PREGABALIN

Pre-Review Report

Agenda Item 5.1

Expert Committee on Drug Dependence

Thirty-ninth Meeting

Geneva, 6-10 November 2017

39th ECDD (2017) Agenda item 5.1 Pregabalin

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Contents

Acknowledgements.................................................................................................................................. 4

Summary...................................................................................................................................................... 5

1. Substance identification ....................................................................................................................... 7

A. International Nonproprietary Name (INN).......................................................................................................... 7 B. Chemical Abstract Service (CAS) Registry Number .......................................................................................... 7 C. Other Chemical Names ................................................................................................................................................... 7 D. Trade Names ....................................................................................................................................................................... 7 E. Street Names ....................................................................................................................................................................... 9 F. Physical Appearance ....................................................................................................................................................... 9 G. WHO Review History ....................................................................................................................................................... 9

2. Chemistry ................................................................................................................................................... 9

A. Chemical Name .................................................................................................................................................................. 9 B. Chemical Structure ........................................................................................................................................................... 9 C. Stereoisomers ...................................................................................................................................................................... 9 D. Methods and Ease of Illicit Manufacturing ........................................................................................................... 9 E. Identification and Analysis ........................................................................................................................................ 10

3. Ease of Convertibility Into Controlled Substances ...................................................................... 10

4. General Pharmacology ........................................................................................................................ 10

A. Routes of administration and dosage ................................................................................................................... 10 B. Pharmacokinetics .......................................................................................................................................................... 10 C. Pharmacodynamics ....................................................................................................................................................... 11

5. Toxicology ................................................................................................................................................ 12

6. Adverse Reactions in Humans ........................................................................................................... 12

7. Dependence Potential .......................................................................................................................... 14

A. Animal Studies ................................................................................................................................................................. 14 B. Human Studies................................................................................................................................................................. 14

8. Abuse Potential ...................................................................................................................................... 16

A. Animal Studies ................................................................................................................................................................. 16 B. Human Studies................................................................................................................................................................. 16

9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical

Use .............................................................................................................................................................. 17

10. Listing on the WHO Model List of Essential Medicines .............................................................. 17

11. Marketing Authorizations (as a Medicinal Product) ................................................................. 17

12. Industrial Use ......................................................................................................................................... 18

13. Non-Medical Use, Abuse and Dependence ..................................................................................... 18

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14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and

Dependence ............................................................................................................................................. 20

15. Licit Production, Consumption and International Trade ......................................................... 22

16. Illicit Manufacture and Traffic and Related Information ........................................................ 22

17. Current International Controls and Their Impact ...................................................................... 22

18. Current and Past National Controls ................................................................................................ 22

19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling

of the Substance ..................................................................................................................................... 22

References ................................................................................................................................................ 23

Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 39th ECDD: Evaluation of Pregabalin ............................................................................................. 30

39th ECDD (2017) Agenda item 5.1 Pregabalin

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Acknowledgements

This report has been drafted under the responsibility of the WHO Secretariat, Department of

Essential Medicines and Health Products, Teams of Innovation, Access and Use and Policy,

Governance and Knowledge. The WHO Secretariat would like to thank the following people for

their contribution in producing this review report: Associate Professor Beth Sproule, Toronto,

Canada (literature search, review and drafting), Ms. Dilkushi Poovendran, Geneva, Switzerland

(questionnaire analysis and report drafting) and Dr. Stephanie Kershaw, Adelaide, Australia (review

report editing, questionnaire analysis and report drafting).

39th ECDD (2017) Agenda item 5.1 Pregabalin

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Summary

Pregabalin is a medication used world-wide in the treatment of partial onset seizures, post-herpetic

neuralgia, diabetic neuropathy, fibromyalgia, spinal cord injury neuropathic pain, and generalized

anxiety disorder. The actions of pregabalin are mediated through binding with high affinity to

alpha-2-delta proteins, which attenuates calcium influx into presynaptic neurons and thereby

blocks the release of neurotransmitters, including the excitatory neurotransmitter l-glutamate.

Most information on the abuse potential of pregabalin comes from therapeutic clinical trial data,

pharmacoepidemiological surveillance, and case reports/anecdotal reports, with only one

published formal human abuse liability study. Euphoria has been noted as an adverse event in

therapeutic clinical trial patients and pharmacokinetic study healthy participants. Evidence from

preclinical and therapeutic clinical trials suggests the development of tolerance to the euphoric

effects. Withdrawal symptoms manifest in some patients following abrupt discontinuation of

pregabalin treatment (e.g., insomnia, headache, nausea, anxiety, sweating and diarrhea). For this

reason it is recommended that patients undergo a short taper period (1 week) when discontinuing

treatment. The one published abuse liability study assessed single doses of pregabalin 75 mg and

150 mg. This low pregabalin exposure in people without psychiatric and substance use disorder

histories was not associated with increased ratings for liking. In a study submitted with the

manufacturer’s New Drug Application in the United States in 2004, a single dose of pregabalin

450 mg was rated similarly to a single dose of diazepam 30 mg on measures of liking in alcohol

and sedative/hypnotic recreational users. This finding contributed to the assignment of pregabalin

to Schedule V of the Controlled Substance Act in the United States.

Epidemiological evidence for pregabalin abuse and dependence has been growing. It is available

from adverse drug reaction reporting databases (representing 3-7% of pregabalin reports) and

drug utilization reviews (with high doses prescribed at rates ranging from 1-10% of patients). In

surveys of substance using populations, 3-68% of respondents endorsed non-prescribed or misuse

of pregabalin. Pregabalin has been detected in urine samples of patients in opioid dependence

treatment (9-12%) and in postmortem toxicological samples, with increasingly higher rates within

drug dependent populations in combination with other substances. The risk of overdose death

from pregabalin alone appears to be low, however, there is concern about the combination of

pregabalin with opioids. Very high maximum daily doses (up to 7500 mg/day) have been

described in published case reports and online anecdotal reports of pregabalin abuse.

