kratom from head to toe—case reviews of adverse events and ... · kratom from head to toe—case...

PHARMACOLOGY CARE (J FANIKOS, SECTION EDITOR)

Kratom from Head to Toe—Case Reviews of Adverse Eventsand Toxicities

Emad Alsarraf1 & Jamie Myers2 & Sarah Culbreth1& John Fanikos1

# The Author(s) 2019

AbstractPurpose of Review This review describes case reports for patients with kratom-associated adverse events in order to assistclinicians with patient management. A stepwise approach is proposed for assessing active kratom users as well as considerationsfor the management of toxicities or withdrawal.Recent Findings Multiple in vitro and in vivo studies illustrate the pharmacologic and toxicologic effects of kratom extract. Norandomized controlled trials in humans exist that assess the safety and efficacy of the substance. Cross-sectional surveys fromactive users and reports from poison control centers have shown acute and chronic physiological and psychological adverseevents.Summary Reports of adverse effects associated with kratom use have demonstrated hypothyroidism, hypogonadism, hepatitis,acute respiratory distress syndrome, posterior reversible encephalopathy syndrome, seizure, and coma. Overdose toxidrome leadsto respiratory failure, cardiac arrest, and fatalities. Adult and neonatal withdrawal symptoms have also occurred. Cliniciansshould be aware of the risks and benefits of kratom use.

Keywords Kratom .Mitragyna speciosa . Adverse events . Toxicity

Introduction

We completed a review ofMitragyna speciosa (MS), which is apsychoactive plant that belongs to the Rubiaceae family, orcoffee family (Fig. 1) [1, 2]. Human consumption of the plantleaves was first documented in the late nineteenth century whennative’s used it for ceremonial and medicinal purposes in thetropical and subtropical regions of southeast Asia and Africa [2,3]. Traditionally,MSwas used to control ailments such as fever,diarrhea, cough, fatigue, and decreased libido, in addition totreat conditions such as enteritis, parasitic and herpes zosterinfections, diabetes, hypertension, and depression [2–8].Natives consumed MS by various routes: chewed raw, boiledin water as a beverage, or inhaled as a vapor [6–8]. Today, MS

is known as kratom, first named by natives in Thailand [8].Kratom use has surpassed its region of origin and reached con-sumers around the world, mainly for its proclaimed psychoac-tive properties [9]. In 2016, The American Kratom Association(AKA) estimated that there are 3–5 million active and regularkratom users in the United States (USA). [10] Despitelongstanding and increasing kratom use, controlled trials eval-uating efficacy and safety have not been performed [11••].Surveys of active kratom users reported dual and dose-dependent stimulant-like properties and opioid-like euphoriceffects: as decreased pain (85%), increased energy (84%), andless depressive mood (80%) [12••]. These effects are exploitedmedicinally for analgesia, withdrawal from illicit drug or pre-scription opioidmedicine, or backgroundmental/emotional dis-order [13]. The positive experiences from kratom such as eu-phoria, relaxation, sociability, and productivity have been at-tractive for recreational use in substance use disorder and incultural festivities [14, 15].

Pharmacology and Preclinical Studies

Kratom contains about 25 pharmacologically active alkaloids,of which mitragynine (MG) and 7-hydroxymitragynine (7-

This article is part of the Topical Collection on Pharmacology Care

* Emad [email protected]

1 Department of Pharmacy Services, Brigham and Women’s Hospital,75 Francis Street, Boston, MA 02115, USA

2 Department of Investigational Drug Services, Brigham andWomen’sHospital, 75 Francis Street, Boston, MA 02115, USA

https://doi.org/10.1007/s40138-019-00194-1Current Emergency and Hospital Medicine Reports (2019) 7:141–168

Published online: 11 September 2019

http://crossmark.crossref.org/dialog/?doi=10.1007/s40138-019-00194-1&domain=pdf

mailto:[email protected]

HMG) are the most prevalent [16]. MG and 7-HMG are dose-dependent agonists of the μ-, κ-, and δ-opioid receptors in thecentral nervous system (CNS) as well as non-opioid receptors[6, 7, 16, 17••, 18, 19]. Their non-selectivity likely results inthe beneficial multimodal effects of kratom especially for an-algesia and mood elevation [20]. In vitro studies have exhib-ited cytotoxic effects on human neuronal, hepatic, and cardiacmyocyte cell lines and have shown neuromuscular blockingeffects [21–24]. Kratom was also reported to inhibit CYP 450hepatic enzyme, particularly CYP 3A4, 2D6, and 1A2 [29,30]. In toxicological in vivo animal studies, test subjects ex-hibited adverse effects such as hepatitis, nephrotoxicity, re-duced sperm production, addiction and tolerance, long-termcognitive deficits, generalized convulsions, and fatalities withhigh doses [18, 19, 25–28].

Emerging Use and Regulatory Concerns

Increasing kratom use has resulted in increased reports of ad-verse events. Attributing these reports solely to kratom is com-plicated by the absence of standardized product manufacturingand voluntary adverse event reporting. Between 2011 and2017, calls to US Poison Control Centers (PCC) show thatkratom poisoning and fatality cases have increased 58-fold in6 years. One-third of these cases resulted in healthcare facilityadmission [31••]. Cross-sectional surveys highlighted opioid-like adverse events such as intoxication, addiction, and kratom-associated withdrawal symptoms [11••, 33–38]. Many westerncountries and a number of US states have banned kratom pos-session and/or sales. Despite these control efforts, availabilityonline has eased the accessibility to kratom products. In theUSA, many kratom products used are without goodmanufacturing practices outlined by the Food and DrugAdministration (FDA) or subject to quality assessments. InFebruary 2018, the FDA issued warnings regarding 44 fatalitiesassociated with kratom [32]. In 2019, twowarnings were issuedregarding selected kratom product impurities; a warning inFebruary for potential heavy metal poisoning following labora-tory discovery of elevated lead and nickel levels and anotherwarning inMarch for nationwide recall for potential Salmonella

contamination following a series of Salmonella infection out-breaks [39, 40]. A 2017 survey showed that about 40% ofactive kratom users consult their healthcare professionals (phy-sician, nurse, or pharmacist) about use indicating that there is apublic need for evaluating risks and benefits [11••]. This reviewis intended to help healthcare professionals assess the adverseevents associated with kratom use. In addition, we propose astepwise algorithm for assessing patients actively using kratomand discuss considerations for management of kratom-associated adverse events and toxicities.

Literature Case Review

We performed a systematic literature review usingMEDLINE, Embase, and Google Scholar. Main search termswere “Mitragyna speciosa” and “kratom” combined with ap-propriate Boolean phrase. We included only case reports andcase series written in English that were published fromJanuary 2008 to March 2019. Botanical, pharmacokinetic,analytical, or preclinical studies, and surveys were excluded.Overall, there were 41 cases on kratom-associated adverseevents or toxicities (Table 1). Kratom-associated adverseevents were as follows: kratom-associated withdrawal symp-toms (KAWS) in adults [41–52], kratom-associated neonatalabstinence syndrome (KANAS) [48, 52–56], hypothyroidism[43], hypogonadism [57], kratom-induced hepatoxicity (KIH)[58–65], CNS effects causing seizure and coma or posteriorreversible encephalopathy syndrome (PRES) [39, 66, 67],acute respiratory distress syndrome (ARDS) [68, 69], over-dose toxidrome [70, 71], and fatalities [72–80]. There weresix case series of aggregated patient’s data [48, 49, 51, 73, 77,80]. There were also mixed presentations: KAWS and seizure[41], hypothyroidism [43], or KANAS [48].

Kratom-Associated Withdrawal in Adults[41–52]

Tolerance generally occurred after 3 months [42], and afew patients described escalating their doses four to ten

Fig. 1 Mitragyna Speciosa tree, leaf, and capsules. a Tree. b Leaf. c Capsules. Adopted from Drug Enforcement Agency (DEA) [1]

Curr Emerg Hosp Med Rep (2019) 7:141–168142

Table1

Summaryof

case

reportson

kratom

-associatedadverseevents

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

Cases

ofkratom

-associatedwith

draw

alsyndrome(K

AWS)

inadults

Boyer

etal.

[41]

2008

(USA

)

A43-year-oldman

admitted

forevaluatio

nof

ageneralized

tonic-clonicseizureand

coincidedwith

signsof

opioid

with

draw

al

ACTIV

E•Chronicpain

HISTORY

•Su

bstanceabuse

(hydromorphone)

PURPO

SE•Chronicpain

•Opioidsparing

DOSE

•Fo

urtim

esdaily

FORM

•Tea

DURATIO

N3.5years

SUBJECTIV

E•Tim

esincelastdose:N

R•KAWS:

reported

symptom

ssimilar

toopioid

withdraw

al•Pattern

ofaddiction:

only

asshe

triesto

cutb

ackon

use,KAWS

develop

•Experiences

from

kratom

:substantialp

ainrelief,im

proved

alertnesswithoutd

rowsiness

•Described

co-ingestin

gmodafinil

OBJECTIV

E•Ph

ysicianobserved

features

ofKAWSsuch

asrhinorrhea,

insomnia,poor

concentration,and

myalgiaspersistin

gfor10

days

from

hislastkratom

dose

•Vitals:p

ulse

123beatsperminute,

bloodpressure

130/74

mm/Hg

•Confirm

edidentityof

kratom

via

high-perform

ance

liquid

chromatographyprotocols

INTERVENTIO

N•Induction/maintenance

•Buprenorphine/naloxone,reaching

amaintenance

dose

of16

mgperday

EFF

ECT

•Im

mediateeffects

•Rhinorrheaandpain

ceased

ontheday1

•Upondischarge,thepatientceased

useofkratom

abruptly

•Betterpain

control

•Long-term

effects

•Fo

llow-upurinescreens(unknowninterval)fordrugsof

abusehave

remainednegativ

e

McW

hirter

&Morris

[42]

2010

(UK)

A44-year-oldman

was

referred

tothe

substancemisuseserviceby

ageneral

psychiatristforassistance

with

akratom

detoxificatio

n.

ACTIV

E•Anxiety

anddepression

(mirtazapine)

HISTORY

•Alcohol

dependence

andpolysubstance

misuse

PURPO

SE•Well-beingand

anxiety

DOSE

•40

gin

4dosesdaily

FORM

•Oralliquid

DURATIO

N•Three

years

SUBJECTIV

E•Tim

esincelastdose:1

2h

•KAWS:

cravings,anxiety,

restlessness,sweatin

ganditch

•Pattern

ofaddiction:

Initially

took

single4-gdose.T

hen,dueto

toleranceafter3months,dose

increasedto8g,then

12.5

gtwice

daily,and

finally

10gevery6h.

Attempted

toself-detoxifyusing

diazepam

.•Experiences

followingkratom

:initially,experienced

4hof

euphoria,increased

productiv

ity,

industriousnessandrelaxatio

n.Later,experienced

withdraw

alsymptom

sdespite

beingon

every

6hdose

•Motive:Patient

wishedto

detoxify

becauseof

costandKAWS

OBJECTIV

E

INTERVENTIO

N•Detoxification(adm

itted

atdetoxificatio

nward)

•Dihydrocodeine60

mg4tim

esdaily

plus

lofexidine

0.2mgtwicedaily,titrated

againstthe

severity

ofwith

draw

alsymptom

s•Usedopioid

with

draw

alsymptom

schart:pulse,

sweatin

g,restlessness,pupilsize,boneor

jointaches,

runnynose

ortearing,gastrointestinalupset,trem

or,

yawning,anxiety

orirritability,andgooseflesh

skin

EFF

ECT

•Im

mediateeffects

•Day

1:Patient

feltvery

anxious,cold,restless

and

nauseatedbutreduced

bydihydrocodeine.D

ueto

poor

sleep,patient

took

hiskratom

asnorm

al•Day

2:Patient

feltcravings,chills,nausea,aches,pains,

irritable,andvisiblytrem

ulouswhich

allimproved

follo

wingdose.B

lood

pressure

andheartrate

norm

alized.

