.

Unofficial data

The diverted use of tropicamide eye drops has been covered on the Internet by some journalists and specific websites since 2011. However, since this date, newspaper articles are quite rare, as are discussions among drug users. On the other hand, the topic seems of interest as highlighted by the number of occurrences of tropicamide‐related online searches.

Google Trends^®

It seems that the public's interest in tropicamide has increased over the last 5 years compared to the five previous years (Figure 4). Since 2013, most of the searches come from Russia and Ukraine; before 2013, the number of searches was too small to warrant making any geographical distinctions.

Figure 4.

Evolution of the interest in the search term ‘tropicamide‐chemical element’ as a function of time (left) and geographical distribution (right) (extracted from Google Trends^®)

Media and Internet forums 16, 17, 18, 19

According to the English newspaper The Independent in 2011, a young Russian man aged 25 died after repeated femoral artery injections of tropicamide eye drops. To our knowledge, this fatality was not reported in scientific publications. In online drug forums, subjects about tropicamide are rare but we cannot exclude the use of another ‘street name’ for the drug. Generally speaking, tropicamide seems to frighten: for some users it is one of the drugs contained in ‘krokodil’ (a substance renowned for necrosis‐induced injection) or coming from ‘the country that brought us krokodil abuse’ and members appeared not to be attracted by this new risky trend. We found the testimony of a man who was present at a party where someone injected tropicamide in addition to taking cannabis and alcohol. He reported slow thought, confusional state, unresponsiveness and difficulty walking. Another user wrote his ‘trip report’ after tropicamide injection and described euphoria and dizziness with 0.5 ml, tachycardia and dry mouth with 1 ml. A member of drugs‐forum.com notes that mixing heroin and tropicamide is a known practice in Egypt.

Discussion

The misuse of tropicamide eye drops has been the subject of some sporadic case reports and studies. To our knowledge, the first publication of tropicamide abuse in 1975 reported the case of a 25‐year‐old man who developed tolerance and addiction to a topical use of tropicamide combined with cyclopentolate 20. These eye drops were prescribed for ophthalmic indications, but the patient began to increase the dosage when not gaining relief. Abuse of cyclopentolate alone by topical and intranasal route was also reported in patients with psychiatric or substance abuse comorbidities 21, 22, 23, 24. Aside from this, three case reports and a study were recently published, showing tropicamide non‐medical use in opioid users among Eastern Europe and Central Asian citizens 25, 26, 27 (Table 3). All subjects reported injecting tropicamide, alone or in combination with heroin, to prolong or enhance pleasant heroin effects or decrease opioid consumption. Results of animal and human studies suggest that muscarinic antagonists would reduce the severity of opioid withdrawal symptoms and rewarding effects of morphine 28, 29, 30. Tropicamide abusers declared consuming up to 1500 mg daily, whereas psychiatric adverse effects following a medical use appeared from 1 mg of tropicamide topical cumulative dose; this suggests a high drug tolerance. Systemic atropinic effects could lead to severe complications like urinary retention, paralytic ileus, acute angle‐closure glaucoma or memory and behaviour disorders. To this can be added intravenous route‐related complications such as skin infections, endocarditis, transmission of virus and overdose.

Table 3.

Description of the published case reports and studies

Authors	Sex Age (years)	Substance use disorder (past or actual)	Tropicamide consumption					Complications related to drug abuse
			Route	Dose	Length (years)	Desired effects	Contributing factors (users’ point of view)
Ostler 20	M 25		Topical	Tropicamide + Cyclopentolate: 100 to 200 drops daily instead of occasional use	2	To relieve photophobia, then he has to increase the dosage		Severe epithelial keratitis Loss of 14 kg in 9 months Severe withdrawal syndrome with increased anxiety, agitation, tremors Assault on his mother to obtain tropicamide
Spagnolo et al. 25	F 22 Georgian	Heroin (up to 0.5 g once a week) substituted by methadone 20 mg day–1	IV	1.5 g (150 ml) almost daily	2	To attenuate opiate withdrawal symptoms To decrease opioid use For calming and euphoric effects	Readily available Cheapness	Hospitalized for anticholinergic by atropinic syndrome
Bozkurt et al. 26	M 37	Cannabinoids Cocaine Clonazepam Ecstasy Heroin (for 20 years)	IV mixed with heroin	10 mg (1 ml) 3–5 times a day	1	To enhance heroin effects: relief and relaxation To attenuate heroin use		Forgetfulness, concentration difficulties Decreased appetite and loss of 15 kg in a year Hepatitis C
Bozkurt et al. 26	M 38	Alprazolam Cannabis Cocaine Codeine Ecstasy Heroin IV (for 25 years)	IV mixed with heroin (because tropicamide alone cause palpitations, dissociation, anxiety and sweating)	200–250 mg (20–25 ml) daily Divided into 7–8 injections	< 1	To increase pleasurable effects of heroin To decrease heroin use		Forgetfulness, concentration difficulties Insomnia Loss of 15 kg in a year Hepatitis C
Prilutskaya and Kuliev 27	118 patients M, 83.9% Average age 29.1	Heroin (78%) Opium (14.4%) Tramadol or desomorphine (7.6%)	IV	Average of 2–3 injections a day Average of 6.5 ± 3.2 ml day–1 (up to 20.8 ml)	Average 3.5 (1 to 9)	To support a lack of opioids (44.1%) To attenuate unintended opioids effects (39.8%) To seek/need for tropicamide effects (16.1%)	Cheap price compared to others drugs (43.2%) Over‐the‐counter availability (33.1%) More pleasant experience (23.7%)	53 patients with clinical complications (44.9%): Cardiovascular toxicity (20.8%) Intoxication‐related psychosis (16.1%) Post‐injection infections (5.9%) Nervous system involvement (39.6%)