From the available evidence, pregabalin clearly has the potential for abuse and dependence. Most

published evidence is relatively recent and the extent to which pregabalin abuse may increase is

not known. There is interest in pregabalin for its use in the treatment of substance use disorders

(e.g., alcohol, benzodiazepine, opioids), however its use for these indications must be balanced

39th ECDD (2017) Agenda item 5.1 Pregabalin

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with its potential to be abused in this population. Its abuse potential appears lower than for opioids.

Its relative abuse liability compared to other substances, particularly other psychotropic

medications that people may be exposed to therapeutically (for example, benzodiazepines), has

not been well studied.

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1. Substance identification

A. International Nonproprietary Name (INN)

Pregabalin

B. Chemical Abstract Service (CAS) Registry Number

148553-50-8

C. Other Chemical Names

(S)-3-(aminomethyl)-5-methylhexanoic acid; (S+)-3-isobutyl-GABA

D. Trade Names

Lyrica: Argentina; Australia; Austria; Belgium; Bosnia & Herzegovina; Brazil;

Canada; Chile; China; Croatia (Hrvatska); Czech Republic; Denmark;

Ecuador; Egypt; Finland; France; Georgia; Germany; Greece; Hong

Kong; Hungary; Iceland; India; Indonesia; Ireland; Israel; Italy South

Korea; Japan; Latvia; Lebanon; Lithuania; Luxembourg; Malaysia;

Myanmar; Netherlands; New Zealand; Norway; Norway; Oman; Peru;

Philippines; Poland; Portugal; Romania; Russian Federation; Serbia;

Singapore; Slovakia; Slovenia; South Africa; Spain; Sweden;

Switzerland; Thailand; Tunisia; Turkey; United Kingdom; United States;

Vietnam.

Others:

Argentina Axual. Balifibro. Clasica, Dolgenal, Gavin, Kabian,

Linprel, Mystika, Neuristan, Plenica, Prebanal,

Prebictal, Prebien

Bangladesh Gaba-PGabarol, Lyric, Neurega, Neurolin, Neurovan,

PG, Prebalin, Pregaba, Pregaben, Pregadel, Pregan,

Prelin, Pretor, Priga, Xablin, Xil

Bosnia & Herzegowina Epica, Epiron, Pagamax

Canada Apo-Pregabalin, PMS-Pregabalin, Pregabalin Sanis

Health, RAN-Pregabalin, Sandoz Pregabalin, Teva-

Pregabalin

Chile Alivax, Neurum, Plenica, Prebictal, Prefaxil, Pregalex,

Pregalin, Pregobin, Prestat

Colombia Dolica, Martesia, Pregabalina Ecar, Pregabalina MK,

Preludyo

Costa Rica Martesia

Egypt Andogablin, Averopreg, Convugabalin, Dapapalin,

Dragonor, Gablovac, Glonervya, Hexgabalin,

Irenypathic, Kemirica, Lyrineur, Lyrolin, Neuragabalin,

Painica, Pregaba, Pregatrend, Pregavalex, Pregdin

Apex, Serigabtin, Vronogabic

El Salvador Martesia, Pregabateg, Prelyx

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Equador Neurum, Prebictal, Pregobin

Estonia Brieka, Pragiola, Pregabalin Alvogen, Pregabalin Teva,

Pregagamma, Pregamid

France Pregabaline Sandoz GmbH

Georgia Helimon

Guatamala Martesia, Pregabateg

Honduras Martesia

Hong Kong Apo-Pregabalin

Iceland Pregabalin Krka

India Gabanext, Nuramed, Pevesca, Prebel, Pregaba,

Pregabin, Pregacent, Preganerve, Pregastar, Pregeb-OD,

Prejunate, Preneurolin, Resenz

Indonesia Aprion, Provelyn

Lebanon Gabrika, Plenica

Mexico Dismedox, Gialtyn, Kineptia

Myanmar Maxgalin

Netherlands Lingabat

Nicaragua Martesia

Panama Martesia

Peru Neurum, Prebictal, Pregalex, Pregobin

Poland Pragiola, Pregabalin Pfizer

Portugal Pregabalina Alter, Pregabalina Baldacci, Pregabalina

Cinfa, Pregabalina Farmoz, Pregabalina Gática,

Pregabalina Generis, Pregabalina Jaba, Pregabalina

Kipa, Pregabalina Pentafarma, Pregabalina Pharmakern,

Pregabalina Ratiopharm, Pregabalina Tetrafarma,

Pregabalina Teva, Pregabalina ToLife

Netherlands Pregabaline AET, Pregabaline Aurobindo, Pregabaline,

CFPregabaline Hetero, Pregabaline Krka, Pregabaline

Ranbaxy, Pregabaline Teva, Pregabaline Torrent,

Pregabaline Wockhardt, Pregagamma, Pregamid

Russian Federation Algerika, Pregabalin-Richter

Slovakia Pregabalin Sandoz

Slovenia Ecubalin, Pragiola

South Korea Newrica, Pregalin

Spain Pregabalina Apotex, Pregabalina Cinfa, Pregabalina

Kern Pharma, Pregabalina Stada Genericos, Pregabalina

Tarbis

Switzerland Pregabalin Pfizer, Pregabalin-Mepha

Thailand Pregabalin Sandoz

Turkey Alyse, NeuricaPaden, Pagadin, Regapen, Symra

United Kingdom Lecaent, Rewisca,

Vietnam Gabica, Gablin, Pregobin, Premilin

(Drugs.com 2017)

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E. Street Names

Gabbies; Budweisers, Bud, Bud light, Fizers

(Millar 2013, DRUGS.ie 2017, Extern 2017)

F. Physical Appearance

White to off-white crystalline solid

G. WHO Review History

Pregabalin has not been previously reviewed by the WHO Expert Committee on

Drug Dependence.

