18 - opioid analgesics

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Overview


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Pain pathways:

Targets for opioid analgesics located mainly in the dorsal horn of the spinal

cord, the periaqueductal gray matter, and the thalamus

- Also areas of the cortex (such as the limbic cortex)

Targets in the ventral brainstem mediate the effects on respiration, cough,

vomiting, pupil dilation

Targets in the hypothalamus mediate endocrine effects

Targets in the limbic system (amygdala, hippocampus) mediate the mood

and behavioral effects

Pain


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PainPHM331PHM331


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The opium poppy:

Papaver somniferumUsed 5000+ years for pain relief, sleep induction, relief of diarrhea, euphoria

Narcotics, from the Greek narke, meaning stupor, formerly used to

describe agents that produced drowsiness, analgesia, dreamy/stupurous

state (no longer used due to confusion with the definition of narcotics used

to describe banned/illegal drugs)

Opiates are derived from Papaver somniferum seedpod residue

Opioids are drugs with morphine-like action

OpiatesPHM331PHM331


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Opiates:Benzylisoquinoline alkaloids

e.g. papaverine

- smooth muscle depressants: relaxes arterioles to decrease blood

pressure and decreases GI motility

- no analgesic effect

- little to no binding to opioid receptors

Phenanthrene alkaloids

e.g. morphine (10%), codeine (0.5%), thebaine (not an analgesic, but

precursor to several opioids)

- analgesic

- euphoric- only the l or levorotary forms are active

OpiatesPHM331PHM331


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Endogenous opioid receptor agonists:

At least 20 different peptides have been identified

3 classes:

endorphins (beta-endorphin)

enkephalins (leu- and met-enkephalin)

dynorphins

Derived from 3 genes:

pre-proopiomelanocortin

- contains the beta-endorphin sequence, met-enkephalin, 6 non-opioid

peptide sequences

pre-proenkephalin A

- contains 6 met-enkephalin sequences and 1 leu-enkephalin sequence

pre-prodynorphin

- several dynorphine peptides

NeurotransmittersPHM331PHM331


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NeurotransmittersPHM331PHM331


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ReceptorsPHM331PHM331


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Opioid receptors:

Three major classes of opioid receptors have been cloned and

characterized

They are all G-protein coupled receptors Galphai/o-coupled, inhibition of

adenylate cyclase, decreases in voltage-gated calcium current (decreasedneurotransmitter release), and activation of potassium currents

Analgesia occurs mostly due to mu opioid receptor activity

Delta and kappa contribute to analgesia at the spinal level

High structural and stereo specificity

Competitive, reversible binding

ReceptorsPHM331PHM331


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Neuronal activity:

Opioids inhibit spontaneous and evoked activity and neurotransmitterrelease

In the hippocampus, there may be increased activity due to the blockade of

inhibitory interneuron neurotransmitter release

Analgesia:

i) Raised pain perception threshold - can be specifically measured

ii) Increased pain tolerance - more subjective

A greater effect on pain tolerance than perception, so patients may still

perceive the pain, but it wont cause too much discomfort

Relief of all types of pain: visceral, somatic, cutaneous

Better for dull, constant pain than sharp, severe, or intermittent pain

MechanismsPHM331PHM331


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Respiration:

mu-Opioid receptor activation can cause respiratory depression by decreasing the

sensitivity of the respiratory center to CO2

Respiratory depression is often the cause of death due to opioids

Additive with alcohol, anxiolytics, antidepressants and all CNS depressants for respiratory

depression

Respiratory depression parallels analgesic efficacy

Opioids can also increase the tone and rigidity of the trunk muscles to impair breathing

Mood:

Foggy, unreal, detached feeling, usually pleasant, euphoric and relaxing but may bealarming or unpleasant in some people

Sedation:

All opioids produce sedation to varying degrees, correlated with mu receptor agonism

Sedation is additive with alcohol and anti-depressants



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Excitation:

Low doses of morphine can cause restlessness, fever, and hyperactivityIn some patients, convulsions may occur

