Drug abuse & addiction and treatment of addiction

MUDr. T. Páleníček, PhD

Prague Psychiatric Center,

3. LFUK

Main drug classes• Stimulants: nicotine, cocaine, amphetamines, piperazines (BZP), caffeine

• Depressants: alcohol, barbiturates, BZD

• Hallucinogens: LSD, mescaline, psilocin, DOB, harmin, DMT (Ayahuasca) etc.

• Entactogens: MDMA (ecstasy), MDA, MBDB, 2C-B, piperazines (TFMPP,

mCPP), PMA etc.

• Cannabinoids: THC

• Dissociative anesthetics: Ketamine, PCP

• Narcotics: opioids

• natural: morphine

• synthetic: phentanyl, heroin, meperidine, methadon, oxycodeine

• Others: inhalants, sedatives and hypnotics

Prevalence of drug use• Lifetime prevalence:

– Amphetamine 15–34 years 5 %

– Ecstasy 15–34 years 5.6 %

– Cocaine 15–34 years 5.6 %

– Cannabis 15–64 years 22.1 %

– Cannabis 15-34 years 31.1 %

• Cannabis

last year prevalence in young population 15-24 years 15.8 %

• Estimated numbers of:

– Problem opioid users in EU 1.2 -1.5 milions

• New HIV infections between i.v. drug users in 2007 4.7 per million of population

– Highest rates in Estonia • HCV and HBV antibody positivity in i.v. users 40 % (18 – 95 %)

– Czech Rep. – less than 25%

2009 Annual report on the state of the drugs problem in Europe, EMCDDA

Prevalence of HIV and Hep C in EU

Annual report 2012: the state of the drugs problem in Europe, EMCDDA

Cannabis use in EU

Annual report 2012: the state of the drugs problem in Europe, EMCDDA

Cannabis use in EU

Annual report 2012: the state of the drugs problem in Europe, EMCDDA

Opioid and Cocaine use in EU

Annual report 2012: the state of the drugs problem in Europe, EMCDDA

Deaths associated with overdoses in the Czech Rep.

unspecified

Synthetic drugs

Cocaine

Amphetamines

Opioids

benzodiazepines

Illegul drugs and solvents in total

Solvents

Overdoses

Prevalence in the Czech Rep.

• Lifetime prevalence: 2008 2012

– Any drug in population 15–64 years 36,5 % -

– Cannabis in population 15–64 years 34,3 % 29,7%

– Cannabis in population 15-34 years 53,7 % 45,9%

• Use of cannabis

in last year in population 15-34 let 28,8 % 18,3%

• Estimated numbers of: 2008 2012

– Problem drug users 32 500 40 200

– Intravenous drug users 31 200 38 600

– Problem drug users of meth 21 200 30 900

– Problem drug users of opiates 11 300 9 300

2011• HIV incidence in i.v. users < 1 % - in total 96 cases (7 new in 2011)

• VHC incidence – 812 newe cases in 2011, in total approximately 12% of positive i.v. users

Výroční zpráva o stavu ve věcech drog v České republice v roce 2008,2011,2012Národní monitorovací středisko pro drogy a drogové závislosti, Úřad vlády ČR

Total number of problem drug users

Prevalence - opioid and meth use in the Czech Rep.

Výroční zpráva o stavu ve věcech drog v České republice v roce 2008Národní monitorovací středisko pro drogy a drogové závislosti, Úřad vlády ČR

Number of problem drug users per 1000 in population 15-64 years and number of problem opiate and methamphetamine users in Czech regions

Heroin users

Subutex users

Methamphetamine users

Lifetime prevalence with illegal drugs in 11 – 13 years old children in % in the Czech Rep.(Prev-Centrum, 2003 a 2005; Miovská, 2006)

(Výroční zpráva o stavu ve věcech drog v České republice v roce 2005, národní monitorovací středisko pro drogy a drogové závislosti (NMS))

Cannabis

Group A (experimental)

Ecstasy

Meth

Heroin

Solvents

years old years old years old years old

Groups B + C (controls)

Mental and behavioral disorders due to psychoactive substance use

F10. – Mental and behavioral disorders due to use of alcohol

F11. – Mental and behavioral disorders due to use of opioids

F12. – Mental and behavioral disorders due to use of cannabinoids

F13. – Mental and behavioral disorders due to use of hypnotics

F14. – Mental and behavioral disorders due to use of cocaine

F15. – Mental and behavioral disorders due to use of other stimulants, including caffeine