2. Chemistry

A. Chemical Name

IUPAC Name: (3S)-3-(aminomethyl)-5-methylhexanoic acid

CA Index Name: Hexanoic acid, 3-(aminomethyl)-5-methyl-, (3S)-

B. Chemical Structure

Free base:

(Pfizer, 2016)

Molecular Formula: C8H17NO2

Molecular Weight: 159.23

C. Stereoisomers

Pregabalin is the (S)-(+)-isomer of 3-isobutyl-GABA

D. Methods and Ease of Illicit Manufacturing

No information was found on methods of illicit manufacturing. Published

literature describes enantioselective synthesis methods. (Burk 2003, Yu 2012)

Melting point: 176 - 178 oC

Boiling point: 144 – 147 oC

Solubility: Freely soluble in water (both basic and acidic aqueous solutions)

(ChemSpider 2017, Pfizer 2016)

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E. Identification and Analysis

Several methods have been developed for identification of pregabalin. This includes

liquid chromatography–tandem mass spectrometry (LC–MS–MS) methods in

human urine (Heltsley 2011) and human serum (Oertel 2009); high-performance

liquid chromatography (HPLC) methods in human serum (Vermeij 2004) and for

capsule contents (Kasawar 2010); a high-performance liquid chromatography –

mass spectrometry (HPLC-MS) method in post-mortem samples (Priez-Barallon

2014); a spectrophotometric method for capsule contents (Bali 2011); and

immunoassay methods for human urine (e.g., ARK 2017).

3. Ease of Convertibility Into Controlled Substances

No information was found on the conversion of pregabalin into other controlled

substances.

4. General Pharmacology

A. Routes of administration and dosage

Pregabalin pharmaceutical products are available to be taken orally.

Capsule strengths: 25, 50, 75, 100, 150, 200, 225, 300 mg

Oral Solution: 20 mg/ml

Dosage (administered orally in 2 – 3 divided doses)

Partial Onset Seizures: Initially 150 mg daily;

Maintenance 150-600 mg daily.

Post-herpetic Neuralgia: Initially 150 mg daily;

Maintenance 150-300 mg daily;

Maximum dosage 600 mg daily.

Diabetic Neuropathy: Initially 150 mg daily;

Maintenance 150-300 mg daily.

Fibromyalgia: Initially 150 mg daily;

Maintenance 150-450 mg daily.

Spinal Cord Injury Neuropathic Pain: Initially 150 mg daily;

Maintenance 150-300 mg daily;

Maximum dosage 600 mg daily.

Generalized Anxiety Disorder: Initially 150 mg daily;

Maintenance 150-600 mg daily.

Dosage needs to be lowered with renal impairment (Clcr <60 mL/minute). (AHFS

2017, Pfizer 2016 Canada, Pfizer 2016 USA, Pfizer 2017 UK)

B. Pharmacokinetics

Pregabalin has a relatively simple pharmacokinetic parameter profile compared to

many psychotropic drugs.

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Absorption: Pregabalin is rapidly and extensively absorbed. Plasma concentrations

peak within 1.5 hours after administration, with oral bioavailability greater than

90% that is independent of dose and frequency of administration. Peak

concentrations and area under the plasma concentration-time curve increase

proportionally with dosage. Food slows the rate of absorption but not the extent of

absorption.

Distribution: Pregabalin is a substrate for system L transporter across the blood-

brain barrier. The apparent volume of distribution of pregabalin following oral

administration is approximately 0.5 L/kg. Pregabalin is not bound to plasma

proteins.

Metabolism: Pregabalin undergoes negligible metabolism. The N-methylated

metabolite accounts for less than 1% of the dose.

Elimination: Pregabalin is eliminated primarily (98%) by renal excretion as

unchanged drug, with elimination proportional to creatinine clearance. Less than

0.1% is eliminated in faeces. The mean half-live of pregabalin is approximately 6

hours (range 4 to 7 hours) and is not dose dependent. Steady-state is reached within

2 days of regular dosing. (Warner 2005, Bockbrader 2010, Schulze-Bonhage 2013)

C. Pharmacodynamics

Pregabalin binds with high affinity to the alpha-2-delta protein – a subunit of

voltage-gated calcium channels located at presynaptic endings of neurons in the

brain and spinal cord. This attenuates Ca2+ flux into neurons, which blocks the

release of neurotransmitters, including the excitatory neurotransmitter l-glutamate.

Endogenous ligands include the amino acids L-leucine, L-isoleucine, and L-valine.

Despite similarities to gamma-aminobutyric acid (GABA), it does not act at GABA

receptors or synapses. Pregabalin has approved indications for the treatment of

partial seizures, post-herpetic neuralgia, diabetic neuropathy, fibromyalgia, spinal

cord injury neuropathic pain and generalize anxiety disorder. It appears that the

therapeutic actions for all of these conditions are mediated through pregabalin’s

actions on the alpha-2-delta protein. It has been suggested that these disorders may

share neuronal hyperactivity in a variety of brain circuits that pregabalin helps to

normalize. Further study on the actions of pregabalin in different brain regions is

needed. The exact mechanism for producing euphoric effects or physical

dependence is not known at this time. (Schulze-Bonhage 2013, Stahl 2013,

Silverman 2008, Taylor 2007)

Pregabalin has been used off-label in the treatment of drug and alcohol withdrawal.

(Freynhagen 2016) Although limited, most evidence is for the treatment of alcohol

and benzodiazepine withdrawal. For example, there have been 3 small randomized-

controlled studies for alcohol withdrawal (Freynhagen 2016); and there are case

reports (Biermann 2007, Oulis 2008a), open-label studies (Oulis 2008b, Bobes

2012, Cho 2014), a prescription database study (Bramness 2010), and one small

randomized controlled trial for the treatment of benzodiazepine withdrawal.

(Hadley 2012)

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5. Toxicology

Preclinical Acute Toxicology

There were no deaths following administration of single oral doses of pregabalin 5000

mg/kg or single IV doses of 300 mg/kg to mice and rats, nor changes in biochemical

parameters, however, there were observations of hypoactivity, diarrhea and urine staining.

Pregabalin was not genotoxic in vitro, nor in rats in doses up to 2000 mg/kg. (Pfizer

2016)

Preclinical Chronic Toxicology

There was a dose-dependent increase in hemangiosarcomas in 2 strains of mice with 200 to

5000 mg/kg in their diet for 2 years. The exposure was considered to be similar to human

exposure at 600 mg/day. Tumorigenic potential is included in the Warnings and Precaution

section of the product monograph. Skin lesions were seen at exposures equivalent to 2 to 8

times that of human exposure at 600 mg/day, ranging from erythema to necrosis. Ocular

lesions were detected in rats at exposures more than twice those in humans at 600 mg/day.

