Non-Medical Use of Benzodiazepines: A Growing Threat to Public Health?

2017·2.3 MB·English

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Non-medical use of
benzodiazepines:
a growing threat to
public health?
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2017
Research
GLOBAL
SMART
UPDATE
About the SMART Update
Synthetic drugs constitute one of the most significant The Global SMART Update (GSU) series is published
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substances (NPS) market over the last years has become interest.* This issue is fully dedicated to the topic of
a policy challenge and a major international concern. A the concomitant use of benzodiazepines and opioids,
growing interplay between these new drugs and tradi- and does not contain country-specific segments. Past
tional illicit drug markets is being observed. By August issues have covered topics such as the fentanyl group
2017, the emergence of NPS had been reported from of synthetic opioids, UNGASS 2016 recommendations,
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or contributory organizations and neither do they imply any endorsement. Suggested citation: UNODC, Global SMART Update Volume 18, September 2017.
2
Volume 18
Non-medical use of benzodiazepines:
a growing threat to public health?
ABSTRACT non-medical use of opioids however
presents serious risks including the
Non-medical use of prescription benzodiazepines, has been a long-
potential for abuse, dependence,
established problem that has been associated with a large number
overdose and fatalities. Benzodi-
of overdose deaths worldwide. Most recently, the concomitant
azepines are a class of medicines
use of benzodiazepines and opioids has been linked to a number
widely used to treat conditions such
of deaths that occurred in the recent opioid crisis, featuring in a as anxiety, insomnia and seizures. In
rising number of fatalities and adverse events in North America terms of non-medical use, benzodi-
and in Europe. In recent years, several new psychoactive substanc- azepines have been used to produce
es (NPS) belonging to the benzodiazepine class have also emerged effects such as relief of mental stress
and anxiety, improved coping with
on the market and are being sold under street names such as “le-
situational pressures or psychologi-
gal benzodiazepines”, “designer benzodiazepines”, and “research
cal problems, or relief of side-effects
chemicals”. The use of such NPS belonging to the benzodiazepine
associated with over-stimulation or
class and the non-medical use of pharmaceutical benzodiazepines
withdrawal of other drugs. Chronic
pose a great threat to public health. use of benzodiazepines may result
in the development of tolerance
Introduction
and dependence. Both opioids and
The previous Global SMART Update benzodiazepines have been placed benzodiazepines are central nervous
Volume 17 provided an overview of under international control to pre- system depressants and concomitant
the rapidly unfolding public health vent their abuse whilst ensuring the use may lead to pronounced drowsi-
threat posed by extremely potent availability of some of these benzo- ness, respiratory depression, coma
synthetic opioids, fentanyl and its diazepines as essential medicines.1 or death.
analogues in light of the sharp rise
In recent years, the documented Non-medical use of benzodiazepines
in opioid-related deaths (mainly
risks entailed in the concomitant in combination with prescription
in North America and, to a lesser
non-medical use of opioids and opioids has been implicated in a
extent, in Europe). Recently, increas-
sedatives/hypnotics have been number of overdose deaths. In the
ing evidence has emerged that
further exacerbated by the ready United States, the use of prescrip-
polydrug use particularly involving
availability of counterfeited ben- tion benzodiazepines and opioids
sedatives/hypnotics such as benzo-
zodiazepines and the increasing coupled with the use of additional
diazepines, might be linked to some
emergence of “designer benzodi- drugs, such as heroin, have culmi-
of these fatalities.
azepines”, a common street name nated in several fatalities. From
The current Global SMART Update for new psychoactive substances 1999 to 2013, data from the United
focusses on the concomitant use of (NPS) belonging to the benzodiaz- States has shown that drug-related
benzodiazepines and opioids in the epine class. Many NPS belonging to deaths involving opioid medications
context of the recent opioid crisis the benzodiazepine class are sub- have accounted for around 175,000
in certain parts of the world. Non- stances that have not been approved fatalities.2 Over this period, the rate
medical use of benzodiazepines as medicines in the pharmaceuti- of deaths involving benzodiazepines
in combination with the misuse cal industry on the basis of safety increased by 514 per cent and the
of prescription opioids has been and/or efficacy. Such substances
rate of deaths encompassing both
implicated in a growing number of are potentially more harmful than
prescription benzodiazepines and
deaths in the United States. Benzodi- pharmaceutical benzodiazepines opioids rose by 819 per cent.3 Over
azepines are also the most common with unknown pharmacological/toxi-
a five-year period, between 2010
prescription medicines associated cological profiles and have added to
and 2014, alprazolam and diazepam
with acute intoxication cases in the complexity and dangers of the
were among the 10 drugs most fre-
Europe. Whereas benzodiazepines illicit market for benzodiazepines.
quently involved in drug overdose
are a class of medicines widely used
The threat of benzodiaz- deaths. Among the deaths involving
to treat various medical conditions,
alprazolam and diazepam, more than
epines: deaths and intoxica-
both opioids and benzodiazepines
95 per cent also involved more than
are central nervous system depres- tions associated with opioid
two other additional drugs. Based
sants in which concomitant use and polydrug use on 47,055 drug overdose deaths
may lead to pronounced drowsi-
Opioids represent a class of power-
ness, respiratory depression, coma
ful substances used in medicine for 2 Office of National Drug Control Policy
or death. The non-medical use of (2015) National Drug Control Strategy 2015.
the treatment of severe pain. The
benzodiazepines with opioids has 3 Centers for Disease Control and Prevention
been, and continues to be, a factor (CDC); National Center for Health Statistics.
