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AMITY INSTITUTE OF PHARMACY

OPIOID ANALGESICS

SUBMITTED By : Ms. Shikha Chauhan

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INDEX

CONTENT PAGE NO.

ABSTRACT 4

INTRODUCTION 5

DISCUSSION

1. Opioid analgesics 6

2. Opioid receptors 7

3. Mechanism of action of opioids 10

4. Endogeneous opioid peptides 16

5. Opioid analgesic drugs 18

6. Pharmacological action of opioids 31

7. Side effects 33

8. Proper use of the medicine 34

9. Physical dependence 34

10. Psychological addiction 34

11. Tolerance 34

CONCLUSION 35

REFERENCE 36

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ABSTRACT

The opium poppy is the source of crude opium from which Serturner in 1803 isolated the pure

alkaloid morphine—named after Morpheus, the Greek god of dreams. It remains the standard

against which all drugs that have strong analgesic action are compared. These drugs are

collectively known as "opioid analgesics" and include not only the natural and semisynthetic

alkaloid derivatives from opium but also include synthetic surrogates, other opioid-like drugs

whose actions are blocked by the nonselective antagonist naloxone, plus several endogenous

peptides that interact with the several subtypes of opioid receptors...." Morphine, the

prototypical opioid agonist, has long been known to relieve severe pain with remarkable

efficacy.

The importance of the first use of opioids in developing drug dependence of the opioid type was

discussed. Seven major factors were clinically observed to influence first heroin use. The factors

are diminished self-esteem, interpersonal strivings, proselytizing, ignorance of opioid effects,

pleasure, transquilization and pain. More than one factor is usually operative in a particular

instance. Ready availability of opioids is usually essential to first use, even when the described

factors are present. An understanding of these determinants should improve educational efforts

aimed at prevention of opioid drug use.

The expert panel concluded that opioid pain medications are safe and effective for carefully

selected, well-monitored patients with chronic non-cancer pain.

Opioid prescribing has increased significantly due to growing professional acceptance that the

drugs can relieve chronic non-cancer pain, and the guideline acknowledges there are

widespread concerns about increases in prescription opioid abuse, addiction and diversion.

Opioids, such as morphine, oxycodone, oxymorphone and fentanyl are potent analgesics. They

traditionally have been used to relieve pain following surgery, from cancer and at the end of life.

Today opioids are used widely to relieve severe pain caused by chronic low-back injury,

accident trauma, crippling arthritis, sickle cell, fibromyalgia, and other painful conditions.

Prior to initiating chronic opioid therapy, the guideline advises clinicians to determine if the pain

can be treated with other medications. If opioids are appropriate, the clinician should conduct a

thorough medical history and examination and assess potential risk for substance abuse,

misuse or addiction.

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INTRODUCTION

Opioids are powerful pain-relieving substances that are used as analgesics, or pain

medications. They come from one of three places, some are derived from plants, some are

manufactured in a lab and others, such as endorphins, occur naturally in the body.

Opioids act by attaching to specific proteins called opioid receptors, which are found in the

brain, spinal cord, and gastrointestinal tract. When these compounds attach to certain opioid

receptors in the brain and spinal cord, they can effectively change the way a person

experiences pain

Opioids are very effective in the treatment of severe pain. In fact, they are frequently used to

treat acute pain, such as post-surgical pain, as well as severe pain caused by diseases such as

cancer. While opioid use for the long-term treatment of chronic pain is still somewhat

controversial, these drugs can be effective and safe when taken under close medical

supervision.

Some opioids, such as oxycodone and hydromorphone, are straight narcotics. Others, such as

codeine and hydrocodone, may be mixed with other analgesics such as acetaminophen.

Another class of opioids, defined as agonist/antagonist, combine medications to decrease pain

and to decrease the potential for dependence. These include buprenorphine and butorphanol.

Unfortunately, many chronic pain sufferers who take opioids may wrongly be labeled as addicts,

even if they do not meet the actual criteria for addiction. There is sometimes a certain stigma

associated with taking narcotic pain medication, which can be frustrating for the person with

severe chronic pain.

In addition, opioid medications can affect regions of the brain that mediate what we perceive as

pleasure, resulting in the initial euphoria that many opioids produce. They can also produce

drowsiness, cause constipation, and, depending upon the amount taken, depress breathing.

Taking a large single dose could cause severe respiratory depression or death.

Opioids may interact with other medications and are only safe to use with other medications

under a physician's supervision. Typically, they should not be used with substances such as

alcohol, antihistamines, barbiturates, or benzodiazepines. Since these substances slow

breathing, their combined effects could lead to life-threatening respiratory depression.

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DISCUSSION

ANALGESIC : A drug that selectively relieves pain by acting in the CNS or on the peripheral

pain mechanism, without significantly altering consciousness is called an analgesic.

Analgesics are dIvided into two groups :

A. Opioids/Narcotics/Morphine like analgesics

B. Nonopioid/Non-narcotic/Aspirin like/Antipyretic/Anti-inflammatory analgesics

OPIOIDS ANALGESICS

OPIUM : It is a dark brown, resinous material obtained from poppy (Papaver somniferum),

capsule.