The following have been observed in animal toxicology studies with exposures from 2 to

69 weeks: ataxia and hypoactivity in rats and monkeys at repeated oral doses ≥ 500 mg/kg;

tail dermatopathy and urine staining in rats ≥ 250 mg/kg and monkeys up to 500 mg/kg;

urinary bladder changes and mortality with pyelonephritis/cystitis in rats at ≥ 250 mg/kg;

reversible platelet count decreases of 14-36% in rats at ≥50 mg/kg in males and ≥ 100

mg/kg in females; no changes in hematology up to 500 mg/kg in monkeys; bone marrow

total nucleated cell decreases 18-44% in rats at 150-1250 mg/kg, with no changes up to 50

mg/kg in rats nor in monkeys; no effects on body weight gain at 50 mg/kg or 150 mg/kg

and no effects on monkeys up to 500 mg/kg; nasal discharge and diarrhea in monkeys at ≥

100mg/kg; and deaths in 3 days in monkeys at doses of 1000 or 2000 mg/kg. (Pfizer 2016).

Preclinical Reproduction

Epididymal hypospermia and spermatogenic epithelial degeneration were observed after 4

weeks at 1250 mg/kg in rats, but not in doses up to 500 mg/kg. There were no changes in

sperm count, motility or morphology in monkeys at 500 mg/kg for up to 69 weeks. There

were no effects on female rat fertility when given high doses. However, male rats had

reversible decreased sperm motility and fertility at ≥ 27 times human exposure. This was

not seen in monkeys. Maternal toxicity in embryo-fetal development was seen in rats at ≥

500 mg/kg and rabbits at ≥ 250 mg/kg. Fetal toxicity was observed at 2500 mg/kg in rats

and at 1250 mg/kg in rabbits. Pregabalin was not teratogenetic in mice, rats or rabbits at 31

to 77 times the mean human exposure at 600 mg/day. Developmental toxicity in rat

offspring was observed at ≥ 5 times the mean human exposure. (Morse 2016, Morse

2016a, Pfizer 2016)

6. Adverse Reactions in Humans

The adverse events associated with pregabalin treatment were assessed in a systematic

review of 39 randomized controlled trials published between 1990 to 2010. Adverse effects

significantly associated with pregabalin were dizziness, vertigo, incoordination, balance

disorder, ataxia, diplopia, blurred vision, amblyopia, tremor, somnolence, confusional

state, disturbance in attention, thinking abnormal, euphoria, asthenia, fatigue, edema,

peripheral edema, dry mouth, constipation. The adverse events associated with the highest

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relative risks (RR, 95% CI) were balance disorder (8.22, 1.75 to 38.57), euphoria (6.18,

2.76 to 13.87), incoordination (4.88, 2.18 to 10.95), ataxia (4.77, 2.77 to 8.20), and edema

(4.63, 2.15 to 9.95). In 28 of the studies, the relationship between dose and effects could be

evaluated and it was determined that adverse events first presenting at 150 mg/day were

dizziness, ataxia, somnolence, edema, and dry mouth; at 300 mg/day were vertigo,

incoordination, blurred vision, amblyopia, confusional state, disturbance in attention,

thinking abnormal, euphoria, asthenia, peripheral edema, and constipation; at 450 mg/day

were balance disorder and fatigue; and at 600 mg/day were diplopia and tremor. (Zaccara

2011)

The most commonly observed adverse events according to pre-marketing clinical trials

were mild to moderate dizziness, somnolence, peripheral edema and dry mouth. These

were seen at a rate of at least 5% and were twice the rate seen with placebo. The most

common adverse events leading to discontinuation were dizziness, somnolence, ataxia,

asthenia, confusion, headache and nausea. Adverse events were similar between women

and men. Warnings highlighted in the product monograph include peripheral edema,

weight gain and creatinine kinase elevations. (Pfizer 2016)

Adverse symptoms reported through poisoning events were summarized in a retrospective

review of records from 2002-2011 involving newer anticonvulsants from the Virginia

Poison Centre. Twenty-three cases involving pregabalin were described in which 70%

were female, with an age range of 16 to 85 years, and pregabalin doses ranging from 100 –

9,000 mg (median 2,375 mg). The clinical signs or symptoms were reported broadly to be

within neuromuscular, CNS, gastrointestinal, cardiac, blood pressure and metabolic

categories. The outcome severities were assessed as having no effect in 35% of cases, a

minor effect in 22%, a moderate effect in 44%, with no severe effects noted (i.e., death).

(Wills 2014) In addition, there are 2 published case reports of pregabalin overdose

indicating minimal clinical symptoms (Miljevic 2012 – 4.2 g ingestion, Spiller 2008 –

unknown amount). In another case report, ingestion of pregabalin 8.4 g resulted in loss of

consciousness which was treated with supportive care. (Wood 2010)

Drug Interactions

The pharmacokinetic profile of pregabalin limits the potential for pharmacokinetic

mediated drug-drug interactions (i.e., it is not metabolized and does not exhibit plasma

protein binding). In addition, pregabalin does not inhibit or induce drug metabolizing

enzymes. (Ben-Menachem 2004) The lack of interactions has been supported in published

reviews where the only interactions noted were reports that carbamazepine, phenytoin,

phenobarbital, gabapentin, and oxcarbazepine could reduce pregabalin levels 11 to 22%

(Patsalos 2013), and that pregabalin has additive effects with oxycodone on cognitive and

motor functions, and increases the effects of ethanol and lorazepam. (Ben-Menachem

2004, Patsalos 2013a)

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7. Dependence Potential

A. Animal Studies

Reviews by the US Centre for Drug Evaluation and Research for Pfizer’s New Drug

Application submission indicated that preclinical studies conducted in monkeys

using a self-injection paradigm suggest that tolerance may develop to the euphoric

effects pregabalin since self-administration decreased after one week. (Bonson

2004)

B. Human Studies

Tolerance

Reviews by the US Centre for Drug Evaluation and Research for Pfizer’s New Drug

Application submission indicated that evidence from Phase2/3 clinical studies

support the development of tolerance to the euphoric effects since the euphoria

receded while patients were still taking pregabalin. (Bonson 2004)

Withdrawal

The US Centre for Drug Evaluation and Research reviewed evidence from the

Pfizer’s New Drug Application submission in 2004 and summarized the following

points which were suggestive of withdrawal symptoms and indicative of physical

dependence (Bonson 2004b):

▪ Discontinuation-emergent symptoms from short- and long-term psychiatric

studies that were more frequent in pregabalin treated patients compared to

placebo treated patients were insomnia, headache, nausea, infections, diarrhea,

and chills.