1 World Health Organization (WHO) 20th “Underlying Cause of Death on CDC Wide-
of concern for control and preven-
WHO Model List of Essential Medicines: 20th ranging Online data for Epidemiology for
tive measures. Since 1984, certain List. March 2017. Research.” 2015.
3
GLOBAL
SMART
UPDATE
Table 1: Most frequent concomitantly used drugs in cases of drug overdose deaths involving alprazolam and
diazepam – United States, 2014
BENZODIAZEPINES Most frequent concomitantly used drug in cases of drug overdose deaths
First Second Third Fourth Fifth
Alprazolam Oxycodone Heroin Hydrocodone Methadone Morphine
Diazepam Oxycodone Hydrocodone Alprazolam Heroin Morphine
Source: Warner, M. et al. (December 2016) “Drugs most frequently involved in drug overdose deaths: United States, 2010-2014.”
National Vital Statistics Reports 65 (10): 1-5.
examined in the report, the most
frequent drug used concomitantly
with alprazolam and diazepam was
the opioid, oxycodone.4
Moreover, according to the European
Drug Emergencies Network (Euro-
DEN), the most common substances
associated with acute intoxica-
tion cases related to prescription
medicines in Europe included ben-
Source: UNODC
zodiazepines and opioids.5 National
Statistics of Scotland also reported Australia: Benzodiazepines associated with more than
that of the 706 drug-related deaths half of non-fatal overdoses of PWID
in 2015, the use of benzodiazepines
(e.g. diazepam) was implicated in, QUEENSLAND, Australia – February 2017. A drug use study conducted
or potentially contributed to, 27 per during September and October 2013, among 50 people who inject drugs
cent of drug-related deaths in Scot- (PWID) and who reported to have had a non-fatal overdose in the past 12
land. Also, among the total number months, found that the non-medical use of benzodiazepines were associ-
ated with 52 per cent of the overdoses. In this regard, these substances have
of drug-related deaths in 2015 in
been associated with more than half of non-fatal overdoses of people who
Scotland, 57 deaths involved the use
inject drugs. In these cases of non-fatal overdose, benzodiazepines (mostly
of benzodiazepine NPS (such as eti-
under the brand name of either “Xanax®” or “Valium”) had been used by
zolam, diclazepam or phenazepam).6
participants within 24 hours before the overdose occurred. Polydrug use was
Although benzodiazepines are rarely also commonly reported among participants. After benzodiazepines, 44 per
identified in post-mortem toxicology cent of participants reported to have used heroin, followed by 42 per cent
as the only drug involved in a case of reporting the use of other prescription drugs, and 36 per cent reporting the
death, evidence suggests that ben- use of fentanyl and its analogues. In the presence of other drugs is it difficult
zodiazepines are present in a large to establish a direct link between the benzodiazepines either on their own
proportion of opioid overdose cases or in synergy with other substances as a cause of the non-fatal intoxication.
recorded in recent years in North
Najman, J. M., et al. (March 2017) “When Knowledge and Experience Do Not Help:
America and Europe.7
A Study of Nonfatal Drug Overdoses.” Journal of Addiction Medicine: 1-6. Abstract
available at: www.ncbi.nlm.nih.gov/pubmed/28368905
4 Warner, M. et. al. (December 2016) “Drugs Pharmaceutical benzodiazepines hospital emergency departments
most frequently involved in drug overdose
have also often been misused by in 10 European countries (constitut-
deaths: United States, 2010-2014.” National
Vital Statistics Reports 65 (10): 1-5. polydrug users in concomitance ing the European Drug Emergencies
5 European Monitoring Centre for Drugs with other drugs, such as opioids Network, Euro-DEN) showed that,
and Drug Addiction (EMCDDA) “Addic- and cannabis. For high-risk opioid after alcohol at 59.4 per cent, ben-
tion Hospital emergency presentations and
users in Europe, the most commonly zodiazepines at 22.8 per cent were
acute drug toxicity in Europe: update from
the Euro-DEN Plus research group and the reported pharmaceutical benzodi- most commonly used in combination
EMCDDA.” Lisbon, August 2016. azepines associated in drug-related with cannabis among the 320 hos-
6 National Records of Scotland. Drug-related deaths are alprazolam, clonazepam, pital cases involving cannabis use.9
deaths in Scotland in 2015, August 2016.
diazepam, flunitrazepam and oxaz-
7 Sun, E.C. et. al. (March 2017) “Associa-
epam.8 Between October 2013 to
tion between concurrent use of prescription
opioids and benzodiazepines and overdose: March 2014, data collected from
retrospective analysis.” The BMJ: 356; Abra-
hamsson, T. et. al. (May 2017) “Benzodiaz- 9 Dines, A. M. et. al. and Euro-DEN Research
epine, z-drug and pregabalin prescriptions 8 European Monitoring Centre for Drugs and Group (December 2015) “Presentations to
and mortality among patients in opioid Drug Addiction (EMCDDA) “Perspectives the emergency department following can-
maintenance treatment—A nation-wide on Drugs: The misuse of benzodiazepines nabis use—a multi-centre case series from
register-based open cohort study.” Drug and among high-risk opioid users in Europe.” ten European countries.” Journal of Medical
Alcohol Dependence 174: 58-64. Lisbon, June 2015. Toxicology 11(4): 415-421.