F16. – Mental and behavioral disorders due to use of hallucinogens

F17. – Mental and behavioral disorders due to use of tobacco

F18. – Mental and behavioral disorders due to use of volatile solvents

F19. – Mental and behavioral disorders due to multiple drug use and use of other psychoactive substances

Mental and behavioral disorders due to psychoactive substance use

F1x.0 - Acute intoxication

F1x.1 - Harmful use

F1x.2 - Dependence syndrome

F1x.3 - Withdrawal state

F1x.4 - Withdrawal state with delirium

F1x.5 - Psychotic disorder

F1x.6 - Amnesic syndrome

F1x.7 - Residual and late-onset psychotic disorder

F1x.8 - Other mental and behavioral disorders

F1x.9 - Unspecified mental and behavioral disorder

Condition that follows the administration of a psychoactive substance. Disturbances are directly related to the acute pharmacological effects of the substance and resolve with time, with complete recovery, except where tissue damage or other complications have arisen.

disturbances in:level of consciousnessCognitionPerceptionaffect or behaviourother psycho-physiological functions and responses.

Depends on:The drug usedThe dose usedActual somatic or psychological condition

Acute intoxication

• Acute drunkenness in alcoholism

• "Bad trips" (drugs)

• Drunkenness NOS

• pathological intoxication

• Trance and possession disorders in psychoactive substance intoxication

Complications:TraumaInhalation of vomitusDeliriumComaConvulsions

Other medical complications.

Alcohol - effects

Alcoholemia [%]

Effects

0.02-0.03 Mood elevation, slight muscle relaxation

0.05-0.06 Relaxation, decreased reaction times, impaired fine motor functions

0.08-0.09 Impaired balance, speech, vision, muscle coordination, euphoria

0.14-0.15 Severe impairment of motor control as well as psychic functions.

0.20-0.30 Severe intoxication, minimal control of motor or psychic functions

0.40-0.50 Unconsciousness, deep coma, dead from suppression of breath center

A pattern of psychoactive substance use that is causing damage to health:

• physical (as in cases of hepatitis from the self-administration of injected drugs)

• mental (e.g. episodes of depressive disorder secondary to heavy consumption of alcohol).

Harmful use

Duration: at least 1 month, or several shorter periods during last 12 months

Not present:

• dependence

• Psychotic disorder

• Other specific disorders associated with alcohol or drug use

Cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and that typically include:

• strong desire to take the drug

• difficulties in controlling its use

• persisting in its use despite harmful consequences

• higher priority given to drug use than to other activities and obligations

• increased tolerance

• (physical withdrawal state)

Faster reapperance of the syndrom after prolonged abstinence

Includes:• Chronic alcoholism• Dipsomania• Drug addiction

Dependence

•abstinent •abstinent in protected areas•abstinent on substitution therapy •active in use•continuously uses•use (dipsomania)

Duration: at least 1 month, or several

shorter periods during last 12 months

Drug addiction - neurobiology

All known compounds that induce dependence ↑ the dopamine release in nucleus accumbens

• Acute drug effects –– ↑ DA in nucleus accumbens (and in PFC) (mesolimbic areas) → euforia– Induction of early genes e.g. cFos– Short term neuroplastic alterations (hours – days)

• Transition to addcition –– Neuronal changes accumulate, but still not persistent

– Stimulation of synthesis of proteins with long biological half life (e.g. ∆FosB – transcription regulator which modulates synthesis of AMPA GLU receptors)

– Changes in DA and GLU systems play probably the key role in development of dependence (changes in expression of mGLUR1, DAT, RGS9-2, D2 autoreceptors…)

• Dependece– Many changes become irreversible or long lasting

– As a result of that is a vulnerability to relapse

– Many changes involve glutamatergic system, mainly projections from prefrontal cortex to striatum (nucleus accumbens)

Drug addiction - neurobiology

Withdrawal and deliriumA group of symptoms of variable clustering and severity occurring on absolute or relative withdrawal of a psychoactive substance after persistent use of that substance.

