Download New Psychoactive Substances-High index of suspicion needed in

New Psychoactive Substances-High index of suspicion needed in Emergency services
Dr Lambert Low, Dr Christopher Cheok
Abstract:
Intro: The proliferation of New Psychoactive Substances (NPS) in many countries has resulted in social,
legal and medical ramifications. While the authorities come up with policies to battle this increasing
phenomenon, emergency physicians have to contend with problems of overdose or intoxication from a
gamut of potentially unknown drugs with their attendant consequences. Methods: Here we present a
review of recent literature on the common presenting complaints associated with NPS and guide
emergency services into developing an index of suspicion based on the clinical scenario. We also discuss
briefly on treatment options. Findings: Common presenting complaints associated with NPS stem from
central nervous system (CNS) and cardiovascular (CVS) excitation from sympathetic overdrive.
Treatment with benzodiazepines have provided some measure of relief from the symptoms but
antipsychotic use is more controversial. Conclusion: A high index of suspicion based on a clinical
syndrome comprising both CNS and CVS hyperactivity can point physicians toward expedient medical
treatment for NPS once other medical causes are ruled out.
Keywords: New Psychoactive Substances; NPS; intoxication; emergency services
Introduction:
New Psychoactive substances (NPS) commonly marketed as “bath salts” or “plant food” are chemical
compounds designed by chemists to circumvent the current legislation against drugs of abuse.1,2 They
have been touted as „legal‟ highs as many of these synthetic compounds do not fall under the scheduled
controlled substances list in many nations. This has prompted many nations to take legislative action
against these new substances.2 These drugs are synthetic derivatives from many drug classes including
phenethylamines, cannabinoids, cathinones and piperazines.3 However they frequently escape detection
from our commonly used immunoassay kits used in routine laboratories.2 The Central Narcotics Bureau
website reports that Heroin and Methamphetamine („ICE‟) are the two most commonly abused drugs in
Singapore4 but little is known about the prevalence and problems associated with NPS use in our local
context. Taking reference from drug trends in European countries which have seen an increase in the
prevalence of NPS use in the recent years3, it is prudent therefore to be aware of this phenomenon. Whilst
much is known regarding traditional drugs of abuse such as Heroin, Cannabis and ICE, the paucity of
literature concerning NPS makes it difficult for practicing clinicians in our emergency departments to
suspect, let alone diagnose conditions associated with NPS use confidently and expediently. This has
important implications in the subsequent management of these patients who may present with an
overdose and end up developing systemic multi-organ failure or other complications of this problem.
Here in this review paper, we discuss current literature on patients who had taken NPS, focusing on their
clinical presentation, investigations as well as subsequent management. We also provide updates
regarding the Central Narcotics Bureau (CNB) management of this increasing scourge.
Background:
Gamma-hydroxybutyric acid (GHB), a metabolite of GABA has its origins as early as the 1960s and
which later became notoriously known as a date-rape drug was one of the first NPS which was
synthesized5 but has since become scheduled as a controlled drug in many countries including Singapore.
Thereafter the market saw the emergence of other types of NPS such as synthetic cathinones, eg.
Mephedrone and synthetic Cannabinoids which have been marketed as Spice or K2. Perhaps, an inherent
difficulty classifying these substances as illegal just based on the class of drugs they are from stem from
the fact that certain other members in that same class may already have been used for therapeutic
properties, eg. Bupropion is a synthetic cathinone which is commonly used as an anti-depressant and
smoking cessation agent.6 Therefore it is difficult if not impossible to have a market ban on whole classes
of chemicals. This belies the fact that newer and newer NPS are hitting the market as the older ones get
outlawed and enter the controlled drugs registry.
On average, one new substance every week has been reported in Europe over the past 5 years 7 and this
can only continue to grow as more clandestine chemists seek to outmaneuver legislation. The increase in
supply of NPS is partly facilitated by the increased demand due to retailers advertising their goods online
as “plant food”, “research chemicals” or “bath salts”. It is hence difficult to be sure when we are dealing
with a clinical syndrome due to NPS due to the myriad of such chemicals present. However an index of
suspicion based on certain recurring clinical patterns can possibly lead to an expedient diagnosis and
treatment when other acute medical conditions are ruled out.