4
Volume 18
Table 2: International control of benzodiazepines under the United Nations Convention
on Psychotropic Substances of 1971
YEAR OF SCHEDULING
SCHEDULE SUBSTANCE NAME
DECISION
1984 IV Alprazolam Haloxazolam
Bromazepam Ketazolam
Camazepam Loprazolam
Chlordiazepoxide Lorazepam
Clobazam Lormetazepam
Clonazepam Medazepam
Clorazepate Nimetazepam
Clotiazepam Nitrazepam
Cloxazolam Nordazepam
Delorazepam Oxazepam
Diazepam Oxazolam
Estazolam Pinazepam
Ethyl loflazepate Prazepam
Fludiazepam Temazepam
Flurazepam Tetrazepam
Halazepam Triazolam
1990 IV Midazolam
1995 III Flunitrazepam
IV Brotizolam
2016 IV Phenazepam
Source: UNODC Early Warning Advisory (EWA) on NPS. “April 2017 – UNODC: Several countries place benzodiazepine derivatives under
national control.” April 2017. Available at: www.unodc.org/LSS/Announcement/Details/065118d5-b238-48d8-9d7f-b95fb5d11411
Various forms of polydrug use involv- Benzodiazepines – thus considered effective and safe
ing benzodiazepines have been medicines that should be accessible
Ensuring access for treat-
associated with a number of health in healthcare systems.
ment while countering
consequences, which has been of
Over time, some pharmaceuti-
abuse
public concern for some years (see
cal benzodiazepine products have
Box for case of benzodiazepines Benzodiazepines are extensively been discontinued. For instance,
associated with non-fatal overdoses used in the treatment of conditions nimetazepam (frequently sold
of people who inject drugs and fre- including anxiety, insomnia and sei- under the brand name “Erimin”) is
quent polydrug users). Generally, the zures. However, their non-medical/ a pharmaceutical benzodiazepine
combined use of benzodiazepines recreational use has been a long- for which licensed production was
and other CNS depressant drugs is established problem that has been discontinued in 2015.11 Despite this
associated with an overall greater associated with abuse, dependence measure, unlicensed preparations
risk of overdose and HIV transmis- and a large number of overdose of nimetazepam are available and,
sion that can impede treatment for deaths worldwide. More recently, in recent years, it has become avail-
opioid addiction and exacerbate in North America and in Europe, the able online and is reportedly used
respiratory depression, leading to non-medical use of benzodiazepines in a club-drug context in the United
potential fatalities.10 has featured in a rising number of Kingdom.12 Nimetazepam also con-
fatalities and adverse events. tinues to be illicitly sold in some
Since 1984, a total of 36 benzodi- regions.
azepines have been placed under Some benzodiazepines not under
10 Horsfall, J.T. and Sprague, J.E. (February international control under the international control, were approved
2017) “The Pharmacology and Toxicology United Nations Convention on
of the ‘Holy Trinity’.” Basic and Clinical Psychotropic Substances of 1971,
Pharmacology and Toxicology 120 (2): 115-9;
Jones, J.D., Mogali, S., and Comer, S.D. designed to ensure access to these 11 Lim, W. J. L. et al. (February 2017) “Detec-
(September 2012) “Polydrug abuse: a review useful medicines whilst countering tion of phenazepam in illicitly manufactured
of opioid and benzodiazepine combination their liability for abuse and depen- Erimin 5 tablets.” Drug Testing and Analysis 9
use.” Drug and Alcohol Dependence 125 (1-2): (2): 293-305.
dence. Benzodiazepines, diazepam,
8-18; Ickowicz, S. et. al. (October 2015) 12 NEPTUNE (Novel Psychoactive Treatment
“Benzodiazepine use as an independent risk lorazepam and midazolam, are cur- UK Network) “Guidance on the Clinical
factor for HIV infection in a Canadian set- rently listed in the 20th WHO Model Management of Acute and Chronic Harms
ting.” Drug and Alcohol Dependence 155: of Club Drugs and Novel Psychoactive Sub-
List of Essential Medicines and are
190-4. stances.” London, 2015.
5
GLOBAL
SMART
UPDATE
Table 3: List of effects of benzodiazepines
DESIRED EFFECTS UNDESIRED ACUTE EFFECTS EFFECTS OF CHRONIC USE
• Relief of tension, mental stress • Reduced mental activity and • Development of tolerance,
and anxiety alertness, drowsiness, lethargy psychological and physical
and impairment of clarity of dependence
• Positive feelings of calmness,
thought and judgement may
relaxation and well-being in • Headache, irritability, confusion,
occur
anxious individuals memory impairment, depres-
• Potential impairment of muscle sion, insomnia and tremor
• Improved coping with
coordination, dizziness, low
situational pressures or • Abrupt cessation may lead to
blood pressure, or fainting
psychological problems withdrawal syndrome which
• Diminished emotional responses can include insomnia, anxiety,
• Relief of side effects associ-
to external stimuli, e.g. pain perceptual hypersensitivity,
ated with over-stimulation or
tremors, irritability, nausea and
withdrawal of other drugs (i.e.
