<div>Abstract</div><div>Prescription medicine misuse, especially misuse of opioids has become a
major public healthcare issue in many developed countries such as the
United States of America and Australia where this is associated with
significant morbidity (Emergency Department visits due to acute
toxicity) and mortality. In this review, we looked at the available data
obtained from peer-reviewed articles and population surveys to gain an
insight into the current situation in the Asia Pacific region. There is
currently limited information available, but data from subpopulation
surveys in a number of countries suggests that prescription medicine
misuse is likely to be an issue of concern from a public health
perspective in the Asia Pacific region. The available data suggest that
misuse prevalence rates and the medicines that are commonly misused are
similar to countries such as the USA and United Kingdom. Further studies
are required to determine the overall prevalence of misuse, the harms
associated with this and the sources of drugs being misused so that
appropriate interventions can be implemented to tackle issues related to
prescription medicine misuse in this region.</div><div>Keywords:</div><div>Prescription medicine misuse, drug abuse, opioids, benzodiazepines, GABA
analogues</div><div>Introduction</div><div>Prescription medicine misuse is the use of medications without a
prescription or in a way other than their intended or prescribed
indication, or the use of prescription medicines that are sold on the
illicit market [1-2]. Using medications at larger doses, more
frequent dosing, prolonged duration of use, changing the route of
administration and/or use together with other medicines (e.g.
recreational drugs or novel psychoactive substances) are examples of how
medicine can be misused and potentially be harmful or fatal [3].</div><div>Prescription medicine, especially that of prescription opioids, has been
shown to be a major public healthcare issue in the United State of
America (USA) where two thirds of drug overdose deaths were related to
opioid use in 2016 [4-6]. An average of 41 people died daily from
prescription opioids overdose, totalling nearly 15,000 deaths in the USA
in 2018 [7]; and prescription opioids were involved in 32% of all
opioid overdose deaths in 2018 [8].</div><div>Prescription medicine misuse is becoming a global concern as data from
Australia [9] and Europe [10-12] have shown that these countries
are reporting increasing rates of misuse, overdose or death related to
misuse of prescription medicine including opioids, benzodiazepines and
gabapentinoids.</div><div>Unfortunately, the data on prescription medicine misuse in the Asia
Pacific region is lacking for the following reasons: 1) there is paucity
of national surveys on drug use in general and prescription medicine
misuse in particular, 2) most peer-reviewed literature on this topic are
from North America, Europe and Australasia and 3) some of the data that
are available are published in non-English native languages and are not
easily available.</div><div>According to a report from the United Nations Office on Drugs and Crime
(UNODC) [13], prescription medicine misuse is an increasing
phenomenon in South Asia amongst recreational drugs users. In
Bangladesh, statistics from the Department of Narcotics Control (DNC)
indicate that 12% of drug users seeking treatment are users of
prescription medicines. Medications including psychotropic agents are
known to substitute illicit drugs when the supply of illicit drugs is
short. In India, among the patients seeking treatment for drug related
issues, opiate use accounts for 40% of the total drug use of which
14.3% is heroin, 14.2% is opium and 12.1% is pharmaceutical opioids.</div><div>The factors that have been proposed to contribute to this increase are:</div><ul><li>Prescription medicines can be easily and legally obtained from
pharmacies in many countries in the region, often without the need for
a prescription.</li><li>There is less stigma associated with the use of prescription medicines
compared to the use of recreational drugs. Use of recreational/illicit
drugs is still frowned upon in many Asia societies and users can be
persecuted for illicit drug use if they are caught by law enforcement
in many of the countries in the Asia Pacific region [14].</li><li>Lastly, as seen in North America, Australia and Europe [15], there
is an increased prescribing by physicians of opioid analgesics in the
management of patients with pain. This increased exposure to opioids
has the potential to be associated with an increase in the number of
patients developing opioid dependence.</li></ul><div>The commonly misused medicines reported in South Asia countries in the
UNODC report are similar to that reported in the Western literature.