▪ Scores on the Physician’s Withdrawal Checklist in psychiatric studies were

significantly different between pregabalin and placebo groups.

▪ Analysis of two pharmacokinetic studies showed discontinuation-emergent

symptoms from pregabalin of headache, nausea and diarrhea, whereas from

placebo the reports were of accidental injury, infection, skin disorder and

ventricular extrasystoles.

The current product monograph from Pfizer Canada Inc. indicates that following

abrupt discontinuation of pregabalin in clinical studies some patients reported

symptoms of insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. In

the adverse effects information section, information is included from a study of

patients with pain associated with spinal cord injury. A withdrawal syndrome was

reported in 4.3% of patients in the pregabalin group (n=70) at doses from 150 to

600 mg/day, with no reports in the placebo group (n=67). (Pfizer 2016) The

apparent published paper of this study describes a serious adverse event in a patient

one day following pregabalin discontinuation. The patient exhibited severe

symptoms of spasticity with impaired coordination (more severe that previous

episodes). (Siddall 2006) The monograph explicitly recommends to gradually taper

pregabalin over one week when stopping treatment. (Pfizer 2016)

Published Pfizer-funded clinical trials using a discontinuation design rather than a

placebo-control group have been conducted which incorporated a 1-week taper

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when pregabalin was stopped (i.e., for those randomized from pregabalin to placebo

and at the end of the study for those taking pregabalin throughout). In general, the

adverse event rates for nausea, headache, and diarrhea did not appear to be elevated

for the placebo groups. However, treatment-emergent adverse events were reported

globally for the treatment groups and not specifically during or after the taper

periods, making interpretation of withdrawal effects difficult. (Gilron 2011, Raskin

2014, Arnold 2014)

Discontinuation symptoms associated with a 1-week taper were specifically studied

in a Pfizer-funded multi-centre, double-blind, clinical trial. (Kasper 2014) A total of

615 patients with generalized anxiety disorder were randomized to pregabalin

higher dose (450-600 mg/day), pregabalin lower dose (150-300 mg/day), or

lorazepam (3-4 mg/day). After 12 weeks of flexible dosing, 25% of patients in each

group were randomized to undergo a 1 week blinded taper and to continue placebo

for another 11 weeks, while the remainder continued on a fixed dose of active

medication for another 12 weeks. At the end of 24 weeks, all subjects underwent a

1-week taper. Anyone experiencing severe withdrawal symptoms could have the

taper period extended to 4 weeks. The primary outcome measure was the Physician

Withdrawal Checklist (PWC) which has 20 items related to anxiolytic drug

withdrawal signs and symptoms, with scores ranging from 0-60. The secondary

measure was the spontaneously reported Discontinuation-Emergent Signs and

Symptoms (DESS). Rates of rescue tapers were also reported. Measures were taken

start of taper week and 1 and 2 weeks later. The changes in the Physician Checklist

Scores from before and after the taper appear to be low, however, approximately

1/3 (range 22%-36%) of patients exhibited discontinuation-emergent signs and

symptoms during the taper, and some patients in all groups required rescue taper

procedures. The authors characterized these discontinuation symptoms as not

clinically significant. (Kasper 2014)

Summary of discontinuation symptom outcomes (Kasper 2014) Groups PWC

Mean Change* (95% CI)

% with

DESS+

Rescue Taper**

# patients Pregabalin Higher Dose – taper at 12 weeks 2.1 (0.4-3.7)

N=54 36.2% N=58

4

Pregabalin Higher Dose – taper at 24 weeks 2.8 (1.6, 3.9) N=106

31.2% N=109

6

Pregabalin Lower Dose – taper at 12 weeks 2.0 (0.5, 3.6) N=49

32.7% N=52

6

Pregabalin Lower Dose – taper at 24 weeks 1.7 (0.7, 2.8) N=84

22.3% N=94

5

Lorazepam – taper at 12 weeks 1.6 (-0.3, 3.6) N=44

32.7% N=52

2

Lorazepam – taper at 24 weeks 2.2 (1.0, 3.5) N=93

28% N=100

8

*difference between start of 1-week taper and 2 weeks later +symptoms included anxiety, dizziness, headache, insomnia and nausea

**includes patients who discontinued treatment early or entered the taper period

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A withdrawal syndrome was noted in 32.7% (18/55) of pregabalin

abuse/dependence-related reports to the German Federal Institute for Drugs and

Medical Devices from 2008-2012. (Gahr 2013a)

In a review of 102 pregabalin clinical studies, none of the adverse effects described

withdrawal symptoms, although the authors comment that this may have been

influenced by the short treatment durations. (Schjerning 2016)

8. Abuse Potential

A. Animal Studies

Preclinical conditioned place preference studies in mice and self-administration or

drug discrimination studies in monkeys have yielded conflicting results, which have

been attributed to varying study conditions, including different routes of

administration. (Schjerning 2016) The US Centre for Drug Evaluation and Research

(Bosnon 2004, Throckmorten 2004) reviewed of evidence from Pfizer’s New Drug

Application submission of preclinical behavioural studies and deemed them not

valid for assessing abuse potential for a variety of reasons. However, the review

pointed out a study in monkeys (n=4) that showed pregabalin produced reinforcing

effects by demonstrating self-administration of greater than 10 injections per day at

the 3.2 and 10 mg/kg/infusion doses during initial access to the drug.

