OPIOID ANALGESICS Anton Kohút. Popy seeds Although it is almost certain that the analgesic effects of an extract of poppy seeds was known long before.

OPIOID ANALGESICS

Anton Kohút

Popy seeds

• Although it is almost certain that the analgesic effects of an extract of poppy seeds was known long before then: for opium was imported from Cyprus to Egypt in the early 18th Dynasty (1551-1436 BC).

• The first authentic account of the use of opium, especially to relieve pain, can be found in the writing of Theophrastus in the third century BC

•

• The most active constituent of opium - morphine - was isolated in 1806.

This was an important event because it was then possible to prepare a purified drug.

• Morphine was first used in labour in 1906 as one of the constituents of 'twilight sleep'.

• Pethidine was introduced in Germany in 1939 and was first used during labour in the following year.

OPIOID ANALGESICS

Terminology• Opioids: any substances that produce morphine-like

effects antagonised by naloxone. The structure of which may be quite different of opiate. An opioid is a chemical that works by binding to opioid receptors. Opiate: morphine-like drugs with close structural similarity to morphine. The term opiate is properly limited to only the natural alkaloids

• Opium: is an extract of the juice from the poppy Papaver somniferum.

Mechanisms of action

OPIOID RECEPTORS

Specific protein receptors on the membranes of certain cells mostly in the CNS and the GIT.

All are coupled to inhibitory G proteins, and inhibit adenylyl cyclase.

Receptors: (mu) - analgesic activity, euphoria, sedation, depression, dependence (sigma) - peripheral action, interaction with enkephalins (kappa) - analgesia at the spinal level

Endogenous agonists: endorphins, enkephalins

Actions of agonists at opioid receptors

Distribution of receptors:

1. Brainstem: mediate respiration, cough, nausea and vomiting, maintenance of blood pressure, pupillary diameter, control of stomach secretion.

2. Medial thalamus: mediate deep pain that is poorly localized and emotionally influenced.

3. Hypothalamus: affect neuroendocrine secretion.

4. Spinal cord: In the substantia gelatinosa - the attenuation of painful afferent stimuli.5. Limbic system: emotional behaviour.6. Periphery: binding to peripheral sensory nerve fibers and terminals ( inhibition of the Ca-dependent release of pro-inflammatory substances (Substance P) from endings) – contribution to anti-inflammatory effects of opioids?

Activation of the peripheral terminal by a noxious stimulus leads to the generation of action potentials, which are conducted to the dorsal horn of the spinal cord. Neurotransmission in the dorsal horn relays the signal to CNS neurons, which send the signal to the brain. This circuit is also subject to descending modulatory control.                                                                                                                              Opioids produce analgesia because of their action in the brain, brainstem, spinal cord, and peripheral terminals of primary afferent neurons

Classification of opioids

OPIOIDS (MORPHINE-LIKE) ANALGESICS

Opioids - natural or synthetic; produce morphine-like effects.

They act by binding to specific opioid receptors in the CNS »»» effects mimic the action of endogenous peptide neurotransmitters (e.g., leu- and met-enkephalins).

They relieve severe pain - essential in treatment of major diseases, trauma, and surgery.

OPIOID ANALGESICS AND ANTAGONISTS

STRONG AGONISTS

MODERATE/LOW AGONISTS

MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS

ANTAGONISTS

OTHER ANALGESICS

AlfentanilFentanyl

MeperidineMethadone

Heroin

MorphineRemifentanilSufentanil

CodeineOxycodonePropoxyphene

BuprenorphineButorphanolNalbuphinePentazocine

NaloxoneNaltrexone

Tramadol

I. morphine analogues:

1. agonists - e.g. morphine, diamorphine (heroin) and codeine,

2. partial agonists - e.g. nalorphine and levallorphan,

3. antagonists (e.g. naloxone)

.

