Chiappini, Stephania

Schifano, Fabrizio

CNS Neuroscience & Therapeutics

English

Cairns R

Häkkinen M

Crossref

Pregabalin: A range of misuse‐related unanswered questions

Letter: Although initially marketed as having a low abuse potential, further recent, large‐scale, papers1 have once again convincingly emphasized the pregabalin potential of misuse. However, after a decade of intensive pregabalin‐focused studies, still a few issues remain open. ......

National Documentation Centre on Drug Use

Pregabalin: a range of misuse‐related unanswered questions.

University of Hertfordshire Research Archive

CNS Neurosci Ther. 2019;1–2.	 	 	 | 	1wileyonlinelibrary.com/journal/cns Received:	11	January	2019  |  Revised:	11	February	2019  |  Accepted:	13	February	2019DOI:	10.1111/cns.13115L E T T E R  T O  T H E  E D I T O RPregabalin: A range of misuse‐related unanswered questionsAlthough	initially	marketed	as	having	a	low	abuse	potential,	further	recent,	 large‐scale,	 papers1	 have	 once	 again	 convincingly	 empha‐sized	the	pregabalin	potential	of	misuse.	However,	after	a	decade	of	intensive	pregabalin‐focused	studies,	still	a	few	issues	remain	open.Indeed,	the	first	to	explore	is	why	a	potential	for	misuse	for	pre‐gabalin	is	there.	Is	it	related	to	a	direct/indirect	dopaminergic	activity	similar	to	remaining	drugs	of	misuse?	Why	is	pregabalin	being	typically	misused	in	combination	with	opiates/opioids?	Pregabalin	is	a	known	inhibitor	of	α2δ‐subunit‐containing	voltage‐dependent	calcium	chan‐nels.2	The	entry	of	calcium	 ions	 into	neurons	allows	 the	process	of	vesicle	fusion	with	the	cell	membrane,	which	facilitates	proper	release	of	neurotransmitters.	Ultimately,	the	potent	binding	of	pregabalin	at	the	calcium	channel	will	 reduce	the	release	of	excitatory	molecules	(eg,	 glutamate,	 noradrenaline,	 and	 substance	 P,	 but	 not	 dopamine),	acting	 against	 aberrant	 neuronal	 stimulation.2	 Several	 addictive	drugs	have	 in	common	that	 they	 increase	 the	extracellular	dopami‐nergic	activity	in	the	mesolimbic	reward	system.3	In	rats,	conditioned	place	preference	was,	however,	 induced	only	with	high	 intraperito‐neal	(but	not	oral)	pregabalin	doses,	restricting	the	ability	to	develop	a	substantial	addictive	power.4	Accordingly,	patients	reported	pleas‐ant	stimulation	and	euphoria	when	using	supratherapeutic/mega	(eg	1500‐12	000	mg)	pregabalin	dosages.5,6	Hence,	one	could	wonder	if	there	may	be	a	different/unclear	range	of	neurotransmitter	involve‐ment,	and	receptors’	activation	intensity,	in	high/very	high	pregabalin	dosage	ingestion.	Overall,	similar	to	what	was	observed	with	a	range	of	 further	medications	 (eg,	 venlafaxine,	 bupropion,	 quetiapine,	 and	loperamide),6	it	has	been	suggested	that	gabapentinoids	may	induce	a	“liking”	(euphoric	high)	subjective	feeling,	due	to	their	gamma‐am‐inobutyric	 acid	 (GABA)‐mimetic	 action,	 but	 more	 limited	 levels	 of	“wanting”/behavioral	dependence.7	Cairns	et	al1	have	identified	that	pregabalin	was	typically	ingested	in	combination	with	opiates/opioids.	