•Day

3:symptom

sweresubjectiv

elyandobjectively

muchim

proved.D

ihydrocodeinewas

reducedto30

mg

twicedaily

andlofexidine

was

discontinued.

Curr Emerg Hosp Med Rep (2019) 7:141–168 143

Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Appearedhighly

anxiouswith

evidence

ofpsychomotor

agitatio

n•Slight

fine

trem

orandthepupils

weremidsizedandreactiv

e•Nopsychotic

symptom

sor

cognitive

deficitsevidentu

pon

testing

•Vitals:h

ighbloodpressure

150/100mmHgandaregular

pulseof

80•Negativeforam

phetam

ines,

benzodiazepines,cocaine,and

opiates

•Elevatedgamma-glutam

yltranspeptidase(107

U/l)

anda

whitebloodcellcounto

f13.3×109/Lbutw

ereotherw

ise

norm

al•Alaboratory

analysisof

thekratom

was

notp

erform

ed.

•Day

4:patient

reported

feeling“backto

norm

al”albeit

andwas

discharged

with

nofurtherdihydrocodeine

orlofexidine

•Long-term

efficacy

•Patient

hadremainedabstinentfrom

kratom

when

followed

upin

theoutpatient

clinicat2weeks

after

discharge

•Detoxificationfrom

kratom

was

describedas

more

difficultthanalcohol.

•Ongoing

sleepdisturbanceandcravings

forthe

substance

reem

ergedandhadstartedto

meetin

gsforaidin

abstinence

Sheleg

&Collin

s[43]

2011

(USA

)

A44-year-oldman

presentedto

specialty

clinicforalcoholand

drug

recovery

ACTIV

E•Chronicpain

syndrome

(methadone

and

oxycodone)

HISTORY

•Alcohol

abuse

PURPO

SE•Pain

•Opioidspare

DOSE

•6drops4–6h

FORM

•Oralliquid

DURATIO

N•One

year

SUBJECTIV

E•Tim

esincelastdose:1

2h

•KAWS:

cram

ping

abdominalpain,

sweating,anddiarrhea

•Pattern

ofaddiction:

NR

INTERVENTIO

N•Detoxification

•Buprenorphine

inductionforKAWS

EFF

ECT

•KAWSsubsided

with

in3days

andpatient

was

discharged

•Fifteenmonthslater,thepatient

was

still

onoralopiates

(methadone

andoxycodone)

forhischronicpain

syndrome

Galbis-Reig

[44]

2016

(USA

)

A37-year-oldwhitewom

anadmitted

tothe

inpatient

mentalh

ealth

andaddiction

serviceaftercontactin

gtheunitfor

treatm

ento

fan

“addictio

nto

kratom

”

ACTIV

E•None

HISTORY

•Po

stpartum

depression

(sertraline)

PURPO

SE•Pain

from

Capel

tunnelsurgery

FORM

•Oralcapsule

DURATIO

N•Tw

oyears

SUBJECTIV

E•Tim

esincelastdose

10h

•KAWS:

cravings,severeabdominal

cram

ps,sweats,blurred

vision,

nausea,vom

iting,and

diarrhea

•Experiences

from

kratom

:pain

reliefand“boostof

energy”

•Pattern

ofaddiction:

hiding

the

bottles,failedattempt

tocutb

ack

with

outexperiencingwith

draw

alsymptom

s.Increasedtheuseover

aperiod

of6months

unintentionally

(tolerance).Was

trialedon

clonidinewithout

success

OBJECTIV

E

INTERVENTIO

N•Detoxification

•Sy

mptom

-triggered

clonidineatadose

of0.1–0.2mg

every2hbasedon

theclinicalopioid

with

draw

alscale

(COWS)

+scheduledhydroxyzine50

mgevery

6h+0.1mg/dayclonidinepatch

•COWSusethefollo

wingto

assess

severity:p

upillary

dilatatio

n,diaphoresis,gastrointestinaldistress,anxiety,

fever,bone

andjointp

ains,increased

lacrim

ationor

rhinorrhea,tremors,andyawning

EFF

ECT

•Im

mediateeffects

•COWSscorewas

high

enough

forp

atientrequiringup

to2mgof

oralclonidineover

thenext

36h.

Hyper-autonom

icsymptom

sim

proved

rapidlyoverthe

course

of2to

3days.


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Examinationwas

unremarkable

except

formild

diaphoresisof

the

palm

sandback

oftheneck,

dilatedpupil(2–3mm)and

significantcachexia.

•Urine

toxicology

was

negativ

efor

alld

rugs

ofabuse.

•Urine

MGwas

positive(cutoff

10mcg/L)usingliq

uid

chromatography–mass

spectrom

etry

method

•Startedvenlafaxinefordepression

andpregabalin

for

anxietysincethisoccurred

with

previous

attemptsto

detoxify

from

kratom

•Fo

llowing3days

ofadmission,the

patient

was

discharged

andprovided

with

aprescriptio

nto

start

naltrexone50

mgby

mouth

daily

tobeginno

sooner

than

7days

foranycravings

•Long-term

effects

•NR

Tavakoli

etal.[45]

2016

(USA

)

A33-year-oldman

presentedto

family

physicianforaworsening

ofuncontrolled

back

pain

from

motor

accident

3months

ago

ACTIV

E•Backpain

•Auditory

hallu

cinations

HISTORY

•Violenceandhomicide

attempt

PURPO

SE•Pain

•Opioidspare

FORM

•Oralp

ills

SUBJECTIV

E•KAWS:

body

aches,chills,

rhinorrhea,and

significantly

worsenedirritabilityfrom

his

baselin

e•Experiences

from

kratom

:exacerbatio

nof

patient’s

background

psychotic

symptom

sof

hallu

cinatio

nsandpersecutory

delusions.Itwas

beneficialfor

pain,but

hedidnoticeworsening

inhisaggression

towardhis

spouse

andcoworkers.

OBJECTIV

E•Urine

testsnegativeforsynthetic

opioidsandcannabinoids

INTERVENTIO

N•None,patient

was

admitted

topsychiatricunitand

diagnosedwith

schizoaffectivedisorder,depressive

type

inadditio

nto

opioid

usedisorder

•Proposed

todiscontin

uekratom

use

•Antipsychoticmedications

startedandpatient

was

discharged

onday16

EFF

ECTS

•Im

mediateeffectandlong-term

effects

•NR

Jayadeva

etal.[46]

2017

(USA

)

A34-year-oldCaucasian

man

presentedto

hospitalrequestingdetoxificatio

nunderinpatient

detoxificatio

nunit

HISTORY

•Opioidusedisorder

•Po

sttraumaticstress

disorder

•Major

depressive

disorder

PURPO

SE•Opioiduse

DOSE

•10

gtwicedaily

FORM

•Tea

SUBJECTIV

E•Tim

esincelastdose:N

R,

self-transitioned

from

kratom

tobuprenorphine/naloxone

(4mg/1mg)

priorpresentatio

n•KAWS:

restlessness,anxiety,sleep

disturbance,sw

eats,and

diarrhea

•Pattern

ofaddiction:

escalatedhis

useof

kratom

to10

gtwicedaily

dueto

KAWS

•Experiences

followingkratom

administration:

nofeelings

ofeuphoria,instead

experiences

relieffrom

theelim

inationof

KAWS

•Motive:patient

wishedto

detoxify

underspecialistsupervision.

OBJECTIV

E

INTERVENTIO

N•Detoxification

•Self-transitioned

from

kratom

tobuprenorphine/naloxone

(4mg/1mg)

athome

•Continuedon

buprenorphine/naloxone

atthehospital

EFF

ECT

•Im

mediateeffects

•Com

pleted

a3-dayuncomplicated

detoxificatio

nand

discharged

toresidentialaddictio

nprogram

after

detoxificatio

n•Long-term

effects

•NR


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Urine

toxicology

was

positiv

efor

opioids.

Lydecker

etal.[47]

2017

(USA

)

A29-year-oldman

presentedto

theED

complaining

ofpain

inarms

HISTORY

•Substance

usedisorder

PURPO

SE•Opioidspare

DOSE

•1ml6

times

daily

FORM

•Intravenous

SUBJECTIV

E•Tim

esincelastdose:6

h•KAWS:

runnynose,w

ateryeyes,

goosebumps,the

pukesandthe

shakes,allareless

intensethan

opioid

•Experiences

from

kratom

:initially,

stim

ulanteffectsthen

thiseffect

weanedhenceincreasedtheuseof

theproduct

•Pattern

ofaddiction:

initially

drinking

kratom

teadaily,then

severaltim

esdaily,untilhe

found

away

toinjectitintravenously.

Now

injectingkratom

extractin

alcohol.Tried

tram

adol

and

diphenhydram

ineto

help

with

KAWS

OBJECTIV

E•Normalvitals:afebrile

with

apulse

of95

beatsperminute,blood

pressure

of138/82

mmHg

•Cubitalfossaenotableforerythem

a,consistent

with

superficial

thrombophlebitis

•Elevatedwhitebloodcellcounto

f12.1

cells/μl

•Urine

positiv

efortram

adol,

meprobamate,diphenhydram

ine,

andAPA

P,butn

egativeforMG

and7-HMG

INTERVENTIO

N•Plannedto

detoxify

butlosto

nfollo

w-up

•Provided

1gof

cefazolin

forthrombophlebitis

Mackay&

Abraham

s[48]

2017

(Canada)

A29-year-oldwom

anadmitted

onpostpartum

day2from

anotherhospitalw

iththegoal

oftapering

herdaily

kratom

usewhile

admitted

toperinataladdictio

nsunit

ACTIV

E•Backpain

HISTORY

•Anxiety

•threeabortio

ns•Su

bstanceabuse

(Oxycodone)

PURPO

SE•Pain

DOSE

•18–20gthreetim

esdaily

FORM

•Po

wder

DURATIO

N•Tw

oyears

SUBJECTIV

E•Tim

esincelastdose:4

–6h

•KAWS:

diaphoresis,rhinorrhea,

myalgia,anxiety,nausea,diarrhea,

andpiloerectio

n•Experiences

from

kratom

:effectivelytreatedherback

pain

andim

proved

hermoodand

anxiety.

•Pattern

ofaddiction:

symptom

sdevelopifdose

was

delayedby

4to

6h.To

leranceoccurred

butN

Rtheinterval.

INTERVENTIO

N•Detoxification(aim

toreduce

kratom

use)

•Morphine10

mgorally3tim

esdaily,offered

becauseof

affordability

EFF

ECTS

•Im

mediateeffects

•Kratom

dose

was

reducedto

10g(instead

of20

g)•Sy

mptom

sim

proved

over

fewdays

ofadministration

•Patient

was

slow

lyweanedoffkratom

andmorphine.

•Long-term

effects

•Kratom

was

stoppedin

4weeks

afterstarting

detoxificationwhich

was

theentirelength

ofhospitalization.


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

OBJECTIV

E•Recently

deliv

ered

mother

•Thoughdiscussed,patient

wantedto

beoffkratom

and

othersubstance,so

maintenance

was

notp

rovided.

Buresh[49]

2018

(USA

)A60-year-oldwom

anwho

was

referred

from

intensivecare

forunintentional

opioid

overdose

andnowpresentingto

buprenorphinepracticeclinicfor

maintenance

course

ACTIV

E•Alcohol

dependence

(rem

ission)

•Chronicpain(tramadol,

duloxetin

e,pregabalin)

•Opioids

misuse

(methadone)

PURPO

SE•Pain

DOSE

•0.25

ozfour

times

daily

SUBJECTIV

E•Tim

esincelastdose:

Self-transitioned

detoxafter17

hof

with

draw

alsymptom

,now

unknow

nwhendetoxwas

taken

priorto

presentatio

n.•KAWS:

rhinorrhea,irritability,and

increasedpain

•Pattern

ofaddiction:

unableto

stop

usingkratom

dueto

reboundpain

andwith

draw

alsymptom

swhen

dose

isdecreased

OBJECTIV

E•Urine

toxicology

was

positiv

efor

tram

adol

andnegativ

eforopiates.