Synthetic derivatives

• II. synthetic derivatives with structures unrelated to morphine:

― phenylpiperidine series, e.g. pethidine, fentanyl ― methadone series, e.g. methadone,

dextropropoxyphene, ― benzomorphan series, e.g. pentazocine, cyclazocine ― semisynthetic thebaine derivatives, e.g. etorphine,

buprenorphine. • Loperamide - an opiate – but it does not enter the CNS

- it lacks analgesic activity. However, like other

STRONG AGONISTS

MORPHINE

The major analgesic drug contained in crude opium – the prototype agonist (codeine is present in lower concentrations and is less potent).

The opioid agonists all have similar actions, high affinity for receptors, varying affinities for and receptors.

Activation of the opioid receptor decreasesCa2+ influx in response toincoming action potential.This decreases release of

excitatory neurotransmitters,such as glutamate.

Opioidreceptor

Opioidreceptor

PRESYNAPTICNEURON

POSTSYNAPTIC NEURON

Activation of the opioid receptor increasesK+ efflux and decreases

the response of thepost-synaptic neuronto excitatory neuro-

transmitters.

Ca2+

Ca2+

K+

K+

Excitatoryresponse

Glutamate

Synapticvesicle

Mechanism of action ofopioid receptor agonistsin the spinal cord.

• Opioids: G protein linked-- affecting – Ion channel state – Intracellular Ca2+ levels – Protein phosphorylations states

• Two well-defined opioid actions: – Reduce neurotransmitter release; by closing a voltage-

gated Ca2+ channel on presynaptic neuronal terminals Or

– Inhibit postsynaptic neurons (hyperpolarization) by increasing and K+ channel conductance

• • Serotonin, bradykinin, glutamate, histamine,

prostaglandins, substance P (sP) ,

Mechanism of action:

1. opioids cause hyperpolarization of nerve cells (by opening of K+ channel)

2. presynaptic inhibition of transmitter release

3. decreas the release of substancia P and glutamate which modulate pain perception in the spinal cord

4. inhibition of adenylate cyclase

Morphine acts at receptors in the substantia gelatinosa of the

spinal cord; it decreases the release of substance P (which

modulates pain perception in the spinal cord).

It also appears to inhibit the release of many excitatory

transmitters from nerve terminals carrying nociceptive (painful)

stimuli.

Pharmacological actions

1. CNSa. Analgesia: - relief of pain without the loss of consciousness. (both by enhancing the pain threshold at the spinal cord level, and more importantly, by altering the brain’s interpretation of pain). Elderly patients are more sensitive to the analgesic effects b. Euphoria: powerful sense of contentment and well-being (may be caused by stimulation of the ventral tegmentum).c. Respiratory depression: by reduction of the sensitivity of respiratory center neurons to carbon dioxide. Respiratory depression - the most common cause of death in acute opioid overdose.

d. Depression of cough reflex: Morphine and codeine have antitussive properties.

e. Miosis (pupillary constriction): The pinpoint pupil - characteristic of morphine use - results from stimulation of and receptors.

f. Nausea and emesis: stimulation of the chemoreceptor trigger zone in the area postrema »»» vomiting. However, the emesis does not produce unpleasant sensations.

2. GIT and uropoetic systemIt decreases motility and increases tone of smooth muscle. It relieves diarrhea.

Morphine increases pressure in the biliary tract.

!! Morphine also increases the tone of the anal sphincter and ureteric spasm »»» harmful in biliary colic due to gallstones, retention of urine (catheterization in intoxication with M.) !!

Morphine produces constipation, with little tolerance developing.

3. Bronchi

3. Inhibition of cilia motility

Important in bronchi (disturbances with expectoration) and in ovary tube (sterility).

4. Cardiovascular systemHigh doses – hypotension and bradycardia - action on the medulla).

Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase the cerebrospinal fluid pressure »»» usually contraindicated in severe brain injury.

5. Histamine release»»» bronchoconstriction, hypotension, urticaria, itching, sweating.

Asthmatics should not receive the drug.

6. Hormonal actionsInhibition gonadotropin-releasing h. and corticotropin-releasing h.,

luteinizing h., follicle-stimulating h., ACTH, and ß-endorphin. Testosterone and cortisol levels decrease.