Indeed,	opioids	may	well	be	prescribed	to	potentiate	gabapentinoid	analgesic	 effects	 for	 treating	 specific	 medical	 conditions/intracta‐ble	pain.5	However,	pregabalin	may	clinically	counteract	the	opioids’	withdrawal	effects	while	presenting	as	well	with	potentiating	effects	when	given	to	mice	with	existing	opioid	levels.8Second,	it	has	been1	suggested	that	the	misuse	of	pregabalin	may	typically	be	associated	with	a	history	of	polydrug	misuse.	However,	what	is	the	potential	for	misuse	among	those	with	different	drug	use	experiences	and	who	may	not	increase	dosages	overtime?	According	to	Bonnet	and	Scherbaum7	with	 respect	 to	 remaining	 recreational	drugs	of	misuse,	there	is	less	evidence	for	gabapentinoids	being	mis‐used	 in	a	 long‐term	manner.	However,	 there	are	no	 formal	data	 in	the	 literature	about	clients	who	have	voluntarily	sought	treatment	for	their	pregabalin	addiction	or	pregabalin	relapses	after	detoxifi‐cation.7	Although	observations	of	behavioral	dependence	were	de‐scribed	in	patients	who	had	no	prior	substance	abuse	history,	these	cases	appeared	to	be	quite	rare.7	Kapil	et	al9 used an online survey to	assess	the	self‐reported	lifetime	prevalence	of	misuse	of	GABA‐analogues	 in	 the	 younger	 and	mid‐life	UK	 general	 population	 and	found	that	gabapentin	and	pregabalin	were,	respectively,	being	mis‐used	by	1.1%	and	0.5%	of	 the	survey's	 respondents.	Further	valid	prevalence	data	of	gabapentinoid	abuse	from	large‐scale	structured	interviews	have	recently	been	made.	Snellgrove	et	al10	carried	out	a	cross‐sectional	 study	with	 some	253	addicts	on	a	detoxification	ward	in	southern	Germany.	They	found	that	some	56%	had	used	pre‐gabalin	at	least	once	and	that	DSM‐IV	dependence	criteria	were	met	by	11%	of	pregabalin	users.	Further	systematic	prevalence	data	from	a	cohort	of	400	randomly	selected	elderly	hospitalized	population	were	provided	by	Cossmann	et	al11	A	fifth	of	the	cohort	was	found	to	be	mildly	dependent	on	nonopioid	analgesics,	but	one	case	with	a	previous	dependence	on	gabapentinoids	was	identifiedThird,	 in	many	studies1,5	 it	was	unclear	 if	pregabalin	was	most	typically	prescribed	 to	 those	affected	by	anxiety	 conditions	 to	ei‐ther	 “boost”	 and/or	 to	 replace	 existing	 benzodiazepine	 prescrip‐tions.	Is	the	pregabalin	state	of	mind	different	from	that	associated	with	benzodiazepines’	intake?	Even	though	pregabalin	is	structurally	related	to	GABA,	and	although	there	are	not	any	known	direct	ac‐tions	on	GABA	or	its	receptors,	therapeutic	doses	of	pregabalin	are	dose‐dependently	 associated	 with	 increase	 in	 extracellular	 GABA	levels.7	Most	 likely,	 this	 drives	 the	 relaxation	 and	 euphoria	which	are	reported	at	 the	commencement	of	prescribed	pregabalin	use.7 However,	 different	 from	 clonazepam,	 high‐dosage	 pregabalin	 has	been	anecdotally	described	as	an	“ideal	psychotropic	drug”	for	rec‐reational	purposes	to	achieve	specific	mindsets,	including	relaxation	and	disinhibition,	for	example,	alcohol/GHB/benzodiazepine‐like	ef‐fects	mixed	with	euphoria;	to	achieve	entactogenic	feelings/dissoci‐ation;	and	to	cope	with	opiate/opioid	withdrawal.10,12Consistent	with	 these	 concerns,	 the	 rate	 of	 pregabalin‐related	ambulance	attendances	has	recently	increased13	and	growing	num‐bers	of	deaths	have	been	associated	with	pregabalin	misuse.	