INTERVENTIO


(aim

tobe

offopioids

andkratom

)•Startedonedose

ofbuprenorphine/naloxone

4–1mgat

homeandnowincreasedto

4–1mg4tim

esdaily

athospital.

EFF

ECT

•Im

mediateeffects

•Resolutionof

herpain

symptom

s•Urine

drug

testinghasbeen

negativ

eforfull-agonist

opioidsandpositiv

efor

buprenorphine/norbuprenorphine.

•Long-term

effects

•Fo

llowup

in9monthsshow

scontinuedpaincontroland

functionalg

oal

•Reduced

pregabalindose

(from300mgto200mgBID

)A57-year-oldman

who

was

referred

byhis

prim

ary

care

doctor

totheclinic’sbuprenorphine

practice

toaidwith

hiskratom

addiction

ACTIV

E•Chronicpain

•Anxiety

•Depression

•Opioids

misuse

(Oxycodone)

PURPO

SE•Energy

•Opioidspare

DURATIO

N•One

year

SUBJECTIV

E•Tim

esincelastdose:

Self-transitioned

detoxafter14

hof

with

draw

alsymptom

,now

unknow

nwhendetoxwas

taken

priorto

present.

•KAWS:

anxiety,edginess,and

leg

shaking

•Pattern

ofaddiction:Afterinitiation,

patient

quicklydevelopeda

toleranceandescalateduse

(intervalN

R).Oncestopped,

patient

reported

KAWS.

OBJECTIV

E•Urine

toxicology

was

positiv

efor

codeineandmorphineand

negativ

eforallo

ther

substances.

INTERVENTIO


(aim

tocontrolchronicpain

and

KAWS)

•Startedonedose

ofbuprenorphine/norbuprenorphine

8–2mgathome

EFF

ECT

•Im

mediateeffects

•During1-month

use,dose

increasedto

24mgdaily

(dosed

6mg4tim

esdaily)basedon

pain

intensity

•Long-term

effects

•Sevenmonthsafterstart,urinetoxicology

was

positive

forbuprenorphine/norbuprenorphine

andnegativefor

otheropiates

Khazaeli

etal.[50]

2018

(USA

)

A52-year-oldwom

anadmitted

toan

inpatient

acutepsychiatry

unit

with

achiefcomplaint

ofincreased

depression,anxiety,and

fleetin

gsuicidal

thoughts.S

healso

reported

symptom

sconsistent

with

opioid

withdraw

al.

ACTIV

E•Depression

•Opioidmisuse

•Chronicpain

•Anxiety

(trazadone,

sertaline,gabapentin,

clonazepam

)

PURPO

SE•Pain

DOSE

•1tsp.every4–6h

DURATIO

N•Ninemonths

SUBJECTIV

E•Tim

esincelastdose:6

–12h

•KAWS:

dysphoria,nausea,m

uscle

aches,sw

eating,goosebumps,and

insomnia,rhinorrhea,diarrhea,

upsetstomach,anxiety,restless

legs,and

increasedpain

•Pattern

ofaddiction:

Powderwas

hidden

from

family.D

ose

escalatedfrom

a¼

to1tsp.4to

6tim

esdaily

inan

effortto

achieve

INTERVENTIO


•Startedbuprenorphine/naloxone

4/1mggivenevery2h

with

closemonitoring

formentalstatusandwith

draw

alsymptom

sEFF

ECT

•Im

mediateeffects

•Day

1:totaloffourd

oses

weregivenandpatientreported

improvem

ento

fKAWS

•Day

2:taperoff,dose

was

decreasedto2/0.5mg4tim

esdaily


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

pain

relief,gradually

over

9months.

OBJECTIV

E•Urine

toxicology

screeningwas

positiv

eonly

forbenzodiazepines.

•Urine

testingforkratom

was

not

done.

•Day

3:kepton

samedoseasmaintenance

doseforthe

rest

ofadmission

•Day

6:patient

was

discharged

homeon

buprenorphine/naloxone

2/0.5mg4tim

es•Patient’svitalsigns

werestablein

admission.

•Othermedications

athospitalization:lorazepam

forjerks

andbaclofen

tohelp

with

clonazepam

dose

tapering.

Hom

emedications

wereresumed

•Long-term

effects

•Dosewas

laterincreasedto

8/2mgtwice

•Self-reportedsoberwith

nosymptom

sof

opioid

withdraw

alor

craving

•Self-reportedcomplianceto

maintenance

treatm

entfor

18months(urine

samples

check)

Stanciu

etal.[51]

2018

(USA

)


femalepresentedto

theEDvery

tearful,endorsingsymptom

sof

restlessness,generalized

body

aches,

overwhelm

inganxiety,andthoughtsof

suicidewith

noparticularplan

ACTIV

E•None

PURPO

SE•Energy

DURATIO

N•Tw

oyears

SUBJECTIV

E•Tim

esincelastdose:n

otreported

•KAWS:

anxiety

•Pattern

ofaddiction:

cannot

gowith

outthem

over

12h

•Experiences

from

kratom

:initially

beganexperimentin

gwith

kratom

asa“natural”energy

supplement

giving

herenergy,staminaand

“intothemoon.”

•Nobackground

mentald

isorder

OBJECTIV

E•Vitals:tachycardiaof

102beatsper

minute,hypertension

of158/100,

andabody

temperature

of107°F

with

norm

alpulse

•COWSscoreof

16

INTERVENTIO

N•Detoxification

•Startedsymptom

-triggered

clonidine0.1mgevery2has

needed,and

onscheduledgabapentin,300

mg,three

times

daily

•Other:lorazepam

0.5mgPO

ontwooccasions,30

min

apart,with

little

resolutionof

anxietysymptom

swhile

waitin

gforevaluatio

nEFF

ECT

•Im

mediateeffects

•Day

1:four

dosesof

clonidine.Gabapentin

didcontrol

someof

therestlessness,but

shehadadifficulttim

esleeping

dueto

sweating

•Day

2:COWSreducedto

8andonly

required

1dose

ofClonidine.Irritabilitywas

challenging

•Day

3:COWSreducedto

1andno

clonidinewas

not

required,and

gabapentin

was

discontinued

•Day

5:discharged

from

hospitalw

ithoutany

drug

•Long-term

effects

•NR

A27-year-oldunmarried

malewas

referred

toapsychiatrichospitalfollowing

presentatio

nto

anEDatageneralh

ospital

with

complaint

ofsuicidalideatio

nand

feelings

ofhopelessness

andhelplessness

ACTIV

E•Bipolar

•Schizophrenia

•Su

bstanceabuse

(Clonazepam)

HISTORY

•Opioidabuse

(Methadone

maintenance)

PURPO

SE•Opioidspare

DOSE

•5gperday

DURATIO

N•Three

years

SUBJECTIV

E•Tim

esincelastdose:2

4h

•KAWS:

•Pattern

ofaddiction:

requestedto

continue

tousethem

during

his

hospitalization

•Experiences

from

kratom

:decreasedhiscravingforopioids

OBJECTIV

E•Vitals:tachycardiaof

102beatsper

minute,hypertension

of158/100,

INTERVENTIO

N•Fo

rmoodim

provem

entand

hallu

cinations,quetiapine

was

started.

•Fo

rbenzodiazepine

with

draw

al,diazepam

taperwas

giventhen

gabapentin

•For

KAWS(based

ondaily

COWSassessment),patient

was

offeredclonidine0.1mgthreetim

esas

needed

EFF

ECTS

•Im

mediateeffects

•NoCOWSscoreexceeded

8andthepatient

received

atotalo

fsixdosesof

clonidine.


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

andabody

temperature

of107°F

with

norm

alpulse

•COWSscoreof

16

•Atd

ischarge,patient

show

edno

depressive

orpsychotic

symptom

s,andno

residualcravingforopioids

•Long-term

effects

•NR

Smid

etal.

[52]

2018

(USA

)

A32-year-oldpregnant

whitewom

anat

22weeks

(6months)of

gestationwas

referred

toaspecialty

prenatalclinicforpregnant

wom

enwith

substanceusedisordersforkratom

dependence.

ACTIV

E•Su

bstanceusedisorders

•Pain

(oxycodone)

•Anxiety

HISTORY

•Hodgkin’slymphom

a(treated

with

radiation)

PURPO

SE•Pain

andanxiety

FORM

•Tea

DURATIO

N•Severalm

onthsuntil

week16

ofgestation

(4months),but

couldnotstopit

•Overlap

with

pregnancy:

6months

SUBJECTIV

E•Tim

esincelastdose:N

R•KAWS:

notreported,only

asshe

triesto

cutd

ownon

use

•Pattern

ofaddiction:

only

asshe

triesto

cutb

ackon

use,KAWS

develop

OBJECTIV

E•Urine

toxicology

was

negativ

efor

opioidsandpositiveforMGand

7-HMG(61and980ng/dL,

respectiv

ely)

usinggas

chromatographyandmass

spectrom

etry.

INTERVENTIO


(aim

tocontrolK

AWS,

pain,and

preventK

ANAS)

butinitially,detoxificationwas

intended

•Buprenorphine

8mg

EFF

ECT

•Im

mediateeffects

•Initiationandstabilizatio

nwereachieved

at8mgfor

KAWSandpain

•Maintainedon

buprenorphine2mgduring

pregnancy

•Long-term

effects

•Delivered

ahealthybaby

with

noNAS,

andmotherwas

kept

onbuprenorphinewhileathospital

•Motherand

neonatecontinuedtodo

well,with

outclinical

ortoxicologicevidence

ofmaternalrelapse

orNAS

Aterm

femaleneonatewas

born

from

adetoxified

mother,yetthe

neonateshow

edsignsof

NASatday4of

age.

MOTHER

•Activebipolardisorder

(escitalopram

,lamotrigine,and

quetiapine)

•History

ofsubstance

usedisorders(IV

heroin)

•History

ofalcoholu

sedisorder

(rem

ission)

NEONATE

•NR

PURPO

SE•Recreational

FORM

•Inhaled

DURATIO

N•Started4months

beforepresentatio

n(presented

onweek

19of

gestation)

•Overlap

with

pregnancy:

4months

SUBJECTIV

E•Pregnant

motherwas

initiated

onbuprenorphine/naloxone

onweek

19of

gestationforpreventio

nof

neonatalKAWSandmaintainedat

adose

of20

mgbuprenorphine

and3mgnaloxone

daily

until

deliv

eryon

week39

ofgestation

•Buprenorphine/naloxone

overlap=last20

weeks

ofpregnancy

OBJECTIV

E•Healthyinfant

delivered

butshown

KANASon

day4of

lifeafter

deliv

ery

•KANAS:

NR

INTERVENTIO

N•Pregnant

motherwas

initiated


onweek19

ofgestationfor

preventionof

neonatalKAWSandmaintainedatadose

of20

mgbuprenorphineand3mgnaloxone

daily

until

deliveryon

week39

ofgestation

•Buprenorphine/naloxoneoverlap=last20

weeks

ofpregnancy

EFF

ECT

•Health

yinfantdeliv

ered

butshownKANASon

day4of

lifeafterd

elivery.Morphinewas

startedandpatientwas

weanedanddischarged

onhospitald

ay12

Cases

ofkratom

-associatedneonatalabstinence

syndrome(K

ANAS)

Pizarro-Osi-

lla[53]2017

(USA

)

A1-day-old,tertcsm

infant

presentedto

the

ED

with

signsof

opioid

withdraw

al

MOTHER

•Anxiety

NEONATE

•Hypoglycemia

PURPO

SE•Relaxation

DURATIO

N•Overlap

with

pregnancy:

4months

OBJECTIV

E•KANASobserved:b

reathing

difficulties,irritability,jitteriness,

musclehypertonicity,and

ahigh-pitched,inconsolablecry

INTERVENTIO

N•Methadone

IVEFF

ECTS

•NR

Mackay&

Abraham

sAninfant,37preterm,w

astransferredto

atertiary

neonatalintensivecare

unit(N

ICU)to

be

MOTHER

•Backpain

NEONATE

PURPO

SE•Pain

DOSE

OBJECTIV

EIN

TERVENTIO

N•MorphineIV

upto

amaxim

umof

10mcg/kg/h

EFF

ECT


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

[48]

2017

(Canada)

treated

forNAS,

diagnosedatday2of

birth.

