Guide to the management of gabapentinoid misuse
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THERAPY FOCUS ■
Guide to the management of
gabapentinoid misuse
GRAHAM PARSONS
In light of the
SPL
government’s proposals
to reclassify pregabalin
and gabapentin as Class
C controlled drugs due
to the risk of misuse,
this article examines the
extent of the problem of
gabapentinoid misuse
and its effects, and
provides practical advice
to prescribers on reducing
these harms.
P regabalin was launched in the UK
in 2004 while gabapentin was first
authorised in the UK in 1997. Both drugs
were originally licensed for seizure dis
orders but now have multiple licensed
indications. In England during 2016, over current (licensed and unlicensed) indica
12 million prescription items were dis tions and the pharmacology of the two
pensed for gabapentinoids as a group.1 drugs, aspects of their misuse potential
The Advisory Council on the Misuse of and effects of this misuse on the indi
Drugs (ACMD) reported that pregabalin vidual. Finally, it provides advice for
prescribing in the UK increased by 350% prescribers on managing the misuse of
in the five years to 2012 while gabapen gabapentinoids and supporting patients
tin prescribing increased by 150% during who are discontinuing a gabapentinoid.
the same period.2
There has been growing concern Licensed uses
about the misuse potential of the gaba The gabapentinoids have a wide range
pentinoids as a group and in particular of licensed uses. Pregabalin and gaba
pregabalin, as reported in the 2016 pentin are both licensed for neuropathic
ACMD review of this class of drugs.2 This pain and epilepsy.3,4 Pregabalin also has
concern led to the government launch a licence for the treatment of generalised
ing a consultation on the reclassification anxiety disorder (GAD).3 Pregabalin is
of pregabalin and gabapentin as Class recommended by NICE as a second-line
C controlled drugs under the Misuse of pharmacotherapy for GAD if a patient
Drugs Act, which ended on 22 January cannot tolerate SSRIs or SNRIs.5 NICE
2018.1 recommends offering a choice of amitrip
This article discusses both drugs but tyline, duloxetine, gabapentin or pregab
with a particular emphasis on pregaba alin as initial treatment for neuropathic
lin, which presents with a greater misuse pain (except trigeminal neuralgia).6 Off-
potential than gabapentin. It explores the label uses for gabapentinoids include
prescriber.co.uk Prescriber April 2018 ❚ 25■ THERAPY FOCUS l Gabapentinoid misuse
the treatment of migraine, alcohol use
•P resenting intoxicated, impaired or dishevelled (especially if this is a change to
disorders, mania and bipolar disorder.7
the normal presentation)
NICE recommends early and regu
• Loss of interest in alternative pleasures or activities (the medication becomes
lar assessments of patients prescribed
the focus)
pharmacotherapies for neuropathic
• Early requests for prescriptions
pain, including the gabapentinoids. The
• ‘Lost’ prescriptions
assessment should include dosage titra
• Increasing use of current prescription due to unsanctioned dose increases
tion, tolerability and adverse effects. 6
• Concurrent misuse of related illicit drugs
While markers for potential misuse (see
• Acquisition of medication from other sources, eg out-of-hours services
Table 1) may emerge later in treatment,
• Subjective and objective withdrawals when the patient does not have the medication
prescribers should always be alert to
• No interest in the diagnosis (the medication becomes the focus)
these even at the start of a treatment
• Failure to keep appointments for further diagnostic tests or refusal to see
episode so that misuse can be avoided.
another practitioner for consultation
• Worsening mental health presentation
Pharmacology • Aggressive complaining
Both gabapentin and pregabalin are
• Reporting unintended psychotropic effects from prescription medication
structurally similar to the inhibitory neu
• Prescription forgery
rotransmitter gamma-aminobutyric acid
(GABA) and rapidly cross the blood-brain
Table 1. Markers for potential misuse of gabapentinoids
barrier. The gabapentinoids bind to the
alpha-2-delta subunit of the voltage-de bility is reported as 60% for a 300mg needed to provide a similar psychoactive
pendent calcium channels in the CNS capsule.4 Gabapentin is also eliminated effect. Mixed misuse with antipsychotic
resulting in a decrease in the excitatory unchanged through renal excretion with drugs can also be a problem – as demon
neurotransmitters glutamate, noradrena an elimination half-life of between five to strated in a case report describing the
line, substance P and calcitonin gene-re seven hours.4 misuse of gabapentin and quetiapine.9
lated peptide. Both drugs produce Pregabalin and gabapentin have also
pharmacological effects that are sim Why are gabapentinoids been used to enhance the effects of
ilar in nature to those produced by the misused? alcohol and other prescribed and non-pre
inhibitory neurotransmitter GABA, ie they Gabapentinoids have been reported to scribed drugs including methadone.7,8,10
exhibit GABA-mimetic properties. produce alcohol/gamma hydroxybutyrate Animal models also support the hypoth
Pregabalin is rapidly absorbed on (GHB)/benzodiazepine-type effects esis that the effects of morphine and
an empty stomach with peak plasma mixed with euphoria. Rates of euphoria pregabalin are potentiated when taken
concentrations occurring within one have been reported at between 1 and together.
