Lectures 20-21: Opioids and Antagonists

Mu opioid receptor

Analgesia, euphoria, sedation, side effects

Kappa opioid receptor

analgesia in some people, dysphoria in others

endogenous pain modulation

Delta opioid receptor

Dysphoria

endogenous pain modulation

Opioid receptors

All of the opioid receptors are coupled to Gi/o

All subtypes close voltage-gated Ca++ channels on presynaptic nerve terminals

decreases neurotransmitter release (glutamate and Substance P) + decreases neuronal activity

μ receptors also open K + channels, causing hyperpolarization → inhibiting nerve transmission

Effect of Opioids- Pain Pathway

Direct Action at inflamed and damaged tissue

Inhibition of release of excitatory transmitters in the dorsal horn: spinal anesthesia

Thalamic action to decrease transmission to cortex

descending neurons that normally inhibit pathway from Rostral ventral medulla → inhibited

allows activation of neuron from rostral medulla to dorsal horn, that inhibits pain transmission

endogenous opioids released from periaqueductal gray

Pain Modulation

GABA normally inhibits descending neuronal pathways that modulate pain

Opioids decrease release of GABA, allowing the pathways to be activated

This inhibits pain transmission in the dorsal horn of the spinal cord

Effects of Opioids- pain and consciousness

Analgesia: Decreases sensation of pain + reaction to pain

Tolerance develops

Sedation/mental clouding

Not used as sleep aids- different quality of sedation

Disrupt REM

Codeine, meperidine may cause excitement in overdose

Therapeutic doses of morphine produce floating, dream-like state- can be aroused

Morphine causes CNS depression in overdose

Overdose: Mental Clouding and Sedation → Hypnosis or Stupor → Coma → Death

Effects of Opioids- feelings

Euphoria or dysphoria

Sense of floating, pleasure

Kappa and delta receptors involved in dysphoria

Effects of Opioids- Emesis and cough

Nausea and vomiting in some

Opioids stimulate chemoreceptor trigger zone (CTZ)

Depression of cough reflex (antitussive)

Lower doses than those for analgesia

Codeine and dextromethorphan very effective

Dextromethorphan not an analgesic

Meperidine DOESN’T suppress cough

Effects of Opioids- lungs and brain

Respiratory depression

More common in overdose, but also with therapeutic doses

Decreases response of brain stem to elevated CO2

Useful in pulmonary edema

Not good in people with pulmonary diseases

May also cause bronchoconstriction

Elevated intracranial pressure

Increased CO2 → vasodilation, increases cerebral blood flow and increases pressure

Watch out with head trauma

Effects of Opioids- pupils + temp

Miosis (pupil constriction) except with meperidine

No tolerance develops

Parasympathomimetic- blocked by atropine

Common in overdose, but may convert to dilation in comatose patients

Dysregulation in hypothalamus → Decreased body temperature

Effects of Opioids- muscles

Truncal rigidity

Supraspinal effect increases tone of the large trunk muscles

May interfere with respiration or with attempts to ventilate patient

Most common with highly lipid soluble drugs, like fentanyl, IV

Inject slowly or use neuromuscular blockers to prevent this effect

Effects of Opioids- Cardiovascular

No direct effect, but bradycardia may occur

Decreased blood pressure

Tachycardia may occur with meperidine

Effects of Opioids- Gastrointestinal

Decreased gastric activity both CNS and local effect- inhibition of transmitter release

Constipation!!!!!

Decreased gastric motility

Biliary colic, constriction of sphincter of Oddi

Decreased biliary, pancreatic, intestinal secretions

Effects of Opioids- GU, uterus, endocrine

Increases ADH, prolactin, somatotropin

Inhibits luteinizing hormone

Antidiuretic effect- decreases urine output

Decreases renal blood flow

Increases sphincter tone- harder to urinate

Increases urethral tone- harder to pass kidney stone

May prolong labor

Opioids and histamine

Opioids can produce histamine release

Histamine can cause flushing, itching, sweating

More common when opioids are injected, especially morphine

This is generally treated or prevented with antihistamines

Tolerance and Dependence

Hyperalgesia may occur with long-term opioid use → Decreased by NMDA receptor antagonists

tolerance to analgesia, sedation, euphoria, nausea and vomiting, respiratory depression

No tolerance to miosis, constipation, seizures

Opioid Adverse Effects

Nausea and vomiting- Less w/ food; Worst w/ injected morphine

Constipation

Urinary retention worse if BPH present

Itching and hives (histamine release)

Respiratory depression will be worse with higher doses

Caution in pulmonary disease

Postural hypotension

Restlessness and hyperactivity with codeine, meperidine

Dysphoria

Opioid Withdrawal

Dysphoria, anxiety, insomnia

Anorexia, Yawning

Chills, goose bumps (piloerection)

Vomiting, diarrhea

Rhinorrhea, lacrimation

Increased blood pressure, heart rate, temperature

Muscle aches and twitches

Symptoms can be reduced by use of clonidine or another opioid (methadone)

Opioid antagonists can precipitate withdrawal if dependent

Opioid Overdose

CNS depression

Respiratory depression

Pin point pupils

May dilate if severely hypoxic

Treat by supporting respiration

Use opioid antagonist like naloxone (Narcan)