•NR

•18–20gthreetim

esdaily

FORM

•Po

wder

DURATIO

N•Tw

oyears

•Overlap

with

pregnancy:

entire

pregnancy

•KANASobserved:feeding

intolerance,jitteriness,irritability,

andem

esis

•Increasing

neonatalabstinence

(NAS)

scores

(scoretype

was

NR)

•Steppeddownto

oralmorphineonce

ableto

tolerate

•Transferred

tomotheron

day7of

birth

Eldridge

etal.[54]

2018

(USA

)

Aterm

maleneonatewas

admitted

following

birthafterexhibitin

gsignsopioid

with

draw

alat33-h

ofage.

MOTHER

•History

ofsubstance

abuse(oxycodone,

lasttaken2years

before

pregnancy)

PURPO

SE•Sleep

•Opioiduse

FORM

•Tea

DURATIO

N•Overlap

with

pregnancy:

entire

pregnancy

SUBJECTIV

E•Motherdenies

KAWSon

herself.

•Mothertoxicologicalscreen

yielded

negativ

eforopioids

OBJECTIV

E•KANASobserved:sneezing,

jitteriness,excessive

suck,facial

excoriations,restingtrem

ors,

irritability,high-pitchedcry,and

hypertonia

•Urine

drug

screen

yieldeda

negativ

eresultof

MGand7-HMG

•Finnegan

scores

wereelevated,

rangingfrom

9to

14

INTERVENTIO

N•1stlinetrialed:

morphine30

mcg/kg/3htitratedper

Finnegan

score

•2ndlinetrialedforthisrefractory

case:clonidine

1μg/kg

every3h

EFF

ECT

•Firstd

ayof

life:Finnegan

scoredroppedsignificantly

to2to

3•Excessive

sedatio

nandbradycardiaoccurred

despite

rapidweaning

ofmorphinedose

andfrequency,but

Finnegan

scores

also

was

low

•Third

dayof

life:Morphinewas

discontinued,butpatient

developedreboundwith

draw

alandFinnegan

scores

were11

to13

•Clonidine

(1mcg/kgevery3h)

was

trialed,Finnegan

scores

improved,but

also

patient

was

bradycardic

•Fifthdayof

life:clonidinewas

discontin

ued

•Sp

ontaneousim

provem

entw

hileoffdetox

•Eighthdayof

life:patient

discharged

Smid

etal.

[52]

2018

(USA

)

Aterm

femaleneonatewas

born

from

adetoxified

mother,yetthe

neonateshow

edsignsof

NASatday4of

age

MOTHER

•Activebipolardisorder

(escitalopram

,lamotrigine,and

quetiapine)

•History

ofsubstance

usedisorders(IV

heroin)

•History

ofalcoholu

sedisorder

(rem

ission)

NEONATE

•NR

PURPO

SE•Recreational

FORM

•Inhaled

DURATIO

N•Startedfour

months

beforepresentatio

n(presented

onweek

19of

gestation)

•Overlap

with

pregnancy:

4months

SUBJECTIV

E•Pregnant

motherwas

initiated


onweek

19of

gestationforpreventio

nof

neonatalKAWSandmaintainedat

adose

of20

mgbuprenorphine

and3mgnaloxone

daily

until

deliv

eryon

week39

ofgestation.

•Buprenorphine/naloxone

overlap=last20

weeks

ofpregnancy

OBJECTIV

E•Healthyinfant

delivered

butshown

KANASon

day4of

lifeafter

deliv

ery

•KANAS:

NR

INTERVENTIO

N•Morphine

EFF

ECT

•Patient

was

weanedanddischarged

onhospitald

ay12.

Davidson

etal.[55]

Afull-term

femaleneonatewas

transferredto

aMOTHER

•Pain

DOSE

•5g1–3tim

esdaily

SUBJECTIV

E•Motherdenied

KAWSon

herself

INTERVENTIO

N


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

2018

(USA

)tertiary

carecenterafter2

4hof

birthdueto

signsof

with

draw

alsymptom

s•Sm

oking

•Anxiety

(pregabalin

,clonazepam

)NEONATE

•NR

FORM

•Oraltablets

OBJECTIV

E•KANAS:

reducedoralintake,

jitteriness,hypertonia,sneezing,

andexcessivecrying

•Sm

allo

fgestationalage

and

attributed

tomothersm

oking

•CBCwas

within

norm

allim

itsand

theurinetoxicology

panelw

asnegativ

e.•Finnegan

scorewas

consistent

with

KANAS(severity

was

>10).

•MorphinePO

0.1mg/kg/day

titratedunderFinnegan

scoremonito

redevery3–4h

EFF

ECTS

•Infantrespondedtotherapyandweaning

was

initiated

onday3of

treatm

ent.

•Infant

was

observed

for48

hafterdiscontin

uing

and

discharged

after14

days

ofstay.

Murthyand

Clark

[56]

2019

(Canada)

Aliv

efemaleneonateborn

inexcellent

was

admitted

toneonatalintensivecareunitfor

irritability,sleeplessnessbetweenfeedsand

excessivesuckingat22

hof

age

MOTHER

•Asthm

a•Restless

legsyndrome

•Anxiety

•Urinary

tractinfectio

n

PURPO

SE•Anxiety

DOSE

•3–4tim

esdaily

FORM

•Tea

FORM

•Oraltablets

DURATIO

N•Ayear

prior

pregnancy

SUBJECTIV

E•MotherdidnotreportK

AWS

OBJECTIV

E•KANASobserved:jitteryandhave

increasedtone

with

handling(6

to8hof

birth),excessive

suckingto

irritability(12-h-of-life)

•Finnegan

scores

wereelevated,at

18

INTERVENTIO

N•Morphine

EFF

ECTS

•Sy

mptom

sim

proved

byreflectio

nof

lowNASscore

•Attemptsto

weanhermorphinedose

wereunsuccessful

ontwooccasions,once

2days

aftercommencing

treatm

entand

thesecond

attempt,a

fewdays

later

•Dischargedon

day12

with

oralmorphine

•Continuedto

beon

morphinedueto

residualKANAS

•Tim

eto

starweaning

took

slightly

morethan

2months

•Motherwas

motivated

todetoxify

sounderw

enta

psychiatry

andtheaddictionprogramandgotdetoxified

from

kratom

after7days

Caseof

hypogonadotropichypogonadism

andhyperprolactinem

ia

LaB

ryer

etal.[57]

2018

(USA

)

A42-year-oldwhiteman

who

presentedto

prim

arycare

physicianwith

complaintsof

lowenergy

andpoor

libido

•NR

•NR

SUBJECTIV

E•Low

energy

andpoor

libido

OBJECTIV

E•Prolactin

=24

ng/m

L(reference

=2.6–12

ng/m

l)•Testosterone

=8.4(reference

8.7–25.1

pg/m

l)•Normalluteinizinghorm

oneand

follicle-stim

ulatinghorm

onetests

•Normalthyroid-stim

ulating

horm

onetest

•Free

T4was

NR

INTERVENTIO

N•Cessatio

nof

kratom

for2months

EFF

ECT

•Sy

mptom

sresolutio

nandlevelsof

prolactin

and

testosterone

norm

alized

after2months

•Prolactin=6mg/ml(reference=2.6–12

ng/m

l)•Testosterone

=14.6

pg/m

l(reference=8.7–25.1

ng/m

l)

Caseof

severe

prim

aryhypothyroidism

Sheleg

and

Collin

s[43]

2011

(USA

)

A44-year-oldman

presentedto

specialty

clinicforalcoholand

drug

recovery

ACTIV

E•Chronicpain

syndrome

(methadone

and

oxycodone)

HISTORY

•Alcohol

abuse

PURPO

SE•Pain

•Opioidspare

DOSE

•6drops4–6h

FORM

SUBJECTIV

E•Hypothyroidism:gained60

pounds,

lethargy,and

myxedem

atousface

developing

after7monthsof

use

OBJECTIV

E

INTERVENTIO

N•Levothyroxine

150mcg

POdaily

forhypothyroidism

•Fifteenmonthsafterdischarge,orallevothyroxinedose

was

reducedfrom

150μgto

50μgdaily

indicatin

gim

provem

ento

fthyroidfunctio

n


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Oralliquid

DURATIO

NOne

year

•Thyroid

panelshowed

severe

prim

aryhypothyroidism

Cases

ofkratom

-induced

hepatitis(K

IH)

Kappetal.

[58]

2011

(USA

)

A25-year-oldman

who

was

admitted

tohospitalfor

noticeablejaundice

and

pruritu

sfollo

wing3weeks

oflastkratom

dose

•NR

DOSE

•1–2tsp.(2.3–3.5

g)twicedaily

increasedto4–6tsp.

FORM

•Tea

DURATIO

N•Three

weeks

SUBJECTIV

E•Experience:mild

lyrelaxing,

causingtiredness,and

noticed

alossof

appetite,withoutobserving

anystim

ulatingeffects.

•Increaseddose

by3-

to6-tim

esstartin

gdose

over

2weeks

then

stoppedabruptly

•Pertinentp

ositive:feverandchills

(day

2aftercessation),intense

abdominalpain

andconcom

itant

brow

ndiscolorationof

theurine

(day

8aftercessation),and

noticeablejaundice

andpruritu

s(day

9aftercessation).P

resented

onday10

aftercessation

OBJECTIV

E•Vitalswereunremarkable;jaundice

was

prom

inent.

•Labson

admission:B

ilirubin:

28.6

mg/dL

(Ref.<

0.3mg/dL

),ALP173U/L

(ref.40–130U/L),

AST

66U/L

(Ref.<

50U/L),

ALT

94U/L

(Ref.<

50U/L),IN

R1.15

•Infectionanddrug

screenswere

negativ

e.•Abdom

enscansshow

edsignsof

steatosisof

theliv

er.N

either

gallstonesnorintra-

orextrahepaticbileductdilatio

nwas

detected.

•Liver

biopsy

identifieda

drug-induced

cholestatic

injury

with

outh

epatocellulardamage

(so-calledpure

cholestasis).

•Day

12andday14

aftercessation,

serum

MGwas

20mcg/L.

•Urine

MGwas

positiveon

day14

andnegativ

eon

day47

usinggas

INTERVENTIO

N•Nointervention

EFF

ECT

•Fo

llow-upin

clinicandshow

edslow

lyfalling

direct

bilirubinlevelson

day35

and47

from

kratom

cessation


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

chromatography–mass

spectrom

etry

Dorman

etal.[59]

2014

(Germany)


man

was

admitted

tothehospitalfor

jaundice

andliv

erinjury

suspectedto

befrom

kratom

use.

ACTIV

E•Schizoaffectiv

edisorder

(Quetiapine,

sertraline)

HISTORY

•KIH

(1tsp.daily

for

3months)

PURPO

SE•Relaxation

DOSE

•Daily

FORM

•Tea

DURATIO

N•Tw

oto

4weeks

SUBJECTIV

E•Pertinentp

ositive:jaundice,dark

urine

•Pertinentn

egative:fever,rash,or

pruritu

s•Hestoppedtaking

kratom

whenhe

developeddark

urineandthen

sought

medicalattentionwhenhe

developedjaundice

fewdays

after

cessation.

