9.0 Opiates/opioids

Opioid drugs are

analgesic and sedative-hypnotic

At high doses of opioids

high doses can lead to coma and death

Opioids are

best painkillers known

Opioids produce a sense of

euphoria

Opioid forms (natural):

Opiates" are naturally-occurring alkaloids found in the sap of the opium poppy

Raw opium contains

~10% morphine, ~0.5% codeine

Opium routes of administration:

oral, smoking

Opium: History of use

Since before recorded history, opium has been used in many medicinal preparations

Opium: History of medical use

Laudanum tinctures of opium

Primarily for pain; also diarrhea, coughing

For recreational use, raw opium is usually

raw opium is usually smoked

Opiates =

natural opioids derived from opium poppy

Opioids =

all ligands for opioid receptors

Principal active ingredients in opium:

morphine and codeine(natural source)

Morphine

Medical use as analgesic

Codeine

Medical use: some analgesic effects, really good for cough

Heroin (diacetylmorphine) is a semi-synthetic opioid formed from

Adding two acetyl groups to morphine

increased lipid solubility and speed to brain

First marketed by Bayer as

a less addictive replacement for morphine.

Heroin is inactive but is

Quickly metabolized into morphine in the brain

Heroin illegal in U.S.

Schedule I

Pure heroin can be

smoked, snorted, or taken IV

The purity of street heroin varies and may include

Adulterants to enhance the effects (e.g., fentanyl, which is more potent)

Opioid forms (semi-synthetic): Oxycodone

(semi-synthetic)

- OxyContin

Opioid forms (semi-synthetic): Hydrocodone

semi-synthetic

Used to treat severe pain

Opioid forms (semi-synthetic): Buprenorphine

Buprenorphine is a partial opioid agonist. It is semi-synthetic

Low doses of Buprenorphine:

used for mild to moderate pain

Higher doses of Buprenorphine:

can be used to treat opioid addiction

Opioid forms (semi-synthetic): Desomorphine (krokodil)

- "Flesh-eating drug"

- 8-10x more potent than morphine.

Opioid forms (synthetic): Methadone

- Methadone is a synthetic opioid.

- Commonly used to treat opioid addiction

- Long duration of action with oral consumption.

Opioid forms (synthetic): Fentanyl

- Fentanyl is a synthetic opioid used to treat pain (prescription drug).

Fentanyl is highly lipid soluble and has high potency:

100x more than morphine, 50x more than heroin.

Xylazine additive

Recently, illicit fentanyl and opioids are laced with xylazine("tranq").

- Increased risk of respiratory depression and overdose

Current use and abuse: Prescription opioids (1)

- Prescription opioids are used for severe pain (analgesic) and cough (antitussive)

- chronic use of opioids seems to increase potential for abuse, addiction, and overdose

Over the last 20 years

Large increase in opioid overdose deaths (prescription, heroin, synthetic opioids)

One factor that contributed to the prescription opioid and heroin epidemic:

Purdue aggressively marketed OxyContin® (controlled release oxycodone)

Opioids: Recreational Routes of Administration

-IV injection

-SC injection

-smoking/inhalation

-snorting

Opioid drugs differ in onset and duration

Onset: Heroin and fentanyl have high lipid solubility

Duration (half-life):

Methadone (oral): long half life (24 h) due to depot binding

Effects of opioids: Low to moderate doses

- Analgesia (pain relief)

- Suppression of cough reflex

- Reduced gastrointestinal (GI) motility (constipation)

- Euphoria (reward)

- Some dysphoria

- Nausea/vomiting

slowed respiration, pupil constriction, drowsiness, decreased concentration. not at all pleasant, at least at first.