Clinical presentation:
There are currently more than 450 different NPS identified in the world8 and there is no published data on
which NPS are in the Singapore market. There are no routine clinical laboratory tests that can detect
NPS. Patients may not disclose they have used a NPS during history taking and they may not perceive
NPS to be drugs as they are marketed as supplements, legal substitutes to established illicit drugs or other
types of product such as “plant food” or “bath salts”. The authors speculates that a common presentation
of NPS abuse is a patient with altered mental status or delirium of short duration presenting at emergency
rooms, general medical in patient units and the clinics of psychiatrists and general practitioners. In the
absence of clinical tests, clinicians should have a high index of suspicion that patient presenting with
brief delirium with no other organic cause may in reality be due to the action of a NPS.
Synthetic cathinones such as Mephredrone are stimulants which resemble amphetamines in their action.
This implies that there is an increased release of monoamines in the synapses, resulting in increased
neurotransmission, autonomic stimulation and heightened sensations , even euphoria.5 The clinical
syndrome is therefore one of CVS, CNS and sympathetic overdrive as manifested by agitation,
tachycardia, raised arterial blood pressure, dilated pupils, hyperthermia, muscle clonus and sialorrhea. As
the syndrome worsens, confusion, seizures, arrhythmias and respiratory arrest may ensue. Biochemical
abnormalities reported include renal impairment with elevated potassium and creatinine as well as
elevated liver enzymes and creatine kinase. QT prolongation on ECG has also been demonstrated.5,9,10
The group of phenethylamine compounds, also known as the “2C” compounds also interact with alphaadrenergic receptors to produce stimulant effects but also show hallucinogenic properties due to them
being potent serotonin 5-HT2A receptor agonists. These drugs can thus also produce sympathomimetic
effects such as agitation, raised blood pressure, tachycardia, dilated pupils, clonus and seizures as seen
with the synthetic cathinones. Hallucinations due to 5HT2A agonism however are more prominent in this
group of compounds. Biochemical abnormalities reported include elevated creatine kinase, deranged liver
enzymes, renal impairment with consequent increased creatinine and serum potassium.11 Hence one can
see the similarities in clinical presentation and biochemical abnormalities between the cathinones and
phenethylamine compounds which are both stimulants.
Besides cathinones and phenethylamine compounds which have stimulant properties, the piperazine
family of drugs such as benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) which
have been marketed as safe alternatives to the ICE and Ecstasy also produce stimulant effects. 2,12 Caution
though must be exercised as not all piperazine derivatives exhibit such stimulant properties. Recently
MT-45, an NPS newly appearing on the market from this family has demonstrated opioid-like symptoms
in patients using it instead, such as respiratory depression and decreased levels of consciousness. Some of
these patients have responded well with the competitive opioid receptor antagonist Naloxone.1
Patients who have taken synthetic cannabinoids such as Spice/K2 have also shown have also been known
to demonstrate symptoms of sympathetic overdrive such as elevated heart rate, agitation, excessive
sweating, high blood pressure and muscle twitches. Confusion, hallucinations, paranoia and cognitive
impairment can also ensue.13
As can be seen from the various classes of NPS described in literature, most produce stimulant and
sympathomimetic effects which results in the symptoms mentioned, the few exceptions being GHB and
MT-45 mentioned earlier which behave more like depressants. This is not surprising considering that
most of these are “party” drugs used to heighten sensory perceptions and produce a “high”. Of course one
can argue that the most common party drug is alcohol which is a CNS depressant, however alcohol
commonly results in an acute phase of disinhibition, including sexual disinhibition prior to its depressant
effects setting in.14
Management of NPS overdose and toxicity:
Although preferable methods for diagnosing the presence of NPS in urine or serum using Liquid
Chromatography-Mass Spectroscopy (LC-MS)2 is not feasible in the emergency room of our hospitals
due to the time and costs required, having an index of suspicion based on the pattern of common
presenting complaints above would help one decide on appropriate management.