Deniedtaking

otherherbals,dietary

supplements,ordrugsof

abuseor

drinking

excessivealcohol

OBJECTIV

E•Vitalswerenorm

al.

•Mild

confusion,butn

oevidence

ofedem

aor

ascites

•Labson

admission:B

ilirubin:

25.6

mg/dL

(Ref.<

0.3mg/dL

),ALP790U/L

(ref.40–130U/L),

AST

49U/L

(Ref.<

50U/L),

ALT

106U/L

(Ref.<

50U/L),

INR1.1

•Infectionanddrug

screenswere

negativ

e.•Abdom

inalscan

show

edirregular

hepatic

texture,butn

obiliary

obstructionandaliverbiopsy

was

notp

erform

ed.

INTERVENTIO

N•Nointervention

EFF

ECT

•Patient

appeared

stableoveralland

discharged

2days

lateratwhich

timeliv

ertestswereim

proving(but

not

norm

alized)andpsychotropicmedications

were

resumed.

•Labsatdischarge:Bilirubin:

20.8

mg/dL

(Ref.

<0.3mg/dL

),ALP:

730U/L

(ref.4

0–130U/L),ALT

93U/L

(Ref.<

50U/L),IN

R1.0

Riverso

etal.[60]

2018

(USA

)

A38-year-oldman

presentedto

theED

complaining

ofdark-colored

urineand

light-colored

stools.

•NR

PURPO

SE•Fatigue

SUBJECTIV

E•Co-ingested

APA

P,butnoton

other

medication

•Pertinentp

ositive:d

ark-colored

urineandlight-colored

stools.

Dark-coloredurinecontinuedto

worsenwhereas

feverandchills

improved

over

4days.

•LaterattheEDpresentatio

n,patient

also

reported

sternalp

leuriticno

radiatingchestp

ain,mild

shortnessof

breath,m

ildcough.

OBJECTIV

E•Noscleralicterus

orjaundice

show

n

INTERVENTIO

N•Su

pportivecare

with

intravenousfluid

EFF

ECT

•Appearedstableoveralland

was

discharged

8days

after

presentatio

natwhich

liver

functio

nhadim

proved

•Labson

discharge:Bilirubin:

1.6mg/dL

(Ref.

<1mg/dL

),ALP:

266U/L

(ref.40–130U/L),AST

142U/L

(Ref.<

50U/L),ALT

410U/L

(Ref.

<50

U/L)


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Labson

admission:B

ilirubin:

5.1mg/dL

(Ref.<

1mg/dL

),ALP:

304U/L

(ref.40–130U/L),

AST

220U/L

(Ref.<

50U/L),

ALT

389U/L

•Abdom

inalscan

show

nno

biliary

obstruction

•Liver

biopsy

show

edmild

portal

mixed

inflam

mationandbileduct

injury.

Mousa

etal.

[61]

2018

(USA

)

A31-year-oldman

reported

totheEDwith

a4-dayhistoryof

tea-coloredurine,malaise,

fatig

ue,and

fever.

•NR

PURPO

SE•Fatigue

•Opioiduse

DURATIO

N•2weeks

SUBJECTIV

E•Pertinentp

ositive:4

-day

historyof

tea-coloredurine,malaise,fatigue,

andinterm

ittentfever

OBJECTIV


was

presento

rjaundice

•Medicalhistory,review

ofsystem

s,vitals,physicalexamination,basic

laboratory

tests,viralh

epatitis

panel,andabdominalim

aging

wereotherw

isenegativ

eexceptfor

abnorm

alliverfunctio

ntest.

•Labson

admission:B

ilirubin:

2.2mg/dL

(Ref.<

1mg/dL

),ALP

191U/L


191U/L

(Ref.<

50U/L),ALT

578U/L

(Ref.<

50U/L)

INTERVENTIO

N•Loading

dose

ofN-acetylcysteine(N

AC)140

mg/kg

followed

by70

mg/kg

maintenance

dose

every4hfor

17doses(total18

doses)

EFF

ECT

•Sy

mptom

sresolved

afterNACanddischarged

onday4

ofadmission

•Fu

rtheroutpatient

follow-upshow

edresolutio

nof

the

liver

injury

•Labson

discharge/lastdayof

NAC:B

ilirubin:1.7mg/dL

(Ref.<

1mg/dL

),ALP:

208U/L

(ref.40–130U/L),

AST

191U/L

(Ref.<

50U/L),ALT

624U/L

(Ref.

<50

U/L)

•Labson

2monthspost-discharge:B

ilirubin:

0.4mg/dL

(Ref.<

1mg/dL

),ALP:

52U/L

(ref.40–130U/L),

AST

16U/L

(Ref.<

50U/L),ALT

34U/L

(Ref.

<50

U/L)

Griffith

setal.[62]

2018

(USA

)

A21-year-oldman

presentedtoalocalurgent

careproviderwith

complaintsof

vomiting,

fatig

ue,abdom

inalpain,and

brow

nurine.

•So

cialsubstances

(alcohol)

•Illicitdrugsuse

(Mushrooms)

PURPO

SE•Recreational

DOSE

•12

capsules

daily

(10g2days

before

admission)

FORM

•Oralcapsules

DURATIO

N•One

month

SUBJECTIV

E•Pertinentp

ositive:v

omiting,

fatigue,abdom

inalpain,and

brow

nurine

•Not

taking

othermedications

orover-the-counter

products

OBJECTIV


•Aurinedrug

screeningwas

positive

forcannabis(>

50ng/m

l)•Ethanol,A

PAP,andsalicylates

were

with

innorm

allim

itsor

undetectable.

•Aviralh

epatitispanelw

asnegative

•Labson

admission:B

ilirubin:

2.8mg/dL

(Ref.<

1mg/dL

),ALP:

193U/L

(ref.40–130U/L),

INTERVENTIO

N•Su

pportiv

ecarewith

intravenousfluid200-mlbolus

then

150ml/h

infusion,1

dose

of4mgondansetron

intravenousfornausea,20mgfamotidineby

mouth

twicedaily,and

50mgtram

adolby

mouthevery6has

needed

EFF

ECT

•Fluids

werestartedin

theEDandcontinuedfor24

h•Received3dosesof

tram

adol,eachdose

about12hapart

•Dischargedafter2days

with

outindicationof

liver

functiontrends

•Labson

discharge:Bilirubin:

2.3mg/dL

(Ref.

<1mg/dL

),ALP:

152U/L


166U/L

(Ref.<

50U/L),139U/L

(Ref.<

50U/L),

INR1.09


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

AST

294U/L

(Ref.<

50U/L),

ALT

139U/L

(Ref.<

50U/L)

•Abdom

inalscan

show

ndilationof

thebileduct

•Abdom

inalim

agingrevealed

hepatosplenomegalywith

asm

all

ascites

•WorldHealth

OrganizationUppsala

Monito

ring

Centreclassified

KIH

risk

underpossible.”

Antony&

Lee

[63]

2018

(USA

)

A70-year-oldman

presentedwith

jaundice.e

ACTIV

E•Hypertension

(amlodipine)

•Osteoarthritis

(oxycodone)

PURPO

SE•Pain

DOSE

•Tw

icedaily

DURATIO

N•Tw

o-threeweeks

SUBJECTIV

E•Po

sitiv

epertinent:yello

wskin,

nausea,fatigue,w

eakness,and

9kg

ofweightlossin

3weeks

•Negativepertinent:fever,chills,

vomiting,abdom

inalpain,

diarrhea

OBJECTIV

E•Afebrile,stable,andno

encephalopathy

•Viralhepatitis,and

jaundice

work

upwas

negativ

e•Abdom

inalscanswereunrevealing.

•Labson

admission:B

ilirubin:

33.7

mg/dL

(Ref.<

1mg/dL

),ALP:

230U/L

(ref.40–130U/L),

AST

53U/L

(Ref.<

50U/L),

ALT

59U/L

•Serum

creatin

inewas

2.27

mg/dL

indicatingkidney

injury

•The

extensiveworkupforacute

viralh

epatitis,variousliver

diseases,and

jaundice

was

negativ

e,andim

agingof

the

abdomen

was

•RousselUclafCausality

Assessm

entM

ethod(RUCAM)

classified

risk

under“highly

probable”

INTERVENTIO

N•Su

pportivecare

with

intravenousfluid

EFF

ECT

•Initially,sym

ptom

sof

cholestasisim

proved

with

supportivecare

which

allowed

thepatient

tobe

discharged.P

atient

was

readmitted

againforanem

ia3days

after.

•Bilirubinon

readmission

was

17.8

mg/dL

andim

proved

to15.7before

discharge

•Serum

creatinineon

readmission

was

2.94

mg/dl

and

improved

to2.05

mg/dl

afterhydration

•Creatinineim

proved

butrem

ainedmildly

elevated

at1.8mg/dL

after3months

Tayabali

etal.[64]

2018

(USA

)


man

presentedtothe

EDwith

yello

wlookingskin

associated

with

nausea,fatigue,joint

pains,andnight

sweats

of2weeks

duratio

n.

ACTIV

E•Hypertension

•Anxiety

•Backpain

(APA

P)

PURPO

SE•Pain

DOSE

•60

tabletsperweek

FORM

•Oraltablets

SUBJECTIV

E•Po

sitiv

epertinent:yello

wskin,

fatigue,joint

pains,nightsweats,

palestoolsanddark

urine

•Negativepertinent:pruritu

s,weight

changesor

appetite

INTERVENTIO

N•Receivedaloadingdose

of150mg/kg/h

ofNAC,but

patient

developedan

anaphylacticreactionanddoses

wereheld

EFF

ECT


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Noallergies,no

smoking,no

illicit

drug

use,no

sick

contacts,recent

hospitalizations,ortravel

OBJECTIV

E•Clin

ically

stablewith

aslightly

elevated

bloodpressure

of141/82

mmHg

•Jaundicedskin

andicterusin

the

sclera

andoralmucosa

•Infectionanddrug

screenswere

negativ

e.•Labson

admission

(day

1):

Bilirubin:

6.3mg/dL

(Ref.

<1mg/dL

),ALP:

391U/L

(ref.

40–130

U/L),AST

222U/L

(Ref.

<50

U/L),ALT

365U/L

(Ref.

<50

U/L)

•Abdom

inalscan

ruledoutb

iliary

tractd

isease

•InternationalO

rganizations

ofMedicalSciences

Scaleclassified

KIH

risk

under“probable”

•Urine

MG=47.8

mg/Landurine

7-HMG(Q

ualitative)=Po

sitiv

eusingliq

uidmasschromatography

spectrom

etry

test

•Adm

itted

for2days,liverenzymes

startedtrending

down,jaundice

resolved,and

thepatient

reported

feelingbetter.

•Upondischarge,liver

enzymes

hadnotn

ormalized,but

considered

stableandsafe

fordischarge.

•Labson

discharge(day

3):B

ilirubin:

2.8mg/dL

(Ref.

<1mg/dL

),ALP:

314U/L


136U/L

(Ref.<

50U/L),ALT

299U/L

(Ref.

<50

U/L)

Osborne

etal.[65]

2019

(USA

)

A47-year-oldman

presentedto

internal

medicineclinicwith

complaintsof

dark

urine,pruritu

s,subjectivefevers,and

fatig

ueforseverald

ays’duratio

n.