vomiting, mental confusion and
as part of a pattern of multiple
life-threatening convulsions
drug use)
Source: United Nations (2016) Terminology and Information on Drugs.
as pharmaceuticals only in a placed under international control Singapore and the Taiwan Province
restricted number of countries and in 2016.16 of China, have reported non-medical
remained largely unknown in most use of benzodiazepines.21 In Malay-
Etizolam, a pharmaceutical product
countries. For example, phenaz- sia, nimetazepam is a commonly
licensed in Japan, Italy and India,
epam, a benzodiazepine developed abused sedative and is used as a
was first reported in 2011 in the
in the former Soviet Union in the substitute of heroin. It is also increas-
United Kingdom on the internet.17
1970s, was only licensed in the ingly used by methamphetamine
Particularly, the recreational use of
Russian Federation and some parts users to facilitate a come-down after
etizolam has been widespread in
of the Commonwealth of Indepen- excessive use.22
Scotland and has been associated
dent States (CIS) as a pharmaceutical
with drug-related deaths in various In recent years, several new psycho-
product prescribed to treat anxiety
parts of the United Kingdom.18 How- active substances (NPS) belonging
and withdrawal symptoms.13
ever, there is limited information on to the benzodiazepine class have
Over time, there have been increas- the dependence potential or the also emerged on the market and
ing reports of non-medical use number of fatalities associated with are being sold under street names
of phenazepam, which has been etizolam.19 For this reason, etizolam such as “legal benzodiazepines”,
associated with a rising number of is currently under surveillance by the “designer benzodiazepines”, and
fatalities, particularly in Europe.14 In World Health Organization (WHO).20 “research chemicals”. The use of
some cases, phenazepam has been such NPS belonging to the benzodi-
Several countries in East and
found to remain in the human body azepine class pose a great threat to
South-East Asia, including Brunei
for a long period of time after inges- public health, particularly in view of
Darussalam, Hong Kong (China),
tion, with some reports of severe the absence of information on their
Indonesia, Malaysia, the Philippines,
adverse effects lasting up to five days pharmacological and toxicological
or to three weeks following inges- profiles.
16 Phenazepam is currently under international
tion.15 As a result, phenazepam was control under Schedule IV of the United The complex nature of the
Nations Convention on Psychotropic Sub-
stances of 1971. illicit market for benzodiaz-
13 World Health Organization (WHO) Expert 17 O’Connor, L.C., Torrance, H.J., and McK- epines
Committee on Drug Dependence. “Phen- eown, D.A. (March 2016) “ELISA detec-
azepam: Pre-Review Report. Agenda item tion of phenazepam, etizolam, pyrazolam, Benzodiazepines encountered on
5.8.” Thirty-seventh Meeting, Geneva, 16-20 flubromazepam, diclazepam and delorazepam the illicit drug market are primarily
November 2015; Drug Enforcement Admin- in blood using Immunalysis® Benzodiazepine
istration (DEA) “Phenazepam.” April 2014. Kit.” Journal of Analytical Toxicology 40 (2): diverted from the legitimate trade of
159-161. medicines rather than synthesized in
14 Corkery, J.M., Schifano F., and Ghodse, A.H.
(May 2012) “Phenazepam abuse in the UK: 18 Advisory Council on the Misuse of Drugs clandestine laboratories.23 The risk
an emerging problem causing serious adverse (ACMD) “Advice on U-47,700, etizolam
health problems, including death.” Human and other designer benzodiazepines.” United
Psychopharmacology 27 (3): 254-61; Kriikku Kingdom, 2 December 2016.
P., et. al. (July 2012) “Phenazepam abuse in 19 World Health Organization (WHO) Expert 21 UNODC, Annual Report Questionnaire;
Finland: findings from apprehended drivers, Committee on Drug Dependence. “Etizolam Drug Abuse Information Network for Asia
post-mortem cases and police confiscations.” (INN): Pre-Review Report. Agenda item and the Pacific (DAINAP).
Forensic science international 220 (1-3): 5.7.” Thirty-seventh Meeting, Geneva, 16-20 22 Abdullah, A. F. L. et. al. (January 2012)
111-7. November 2015. “Forensic drug profiling of Erimin-5 using
15 World Health Organization (WHO) Expert 20 World Health Organization (WHO) “Sub- TLC and GC-MS.” Malaysian Journal of
Committee on Drug Dependence. “Phen- stances under Surveillance.” Available at: Forensic Sciences 3(1): 11-15.
azepam: Pre-Review Report. Agenda item www.who.int/medicines/access/controlled- 23 United Nations Office on Drugs and Crime
5.8.” Thirty-seventh Meeting, Geneva, 16-20 substances/substancesundersurveillance. (UNODC) Terminology and Information on
November 2015. pdf?ua=1 Drugs. 3rd edition. March 2016.