Onset and course:

temporally restricted

depends on the drug and dose used that was abused before abstinence

F1x.3 Withdrawal

.30 uncomplicated

.31 with convulsions

F1x.4 Withdrawal with delerium

.40 without convulsions

.41 with convulsions

Delirium tremens = short life threatening state of confuse and somatic complications during alcohol abstinence in strongly addicted, sometimes after alcoholic excess

Prodromes sleeplessness, anxiety and fear, convulsions

Manifested delirium

• blunted consciousness and fuzziness

• hallucinations and illusions

• intense tremor

• delusions, agitation, sleeplessness, reversed sleep cycle and increased vegetative functions

Diagnosis of delirium (ICD 10)

Příznaky mírné nebo závažné musí být přítomné ve všech následujících oblastech:

(a) impairment of consciousness and attention (b) global disturbance of cognition (impairment of immediate recall and of

recent memory; disorientation for time, place and person); (c) psychomotor disturbances (hypo- or hyperactivity and unpredictable shifts

from one to the other) (d) disturbance of the sleep-wake cycle (e) emotional disturbances, (e.g. depression,

anxiety or fear, irritability, euphoria, apathy)

Začátek je obvykle rychlý, průběh během dne kolísá a celkový stav trvá nejdéle 6 měsíců.

Pathophysiology of alcohol withdrawal and delirium

• Alcohol facilitates the effects of GABA on GABA A receptors

• In chronic abuse there is generally decreased excitability of brain via GABA system, there is down regulation of GABA A receptors

• Concomitantly long-time alcohol abuse inhibits glutamatergic system

• This leads to up regulation of NMDA receptors

• During alcohol cessation the main consequence is hyperexcitability of he brain (NMDA mediated effects dominate) → withdrawal symptoms, increased excitability, altered sleep cycle, convulsions

• Altered homeostasis, altered permeability of membranes + worsening of oxidative metabolism → defect of neurotransmitter synthesis (mainly acetylcholine → delirium)

• Also altered serotonin, noradrenalin and dopamine systems

Somatic and neurological symptoms of delirium

Neurological: tremor, Asterixis („flapping tremor" originally in hepatic hepatopathy)

Dysnomia = amnestic afazia

dysgrafia.

Vegetative: tachycardia

increased blood pressure

Sweating

face blush (getting red)

mydriasis.

Complications      

falling from the bed with an injury,

   attack against imaginary invaider with injury,

   agitation which complicates the medical care,

transition to dementia, amnestic syndrome or organic personality disorder

1) Full recovery: usually in 1 – 4 weeks, in elderly patients tends to také longer ….

2) Fatalities: 20 – 30 %

3) Transition to dementia

4) Transition to functional psychotic disorder : 10 %

Prognosis

Therapy of delirium tremens

•identification of cause, eliminate influence of anticholinergics (delirogens)

•start symptomatic treatment and supportive care

•correction of water and ion disbalance (infusions, ions, vitamins)

•adequate alimentation

•sufficient sleep

•safe environment

•reorientation and not disturbing patient in between 21 and 6 during the sleep.

•Pharmacotherapy:

a) sedation

• benzodiazepines: (e.g. midazolam, lorazepam, tenazepam)

• clomethiazol (Heminevrin)

• combination of BZD and antipsychotics

• antipsychotics: (haloperidol, sulpirid, tiaprid) • nootropics (e.g. piracetam – f.o. Kalikor, Nootropil, 2400 – 3200 mg/day or

pyritinol 300 - 500 mg/day etc.).

• Chronic prominent impairment of recent and remote memory

• Disturbances of time sense and ordering of events

• Difficulties in learning new material

• Confabulation may be marked but is not invariably present.

• Other cognitive functions are usually relatively well preserved

• Amnestic disorder, alcohol- or drug-induced

• Korsakov's psychosis or syndrome, alcohol- or other psychoactive substance-induced or unspecified

Amnesic syndrome Excludes: nonalcoholic Korsakov's psychosis or syndrome ( F04 )

Prognosis:

25% - full recovery

50% - partial recovery

Therapy: Thiamin 50-100mg p.o. for months

A cluster of psychotic phenomena that occur during or following psychoactive substance use but that are not explained on the basis of acute intoxication alone and do not form part of a withdrawal state.

