ketamine an overview of its effects on mental and physical health ketamine an overview of its...
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KetamineKetamine
An overview of its effects on mental and An overview of its effects on mental and
physical health physical health
Val Curran Val Curran SSA 8SSA 8thth November 2012 November 2012
NMDA-receptor antagonistNMDA-receptor antagonist
NMDA-receptor antagonistNMDA-receptor antagonist Snorted, effects within ~ 5 minsSnorted, effects within ~ 5 mins Short half life, duration of effects about Short half life, duration of effects about
1-2 hours.1-2 hours.
NMDA-receptor antagonistNMDA-receptor antagonist Snorted, effects within ~ 5 minsSnorted, effects within ~ 5 mins Short half life, duration of effects about Short half life, duration of effects about
1-2 hours.1-2 hours.
1964: anaesthetic
Withdrawn from mainstream use because of
‘emergence phenomena’ Still key in specialist anaesthesia: veterinary,
paediatrics and field medicine.
WHO K report, June 4-8th 2012: “Anaesthesia withoutketamine in this part of the world is
unthinkable.” (Africa).
Ketamine: medical uses
Acute & chronic pain particularly neuropathic pain (Lynch et al 2005) &
complex regional pain syndrome (Correll et al 2004)
Ketamine: medical uses
Ketamine: medical uses
Depression Depression (Berman et al 2000) (Berman et al 2000)
Antidepressants take weeks to produce a Antidepressants take weeks to produce a response, are only moderately effective and response, are only moderately effective and >1/3>1/3rdrd do not respond. do not respond.
Ketamine improves mood within hours in Ketamine improves mood within hours in treatment resistant depressed patients.treatment resistant depressed patients.
Review by Duman & Aghajanian (2012) Science Review by Duman & Aghajanian (2012) Science calls this “perhaps the mostcalls this “perhaps the most
important discovery in half a century.”important discovery in half a century.”
Ketamine may also be effective for treatment resistant bipolar depression (Diazgranados et al, 2010).
And decrease suicidal ideation (Machado-Vieira et al, 2012)
Krupitsky: Evidence from Russia (1980 – 2008) – effective adjunct to psycho-therapy for alcohol and heroin dependence.
Ketamine: recreational useKetamine: recreational use Prevalence increased and Prevalence increased and
price decreased since price decreased since 2005/6 (Drugscope, 2008; 2005/6 (Drugscope, 2008; BCS 2008/2009)BCS 2008/2009)
Mixmag surveys ketamine Mixmag surveys ketamine ever used ever used
2001 25.5% 2001 25.5% 2010 67.8% 2010 67.8% 2012 (Guardian) 2012 (Guardian)
48%48%
Extent of last year illicit drug use for most prevalent drugs among young people aged 16 to 24, 2011/12 Crime Survey for England and Wales
Chart notes
Source: Home Office, Illicit drug use among 16–24s tables: Tables EY.02 and EY.04
British Crime Survey 2011/2: 16-24 year olds England & Wales last year use of drugs.
Ketamine: 2006/07 0.8%; 2008/09 1.9%; 2011/12 1.8% .
User’s acute experiencesUser’s acute experiences
StimulantStimulant Sense of melting into people Sense of melting into people
or thingsor things Distorted perceptions e.g. Distorted perceptions e.g.
feeling "as big as the feeling "as big as the universe" or "as small as an universe" or "as small as an electron", often electron", often simultaneously simultaneously
Visions and hallucinationsVisions and hallucinations Spiritual and out of body Spiritual and out of body
experiencesexperiences K-holeK-hole
DOSE
Emergence phenomena
What do you like about What do you like about taking ketamine?taking ketamine?
““I love the ego dissolution, my I love the ego dissolution, my consciousness becomes intertwined consciousness becomes intertwined with divine entities and all semblance with divine entities and all semblance of the physical realm disappears.”of the physical realm disappears.”
Muetzelfeldt et al (2008) Drug & Alc Dependence
What do you like about What do you like about taking ketamine?taking ketamine?
““I love the ego dissolution, my I love the ego dissolution, my consciousness becomes intertwined consciousness becomes intertwined with divine entities and all semblance with divine entities and all semblance of the physical realm disappears.”of the physical realm disappears.”
