toxicology of opiates

Opiates and Opioids• Opiate refers to a substance that originates from opium, and is gained out of the latex of the capsule of the opium plant, Papaver somniferous • Opioid is the term

Toxicology of Opiates

Dr George Braitberg Austin and Repatriation Medical Centre

Heidelberg Victoria

Opiates and Opioids

• Opiate refers to a substance that originates from opium, and is gained out of the latex of the capsule of the opium plant, Papaver somniferous

• Opioid is the term used for substances with an analogue effect to morphine Opioids are ligands on opioid-receptors and they possess

an intrinsic activity.

Opiates and Opioids

Not all opiates bond to receptors: not all opiates are opioids

Opiates are the approximately 20 natural substances

from the opium-juice of poppy seed capsule

Morphine Codeine (3-ortho-methyl- morphine)

Papaverine Noscapine

Opioids are substances with effects similar to morphine:

• Natural opioids, opioid opiates

• Semi -synthetic opioids

Opioids with morphine like action

Phenanthrenes: are opium alkaloids that have

an effect analogue to that of morphine They

are opioid effective opiates

Morphine (Morphium): raw opium contains

10-17% morphine

Codeine: is used mainly as an antitussive

Opioids with no morphine like

action

Thebaine:starting substance for synthesis of

naloxone, naltrexone and buprenorphine; has only a very slight effect on it’s own

Benzylisochinoline: are opium alkaloids which

have no effect analogue to that of morphine

Papaverine: Phosphodiesterase inhibitor:

works mainly spasmolytic

Noscapine: antitussive without addiction

potential Raw opium contains 2-9% noscapine

Semisynthetic Opioids

Heroin (DAM, Diamorphine 3,6-O-Diacetylmorphine)

Hydromorphone Nicomorphine Dihydrocodeine Hydrocodone (Dihydrocodeinone)

Endogenous opioids

Beta-endorphin is a peptide-opioid substance found in the body

Morphine - opioid and opiate

Morphine –Analgesic, natural opioid

–Duration of effect:

4-5 hours; in retard form 6-12 hours

–Elimination half-life:

3 hours (also in retard form)

–Minimal deadly dose:

• 25 mg i.v./ 50 mg po.

Codeine - opioid and opiate

Semisynthetic Opioids

Heroin

Hydromorphone

• Analgesic

• Duration of effect: 4-5 hours

• Elimination half-life: 0.5 hours

• Minimal deadly dose: 25 mg i.v.

• from morphine through acetylation by acetic acid anhydride

• Analgesic

• Duration of effect: 4-5 hours

• Elimination half-life: 2.5 hours

Semisynthetic Opioids

Nicomorphine

Dihydrocodeine

AnalgesicDuration of effect: 4-5 hoursElimination half-life: 2-3 hours

Antitussive, (Analgesic)Duration of effect: 4-5 hours

Semisynthetic Opioids

Hydrocodone

Buprenorphine

antitussive Duration of effect: 8-10 hours Elimination half-life: 4 hours

Analgesic Duration of analgetic effect: 6-8 hours Duration of withdrawal prevention effect in high doses up to 48 hours

Elimination half-life: 5 hours

Agonist/Antagonist; synthetised out of Thebain

Synthetic Opioids

Methadone

• Analgesic

• Duration of analgetic effect: 8-48 hours

• Duration of withdrawal prevention effect in high doses: rarely less than 24 hours

• Elimination half-life: 15-22 hours

• Minimal deadly dose : 25 mg i.v.;

• 50 mg p.o.; (25 mg L-Methadone p.o)

•Analgesic –Duration of effect: 3 hours –Elimination half-life: 2-3 hours –Takes effect on κ -Receptoren agonistically and on the µ -Receptoren antagonistially

• Analgesic

–Duration of effect: 2-4 hours–Elimination half-life: 2.5-3 hours

Heroin Addiction

Heroin is an opioid that is

biotransformed in the body ultimately to morphine (Heroin -> 6-

monoacetylmorphine (6MAM) ->

morphine).