hour. It has a high bioavailability (≥90%) 12% but this has been for therapeutic The onset of action of the gabapenti
and a mean elimination half-life of 6.3 doses.8 Other reported actions include noids ranges from between 10 minutes,
hours and undergoes almost no metab dissociative effects, improved sociability, ie quick acting, and two hours depend
olism with the parent drug being largely relaxation and sense of calm, and psy ing on the route of administration and
excreted unchanged in the urine. The chedelic effects. both dependent and recreational use
linear pharmacokinetics of pregabalin Schifano et al. reported that signifi has been reported. Rapid development
(compared with the non-linear phar cant psychotropic effects are associated and extinction of tolerance to the effects
macokinetics of gabapentin) allows with higher doses and “idiosyncratic (ie of gabapentinoids has also been docu
straightforward dosing regimens and a IV, rectal, intranasal) drug intake modali mented.11
predictable response. Pregabalin also ties” but the most common route of mis The effects associated with pregab
has a higher binding efficiency than gaba use remains oral.8 alin at increasing doses, as reported by
pentin and higher potency (2.5 times Polydrug misuse remains a signifi users, is summarised in Box 1.
greater than gabapentin). The higher cant concern with the cohort of service
potency, quicker absorption and greater users that may misuse gabapentinoids Evidence for and prevalence of
availability of pregabalin vs gabapentin and has been implicated in the recent gabapentinoid misuse
makes pregabalin more attractive as a rise in drug-related deaths for the gaba There is now a rich source of anecdotal
drug of misuse pentinoids. A recent review in the jour reports that support significant misuse of
The absorption of gabapentin follow nal Addiction suggests that pregabalin gabapentinoids both in the UK and inter
ing oral administration is less rapid than is used to enhance the effects of heroin nationally, such as the user reports on
pregabalin. Peak plasma concentrations but for some people it may also be used the Erowid website.12 Following the intro
are observed within two to three hours to help support the reduction in use of duction of pregabalin to the UK in 2004,
with oral bioavailability decreasing with heroin.7 This synergistic effect can also the Medicines and Healthcare products
increasing dose. Absolute bioavaila be used to reduce the amount of heroin Regulatory Agency (MHRA) received its
26 ❚ Prescriber April 2018 prescriber.co.ukGabapentinoid misuse l THERAPY FOCUS ■
which increased to 15–22% within “opi
According to pregabalin (mis)users, different doses are associated with a vast
oid abuse samples”.18
range of effects:
Drug-related deaths and
600mg: stumbling, disorientation, increased physical and psychological
gabapentinoid misuse
awareness, difficulty driving, slurred and broken speech, hearing and visual
The CNS depressant effects of the gaba
alterations/hallucinations, double and blurred vision, uninhibited behaviours,
pentinoids and opioids (drowsiness,
talkativeness, increased body energy, increased sexual performance
respiratory depression and respiratory
failure) are a significant risk and have
900mg: strong feelings of drunkenness, difficulty walking, alteration of colour
been implicated in drug-related deaths.
perception, little euphoria
Deaths where gabapentinoids were men
tioned on death certificates in England
1200mg: drowsiness, euphoria, entactogenic (empathetic) feelings, ie similar to
and Wales have increased from less than
Ecstasy
one a year before 2009 to 137 deaths in
2015.7 In 79% of these deaths, opioids
>1500mg (to 5g): uncontrollable drowsiness, frequent hallucinations, great
were also mentioned. This increase in
euphoria, frequent dissociative events (described as dextromethorphan/DXM-like
drug-related deaths was also shown to
dissociative effects), behavioural inhibition, anxiety, and necessity to move
correlate highly with prescribing data, ie
increased prescribing of gabapentinoids
Box 1. Online user accounts of pregabalin effects, according to dose8
(see Figure 1).