These	misusing	levels	mostly	occur	together	with	other	sedatives,	such	as	benzodiazepines,	alcohol,	and	opioids.13,14	 In	all	 these	polydrug	 in‐toxication	 cases,	pregabalin,	while	 contributing	 in	 terms	of	overall	central	nervous	system	depression,1,6	may	well	have	worsened	the	observed	clinical	outcomes.	However,	one	could	still	argue	that	at	This	is	an	open	access	article	under	the	terms	of	the	Creative	Commons	Attribution	License,	which	permits	use,	distribution	and	reproduction	in	any	medium,	provided	the	original	work	is	properly	cited.©	2019	The	Authors.	CNS Neuroscience & Therapeutics	Published	by	John	Wiley	&	Sons	Ltd.2  |     LETTER TO THE EDITORleast	 in	 some	cases,	 pregabalin	may	be	 identified	 as	 just	 an	easily	accessible	molecule	with	a	“liking”	feature,	and	this	issue	may	need	more	debate	and	research….’.Both	pregabalin	and	gabapentin	have	been	reclassified	as	class	C	controlled	substances	in	the	UK.	Nonetheless,	in	the	US,	pregabalin	is	designated	as	a	Schedule	V	controlled	substance,	while	gabapentin	is	a	controlled	substance	only	in	some	states	(Tennessee,	Kentucky).	Moreover,	in	Australia,	pregabalin	and	gabapentin	are	still	classified	as	Prescription	Only	(Schedule	4)	medications,	meaning	that,	similar	todrugs	like	statins	and	antibiotics,	they	are	not	associated	with	any	special	controls	on	supply	or	possession.13	It	is	here	suggested	that,	whenever	psychotropics	are	to	be	made	available	on	prescription,	a	range	of	abuse	liability‐focused	and	pre‐marketing	laboratory	test‐ing	may	need	to	be	carried	out.	These	phase	3	studies	should	also	assess	 how	 the	 new	drug	may	 interact	with	 alcohol	 and/or	 other	drugs.	Also,	post‐marketing	surveillance	studies	should	be	encour‐aged	to	more	accurately	assess	 the	true	misusing	potential	of	any	psychotropic	molecule.	Physicians	should	be	vigilant	when	prescrib‐ing	drugs	with	a	misuse/diversion	potential	and	carefully	evaluate	the	possibility	 that	some	clients	 (including	people	with	a	personal	history	of	drug	misuse	or	abuse)	may	be	more	vulnerable.DISCLOSURE S TATEMENTFS	is	a	UK	Advisory	Council	on	the	Misuse	of	Drugs	(ACMD)	member;	and	European	Medicines	Agency	(EMA)	Advisory	Board	(Psychiatry)	member.ORCIDStefania Chiappini  https://orcid.org/0000‐0002‐6810‐1540 Fabrizio	SchifanoStefania	ChiappiniPsychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UKEmail: stefaniachiappini9@gmail.comCorrespondenceStefania Chiappini, Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK.Email: stefaniachiappini9@gmail.comR E FE R E N C E S	 1.	 Cairns	 R,	 Schaffer	 AL,	 Ryan	 N,	 Pearson	 SA,	 Buckley	 NA.	 Rising	pregabalin	 use	 and	 misuse	 in	 Australia:	 trends	 in	 utilization	 and	intentional	 poisonings.	 Addiction.	 2018;Aug:1–9.	 https://doi.org/10.1111/add.14412.	 2.	 Tran‐Van‐Minh	A,	Dolphin	AC.	The	alpha2delta	ligand	gabapentin	inhibits	the	Rab11‐dependent	recycling	of	the	calcium	channel	sub‐unit	alpha2delta‐2.	