While much of the treatment involve supportive measures like hydration and monitoring with no specific
antidote present for most of the NPS, thus far the evidence suggests that benzodiazepines may be helpful
in ameliorating the sympathomimetic overdrive effects associated with ingestion of NPS.10,14
Benzodiazepines can be given intravenously to counteract the sympathomimetic effects on the heart,
reducing the chance of arrhythmia and a heart attack. They can also prevent seizures. The use of
antipsychotics is controversial and some have suggested that the drug interactions with NPS may render
them unsafe.9,15 This is compounded by the QTC prolongation caused by many of the NPS.9 Whilst the
full emergency management of acute NPS toxicity and overdose really depends on the clinical situation
and is beyond the scope of this paper, suffice to say that thus far benzodiazepines are a safe treatment
option. Specific antidotes for eg. Naloxone as in the case of MT-45 discussed above1 are rare but can be
considered if the index of suspicion for opioid family NPS is suspected as when the symptoms and signs
are not typical of an excitatory state.
Many times, NPS come in various combinations of chemicals and the labelled preparation may not
coincide with the actual constituents. Hence very often, the history from the patient may not point us
towards the offending agent even if we find the sample on them. It is useful hence to know that any
suspected presentation of NPS ingestion to the Emergency room can be potentially life threatening due to
the combinations of drugs available and the varied potencies. Hence as such, immediate and supportive
management must be instituted.
Tackling NPS supply and use in Singapore
The challenges posed by the rampant abuse and trafficking of NPS in European markets became
prominent around 2009. Given the increasing popularity of these substances overseas and their promotion
as legal substitutes to established illicit drugs, Singapore decided that pre-emptive action was necessary
to prevent these substances from gaining a foothold in the local population. In 2013, new provisions
aimed at addressing local NPS supply and abuse were introduced in the Misuse of Drugs Act (MDA). A
new Fifth Schedule which provided for quick temporary listing and use of generic listing methods to
control at once a large number of synthetic cannabinoids and synthetic cathinones were adopted.
Under the generic listing method, the legislation describes particular variations of a core molecular
structure (particularly substitution groups in specified positions in the molecule) which would lead to a
substance being controlled.
Prior to the Fifth Schedule, substances were only listed to the MDA after research to understand the
harmful effects and industry consultation to identify possible legitimate uses were completed. However,
such processes take time, and in some cases, the NPS may be in circulation, causing harm, long before
these processes are completed. The Fifth Schedule therefore allows authorities to list NPS quickly, for a
period of one year. Industrial consultation is undertaken during the one year period, to determine if there
are any possible legitimate uses for the NPS. The Central Narcotics Bureau is empowered to seize the
substances listed in the Fifth Schedule so that circulation of such substances can be restricted. However,
the trafficking, manufacture, import, export, possession or consumption of any substance which is
temporarily listed in the Fifth Schedule will not constitute an offence under the MDA, until that
substance is removed from the Fifth Schedule and is subsequently listed as a controlled drug in the First
Schedule whereupon all these offences will apply. The substances listed in the Fifth Schedule are updated
to ensure that the supply of such harmful substances is not allowed to proliferate here.
Conclusion: Complications arising from NPS ingestion present an interesting challenge to emergency
physicians due to the sheer numbers of such available products. However knowing the common
presenting complaints can help us identify this possibility rapidly and institute appropriate and supportive
treatment rapidly. A high index of suspicion in anyone presenting with cardiovascular and central
nervous system excitation once other medical causes ruled out can be timely in the treatment of such
patients.
Acknowledgement: We would like to thank Ms. Low Wee Choo and her colleagues from the Central
Narcotics Bureau for their contributions in updating the legislative measures that our authorities have
undertaken to tackle this growing drug problem.
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