It contain two type of alkaloids:

A. Phenathrene derivatives

Morphine(10% in opium)

Codeine(0.5% in opium)

Thebaine(0.2% in opium) – Nonanalgesic

B. Benzoisoquinoline derivatives

Papaverine (1%) - Nonanalgesic

Noscapine (6%) - Nonanalgesic

USES - Used for thousands of years to produce:

– Euphoria

– Analgesia

– Sedation

– Relief from diarrhea

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– Cough suppression

HISTORY – It was introduced in Britain at the end of 17th century, usually taken orally as

“Tincture of Laudanum”.

OPIOIDS – These are the substances that can be endogenous or synthetic, which produce

morphine like effect.

OPIATES – It is a older term that is restricted to the synthetic morphine like drugs with non-

peptidic structures.

The main group of drugs that are discussed in this section are :-

Morphine Analogues – These are the compounds closely related in structures to morphine and

often synthesized from it.

AGONISTS MIXED AGONIST-ANTAGONISTS ANTAGONISTS

(BUPRENORPHINE, NALBUPHINE) (NALOXONE,NALTREXONE)

STRONG MODERATE WEAK

(MORPHINE, (CODEINE (PROPOXYPHENE)

METHADONE OXYCODONE)

MEPERIDINE)

Synthetic derivatives – Their structures are unrelated to morphine.

A. Phenylpiperidine series (pethidine,fentanyl)

B. Methadone series (methadone,dextropropoxyphene)

C. Benzomorphan series (pentazocine,cyclazocine)

D. Semisynthetic thebaine derivatives (etorphine,buprenorphine) (1)(2)

OPIOIDS RECEPTORS

There are 4 types of opioid receptors, with multiple receptor subtypes:

Mu- These receptors produce the most profound analgesia, and can cause euphoria,

respiratory depression, physical dependence and bradycardia. They are responsible for most of

the analgesic effect of opioid.

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Kappa – These contribute to analgesia at the spinal level. These receptors trigger a lesser

analgesic response, and may cause miosis, sedation and dysphoria.

Delta – These receptors modulate mu receptor activity and are more important in the periphery.

Sigma – These receptors provide little to no analgesia. They are responsible for many of the

adverse effects associated with opioids (dysphoria, hallucinations, respiratory and vasomotor

stimulation). Some investigators classify sigma receptors as phencyclidine, rather than opioid,

receptors.

The receptors were named using the first letter of the first ligand that was found to bind to them.

Morphine was the first chemical shown to bind to mu receptors.

Receptor Subtypes Location Function

delta (δ)

OP1 (I)δ1, δ2

• brain

o pontine nuclei

o amygdala

o olfactory bulbs

o deep cortex

• analgesia

• antidepressant effects

• physical dependence

kappa (κ)

OP2 (I)κ1, κ2, κ3

• brain

o hypothalamus

o periaqueductal gray

o claustrum

• spinal cord

o substantia

gelatinosa

• spinal analgesia

• sedation

• miosis

• inhibition of ADH release

• dysphoria

mu (μ)

OP3 (I)

μ1, μ2, μ3 • brain

o cortex (laminae III

and IV)

o thalamus

o striosomes

o periaqueductal gray

• spinal cord

o substantia

gelatinosa

• intestinal tract

μ1:

• supraspinal analgesia

• ph ysical dependence

μ2:

• respiratory depression

• miosis

• euphoria

• reduced GI motility

• physical dependence

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Nociceptin

receptor

OP4

ORL1

• brain

o cortex

o hippocampus

o habenula

o hypothalamus

• spinal cord

• anxiety

• depression

• appetite

• development of tolerance

to μ agonists

Selectivity of opioid drugs and peptides for receptor subtypes : (3)

Drug Mu (m) Delta (d) Kappa (k)

Opioid Peptides

Enkephalins Antagonist Agonist --

beta-endorphin Agonist Agonist --

Dynorphin Weak Agonist -- Agonist

Agonists

Codeine Weak Agonist Weak Agonist --

Etorphine Agonist Agonist Agonist

fentanyl (Sublimaze) Agonist -- --

meperidine (Demerol) Agonist -- --

methadone (Dolophine) Agonist -- --

Morphine Agonist Weak Agonist --

Agonist-antagonists

Buprenorphine Partial Agonist -- --

dezocine (Dalgan) Partial Agonist Agonist --

nalbuphine (Nubain) Antagonist -- Agonist

pentazocine (Talwain)Antagonist or

Partial Agonist -- Agonist

Antagonist:

naloxone (Narcan) Antagonist Antagonist Antagonist

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MECHANISM OF ACTION OF OPIATES

CELLULAR ACTION

Opioids: G protein linked-- affecting

Ion channel state

Intracellular Ca2+ levels

Protein phosphorylations states

Two well-defined opioid actions:

1. Reduce neurotransmitter release; by closing a voltage-gated Ca2+

channel on presynaptic neuronal terminals.