B. Human Studies

There is one published study that used an abuse liability study design to evaluate

the effects of pregabalin alone and in combination with oxycodone. (Zacny 2012)

This was a double-blind, randomized study in 16 healthy volunteers. The

participants were each administered single doses of pregabalin 75 mg, pregabalin

150 mg, oxycodone 10 mg, and pregabalin 75 mg combined with oxycodone 10 mg

in a cross-over design. Neither dose of pregabalin alone increased ratings of “like

drug” or “take drug again”. This study demonstrated low abuse liability associated

with low doses of pregabalin in people without psychiatric and substance use

disorders histories.

The US Centre for Drug Evaluation and Research (Bosnon 2004, Throckmorten

2004) reviewed evidence from Pfizer’s New Drug Application submission and

summarized a study that showed a single dose of pregabalin 450 mg administered to

alcohol or sedative/hypnotic recreational users (n=15) was rated similarly to a

single dose of diazepam 30 mg on measures of “good drug effect”, “high”, and

“liking”. A 200 mg dose of pregabalin was identified as a sedative.

In a review of 102 pregabalin clinical trials, it was reported that 14 studies indicated

euphoria as an adverse effect with a prevalence primarily between 1-10% (with one

study reporting 26%). (Schjerning 2016) These studies spanned cohorts with

fibromyalgia, painful neuropathies, postherpetic neuralgia, generalized anxiety

disorder and healthy volunteers. Many studies did not indicate explicitly whether

people with substance abuse were excluded or not. It was determined that euphoria

39th ECDD (2017) Agenda item 5.1 Pregabalin

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appeared to be a dose-dependent effect and transient effect. In addition,

endorsements of ‘feeling good’, ‘feeling dazed’, ‘being drunk’ or ‘overdosed’ were

reported in one clinical trial each. (Schjerning 2016).

9. Therapeutic Applications and Extent of Therapeutic Use and

Epidemiology of Medical Use

Pregabalin is indicated for partial onset seizures, post-herpetic neuralgia, diabetic

neuropathy, fibromyalgia, spinal cord injury neuropathic pain, and generalized anxiety

disorder. From July 2004 to March 2012, there has been an estimated 15,951,859 million

patient-years of exposure to LYRICA®. (Pfizer 2016) In England, there was a 53%

increase in pregabalin prescribing between 2011 and 2013. (PHE/NHS 2014) In Denmark,

pregabalin prescribing increased 10-fold over a 10 year period. (Schjerning 2016)

Worldwide sales of pregabalin have had an annual growth rate of approximately 12%.

(Schjerning 2016)

10. Listing on the WHO Model List of Essential Medicines

Pregabalin is not listed on the WHO Model List of Essential Medicines (20th List) or the

WHO Model List of Essential Medicines for Children (6th List).

11. Marketing Authorizations (as a Medicinal Product)

Marketing authorizations for pregabalin as a medicine are held by many companies.

Examples (not limited) are: Pliva Pliva Hrvatska, Laboratorio Chile, Abdi Ibrahim,

Andalous, Apotex, Pharos, Averroes, Ivax, Buxton, Actavis Baltics Eesti, Craveri, Al

Rowad, Debeiky, Pisa, Beta, Medley, Bioxell, Ecupharma, Actavis, Bosnalijek, AHPL,

Renata, ACI, Getz Pharma, CCL, Gast Ph, Benta, Gador, Teva, Globe, Aversi, GNP,

Amoun, Temis Lostalo, Chemi ph, Sandoz, Actavis UK, PharmaSwiss, Baliarda,

Healthcare, Elite Ph, Hikma, Roemmers, Sun Pharma, Penn Pharmaceut, Grand Pharma,

Ibn Sina, Koçak, Casasco, Square, Aristopharma, Laboratorio Saval, Icarus, Dong-A,

Zydus, Wockhardt, Invision, Innokon, Bilim, Gen, Nobel, Alpha Gp, Peerage, USV,

Eskayef, Laboratorios Raffo, Pharmascience, Krka, General Pharma, LKM, Johnlee,

Johnlee, Medicamenta Ecuatoriana, Ariston, Andic, Royal Pharma, Egpi, Alvogen, Krka,

Pfizer, Sandoz, Sanis Health, Teva Eesti, Alter, Apotex, Baldacci, Cinfa, Ecar, Farmoz,

Alter, Generis, Jaba, Kern, Kipa, MK, Pentafarma, Pharmakern, Ratiopharm, STADA,

Tarbis, Tetrafarma, Teva Pharma, ToLife, Alfred E. Tiefenbacher, Aurobindo, Centrafarm,

Hetero, Krka, Ranbaxy, Sandoz, Teva, Torrent, Wockhardt, Mepha Pharma, Gedeon

Richter, Laboratorio Tecnoquímicas, Incepta, Molekule, Crescent, Crescent, Delta,

Wörwag, ABL Pharma, ITF - Labomed Farmaceutica, AHPL, G.L. Pharma, Navana, East

West, East West, Invision, Lupin, Trend Ph, Eva, Apex, Torrent, Torrent, Little Greave,

Drugtech, Molekule, Molekule, Drug International, Tecnoquimicas, Paill, Hasan, Franco-

Indian, Franco-Indian, Laboratorio Bago, Malody, Sanofi-Aventis, Monico, Kalbe,

Ranbaxy, Ilko, Sanofi Aventis, Strides Arcolab, Orchid, Consilient Health, Sanify, Sandoz,

Serio Pharm, Sanovel, Teva Canada, FDC, Marcyrl, Novartis, and Orion.

39th ECDD (2017) Agenda item 5.1 Pregabalin

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12. Industrial Use

None.

13. Non-Medical Use, Abuse and Dependence

Although still limited, there is a variety of evidence suggesting pregabalin is subjected to

non-medical use, abuse and dependence; perhaps at increasing rates.

