opiod dependence by dr ajay

OPIOID

DR AJAY KUMAR

Plant was cultivated in ancient civilization of Persia , Egypt and Mesopotamia Archeological evidence shows use by neanderthal manFirst written reference comes from sumerian text , it was k/a HUL-GIL or plant of joy

3,500 Yr old history Even descried in EBER’S

PAPYRUS(1500BC) Papaver semniferum Contains 20 opium compounds AFFIM or DODA(opium husk)- used in

rajasthan,panjab,U.P 1800-morphine and codein isolated By SENTURNER a pharmacist in 1806 1898- first semisynthetic compound –

heroin 1940-first pure synthetic compound

methadone/ meperidine

Thomas syndeham(1680) among” the remedies which it has pleased to God almighty to give man to relieve his suffering none is so universally and efficacious as opium”

What opium contains

Phenanthrene derivative Morphine 1-10% Codeine 0.7-2.5% Thebaine 0.5-1.5% Isoquinoline derivative Papaverine 1% Noscapine 5-10%

classification

1 NATURALLY OCCURING MORPHINE/CODEIN2 SEMISYNTHETIC

HEROIN ;PHOLEODEIN;HYDROMORPHONE;OXYMORPHONE;HYDROCODONE;OXYCODONE

3 SYNTHETIC

PETHIDINE;FENTANYL;METHADONE;TRAMADOL;ALFENTANIL;SUFENTANIL;REMIFENTANIL

ENDOGENOUS

1970 isolated from mammalian brain 1 ENDORPHINS- B-endorphin(b END) 31 AAs

derived from por-opio-melanocortin(POMS) which also give rise to r-MSH,ACTH,

Primary action on u-receptors 2 ENKEPHALINS- methionine-enkephalin(Met-

ENK) and leucine- enkephalin(leu-ENK) both are pentapeptides , act on d-receptor mainly

3 DYNORPHINS DYN-A&B; has 8-17 Aas ,derived from prodynorphin

epidemiology

National institute on drug abuse(NIDA) in 1986 shows eliciting drug use in college student and shift to marihuana and hallucinogens in USA

1986 1991 1992

monthly 25.89% 15.1% 14.8%

annual 41.9% 27.0% 28.3%

Life time 70.5% 62.2% 60.2%

National household survey on drug abuse(NHSD); USA- carried out regularly since 1971

total male female

monthly 6.1 8.1 4.2

annual 10.8 13.9 8.0

Life time 34.8 40.0 29.9

In India earliest report comes from 1960-1970 survey for mentally illness which contains questionnaire on alcohol use , iliciting drug use

Larger survey conducted in 1963-1984 shows 5-56.2% , and high prevalance in medical student

DRUG SERVEY ON MENTAL ILLNESS

SURVEYS IN GENERAL POPULATION

SURVEY IN STUDENTS

CANNABIS 0.4-1% 1.9-33% 1.7-66%

OPIOIDES 0.04-0.1% 0.7-24.8% 4.5-12.7%

ALCOHOL 2.9-82.5% 5.2-58.0%TRAN

TRANQUILIZER 3.5-53.8% 3.5-61.0%

OVER ALL 1.30-2.77% 28.77% 5-56.21%

MINISTRY OF HEALTH AND FAMILY WELFARE govt of India(1995) conducted survey which shows prevalence of opium addiction 6.3-18.9%

1.3% in jodhpur 0.1% in Delhi ICMR study shows prevalence rate of heroin

dependence 0.5% in slum population of Delhi Drug abuse monitoring system(DAMS) in 1990

2/3 of the pt registered in treatment centers in Delhi were heroin user, 33% to 50% of pt were in Lucknow and jodhpur

National survey 2004

Study Sampling Year Number Prevalence

National Household Survey (NHS)

Two stage probability proportional to size 2000-01

40,697 M aged 12 to 60 years in 25 states

A - 21.4%; C-3.0%; O-0.7%

National Family Health Survey (NFHS-2) H-H 1998-99

4,86,011 aged 15-54 in 26 states

A - 17% of men and 2% women

National Family Health Survey (NFHS-3) H-H 2005-06

124,385 F and 74,369 M aged 15-54 in 29 states

A - <1/3 of men and 2% women T - 57% men and 11% women

Injection drug use

The scenario of injection use and HIV seroprevalance in north Eastern state of Manipur is well known

Mynamar,Thailand and Laos in south East Asia ,notoriosly known as the Golden triangle

Fall out en route

Chowdhury and chowdhury observed no case of buprenorphine abuse in 1987 in deaddiction clinic

1988 ,498 out pt opioid addict , 24 (4.08%) were buprenorphene addiction ,20(4%) of these 24 pt used im route .

1989 , 18pt(17.8%)of inj buprenorphene and 9pt (3.2%) of tablets buprenorphine

45 IDU from chandigarh (Malhotra et al) reported both the routes pt who are using cocktail inj mainly with buprenorphine .

