Focus on Over-the-Counter Drugs' Misuse: A Systematic Review on Antihistamines, Cough Medicines, and Decongestants

Background: Over the past 20 years or so, the drug misuse scenario has seen the emergence of both prescription-only and over-the-counter (OTC) medications being reported as ingested for recreational purposes. OTC drugs such as antihistamines, cough/cold medications, and decongestants are reportedly the most popular in being diverted and misused. Objective: While the current related knowledge is limited, the aim here was to examine the published clinical data on OTC misuse, focusing on antihistamines (e.g., diphenhydramine, promethazine, chlorpheniramine, and dimenhydrinate), dextromethorphan (DXM)- and codeine-based cough medicines, and the nasal decongestant pseudoephedrine. Methods: A systematic literature review was carried out with the help of Scopus, Web of Science databases, and the related gray literature. For data gathering purposes, both the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and PROSPERO guidelines were followed (PROSPERO identification code CRD42020209261). Results: After completion of the selection, eligibility, and screening phases, some 92 articles were here taken into consideration; case reports, surveys, and retrospective case series analyses were included. Findings were organized according to the specific OTC recorded. Most articles focused here on DXM (n = 54) and diphenhydramine (n = 12). When specified, dosages, route(s) of administration, toxicity symptoms (including both physical and psychiatric ones), and outcomes were here reported. Conclusion: Results from the systematic review showed that the OTC misusing issues are both widespread worldwide and popular; vulnerable categories include adolescents and young adults, although real prevalence figures remain unknown, due to a lack of appropriate monitoring systems. Considering the potential, and at times serious, adverse effects associated with OTC misusing issues, healthcare professionals should be vigilant, and ad hoc preventative actions should be designed and implemented.


INTRODUCTION
Since generally being considered safe, over-the-counter (OTC) medicines are available without a prescription and can be purchased directly from related pharmacies/stores (1,2). OTC medicines are meant to treat a variety of illnesses and symptoms, including pain, coughs and colds, diarrhea, nausea, etc. OTC availability, while encouraging self-care, has contributed to a public perception of safety and a lack of awareness relating to their potential for misuse, dependence, and harm (3)(4)(5)(6). Indeed, some OTC medicines have active ingredients possessing a misusing potential at higher-than-recommended dosages (7) and are becoming increasingly popular for the possibility of their diversion in order to reach central psychoactive effects (8)(9)(10)(11).
Currently, there is minimal information about the prevalence of OTC misuse, abuse, and dependence (8)(9)(10)12). Indeed, current lack of knowledge may partly be due to poor sales' monitoring because of OTCs' favorable legal status. However, the so-called "pharming" phenomenon (13)(14)(15) has been requiring attention at different levels because of increased treatment admissions, dangerous behavior, more emergency room visits, drug-related deaths, and overdoses (11,16,17). Most implicated drugs include certain cough suppressants, sleep aids, and antihistamines, which can at times be ingested in combination with remaining recreational psychotropics and/or prescription drugs and/or alcohol (17,18). Overall, the misuse of OTC drugs is considered as more socially acceptable, less stigmatizing, and safer than the intake of illicit substances, also due to their likely lack of detection in standard drug screens (16). OTC drugs' intake may involve snorting or injecting the crushed tablets' powder to amplify the effects of a drug or ingesting these molecules for a purpose different from the therapeutic one. This may be the case for dextromethorphan (DXM) and codeine-based cough mixtures, being possibly misused at high dosages for recreational or euphoric effects; conversely, loperamide is at times being ingested for self-medicating withdrawal symptoms (7, 16,[18][19][20]. OTC misuse has also been associated with notable drug interactions, physical and mental health effects, individual variation in responses, and significant socioeconomic impact for the users, their family, and the wider community (13)(14)(15). Currently, most OTC misusing data are obtained through clinical records (e.g., case reports and case series) and surveys.

Aims of the Study
Thus, the current review aimed at (i) examining the current literature on the misuse of OTC drugs, focusing on the following OTCs: among antihistamines, diphenhydramine (DPH), promethazine, chlorpheniramine, and dimenhydrinate (DH); DXM-and codeine-based cough medicines; and the nasal decongestant pseudoephedrine; (ii) illustrating patterns of OTCs' misuse, psychopathological effects, and harms associated; and (iii) better understanding the psychotropic molecular mechanisms underlying their recreational use.