6
Volume 18
of diversion of medicines from their
intended use in medical treatment
to non-medical use and sale on illicit
drug markets can occur at all points
of the pharmaceutical trade. Diver-
sion can occur at pharmaceutical
manufacturing sites, at wholesale
distribution of medicines, at the phy-
Source: UNODC
sician’s office, at retail pharmacies,
or when patients receive treat-
United States: Leader of an online pharmacy that
ment.24 Methods of diversion are
illegally distributed prescription drugs was sentenced
also wide-ranging and can include:
to prison
the illegal sale and repeated use
of prescriptions by physicians and
SEATTLE, United States – 27 January 2017. In early 2017, a man pleaded
pharmacists; patients obtaining pre-
guilty at the United States District Court for the Western District of Virginia in
scriptions from several doctors (also
Harrisonburg for purchasing tablets containing flubromazolam between June
known as the “doctor shopping”
2015 and September 2015 and distributing these with the false claim that
phenomenon); theft of medicines; they contained alprazolam (often sold under the brand name of “Xanax®”).27
and forgery and/or alteration of pre- According to the defendant, the tablets he distributed did not contain any
scriptions by patients.25 labeling to inform users of their flubromazolam content. Under the names
of “Discount Pharmacy” and “A-1 Pharmacy”, this internet operation had
Over the years, benzodiazepines
shipped hundreds of thousands of alprazolam (“Xanax®”), as well as hydro-
have been diverted from legitimate
codone, phentermine, and codeine (sold under various brand names such as
trade on a large scale in various
“Tylenol 4”) tablets to thousands of people across the country who did not
regions worldwide for onward sale
have valid prescriptions for these substances. The investigation of this case
at illegal drug markets. For instance,
revealed that the defendant employed this approach to misbrand 100-300
in the United States, the leader of an
tablets purchased from the “dark web”.
online pharmacy that illegally dis-
tributed benzodiazepines including United States Attorney’s Office Western District of Virginia. “Cross Junction Man
other prescription drugs and illegal Pleads Guilty to Misbranding Charge.” 3 February 2017. Available at: www.justice.
gov/usao-wdva/pr/cross-junction-man-pleads-guilty-misbranding-charge
tablets was sentenced to prison in
January 2017.26 Under the names
of “Discount Pharmacy” and “A-1
almost 40,000 alprazolam reports In the course of the investigation,
Pharmacy”, this internet operation
from federal, state and local foren- authorities discovered an extensive
had shipped hundreds of thousands
sic laboratories in 2011 and another network engaging in the diversion of
of tablets, including the opioid
18,068 reports between January and prescription medicines that involved
hydrocodone and the benzodiaz-
June 2012.28 wholesale dealers and other busi-
epine alprazolam (under the brand
nesses as well as some registered
name “Xanax®”), across the United Large scale diversion of benzodi-
pharmacies in the United Kingdom.
States to thousands of people who azepines has also been reported
did not have valid prescriptions for in the United Kingdom, where the The diversion of benzodiazepines
these substances. Over a three-year Medicines and Healthcare products and other medicines from licit trade
period, the operation generated a Regulatory Agency (MHRA) con- is a problem in a number of regions.
revenue of more than USD 9 million. ducted a large scale investigation into However, quantifying the magnitude
the diversion of prescription medi- of such diversion remains difficult
In the United States, alprazolam is
cines to the illegal drug market in given that there is a lack of data and
considered to be among the top
December 2016.29 Two pharmacists information on this subject and few
three prescription medicines that
available systematic monitoring and
based in the Yorkshire region of the
are diverted from the licit market.
data collection mechanisms.
country were arrested after having
According to the Drug Enforcement
purchased more than 200,000 packs
Administration (DEA), there were Counterfeiting and substitu-
of benzodiazepines and other drugs.
tion of pharmaceuticals
involving benzodiazepines
24 European Monitoring Centre for Drugs and 27 United States Attorney’s Office Western Dis-
Drug Addiction (EMCDDA) “Perspectives trict of Virginia. “Cross Junction Man Pleads
Over the years, benzodiazepines
on Drugs: Strategies to prevent diversion of Guilty to Misbranding Charge.” 3 February
opioid substitution treatment medications.” 2017. Available at: www.justice.gov/usao- have also been employed in the
May 2016. wdva/pr/cross-junction-man-pleads-guilty- large scale manufacture of coun-
25 European Monitoring Centre for Drugs and misbranding-charge terfeit medicines, also referred
Drug Addiction (EMCDDA) “Perspectives 28 Drug Enforcement Administration (DEA)
to as “fraudulent medicines” or
on Drugs: Strategies to prevent diversion of “Benzodiazepines.” January 2013.
opioid substitution treatment medications.” 29 Medicines and Healthcare products Regu- “falsified medicines”.30 Such coun-
May 2016. latory Agency (MHRA) “Press Release: terfeit medicines are usually made to
26 United States Drug Enforcement Adminis- Regulator investigating the diversion of
tration. “Leader of Illegal Online Pharmacy prescription only medicines.” 16 December
Sentenced to 8 Years in Prison.” 27 January 2016. Available at: www.gov.uk/government/ 30 United Nations “Countering fraudulent
2017. Available at: www.dea.gov/divisions/ news/regulator-investigating-the-diversion-of- medicines, in particular their trafficking.”
sea/2017/sea012717.shtml1 prescription-only-medicines Resolution 20/6.