first report of withdrawal symptoms in of patients with a history of drug or sub In summary, we have the “perfect
2005. Following this, the first report of stance abuse.3,4 storm” of the summation of CNS effects
drug use disorder was reported in 2006 International reports from Finland, through polydrug misuse, an increase in
and drug dependence in 2009.13 Germany and the USA suggest a global prescription numbers, and drug effects
Evidence from UK secure settings problem with gabapentinoid misuse. In that cannot be reversed with an antidote
suggests significant use of gabapenti Finland, a study of toxicology reports of (although naloxone will support the rever
noids. Prescribing of gabapentin and drug-related deaths between 2010 and sal of the opioid element of a drug over
pregabalin occurs in 2.8% of the prison 2011 suggest a “substantial increase” dose), which all contribute to the risk of
population, which is twice the rate found in drug-related deaths involving pregab drug-related death.
in the general population. Category A alin and opioids, with opioids present in
prisons having the highest rates and 47% 90% of deaths involving gabapentinoids. How can patients be supported
of prisoners in this cohort are also pre The study also reported a seven times to discontinue gabapentinoids
scribed opioid substitution treatments greater incidence of pregabalin misuse in safely?
(OST).14 The ACMD has also noted that drug-related deaths compared with gaba Although there is insufficient evidence to
the prescribing of the gabapentinoids pentin.7 In Germany, pregabalin misuse support practitioners in helping patients
in secure environments often does not has been reported to the German med discontinue gabapentinoids, there are
meet “best practice guidelines”.2 The ical regulatory body with an increasing some practical guidelines that provide
Pain Management Formulary for Prisons frequency since 2008, while the USA a framework for the development of an
classifies the gabapentinoids as drugs placed pregabalin under the Controlled appropriate recovery plan. Harm reduc
for “limited use” and aims to challenge Substances Act in 2005, citing that mis tion also remains an important compo
current practice and introduce a frame use may lead to “limited physical depend nent of the advice practitioners should
work around the management of pain in ence or psychological dependence”.2 provide to patients.
secure settings.15 The prevalence of gabapentinoid Discontinuation symptoms of gaba
The DrugScope 2014 street survey misuse has been assessed in two sys pentinoids are varied and will be depend
highlighted the problem of misuse quot tematic reviews. An international sys ent on the dose consumed and the route
ing “significant use… chiefly among tematic review of 59 studies indicates of administration. Table 2 summarises
Britain’s opiate-using and prison popu a gabapentinoid abuse prevalence of these symptoms for both gabapentin
lation”.16 The effects of gabapentinoids 1.6% in the general population. This and pregabalin for patients reducing
are described within the report as “hor prevalence increased to 3–68% among from therapeutic doses, as outlined in
rendous and life threatening” with one opioid abusers. Risk factors for misuse the summaries of product characteris
drug worker reporting the prevalence of were identified as a history of substance tics. The manufacturer of pregabalin has
use in one homeless hostel at 70% of abuse (particularly opioids) and psychi noted that the severity of symptoms and
residents.16 The manufacturers of both atric co-morbidities.17 Another system their incidence “may be dose-related”3
drugs have also warned prescribers of atic review looking at gabapentin only and prescribers should take this into
the risk of abuse and dependence, high reported a 1.1% prevalence of gabap account when managing a pharmacologi
lighting the need for a careful evaluation entin misuse in the general population, cal withdrawal episode.
prescriber.co.uk Prescriber April 2018 ❚ 27■ THERAPY FOCUS l Gabapentinoid misuse
• Tight chest
120 160 • Sweating with alternate chills
Gabapentinoid prescriptions (100,000s) • Inability to think or concentrate properly
Deaths mentioning pregabalin 140 • “No energy”.