Systematic Review Procedures
A systematic electronic search was conducted from October 2020 to December 2020 and was set without a timeframe on the following scientific search engines: PubMed, Scopus, and Web of Science (WoS). The gray literature was also checked for relevant information. The following search strategies were used, respectively, in PubMed: ("diphenhydramine" OR "promethazine" OR "chlorpheniramine" OR "dimenhydrinate" OR "dextromethorphan" OR "pseudoephedrine" OR codeinebased cough medicines) AND ("abuse" OR "misuse" OR "craving" OR "addiction") NOT review NOT (animal OR rat OR mouse) NOT "in vitro;" in Scopus: [TITLE-ABS-KEY ("Diphenhydramine") OR TITLE-ABS-KEY ("Promethazine") OR TITLE-ABS-KEY ("Chlorpheniramine") OR TITLE-ABS-KEY ("Dimenhydrinate") OR TITLE-ABS-KEY ("Dextromethorphan") OR TITLE-ABS-KEY ("Pseudoephedrine") OR TITLE-ABS-KEY (codeine-based cough medicines) AND TITLE-ABS-KEY ("Abuse") OR TITLE-ABS-KEY ("Misuse") OR TITLE-ABS-KEY ("Craving") OR TITLE-ABS-KEY ("Addiction") AND NOT TITLE-ABS-KEY (Review) AND NOT TITLE-ABS-KEY (animal) OR TITLE-ABS-KEY (rat) OR TITLE-ABS-KEY (mouse) AND NOT TITLE-ABS-KEY ("in vitro")]; and WoS: ("diphenhydramine" OR "promethazine" OR "chlorpheniramine" OR "dimenhydrinate" OR "dextromethorphan" OR "pseudoephedrine" OR codeinebased cough medicines) AND ("abuse" OR "misuse" OR "craving" OR "addiction") NOT Review NOT (animal OR rat OR mouse) NOT "in vitro." The systematic review was structured in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (21) and PROSPERO guidelines (22). All data collected were tabulated on an Excel sheet to enable easy comparison and analysis.

Data Synthesis Strategy
The selection and eligibility phase of the articles was carried out by three independent reviewers (AM, AMo, and MCS), who screened articles based on title and abstract; the first screening was followed by full text reviews, using predetermined criteria for inclusion and exclusion. Eligible articles were considered if the published studies met all the following criteria: (i) original articles (open-label or double-blind trials, prospective or retrospective observational studies, case series and case reports); (ii) studies involving all age individuals misusing the OTC drugs selected. There were no other restrictions on the type of study population or publication time period. Exclusion criteria were as follows: (i) nonoriginal research articles (e.g., review, letter, commentary, editorial, book chapter, professional or clients' opinions); (ii) non fulltext articles (e.g., meeting/conference abstracts); (iii) languages other than English; (iv) animal/in vitro studies; (v) articles mentioning OTC drugs only as an example in the context of OTC drugs misuse; and (vi) articles not dealing with the misuse of the OTC drugs selected (e.g., DPH, promethazine, chlorpheniramine, and DH; DXM-and codeine-based cough medicines; and pseudoephedrine). Individual studies were also manually searched to identify additional citations. A final, between reviewers, cross-check was carried out, supervised by SC and MP, with both doubtful cases and possible inclusion/exclusion disagreements resolved through discussion with GM, MDG, and FS.

Protocol and Registration
Current research methods were approved by PROSPERO (identification code CRD42020209261).

Risk of Bias
The assessment of risk of bias was made in accordance with the Cochrane risk of bias 2 (RoB 2) tool (23).