7
GLOBAL
SMART
UPDATE
resemble pharmaceutical products
that instead contain different sub- India: Authorities
stances that may be harmful. Thus, dismantle a clandestine
the content of counterfeit medicines
laboratory manufacturing
can vary significantly, ranging from
alprazolam
products that contain the wrong
ingredients, or that are without
ANDHRA PRADESH, India – Octo-
The Democratic Republic
active ingredients, or that have an ber 2016. On 5th October 2016,
insufficient or excessive quantity of Congo: 400 patients officers of the Vishakhapatnam
of the active ingredients.31 Cases of suffer acute intoxication Directorate of Revenue Intelligence
counterfeit medicine use involving after use of counterfeit dismantled a clandestine labora-
benzodiazepines discussed in this tory in Jawaharlal Nehru Pharma
diazepam
report are a global phenomenon that City in the Andhra Pradesh State of
can potentially result in unexpected NONO, Democratic Republic of India. In addition, a total of 101 kg
adverse effects and/or a deteriora- Congo – July 2015. On 2nd July 2015, of alprazolam were seized at the
tion of medical conditions. the WHO issued an alert when over site and authorities also arrested
400 patients in the area of Nono to 5 people in connection with this
Given that the counterfeiting of
the north-east of the Democratic case. A day earlier, on 4th October
medicines is difficult to detect and
Republic of Congo suffered acute 2016, the Central Bureau of Narcot-
quantify, the extent of the prob-
intoxications after having used diaz- ics seized 700 grams of alprazolam
lem and the size of the market for
epam for their health treatment. in Indore in Madhya Pradesh State
counterfeit medicines involving ben- Laboratory analysis of the tablets and arrested 3 people in connec-
zodiazepines is unknown. However, labeled as diazepam showed that tion with the case.
reports show that benzodiazepines
the tablets did not contain any diaz-
Narcotics Control Bureau. Drug Situa-
feature in cases concerning counter-
epam but instead had a content of
tion Report/Significant Events Report
feit products worldwide.
10-20 milligrams of haloperidol for India for the Month of October
In Europe, there have been various per tablet. Although most acute 2016. October 2016.
reports in recent years of counterfeit intoxications occurred in the area
medicines that had been intercepted of Nono, large quantities of such
tablets were also reported to have tablets seized in both countries usu-
and found to contain benzodiazepine
been observed in other parts of the ally solely contained nimetazepam or
NPS. For instance, in 2016, Police
Democratic Republic of Congo such nimetazepam together with a rela-
Scotland reported that seized tablets
as the Ituri Health District. tively small quantity of nitrazepam.
sold as diazepam on the illicit drug
market have instead been found to World Health Organization (WHO), In North America, cases of counterfeit
contain various other benzodiaze- “Medical Product Alert No. 4/2015: medicines involving benzodiazepines
pines such as etizolam, diclazepam, Adverse reactions caused by Falsified have featured in the United States
flubromazepam and the synthetic Diazepam in Central Africa”, Geneva, for a number of years.36 Recently, in
2 July 2015.
opioid U-47700.32 Moreover, accord- January 2017, the leader of an online
ing to the European Monitoring pharmacy that illegally distributed
Centre for Drugs and Drug Addiction tablets containing flubromazolam
reported to have seized 26 batches
(EMCDDA), tablets sold in Europe as with the false claim that they con-
of phenazepam of which some con-
alprazolam were found to contain tained alprazolam, in addition to
sisted of a mixture of phenazepam
flubromazolam in 2015 whereas tab- and other stimulant drugs.34 illegally distributing various other
lets sold as diazepam tablets in that prescription drugs and narcotic
In South-East Asia, there have also
same year were discovered to have tablets, was sentenced to 8 years in
been reports of nimetazepam being
contained phenazepam.33 In Finland, prison (see Box for more informa-
substituted with phenazepam in
between 1st July 2010 and 30th tion on this online pharmacy in the
the content of “Erimin 5” tablets in
June 2011, the Finish police also United States).
recent years. According to the Illicit
In some regions there have also been
Drugs Laboratory of the Health
reports of products sold as benzo-
31 World Health Organization (WHO) “Sub- Sciences Authority in Singapore,
standard, spurious, falsely labelled, falsified diazepine medicines, that were
phenazepam has been discovered
and counterfeit (SSFFC) medical products.” found to contain other substances.
January 2016. Available at: http://www.who. in the content of “Erimin 5” tablet
For instance, in July 2015, the
int/mediacentre/factsheets/fs275/en/; World seizures in Singapore and in Malaysia
Health Organization (WHO) “Counterfeit since 2012.35 Previously, “Erimin 5” World Health Organization (WHO)
Drugs.” WHO/IFPMA Workshop, Geneva, issued an alert concerning tablets
1-3 April 1992.
