Treatment options in Opioid Dependence

Dr Kevin Stoloff

Today • opiates/opioids

• history of use

• mechanism of action

• intoxication/ withdrawal

• neurobiology of addiction

• treatment options

opiates vs opioids

Derivatives of opium eg heroin and morphine

All substances, natural or synthetic (pethidine, fentanyl etc), that act at mu - opioid receptors in brain

Opium poppy

Opium

• Opium is a complex chemical cocktail containing sugars, proteins, fats, water, meconic acid, plant wax, latex, gums, ammonia, sulphuric and lactic acids, and numerous alkaloids, most notably morphine (10%-15%), codeine (1%-3%), noscapine (4%-8%), papaverine (1%-3%), and thebaine (1%-2%)

Heroin

• On the illicit market, opium gum is filtered into morphine base and then synthesized into heroin.

Short history

• Persia, Egypt and Mesopotamia.

• first known written reference to the poppy appears in a Sumerian text dated around 4,000 BC.

• Homer conveys its effects in The Odyssey

Short history

• Popular in Egyptian civilizations

• Opium bought on streets of Rome

• 8th Century AD spread to India, Arabia ,China

• 16th C Laudenum created by Paracelsus; essentially tincture of morphine: created witches’ brew when he added this to henbane, crushed pearls, and frogspawn

• 19th C laudenum in British Pharmacy’s

Short History

• Youngsters introduced to pleasures of opiates at mothers’ breasts; baby-minders and parents found babies happy and docile

• Godfrey's Cordial

• Street's Infants' Quietness,

• Atkinson's Infants' Preservative,

• Mrs Winslow's Soothing Syrup.

Thomas De Quincy

Whereas wine disorders the mental faculties, opium introduces amongst them the most exquisite order, legislation and harmony. Wine robs a man of self-possession; opium greatly invigorates it....Wine constantly leads a man to the brink of absurdity and extravagance; and, beyond a certain point, it is sure to volatilize and disperse the intellectual energies; whereas opium seems to compose what has been agitated, and to concentrate what had been distracted. ...A man who is inebriated...is often...brutal; but the opium eater...feels that the diviner part of his nature is paramount; that is, the moral affections are in a state of cloudless serenity; and over all is the great light of majestic intellect....”

Confessions of an opium- eater (1821)

Samuel Taylor Coleridge

"In Xanadu did Kubla Khan A stately pleasure-dome decree Where Alph, the sacred river, ran Down to a sunless sea I would build that dome in air, That sunny dome, those caves of ice! And all who heard should see them there, And all should cry, Beware! Beware! His flashing eyes, his floating hair! Weave a circle round him thrice, And close your eyes with holy dread, For he on honey-dew hath fed, And drunk the milk of Paradise."

And…

• Opium wars…

• Advent of hypodermic syringes and upper classes in Europe and America injecting morphine

opiates.net

“God’s own medicine” by Sir William Osler

Neurobiology of addiction

Endogenous opioids

Intoxication

At above pain-relieving does…

occupation of mu-receptors gives very intense brief euphoria

(a “rush”), followed by a profound sense of tranquility, (may last several hours), followed by drowsiness

Dependence

• early on in addiction, intoxication alternates with normal functioning

• later, euphoria absent, and alternates between withdrawal, and lack of withdrawal

Withdrawal?

Inputs to Mesolimbic dopamine pathway of reward

VT

amygdala Nucleus Accumbens

Enkephalin (opioid) 5HT GABA cannabinoid

pleasure

Emotional learning ie fear, reward, pleasure, cues assoc with pleasure

Mesolimbic dopamine pathway of reward Reactive reward system

VT

amygdala Nucleus Accumbens

Repeated exposure, this system pathologically learns to trigger drug-seeking behaviour in response to int/ ext cues

pleasure

Emotional learning ie fear, reward, pleasure, cues assoc with pleasure

Mesolimbic dopamine pathway of reward Reflective reward system

Reactive system regulated by “top-down”

reward system involving regions of pre-fontal cortex

Nucleus Accumbens

“Should I be doing This Is it worth it? Let me weigh it all up?” Connections to NA including CSTC loops

H.C.

Mesolimbic dopamine pathway of reward Reactive reward system

Yes, emotional memories of pleasure are

being triggered, find drugs now

Am I detecting anything rewarding related

to previous drug experience?