M, Male; F, Female; IV, Intravenous

This paper collects multi‐sourced information on tropicamide diverted use proposing a comprehensive explanation of suspicious requests observed by French pharmacists. In 2014 and 2015, 17 falsified prescriptions (0.91%, 95% CI [0.53–1.46%])) collected on French territory involved tropicamide and more precisely the 10 ml bottle (compared with 0%, 95% CI [0–0.19%] for the six beta‐blockers comparators over the same period). Moreover, 37 other suspicious prescriptions were presented in French pharmacies in 2015 (but only notified in 2016), resulting in an overall total of 54 prescriptions collected. The abuse potential of tropicamide eye drops could be supported by the fact that it was the only drug mentioned in 43 prescriptions among 54 presented between 2014 and 2015 and was associated with pregabalin in nine cases. Indeed, pregabalin is known to be diverted in patients on methadone maintenance or in multiple drug users, for sedative effects or recreational purposes (dissociative and euphoric effects notably sought), which may lead to dependence 31, 32, 33, 34. Along with falsified prescriptions, spontaneous requests were reported by community pharmacists. On a regional scale, the network connecting the Midi‐Pyrénées Health Authority, the Toulouse Addictovigilance Centre and community pharmacists permitted restriction to the access to tropicamide eye drops by warning a large number of professionals in the area from December 2014. In July 2015 a second alert was sent to all community pharmacists. From then, half of requests have led to a refusal to issue (65 requests, 33.8% of missing data). To date in France, details are lacking to determine the extent of the diverted use of tropicamide and if subjects obtain the eye drops for individual consumption or for drug trafficking purposes. Given the available (but not exhaustive) data of the 2016 OSIAP survey, the phenomenon continues to escalate (with at least 80 suspicious prescriptions of tropicamide recorded) and to be spreading (with six other areas concerned).

Conclusion

To our knowledge, these results represent the first early warning signs of tropicamide diverted use in France. As a single source of information is rarely sufficient to detect and evaluate an addictovigilance signal, we have combined different sources of information. Data collected support the hypothesis, suggesting an abuse in opioid users and, a priori, in a specific population coming from Eastern Europe and Central Asia. Through exchanges with local professionals working in structures specialized in addiction, welcoming drug users or migrants and refugees, this practice was not known. Tropicamide diverted use may be marginal in France, but as this practice is very high risk and may involve people who are not connected with care or support structures, health professionals and medico‐social workers involved in drug users’ care should be aware of the existence of this divergent use.

Competing Interests

There are no competing interests to declare.

The authors gratefully acknowledge all the pharmacists for their vigilance and participation in the OSIAP survey. We wish to thank the Midi‐Pyrénées Regional Health Authority for helpful investment and the French Addictovigilance Network for sharing data.

Contributors

C. Ponté and M. Lapeyre‐Mestre were responsible for the study conception and design. All authors took part in acquisition, analysis and interpretation of data, as well as drafting of the manuscript and critical revision.

Ponté, C. , Pi, C. , Palmaro, A. , Jouanjus, E. , Lapeyre‐Mestre, M. , and on behalf of the French Addictovigilance Network (2017) Early signal of diverted use of tropicamide eye drops in France. Br J Clin Pharmacol, 83: 1791–1800. doi: 10.1111/bcp.13272.