2. Inhibit postsynaptic neurons (hyperpolarization) by increasing and

K+ channel conductance. (1)

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NOCICEPTION

NOCICEPTION is defined as "the neural processes of encoding and processing noxious

stimuli. It is the afferent activity produced in the peripheral and central nervous system by stimuli

that have the potential to damage tissue. This activity is initiated by nociceptors, (also called

pain receptors), that can detect mechanical, thermal or chemical changes above a set

threshold. Once stimulated, a nociceptor transmits a signal along the spinal cord, to the brain.

Nociception triggers a variety of autonomic responses and may also result in the experience of

pain in sentient beings.

NOCICEPTOR Mechanical, thermal, and chemical stimuli are detected by nerve endings called

nociceptors, which are found in the skin and on internal surfaces such as the periosteum or joint

surfaces. The concentration of nociceptors varies throughout the body, mostly found in the skin

and less so in deep internal surfaces. All nociceptors are free nerve endings that have their cell

bodies outside the spinal column in the dorsal root ganglia and are named according to their

appearance at their sensory ends.

Nociceptors have a certain threshold; that is, they require a minimum level of stimuli before they

trigger a signal. In some conditions, excitation of pain fibers becomes greater as the pain

stimulus continues, leading to a condition called hyperalgesia. Once the threshold is reached a

signal is passed along the axon of the nerve into the spinal cord. (1)(4)

Transmission through central nervous system

Lateral spinothalamic tract

The Lateral spinothalamic tract has two pathways for nociceptive information to reach the brain,

the neospinothalamic tract for "fast spontaneous pain" and the paleospinothalamic tract

for "slow increasing pain".

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Neospinothalamic tract

Fast pain travels via type Aδ fibers to terminate on the dorsal horn of the spinal cord where they

synapse with the dendrites of the neospinothalamic tract. The axons of these neurons travel up

the spine to the brain and cross the midline through the anterior white commissure, passing

upwards in the contralateral anterolateral columns. These fibres terminate on the ventrobasal

complex of the thalamus and synapse with the dendrites of the somatosensory cortex. Fast pain

is felt within a tenth of a second of application of the pain stimulus and is a sharp, acute,

prickling pain felt in response to mechanical and thermal stimulation. It can be localised easily if

Aδ fibres are stimulated together with tactile receptors.

Paleospinothalamic tract

Slow pain is transmitted via slower type C fibers to laminae II and III of the dorsal horns,

together known as the substantia gelatinosa. Impulses are then transmitted to nerve fibers that

terminate in lamina V, also in the dorsal horn, synapsing with neurons that join fibers from the

fast pathway, crossing to the opposite side via the anterior white commissure, and traveling

upwards through the anterolateral pathway. These neurons terminate throughout the brain

stem, with one tenth of fibres stopping in the thalamus and the rest stopping in the medulla,

pons and periaqueductal grey of the midbrain tectum. Slow pain is stimulated by chemical

stimulation, is poorly localized and is described as an aching, throbbing or burning pain.

REGULATION

The body possesses an endogenous analgesia system, which can be supplemented with

analgesic drugs to regulate nociception and pain. There is both an analgesia system in the

central nervous system and peripheral receptors that decreases the grade in which nociception

reaches the higher brain areas. The degree of pain can be modified by the periaqueductal gray

before it reaches the thalamus and consciousness. According to gate control theory of pain, this

area can also reduce pain when non-painful stimuli are received in conjunction with nociception.

Central

The central analgesia system is mediated by 3 major components: the periaquaductal grey

matter, the nucleus raphe magnus and the nociception inhibitory neurons within the dorsal

horns of the spinal cord, which act to inhibit nociception-transmitting neurons also located in the

spinal dorsal horn.

Peripheral

The peripheral regulation consists of several different types of opioid receptors that are

activated in response to the binding of the body's endorphins. These receptors, which exist in a

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variety of areas in the body, inhibit firing of neurons that would otherwise be stimulated to do so

by nociceptors. (4)

Factors

The gate control theory of pain, proposed by Patrick Wall and Ronald Melzack, postulates that

nociception (pain) is "gated" by non-nociception stimuli such as vibration. Thus, rubbing a

bumped knee seems to relieve pain by preventing its transmission to the brain. Pain is also

"gated" by signals that descend from the brain to the spinal cord to suppress incoming

nociception (pain) information.

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Nociception response

When nociceptors are stimulated they transmit signals through sensory neurons in the spinal

cord. These neurons release the excitatory neurotransmitter glutamate at their synapses.

If the signals are sent to the reticular formation and thalamus, the sensation of pain enters

consciousness in a dull poorly localized manner. From the thalamus, the signal can travel to the

somatosensory cortex in the cerebrum, when the pain is experienced as localized and having

more specific qualities.

Nociception can also cause generalized autonomic responses before or without reaching

consciousness to cause pallor, diaphoresis, tachycardia, hypertension, lightheadedness,

nausea and fainting.

EFFECT ON THE NOCICEPTIVE PATHWAY

Opioids receptors are widely distributed in brain. Opiates are effective as analgesics when

given intrathecally in mimute doses, implying that a central action can account for their

analgesic effect.

.There injections into the PAG region causes marked analgesia, which can be prevented by the

surgical interruption of the descending pathway to NRM or by blocking 5-hydroxytryptamine

synthesis pharmacologically with p-chlorophenylalanine. It blocks the 5-hydroxytryptamine

pathway running from NRM to the dorsal horn.