It increases prolactin and growth h. release by diminishing dopaminergic inhibition.

It increases antidiuretic hormone - urinary retention.

[Note: It also can inhibit the urinary bladder voiding reflex –

catheterization may be required.]

7. Increased polysynaptic spinal cord activityIncreased disposition to convulsions (Straub effect)

8. Immunosuppressant activity:Increased susceptibility to infections after long-term abuse.

Pharmacokinetics

1. Resorption

a. Administration: Absorption from GIT is slow and erratic, and the drug is usually not given orally (but new slow-release tablets exist).

Codeine - well absorbed after oral administration.

Significant first-pass metabolism in the liver - therefore, intramuscular, subcutaneous, or i.v. injections produce the most reliable responses.

Note: In cases of chronic pain associated with neoplastic disease – frequent use of the new slow-release tablets orally or pumps that allow the patient to control the pain through self-administration.

Opiates - for nonmedical purposes taken by inhaling powders or smoke from burning crude opium (rapid onset of the action).

b. Distribution:

M. rapidly enters all body tissues, incl. fetuses of pregnant women, and should not be used for analgesia during labor.

Infants born of addicted mothers show physical dependence on opiates and exhibit withdrawal symptoms if opioids are not administered.

Only a small part of morphine crosses the blood-brain barrier, because morphine is the least lipophilic of the common opioids.

(More lipid-soluble opioids - fentanyl, methadone, heroin, - readily penetrate into CNS).

c. Metabolism

M. is conjugated in the liver to glucuronic acid.

Morphine-6-glucuronide - potent analgesic; the conjugate at the 3-position is much less active.

Conjugates - excreted primarily in the urine (small quantities in the bile).

The duration of action of morphine is 4 – 6 hours when administered systemically; longer action when injected epidurally (its low lipophilicity prevents redistribution from the epidural space. [Note: A patient's age can influence the response to morphine.

Elderly patients are more sensitive to the analgesic effects (decreased metabolism, decreased lean body mass, renal function, etc.) They should be treated with lower doses. Neonates should not receive morphine because of their low conjugating capacity.

KeyTime to peak effect

Duration of action

20 minutes

4 hours

15 minutes

2 – 4 hours

5 minutes

15 – 30 minutes

Morphine

Pethidine

Fentanyl(according to Lippincott´s Pharmacology, 2006

Time to peak effect and

duration of action of several opioids

administered intravenously.

Tolerance and physical dependence:

Repeated use produces tolerance to the respiratory depressant, analgesic, euphoric, and sedative effects.

Tolerance usually does not develop to the miosis and constipatiion.

Physical and psychological dependence readily occur.

Withdrawal symptoms - series of autonomic, motor, and psychological responses that incapacitate the individual and cause serious-almost unbearable-symptoms. However, it is very rare that the effects are so profound as to cause death.

Note: Detoxification of heroin- or morphine-dependent individuals - usually methadone or clonidine.

The mechanisms of tolerance: - increased biotransformation, - down-regulation of receptors, - inhibition of the release of endogenous opioids.

Cross-tolerance occurs between drugs acting at the same receptor, but not between opioids that act on different receptors.

Adverse effects

- Severe respiratory depression occurs, coma.- Constipation.- Vomiting, dysphoria.- Allergy-enhanced bronchoconstriction, hypotensive effects, itching, low blood volume.- The elevation of intracranial pressure, particularly in head injury. - It enhances cerebral and spinal ischemia.- In prostatic hypertrophy, morphine may cause acute urinary retention. - A serious action - the stoppage of respiratory exchange in emphysema or cor pulmonale patients. - Use with caution in patients with bronchial asthma or liver failure.

DEPENDENCE

Dependence - physical dependence - associated with a physiological withdrawal syndrome (or abstinence syndrome). - psychological dependence, expressed as craving for the drug.

Abstinence syndrome - somewhat resembling severe influenza, mydriasis, fever, sweating, piloerection, nausea, diarrhoea, insomnia. Extreme restlessness and distress - accompanied by a strong craving for the drug. Maximum - after 2-3 days; mostly disappear in 8-10 days.