Adverse Drug Reaction Database Reports of Abuse

▪ 6.6% (7639/115,616) of reports for pregabalin were related to

abuse/dependence/misuse from 2006-2015 in the European Medicine Agency

Spontaneous Adverse Drug Reaction Reporting System. (Chiappini 2016)

▪ 3.5% (55/1552) of reports for pregabalin were related to abuse (n=11) or dependence

(n=44) reported from 2008-2012 to the German Federal Institute for Drugs and

Medical Devices. (Gahr 2013a)

▪ 1.5% (8/521) of abuse/dependence reports were related to pregabalin from 2010-2015

in the French Pharmacovigilance Database. (Bossard 2016)

▪ 8% (16/198) of drug dependence reports were related to pregabalin (up to 2009) in the

Swedish national register of adverse drug reactions (SWEDIS). (Schwan 2010)

Drug Utilization Reviews Indicating High Dose Prescribing

▪ Of outpatients prescribed pregabalin by UK general practitioners, 1% (136/13,480)

were prescribed greater than 600 mg/day from 2004-2009. (Asomaning 2016)

▪ In Denmark, 9.6% (4090/42,520) of pregablin users were prescribed greater than 600

mg/day between 2004-2013. (Schjerning 2016a)

▪ In Sweden, 8.5% (4130-48,550) of pregabalin users were prescribed greater than 600

mg/day. (Boden 2014)

▪ In Norway in 2009, of 17,111 people using pregabalin, there was high dose use noted

of more than 10 defined daily doses (DDD) (n=25) or between 5-10 DDD (n=118).

(Landmark 2011, Schjerning 2016)

Indications of Non-Medical Use/Misuse/Abuse in Surveys/Questionnaires

▪ 0.5% (8/1500) of respondents to an online survey endorsed misuse of pregabalin. These

respondents had a lifetime prevalence of use of recreational drugs that was comparable

to national UK data. (Kapil 2014)

▪ 7% of opioid dependent patients admitted for inpatient detoxification endorsed

pregabalin misuse. (Wilens 2015)

▪ 3% (4/129) of substance use disorder population in Scotland used non-prescribed

pregabalin. (Baird 2014)

▪ 68% of polysubstance use disorder patients in the National Rehabilitation Centre

(NRC) in the United Arab Emirates endorsed using pregabalin non-medically (mean of

8.3 capsules ± 0.5 per day), particularly in the younger cohort. (Alblooshi 2016)

▪ The Swedish Poisons Information Centre was noted to have cases of intravenous

injection of crushed pregabalin tablets (number not reported). (Jonsson 2014)

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Postmortem Toxicology Associated with Abuse

▪ 2.3% (316/13,766) of all toxicologically investigated medico-legal cases from 2010-

2011 in Finland had pregabalin involved. 48% (152/316) of pregabalin cases were

attributed to abuse. (Hakkinen 2014)

▪ 4.4% (43/982) of all postmortem toxicology cases in Germany had pregabalin detected

from 2010-2012. In the first year studied the rate was 2% (10/489), whereas by the

second year it had substantially increased to 6.7% (33/493). Within drug dependent

individuals the rate went from 5.5% (4/72) to 29.8% (26/87) over the 2 year period.

(Lottner-Nau 2013)

▪ 4.2% (68/1623) of deceased young adults had pregabalin detected over a 3 year period

in Finland. (Launiainen 2011)

Detection in Urine Drug Screening in Opioid Dependent Populations

▪ 9.2% (39/425) of urine samples from opioid dependence treatment patients tested

positive for pregabalin over a 3 month period in 2014 in Ireland, with only 10 patients

prescribed the medication. (McNamara 2015)

▪ 12.1% (15/124) of urine samples from opioid dependence treatment patients tested

positive for pregabalin, compared to 2.7% (3/111) in a cohort of patients with other

substance use disorders. (Grosshans 2013)

Case Reports of Abuse

▪ A systematic review (Schjerning 2016) identified 10 case reports starting in 2010

describing pregabalin abuse-related events according to ACTTION definitions. (Smith

2013) These cases involved supra-therapeutic dosing (n=10 with highest 2400 mg

single dose, range 800-7500mg), diversion (n=3), tampering (n=1), and withdrawal

symptoms (n=2). The people involved had a mean age of 34 years (range 19-47), 6

men and 4 women, 2 had no history of substance abuse, one case had nicotine use

only, and most (n=8) had psychiatric diagnoses, primarily mood and anxiety disorders

or personality disorders. (Schjerning 2016)

▪ Of 30 heroin users interviewed in a treatment service setting in the UK, 19 were

pregabalin users (n=1 daily user, n=3 weekly, n=5 rarely, n=10 once), doses reported

from 300 to 1500mg, prescribed or purchased on the street. (Lyndon 2017)

Anecdotal Online Reports

▪ Qualitative Google searches in 8 European languages of 108 websites were conducted

on a regular basis between 2008 and 2010 documenting posts related pregabalin

recreational use. From these anecdotal reports, the authors noted that primarily high

doses of pregabalin (up to 5 g) were used for the euphoric effects, effects similar to

alcohol, benzodiazepines and GHB, to cope with opioid withdrawal, and for

entactogenic feelings or dissociative effects. Pregabalin was mostly used orally, but

also by injection or rectally. Tolerance developed rapidly leading to increasing

dosages and recommendations to combined use with other sedatives. Tolerance was

also lost quickly once use ceased. (Schifano 2011)

Self-reported Street Prices

▪ Based on self-reported information (via website submission) on street prices of

diverted prescription drugs, prices for pregabalin per pill have ranged from $3-5 in the

39th ECDD (2017) Agenda item 5.1 Pregabalin

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United States, $6 in Canada, £0.05-150 in United Kingdom, €2-3 in Germany and

$<1-$150 in Australia. (Streetrx.com)

▪ Heroin users interviewed in a treatment service setting in the UK who had purchased

pregabalin on the street reported paying approximately £2 per 300 mg tablet. (Lyndon

2017)

Advice for Clinicians

There have been practice guidance documents produced for clinicians reflecting the

concern and growing awareness of pregabalin’s abuse potential. For example:

▪ In Ireland a guidance document has been produced for clinicians entitled “Pregabalin

– Guidance for people working with pregabalin users. How to reduce the risks.” The

document explains what pregabalin is, features of recreational use and harm

reductions strategies. (Extern 2017)

▪ In the UK, the NHS produced a document on “Prescribing advice for Pregabalin”

which recommends that clinicians be aware of the risk of abuse and addiction to

pregabalin, even in patients with no known history of abuse; and consider the street

value of the drug. (NHS 2017)

▪ Also in the UK, a document was developed to provide advice for prescribers on the

risk of the misuse of gabapentin and pregabalin. PHE and NHS England (2014)

Literature Reviews

▪ Evoy 2017 – USA. Systematic Review key points: growth of epidemiological studies;

abuse appears to be more prevalent in opioid abusers; supratherapeutic doses typically

needed to achieve euphoria.