At the spinal level, opioids inhibits transmission of nociceptive impulse through

the dorsal horn and suppresses nociceptive spinal reflexes,even in the patients with spinal cord

transaction. It can inhibit the release of the substance P from the primary afferent terminals in

the dorsal horn neurons.

There are also evidence that opiates inhibit the discharge of the nociceptive afferent terminals in

the periphery, particular under condition of the inflammation, in which the expression of the

opioid receptors by sensory neuron is increased (2)

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ENDOGENOUS OPIOID PEPTIDES

A number of peptides having morphine like actions were isolated from the mammalian brain,

pituitary, gastro intestinal track and spinal cord. These are active in very small amount, their

action are blocked by naloxone and the bind with high affinity with the opioid receptors.

There are three families of opioid peptides. Each is derived from a specific large precursor

polypeptides.

• Endorphins - β-endorphin is having 31 amino acids, is the most important of the

endorphins. It is derived from the Pro-opiomelanocortin (POMC) which also gives rise to

ACTH and two lipoproteins. β-endorphin is primarily µ agonist but also has δ action.

• Enkephalins - Methionie-enkephalin(met-ENK) and leucine-enkephalin (leu-ENK) are

the most important. Both are pentapeptides. The larger precursor peptide proenkephalin

has 4 met-ENK and 1 leu-ENK residues. The two ENKs have a slightly different

spectrum of activity, while met-ENK has equal affinity for µ and δ sites, leu-ENK prefer δ

receptors.

• Dynorphins - Dynorphin A and B (DYN-A and DYN-B) are 8-17 amino acid peptides

derived from prodynorphin which contains 3 leu-ENK residues. DYN are more potent on

k receptors but also activate µ and δ receptors. (2)

Most widely distributed opioid analgesic peptides: Pentapeptides

• Methionine-enkephalin

• Leucine-enkephalin

Three major precursor proteins:

Prepro-opiomelanocortin (POMC)

• met-enkephalin sequence

• ß-endorphin sequence

• some nonopioid peptides:

1. ACTH

2. ß-lipotropin

3. melanocyte-stimulating hormone

Preproenkephalin (proenkephalin A ) {contains}:

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• six copies of met-enkephalin

• one copy of leu-enkephalin

Preprodynorphin (proenkephalin B) contains-- active peptides containing the leu-enkephalin

sequence

1. dynorphin

2. Adynorphin B

3. a and ß neoendorphin

Endogenous opioid precursors which are localized at pain modulation brain regions are

probably released during stress, including pain or pain anticipation.

Also, precursor molecules for endogenous opioids are localized in adrenal medulla and gut

neural plexuses .. (3)

OPIOID ANALGESIC DRUGS

MORPHINE (5)(8)

IUPAC Name - (5α,6α)-Didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

MECHANISM OF ACTION

Morphine relieves both the perception of pain and the emotional response to it, as a result of its

action as a full agonist on opioid receptors (especially µ, but also δ and κ) in the brain and spinal

cord.

Morphine causes pupillary constriction by stimulating µ/δ-receptors in the Edinger-Westphal

nucleus in the mid-brain

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Morphine also causes peripheral histamine release and thus vasodilation and, in some patients,

bronchoconstriction. In some patients it may also cause bradycardia due to stimulation of the

vagal center in the medulla.

PHARMACOKINETICS

Absorption - opioids are well absorbed. After intramuscular injection the peak therapeutic effect

is achieved in about 1 hour and it lasts for 3-4 hours.

Bioavailability is approximately 30%.

Protein Binding is 30-40%

Metabolism - Morphine is metabolized largely by combination with glucuronic acid but also by N-

dealkylation and oxidation. Metabolism occurs in the liver and gut wall. Primarily hepatic (90%),

converted to dihydromorphinone and normorphine. Also converted to morphine-3-glucuronide

(M3G) and morphine-6-glucuronide. Virtually all morphine is converted to glucuronide

metabolites. Only a small fraction (less than 5%) of absorbed morphine is demethylated.

Excretion - About 10% being excreted in the urine as morphine and 60-70% as the glucuronide.

HALF LIFE - 2-4 hours

DOSE

- For acute pain following injury an average adult requires 10 mg subcutaneously or

intramuscularly repeated at 4-6 hour intervals.

- A large patient suffering severe pain may need 15-20 mg.

- The elderly or individuals with renal or hepatic insufficiency will require less than the

usual dose (one-quarter to one-half).

ADMINISTRATION

Intravenous - Morphine may be given as an intravenous bolus if rapid relief is required (e.g.

during myocardial infarction) and the usual dose is 5 mg.

Postoperatively - Morphine can be given continuously by an infusion pump, either intravenously

or subcutaneously

Orally – Morphine is given by mouth initially regularly 4 hourly as an elixir,

Spinal (epidural or intrathecal) administration - Morphine is effective at much lower doses than

when given by other routes and therefore causes fewer systemic side effects

SIDE EFFECT

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- Overdose leads to coma.