RESULTS
In removing duplicate articles (n = 566) from a total of 2,136 papers (PubMed = 393; Scopus = 1,372; WoS = 362; additional sources = 9), some 15,70 records resulted to be relevant for screening. Those considered not relevant to the subject while considering both the title and the abstract (n = 1,103; e.g., animal/in vitro studies; articles only mentioning OTC drugs, or not regarding OTC misuse/abuse, or not giving a clear description of related symptoms), those not written in English (n = 136), and those that were non-original articles (n = 87) were eliminated. Out of the 244 remaining full-text articles assessed for eligibility, some 125 papers did not match the inclusion criteria and 27 were not available. Hence, 92 articles were taken into consideration and properly analyzed (Figure 1). Findings were organized according to the specific OTC recorded, reported in alphabetical order in Supplementary Table 1; conversely, the most relevant characteristics of the misusing potential of the range of OTC drugs commented are summarized in Table 1.
On-drug cases of violent behavior, including suicide, have been reported (97,99). Treatment required hospitalization and supportive care; drugs used were antipsychotics, such as fluphenazine and quetiapine, benzodiazepines, and benztropine (89,90,92,93).  Table 1). All cases involved adolescents and young adults who misused promethazine orally. In most cases (n = 259) promethazine abuse was associated with other substances, such as DXM, codeine, phenylephrine, pseudoephedrine, caffeine, etc. Intoxication symptoms ranged from mild to severe effects, up to seizures and coma, but no fatalities have been reported. Agitation, confusion, slurred speech, and hallucinations were described as well. Promethazinealone abuse cases were mostly managed in healthcare facilities, while promethazine in coformulation mostly required emergency department (ED) care management (100). Moreover, further cases of nonmedical use of promethazine were here identified from (i) the Danish Poison and Information Centre (DPIC) and related registers used within the State Serum Institute of Denmark (SSI) (101); (ii) a prospective database of poisoning admissions (January 1987-May 2007) to a UK regional toxicology service (102); and (iii) a prospective study regarding patterns of misuse of heroin injectors (103). Druginduced delirium was the most represented psychiatric effects; this was managed with antipsychotics and benzodiazepines (101,102). Interestingly, the use of promethazine injection in opioid users was reported as a substitute for heroin or to increase the effects of an inadequate heroin dosing (103). A case of drug-induced delirium deriving from the coingestion of high-dose promethazine, cyproheptadine, and fluvoxamine in a young girl was recorded (104). Finally, a case of promethazine dependence and withdrawal after 2year continuing use of a promethazine-cough mixture was described (105).
Although widely used and generally considered safe, cases of antihistamine abuse and dependence have been recorded (125). These molecules were originally marketed for their antiallergy properties and are now made available as sleeping aids. Antihistamines' toxicity appears to be clinically related to both central and peripheral acetylcholine antagonism. In addition, specifically due to multiple potential mechanisms of action, DPH (e.g., the antihistamine moiety of DH) can acutely block the cell membrane pump mechanism of central 5-hydroxytryptophane and peripheral noradrenaline neurons, causing the euphoria reported by some users ( Table 1). At high dosages, and taken together with other drugs (e.g., alcohol, cannabis, and stimulants), DPH and DH might be used to achieve a stimulant effect (87,91,92,126,127). Reported cases of DPH dependence have resulted from long-term usage of large doses (often over 1,000 mg/day). Gradual tapering has been described to alleviate withdrawal symptoms (17,125). Conversely, promethazine is used in cough syrups for its antihistaminic, antiemetic, and sedative effects, available with codeine in common cough suppressants (128); its abuse potential appears related to its calming and sedating effect and enhancement of other coingested substances ( Table 1). A recreational use of promethazine mixed with a soft drink and/or alcohol ("purple drank") is currently popular among young people for its euphoric effects and easy accessibility (19,20,(129)(130)(131). Promethazine has been reported in SUD clients and is misused as a substitute for another drug or to increase the effects of inadequate dosing (i.e., to delay the onset of opioid withdrawal or to potentiate the sedating effect of benzodiazepines/Z-drugs) (13,19,20,103,129,130,132,133). Overdose of promethazine is associated with an antimuscarinic delirium, agitation, and neuroleptic malignant syndrome (100, 102,104,133). Scott et al. (104) recorded a promethazineinduced delirium treated with physostigmine intravenously, which reversed both central and peripheral anticholinergic effects, similarly to a polydrug overdose due to the ingestion of DPH (94). Chlorpheniramine is used as a cheap sleep aid and/or as an anxiolytic due to its antimuscarinic properties; its abuse has been related to pleasurable feelings, which reinforces the repetitive use and the possibility of developing drug dependence ( Table 1). It may, however, be associated with psychotic symptoms in predisposed individuals [e.g., people with mental illnesses or individuals concomitantly abusing other drugs; (42,43,114,115)].
Codeine was reported within the misusing scenario of codeine-based cough and cold medicines and/or coingested with other substances, e.g., DXM, DPH, ephedrine, pseudoephedrine, methyl ephedrine, chlorpheniramine, promethazine, caffeine (26, 27, 34, 78-80, 100, 114, 134). Codeine is a natural isomer of methylated morphine and, similarly to DXM, is a prodrug, requiring metabolic activation by O-demethylation to morphine by CYP2D6. Thus, codeine-related effects are associated with CYP2D6 metabolism, e.g., ultrarapid CYP2D6 metabolizers produce an unexpectedly large amount of morphine, with resulting life-threatening opioid toxicity. Its recreational use is related to the agonism at mu receptors and the subjective effects of euphoria, elation, analgesia, and "liking" (114,121). Codeine toxicity is characterized by respiratory depression and extreme somnolence progressing to stupor or coma (79); in severe overdosage cases, death may occur (121) (Supplementary Table 1 and Table 1). Idiosyncratic codeine administration procedures have been recorded, e.g., a misuser learned online how the codeine base might be extracted through a process called cold water extraction (CWE) to be then injected. Regular use of codeine is described here together with the development of both tolerance (135) and dependence (80,114).