Reports from Patna shows more use of buprenorphine because of its availability low cost and purity

NIMHANS from 1991-1994 confirmed rising trends of buprenorphine abuse with a noticeable shift from heroin to buprenorphine

Study conducted by all India institute of medical science(AIIMS) in Delhi ,drug dependence treatment centre, in a sample of 100pt diagnosed with opioid dependence syndrome , there was significant multi-drug pattern including alcohal,tobacco,cannabis,BZDs and antihistaminic , 66pt were dependence on one substance ,51 were using heroin through “chasing” 2 were using raw opium, 13 pt using inject able buprenorphine.9pt various inj cocktail with buprenorphine, 34 other pt using more than one drug,

All in all, 42% injection use

etiology

PSYCHOSOCIAL FACTORS more in low socioeconomic classes Urban poverty Social attitude , peer pressure , individual temperament Generally used substance precedes the use of cocaine/

heroin but prescribed opioid are now increased as it may be less socially stigmatized

50% of urban heroin users are children of single parent or divorced ,behavioral problem in school, conduct disorder

Heroin behavior syndrome-agitated type depression, with anxiety symptoms, Impulsiveness, fear of failure ,low self-esteem, hopelessness, aggression, limited coping strategies, needs of immediate gratification

Areas with high prevalence of illicit opioid use has high crime rate, high unemployment , demoralized school system

Biological and genetic factors Genetically transmitted vulnerability Monozygotic>dizygotic concordant for opioid

dependence 3,372 twin study shows 52% genetic libility 16% fopr any drug addiction 38% for opioid compounds Genetically determined hypoactive opioid system Other factors are personality traits, novelty seeking Psychodynamic theory Libidinal fixation , with regression to

pregenital,oral , or even more archaic levels of psychosexual development

LEARNING AND CONDITIONING Drug use itself a positive reinforceser Presence of pain, depression subsided by

use act as negative reinforceser Classical conditioning /pavlovian

conditioning mainly act in relapse

neuropharmacology

Opioid has potent mood elevating properties

When inj or inhale produce intence RUSH:or FLASH lasting for 1-2 min

Long term use produce hyperresponsive ness to stress,reduce responsiveness to pleasurable event (hypophoria)

Family of opioid receptors ,u,k,d and OFQ/N (ORL-1) a/k/a ORPHAN receptor

All G-prot coupled Inhibit locus ceruleous Increased conductence of K+ Decreased inward Na+ Decreased cAMP Repeated use increased CREB protein Contributes to tolerance

mu kappa delta

analgesic analgesia ---

Respiratory depression

Respiratory dep(lower ceiling)

respiratory depression

sedation dysphoria Affective behaviour

euphoria miosis Reinforcing action

miosis sedation

Redused gi motility - - - - - -

Physical dependence - - -

Dopamine Pathways

Functions•reward (motivation)•pleasure,euphoria•motor function (fine tuning)•compulsion•perserveration•decision making

nucleusaccumbens

hippocampus

striatum

frontalcortex

substantianigra/VTA

raphe

INTREGATION

“A CYCLE OF SPIRALING DYSREGULATION OF BRAIN REWARD SYSTEM”

There is a shift to homeostatic point to new set point

Hypofunctioning neural system and increased sensitivity of HPA axis , increased sensitivity to environmental stressors and release of CRF produce response in dopaminergic system

Decreased volume of prefrantal cortex-radio image

Pre frantal cortex inhibites Amygdala

Orally, snorting intranasally, injected iv or s/c Feeling of warmth, heaviness of extremities, dry mouth, itchy

face and facial flushing Euphoria f/b sedation k/a nodding off Effect of opioid- respiratory depression (effect on brainstem) Miosis Constipation smooth muscle contraction including ureter and the bile

ducts change in blood pressure HR body temperature

IDU Vs hepatitis ,HIV Interaction with MAOIs Opioid over dose –respiratory arrest,coma+pinpoint

pupil+resp depression MPTP-induced parkinsonism Ingesion of opioid contaminated with methyl-

phenyltetrahydropyridine Pt develop irreversible parkinsonism 1 methyl-4-phenylpyridinium(MPP+) by enzyme

monoamine oxidase MPP+ binds with melanin in substantia nigra and

cause damage to neurons

basic similarity in DSM- iv –TR; and ICD-10 but later not use the term substance use,but use harm full use

DSM-1v-TR divide opioid related disorder in to OPIOID USE DISORDER(abuse /dependence) and OPIOID INDUCED DISORDER(intoxication/ withdrowal)

Opioid intoxication

A)recent use of an opioid B)clinically maladaptive behaviour OR

psychological changes( euphoria, f/b apathy, dysphoria, agitation, impaired judgment)

C)pupillary constriction(or dilatation) and one of the following

1)drowssiness 2)slurred speech 3)impairment in attention or memory D)the symptoms are not common due to general

medical condition

Management of acute intoxication

Treat as medical emergency NALOXONE-0.4mg …IV and repeat after5-10min

till cardio-respiratory depression reversed Then start NALOXONE infusion at 0.4mg/hr

should be given for at least 12 hr Ipeac-induced emesis/gastric lavage. f./b

administration of activated charcoal Pt with pulmonary edema required PPV Over dose in dependence pt naltrexone avoided