- Morphine depresses the sensitivity of the respiratory center to carbon dioxide, thus

causing a progressively decreased respiratory rate.

- Morphine increases smooth muscle tone throughout the gastrointestinal tract, which is

combined with decreased peristasis, due to an action on receptors in the ganglion

plexus in the gut wall.

METHADONE (6)(7)

IUPAC Name - (RS)-6-(Dimethylamino)-4,4-diphenylheptan-3-one

Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an

analgesic (They gave it the trade name Dolophine ｨ , which is now registered to Roxane

Laboratories). Since then, it has been best known for its use in treating narcotic addiction,

although such a use never became widespread and common until the early 1990's when public

policy sought to find ways to reduce the spread of HIV and AIDS.

MECHANISM OF ACTION

Methadone is a synthetic, long-acting opioid with pharmacologic actions qualitatively similar to

morphine. It is primarily a μ-receptor agonist and may mimic endogenous opioids, enkephalins,

and endorphins and affect the release of other neurotransmitters—acetylcholine, norepinephrine,

substance P, and dopamine.

PHARMACOKINETICS : Readily absorbed orally, it is highly protein bound so remains in

tissues for a prolonged period. It is transformed in the liver and excreted by the urine as mostly

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inactive metabolites.

Onset of action - Oral: Analgesic: 0.5-1 hour

Parenteral: 10-20 minutes

Peak effect - Parenteral: 1-2 hours

Oral: continuous dosing then 3-5 days

Duration of analgesia - Oral: 4-8 hours, increases to 22-48 hours with repeated doses

Protein binding - 85% to 90%

Metabolism - Hepatic, by N-demethylation and cyclization primarily via CYP3A4, CYP2B6, and

CYP2C19 to inactive metabolites.

Bioavailability - Oral: 36% to 100%

Excretion - Urine (<10% as unchanged drug); increased with urine pH <6

HALF LIFE - 15 to 60 hours

DOSE

Children

Oral - 0.1-0.2 mg/kg 4-8 hours initially for 2-3 doses, then every 6-12 hours as needed.

Dosing interval may range from 4-12 hours during initial therapy, decrease in dose or

frequency may be required (~days 2-5) due to accumulation with repeated doses (maximum

dose: 5-10 mg)

I.V. - 0.1 mg/kg every 4-8 hours initially for 2-3 doses, then every 6-12 hours as needed.

Dosing interval may range from 4-12 hours during initial therapy, decrease in dose or

frequency may be required (~days 2-5) due to accumulation with repeated doses (maximum

dose: 5-8 mg)

Adults:

Oral - Opioid-naive: Initial: 2.5-10 mg every 8-12 hours; more frequent administration may be

required during initiation to maintain adequate analgesia.

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Dosage interval may range from 4-12 hours, since duration of analgesia is relatively short

during the first days of therapy, but increases substantially with continued administration.

ADVERSE EFFECT

It causes miosis, respiratory depression, biliary spasm and constipation just like morphine.

MEPERIDINE (9)(10)

IUPAC NAME – Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate

MECHANISM OF ACTION

Inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as

substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit

the release of vasopressin, somatostatin, insulin and glucagon. Meperidine's analgesic activity

is, most likely, due to its conversion to morphine.

PHARMACOKINETIC

Absorption: Oral bioavailability is 50-60% in patients with normal hepatic function. It is well

absorbed from GI track. I.M. - Erratic and highly variable.

Onset of action: Oral -10-15 minutes; I.V - minutes

Peak effect: SubQ. - 1 hour; Oral - 2 hours

Duration: Oral, SubQ. - 2-4 hours

Distribution: Crosses placenta; enters breast milk

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Protein binding: 65% to 75%

Metabolism: Meperidine is metabolized in the liver by hydrolysis to meperidinic acid followed by

partial conjugation with glucuronic acid. Meperidine also undergoes N-demethylation to

normeperidine, which then undergoes hydrolysis and partial conjugation. Normeperidine is about

half as potent as meperidine, but it has twice the CNS stimulation effects.

Bioavailability: 50% to 60%; increased with liver disease

Excretion: Urine (as metabolites)

HALF LIFE : 3-4 hr

DOSE

Children :-

Oral, I.M., I.V. : 1-1.5 mg/kg/dose every 3-4 hours as needed

1-2 mg/kg as a single dose preoperative medication may be used

maximum 100 mg/dose

Adults :-

Oral: Initial 50 mg every 3-4 hours as needed

usual dosage range: 50-150 mg every 2-4 hours as needed (

I.M., SubQ: Initial 50-75 mg every 3-4 hours as needed; patients with prior opiate exposure may

require higher initial doses

Slow I.V.: Initial 5-10 mg every 5 minutes as needed

Elderly :-

Oral: 50 mg every 4 hours

I.M.: 25 mg every 4 hours

Dental Usual Dosing

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Adults - Oral: Initial 50 mg every 3-4 hours as needed

usual dosage range: 50-150 mg every 2-4 hours as needed

SIDE EFFECTS

• Agitation, disorientation, or hallucinations

• Shakiness, seizures, muscle twitches, or other abnormal muscle movements

• A slow heart rate (bradycardia) or fast heart rate (tachycardia)

• Low blood pressure (hypotension) or high blood pressure (hypertension)

• Fainting

FENTANYL (11)(13)

IUPAC NAME - N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-propanamide

N

CH2CH2Ph

O

Et

N

MECHANISM OF ACTION :

Fentanyl is a powerful synthetic opiate with mechanism of action similar to Morphine. It is

considered both faster acting and of shorter duration than Morphine. Interacts with opiate

receptors decreasing pain impulse transmission at the spinal cord level and higher in the CNS.