““The numbness and detachment and The numbness and detachment and the enhancement of music. Combined the enhancement of music. Combined with E it is warm and glowy”with E it is warm and glowy”
Muetzelfeldt et al (2008) Drug & Alc Dependence
What do you like about What do you like about taking ketamine?taking ketamine?
““I love the ego dissolution, my consciousness I love the ego dissolution, my consciousness becomes intertwined with divine entities and all becomes intertwined with divine entities and all semblance of the physical realm disappears.”semblance of the physical realm disappears.”
““The numbness and detachment and the The numbness and detachment and the enhancement of music. Combined with E it is enhancement of music. Combined with E it is warm and glowy”warm and glowy”
““It is cheap and it gets me really off my headIt is cheap and it gets me really off my head””
Muetzelfeldt et al (2008) Drug & Alc Dependence
Acute reinforcing effectsAcute reinforcing effects
In ketamine-naïve In ketamine-naïve
volunteers, get U-volunteers, get U-shapedshaped
reinforcement curve reinforcement curve (Morgan et al., 2004)(Morgan et al., 2004)
Acute physical risksAcute physical risks
Able to maintain airwayAble to maintain airway Increased cardiac outputIncreased cardiac output Gag reflex preserved, less chance of Gag reflex preserved, less chance of
aspiration BUT commonly used with aspiration BUT commonly used with alcohol alcohol (Dillon et al., 2003)(Dillon et al., 2003)
Acute Physical RisksAcute Physical Risks Safety Ratio (Gable, 2004)Safety Ratio (Gable, 2004)
Ketamine - DeathsKetamine - Deaths
UK post-mortem toxicology mentions of ketamine in the UK 1999-2008
Courtesy of Dr J Corkery
Acute IntoxicationAcute Intoxication AccidentsAccidents
Data scarce; 2 of 30 frequent users died in our Data scarce; 2 of 30 frequent users died in our 12month longitudinal study. 12month longitudinal study.
DrivingDriving Hong Kong 9% of fatal vehicle crashes involving Hong Kong 9% of fatal vehicle crashes involving
drugs or alcohol involved ketamine (Cheng et al., drugs or alcohol involved ketamine (Cheng et al., 2005) 2005)
Increased risk of unprotected sex in gay men Increased risk of unprotected sex in gay men More than any other class of drug (Rusch et al., More than any other class of drug (Rusch et al.,
2004)?2004)?
Chronic effectsChronic effects
Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis
Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis Now > 10 papers detailingNow > 10 papers detailing Occurs mainly in frequent usersOccurs mainly in frequent users Symptoms frequency, urgency, urge Symptoms frequency, urgency, urge
incontinence and occasionally painful incontinence and occasionally painful haematuria (blood in urine) haematuria (blood in urine) (e.g. Chu et al. 2008) (e.g. Chu et al. 2008)
Cystoscopic findings of two daily ketamine abusers showing varying degrees of inflammation and neovascularization
C BA
Healthy 7 years 4 years
Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis
CT scans: small bladder CT scans: small bladder capacitycapacity
Marked thickening of the Marked thickening of the bladder wall and severe bladder wall and severe inflammationinflammation
Some symptom relief upon Some symptom relief upon cessation: varying degrees cessation: varying degrees
Ketamine-induced ulcerative cystitisKetamine-induced ulcerative cystitis Prevalence unknownPrevalence unknown
30% of ketamine users experienced it (Muezelfeldt et al., 30% of ketamine users experienced it (Muezelfeldt et al., 2008)2008)
Survey of UK urologists suggests that one third may recover Survey of UK urologists suggests that one third may recover upon cessation, one third will not change, one third will upon cessation, one third will not change, one third will continue to worsen (Cotrell & Gillatt, 2008)continue to worsen (Cotrell & Gillatt, 2008)
Aetiology unknown Aetiology unknown Unlikely to be adulterants as seen in chronic pain Unlikely to be adulterants as seen in chronic pain (Gregoire et (Gregoire et
al., 2008al., 2008).). Can get kidney damage as secondary problem.Can get kidney damage as secondary problem.