labeled as diazepam that were
32 Police Scotland, “The illicit benzodiazepine
market in Scotland.” Drug Trend Bulletin – 34 Kriikku P., et. al. (July 2012) “Phenazepam
Issue 13, September 2016; Police Scotland, abuse in Finland: findings from apprehended 36 For more information, see: Drug Enforce-
“The illicit benzodiazepine market in Scot- drivers, post-mortem cases and police con- ment Administration (DEA) “Micro-
land”, Drug Trend Bulletin – Issue 8, April fiscations.” Forensic science international 220 gram Bulletin.” August 2009; United
2016. (1-3): 111-7. States Food and Drug Administration,
33 European Monitoring Centre for Drugs and 35 Lim, W. J. L. et al. (February 2017) “Detec- “Counterfeit Drugs – An FDA Perspec-
Drug Addiction (EMCDDA) European Drug tion of phenazepam in illicitly manufactured tive.” Available at: http://indy.afdo.org/
Report 2016: Trends and Developments. Lux- Erimin 5 tablets.” Drug Testing and Analysis 9 uploads/1/5/9/4/15948626/ddc-1035-flurer-
embourg, 2016. (2): 293-305. pharma-counterfeiting.pdf
8
Volume 18
Source: UNODC Source: UNODC
Malaysia: 2.5 million nimetazepam tablets seized in a Ireland: Two cases of
container from Taiwan Province of China “Xanax®” tablet seizures
in Kildare and Limerick
PORT KLANG, Malaysia – March 2017. At Port Klang in the state of Selan-
City
gor, the Special Tactical Intelligence Narcotics Group (STING) and the Royal
Malaysian Customs seized 2.5 million nimetazepam tablets, at a value of
KILDARE AND LIMERICK CITY,
around 50 million Malaysian Ringgit, concealed in a container from Taiwan
Ireland – February 2017. On 13th
Province of China in March 2017. According to the Malaysian Narcotics
February 2017, the Irish National
Criminal Investigation Department, these tablets were intended to be sold
Police Service, the Gardaí, seized a
on drug markets in Malaysia, as well as in Indonesia, Singapore, and Thailand.
large quantity of “Xanax®” tablets
Malaysian police arrested 10 men in connection with the case.
(presumed to contain alprazolam)
Free Malaysia Today. “Cops seize Ermin 5 pills worth RM50 million.” 11 March 2017. with an estimated value of EUR
Available at: www.freemalaysiatoday.com/category/nation/2017/03/11/cops-seize- 19,000 and 6.5 kg of “ecstasy” (pre-
erimin-5-pills-worth-rm50-million/ sumed to contain MDMA). These
substances were seized when the
Gardaí from Naas Traffic Corps
found to contain haloperidol in the by countries in North America stopped and searched a car at a
north-eastern parts of the Demo- and South Asia. In North America, checkpoint in Kildare Town after
cratic Republic of Congo (for more Canada reported to have disman- which a man and a woman were
information see box on the acute tled 2 medium-sized packaging arrested in connection with the
intoxication cases in the Democratic operations illicitly manufacturing case. Previously, on 24th June 2016,
Republic of Congo).37 Previously, in alprazolam in 2014, while in South the Gardaí seized “Xanax®” tablets
2011, the United States Food and Asia, the Narcotics Control Bureau in with a street value of EUR 9,000
Drug Administration (FDA) issued a India reported to have dismantled a together with a quantity of canna-
warning on placing orders for alpra- clandestine laboratory in 2016 (see bis herb during a search operation
zolam (often sold under various Box for more information on the at a house in Limerick City.
brand names such as “Xanax®”) and illicit laboratory in India).39
An Garda Síochána – Ireland’s National
certain other pharmaceutical prod- In East and South-East Asia, Malay- Police Service. “Press Release: Drug
ucts over the internet.38 According seizure and arrests in Kildare on the
sia also reported to have dismantled
to the FDA, there had been several 13/2/17.” 14 February 2017. Avail-
an illicit laboratory manufacturing
able at: www.garda.ie/Controller.
cases in which such tablets that had
nimetazepam in 2011 and another aspx?Page=19911&Lang=1
been ordered over the internet were
such laboratory in 2015.40
found to contain haloperidol. An Garda Síochána – Ireland’s National
Seizures and trafficking of Police Service. “Press Release: Drug
Clandestine manufacture seizure and arrest in Limerick on
benzodiazepines
of benzodiazepines the 24/6/16.” 25 June 2016. Avail-
In recent years, countries worldwide able at: www.garda.ie/Controller.
In addition to the diversion of ben- have reported seizures of various aspx?Page=18494&Lang=1
zodiazepines from medical sources, benzodiazepines to UNODC.
there is also some evidence of illicit
Nimetazepam kg).41 In early 2017, it was confirmed
manufacture. In recent years, coun-
that another 2.5 million tablets of
tries in various regions have reported Between 2011 and 2015, nimetaz-
nimetazepam were seized in a single
the dismantling of laboratories illic- epam seizures were reported in
seizure in the Taiwan Province of
itly manufacturing alprazolam and South-East Asian countries that
China (for more information, see Box
nimetazepam. included Brunei Darussalam (totaling
on nimetazepam seizure reported
less than 1 kg) and the Taiwan Prov-
With respect to alprazolam, illicit
in Malaysia that had been trafficked
ince of China (at a total of around 12
manufacture has been reported
from Taiwan Province of China).
Alprazolam
37 World Health Organization (WHO), “Medi-
cal Product Alert No. 4/2015: Adverse reac- Over the years, most alprazolam sei-
tions caused by Falsified Diazepam in Central 39 UNODC, Annual Report Questionnaire for
zures were reported in the United
Africa.” Geneva, 2 July 2015. Canada, 2014; Narcotics Control Bureau.
38 United States Food and Drug Administration “Drug Situation Report/Significant Events States where almost 5 tons were
(FDA), “The Possible Dangers of Buying Report for India for the Month of October
Medicines over the Internet.” 26 January 2016.” October 2016.