Miosis:

Constricted pupils, centrally-induced, but can be blocked by atropine

Nausea and vomiting:

Stimulation of the chemoreceptor trigger zone, aggravated by activation of

vestibular areas, delayed gastric emptying (also caused by opioids)

Anti-tussive:

Direct depression of the cough center

Other, non-opioid derivatives such as dextromethorphan are used for anti-

tussive action specifically



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Endocrine effects:

Due to activation of opioid receptors in the thalamus and hypothalamus

Inhibition of luteinizing hormone release (leading to decreased luteotropin

and follicle-stimulating hormone release and decreased testosterone

production in the testis)

Libido is decreased, in men sperm motility is impaired and in women

anovulatory cycles or amenorrhea occurs

Poikilothermia:

Fluctuations in body temperature and dysregulation



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Histamine release:

Histamine release causes peripheral blood vessels to dilate, decreasing

blood pressure and causing postural hypotension, flushing, increased loss

of body heat that contributes to body temperature dysregulation (feeling

cold)

Contraction of smooth muscle:

Bilary and bladder sphincters contract

Tone of the GI tract may increase, but inhibition of acetylcholine release inthe enteric nervous system also decreases peristalsis this results in the

marked constipation that is long been known to occur in opioid users



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Pharmacokinetics

Absorption:

High absorption but variable bioavailability due to first-pass metabolism

Only 15-30% of an oral dose of morphine may reach the systemic

circulation, therefore oral doses are 5-6 times larger than IV doses, 2-3

times larger for chronic treatment

Codeine and oxycodone are less susceptible to first-pass metabolism

Other routes of administration:

Extended-release oral dosing

Rectal

Percutaneous absorption

e.g. fentanyl patchUsed for chronic pain relief in cancer

Lower frequency of side-effects and breakthrough pain

Epidural

Usually post-operative pain relief, lower risk of respiratory depression

Nasal

Currently in development

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Pharmacokinetics

Distribution:

At plasma pH, the basic opiates such as morphine are ionized, therefore

CNS distribution is limited

Ionization also occurs in the lumen of the GI tract, decreasing the absorption

of large doses, therefore emptying of the GI tract can be used in overdose

situations

Morphine will cross the placenta

Rapid onset of action, 5-15 minutes after IM injection

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Pharmacokinetics

Metabolism and Excretion:

Morphine is highly metabolized in the liver via hydroxylation and

glucoronidation

Half-life is 1.5-4 hrs

90% is excreted in the urine, 10% in the bile

Other opiates and opioids have several different metabolic profiles and

routes of elimination, but liver metabolism and renal excretion are the most

common

Liver impairment may lead to a rise in blood levels, and patients with renal

impairment should not be administered meperidine due to the accumulation

of the toxic metabolite, normeperidine

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Tolerance and

Dependence

Tolerance develops rapidly, increased doses are required for equivalent

therapeutic effects

The development of tolerance is correlated with and increased risk of

(physical) dependence

Withdrawal of morphine or other opioids in dependent patients results in

restlessness, anxiety, vomiting, diarrhea, chills, fever, pupil dilation,

This can be precipitated by opioid antagonists

Mechanisms

Post synaptic receptor levels increased (noradrenaline receptors?)

Excess accumulation of neurotransmitter

Induction of enzymes depressed by opioid administration

Dysregulation of systems controlled by multiple pathwaysDiminished endogenous opioid receptors and neurotransmitters

Addiction

Tolerance and dependence are risk factors for addiction, however addiction

also requires an uncontrolled compulsion to continue taking opioids or other

drugs

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Tolerance and

Dependence

Opioids increase release of dopamine in the nucleus accumbens

Inhibits inhibitory GABAergic neurons on dopaminergic neurons

Increased activity of the reward system

Heroin:

Prodrug for morphine

Rapidly metabolized to monoacetylmorphine and then morphine byesterases

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Tolerance and

Dependence

Overdose:

IV injections of the antagonist, naloxone

Drug interactions and contraindications:

Mixed agonist-antagonist drugs such as pentazocine or partial agonists may

precipitate withdrawal symptoms in patients taking a full agonist such asmorphine

Head trauma - carbon dioxide retention can cause cerebral vasodilation and

exacerbate intracranial pressure

Pregnancy - in addicts especially, slow weaning of opioid therapy and

switching to methadone

Depressed respiratory function, impaired hepatic function

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Other opiates and opioidsPHM331PHM331


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Other opiates and opioidsPHM331PHM331


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Phenanthrenes:

Morphine, hydromorphone, oxymorphone

Prototypical opioids

Strong mu-agonists, hit all receptors

Other opiates and opioids

- strong agonists

Phenylheptylamines:

Methadone

Similar pharmacology to morphine, but much longer acting

Much higher bioavailability compared to morphine and can be taken orally

When tolerance to morphine occurs rotation to methadone improves analgesia

Tolerance and dependence develop more slowly

Withdrawal symptoms are milder, but longer lasting

Used for detoxification and maintenance to prevent addict relapseTolerance to the effects of methadone lead to cross-tolerance to morphine,

therefore a goal of therapy is to actually induce tolerance and dependence

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Phenylpiperidines:

Meperidine and Fentanyl are the most widely used drugs of this class

Meperidine has several anti-muscarinic side-effects and is contra-indicated

in patients with coronary artery disease or heart failure

Seizures may be induced by the metabolite, normeperidine, especially at

high doses or in patients with renal failure

Morphinans:

Levorphanol


- strong agonistsPHM331PHM331


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Phenanthrenes:

Codeine, oxycodone, dihydrocodeine, hydrocodone

All slightly or significantly less efficacious than morphine

Often used in combination formulations


- mild agonists

Phenylheptylamines:

Propoxyphene

Related chemically to methadone

Low analgesic activity

Phenylpiperidines:

Loperamide, Diphenoxylate, and difenoxin are used primarily for the

treatment of diarrhea

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Phenanthrenes:

Nalbuphine

kappa-receptor agonist, mu-receptor antagonist

Some parenteral analgesia and low incidence of respiratory depression

Buprenorphine

Partial mu-receptor agonist

Long duration of action, may be used in place of methadone


- mixed/partial agonists

Morphinans:

Butorphanol

Kappa-receptor agonist

Similar analgesia to nalbuphine, buprenorphine, but more sedating

Benzomorphans:

Pentazocine

Kappa agonist, weak mu agonist

Dezocine

Mu-agonist, weak kappa agonist

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Naloxone, naltrexone, nalmefene:

Bulkier side chains at the N17 position

All have higher affinity for mu than kappa or delta

Poor oral bioavailibilityShort half-life if given by injection

Metabolized and excreted as glucoronide conjugates

IV antagonists reverse morphine action within 1-3 minutes

Will normalize respiration, consciousness, pupil size, bowel activity

Will rapidly induce withdrawal

Opioid antagonistsPHM331PHM331


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Antitussive opioids

The opioid analgesics are very effective for the suppression of cough

The doses that are required are far less than those needed for analgesia (diff. receptors?)

Opioids most commonly used are: dextromethorphan and codeine

Dextromethorphan doesnt display any of the adverse effects associated with opioid use

Dex. Should be used with caution in patients taking monamine oxidase inhibitors

Codeine is used at lower doses than are needed for its analgesic effects (15mg)


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Neonatal abstinence syndrome (NAS) :

Occurs due to opiate withdrawal may result in disruption of the mother-infant

relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures.

Why is combination therapy used?

By combining 2 drugs with different mechanisms of action, such therapy provides

additive analgesic effects while reducing the risk for adverse effects. Combinationtherapies overcome the "ceiling effects" (ie, when further increases in dose provide no

further significant gains in efficacy) of their individual components.

Combination therapy of oxycodone and ibuprofen (Combunox) is more effective in

treating pain than oxycodone and acetaminophen (Percocet) (Litkowski et al. Clin Ther.

2005 27(4) 418)

18 - opioid analgesics

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