Opioid Uses

Analgesia and Anesthesia

Acute pulmonary edema → Relieves dypsnea

Relief of cough: Codeine and dextromethorphan

Treatment of diarrhea: Loperamide, diphenoxylate/atropine

Direct access to dorsal horn decreases some side effects- but itching worse

Opioid Drug Interactions

Sedative hypnotics: Increased CNS and respiratory depression

Antipsychotics: Sedation, maybe respiratory depression

MAO Inhibitors:

Meperidine, dextromethorphan may inhibit serotonin reuptake

Best to avoid ALL opioids with MAOIs

CYP2D6 inhibitors: Inhibit metabolism of codeine, oxycodone, hydrocodone to active compounds

Fluoxetine/paroxetine worst for inhibition

Opioid Contraindications

Use of partial agonist with full agonist can impair analgesia, cause withdrawal

Patients with head injuries → Increase in intracranial pressure

Pregnancy, especially at delivery

Impaired pulmonary function

Impaired hepatic or renal function

Some endocrine diseases

Opioid Precautions

Biliary tract problems

Seizures (especially meperidine)

Pain of unknown cause (esp abdominal)

Chronic non-terminal pain

Inflammatory bowel disease

Urinary retention/BPH

Heroin

Very potent

Gets into the brain well

Commonly abused- produces euphoria

Morphine

Stimulates all opioid receptors → Produces all effects of opioids

Strong agonist → Useful in severe pain

More effective when injected than oral due to high first-pass metabolism

Metabolized in liver by CYP2D6 → Conjugated to glucuronide

Morphine-6-glucuronide is a very potent analgesic

Morphine-3-glucuronide (major metabolite) may cause adverse effects if it accumulates

May cause itching or vomiting when injected

Can cross placenta

Hydromorphone

more potent than morphine

Very effective for moderate to severe pain

Metabolites don’t accumulate, so good if there is renal dysfunction

Less likely to cause histamine release and itching than morphine

Methadone

Long half life and long duration of action

Stimulates mu receptors

maintenance treatment of addicts

Low doses used to prevent withdrawal symptoms without producing euphoria/reward

Withdrawal thought to be milder, but very prolonged

Used in long-term control of chronic pain

Effective in hard-to-treat types of pain

Meperidine

Mu agonist- short term use only

Can cause euphoria

Should not be used for more than 48 hours, in high doses, or in renal failure due to accumulation of metabolite, normeperidine

Normeperidine can cause seizures

Anticholinergic- tachycardia, pupil dilation

No cough suppression

Obstetric

Also inhibits NE/5-HT reuptake- serotonin syndrome with MAOIs

Fentanyl

Very lipid soluble and highly potent

Short duration of action and half-life

High abuse potential

short surgical procedures, often with midazolam

Popular in longer surgeries because of good cardiovascular profile

May cause truncal rigidity if given rapidly IV

transdermal patches or lollipops

Metabolized by CYP3A4

Hydrocodone

Used for moderate to severe pain

Don’t use w/ acetaminophen → liver toxicity

Fairly short half-life, duration of action

Conversion by CYP2D6 needed for some of the analgesic effect

Often abused

Oxycodone

Moderate to severe pain

Tourette’s syndrome and restless leg syndrome

Abuse-deterrent formulations

Don’t use w/ acetaminophen → liver toxicity

Metabolism by CYP2D6 increases analgesic effectiveness

Codeine

Good cough suppressant- doses lower than for analgesia

Mild-to-moderate pain

Must be metabolized to morphine by CYP2D6 to be active

Don’t use w/ acetaminophen → liver toxicity

Some abuse potential

Shouldn’t be used in small children (under age of 2)

Pentazocine/Naloxone

Kappa receptor agonist

Mu receptor partial agonist

Moderate pain

May cause dysphoria (kappa)

May cause withdrawal in patients dependent on opioids- partial mu agonist!

Low abuse potential

Buprenorphine

Partial agonist on mu

Ceiling to the effect- doesn’t cause much euphoria

Low abuse potential

Now maintenance treatment of opioid addiction- decreases craving for drug

Combined with naloxone

Nalbuphine/Butorphanol

Kappa agonists

Mu antagonists or partial agonists

Analgesia similar to pentazocine

Nalbuphine injected

If respiratory depression occurs, not reversible with naloxone

Butorphanol somewhat sedating, can be given by nasal spray

Tramadol

Used for mild to moderate pain; Weak mu agonist

Inhibits NE/5-HT reuptake, which contributes to analgesic effect

Not completely reversed with naloxone

dizziness, sedation, constipation, nausea

Combination with antidepressants may cause seizures

Combination with MAOIs, TCAs, SSRIs: may also cause serotonin syndrome!

Controlled substance

Dextromethorphan

Not an analgesic- good cough suppressant

Not likely to cause constipation

Blocks NMDA receptors- abuse potential in teens

Decreases 5-HT reuptake: serotonin syndrome with MAOIs

Has caused some deaths in teenagers- respiratory depression, tachycardia, psychosis, coma, seizures possible at high doses

Naloxone

Drug of choice for opioid overdose

Can reverse respiratory depression, consciousness, awareness of pain, miosis, constipation

Short duration of action (2 hours)

Repeated dosing may be required

Now being combined with agonists to prevent abuse

Naltrexone

Effective orally, and long acting

treatment of opioid addicts, especially health care professionals

Will precipitate withdrawal in patient dependent opioids!

Decreases craving in recovering alcoholics

May cause liver toxicity when used chronically; concern in alcoholics

Metabolized by CYP2D6

Codeine

oxycodone

hydrocodone

morphine

Metabolized by CYP3A4

Fentanyl