100
Pregabalin and gabapentin
prescriptions per 100,000
or gabapentin
120
Drug-related deaths
Deaths mentioning gabapentinoids Both service users describe their with
80
and opioids 100 drawals from therapeutic doses of pre
gabalin (450mg and 600mg respectively)
60 80 as “hellish”.12
60 The summaries of product character
40 istics suggest that both pregabalin and
40 gabapentin should be discontinued over
20 at least one week. However, this is pri
20 marily to minimise the risk of increased
0 0 seizure frequency where they are being
2004 2005 2006 20072008 2009 2010 2011 2012 2013 2014 2015 used for patients with a seizure disorder.
Year Public Health England (PHE) recommends
a more gradual reduction to reduce with
drawal symptoms. 14 Considering the
5
link between dose and symptoms sug
gested by the manufacturers, a collabo
4 rative and more conservative approach
Log number of deaths
seems a pragmatic response. Patients
on supratherapeutic doses of gaba
3
pentinoids should have a reduction plan
discussed that allows for an illicit reduc
2 tion in the community. If the prescriber
decides to prescribe above the maximum
dose in the summary of product charac
1 teristics, this should be for a short period
of time with an aim to reduce the patient
0 to below the licensed maximum dose
in a short period of time and within the
0 20 40 60 80 100 guidance provided by PHE. The maximum
Gabapentinoid prescriptions (per 100,000) reduction rates suggested for the gaba
pentinoids within the PHE guidelines are:
• 50mg to 100mg a week for pregabalin
Figure 1. Gabapentinoid drug-related deaths and correlation with increase in gabapentinoid
and
prescribing in England and Wales7
• 300mg every four days for gabapentin.
A more varied presentation of with with akathesia, catatonia and seizures.19
drawal symptoms has been reported in Where gabapentin was reintroduced the There is insufficient evidence to suggest
the medical literature for both gabapentin withdrawal symptoms resolved. what adjuvant medication could be used
and pregabalin. A review of gabapentin A case study from Grosshans et al. to support patients, so no recommenda
misuse case studies by Mersfelder et presents the withdrawal symptomology tions can made. Nevertheless, a reduc
al. reported withdrawal symptoms begin associated with pregabalin at supra tion in the pharmacological agent used
ning between 12 hours and seven days therapeutic doses. The authors report to manage the primary indication should
after cessation of use with the majority the case of a 47-year-old male consum necessitate a review. For example, the
of cases occurring between 24 and 48 ing the equivalent of 7500mg pregabalin treatment of GAD may necessitate a
hours. Agitation was reported in more daily. On reduction, the patient experi transition to an SSRI. This should also
than half of the cases with confusion and enced sweating, unrest, arterial hyperten include a review of the psychosocial inter
disorientation reported in 45% of cases. sion, tremor and craving for pregabalin.20 ventions both to support the patient in
Other common symptoms included Two reports on withdrawals from pregaba managing the withdrawal from the gaba
diaphoresis (36%), non-specified GI lin from the user website Erowid describe pentinoid and to support the patient in
symptoms (23%), tremor, tachycardia, the following: managing the presentation of the primary
hypertension (each 18%) and insomnia • Insomnia, anxiety and depression indication. This may include, for example,
(14%). Individual cases also presented • Suicidal ideation engagement with cognitive behavioural
28 ❚ Prescriber April 2018 prescriber.co.ukGabapentinoid misuse l THERAPY FOCUS ■
Pregabalin symptoms Gabapentin symptoms advice on the management of this ser
vice user group.
Insomnia Insomnia • Improve your knowledge as a prescriber
Headache Pains to ensure you can provide appropriate
Nausea and dizziness Nausea advice and treatment when needed. This
Anxiety, nervousness, depression Anxiety article and the associated references
Diarrhoea Sweating should help to support your learning.
Flu syndrome, pain and hyperhidrosis Convulsions
Convulsions Summary
Pregabalin and gabapentin remain impor
Table 2. Discontinuation symptoms for pregabalin and gabapentin withdrawal, as outlined tant evidence-based treatments for a
in the summaries of product characteristics number of conditions. However, emerg
therapy services for supporting patients • If a gabapentinoid is used for neuro ing evidence suggests that prescribers
in the management of their GAD. pathic pain, review at eight weeks follow should adopt a cautious approach to
ing initiation and discontinue (gradually) the assessment and management of
Practical advice for prescribers if ineffective. patients who are prescribed gabapen
To prevent the emergence of problems • Misuse of any psychoactive medication tinoids. Both misuse and dependence
and to support patients in reducing harm is often linked to either a mental health have been reported with gabapentinoids,
associated with the misuse of gaba co-morbidity and/or inadequate man and they have been widely implicated in a
pentinoids, some practical steps can be agement of the primary physical health number of drug-related deaths.