Heroin and morphine produce analgesia

by acting on the mu (µ)-type opioid

receptors in the brain action of heroin

vs morphine are clearly separable

These studies may provide the basis for relating genetic factors to

differences in response between

Heroin Addiction

The analgesic action of µ opioid

agonists such as morphine occurs in the brain but activates neurons in the spinal cord which release

norepinephrine and serotonin When heroin acts on delta receptors in the brain a different set of neurons are

activated which release a different

neurotransmitter, GABA, to produce

Opiate Withdrawal Syndrome

Eye watering, runny nose, yawning, sweatingOccurs within 8-12 hours of last heroin

Followed by restlessness, piloerection,

mydirasis, tremor, anorexia, bone and joint pain, muscle cramps

Symptoms peak at 48-72h

Symptoms disappear at 7-10 days

General malaise and craving lasts months

Naltrexone is a long acting potent pure

narcotic antagonist Clinical pharmacology studies demonstrated that oral naltrexone

at 50, 100 and 150mg effectively blocks

the physiological and subjective effects of parenterally administered heroin,

hydromorphone or morphine for 24, 48

and 72 hours respectively

The lowest effective plasma

naltrexone concentration of 2ng/ml provided an average of 86.5%

blockade of 25mg IV heroin effects

In sustain released therapy for

opiate antagonist activity, plasma

level of naltrexone should be kept

Naltrexone was approved by the FDA in 1984 for use in opioid detoxification, and in 1995 for alcohol detoxification in known substance

abusers Naltrexone is available only in the oral form It is a modification of naloxone made by adding a carbonyl group to C-6 Naltrexone

competes with the opioid agonists for the mu, delta, and kappa receptor sites in the central

nervous system

Naltrexone - Pharmacokinetics

Elimination half-life of 3.9-10.3 hours

Absorption is rapid and almost complete

Bioavailability of only 5-20% (extensive first pass hepatic metabolism)

Metabolised to 6-beta-naltrexol which is a less

potent but active opioid antagonist

Metabolised in the liver to naltrexone-glucuronide and 6-beta-naltrexol Only 2% is excreted

In opioid dependence, a 25 mg test dose is given If there are no signs

of withdrawal, an additional 25 mg

is given, then maintenance

naltrexone therapy is set at 50-100

mg per day

Naltrexone in the Literature

86, 1989,

Loimer N Similar Efficacy of

Abrupt and Gradual Opiate Detoxification

Am J of Drug and Alcohol Abuse 17 (3):.307-312,1991

Naltrexone in the Literature

Resnick RB et

alNaloxone-Precipitated

Withdrawal: A Method for

Rapid Induction Onto

Naltrexone Clin Pharm

Drug and Alcohol Dependence 35 (1994) 91-93

Lance L Rapid Opiate

Detoxification

J of Addictive Diseases.15(2) 1996:117

Naltrexone in the Literature

Naltrexone in the Outpatient Treatment of Heroin

Withdrawal Kleber HD, Topazian M, Gaspari J, Riordan

De, Kosten T Am J Drug Alcohol Abuse 1987; 13:1-17.

Clinical Utility of Rapid Clonidine Naltrexone

Detoxification for Opiod Abusers Vining E, Koste TR,

Kleber HD Br J Addiction 1988; 83:567-575

Ultra-rapid, Antagonist-precititated Opiate

Detoxification Under General anesthesia or Sedation

Brewer C Addiction Biology 1997; 16: 2-291-302

Rapid Opiod Detoxification Using Opiod Antagonist: History, Theory and State of the Art Simon DL, J

Naltrexone in the Literature

LG Am J Drug Alcohol Abuse 1996; 22:489-495

Treatment Options in Addiction Brahen LS,

Brewer, C Medical Management of Alcohol and

Opiate Abuse London: Gaskell, 1993; 46-53

for Heroin Addicts Compared with Drugfree

Community-based Program: the First Cohort Chan

KY J Clin Forensic Med 1996; 3:87-92

Naltrexone in the Literature

Naltrexone Pharmacoltherapy for Opiod Dependent Federal Probationers Cornish JW, Metzger D, Woody