Management of withdrawalDSM-IV-TR

A)cessation of or reduction in opioid use that has been heavy and prolonged

Administration of an opiod antagonist after a period of opiod use

B)three of the following , developing within minutes to several days after criterion A

1)dysphoric mood 2)nausea or vomiting 3)muscle aches 4)lacrimation or rhinorrhea 5)diiarrhea 6)pupillary dilation, piloerection , or sweatin 7)yawning 8)fever 9)insomnia

“COLD TURKY” “KICKING THE HABIT” Starting dose of medication needs to be decided

according to the amount of opiod consumption in 24 hr period

Subsequent dose adjusted on the basis of withdrawal

Usual dose required are 1.2-3.0mg of buprenorphine or 60-120mg of methadone

Medicine tapered by 5-25% each day Usually detoxification medicine required for 2-3 wk

Rapid detoxification

DAY-1(first opioid free day) Clonidine 0.2mg start can be repeated

every 2nd hr ;1.8mg /day can be given Watch BP every 30-60min After 1-3 hr after first dose of clonidine

start NALRTEXON 12.5mg Start oxazepam(serax) to reduce muscle

cramp , 30-60mg oral at same time with clonidine , repeated every 4-6 hr (max 180mg)

DAY-2 Similar dose of oxazepam and clonidine

continue NALTERXON increased to 25mg DAY-3 TO 5 NALTREXON increased to 50 mg Taperd oxazepam and clonidine in such a

way that it stoped on 5-10 day Only NALTREXON 50mg continued

If pt is on NALTREXON posted to surgry? Stop 72hr befor sx No effect on spinal, or nerve root block Intrection of DISULFIRAM and

NELTREXON NO ecsept both are hapatotoxic

LONG TERM MAINTENANCE

OPIOID AGONIST A)METHADONE Most commonly use maintenance therapy,

medically safe , does not produce euphoria and cognitive impairment

80-120mg /day (20-80mg/day acc to synopsis)

Can be taken orally SIDE EFFECT-constipation, sweating, wt gain

B)LEVO-ALPHA-ACETYL-METHADOL:- Methadon derivative Mu receptor agonist Active metabolites are nor-LAAM,dinor

LAAM has long t1/2 of 48-96hr 3 times a wk schedule is reqered

OPIOID PARTIAL AGONIST BUPRENORPHINE Role of buprenorphine in opioid management

suggested by early study of JASIKI and MELLO, MENDELSON, there after many study supported it

It has short plasma t1/2 Has slow dissociation from receptor so can be use

daily dose or even alternate day Ceiling effect on respiratory depression SIDE EFFECT-sedation , constipation , tolerance

develop to this

Dose = 2-8mg/day Risk of its illicit sublingual or parenteral

present Combination of buprenorphene with

naltexone for sublingual use available

ANTAGONIST NALOXONE, CYCLAZOCINE , NOLORPHINE Not suitable as it has short t1/2 1980- NALTREXONE revolution Can be given orally Has more t1/2; plasma t1/2 =6-6hr but it blocking action

sustained for 48-72hr DAILY REGIMEN 50mg/day THRCE A WEEK Monday-100mg;wensday -100mg;150mg on Friday TWICE A WEEK Monday 150mg; 200mg on thursday

Psychosocial treatment

Essential for long term treatment Enhancing motivation to take prescribed

medicine Provide guidance for use of medicine

and their s/e Provide the relationship element INDIVIDUAL PSYCHOTHERAPY Supportive expressive therapy Interpersonal therapy Cognitive behavioral therapy

BRIEG PSYCHOTHERAPY 1-4 session Aimed at deglamorisation of drug use Install optimism Provide realistic feed back GROUP THERAPY Enhancing motivation Stabilize abstinence Psychoeducation Stabilise stable family , social ,occupational functioning Prevent relapse

Models of cognitive and behavior therapy for substance disorder

1 cognitive therapy of beck et al 2 relapse prevention model of Marlatt

and Gordon 3motivational interviewing of Miller and

Rollinick Operant behavior therapy by Hiffins et al Contingency Management by Anker and

Crowley Cue exposure treatment Aversion therapy

REFERENCES

Benjamine J . Sodock MD; comprehensive text book of psychiatry 1360-1380

JN Vyas ,Niraj Ahuja ;text book of post graduate psychiatry;98-127

Clifford T. Morgon; Richad A.King; introduction to psychology

Umesh Babu SB, Chaturvedi SK. Chaging pattern in opiate abuse with a focus on buprenorphine. Abstract of 47th Annual national conference of indian psychiatry society, patna ;Indian J psychiatry 1995;37(suppl):23

Chowdhury AN,chowdury S.Buprenorphine abuse: Report from India Br J addict 1990;85:1349-1350

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