Fentanyl is a potent μ-opiate receptor agonist.

Since it decreases both preload and afterload it may decrease myocardial oxygen demand.

PHARMACOKINETICS - Fentanyl is metabolized to an inactive metabolite by the cytochrome

p4503A4 system. Drug metabolites are eliminated through the urine

HALF-LIFE - 7 hours

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DOSE

Adults :-

IV/IM : 25-50 mcg slow IV push,

100 mcg for ACS/ischemic chest pain.

200 mcg for Pain Control/Sedation/Intubation.

Pediatrics (Greater than 2 years of age) :-

IV, IO, IM: 2-3 mcg/kg to a max of 100 mcg.

For Intubation: 2-5 mcg/kg to a max of 100 mcg

IN: 1-2 mcg/kg (rare)

Transdermal patch (Duragesic -- CII) in 25, 50, 75 and 100 ug/hour strengths

ADVERSE EFFECT

A particular risk of the transmucosal or transdermal routes is respiratory depression; these

delivery routes create a reservoir of drug in the skin or mucosa.

BUPRENORPHINE (12)(15)

IUPAC NAME - (2S)-2-[(-)-(5R,6R,7R,14S)-

9α-cyclopropylmethyl-4,5-epoxy-

6,14-ethanomorphinan-7-yl]-3-hydroxy-

6-methoxy-3,3-dimethylbutan-2-ol

MECHANISM OF ACTION

Buprenorphine is a thebaine derivative with powerful analgesia approximately 25 to 40 times as

potent as morphine, and its analgesic effect is due to partial agonist activity at μ-opioid

receptors, i.e., when the molecule binds to a receptor, it is only partially activated in contrast to a

full agonist such as morphine. Buprenorphine also has very high binding affinity for the μ

receptor such that opioid receptor antagonists (e.g. naloxone) only partially reverse its effects.

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PHARMACOKINETICS

Metabolism - Buprenorphine is metabolised by the liver, via the CYP3A4 isozyme of the

cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation) and other

metabolites. The metabolites are further conjugated with glucuronic acid.

Elimination - Eliminated mainly through excretion into the bile. The elimination half-life of

buprenorphine is 20–73 hours (mean 37). Due to the mainly hepatic elimination there is no risk

of accumulation in patients with renal impairment and in the elderly.

Buprenorphine's main active metabolite, norbuprenorphine, is a μ-opioid, δ-opioid, and

nociceptin receptor full agonist, as well as a κ-opioid receptor partial agonist.

ADMINISTRATION

Buprenorphine hydrochloride is administered by intramuscular injection, intravenous infusion, via

a transdermal patch, or as a sublingual tablet. It is not administered orally, due to very high first-

pass metabolism.

DOSE

To treat opioid addiction in higher dosages (>2 mg)

To control moderate pain in non-opioid tolerant individuals in lower dosages (~200 µg)

Market preprations - Temgesic 0.2 mg sublingual tablets

Buprenex 0.3 mg/ml injectable formulation

HALF LIFE - 37 hours.

NALOXONE (14)(16)(17)

IUPAC NAME - (1S,5R,13R,17S)- 10,17-dihydroxy- 4-(prop-2-en-1-yl)- 12-oxa- 4-azapentacyclo

[9.6.1.01,13.05,17.07,18] octadeca- 7(18),8,10-trien- 14-one

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Naloxone is a drug used to counter the effects of opioid overdose, for example heroin or

morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the

central nervous system and respiratory system. Naloxone is also experimentally used in the

treatment for congenital insensitivity to pain with anhidrosis (CIPA),

MECHANISM OF ACTION

Naloxone has an extremely high affinity for μ-opioid receptors in the central nervous system.

Naloxone is a μ-opioid receptor competitive antagonist, and its rapid blockade of those receptors

often produces rapid onset of withdrawal symptoms. Naloxone also has an antagonist action,

though with a lower affinity, at κ- and δ-opioid receptors .

PHARMACOKINETICS

1. Naloxone is administered parenterally. Although it is relatively well absorbed after oral

administration, it undergoes extensive first-pass metabolism, making this route of

delivery ineffective.

2. After intravenous (IV) administration, naloxone is rapidly distributed throughout the body.

It is highly lipophilic and readily crosses into the brain. Onset of action after IV dosing is

within 2 minutes, and is only slightly longer with intramuscular (IM), subcutaneous, or

endotracheal administration.

3. Duration of action is dependent on route and dose. IV dosing typically provides a

duration of action of 20 to 60 minutes. IM use produces a longer effect than IV

administration, but absorption from this route is erratic.