employed. These practical advice tips presentation. Ensure this is reviewed and Prescribers should make a balanced
have been brought together from a vari managed appropriately especially if the judgement on prescribing gabapentinoids
ety of sources. An excellent document gabapentinoid is removed from the phar based on a robust assessment process,
supported by the Northern Ireland Public macotherapies available. especially when prescribing to patients
Health Agency – Pregabalin: Guidance • Harm reduction advice for illicit users who may be at risk of misusing the medi
for People Working with Pregabalin should include advice to take the medica cations. Patients should be provided with
Users – is available, 21 which provides tion orally and avoid injecting, and to fol information about the benefits and risks
more comprehensive advice, especially low the adage of “start low and go slow”. of taking gabapentinoids and should be
around harm reduction, for patients mis The dangers of polydrug use, including supported if they want to undertake a
using pregabalin. the increased risk of drug-related death, detoxification programme. Harm reduc
• Ensure a robust assessment process is should also be discussed. tion interventions remain an important
undertaken and careful consideration is • Ensure naloxone (Prenoxad injection) approach to this complex phenomenon.
given before prescribing gabapentinoids is issued to service users who also use
to patients with a history of substance opioids (and provide advice on its use References
misuse or those who have recently been as well as basic harm reduction advice). 1. Home Office. Pregabalin and gabapentin:
released from prison. Use an alternative Many drug and alcohol specialist provid proposal to schedule under the Misuse of
medication when clinically appropriate. ers now supply this routinely to service Drugs Regulations 2001. Closed consultation.
• When gabapentinoids are prescribed, users who misuse opioids – contact your November 2017. Available from: https://www.
gov.uk/government/consultations/pregabalin-
warn patients about the benefits and local provider for more details.
and-gabapentin-proposal-to-schedule-un
risks (including dependence) of the med • When supporting service users with a
der-the-misuse-of-drugs-regulations-2001.
ications. planned reduction in gabapentinoid use, 2. Advisory Council on the Misuse of Drugs
• Review treatment regularly to ensure use the schedules recommended by PHE (ACMD). Pregabalin and gabapentin advice.
efficacious prescribing and monitor for to plan a collaborative process. Januar y 2016. Available from: https://
potential misuse markers (see Table 1). • Be aware of services such as the Battle www.gov.uk/government/uploads/system/
• Ensure prescribed doses do not exceed Against Tranquilisers (BAT), who provide uploads/attachment_data/file/491854/
the therapeutic dose ranges (doses will support for service users with pregaba ACMD_Advice_-_Pregabalin_and_gabapentin.
also need to be adjusted in patients with lin use disorders in the Bristol area,22 as pdf [accessed 3 February 2018].
reduced renal function). well as nationally through their website 3. eMC. Lyrica Capsules 25mg, 50mg, 75mg,
• If there is a clinical need to prescribe and national support helpline. UK SMART 100mg, 150mg, 200mg, 225mg and 300mg.
Available from: https://www.medicines.
a gabapentinoid to a service user with a Recovery®also provides support for indi
org.uk/emc/medicine/14651 [accessed 3
history of drug or alcohol misuse, ensure viduals who want to seek abstinence
February 2018].
that it is prescribed as regular short from drug misuse through a network of 4. eMC. Neurontin 100mg Hard Capsules.
courses, eg every seven days, rather self-help and mutual aid meetings. 23 If Available from: https://www.medicines.org.
than the standard 28-day prescription to you need support, please speak to your uk/emc/product/158 [accessed 3 February
improve monitoring for overuse and to local specialist drug and alcohol provider 2018].
minimise the risk of binge use. who can also give practical support and 5. National Institute for Health and Care
prescriber.co.uk Prescriber April 2018 ❚ 29■ THERAPY FOCUS l Gabapentinoid misuse
Excellence. Generalised anxiety disor- Dependence Update 2017 Independent Januar y 2015. Available from: http://
der and panic disorder in adults: manage- Exper t Working Group. Drug misuse and w w w. s f a d . o r g . u k / u s e r f i l e s / f i l e s /
ment. CG113. Januar y 2011. Available dependence: UK guidelines on clinical man- DownAStonyRoadDrugTrendsSurvey2014.pdf
from: https://www.nice.org.uk/guidance/ agement. London: Department of Health, [accessed 3 February 2018].
cg113/resources/generalised-anxiety- July 2017. Available from: https://www.gov. 17. Evoy KE, et al. Abuse and misuse of
disorder-and-panic-disorder-in-adults-manage uk/government/uploads/system/uploads/ pregabalin and gabapentin. Drugs 2017;
ment-pdf-35109387756997 [accessed 13 attachment_data/file/673978/clinical_ 77(4):403–26.