They consist of opioid containing drugs such as codeine containing cough
mixtures and opioid analgesics, and benzodiazepines [13].</div><div>Data on the worldwide availability of opioids revealed the availability
in many countries in Asia Pacific (0.1-1mg/capita) is much lesser
compared to USA and countries in Europe where the availability of
opioids is more than 10mg per capita in many of the states or countries
in these areas where prescription opioids misuse is a growing public and
healthcare problem [16].</div><div>Literature Review</div><div>A systematic search was performed using PubMed and the search strategy
included the following keywords: prescription medicine or drugs and
misuse or abuse and Asia. The search yield 451 papers, of which we
identified the following papers
which gave us an insight into the current situation in Asia Pacific,
indicating that countries in this region are also facing the similar
public healthcare issue with the misuse of medications. The first 2
papers describe the trend of prescription medicine misuses in teenagers/
young adults in China, the next 2 are subpopulation surveys on
prescription medicine misuse in Thailand and Japan and the last 6 papers
describe the misuse of medications especially that of tramadol in the
Gulf region.</div><div>We shall now look at two papers describing the prevalence of misuse of
prescription medicines among students in China. Tam et al [17]
reported that from January 2017 to April 2017, 849 undergraduates
participated in online survey on non-medical use of prescription
medicines. The mean age of the participants was 20 years old and 72.2%
were female. The lifetime and past three months misuse prevalence rate
for any prescription medicines were 62.9% and 33.4% respectively among
299 students in Beijing and 35.9% and 21.8% respectively among 550
students in Macau. The most commonly reported drugs were analgesics
(62.9% Beijing; 35.5% Macau), followed by sedatives (4.0% Beijing;
0.9% Macau), anxiolytics (2.7% Beijing; 0.6% Macau), and stimulants
(1.0% Beijing; 0.2% Macau).</div><div>Another study on prescription medicine misuse in the Guangdong Province
China [18] was conducted in 2007 to 2009 by Wang Hui et al. This
study involved 21,672 middle and high school students whose mean (±SD)
age was 16 (±1.9) years. 5.3% of the female respondents (584 out of 11
056 female respondents) and 6.6% of the male respondents (705 out of 10
616 male respondents) reported lifetime misuse of prescription
medications. The most common misused medicines were analgesics (3.9%),
followed by cough medicines with codeine (2.1%).</div><div>These 2 studies suggest that the prevalence of prescription medicine
misuse among adolescents and young adults in China and the types of
medications they misuse are similar to the West. There have also been
subpopulation surveys on prescription medicine misuse in Japan and
Thailand.</div><div>The first of these was a random sampling of residents in seven cities/
municipalities in Japan from 2002 to 2004[19]. Face-to-face
household surveys were conducted for 887 participants. The lifetime
misuse prevalence of prescription medicines was 6.4% whereas the
lifetime use of marijuana and cocaine was 1.5% and 0.3% respectively.
Misuse prevalence of prescription medicines in the last 12 months was
reported to be 1.5% and use of marijuana was 0.3%. None of the
respondents reported use of cocaine in the last 12 months. The study
also found that prescription medicine misuse was significantly more
common among the middle-aged (35-49 years) group (df = 3, P = 0.029) and
those who were married/cohabitating (df = 2, P = 0.019). Misusers of
psychotropic agents were more commonly associated with the following
conditions: presence of mood disorder (OR = 2.82), anxiety disorder (OR
= 2.54), intermittent explosive disorder (OR = 3.62), and alcohol abuse/
dependence (OR = 1.99) (all <i>p</i> &lt; 0.05). The authors
commented that although the misuse prevalence rate of prescription
medicine was higher than the use of illicit drugs in this study, the
overall prevalence for both prescription medicine misuse and illicit
drugs use was lower than that reported in countries such as the USA and
in Europe. They postulated that this might be the effect of the Japanese
government’s policy on controlling the use of illicit and other
psychotropic drugs.</div><div>In a household survey conducted in Thailand in 2007 [20], 26,633
individuals aged between 12 to 65-year-old participated in a face to
face structured interview questionnaire. The lifetime misuse prevalence
rate of anxiolytics and hypnotics was 1.58% whereas the misuse
prevalence rate in the last one year was 0.92% (anxiolytics) and 0.8%
(hypnotics). The findings of this Thai household survey was similar to
that from Japan, suggesting that there is an issue with prescription
medicine misuse in Thailand – the prevalence rate appears to be lower
than that reported in the developed countries but it is important to
note that these studies were undertaken a number of years ago.</div><div>In India, a retrospective study of 950 patients who were admitted from
2007 to 2014 in a tertiary addiction centre revealed that alprazolam
(50.6%), nitrazepam (23.5%), and zolpidem (11.2%) were the most
commonly reported drugs of abuse [21]. High misuse prevalence of
benzodiazepines and Z-drugs in this study of patients with drug
dependence may suggest that there are significant problems with the
misuse of benzodiazepines and Z-drugs in India which is similar to the
findings of the UNODC report on prescription medicine misuse in South
Asia [13].</div><div>Next, we will look at studies from the Iraq, Iran and Yemen to