4. Metabolism - Naloxone is hepatically metabolized, primarily through conjugation to

naloxone-3-glucuronide.

5. Elimination - The elimination half-life in adults is approximately 60 minutes.

ADMINISTRATION

Naloxone is most commonly injected intravenously for fastest action. The drug generally acts

within a minute, and its effects may last up to 45 minutes. It can also be administered via

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intramuscular or subcutaneous injection. Use of a wedge device (nasal atomizer) attached to a

syringe to create a mist delivering the drug to the nasal mucosa may also be utilized, although

this solution is more likely utilized outside of a clinical facility.

HALF LIFE - 30-81 minutes

DOSE

Infants - 0.1 mg/kg ,children from birth to 5 years of age or 20 kg of body weight.

Children - 2.0 mg , 5 years of age or weighing more than 20 kg may be given

Pediatric - ranging from 0.005 to 0.4 mg/kg have

SIDE EFFECT

Possible side effects include - change in mood, increased sweating, nausea, nervousness,

restlessness, trembling, vomiting, allergic reactions such as rash or swelling, dizziness, fainting,

fast or irregular pulse, flushing, headache, heart rhythm changes, seizures, sudden chest pain.

NALTREXONE (18)(19)

IUPAC NAME - 17-(cyclopropylmethyl)-4,5α-epoxy- 3,14-dihydroxymorphinan-6-one

Used in the treatment of alcohol dependence and for the blockade of the effects of exogenously

administered opioids.

MECHANISM OF ACTION

Naltrexone binds to the opioid mu receptor antagonistically, thereby preventing conventional

opiate (heroin, morphine) drugs from binding and inducing opioid neural responses. The

mechanism of action of naltrexone in alcoholism is not understood, however, involvement of the

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endogenous opioid system is suggested by preclinical data. Naltrexone competitively binds to

such receptors and may block the effects of endogenous opioids.

PHARMACOKINETIC

Absorption - well absorbed orally, naltrexone is subject to significant first pass metabolism with

oral bioavailability estimates ranging from 5 to 40%.

Protein Binding - 21% bound to plasma proteins over the therapeutic dose range.

Metabolism - Hepatic. Naltrexone is metabolised mainly to 6β-naltrexol by the liver enzyme

dihydrodiol dehydrogenase. Other metabolites include 2-hydroxy-3-methoxy-6β-naltrexol and 2-

hydroxy-3-methoxy-naltrexone. These are then further metabolised by conjugation with

glucuronide.

HALF LIFE - 4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol.

DOSE

Oral - The initial dose of Nalorex should be 25 mg (half a tablet) followed by 50 mg (one tablet)

daily.

A three-times-a-week dosing schedule may be considered if it is likely to result in better

compliance e.g. 100 mg on Monday, 100 mg on Wednesday and 150 mg on Friday.

SIDE EFFECT

High doses of naltrexone (generally ≥1,000 mg/kg) produce salivation, depression/reduced

activity, tremors, and convulsions.

General outline of opioid analgesics

Drug Route of

administration

Onset of

action (min)

Time to peak

effect (min)

Duration of

action (h) Strong agonists Fentanyl (Sublimaze) IM 7–15 20–30 1–2 IV 1–2 3–5 0.5–1 Hydromorphone

(Dilaudid) Oral 30 90–120 4

IM 15 IV 10–15 30–60 2–3 Sub-Q 30 15–30 Levorphanol (Levo- Oral 10–60 90–120 4–5

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Drug Route of

administration

Onset of

action (min)

Time to peak

effect (min)

Duration of

action (h) Dromoran) IM IV — 60 4–5 Sub-Q 10–60 within 20 Meperidine (Demerol) Oral 15 60–90 2–4 IM 10–15 IV 30–50 2–4 Sub-Q 1 Methadone (Dolophine) Oral 30–60 90–120 4–6 IM IV 10–20 60–120 4–5 Morphine (many trade

names) Oral — 60–120 4–5

IM 10–30 IV 30–60 4–5 Sub-Q — Epidural 10–30 20 4–5 Oxymorphone

(Numorphan) IM 10–15 30–90 3–6

IV Sub-Q 5–10 15–30 3–4 Rectal Mild-to-moderate agonists Codiene (many trade

names) Oral 30–40 60–120 4

Im 10–30 30–60 4 Sub-Q 10–30 4 Hydrocodone (Hycodan) Oral 10–30 30–60 4–6 Oxycodone (Percodan) Oral — 60 3–4 Propoxyphene (Darvon,

Dolene) Oral 15–60 120 4–6

Butophanol (Stadol) IM 10–30 30–60 3–4 IV 2–3 30 2–4 Nalbuphine (Nubian) IM within 15 60 3–6 IV 2–3 30 3–4 Sub-Q within 15 — 3–6 Pentazocine (Talwin) Oral 15–30 60–90 3 IM 15–20 30–60 2–3 IV 2–3 15–30 2–3 Sub-Q 15–20 30–60 2–3

PHARMACOLOGICAL ACTION

Effect On Central Nervous System (1)(2)

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ANALGESIA – Opiates are used to treat both chronic and acute pain. But mainly used to treat

the neuropathic pain.syndromes.