ACTIV

E•Hypertension

•Prediabetes

•Anxiety

•Depression

(Valsartan,m

etoprolol,

escitalopram

,clonazepam

)

PURPO

SE•Pain

DOSE

•Multipletim

esDURATIO

N•Aroundtim

eof

presentatio

n

SUBJECTIV

E•Po

sitiv

epertinent:fevers(ranging

from

100°F

to101°F

for2

days),

dysuria,urinaryfrequency,urinary

urgency,anddarkeningof

his

urinedespite

largevolumes

oforal

intake,generalized

malaise,a

reductionin

appetite,andpruritu

s•Norecent

travel,hospitalizations,

newmedications

•APA

Pforsymptom

control(not

morethan

3000

mglim

it)•Negativepertinent:rash

orchange

inskin

color

OBJECTIV

E•Vitalsarenorm

al.

•Non-ictericscleraandsublingual

jaundice

•Viralhepatitisworkupwas

negativ

e.

•IN

TERVENTIO

N•Nonementioned,kratom

stopped?

•EFF

ECT

•The

patientremainedoutofthehospitalduringtheentire

clinicalcourse

with

outcom

plications.

•Labson

day58

from

firstp

resentation:

Bilirubin:

0.6mg/dL

(Ref.<

1mg/dL

),ALP:

73U/L

(ref.

40–130

U/L),AST

25U/L

(Ref.<

50U/L),60

U/L

(Ref.<

50U/L)andpatient

was

asym

ptom

atic

•Ninemonthsaftertheresolutio

nof

hissymptom

sand

livertestabnorm

alities,the

patientagainpresentedwith

2days

offatig

ue,lossof

appetite,andintensepruritu

swithoutrash.

•Labson

second

presentation:

Bilirubin:

3.2mg/dL

(Ref.

<1mg/dL

),ALP:

211U/L


185U/L

(Ref.<

50U/L),ALT

566U/L

(Ref.

<50

U/L)

•Labson

19days

afterthesecond

presentatio

n:Bilirubin:

1.2mg/dL

(Ref.<

1mg/dL

),ALP150U/L

(ref.


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Labson

admission:B

ilirubin:

5.8mg/dL

(Ref.<

1mg/dL

),ALP:

170U/L

(ref.40–130U/L),

AST

108U/L

(Ref.<

50U/L),

ALT

265U/L

(Ref.<

50U/L)

•Ultrasound

identifiedhepatic

steatosis

•Abnormallabs:ferretin,C

MVIgM

•RUCAM

scorewas

suggestiveof

a“probable”

diagnosis.

40–130

U/L),AST

34U/L

(Ref.<

50U/L),ALT

:45

U/L

(Ref.<

50U/L)

Caseof

posteriorreversibleleukoencephalopathysyndrome(PRES)

Castillo

etal.[66]

2017

(USA

)

A22-year-oldman

presentedwith

asevere

headache

(“absoluteworse

pounding”)

thathadstartedearlierthatmorning.

ACTIV

E•Depression(fluoxetine)

•Insomnia(quetiapine)

•Su

bstancemisuse

(dextroamphetam

ine

andmariju

ana)

PURPO

SE•Abuse

SUBJECTIV

E•Severe

headache

notu

nrelievedby

APA

P•Co-ingested

dextroam

phetam

ine

OBJECTIV

E•Disorientationandaphasia,

Glasgow

comascalescore14

•Blood

pressure

180/105mmHg,

heartrate54

beatsperminute

•Headim

agingconsistentwith

PRES

andaleftoccipitoparietal

intraparenchym

albleed

•Drugscreen

was

positivefor

amphetam

ine,benzodiazepine,

cannabinoids,and

opiates.

INTERVENTIO

N•Su

pportiv

emeasure

with

nicardipineinfusion

•Patientwashospitalized

for5

days

during

which

hishead

imagingim

proved,and

bloodpressure

was

with

innorm

allim

it

Cases

ofseizureandcoma

Boyer

etal.

[41]

2008

(USA

)

A43-year-oldman

admitted

forevaluationof

ageneralized

tonic-clonicseizureand

coincidedwith

KAWS.

ACTIV

E•Chronicpain

HISTORY

•Su

bstanceabuse

(hydromorphone

injection)

PURPO

SE•Pain

•Opioidspare

FORM

•Tea

DURATIO

N•3.5years

SUBJECTIV

E•Co-ingested

with

100mgof

modafinilwith

kratom

and

developedtonic-clonicseizure

lastingfor5min

•Deniedprevious

historyof

seizures

orhead

trauma,alcohol,or

recent

illicitdrug

abuse

OBJECTIV

E•Ph

ysicalexam

was

norm

alexcept

formeiosis.

•Laboratorystudieswerenorm

al.

•To

xicology

screeningidentified

modafinil

INTERVENTIO

N•Nothing

provided

forseizureprophylaxis

Nelsenetal.

[67]

2010

(USA

)

A64-year-oldman

was

broughtu

pto

theED

byem

ergencyservices

afterfound

ACTIV

E•Recentcolostomy

PURPO

SE•Pain

SUBJECTIV

E•Co-ingested

with

Datura

stramoniumteas

INTERVENTIO

N•Lorazepam

2mgandaloadingdose

of1gof

phenytoin

EFF

ECT


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

unconscious

andseizingathome.

•Chronicpain

(Oxycodone)

•Depression

(Amitriptyline)

•1stseizure:o

ccurred30

min

after

administering

kratom

athomeand

witn

essedby

wife.OnceEMS

arrived,theseizurehasalready

term

inated.

•2ndseizure:occurred

after1hof

arrivalatE

DOBJECTIV

E•Glasgow

comascorewas

6,heart

rate110bpm,blood

pressure

143/70

mmHg

•Low

erextrem

ityspasticity

onmanipulation

•APA

P,salicylate,andethanolw

ere

negativ

e,butu

rine

screeningwas

positiveforoxycodone,

cannabinoid,andantid

epressants.

•MGin

theurinewas

0.167±0.015mg/Lusing

high-perform

ance

liquid

chromatographycoupledto

anelectrospray

tandem

mass

spectrom

etry.

•Headim

agingwith

outcontrastw

assuspicious

forapossible

hyperdensity

intherighto

ccipital

lobe.

•Patient

was

intubatedandextubatedafter30

h(fully

awake)

Cases

ofacuterespiratorydistress

syndrome(A

RDS)

Pathak

etal.

[68]

2014

(USA

)

A22-year-oldHispanicman

who

wasbrought

totheEDafterfounddownin

theyard

ingestingkratom

capsules.

•NR

FORM

•Oralcapsule

SUBJECTIV

E•Co-ingested

alcohol

OBJECTIV

E•Hypoxicandchestradiograph

show

edbilateralo

pacity

•Blood

ethanollevelwas

high,other

toxicology

screen

was

negative

•Bronchoscopydidnotshow

infectionor

alveolar

hemorrhage

•Echocardiogram

was

norm

al

INTERVENTIO

N•Startedon

volumecontrolventilationbuthecontinuedto

behypoxicdespite

beingon

100%

FIO2andPE

EPof

15.H

ewas

switchedto

airw

aypressure

release

ventilationandwas

onFIO2of

100%

EFF

ECT

•Alsodevelopedrenalfailure

requiringdialysis

•Im

provem

entoccurred,so

patientwas

slow

lyweanedoff

theventilatorandwas

extubatedafter2weeks

Jaliawala

etal.[69]

2018

(USA

)

A32-year-oldwom

anpresentedwith

worsening

coughanddyspnearequiringreadmission

from

recent

community

-acquiredpneumonia.

•Hypertension

•Backpain

(Opiates)

•Recenth

ospitalization

from

community

-acquired

pneumonia

•NR

SUBJECTIV

E•Worsening

coughanddyspnea

requiringreadmission

OBJECTIV

E•Chestradiograph

demonstrated

bilateralp

atchyairspace

disease

INTERVENTIO

N•Startedon

broad-spectrum

antibiotics

•Developed

severe

hypoxemicrespiratoryfailu

rerequiringmechanicalintubation

EFF

ECT

•Patient

improved

andwas

extubated3days

diuresisand

lung

protectiveventilatio

n


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Infectious

workup,including

respiratoryviralp

anel,

bronchoalveolarlavage,andblood

cultu

reswas

negative

•Bronchoscopydidnotshow

infectionor

alveolar

hemorrhage

•Echocardiogram

ofleftventricular

ejectio

nwas

norm

alCases

ofoverdose

Overbeek

etal.[70]

2019

(USA

)

A38-year-oldfemalepresentedto

EDfor

alteredmentalstatusanddecreased

respiratoryrate.

ACTIV

E•Depression

HISTORY

•Priorhospitalizationfor

alteredmentalstatus,

likelydueto

polysubstance

overdose

•NR

SUBJECTIV

E•Adm

itted

usingkratom

upon

dischargethough

shedenied

intentionalo

verdose

OBJECTIV

E•Obtundedwith

minim

alresponsiveness

topainfulstim

uli

•Experiencingrespiratorydepression

with

bradypnea

•Urine

was

positiv

eforkratom

only,

whengaschromatography/m

ass

spectrom

etry

was

used

INTERVENTIO

N•Receivedtwodosesof

0.4mgof

naloxone

forconcern

ofopioid

toxidrom

eandrespiratorydepression

EFF

ECT

•Patient’sdepressedmentalstatusresolved,and

respiratoryrateincreased

•Other:she

was

monitoredintheED,receiving

supportive

care

andintravenousfluids,haloperidol

foracute

agitation(thoughthatworsenedhermentalstatusfor

12hwithoutaffectingrespiratorydrive)

Patient

improved

with

supportiv

ecare

over

thenext

24h

Palasamudr-

amSh

ekar

etal.[71]

2019

(USA

)


malepresentedto

EDintubatedby

EMSafterfound

unresponsive

athomeby

hisfamily.

PURPO

SE•Stam

ina

DOSE

•60

tabletsperweek

FORM

•Oraltablets

SUBJECTIV

E•Kratom

was

broughttoEDwith

family

OBJECTIV

E•Naloxonewas

administeredby

the

EMSandfurtherintubated

•Glasgow

comascale(G

CS)

of3;

pinpoint

pupiland

notreactiveto

light

andcool

peripheries

•Vitals:h

eartrate(H

R)130bpm,

bloodpressure(BP)

80/40mmHg,

temperature

36.8

°C,partial

pressure

ofoxygen

(PaO

2)of

200

onmechanicalv

entilator

support,

with

fractio

nof

inspired

oxygen

80%

•Labson

admission:A

ST1347

U/L,

ALT

3717

U/L,hyperkalemia,

acutekidney

injury,increased

serum

aniongapof

18,lactic

acid

of7.1mmol/L,and

creatin

ine

kinase

of700U/L

•Urine

andbloodtoxicology

screens

werenegativ

e,andonlypositiv

eto

INTERVENTIO

N•Patient

was

hemodynam

ically

stabilizedwith

fluid

resuscitatio

nandintravenousnorepinephrine

EFF

ECT

•Overtheweek,pupillary

reflexes

returned

tonorm

al,

neurologicalexam

ination,vitalsigns

andtheabnorm

allaboratory

values

also

norm

alized.

•Patientwas

extubatedby

theendof

weektwodischarged

toan

acuterehabilitationinstitu

teforphysicaltherapy


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

positiv

efor7-HMG>500mcg/L,

indicatingoverdose

Cases

offatalities

Authors,

year

(country)

Presentatio

nCom

orbidity

Tim

eto

au-

tops-

y

Autopsy

results

Mitragynineleveld

etected

Other

substances

foundin

blood

Holleretal.