Re-administration of M. rapidly abolishes the abstinence syndrome.

The noradrenergic pathways may also play an important role in causing the abstinence syndrome - 2- agonist clonidine is sometimes used.

Interactions:

The depressant actions of morphine - enhanced by phenothiazines, MAO inhibitors, tricyclic antidepressants.

Low doses of amphetamine enhance analgesia, as does hydroxyzine.

NarcoticanalgesicsNarcotic

analgesics

MAO inhibitors

Sedative- hypnotics

Tricyclic anti-depressants

Antipsychotic drugs

Increased sedation; variable effects on respiratory depression

Absolute contraindication to pethidine and relative contraindication to othernarcotic analgesics because of high incidence of hyperpyretic coma

Increased CNS depression,particularly respiratorydepression

(according to Lippincott´s Pharmacology, 2006

Drugs interacting with narcotic analgesics.

CNS = central nervous system;

MAO = monoamine oxidase

Pethidine (MEPERIDINE)

A synthetic opioid structurally unrelated to morphine. Used for acute pain.

1. Mechanism of action: binding particularly to receptors. It also binds to receptors.

2. Actions: Depression of respiration, no significant cardiovascular action when given orally.

i.v. - a decrease in peripheral resistance and an increase in peripheral blood flow, and increase in cardiac rate.

Pethidine does not cause pinpoint pupils but causes the pupils to dilate - because of an atropine-like action.

3. Therapeutic uses:

Analgesia for any type of severe pain. It is not useful in the treatment of diarrhea or cough. Commonly employed in obstetrics.

4. Pharmacokinetics:

Well absorbed from GIT, useful when administered orally.

Mostly administered i.m.

Duration of action of 2 - 4 hours.

Because of its shorter action and different route of metabolism,

is preferred over morphine for analgesia during labor.

5. Adverse effects:

Large or repetitive doses - anxiety, tremors, muscle twitches, convulsions (rarely) due to the accumulation of norpethidine (metabolite of pethidine).

Severe hypotension can occur if administered postoperatively.

Due to its antimuscarinic action - dry mouth and blurred vision.

Pethidine can cause dependence.

Differences of pethidine against morphine:

- shorter duration of the action (particularly marked in neonate) »»» preferred during labour- not biotransformed by conjugation (which is deficient in newborns)- N-demethylated in the liver to norpethidine (hallucinogenic and convulsant effects - after large oral dose)- no miosis- lower antitussive effect- antimuscarinic (i.e., parasympatholytic) activity »»» lower spasm of smooth muscle, dry mouth, blurring of vision

MMETHADONE

A synthetic, orally effective opioid, cca equal in potency to morphine but induces less euphoria and has a somewhat longer duration of action.

Actions: Well-absorbed orally, in contrast to morphine. The miotic and respiratory-depressant actions have average half-lives of 24 hours.

It also increases biliary pressure and is also constipating.

3. Therapeutic uses: Used in the controlled withdrawal of dependent abusers from heroin and morphine. It can produce physical dependence like morphine.

FENTANYL

related to pethidine, it has 100-fold analgesic potency of morphine, used in anesthesia.

A rapid onset and short duration of action (15 - 30 minutes),

- usually injected i.v., epidurally, or intrathecally. Epidural use for analgesia postoperatively and during labor.

- oral transmucosal preparation and a transdermal patch are also available (used in the treatment of cancer)

- transdermal patch creates a reservoir of the drug in the skin. Hence, the onset is delayed 12 hours, and the offset is prolonged.

It is used in neuroleptanalgesia (with droperidol) !!

SUFENTANIL, ALFENTANIL, REMIFENTANIL related to fentanyl - they differ in their potency and metabolic disposition. Sufentanil is even more potent than fentanyl, whereas the other two are less potent but much shorter-acting.