February 2018]. guidelines_2017.pdf 18. Smith RV, et al. Gabapentin misuse, abuse
6. National Institute for Health and Care 12. Erowid. Documenting the complex rela and diversion: a systematic review. Addiction
Excellence. Neuropathic pain in adults: phar- tionship between humans and psychoac 2016;111(7):1160–74.
macological management in non-specialist tives. Available at: https://www.erowid.org/ 19. Mersfelder TL, Nichols WH. Gabapentin:
settings. CG173. November 2013. Available [accessed 13 February 2018]. abuse, dependence and withdrawal. Annals of
from: https://www.nice.org.uk/guidance/ 13. Medicines and Healthcare products Pharmacotherapy 2016;50(3):229–33.
cg173/resources/neuropathic-pain-in-adults- Regulatory agency (MHRA). Interactive drug 20. Grosshans M, et al. Pregabalin abuse,
pharmacological-management-in- analysis profile. Pregabalin. Available from: dependence, and withdrawal: a case report.
nonspecialist-settings-pdf-35109750554053 https://info.mhra.gov.uk/drug-analysis- Am J Psychiatry 2010;167(7):869.
[accessed 13 February 2018]. profiles/dap.html?drug=./UK_EXTERNAL/ 21. Extern. Pregabalin: Guidance for people
7. Lyndon A, et al. Risk to heroin users of NONCOMBINED/UK_NON_000416710145. working with pregabalin users. Available from:
polydrug use of pregabalin or gabapentin. zip&agency=MHRA [accessed 3 February http://www.extern.org/sites/default/files/
Addiction 2017;112(9):1580–9. 2018]. news_docs/pregabalin_guidance_booklet_
8. Schifano F, et al. Is there a recreational 14. Public Health England, NHS England. a4_final_web.pdf
potential for pregabalin? Analysis of anecdo Advice for prescribers on the risk of the mis 22. Battle Against Tranquillisers (BAT).
tal online reports in comparison with related use of pregabalin and gabapentin. December Available at: http://bataid.org/
gabapentin and clonazepam data. 2011. 2014. Available from: https://www.gov.uk/ 23. UK SMART Recovery®. Self-management
Available from: https://uhra.herts.ac.uk/ government/uploads/system/uploads/ and recovery training. Available at: https://
bitstream/handle/2299/9328/905139. attachment_data/file/385791/PHE-NHS_ www.smartrecovery.org.uk/
pdf?sequence=1 [accessed 13 Februar y England_pregabalin_and_gabapentin_advice_
2018]. Dec_2014.pdf [accessed 3 February 2018]. Declaration of interests
9. Reeves RR, Burke RS. Abuse of combi 15. NHS England. Pain management formu- Graham Parsons has received funding
nations of gabapentin and quetiapine. Prim lary for prisons: The formulary for acute, per- from Martindale Pharma to provide edu
Care Companion CNS Disord 2014;16(5), doi: sistent and neuropathic pain, 2nd edn. October
cational talks at conferences and from
10.4088/PCC.14I01660. 2017. Available from: https://www.england.
Indivior to attend a conference.
10. Baird CRW, et al. Gabapentinoid abuse in nhs.uk/wp-content/uploads/2017/11/
order to potentiate the effect of methadone: a prison-pain-management-for mular y.pdf
survey among substance misusers. Eur Addict [accessed 3 February 2018]. Graham Parsons is chielf pharmacist and
Res 2014;20:115–8. 16. DrugScope. Down a stony road: The pharmacist independent prescriber at
11. Clinical Guidelines on Drug Misuse and 2014 Drug Scope Street Drug Sur vey. Turning Point, London
30 ❚ Prescriber April 2018 prescriber.co.ukYou can also read