IF EXPERIENCING SYMPTOMS, STOP USING IF EXPERIENCING SYMPTOMS, STOP USING
K-crampsK-cramps
Spontaneously reported in 33% of 90Spontaneously reported in 33% of 90 ketamine users interviewed ketamine users interviewed (Muetzelfeldt et al., 2008)(Muetzelfeldt et al., 2008)
Frequent usersFrequent users Severe gastric painSevere gastric pain Some evidence users take ketamine to avoidSome evidence users take ketamine to avoid
Neurological ChangesNeurological Changes
Emerging evidence of frontal-temporal Emerging evidence of frontal-temporal reduction in grey matter reduction in grey matter (Fletcher, Morgan, pers comm)(Fletcher, Morgan, pers comm)
White matter density reduction noted in White matter density reduction noted in frontal and parietal regions.frontal and parietal regions.
Evidence of differences in neural correlates of Evidence of differences in neural correlates of associative learning DLPFC and OFC associative learning DLPFC and OFC (Morgan et al., in (Morgan et al., in prep). prep).
Cognitive ImpairmentCognitive Impairment Clear evidence with frequent ketamine usersClear evidence with frequent ketamine users
short and long term memory deficits short and long term memory deficits (Morgan et al., (Morgan et al., 2010).2010).
Spatial working memory & pattern recognition Spatial working memory & pattern recognition memory deficits related to increase over a year in memory deficits related to increase over a year in extent of ketamine use (longitudinal study - extent of ketamine use (longitudinal study - Morgan et al., 2010).Morgan et al., 2010).
Few cognitive deficits seen in infrequent users Few cognitive deficits seen in infrequent users (Morgan & Curran, 2006)(Morgan & Curran, 2006)
Schizophrenia-like symptomsSchizophrenia-like symptoms Acute ketamine is the best pharmacological Acute ketamine is the best pharmacological
model of schizophrenia.model of schizophrenia. Brings back symptoms in patientsBrings back symptoms in patients Anecdotal reports of ketamine-induced Anecdotal reports of ketamine-induced
psychosis psychosis (Lilly, 1979; Jansen, 1991) (Lilly, 1979; Jansen, 1991) but little evidencebut little evidence Sub-clinical psychotic symptoms – especially Sub-clinical psychotic symptoms – especially
delusions – are increased in ketamine users delusions – are increased in ketamine users (inc. infrequent: Morgan et al., 2010). (inc. infrequent: Morgan et al., 2010).
The schizophrenia prodrome? The schizophrenia prodrome?
The Schizophrenia Proneness Instrument The Schizophrenia Proneness Instrument (SPIA - Schultze-Lutter et al., 2001; in (SPIA - Schultze-Lutter et al., 2001; in press). press).
Clinical interview/symptom rating - predicts later Clinical interview/symptom rating - predicts later schizophrenia and distinguishes between non-schizophrenia and distinguishes between non-psychotic affective disorders and schizophrenia psychotic affective disorders and schizophrenia (Klosterkötter (Klosterkötter et alet al, 1996; 2001), 1996; 2001)
SPIA Produces a profile of ‘SPIA Produces a profile of ‘Basic symptoms’Basic symptoms’
SPIA Basic symptomsSPIA Basic symptoms Affective-Dynamic Disturbances’Affective-Dynamic Disturbances’
e.g. reduced tolerance of stress, decreased emotional responsivenesse.g. reduced tolerance of stress, decreased emotional responsiveness
‘‘Cognitive-Attentional ImpedimentsCognitive-Attentional Impediments’’ e.g. attention and short term memory deficits, concentration problems.e.g. attention and short term memory deficits, concentration problems.
‘‘Cognitive disturbancesCognitive disturbances’’e.g. indecisiveness, thought interference and blockages, odd speech e.g. indecisiveness, thought interference and blockages, odd speech
‘‘Disturbances in Experiencing Self & Surroundings’Disturbances in Experiencing Self & Surroundings’ e.g. self-reported pressure of thought and unstable ideas of referencee.g. self-reported pressure of thought and unstable ideas of reference
‘‘Body Perception DisturbancesBody Perception Disturbances’’`̀ e.g unusual bodily perceptual experiences e.g unusual bodily perceptual experiences
‘‘Perception Disturbances’Perception Disturbances’
e.g. changes in the intensity or quality of perceptual stimuli.e.g. changes in the intensity or quality of perceptual stimuli.