KeyTime to peak effect

Duration of action

20 minutes

4 hours

15 minutes

2 – 4 hours

5 minutes

15 – 30 minutes

Morphine

Pethidine

Fentanyl(according to Lippincott´s Pharmacology, 2006

Time to peak effect and

duration of action of several opioids

administered intravenously.

HEROIN (diamorphine) - does not occur naturally.

Produced by di- acetylation of morphine, it leads to a 3-fold increase in its potency. Its greater lipid solubility - it crosses the blood-brain barrier more rapidly than morphine (a more exaggerated euphoria when taken by injection).

Great lipid solubility »»» rapidly crosses the HEB and gives greater "rush", shorter duration of action (2 hrs), very strong dependence.

Converted to morphine in the body, but its effects last about half as long.

In most countries it has no accepted medical use.

MODERATE AGONISTS

CODEINE (methylmorphine) - a much less potent analgesic than morphine, but a higher oral effectiveness. It shows good antitussive activity. It has a lower potential for abuse than morphine, and rarely produces dependence. In most cough preparations it has been replaced by, e.g. dextromethorphan.Frequently combined in analgesic-antipyretic preparations with salicylates or paracetamol. .

OXYCODONE - a semisynthetic derivative of morphine. Orally active; sometimes formulated with aspirin or acetaminophen.

PROPOXYPHENE - a derivative of methadone. A weaker analgesic action than codeine. Often used in combination with aspirin or paracetamol.

MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS

PENTAZOCINE - agonist on receptors, a weak antagonist at and .

It promotes analgesia by activating receptors in the spinal cord - used to relieve moderate pain.

BUPRENORPHINE - a partial agonist at the mu receptor. A major use - in opiate detoxication (it has a less severe and shorter duration of withdrawal symptoms compared to methadone). It causes little sedation, respiratory depression, and hypotension, even at high doses. In contrast to methadone (available only at specialized clinics) - buprenorphine is approved for office-based detoxification or maintenance.

OTHER ANALGESICS

TRAMADOL - a centrally acting analgesic that binds to the mu-receptor. Used in moderate to moderately severe pain. Its respiratory-depressant activity is less than that of morphine. Naloxone can only partially reverse the analgesia produced by tramadol.

ANTAGONISTS

NALOXONE - used to reverse the coma and respiratory depression of opioid overdose. Within 30 seconds of i. v. administration, the respiratory depression and coma are reversed. A half-life of 60 to 100 minutes

NALTREXONE - actions similar to those of naloxone. Longer duration of action - a single oral dose blocks the effect of injected heroin for up to 48 hours. Naltrexone in combination with clonidine - and, sometimes, with buprenorphine - is employed for rapid opioid detoxification.

It may also be beneficial in treating chronic alcoholism by an unknown mechanism, but benzodiazopines and clonidine are preferred.

Adverse effect: hepatotoxicity.

Used to treat and prevent pain, e.g. ― pre- and postoperatively ― common painful conditions including headache, dysmenorrhoea,

labour, trauma, burns ― many medical and surgical emergencies (e.g. myocardial infarction, renal colic) ― terminal disease (especially metatastic cancer).

Opioid analgesics - used also in some non-painful conditions, e.g. acute heart failure (because of their haemodynamic effects),

terminal chronic heart failure (to relieve distress),

the treatment of diarrhoe (loperamide)

Clinical uses of opioidsClinical uses of opioids

Treatment of pain

A progressive approach is often used, starting with NSAIDs, supplemented first by weak opioids and then by strong opioids.

Generally - severe acute pain - treated with strong opioids given by injection. Mild inflammatory pain (e.g. sprains, mild arthralgia) - treated with NSAIDs (e.g. ibuprofen) or by paracetamol supplemented by weak opioids (e.g. codeine, dextropropoxyphene).

Severe pain (e.g. cancer pain) - treated with strong opioids. Patient - controlled infusion systems are useful postoperatively.

Chronic neuropathic pain - often unresponsive to opioids and treated with tricyclic antidepressants (e.g. amitrityline) or anticonvulsants (e.g. carbamazepine, gabapentin).

Indications for morphine and other opioids