[72]

2011

(USA

)

20-year-oldman

founddead

atsite

•NR

•NR

•Pu

lmonaryedem

aB:0

.39mg/L

U:1

.2mg/L

Propylhexedrine

Kronstrand

etal.[73]

2011

(Sweden)

Caseseries

of9fatalitiesaged

22(least)to

35(highest)

•NR(2

cases)

•Su

bstanceabuse(7

cases)

•NR

•Pu

lmonarycongestio

nand/or

edem

a:(11cases)

•Liver

steatosis(2

cases)

•Brain

edem

a(4

cases)

B:0

.07mg/L(least)to

0.18

mg/L(highest)

U:N

R

Allcaseshadatleast2

other

substances/m

etabolite

Allcaseshadtram

adol

metabolite

Ethanol

(2),

benzodiazepine

(8),

antid

epressant(5),

cannabinoid(3)

Neerm

anetal.[74]

2013

(USA

)

17-year-oldman

founddead

atsite

•Su

bstanceabuse

•Backpain

•NR

•Pu

lmonaryedem

aand

congestio

nB:0

.60mg/L

U:N

RTemazepam

,diphenhydram

ine

clonazepam

,dextromethorphan

McIntyre

etal.[75]

2014

(USA

)

24-year-oldman

pronounced

dead

afterEMS

arrivaltosite

•Alcohol

abuse

•Depression

•29

h•Pu

lmonaryedem

aand

congestio

nB:0

.23mg/L

U:0

.37mg/L

Venlafaxine,m

irtazapine,

diphenhydram

ine,

ethanol

;Karinen

etal.[76]

2014

(Norway)

Aman

founddead

atsite

•Su

bstanceabuse

•72

h•Pu

lmonaryedem

aand

congestio

nB:1

.06mg/L

U:3

.47mg/L

Zopiclone,citalopram

,lamotrigine

BandUof

7-HMG:

0.15

mg/Land2.2mg/L

respectiv

ely

Dom

ingo

etal.[77]

2017

(Germany)

Caseseries

of2fatalitiesaged

20and22

males

that

werefounddead

atsite

•1stcase:abuseand

psychosis

•2ndcase:autism

•Both

in 48h

•1stcase:Pu

lmonary

edem

a•2ndcase:N

R

B:0

.79mg/Land

0.01

mg/L

U:N

Rand1.2mg/L

1stcase:benzodiazepine,

olanzapine,quetiapine,

fluoxetine

2ndcase:amphetam

ine,

APA

P,pseudoephedrine,

morphine,codeine,

g-hydroxybutyricacid

Aggarwal

etal.[78]

2018

(UK)

26-year-oldpronounced

dead

afterarrivaltoED

•NR

•NR

•NR

B:n

egative

U:n

egative

Codeine

Hughes[79]

2018

(USA

)A27-year-oldman

was

founddeceased

inside

hissecuredresidence.

•Asperger

syndrome

•Bipolar

disorder

•NR

•Hyperthermia

(suggested

bythepileof

B:p

ositive

U:N

RValproicacid,quetiapine


Tab

le1

(contin

ued)

Authors,year

(country)

Patient

Com

orbidity

Kratom

use

Assessm

ent

Interventio

nandprogress

•Su

bstanceabuse

wetclothing

adjacent

toabathtubfullof

water)

•Seizure/convulsions

(evidenced

bythe

intram

uscular

hemorrhageof

the

tongue)

Gershman

etal.[80]

2019

(USA

)

Caseseries

15fatalitiesmedianageof

28years

(range,24to

53)whom

13weremales

and

2werefemales

ofwhich

14werefound

unresponsive

atsiteandonepatient

developed

apparent

seizureandcardiacarrest

•Varied

•NR

•Deathsfrom

MGonly

(4)

•Hepatom

egalyor

hepatic

injury

(2)

•Interstitialn

ephritis(1)

•Mechanicalasphyxia(1)

•Seizureandcardiacarrest

(1)

B:5

werepositiveand

10hadquantifiedlevels

between16

mcg/L

(least)

to4.8mg/L(highest)

U:N

R

11casesinvolved

multid

rugingestion(two

tosixdrugs)

8personshadpositiv

etest

results

foropioids

APA

Pacetam

inophen,Bblood,EDem

ergencydepartment,EMSem

ergencymedicalservice,MGmitragynine,NACN-acetylcysteine,NRnotreportedin

case,tsp

teaspoonful,Uurine


times their initial dose within as early as a few weeks [44,50] to achieve the same effect. Perceived experiences mayalso change with the course of intake. Generally, initialexperience is beneficial; some patients describe a sense ofeuphoria, productivity, relaxation, and pain control.Addiction has led to intravenous administration of kratomextract with reported occurrences of thrombophlebitis andinfection requiring antibiotics [47]. Duration of kratomaddiction ranges from 1 to 3 years, and the doses usedby addicted patients ranged from 14 to 42 g per day.KAW was described in several adult populations: thosewith chronic pain, substance use disorder, pregnant wom-en, and recently delivered mothers. Most patients present-ed to a healthcare professional with self-identified symp-toms of withdrawal and expressed their desire to obtain asuperv ised kra tom detoxi f ica t ion or induc t ion/maintenance regimen because of a failed attempt to self-abstain. Many patients often encounter KAW followinguse as an opioid alternative for pain control or reductionof chronic opioid use. Patients have also described with-drawal after recreational intravenous use along with otherillicit substances. Symptoms of KAW generally developwithin 6–12 h after last reported use. Symptoms haveincluded rhinorrhea, restlessness, anxiety, irritability,sleep disturbance, sweating, chills, craving, pain, pruritis,goose bumps, abdominal cramps, and diarrhea. Thoughsimilar to opioid withdrawal, KAW has been reported tobe less severe. Change in patient’s psychiatric functioninghas not been reported except in patient with a diagnosedschizoaffective disorder [45, 51]. Substance-seeking be-havior has been observed, and some patients may hidedoses after claiming abstinence. Case reports havehighlighted the benefits of using pharmacological inter-ventions for the purpose of long-term abstinence fromkratom use via maintenance therapies [41, 49, 50, 52] oracute control of KAW [42–44, 46, 48, 51] via detoxifyingregimens.

For induction/maintenance, only partial μ-opioid receptoragonist regimens have been used, such as buprenorphine plusnaloxone [41, 49, 50, 52], buprenorphine/norbuprenorphine[49], or buprenorphine [52]. These regimens showed benefitsbeyond control of KAW such as reducing dose requirementsof pain medication [49], or prevention of KANAS [52].Symptom-triggered dose-escalation was used for immediateeffects, often escalating the buprenorphine dose by 2–4 mg asneeded. To monitor adherence to therapy and abstinence fromkratom, blood and urine testing for buprenorphine, MG, and7-HMG was performed.

For detoxification regimens, shorter course therapies wereused and their efficacy on kratom abstinence beyond the su-pervised course is not reported. Agents used included partialμ-opioid receptor agonists such as buprenorphine [43] orbuprenorphine/naloxone [46], weak or full μ-opioid receptor

agonists such as dihydrocodeine [42], morphine [48], oralpha-2 agonists such as oral clonidine [44, 51].Antihistamines or pregabalin were added in some instancesfor symptom management.

Kratom-Associated Neonatal AbstinenceSyndrome [48, 52–56]

In Smid and colleagues’ case, kratom use was stopped andkratom-associated neonatal abstinence syndrome (KANAS)was prevented when a buprenorphine regimen was started inweek 22 of gestation. However, this same regimen failed toprevent KANAS in another pregnant woman when it wasstarted at week 19 of gestation [52]. In one case report, kratomwas used by the mother regularly for 2 years [48]. In all cases,kratom use overlapped with the entire course of pregnancy.KANAS occurred in 6–96 h after birth, with noted effectsincluding reduced oral intake, excessive sucking, jitteriness,irritability, facial excoriations, hypertonia, sneezing, and ex-cessive inconsolable high-pitched cry. The Finnegan score is anursing assessment tool that grades the severity of the mostcommon signs and symptoms of NAS, producing a final scorewith increasing severity.

It was used in three KANAS cases to grade the severityand guide therapy [54–56]. Their Finnegan score was cal-culated to be at the “Severe” category threshold (> 9 points)on presentation. Management of KANAS involved admin-istration of full μ-opioid receptor agonists for detoxifica-tion. Almost all cases used morphine; only one case usedintravenous methadone. Two cases reported usingmorphineas 10 mcg/kg/h either continuously or administered every3 h [48, 54] and one case used 100 mcg/kg/day [55]. In allcases, the neonate responded to therapy on initiation. TheFinnegan score was reported to drop by 7–9 points frombaseline presentation indicating an improvement ofKANAS. However, bradycardia and excessive sedationwere associated with morphine use [54]. Weaning frommorphine therapy was initiated by day 2 or 3. Oral morphinewas used as a step-down approach once oral intake wastolerated. Though morphine has shown success inKANAS, Eldridge and colleagues’ case report has indicatedpossible rebound of KANAS following morphine discon-tinuation [54]. The cause was thought to be premature dis-continuation 2 days after the start of morphine therapy. Inthis circumstance, clonidine 1 mcg/kg every 3 h subse-quently showed improvement in NAS scores. This therapywas used for 1 day and discontinued thereafter. Total days ofstay for patients ranged from 8 to 14 days but weaning offmorphine can take up to 2 months due to risk of reboundKANAS [56]. In Davidson and colleagues’ case report, theneonate was monitored for 48 h after discontinuation oftherapy [55].


Endocrine Effects: Hypothyroidismand Primary Hyperprolinemica [43, 57]

There were two cases that reported effects on the endocrinesystem. In LaBryer and colleagues’ case report, kratom ad-ministration was associated with elevated prolactin and re-duced testosterone levels leading to hyperprolactinemia andhypogonadotropic hypogonadism without an alternative iden-tifiable cause [57]. The clinical significance of this changewasmanifested by decreased energy and libido. Cessation of ad-ministration for 2 months lead to normalization of these hor-mones without a need for intervention. Notably, thyroid-stimulating hormone (TSH) levels were normal in this case.Sheleg and Collins presented a case with KAWS which in-cluded signs and symptoms of hypothyroidism confirmed byelevated TSH [43]. This developed after 7 months of consum-ing kratom tincture daily. The patient received an opioid de-toxification regimen using buprenorphine for KAWS andlevothyroxine for hypothyroidism. Fifteen months later,levothyroxine dose was reduced to 50 mcg per day after im-provement in thyroid function. Conversely, a cross-sectionalstudy of 19 long-term kratom consumers (76 to 94 mg of MGper day for more than 2 years) neither found the substanceimpairing to the levels of tetraiodothyronine, testosterone, orgonadotrophins nor did it show a dose-dependent effect ofkratom on these hormones [81].

Kratom-Induced Hepatoxicity [58–65]

Kratom-induced hepatotoxicity (KIH) has been reported after2 to 4 weeks of use and rechallenge has led to recurrence [59,65]. The reported dose resulting in KIH was 14 to 21 g perday. In one case report, there was rapid dose-escalation (3 to 6times the starting dose in 2 weeks) [58]. In all cases, patientspresented to the emergency department for symptoms associ-ated with hepatotoxicity including at least one of the followingsymptoms: dark-colored urine, light-colored stools, profoundweakness, weight loss, nausea, vomiting, fever, or nightsweats. Dark-colored urine was the most commonly reportedsymptom. Yellow skin, scleral icterus, and pruritus were alsoreported. Most patients were hemodynamically stable on pre-sentation; one case showed mildly elevated blood pressure at> 140/80 mmHg in a patient with chronic hypertension [64].The diagnosis of KIH was made on the basis of exclusion ofall other causes of hepatotoxicity. An extensive workup foracute viral hepatitis A, B, and C and assays of hepatotoxicsubstances such as salicylates, acetaminophen, and CNSmed-ications were used to determine if the exhibited hepatotoxiceffects were correlated. Four case reports studied the likeli-hood of KIH using association scales in which all found a‘probable’ association [62–65]. Scales used included theRoussel Uclaf Causality Assessment Method, World Health

Organization Uppsala Monitoring Centre and theInternational Organizations of Medical Sciences Scale.Jaundice was reported in four cases where the total bilirubinwas the highest of all KIH cases, ranging from 6.5 mg/dL to33.7 mg/dL (reference < 1 mg/dL) [58, 59, 63, 64]. Afterkratom cessation, total bilirubin decreased within 2 days to7 days [58–64]. The highest alkaline phosphatase recordedwas 790 units/L (reference 35–129 units/L). Complete nor-malization of total bilirubin and alkaline phosphatase occurredapproximately 2 months after cessation [61, 65]. Early reportsof KIH confirmed intrahepatic cholestasis based on hepaticfunction tests, abdominal and hepatic imaging, and histologi-cal findings. More recently, two case reports highlighted thepossibility of a hepatocellular injury [62, 65]. Both of thesetwo cases had confounding causes for hepatocellular injury,including positive IgM for cytomegalovirus [65] and positiveurine cannabinoid [62].