understand the extent of prescription medicine misuse in the Gulf
region. The Iraqi Ministry of Health, together with USA government
researchers, held an Iraqi Community Epidemiology Work Group meeting in
May 2012 in Baghdad [22]. This workgroup evaluated information from
drug seizure data, records from hospitals, outpatient clinics, and
health centres, as well as from surveys of patients, and prisoners. The
findings revealed that the most widely misused substance in Iraq was
alcohol, followed by prescription drugs such as benzodiazepines,
benzhexol and codeine. It was also highlighted that the use of hashish
(cannabis resin), tramadol, and amphetamine-type substances (ATS) were
increasing in some parts of Iraq.</div><div>In a study analysing biological samples obtained during autopsy in Iran
to evaluate the trends of tramadol-related deaths that occurred between
2005 and 2008 in Tehran it was found that tramadol-related deaths were
32.5 more common in 2008 than in 2005, however data were not reported on
the circumstances of these deaths and whether they related to deliberate
self-poisoning or overdose in the context of tramadol misuse [23].</div><div>Another study performed in Iran evaluated the misuse prevalence of
tramadol in Iranian adolescents in 2012 [24]. 2000 students
participated in this study using a self-administered multiple-choice
questionnaire. It was found that the lifetime misuse prevalence of
tramadol was 4.8% (7.6% males; 1.8% females). Adjusted odds ratios
and confidence intervals for lifetime tramadol misusers reporting
substance use during the past month were 2.2 (1.1-4.4) for alcohol, 5.0
(1.5-21.9) for cannabis, 8.9 (2.7-29.4) for ecstasy, 0.5 (0.03-7.0) for
methamphetamine and 2.3 (0.7-7.4) for opium.</div><div>A systematic review of tramadol use and public health consequences by
Rostam-Abadi Y et al revealed that the pooled estimates of last 12-month
use of tramadol in the Iranian general population were 4.9% [95%
confidence interval (CI) = 4.1-5.9] among males and 0.8% (95% CI =
0.2-1.8) among females. In the subgroup of Iranian university students,
the estimates for last 12-month use were 4.8% (95% CI = 1.9-8.9) for
males and 0.7% (95% CI = 0.3-1.1) for females. The pooled estimate of
tramadol poisoning was 13.1% (95% CI = 5.7-22.9) and the pooled
percentage of tramadol-related fatalities was 5.7% (95% CI = 0.5-15.4)
among the patients who had drug related overdoses [25].</div><div>Another study looking at population size estimation of tramadol misusers
in Iran was published in 2019. The surveyed pharmacists estimated that
5.67 people (71560 people) per 1000 population aged 15-49 years were
estimated to have misused tramadol [95% uncertainty limits (UL):
2.61-9.25] whereas the surveyed medicinal herb sellers estimated the
abuse rate to be 8.1 people (102230 people) per 1000 population aged
15-49 years (95% UL: 5.50-27.35) [26].</div><div>These studies suggest that tramadol misuse in Iran is significant and
mirrors the trend described in United States of America and China in a
recent World Health Organisation (WHO) report [27]. In this report,
it is stated that the estimated number of individuals who have used
tramadol products non-medically at least once in their lifetime
increased from 1,990,000 in 2008 to 2,614,000 in 2011 in the USA; and
tramadol was found to be the most commonly used prescription opioid
(27.3%) amongst opioid dependent users in China.</div><div>This trend of tramadol misuse was also observed by the pharmacists
working in community pharmacies in Aden city, Yemen [28]. 170
pharmacists participated in a questionnaire survey in 2013. 57.7% of
them suspected drug abuse/misuse in their pharmacies and the top three
medications for which they suspected misuse were alprazolam, ketoprofen,
and tramadol. 83.3% of them also reported that they observed an
increasing pattern of abuse/misuse in their pharmacies.</div><div>Prescription Medicine Misuse in Singapore</div><div>Singapore is known for its strict legislation on drug use as the country
aims to strive for a drug free society through active enforcement
against drug activities, preventive education and engagement of the
local communities [29]. There is limited literature or population
surveys to determine the prevalence of prescription medicine misuse in
Singapore.</div><div>Newspaper articles describing students misusing medications for
attention deficit hyperactivity disorder (ADHD) as a study aid, in the
hope of getting better results were published in 2017 [30] and 2013
[31]. These medications can only be prescribed by doctors in
Singapore and the article [30] described that students share these
medications among their peers and it was also possible to obtain these
drugs from online platforms and messaging services. Such diversion of
drugs is consistent with the global drug trends where more consumers
were observed to be using darknet markets to obtain drugs in most
countries with over 25% reporting first time access to Darknet in 2018
in the annual global drug survey report [32].</div><div>An article by Winslow et al described the demographics of one hundred
and twenty buprenorphine abusers who fulfilled the diagnostic criteria
for opiate dependence [33]. The majority of these buprenorphine
abusers were male (90%) with a mean age of 39.2 (SD 8.0) years. 52.5%
were currently employed and 98% had at least primary education. A
family history of drug abuse was reported by 27%. Early onset of
Illicit drug abuse occurred at the mean age 16.9 (SD 4.8) years. The
finding of this study indicates a possible trend of local drugs misusers
moving from abuse of illicit substances to prescription medicines.