Given link between cannabis and psychosis, Given link between cannabis and psychosis, we compared ketamine users with high we compared ketamine users with high potency cannabis users. potency cannabis users.
Daily ‘skunk’ users (n=29), daily ketamine Daily ‘skunk’ users (n=29), daily ketamine users (n=21) and users (n=21) and controls (n= 30) naïve to controls (n= 30) naïve to illicit drugs.illicit drugs.
Daily skunk users Daily skunk users
0
2
4
6
8
10
12
14
16
18
AffectiveDynamic
Cognitive-Attentional
CognitiveDisturbances
Self andSurroundings
Body Perception PerceptionDisturbances
Me
an
SP
I-A
sc
ore
Cannabis
Non-drug
Daily ketamine usersDaily ketamine users
0
2
4
6
8
10
12
14
16
18
20
AffectiveDynamic
Cognitive-Attentional
CognitiveDisturbances
Self andSurroundings
BodyPerception
PerceptionDisturbances
Me
an
SP
I-A
sc
ore
Ketamine
Cannabis
Non-drug
Prodromal individuals who Prodromal individuals who later transitioned to later transitioned to
psychosispsychosis
0
2
4
6
8
10
12
14
16
18
20
AffectiveDynamic
Cognitive-Attentional
CognitiveDisturbances
Self andSurroundings
Body Perception PerceptionDisturbances
Me
an
SP
I-A
sc
ore
Prodromal
Ketamine
Cannabis
Non-drug
Data for prodromal group (N=51) who transitioned to psychosis courtesy of Schultze-Lutter et al, 2007.
Non-drug Skunk Ketamine F(3,125), p
Immediate prose 7.93 (2.82) 5.57
(2.27)*
5.88
(2.32)*
4.637, 0.002
Delayed
prose
6.53 (3.25) 3.72
(2.02)***
4.70 (2.10)
4.518, 0.002
Verbal fluency 17.70
(6.82)
12.28
(2.64)**
13.40
(3.99)**
5.472,
<0.001
Category fluency 18.10 (6.43) 16.93
(4.58)
14.40 (4.44)
2.155, 0.078
Digit Forwards 9.87 (2.24) 9.51 (2.37) 8.75 (2.36)
0.979, 0.422
Digit Backwards 7.27 (2.39) 6.21 (1.84) 4.75
(2.12)**
5.998,
<0.001
Cognitive performance
Depression Depression
Increased depression in frequent ketamine users Increased depression in frequent ketamine users (Morgan et al., 2009).(Morgan et al., 2009).
BUT subclinical and not related to change in dose BUT subclinical and not related to change in dose (Morgan et al., 2010)(Morgan et al., 2010)
Dependence: ToleranceDependence: Tolerance
Tachyphylaxis – rats, monkeys and man.Tachyphylaxis – rats, monkeys and man. Frequent ketamine users increased dose 600% Frequent ketamine users increased dose 600%
(Morgan et al., 2010)(Morgan et al., 2010)
Hair concentration doubled in recreational Hair concentration doubled in recreational users users (baseline 21.82 ± 46.27; 1 year follow-up 48.43± (baseline 21.82 ± 46.27; 1 year follow-up 48.43± 104.56104.56 ) )
DependenceDependence
Attentional bias & towards Ketamine related Attentional bias & towards Ketamine related images images
Ketamine related cues overshadow other Ketamine related cues overshadow other predictors of reward in an associative learning predictors of reward in an associative learning task (Freeman et al, 2012)task (Freeman et al, 2012)
Dependence: Dependence: Withdrawal?Withdrawal?
‘‘Discontinuation syndrome’Discontinuation syndrome’ 28 out of 30 daily users tried but failed to give 28 out of 30 daily users tried but failed to give
up – all reported K craving as the reason - up – all reported K craving as the reason - mainly to alleviate pain (bladder; K-cramps).mainly to alleviate pain (bladder; K-cramps).
12 out of 30 of the same group reported 12 out of 30 of the same group reported withdrawal symptoms characterised by withdrawal symptoms characterised by anxiety, shaking, sweating, palpitations anxiety, shaking, sweating, palpitations (Morgan et (Morgan et al. 2009).al. 2009).
Case studies: Case studies: Critchlow et al., 2008; Lim et al., 2003; Blatchut et al., Critchlow et al., 2008; Lim et al., 2003; Blatchut et al., 2009.2009.