Reward circuitry HIJACKED, cannot base decisions on consequences

Amygdala ?

VT

Nucleus Accumbens

Take drugs or not to take drugs?

Reactive pathway

(temptation)

Reflective pathway

(will power)

In addiction, balance is disturbed

Heroin in RSA

• Main illicit opioid

• Statistics from inpatient treatment centres

• 8 to 23% in 2008 heroin primary

• 76% are repeat treatment seekers

• Mostly smoked

• 6 to 18% report ivi

• % black/African increasing ie 65% Gauteng; 73% NR

Medical model

• Aim for abstinence from all opioids

• In clinical practice, short-term success for total abstinence is low eg in 1 study, 34% relapsed within 3 days, 45% within a week, and 60% within 90 days

• Abstinence assoc with completing programs, and aftercare

options

• Rapid detoxification from all opiates, and relapse prevention

• Harm reduction method, which is substitute opioid prescribing – international trends

Medications used

• Methadone

• Buprenorphine (Subutex)

• Suboxone

Rapid detoxification

• 7 to 21 days

• Graded lowering of opioid dose

• Use opioid substitution medication (methadone or bubrenorphine), and/ or symptomatic treatment (for mild dependence)

Aspects to consider

• Identification and motivation

• Detoxification

• Management of co-morbid medical and mental health problems

• Relapse prevention

About detoxification

• Using substitution medication, need to start with enough to alleviate withdrawal symptoms, without intoxication (baseline dose – usually worked out in first 3 days)

• Thereafter, gradual reduction of dose

• Non-substitute medications include alpha-2 agonist, clonidine (blocks sympathetic hyperarousal), but not muscle aches, dysphoria, craving

• Buscopan, paracetamol, immodium, diazepam

Relapse prevention

• Psychosocial: various, including CBT, relapse-prevention therapy, 12-step programs like NA

• Pharmacological: Naltrexone – opioid antagonist (blocker), can be injected, implanted or taken orally. Was not available except on case-by-case basis but now oral naltrexone has become availabe

• Risks: overdose, and precipitate withdrawal

Susbtitute opioid prescribing

• Some unable to give up, so intervention to reduce harm till ready

• Harm reduction strategies popular internationally due to chronic relapsing nature, and poor results of rapid detox

• Cochrane: proven effectiveness, and methadone maintenance Rx reduces morbidity (incl HIV risk, incarceration and other substance use), and mortality, and increases retention in care

Methadone

• Until recently, only physeptone (cough mixture at 2mg/5ml so inaccurate dispensing

• Now equity elixir is available in RSA – 2mg/ml • Full mu-opioid agonist, and therefore toxicity/

overdose possible – given daily • QTc prolongation • Metabolized CYP2B6/3A4P450 – PI’s in HIV

toxicity, and Rifampicin and anti-covulsants can cause withdrawal

• Benzo’s/ alcohol

Buprenorphine (Subutex)

• Partial mu-receptor agonist with low intrinsic activity but high R affinity (so if heroin added, diff to displace)

• Ceiling effect so reduces risk of toxicity, so reduces overdose risk

• Can precipitate withdrawal in highly dependent

Suboxone

• Buprenorphine thought to have low abuse potential but still happening

• So developed buprenorphine-naloxone combo as deterrent to injecting of buprenorphine

Suboxone

• Naloxone S/L absorbtion poor, buprenorphine good, so S/L will not precipitate withdrawal; but if ivi, nalaxone absorbed well, and highly unpleasant but safe withdrawal precipitated

• 4:1 orally is equally effective for SOT

Cape Town

Stikland Hospital inpatient detoxification

• 1 week; Suboxone 1st line, equity methadone 2nd line • Both have been applied for at district/ secondary

hospital level (obstetrics, psychiatry etc) OST clinic Above not registered as substitute drugs in RSA but

because detox outcomes poor, offer a Monday morning OST Clinic, but patients have to pay privately for meds

Cape Town

• Crescent Clinic, Kenilworth Clinic and others do detox

• Some private practitioners provide substitution therapy

References

Weich, L et al, (2009). South African Guidelines for the Management of Opioid Dependence: Update 2009; S African Med Journal, Jan 2010

South African Community Epidemiology Network on Drug Use (SACENDU)- updarte June 2012 – www.sahealthinfo.orgadmodule/sacendu.htm

“The plant of joy” –opiates.net

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