Effects of opioids: High doses

- Unconsciousness

- Pinpoint pupils

- Reduced temperature and blood pressure (clammy)

- Respiratory depression

Main cause of death due to overdose

Reversed rapidly by naloxone (antagonist)

Withdrawal symptoms are opposite to the acute effects:

Rebound hyperactivity in GI tract, autonomic nervous system, brain, and spinal cord. NOT life-threatening

Repeated administration: Dependence

Cross-dependence and cross-tolerance for all opioids

Repeated administration: Dependence and withdrawal

Longer duration opioid causes longer withdrawal with lower intensity

Rapid tolerance to some effects of opioids

Analgesia

Rapid tolerance to some effects of opioids But not others

GI effects (constipation), pupil constriction

Factors driving tolerance

Metabolic tolerance

Pharmacodynamic tolerance

Psychological tolerance

Drug tolerance can be specific to particular contexts;

Taking the same amount in a new place can be lethal

Repeated administration: Sensitization

stimulant and depressant

- Direct injection into VTA in animals, locomotor stimulant effects that sensitize with repeated administration.

- Opioid reward also sensitizes,

Negative effects of chronic use: Health risks

- Controlled, long-term use of opioids appears not to have serious health consequences.

- Low risk of long-term opioids to organs (unlike alcohol and tobacco use)

- that long-term use of methadone is not harmful

- relapse rates remain high.

Treatment options for opioids: Detoxification

Ultra-rapid detox with opioid antagonists

Treatment options for opioids: Long-term replacement therapy (long-duration opioids)

Methadone maintenance -- most common

• 80% abstinence rates

• Oral once daily, supervised because can be abused if taken IV (IV methadone is reinforcing/rewarding)

- Buprenorphine maintenance

Treatment options for opioids: Recovery programs

Group/individual counseling

Treatment options for opioids: Harm reduction programs

reduce injury and crime.

Treatment options for opioids: Opioid antagonists naloxone (Narcan) and naltrexone (Trexan)

Can be used to rapidly reverse opioid overdose.

- They also can be used for Addiction treatment and Preventing misuse of opioids

The pharmacodynamic action for all opioid drugs

is to bind to opioid receptors in the central nervous system (brain, spinal cord) and periphery (nerves, organ systems)

Endogenous opioids

β-endorphin

- All endogenous opioids are peptide neurotransmitters

- endorphins, enkephalins, and dynorphins. neurotransmitters and hormones

All opioid peptides are products of 4 gene families which encode long propeptides:

The long propeptides are cleaved to give smaller opioid peptides

Endogenous opioids are

peptide transmitters

Synthesis:

Peptides are made insoma, cleaved and packaged into vesicles in Golgi, and then transported to terminals.

Release:

Neuropeptides are not typically the only transmitter at a synapse. Instead, they are co-released together with a classical neurotransmitter.

Inactivation:

After release, peptides are degraded by peptidases (enzymes).

Opioid receptors

Opioid receptors are located in both CNS and periphery

Bioassay for opioids:

Ability of opioids to influence contractions of guinea pig intestine (ileum) strongly predicts human analgesic properties.

Opioid receptors: Discovery

Fig. A. Opioid binding increased until saturated -- all receptors occupied.

Fig. B. Opioid binding related to pharmacological effects (relaxation of intestine).

Opioid receptors: 4 main types

1. μ (mu) opioid receptor (MOR)

2. δ (delta) opioid receptor (DOR)

3. κ (kappa) opioid receptor (KOR)

4. nociceptin/orphanin FQ receptor (NOPR)

Abused opioids all bind to the μ-opioid receptor,

What type of receptors are opioid receptors?

Metabotropic

What proteins are opioid receptors coupled to?

Gi proteins

What happens when opioids bind to their receptors?

Inhibition of adenylate cyclase (AC)

What is the effect of opioid binding on G-protein-gated ion channels?