Educational and professional Educational and professional achievementachievement
General risks associated with addictive illegal General risks associated with addictive illegal drugs?drugs?
Ketamine dependent individuals often on Ketamine dependent individuals often on margins of mainstream societymargins of mainstream society
Significantly less time in education frequent Significantly less time in education frequent users compared to infrequent, poly-drug & users compared to infrequent, poly-drug & controls controls (Morgan et al., 2009)(Morgan et al., 2009)
20% employment related problems in 20% employment related problems in recreational users recreational users (Dillon et al., 2003)(Dillon et al., 2003)
Criminal activitiesCriminal activities
Criminal - unknown Criminal - unknown No DTOsNo DTOs
Ketamine smuggling -Ketamine smuggling -organised crimeorganised crime
Ketamine arrests Ketamine arrests increased over past 4 increased over past 4 yearsyears
Cost to the Health ServiceCost to the Health Service
CystoscopiesCystoscopies Cather insertionCather insertion CystectomyCystectomy Lifetime follow-upLifetime follow-up Cost of treating dependenceCost of treating dependence
When the ketamine supply diminished... When the ketamine supply diminished... Methoxetamine stepped inMethoxetamine stepped in
Marketed as ‘Bladder friendly ketamine’.
First drug ACMD put under a Temp Control Drug Order (TCDO).
18th Oct 2012 ACMD recommended most K analogues put in Schedule 1 (having no medical use).
Will hamper research on non-ketamine agents which may be anti-depressants/analgesics without K’s severe chronic effects.
ConclusionsConclusions
Chronically, mainly in frequent users, bladder problems, cognitive/neurological impairment and difficulty in stopping use are the major concerns.
ConclusionsConclusions
Chronically, mainly in frequent users, bladder problems, cognitive/neurological impairment and difficulty in stopping use are the major concerns.
Ketamine remains an important medicine in anaesthesia and pain management.
ConclusionsConclusions
Chronically, mainly in frequent users, bladder problems, cognitive/neurological impairment and difficulty in stopping use are the major concerns.
Ketamine remains an important medicine in anaesthesia and pain management.
Its antidepressant, psychotic and chronic prodromal effects are now key in mental health research.
ConclusionsConclusions
Chronically, mainly in frequent users, bladder problems, cognitive/neurological impairment and difficulty in stopping use are the major concerns.
Ketamine remains an important medicine in anaesthesia and pain management.
Its antidepressant, psychotic and chronic prodromal effects are now key in mental health research.
Ketamine's mind-altering properties may be far more useful than any clubber ever imagined.
Morgan & Curran (2011) Ketamine use: a review. Addiction
Celia Morgan Leslie Muetzelfeldt Tom Freeman
THANK YOU!
Harms – rated by 6,000 in an Harms – rated by 6,000 in an International Drug Survey International Drug Survey (Morgan et al, in (Morgan et al, in press).press).
ACMD report of 18th October 2012 recommends that a large number of ketamine analogues should be made Schedule 1 controlled drugs, to reduce possible future abuse.
Although ketamine and one analogue [methoxetamine = Mexxy] is abused, the plan to ban so many analogues, some with already proven research utility, seems extreme.
the long-term use of ketamine is associated with an inflammatory cystitis and possibly cognition impairments, so there is a real need to find safer and more effective alternatives. This research will be made extremely difficult under the new proposals since virtually no research or clinical site in the UK has a Schedule 1 license. Moreover experience shows that almost no producers can comply with Schedule 1 requirements, so access to, and development of novel test compounds will almost certainly cease.
While Schedule 1 status has a massive impact on research and clinical use it has no impact on “illicit” use, being just a residual beurocratic category from the old and out of date 1961 UN convention. So we must at all costs avoid putting drugs with clinical potential into it, for the reasons stated above. Also experience tells us that removing a drug from Schedule 1 is extremely difficult even when it has proven utility [cf cannabis].
David Nutt proposes to exempt hospitals and universities from Schedule 1 requirements but this will not affect the production issue. The best way to limit damage to research for patients benefit is to stop potentially useful drugs being made Schedule 1 in the first place.