GE, Wilson D, McLellan AT, Vandergrigft B, and O'Brien

CP, J Substance Abuse Treatment 1997; 14:529-534

Kinetics of a Naltrexone Sustained-release

Preparation Chiang CN, Hollister LE, Kishimoto A,

Barnett G Clin Pharml Ther 1984; 3636:704-708

Clinical Evaluation of a Naltrexone

Sustained-Release Preparation Chiang CN, Hollister LE, Gillespie

HK, Foltz RL Drug Alcohol Dependence 1985; 16:1-8

Natrexone & Opioid

Detoxification

In a double-blind, placebo controlled trial, opioid dependent patients receiving a combination of clonidine and naltrexone exhibited transient,

slight withdrawal symptoms The cost saving for this approach is substantial compared to

methadone tapering

Patients do better in terms of mood, family

relationships, and continued involvement in

psychosocial programs

Naltrexone and Rapid

Detoxification

Patients in Spain have been

successfully detoxified from heroin

in an ICU setting over 4 hours

using midazolam and naltrexone

Similar experiences have been

reported over 24 hours in Israel

Outpatient Naltrexone

Use of clonidine and naltrexone in an outpatient setting was highly successful in detoxifying heroin abusers

Clonidine alone or in combination with methadone has also been successful

In general inpatient success is greater than outpatient success for all modalities (80% v 17%)

Naltrexone & Recidivism

Naltrexone appears to be useful in preventing recidivism in opioid

abusers In doses of 25 mg 2 times per week for 2 weeks, and then 55

mg 3 times per week, a significant number of patients were prevented from reabusing opioids

Naltrexone & Concerns

Naltrexone may produce a

"sensitization" phenomenon Animal studies have demonstrated that

even once weekly doses of naltrexone can sensitize the animal such that it needs much less of the drug to decrease food-reinforced responding to opioids

Naltrexone & Concerns

Up-regulation of mu opioid receptors in the brain occurs

The reintroduction of an opioid induces a much larger response

There is a theoretical risk that patients who leave naltrexone programs to reabuse heroin may be more likely to have a lethal overdose because

they are more sensitive to the respiratory effects

of the drug

Naltrexone & Alcohol

Naltrexone in doses of 50 mg per day significantly reduces the craving for, and consumption of ethanol, and decreases relapse rates

All treatment successes have required intensive counselling programs, but

regardless of the type of counselling, the naltrexone treated groups do better

Naltrexone on the Net

member of the American Society of Addiction Medicine (ASAM) Dr X has many years of medical experience and frequently appears in court as an expert witness Dr X is currently collecting data and is publishing a paper

soon showing that Antagonist Assisted

Abstinence patients are much more

successful in staying off opiates than patients from traditional detox programs.”

Naltrexone on the Net

“Our clinic has state-of-the-art facilities for monitoring patients under deep sedation The deep sedation is always performed under the supervision of an experienced licensed physician.

Our clinic is located in southern

Naltrexone on the Net - A

Testimonial

“Through the internet I found that some people

had found relief using a drug called Naltrexone Following the thread on down it lead me to the

Assisted Recovery Program I contacted L one

desperate evening and asked what kind of help they could provide He told me that within 1 hour they could remove the cravings and after 90 days have my own endorphins back in service no

more cravings It sounded too good to be true .”

Naltrexone on the Net

“I don't think I really noticed at the

time, but, the cravings did stop that day I have been in the program for

39 days today not even a twinge

of need - absolutely no craving This treatment is phenomenal The fact that it is relatively unknown is

In post-op patients, 0.5 mg IV of

nalmefene is given at 2-5 minute

intervals until the desired effect is achieved with respect to respiratory rate and sedation For opioid

overdose, 0.5 mg increments to a maximum of 1.5 mg IV are given

Nalmefene is used to block the respiratory

depressant effects of narcotics during medical procedures In a randomized, double blind,

placebo-controlled trial, subjects were given up

to 2.0 mg of IV nalmefene The effects were

clearly dose-related, since 0.5 mg of

nalmefene blunted pain tolerance and

respiratory effects of fentanyl for up to 4 hours, while 1.0 mg of nalmefene was effective up to