Opens K+ channels and closes Ca++ channels

Opioid receptors in the synapse

Opioid receptors can be presynaptic or postsynaptic

Locations of neurons containing endogenous opioids

Endogenous opioids are found in multiple brain regions, especially those involved in pain and emotion (affect) signaling

Locations of opioid receptors

CNS: brain, spinal cord

PNS: sensory neurons

Opioid Agonists:

Many Rx and abused opioid drugs

Opioid Competitive antagonists:

Naloxone, naltrexone

Opioid partial agonists:

Buprenorphine

Abused opioids are all

agonists at the μ-opioid receptor

What is the effect of genetic knockout of μ-opioid receptor (MOR -/- mice) on spinal analgesia?

Loss of morphine effects

What is the effect of genetic knockout of μ-opioid receptor (MOR -/- mice) on supraspinal analgesia?

Loss of morphine effects

What is the effect of genetic knockout of μ-opioid receptor (MOR -/- mice) on reward?

Loss of morphine effects

What is the effect of genetic knockout of μ-opioid receptor (MOR -/- mice) on withdrawal?

Loss of morphine effects

What is the effect of genetic knockout of μ-opioid receptor (MOR -/- mice) on respiratory depression?

Loss of morphine effects

What is the effect of genetic knockout of μ-opioid receptor (MOR -/- mice) on inhibition of GI motility?

Loss of morphine effects

What is the effect of genetic knockout of μ-opioid receptor (MOR -/- mice) on psychomotor activation?

Loss of morphine effects

What is MOR

Genetic knockout of μ-opioid receptor and is a critical binding site for all these morphine effects

Analgesia

Analgesic effects of opioids

Analgesic

1. Spinal cord opioids inhibit incoming pain signal

2. Periaqueductal gray

3.. Forebrain sensory and emotional response to pain

Painful stimuli cause release of endogenous opioids

2. Reward μ receptors

- Strongly implicated in reward and euphoria.

- strong self-administration and CPP for selective μ receptor agonists.

Evidence that DA does mediate opioid reward:

- μ agonists: increase VTA DA cell firing and DA release in striatum (NAc).

- DA antagonists: sometimes reduce opioid CPP and self-administration

Evidence that DA does not mediate opioid reward:

- DA receptor antagonists and 6-OHDA lesions do not have large effects on heroin self-administration

- DA-deficient mice still show morphine CPP

What are the GI effects of opioids?

Opioids decrease GI motility and can cause constipation.

What receptors do opioids bind to in the gastrointestinal tract?

Opioids bind to μ and κ receptors in the stomach and small/large intestine.

What is Loperamide (Imodium®) used for?

Loperamide is used to slow GI motility and reduce diarrhea.

How does Loperamide (Imodium®) act?

Loperamide acts peripherally as a modified opioid.

4. Respiratory depression

Respiratory control:

1. Fundamental drive generated by brainstem.

2. Conscious modulations from cortex.

3. Subconscious modulations from blood chemoreceptors

What is considered the 'gold standard' in antitussive therapy?

Codeine

What are the central actions of codeine in cough suppression?

Central actions in the brainstem (cough reflex)

What are the peripheral actions of codeine in cough suppression?

Peripheral actions on sensory nerve endings

What is Dextromethorphan (DM, DXM, Robitussin®) developed as?

A non-addictive substitute for codeine

Does Dextromethorphan act at opioid receptors?

No, it does not act at opioid receptors

6. Nausea and vomiting

Opioid-induced nausea

1. area postrema.

2. Increased vestibular sensitivity.

3. Delayed gastric emptying.

7. Pupil constriction

pupil constriction is due to opioid disinhibition of brainstem nuclei

Where do opioid drugs act to produce their major effects?

1. Analgesia• Spinal cord, periaqueductal gray, forebrain

2. Reward• Brain - dopaminergic and non-dopaminergic mechanisms

3. Gastrointestinal• Stomach, small/large intestine

4. Respiratory depression• Brainstem, cortex, blood chemoreceptors

5. Cough suppression• Brainstem, sensory nerves

6. Nausea and vomiting• Area postrema, vestibular system, GI

7. Pupil constriction• Brainstem