• hallucinations (typically auditory, but often in more than

one sensory modality)

• perceptual distortions

• delusions (often of a paranoid or persecutory nature)

• psychomotor disturbances (excitement or stupor)

• abnormal affect (from intense fear to ecstasy)

• some degree of clouding of consciousness

Disorder vanish (at least partially) within 1 month, fully within 6 months

Psychotic disorder

Examples:

Alcoholic Hallucinosis

Alcoholic Jealousy

Alcoholic Paranoia

Alcoholic psychosis

F1x.5 Psychotic disorder .50 Schizofrenia-like

.51 predominantly delusional

.52 predominantly hallucinatory

.53 predominantly polymorphic

.54 predominantly depressive psychotic symptoms

.55 predominantly manic psychotic symptoms

.56 mixed

• Onset up to two week after withdrawal

• Persistence of psychotic symptoms > 48 hours

A disorder in which alcohol- or psychoactive substance-induced changes of cognition, affect, personality, or behaviour persist beyond the period during which a direct psychoactive substance-related effect might reasonably be assumed to be operating

• Alcoholic dementia NOS

• Chronic alcoholic brain syndrome

• Dementia and other milder forms of persisting impairment of cognitive functions

• Flashbacks

• Late-onset psychoactive substance-induced psychotic disorder

• Posthallucinogen perception disorder

• Residual:

• affective disorder

• disorder of personality and behaviour

Residual and late-onset psychotic disorder

Bio-psycho-social model - Biological level

(Kamil Kalina a kolektiv, Drogy a drogové závislosti, mezioborový přístup. Vydal © Úřad vlády České republiky, 2003, Národní monitorovací středisko pro drogy a drogové závislosti, 2002

• Biological factors e.g. some problematic circumstances during pregnancy:

• if mother was alcoholic or drug addicted

• exposition of fetus to addictive substances (e.g. fetal alcoholic syndrome)

• circumstances of birth (hypoxia, use of psychotropic substances, hypnotics, sedatives)

• factors that influence neurobiology of an individual including all psychomotor maturing of a child during early postnatal period

• presence of trauma, disease and other traumatic and limitating factors

• genetic factors

•Influence of psychogenic factors

•Perinatal period (transpersonal approaches)

•Postnatal care – harmonic development, setting interpersonal and personal borders

•Support during adolescence

•Support during the crises of identity

•Adequate support during pathological states, including mental health (depression, anxiety, psychosis)

•If there is a lack of support, it can be often the self-medication that can lead to the development of substance abuse and addiction

•Some of them are associated with existing abuse and enforce further abuse, e.g.:

• alcohol has anxiolytic and antidepressant effects on the beginning of use, later becomes itself the cause of depression and anxiety, that stimulates further drinking

• activation of paranoid states in chronic stimulant abuse, identity disorders during the abuse of hallucinogenic drugs etc.

(Kamil Kalina a kolektiv, Drogy a drogové závislosti, mezioborový přístup. Vydal © Úřad vlády České republiky, 2003, Národní monitorovací středisko pro drogy a drogové závislosti, 2002

Bio-psycho-social model - psychological level

•Concentrates on the context where everything is happening, especially the relationships with ¨surrounding environment, which formats maturing of an individual and eventually can negatively disturb it :

• race discrimination

• family status in the society

• the level of social indemnity

• the quality of individual relationships in the family, eventually absence of the family

• countryside vs. big cities

• not enough time of adult people for youngsters

• absence of rituals positively forming maturing of young person

• a child in a family grows beside an addicted person

• Young people search identification models outside of the family, in their naturally occurring addictive position they search for strong individuals or groups. They search for feelings of acceptance, belonging, etc.

• collective of equals – often it is said „he/she has found a bad group of friends“(Kamil Kalina a kolektiv, Drogy a drogové závislosti, mezioborový přístup. Vydal © Úřad vlády České republiky, 2003, Národní monitorovací středisko pro drogy a drogové závislosti, 2002

Bio-psycho-social model - Social level

• Motivation

• Decision to stop

• First contact with professionals (K-centre, hospital …)

• Again motivation and testing the decision to stop

• Detoxification

• Therapy – ambulant, in hospital, in community

• Subsequent care – getting back to society

• Relapse

Treatment of addiction

Therapeutic systemOutside healthcare system:

• Contact centers (KC)

• Social welfare institutions

• Therapeutic communities

• After-treatment centers

• Harm reduction

• Family therapy

• Counseling

In healthcare system:

• Acute states (detox, withdrawal symptoms, toxic psychosis)

• Therapeutic programs (ambulant, in psychiatric centers, clinics)

• After-treatments programs

• Substitution therapy

• Family therapy

• Counseling

Treatment of alcohol dependence

Pharmacological interventions• Disulfiram (up to 500mg/die)• Acamprosate (more than a 1g/die 2x2tbl a 333mg)• Naltrexon (25-100mg/die)• Antidepressants, anticonvulsants, ondansetron, antipsychotics,

buspiron, GHB

Psychotherapy• motivational enhancement therapy, 12 step facilitation programs

and CBT seems to be most effective• Psychodynamic psychotherapy and brief interventions are

probably not much effective• Other – family therapy, behavioral partner therapy, education

Treatment of opioid dependence

Pharmacological interventions• methadon (up to 60-100mg/die slow titration)• bubrenorphine (8-16mg/die slow titration)• Bubprenorphine + naloxone (4:1) – Subuxon (sublingual tablets)• Diamorphine (heroin)• Naltrexon, naloxon• LAAM• GHB, ibogain

Psychotherapy• motivational enhancement therapy, supportive expressive therapy, family

therapy, contingency management and CBT seems to be most effective• Therapeutic communities• Other – family therapy, behavioral partner therapy, education

• Pharmacological intervention directed towards involvement of withdrawal symptoms and craving

• Opiates and nicotine

• Per oral administration of medication (or plasters with nicotine)

• Methadone, Subutex (0.4mg, 2mg and 8mg; buprenorphine for per oral use), Temgesic (0.2mg and 0.3mg; buprenorphine for parenteral administration), Diolan (ethylmorphine HCl), heroin, nicotine

• Special centers or physicians

• Helping with motivation to undergo other treatments (re-socialization)

• Minimization of risks associated with drug use, criminality, social problems etc. = harm reduction

Indication:• Severe and long lasting dependence on high doses of opiates, or combined addiction• Repeated unsuccessful attempts of treatments

Factors that support involvement in the program• Anamnestic positive experience with substitution therapy• Opioid dependence in HIV positive patients, repeated criminal activity associated with the drug use, if

normal treatment is not possible• Treatment of pregnant patients if detoxification is not possible

Substitution therapy

Substitution therapy

Replacement of primary drug … :• Illegally obtained• With short action• Often with toxic adjuvants• With unknown concentration• Administered in risky way (i.v., non-sterile)

…with a substance (medication) with favorable profile:• With long-lasting action in the organism• With defined concentration• Without toxic adjuvants and effects• Administered usually p.o.• Used lege artis

Methadone• If classical treatment is possible and convenient

• Primary dependence on other substances (e.g. stimulants)

• Non-occurrence of physical dependence

• Age lower than 16 years

• Severe hepatic illness

• Acute alcohol intoxication

Subutex• Same as for methadone plus:

• IMAO treatment and 14 days after ending such treatment

• Severe respiratory insufficiency

Relative contraindications for both:• Encroaching of the substitution program in anamnesis

• Combined dependence (e.g. Methadone + alcohol)

• Incapability to stop using illegal drugs despite a high dose of substitution drug

• Forthcoming imprisonment without possibility to continue in the substitution program in the prison

Opioid substitution - contraindications

Treatment of stimulant dependencePharmacological interventions

• Antidepressants – not effective• Dopaminergic agonists – no effects• Disulfiram – moderate effects• Antiepileptics (tiagabiaine) – moderate effects• Anti adrenergics (betablckers) – moderate effects• Baclofen – moderate effects• Naltrexon, buspiron, ibogain

Psychotherapy• motivational enhancement therapy, supportive expressive therapy, family

therapy, contingency management, CBT, dynamic psychotherapy, cue exposure therapy

• Therapeutic communities• Other – family therapy, behavioral partner therapy, education

Pharmacological interventions• Substitution with nicotine (chewing gums, plasters, spray, bonbons)

• 1,5x - 2x increase the probability of smoking cessation• 8-12 chewing gums a 2mg daily, might be combined with 24h

plasters• Antidepressants – bupropion (Wellbutrin, Zyban) cca 300 mg/day, 2-3

months• Varenicline – parcial agonist of incotine receptors (Champix)

• 1.-3. day 0,5 mg 1x daily, 4.-7. day 0,5 mg 2x daily; since 8. day until the end of treatment 1 mg 2x daily.