To add To add ACMD review of MXE. Temp Control Drug Order – TCDO -
MXE was the first so we are reviewing the process. First we need to know how ketamine causes bladder pain
and the ability to study analogues will be useful for that goal so why make this analogue Schedule 1.
Schedule 1 - Schedule 1 - Drugs belonging to this schedule are thought Drugs belonging to this schedule are thought to have no therapeutic value and therefore cannot be to have no therapeutic value and therefore cannot be lawfully possessed or prescribed. These include LSD, lawfully possessed or prescribed. These include LSD, MDMA (ecstasy) and cannabis. Schedule 1 drugs may be MDMA (ecstasy) and cannabis. Schedule 1 drugs may be used for the purposes of research but a Home Office used for the purposes of research but a Home Office licence is required.licence is required.
Second, I am not convinced of the reasoning behind having different drugs in this chemical class in Class A, B & C. Is
the message that ketamine is the least harmful?
Berman et al 2000 – 7 patients; decrease Berman et al 2000 – 7 patients; decrease of 14 on HAM-D after K; 0 after placebo.of 14 on HAM-D after K; 0 after placebo.
Depression affects over 120 million people worldwide, making it the fourth largest contributor to the global burden of disease, according to the World Health Organization. At some point in their lives 13 per cent of Americans experience major depression, and globally 850,000 depressed people kill themselves every year.
Zarate et al () 17 patients “Ketamine somehow reboots the brain”. Effects last 7-10 days.
Acts on neuroplasticity. Works on pain too. (Antids often prescribed for pain).
Ketamine's mind-altering properties may be far more useful than any clubber ever imagined.
“Recent studies report what is arguably the most important discovery in half a century: ketamine produces rapid antidepressant action in treatment resistant depressed patients.”
October 5th 2012
Propensity for I.V. usePropensity for I.V. use
Low : hospital workers and Low : hospital workers and psychonautspsychonauts
Awaiting DataAwaiting Data Drugscope (2009)Drugscope (2009) Bristol Drugs Project I.M. – pers commBristol Drugs Project I.M. – pers comm
Suggestions on the increase – little Suggestions on the increase – little evidenceevidence
Thanks for listening!Thanks for listening!
•Depression: Berman et al 2000 - below Zarate et al 2010
e.g. self & surroundingse.g. self & surroundings
Do you sometimes feel that things going Do you sometimes feel that things going on around you have special meaning for on around you have special meaning for you, even though you know this is you, even though you know this is improbable or impossible?improbable or impossible?
Do you sometimes feel as if random Do you sometimes feel as if random things were meant especially for you e.g. things were meant especially for you e.g. comments on rasdio or TV? comments on rasdio or TV?
Rating – frequencyRating – frequency If needed – severity, subjective burden, If needed – severity, subjective burden,
areas of life.areas of life.
Basic symptoms: SPIABasic symptoms: SPIA Affective-Dynamic Disturbances’Affective-Dynamic Disturbances’
e.g. reduced tolerance of stress, decreased emotional responsivenesse.g. reduced tolerance of stress, decreased emotional responsiveness
‘‘Cognitive-Attentional ImpedimentsCognitive-Attentional Impediments’’ e.g. attention and short term memory deficits, concentration e.g. attention and short term memory deficits, concentration problems.problems.
‘‘Cognitive disturbancesCognitive disturbances’’e.g. indecisiveness, thought interference and blockages, odd speech e.g. indecisiveness, thought interference and blockages, odd speech
‘‘Disturbances in Experiencing Self & Surroundings’Disturbances in Experiencing Self & Surroundings’ e.g. self-reported pressure of thought and unstable ideas of referencee.g. self-reported pressure of thought and unstable ideas of reference
‘‘Body Perception DisturbancesBody Perception Disturbances’’`̀ e.g unusual bodily perceptual experiences e.g unusual bodily perceptual experiences
‘‘Perception Disturbances’Perception Disturbances’
e.g. changes in the intensity or quality of perceptual stimuli.e.g. changes in the intensity or quality of perceptual stimuli.
Basic symptoms
Acute Physical Risks: National Acute Physical Risks: National Poisons ServicePoisons Service
• 570 000 TOXBASE sessions (online poisons database): 0.3 % ketamine: 1710 cases
• Up six-fold from 2000: 0.05% - 285 cases