Understanding such trends in addiction and dependence may help to better
tackle the issue of drug misuse locally.</div><div>In another paper evaluating prescription medicine misuse among 2273
individuals who were seeking treatment for substances misuse in
Singapore [34]. 295 misused prescription medicines only, 811 used
illicit drugs, and 263 misused a mixture of both prescription and
illicit drugs. 904 were excluded from the study as they reported using
alcohol only. It is found that those who were misusing prescription
medicines were predominantly male (243, 82.4%) with a mean age of 41.2
(SD 11.4) years. 63.1% among this group (n=186) reported misusing
benzodiazepines as their main drugs and 18.6% (n=5) used codeine. In
the group of illicit drug users, 89.6% (n=727) were male with a mean
age of 41 (SD 14) years. Heroin was reported to be the main substance
used by 63.4% (n=514), followed methamphetamines (18.7%; n=152) and
cannabis (9.1%; n=74). In the group who misused both illicit and
prescription medicines, 89% (n=234) were male with a mean age of 45.2
(SD 11.2) years. 61.6% (n=162) used heroin as their main drug, 14.1%
(n=37) misused benzodiazepines, and 11.8% (n=31) used amphetamines. It
was found that educational level and occupational status were associated
with different types of misuse [34]. Those with primary and
secondary education qualifications had higher odds (2.1 and 2.9 times,
respectively) of misusing both prescriptions and illicit drugs than
those with tertiary qualification and those working in managerial or
professional roles had higher odds (4.4 and 7.4 times, respectively) of
misusing prescription medicines only than those who were unemployed
[34].</div><div>Due to the paucity of data on the prevalence of prescription medicine
misuse in Singapore, we conducted two online internet surveys in 2015
[35] and 2016. The aim of the studies was to determine i) whether
survey respondents had heard of different prescription medicines, ii)
the prevalence of prescription medicine misuse in Singapore, and iii)
identify the demographic characteristics of those reporting misuse. The
demographics of the respondents in 2015 and 2016 are illustrated in
table 1. The level of awareness and lifetime misuse prevalence for each
of the group of medicines surveyed, together with the mean age of the
misusers can be found in table 2.</div><div>To compliment the population survey, we conducted an online survey to
determine the level of awareness of prescription medicine misuse of
doctors in Singapore in 2016[36]. 102 doctors working in the
Emergency Department participated in this online survey, of which 55.9%
were male, 54.5% were consultants and the median (IQR) age was 38
(25-55) years old.</div><div>The results of the study showed majority of the respondents (76.5%)
were concerned about misuse of prescription drugs by their patients.
86.3% were aware that they might be prescribing to patients who were
misusing medicines. 80.8% felt that they needed help to deal with
patients who were misusing prescription medicines and 65.7% indicated
that more training in the management of patients who were prescription
medicines misusers was required, of which 15.1% preferred face-to-face
training, 37.9% preferred online training and 47.0% were keen for both
face-to-face and online training. The top three prescription medicines
that the respondents suspected that their patients might be misusing
were: codeine containing cough mixtures (92.2%), opioids analgesics
(83.8%) and benzodiazepines (64.7%)</div><div>The findings of this survey are consistent with the self-reported misuse
prevalence rates of the earlier online surveys in Singapore and the
UNODC report [13] where the most commonly misused medications in
South Asia were codeine containing cough mixtures, opioid analgesia and
benzodiazepines. In additional, the data from the online survey
conducted in 2015 and 2016 suggests that prescription medicine misuse
may be an issue in Singapore and would require further studies such as
general population survey to look at the extent of misuse in the general
public and to further evaluate the sources of drug diversions.</div><div>Despite the limited data at a population level in many countries in the
Asia Pacific region, we can suggest with current available data,
particularly from Singapore, that prescription medicine misuse is likely
to be a problem in the region.</div><div>More research is required to understand the scale of the problem,
demographics and reasons for misuse and the sources of availability.
This additional information will help determine if changes to
prescribing practices with regular audit and monitoring of physicians’
habits, implementation of preventive educational activities to raise
awareness of the dangers of prescription medicine misuses, provision of
services for drug treatment and rehabilitation and revision of
legislation to tighten control are required. These changes will
eventually help reduce or prevent prescription medicine misuse from
becoming a public healthcare burden in this region.</div><div>References</div><div>1. National Institute on Drug Abuse. Misuse of prescription drugs.
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10.1080/15563650.2018.1457818</div><div>Bottom of Form</div>