J Neurosci.	2010;30:12856‐12867.	 3.	 Pontieri	FE,	Tanda	G,	Di	Chiara	G.	Intravenous	cocaine,	morphine,	and	 amphetamine	 preferentially	 increase	 extracellular	 dopamine	in	 the	 "shell"	 as	 compared	with	 the	 "core"	 of	 the	 rat	 nucleus	 ac‐cumbens. Proc Natl Acad Sci USA.	1995;92:12304‐12308.	 4.	 Rutten	K,	De	Vry	 J,	 Robens	A,	 Tzschentke	 TM,	 van	 der	Kam	EL.	Dissociation	 of	 rewarding,	 anti‐aversive	 and	 anti‐nociceptive	 ef‐fects	of	different	classes	of	anti‐nociceptives	in	the	rat.	Eur J Pain. 2011;15:299‐305.	 5.	 Grosshans	 M,	 Lemenager	 T,	 Vollmert	 C,	 et	 al.	 Pregabalin	abuse	 among	 opiate	 addicted	 patients.	 Eur J Clin Pharmacol. 2013;69:2021‐2025.	 6.	 Schifano	F,	Chiappini	S,	Corkery	JM,	Guirguis	A.	Abuse	of	prescrip‐tion	drugs	in	the	context	of	novel	psychoactive	substances	(NPS).	A	Systematic	Review.	Brain Sci.	2018;8:E73.	 7.	 Bonnet	 U,	 Scherbaum	 N.	 How	 addictive	 are	 gabapentin	 and	pregabalin?	 A	 systematic	 review.	 Eur Neuropsychopharmacol. 2017;27:1185‐1215.	 8.	 Vashchinkina	E,	Piippo	O,	Vekovischeva	O,	et	al.	Addiction‐related	interactions	of	pregabalin	with	morphine	in	mice	and	humans:	rein‐forcing	and	inhibiting	effects.	Addict Biol.	2018;23:945‐958.	 9.	 Kapil	V,	Green	JL,	Le	Lait	MC,	Wood	DM,	Dargan	PI.	Misuse	of	the	γ‐aminobutyric	acid	analogues	baclofen,	gabapentin	and	pregabalin	in	the	UK.	Br J Clin Pharmacol.	2014;78:190‐191.	10.	 Snellgrove	BJ,	Steinert	T,	Jaeger	S.	Pregabalin	use	among	users	of	illicit	 drugs:	 a	 cross‐sectional	 survey	 in	 Southern	 Germany.	 CNS Drugs.	2017;31(10):891‐898.	11.	 Cossman	 JC,	 Scherbaum	 N,	 Bonnet	 U.	 Substance	 addiction	 in	old	 age:	 a	 cross‐sectional	 study	 in	 a	German	hospital.	GeroPsych. 2016;29(1):17‐27.	12.	 Schifano	 F,	 D’Offizi	 S,	 Piccione	 M,	 et	 al.	 Is	 there	 a	 recreational	misuse	 potential	 for	 pregabalin?	 Analysis	 of	 anecdotal	 online	 re‐ports	in	comparison	with	related	gabapentin	and	clonazepam	data.	Psychother Psychosom.	2011;80:118‐122.	13.	 Crossin	R,	 Scott	D,	Arunogiri	 S,	 Smith	K,	Dietze	PM,	Lubman	DI.	Pregabalin	 misuse‐related	 ambulance	 attendances	 in	 Victoria,	2012–2017:	 characteristics	 of	 patients	 and	 attendances.	 Med J Aust.	2019;210(2):75‐79.	14.	 Häkkinen	M,	Vuori	E,	Kalso	E,	Gergov	M,	Ojanperä	I.	Profiles	of	pre‐gabalin	and	gabapentin	abuse	by	postmortem	toxicology.	Forensic Sci Intern.	2014;241:1‐6.	15.	 Abrahamsson	T,	Berge	J,	Öjehagen	A,	Håkansson	A.	Benzodiazepine,	z‐drug	and	pregabalin	prescriptions	and	mortality	among	patients	in	 opioid	 maintenance	 treatment‐A	 nation‐wide	 register‐based	open	cohort	study.	Drug Alcohol Depend.	2017;174:58‐64.How to cite this article:	Schifano	F,	Chiappini	S.	Pregabalin:	A	range	of	misuse‐related	unanswered	questions.	CNS Neurosci Ther. 2019;00:1–2. https://doi.org/10.1111/cns.13115

Pregabalin: a range of misuse-related unanswered questions

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Pregabalin: a range of misuse-related unanswered questions

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University of Hertfordshire Research Archive