2011. Available at: www.fda.gov/ForConsum- 40 UNODC, Annual Report Questionnaire for 41 UNODC, Annual Report Questionnaire,
ers/ConsumerUpdates/ucm048396.htm Malaysia, 2011 and 2015. 2011-2015.
9
GLOBAL
SMART
UPDATE
Table 4: List of benzodiazepine NPS that have been reported by Member States to the UNODC Early Warning
Advisory (EWA) and benzodiazepine NPS that were observed based on other sources of information
BENZODIAZEPINE NPS
3-hydroxyphenazepam Flubromazepam
4-chlorodiazepam Flubromazolam
Adinazolam Flunitrazolam
Alprazolam triazolobenzophenone derivative Meclonazepam
Bromazolam Metizolam
Clonazolam Nifoxipam
Cloniprazepam Nitrazolam
Deschloroetizolam Norfludiazepam
Desmethylflunitrazepam Phenazepam43
Diclazepam Pyrazolam
Etizolam42 Zapizolam
Source: UNODC Early Warning Advisory (EWA) on NPS, 2017.
reported to have been seized in 2014 Other benzodiazepines belonging to the benzodiazepine
and another 0.01 tons were reported class have pharmacological profiles
Other seizures of benzodiazepines
in 2015.44 In addition, seizures of similar to controlled pharmaceutical
(such as clonazepam, flunitrazepam,
this substance, annually totaling benzodiazepines,48 profiles of most
lorazepam, midazolam, nitrazepam,
1-5 kg or less per country, have also of the emerging substances are not
phenazepam, and temazepam) have
been reported between 2011 and well-described.
also been reported in recent years
2015 in various regions worldwide,
from various countries worldwide The risk of polydrug use involving
in countries that include Bahrain,
that mostly consisted of annual sei- benzodiazepines and opioids are
Chile, Gambia, India, Italy, Pakistan,
zures totaling around 1 kg or less. further intensified by NPS belong-
the Russian Federation, the Taiwan
Larger quantities were reported ing to the benzodiazepine class.
Province of China and Yemen. Most
in the Russian Federation in 2014, Given the limited information on the
recently in early 2017, two seizure
where more than 28 kg of clonaz- pharmacology and toxicity of these
cases of “Xanax®” tablets (presumed
epam were reported to have been substances, variations in the dosage,
to contain alprazolam) were also
seized. onset of effects, combination of
reported in Ireland.
substances, potency, and general
The emergence of NPS belong-
Diazepam patient or individual variability, the
ing to the benzodiazepine class
concomitant use of these substances
Since 2010, annual seizures of
As a relatively new phenomenon, with other drugs entails a number
diazepam mostly consisting of less
NPS belonging to the benzodi- of risks.
than 1 kg per country (sold under
azepine class have emerged on
various brand names that include So far, 18 NPS belonging to the
the market and are being sold
“Relanium” and “Valium”) have been benzodiazepine class have been
under street names such as “legal
reported in a number of regions such reported by Member States to the
benzodiazepines”, “designer benzo-
as Europe, Central Asia and Transcau- UNODC Early Warning Advisory
diazepines” or “research chemicals”.
casian countries, South and Central (EWA) and the emergence of an
This group of substances includes
America, South Asia, East and South- additional 4 NPS belonging to the
substances that were tested but
East Asia, Africa, and the Near and benzodiazepine class were observed
not approved as medicines in the
Middle East. Between 2010 and based on other sources of informa-
pharmaceutical industry or that
2015, larger quantities of diazepam tion (for more information see Box
have been manufactured by modi-
were reported to have been seized on the list of benzodiazepine NPS).
fying the core structure of existing
in India (totaling 24 kg), Myanmar In 2011, Germany, Norway and
pharmaceutical benzodiazepines.46
(totaling 7 kg), and the Russian Fed- the United Kingdom were the first
Some of the first NPS belonging to
eration (again totaling 7 kg).45
the benzodiazepine class that were
liminary data on its metabolism and pharma-
available online included substances
cokinetics.” Drug Testing and Analysis 6 (7-8):
42 Etizolam is currently in the ‘Substances under
such as diclazepam, flubromazepam 757-763.
Surveillance’ list of the World Health Organi-
zation. and pyrazolam.47 While certain NPS 48 World Health Organization (WHO) Expert
Committee on Drug Dependence. “Phen-
43 Phenazepam is currently in Schedule II of the
azepam: Pre-Review Report. Agenda item
Convention on Psychotropic Substances of 46 Moosmann, B., King, L. A., and Auwärter, 5.8.” Thirty-seventh Meeting, Geneva, 16-20
1971. V. (June 2015) “Designer benzodiazepines: a November 2015; World Health Organiza-
44 UNODC, Annual Report Questionnaire, new challenge.” World Psychiatry 14 (2): 248. tion (WHO) Expert Committee on Drug
2014-2015. 47 Moosmann, B., Bisel, P., and Auwärter, V. Dependence. “Etizolam (INN): Pre-Review
45 UNODC, Annual Report Questionnaire, (January 2014) “Characterization of the Report. Agenda item 5.7.” Thirty-seventh
2010-2015. designer benzodiazepine diclazepam and pre- Meeting, Geneva, 16-20 November 2015.
10