▪ Schjerning 2016 – Denmark. Systematic Review key points: literature suggest an

important abuse potential; prescribers need to be cautious when prescribing,

particularly to patients with a substance use history, and look for signs of abuse.

▪ Schifanao 2014 – UK. Review key Points: Pregabalin experimenters are those with a

recreational drug histories, administering excessive dosages; physician need to assess

for history of substance use.

▪ CADTH 2012 – Canada. Systematic Review key points: Further

psychopharmacological studies are needed to assess pregabalin abuse liability across a

range of doses in sedative abusers, and in combination with other CNS-active drugs.

14. Nature and Magnitude of Public Health Problems Related to Misuse,

Abuse and Dependence

Overdose

There is a case series describing 10 patients admitted to an Emergency Department in

Belfast over a one year period with pregabalin abuse. All were between 20-35 years old,

with dosages ranging from 500-1400 mg. Nine were admitted for over 24 hours, 6 patients

had seizures, and 2 patients were admitted to the Intensive Care Unit. (Millar 2013)

Pregabalin levels were determined in 70 postmortem cases from a 2 year period in the

United Kingdom. They attributed one death to pregabalin toxicity with a concentration of

76 mg/L. Although the majority of the people had been prescribed pregabalin, other drugs

39th ECDD (2017) Agenda item 5.1 Pregabalin

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were present in all samples. In several cases, death was attributed to multiple drug toxicity

involving opioids and other drugs of abuse. (Eastwood 2016)

In a review of 93 postmortem cases, 9 of them were determined to have pregabalin

contribute to death. The authors comment that the prevalence of methadone and other

opioids in these cases raises the profile of pregabalin as a drug with the potential for abuse,

and recommends that laboratories include pregabalin in their protocols. (Elliot 2017)

In the United Kingdom and Wales there has been an increase of 24% each year in the

number of gabapentoid (pregabalin and gabapentin) prescriptions from 2004 to 2015,

which has been highly correlated with an increase in deaths where a gabapentoid was

mentioned on the death certificate (correlation coefficient 0.96). (Lyndon 2017) In 79% of

these deaths opioids were also mentioned.

Driving

In one study, pregabalin did not interfere with simulated driving ability after 2 doses of 75

mg compared to placebo in healthy volunteers. (Tujii 2014)

In 2012, 206 drivers in Finland who were apprehended for driving under the influence had

pregabalin detected in serum samples at concentrations ranging from 0.68 – 111.6 mg/L.

Over half of the samples were deemed to be above a therapeutic range, suggesting use for

recreational purposes. Interpretation is difficult however since in most cases the driver had

also taken other drugs. (Kriikku 2014)

Pregabalin and Opioids

In light of the frequency of references to pregabalin use in combination with opioids,

particularly cases of overdose death, there are a potential public health implications.

Therefore, understanding the nature of the combined effects is important.

In a study evaluating the respiratory effects of pregabalin and morphine together in mice,

the combination produced additive depression of respiration (rather than synergistic). In

addition, when pregablin was administered to morphine tolerant mice, pregabalin appeared

to reverse the tolerance to respiratory depression. The authors comment that these findings

support the suggestion that the combination increases the risk of overdose death. (Lyndon

2017)

In a series of preclinical studies, mice were more sensitive to sedation by pregabalin in the

context of chronic morphine exposure, without evidence of rewarding effects from

pregabalin. The study also showed that pregabalin may attenuate both morphine self-

administration and morphine withdrawal signs. (Vashchinkina 2017)

In the abuse liability study by Zacny et.al., (2012) the hypothesis was that pregabalin

would potentiate oxycodone’s abuse liability. The combination of pregabalin 75 mg and

oxycodone 10 mg increased the endorsement of “take drug again’ whereas neither drug

alone did. However, since the drug combination also produced negative effects (headaches)

the authors concluded that the study did not support the hypothesis at these doses.

39th ECDD (2017) Agenda item 5.1 Pregabalin

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Pregabalin’s effects on opioid withdrawal symptoms was studied in a small randomized,

controlled trial in 34 opioid dependent participants undergoing opioid withdrawal. Patients

receiving pregabalin 600mg/day over 6 days had better treatment retention compared to

those receiving clonidine 600 μg/day (79% vs 47%, respectively), had lower opioid craving

scores (p=0.03) and lower depression scores (p=0.2), with similar opioid withdrawal

severity. (Vashchinkina 2017)

15. Licit Production, Consumption and International Trade

Refer to Annex 1: Report on WHO questionnaire for review of psychoactive substances.

16. Illicit Manufacture and Traffic and Related Information

Refer to Annex 1: Report on WHO questionnaire for review of psychoactive substances.

17. Current International Controls and Their Impact

Pregabalin is not controlled under the 1961, 1971 or 1988 United Nations Conventions.

18. Current and Past National Controls

In July 2005, the United States Drug Enforcement Administration (DEA) placed pregabalin

and all products containing pregabalin into Schedule V of the Controlled Substances Act

(CSA). (Drug Enforcement Administration 2005)

In the United Kingdom, the Advisory Council on the Misuse of Drugs recommended that

pregabalin be controlled under the Misuse of Drugs Act 1971 as Class C substances, and

scheduled under the Misuse of Drugs Regulations 2001 (as amended) as Schedule 3, so as

not to preclude legitimate use on prescription. (Iverson 2016).

19. Other Medical and Scientific Matters Relevant for a Recommendation on

the Scheduling of the Substance

None.

39th ECDD (2017) Agenda item 5.1 Pregabalin

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Annex 1: Report on WHO Questionnaire for Review of Psychoactive

Substances for the 39th ECDD: Evaluation of Pregabalin

Please refer to separate Annex 1 document published on ECDD website