In two case reports, N-acetylcysteine (NAC) was offered ashepatoprotective agent. Mousa and colleagues case reportedusing intermittent bolus infusion regimen (140 mg/kg follow-ed by 70 mg/kg for 18 doses) in which the patient received thefull 18 doses over a 4-day course and authors reported reso-lution of symptoms and down-trending hepatic enzymes [61].Tayabali and colleagues started NAC with a loading dose of150 mg/kg but the patient developed an anaphylactoid reac-tion soon after the loading dose was administered resulting ina termination of infusion within an hour after initiation [64].Although signs and symptoms were reported to be improvedin 2 days, the role of NAC in KIH is not fully understood orestablished.

Central Nervous System Effects: PosteriorReversible Encephalopathy Syndromeand Seizure [51, 66, 67]

Posterior reversible encephalopathy syndrome and seizure(PRES) has been reported in patients that combined kratomuse with marijuana, fluoxetine, and quetiapine [66]. In thispatient, supportive care and lowering blood pressure withnicardipine infusion helped to improve the patient’s condition.Two cases reported of seizure activity within 30 min of kratomingestion in addition to animal studies previously mentioned[25], indicate that kratom may be a pro-convulsant [41, 67].These cases also detected levels of other substances includingmodafinil and antidepressants which are known to lower sei-zure threshold. The dose and duration of kratom use in thesecases was not reported. Standard medications for seizure con-trol such as lorazepam and phenytoin were used successfully inreversing the onset of the seizure. In one case, the urine con-centration of MG was measured at 0.167 mg/L. Interestingly,this level is half the MG urine concentration in reported fatal-ities (range from 0.37 to 3.47 mg/L) [72, 74, 76, 77].


Acute Respiratory Distress Syndrome [68, 69]

Two patient cases have reported respiratory compromise lead-ing to acute respiratory distress syndrome (ARDS) and sub-sequent need for mechanical ventilation. In both cases, allother causes of respiratory failure from infectious or hemor-rhagic causes were ruled out. In the case reported by Pathakand colleagues, the patient was witnessed to have ingestedboth kratom and alcohol [68]. The duration for mechanicalventilation was for 2 weeks in this patient. In the case reportedby Jaliawala and colleagues, mechanical ventilation was need-ed for 3 days [69]. Both cases reported no attempt to reversekratom with naloxone.

Toxidromes and Fatalities [70–80]

Kratom toxicity is presumed to resemble an opioid toxidrome:manifested by mydriasis, depressed respiratory function, al-tered mental status, hypotension, and hypothermia. Two re-cent case reports showed the role of naloxone reversal on thekratom toxidrome, although it was administered due tosuspected co-intoxication with an opioid [70, 71]. In the caseof Overbeek and colleagues, the patient received twoprehospital doses of naloxone 0.4 mg which led to improve-ment in respiratory rate and mental status [70]. With support-ive care and intravenous fluids, the patient continued to im-prove over a of 24-h period and ultimately survived. Shekarand colleagues reported a case where additional measureswere needed following the naloxone reversal dose [71]. Thepatient was discharged to a rehabilitation institute 2 weeks

after they were admitted to the inpatient facility. The patient’surine 7-HMG was greater than 500 mcg/L.

In the fatal case reported by Aggarwal and colleagues, thepatient presented to the hospital with cardiac arrest [78].Initially, return of spontaneous circulation (ROSC) was achievedwithin 1 h of hospital arrival with advanced cardiac life support(ACLS) including vasopressors, inotropes, and sodium bicarbon-ate. Naloxone was given as an opioid antagonist, but its effectwas non-discernible. A standard lipid emulsion dose (1.5 mL/kgintravenous bolus) was also administered with an observed re-sponse for approximately 1 h, which resulted in a 16% improve-ment in alveolar-arterial oxygenation lasting for only a few mi-nutes followed by a 30% reduction in epinephrine requirementlasting approximately 1 h. However, the patient’s cardiorespira-tory function subsequently deteriorated leading to death 12 hafter ROSC. The author reported modest cardioprotective prop-erties of intralipid on assumption of cardiotoxicity from kratomcomponents. Neither qualitative nor quantitative serum assaysfor kratom were investigated, and the amount of the reportedingestion was unknown. The urine was negative for MG butpositive for codeine, which the patient allegedly took only onestandard dose.

Most fatalities were young males with a history of substanceabuse or psychiatric disorder. All fatalities were pronounced deadat the scene, except two cases in which the patients were broughtto an emergency department. Attempts with ACLS were unsuc-cessful [73, 78]. In both cases that presented to the emergencydepartment, kratom was suspected to be ingested within 24 hprior to presentation [73, 78]. In the majority of fatal cases, thecause of death was attributed to pulmonary congestion and/oredema. Other causes of death were liver steatosis, brain edema,

Fig. 2 Assessment of kratom safety and management of kratom abstinence


Table 2 Management considerations for kratom-associated adverse events and toxicities

Case report summaries Management considerations in addition to standard care

Kratom-associatedwithdrawal symptoms(KAWS)

• Onset occurred within 6–12 h after kratom cessation.• Symptoms presented similar to opioid withdrawal; rhinorrhea,

restlessness, anxiety, irritability, sleep disturbance, sweats,chills, craving, pain, itch, goose bumps, abdominal cramps, anddiarrhea.

• Tolerance occurred weeks to months and patients starteddose-escalation starting in weeks after first intake.

•Blood or urine samples could be tested for principal substances inkratom; mitragynine and 7-hydroxymitragynine.

• Occurred more often in patients with chronic pain orpolysubstance abuse; especially opioids abuse disorder.

• Induction/maintenance therapies may be useful for prevention ofkratom-associated neonatal abstinence syndrome in expectingmother, reducing pain medication dose, reducing pain intensity,or establishing kratom abstinence.

• Detoxification therapies may be used for acute KAWS.• Opioid withdrawal scales used may be used for

symptom-triggered strategy in dose-escalation.• Potential agents: buprenorphine-alone, buprenorphine/naloxone,

or replacement opioids when partials agonist are not available.Adjunctive therapy, such as clonidine, can be used forsymptoms of acute withdrawal.

• Blood or urine samples of mitragynine and7-hydroxymitragynine may be used to establish abstinence fromkratom and buprenorphine levels used to establish adherence tomaintenance therapy.

Kratom-associatedneonatal abstinencesyndrome (KANAS)

• Onset has occurred in 8–96 h-of-life with increasing intensity.• Symptoms may include reduced oral intake, excessive suck,

jitteriness, irritability, facial excoriations, hypertonia, sneezing,and excessive inconsolable high-pitched cry.

• Maternal induction/maintenance therapies may be useful forprevention of kratom-associated neonatal abstinence syndrome.

• Neonatal detoxification therapies include methadone ormorphine-based therapies. Clonidine has been used for patientintolerant to first-line therapy.

• Finnegan score can be used for dose-titrating and monitoring forefficacy.

• Caution with morphine side effects including bradycardia andsedation.

• Neonates should be monitored after discontinuation for reboundsymptoms.

Hypothyroidism • Onset occurred in 7 months after kratom initiation• Symptoms included weight gain, lethargy, and myxedematous

face• Thyroid function panel was consistent with hypothyroidism.

• Correct with levothyroxine and titrate according to thyroidfunction panel.

• Kratom discontinuation and appropriate detoxification schedulemay be needed.

Hypogonadism • Symptoms included low energy and poor libido• Prolactin level and testosterone level were consistent with

primary hypogonadism.

• Symptom resolution and hormonal normalization may not occurfor months after kratom discontinuation.

Kratom-inducedhepatoxicity (KIH)

• Patients may present with jaundice and dark-colored urine,ascites and mild renal failure have also occurred.

• Onset has occurred in 2–4 weeks following ingestion orexcessive dose-escalation.

• Cholestasis injury or hepatocellular injury may occur.

• Kratom discontinuation and appropriate detoxification schedulewas needed.

• Supportive care with intravenous hydrationwas included. Longerhydration up to 24-h session was provided in acute kidneyinjury.

• N-acetylcysteine has been used for symptom improvement.• In cases, bilirubin trended down in 2–7 days and resolution

occurred in 2–3 months. Alkaline phosphatase (ALP)normalized in 60 days.

Posterior reversibleencephalopathysyndrome (PRES)

• Accompanied with severe headache, disorientation, and aphasia• Vital signs and head imaging consistent with PRES including

elevated blood pressure and Glasgow coma scale (GCS)• CNS-modifying medications and illicit substances were

co-ingested causing possible kratom-drug interaction ordrug-drug interaction; namely fluoxetine, dextroamphetamineand quetiapine, amphetamines, and marijuana.


• Supportive care with nicardipine infusion for control of bloodpressure was included.

Seizure • Can occur immediately after kratom ingestion• CNS-modifying medications or herbal products with

pro-convulsant properties were co-ingested; namely modafinilor Datura stramonium extract tea


• Standard anti-epileptic medications such as lorazepam with orwithout phenytoin load showed control.

Acute respiratorydistress syndrome(ARDS)

• Symptoms worsened; started with cough and dyspnea thenprogressed to hypoxia

• Occurred after a week from a recently treatedcommunity-acquired pneumonia

• Ethanol ingestion complicated presentation

• Improvement and successful extubation has occurred within3–14 days of ingestion.

Toxidrome • Occurred within 24 of kratom administration• Associated with altered mental status, pulmonary depression,

cardiac arrest, seizure, or fatalities• Occurred in young users with polysubstance misuse and

psychiatric disorders

• Initiate basic life support (BLS) or advanced cardiac life support(ACLS) as indicated

• Naloxone rescue can be provided and repeated as necessary.• Intralipid intravenous bolus 1.5 ml/kg may be used if all other

supportive care measures are not successful.


seizure, hyperthermia, and mechanical asphyxia. All autopsyblood samples confirmed the presence of at least one otherCNS depressant [78]. There is speculation that these fatalitiesmay be caused by mixed drug ingestions leading to synergisticor additive effects, yet fatalities have also occurred from kratomalone. Significant variability in extraction methods and assays, aswell as the timing of autopsies post mortem, makes it difficult toconclude a lethal blood concentration of MG. Blood concentra-tions in fatal cases have ranged from 10 to 4800 mcg/L. Of note,the report by Karinen and colleagues is the only case that testedfor and reported positive blood concentrations of the other potentcomponent in kratom, 7-HMG at 2200 mcg/L [76].

Assessing Kratom in Active Usersand Managing Associated Complications

Case reports and series are reported voluntarily; therefore,there is inconsistency among reports for assessment and man-agement. Based on available evidence from these reports, wepropose a stepwise approach to assess kratom safety and effi-cacy in active users (Fig. 2) and a summary of kratom-associated adverse events (Table 2).

Conclusion

Kratom has been used bothmedicinally and recreationally andits use has continued to increase. Case reports and case seriesof kratom-associated adverse events, toxicities, and fatalitiesare alarming. Healthcare professionals’ awareness of trends inuse as well as associated risks is necessary to discuss risks andbenefits of use with patients and provide prompt managementof adverse events. Controlled studies are needed in the futureto examine the impacts of kratom use and provide insight intooptimal management and regulation.

Acknowledgments The authors would like to thank Dr. Glee Lenoir forreviewing their manuscript.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict ofinterest.

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors.

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