• Treatment length is 12 weeks

• Nortryptiline, klonidine, moclobemid, selegiline, mecamylamine

Psychotherapy• Minimal interventions, counseling, behavioral approaches incl. CBT,

motivational interventions

Treatment of nicotine dependence

Important features:• usually requirement for further treatment

• usually lasts 1 or more weeks

• Symptoms of acute withdrawal with respect to the abused drugs (including physical symptoms after opiates, BZD, delirium tremens)

• Use of pharmacological interventions – buprenorphin (Temgesic, Subutex, Suboxone), BZD, barbiturates, vitamins, hepatoprotectives

• Many patients break down already on this level

Indication:• Existing or developing withdrawal in patient without vital functions failure

• age: patient older than 15 years (it is relative since there are detoxes for children as well)

• Voluntary admission, informed consent

Contraindications:• Severe intoxication, severe somatic or psychiatric state requiring care in a different or specialized

unit

• Disagreement with the conditions of treatment

• Involuntary admission (adult patient, in children parents are responsible)

Detoxification units

Detoxification – treatment approaches

Ad 1) without specific (substitution) medication• basic daily program (according to the requirements of the patient), structured

therapeutic program (supportive psychotherapy, enhancement of motivation for further treatment, influencing patients attitudes etc.)

• Supportive pharmacotherapy: hypnotics, anxiolytics, hydratation, physiotherapy, psychotherapeutic techniques (relaxation, art therapy, music therapy, …)

Ad 2) with specific medication• opioid assisted detoxification

• methadon – after finding of an optimal dose continuous decline to 0 in 5-14 days

• buprenorphin - after finding of an optimal dose 3-4 day substitution with subsequent abrupt stopping of the treatment

• in BZD and barbiturate withdrawal - continuous decline of the dose which can last several weeks (relatively quickly the 1st 1/2 of the dose, than carefully with smaller reductions, withdrawal symptoms are life threatening, seizures could be typically present if the decline is to fast)

• Supportive pharmacotherapy: hypnotics, anxiolytics, antipsychotics, hydratation• physiotherapy, some very simple psychotherapeutic techniques (relaxation, art

therapy, music therapy, …)

• Strict rules of the treatment

• Often scoring system

• group psychotherapy

• Individual psychotherapy

• Psychotherapeutic techniques, work therapy etc.

• Family therapy

• Several weeks to several years

• Important factor for prognosis is finishing the specified treatment

Therapeutic interventions in therapeutic community

• Very important after finishing treatment

• re-socialization

• In the beginning usually daily, later weekly

• Work with relapse

• Some institutions in patients with dependence on non-alcoholic drugs solve the alcohol and cannabis consumption, others require strict abstinence from all drugs and addictive behaviors

Aftercare

Not causal, it can be combined with other approaches

• Bupropion (Zyban, Wellbutrin) - nicotine

• GHB (gama-hydroxybutyrate) – alcohol

• Ibogain – opiate, alcohol dependence

• Ketamine – opiate, alcohol dependence

Anticraving treatment

• Primary – education, objective information (counseling), etc.

• Secondary – working with abstinent users

• Tertiary – minimization of risks

Prevention

= Minimization of risks• Exchange of used needles for sterile ones, supplying condoms,

sterile water, citric acid, cellulose filters etc., substitution therapy, drug testing (e.g. Ecstasy tablets testing on raves which serves also as a contact method)

• In an institution or as a street-work

• Prevention of transmitting infectious diseases (HIV, hepatitis)

• Countries where it was restricted, e.g. Ukraine – extremely high incidence of HIV and hepatitis among i.v. drug users (90% or more are positive)

• Minimizations of tromboembolic complications, endocarditis, sepsis

• Contact with clients that are difficult to target (serves as a attractor)

Harm reduction

• Dual diagnosis

– in USA almost 50% of addicted

– Specific treatment, important is distinguishing from toxic psychosis

• Treatment of pregnant women

• Combined addiction on several substances (alcohol + gambling + speed, heroin + BZD, …)

• Treatment of associated diseases

– hepatitis, HIV, encephalopathy, neuropathy etc

Other issues

Thanks for attention