Assessing the Extent and Characteristics of Non-medical Use of a Range of Prescribed Drugs: Epidemiological and Pharmacovigilance Approaches

Abstract

Introduction: In the last ten years, the growing use of prescription and over-the-counter (OTC) drugs for recreational purposes has been observed. The use of ‘psychoactive pharmaceuticals’ and ‘pharming’ are new widespread terms describing a worldwide phenomenon involving the non-medical use of prescription (e.g., pain relievers, tranquilisers, stimulants, sedatives, etc.) and OTC drugs, including cough and cold preparations, particularly those containing dextromethorphan and promethazine. However, although data supporting a growing concern on their misuse and diversion are increasing, there is still a lack of evidence regarding the true extent and nature of such phenomena. Aim of the study: This project aimed at assessing the misuse and diversion potential of certain pharmaceuticals, known anecdotally to be used in order to achieve psychoactive effects, as well as described by drug users’ online fora reporting new trends in abuse and experimentation in drugs. The substances of interest of the programme of research included prescription drugs such as gabapentinoids; antidepressants (e.g., venlafaxine, bupropion, and Selective Serotonin Reuptake Inhibitors/SSRIs); antipsychotics (e.g., olanzapine, clozapine, and quetiapine); Z-drugs (e.g., zolpidem, zopiclone, and zaleplon); image and performance enhancing drugs (e.g., clenbuterol and salbutamol); opioids (e.g., fentanyl, tramadol, codeine, dihydrocodeine, oxycodone, and pentazocine); and, among OTCs, the anti-diarrhoeal drug loperamide, the non-steroidal anti-inflammatory drug benzydamine, and the antihistamine promethazine. Methods: Firstly, descriptive analyses of data from the European Medicines Agency pharmacovigilance database (EudraVigilance/EV) collecting voluntarily reported Adverse Drug Reactions (ADRs) related to specific pharmaceuticals were performed. Moreover, to better compare two drugs in the same group, e.g., quetiapine versus olanzapine, the Proportional Reporting Ratio (PRR) approach was used. Inclusion criteria for selecting the ADRs to be studied were all terms containing ‘abuse’, ‘intentional misuse’, ‘dependence’, or ‘drug withdrawal’ as narrow terms according to the Standardised MedDRA Query System; terms relating to events observed with abuse, but which also occurred without abuse (e.g., ‘overdose’ or ‘drug level increased’ or ‘drug toxicity’) were included as broad terms. Finally, in the last section of the PhD, in order to better assess pharmacovigilance issues, statistical analyses included further disproportionality methods, such as the reporting odds ratio, the information component value, and the empirical bayes geometric mean (signals were based on a false discovery rate <0.05). Where possible, EV data, were compared with other pharmacovigilance datasets, such as the United Kingdom (UK) Yellow Card Scheme related to the Medicines and Healthcare products Regulatory Agency (MHRA) data, and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Results: From data analysed, diversion, abuse, and dependence are issues which might present with several of the studied drugs, especially if used in large or extremely large dosages, concomitant licit/illicit drugs, and unconventional routes of administration. To give an example, over years 2004–2015, from the EV database some 7,639 (6.6% of a total of 115,616) and 4,301 (4.8% of 90,166) misuse/abuse/dependence ADR were respectively associated to pregabalin and gabapentin, with an overall reporting frequency increasing over time. According to the PRR, abuse, dependence and intentional product misuse were ADR more frequently reported for pregabalin (1.25, 1.39, and 1.58, respectively) compared to gabapentin. A total of 27 (2.1%) and 86 (21.0%) fatalities, respectively associated with pregabalin and gabapentin, occurred, and mostly in combination with opioids. Among the OTCs, during the years 2005-2017, EV collected a number of 1,983 (out of a total of 7,895; 25.1%) loperamide-related misuse/abuse/dependence/withdrawal ADR reports, with a progressively increasing trend since 2014. Interestingly, most cases were classified as ‘drug use disorder’ (37.4%) or ‘intentional overdose’ (25.4%) and recorded supratherapeutic dosages, e.g., up to 800mg, with an average daily dosage of 4 to 8 mg. Loperamide was mostly used on its own (182/434 = 41.9%); conversely, antidepressants, benzodiazepines, opioids, and other OTCs were concomitantly recorded in the remaining cases (252/434 = 58.1%). Some 1,085 (1,085/7,895 = 13.7%) cardiovascular ADRs were reported, being conduction abnormalities and electrocardiogram alterations the most frequently identified. In all studies, populations at risk have been identified, such as patients with a substance abuse history. Conclusions: Although further studies are needed, both the literature and current data support the principle that some drugs, including both prescription drugs, e.g., gabapentinoids, some antipsychotics and antidepressants, and some OTC drugs, such as loperamide, dextromethorphan, promethazine, etc., should be prescribed with caution owing to the risk of abuse and of idiosyncratic reactions. According to the results presented here, the misuse and abuse of prescription/OTC drugs could be a cause for major concern, especially in vulnerable individuals or in some contexts, such as polysubstance abuse, history of drug abuse or drug addiction. The use of concomitant substances or of high/supra-high doses for recreational purposes may cause unpredictable effects, such as overdoses or drug-related fatalities. Hence, caution should be exercised in prescribing. Healthcare professionals should be warned about the possible misuse of such drugs and be aware of their diversion potential. They should recognise actual cases of abuse; and consider the possibility of polydrug misuse. The Internet through both social media/fora and rogue online pharmacies might be a means for buying drugs. On the other hand, the Internet and social networks are a promising source of data in order to better understand, monitor and treat substance use issues. The present situation represents a challenge for psychiatry, public health, and drug-control policies with enormous implications for clinical practice in terms of harm reduction strategies, preventable morbidity, and mortality.