LIMITATIONS
One of the difficulties regarding the literature on prescription drug misuse is both its heterogeneity and the issues in identifying misusing practices; interpretation was easier for both those cases reported by healthcare professionals, whose intervention was needed, National/Regional Poison Data System information (100, 101), etc. According to UNODC, the misuse of medicines is defined as "the problematic consumption outside of acceptable medical practice or medical guidelines, when self-medicating at higher doses and for longer than is advisable, for intoxicating purposes and when risks and adverse consequences outweigh the benefit" (8)(9)(10)(11). However, levels of terminology variability and inconsistency to describe the OTC phenomenon were identified as well; this use was referred to as non-medical use, problem use, harmful use, recreational use, self-medication, or inappropriate use, which calls into question whether there is a consensus on the negative consequences (i.e., problem, harm) of OTC use. Indeed, some of these terms may not even necessarily refer to the same issue (8).

CONCLUSIONS
The current systematic review showed that OTC misuse is an increasingly relevant health issue associated with potential harms, including drug-related toxicity, addiction, and fatalities. Nowadays, the CoViD-19 pandemic has likely facilitated the occurrence of these misusing practices, as more users turned from street drugs to prescription/OTC products (14,15). Indeed, OTC drugs are both widely accessible and perceived because of their favorable legal status as relatively safe, hence accepted in a "pill-popping culture" (11). There is the need of both drafting ad hoc treatment guidelines and planning preventative measures. These measures should revolve around the implementation of a range of associated issues, including scheduling amendments, proper surveillance, enhanced detection of misuse in clinical and pharmacy practice, and promotion of public health awareness initiatives (9, 11,16,[139][140][141]. As an example, due to the recent rise in opioid abuse and related overdose deaths worldwide, efforts are focusing on strengthening public health surveillance and limiting opioid prescribing (142,143). Specifically, as codeine-containing products misusing levels might be hampered by their widespread and easy availability, upscheduling and pharmacy-based interventions targeting users might limit the purchase of codeine products without a prescription. The recent introduction of new OTC combinations with non-opioid agents may provide a safer alternative to these widely misused products (144). In the case of the antidiarrheal loperamide, found to be misused at high dosages and associated with cardiotoxicity, to support its safe use, the Food and Drug Administration (FDA) approved changes to the packaging for tablet and capsule forms limiting each carton to no more than 48 mg of loperamide and requiring the tablets and capsules to be packaged in individual doses (145). A range of professionals should be involved in tackling the OTC misusing issues, including (i) physicians, especially general practitioners (GP), who can help OTC misusers in early recognizing a drug-related problem and refer them to the appropriate service (e.g., mental or addiction services); they should also take note of rapid increases in the amount of medication needed or frequent, unscheduled refill requests and uncovering possible "doctor shopping" practices. Physicians will continue to have a role in educating users to ensure that they use medications appropriately, following the prescribed directions, while being aware of potential interactions with other licit/illicit drugs (11,16,18,116,135,141). Conversely, pharmacists should be watchful for prescription falsifications or alterations, being at the frontline in recognizing prescription drug abuse issues. Moreover, prescription drug monitoring programs could assist healthcare professionals in identifying patients who are getting prescriptions from multiple sources (11, 13, 16-18, 141, 144, 146). Finally, abuse prevention campaigns might provide valuable resources on raising awareness and preventing medicine abuse [https://stopmedicineabuse.org/; (144)].

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

AUTHOR CONTRIBUTIONS
FS, SC, and GM conceived the idea of this paper. AM, MCS, and AMo extracted the data. FS, MP, GM, AG, and MDG supervised all stages of the process and were consulted to resolve any possible disagreement. SC, AM, and JMC drafted the first version and revised it after contributions from FS, AG, and GM. All authors contributed to the article and approved the submitted version.