Eg - Used to treat phantom limb, deafferentation pain and trigeminal neuralgia.

EUPHORIA – Opioids cause a powerful sense of contentment and well-being. It thus reduce the

agitation and anxiety caused by painful illness and injury. Euphoria is mediated through μ.

Euphoria is more prominent in those previously addicted to opioids.

RESPIRATORY DEPRESSION – Respiratory depression, resulting in increased arterial Pco2,

occurs with the normal dose of opioids. It occur due to decrease in the sensitivity of the

respiratory system to Pco2.

DEPRESSION OF COUGH REFLEX – Generally. Increasing substitution on the phenolic

hydroxyl group of morphine increases antitussive relative to analgesic activity.

Eg. Codiene suppresses cough in subanalgesic doses and is often used in cough medicine.

NAUSEA and VOMITING – It occur un nearly 40% of the patients. The site of action is the area

postrema, a region of the medulla where chemical stimuli of many kind initiate vomiting.

PUPILLARY CONSTRICTION – It is caused by μ and k receptor, mediated stimulation of the

oculomotor nucleus. Pinpoint pupil are an important diagnostic feature in opiate

poisoning, because most other cases of coma and respiratory depression cause pupilary

dilatation.

Effect On The Gastrointestinal Track

Opioids increases tone and reduces motility in many parts of the gastrointestinal system,

resulting in the constipation, which may be severe. The resulting delay in gastric emptying

can considerably retard the absorption of other drug.

Pressure in the biliary track increases because of the contraction of the gallbladder and the

constriction of the biliary sphincter.

SIDE EFFECTS

Some people experience drowsiness, dizziness, lightheadedness, or a false sense of well-being

after taking opioid analgesics. Anyone who takes these drugs should not drive, use machinery,

or do anything else that might be dangerous until they know how the drug affects them. Nausea

and vomiting are common side effects, especially when first beginning to take the medicine. If

these symptoms do not go away after the first few doses, the person should check with the

30

physician or dentist who prescribed the medicine.

(20)

Dry mouth is another common side effect, which can be relieved by sucking on sugarless hard

candy or ice chips or by chewing sugarless gum. Saliva substitutes, which come in liquid or

tablet forms, may also help. Patients who must use opioid analgesics over long periods and who

have dry mouth should see their dentists, as the problem can lead to tooth decay and other

dental problems.

The following side effects are less common. They usually do not need medical attention and will

go away after the first few doses. If they continue or interfere with normal activity, the patient

should check with the physician who prescribed the medicine for:

• headache

• loss of appetite

• restlessness or nervousness

• nightmares, unusual dreams, or problems sleeping

• weakness or tiredness

• mental sluggishness

• stomach pain or cramps

• blurred or double vision or other vision problems

• problems urinating such as pain, difficulty urinating, frequent urge to urinate, or

decreased amount of urine

• constipation

Other side effects may be more serious and may require quick medical attention. These

symptoms could be signs of an overdose. The person should get emergency medical care

immediately:

• cold, clammy skin

• bluish discoloration of the skin

• extremely small pupils

• serious difficulty breathing or extremely slow breathing

• extreme sleepiness or unresponsiveness

• severe weakness

• confusion

• severe dizziness

• severe drowsiness

• slow heartbeat

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• low blood pressure

• severe nervousness or restlessness

PROPER USE OF MEDICINE

Take this medicine only as directed by your doctor. You will start on a low dose of the opioid.

This can be slowly increased, if necessary, over several days with the doctor’s direction.

You must not increase the opioid dose without the doctor’s permission and guidance. Controlled

increases in dosage are safe, but a sudden increase in dosage (overdose) can lead to harmful

side effects including severe sleepiness, trouble breathing, or even death.

Do not change the way you take this medicine without first speaking to your doctor. Pain

medicine works best if taken before the pain is at its worst. Your doctor may, therefore, tell you

to take the medicine on aregular daily schedule rather than on an asneeded basis. Small, regular

doses will provide continuing relief with few or no side effects.

If you are taking this medicine regularly and you miss a dose, take it as soon as possible.

However, if it is almost time for your next dose, skip the missed dose and go back to your regular

schedule – do not take a double dose. If you have been prescribed a long-acting or sustained-

release opioid (examples: Oramorph, MS-Contin, OxyContin), these pills must not be chewed,

crushed, or cut in half. This changes the timed-release actions of the medicine and may cause

an overdose.

The one exception to this rule is methadone which can be cut or crushed. Opioids interact with a

number of other drugs including tranquilizers, sedatives, antihistamines (allergy medicines),

alcohol, and many illegal or “street” drugs. Using any of these drugs with opioids can lower blood

pressure, and cause deep sleepiness or trouble breathing. This may be harmful or even fatal.

Ask your doctor for advice before starting any of these medicines.

Physical dependence is a condition where the body becomes used to regular doses of a

medicine. If the medicine is stopped suddenly, the person has withdrawal symptoms. This can

happen with many medicines, including steroids, blood pressure medicine, anti-seizure or anti-

anxiety medicines, and opioids. Withdrawal usually begins within 24 to 48 hours after the last

dose. Symptoms of opioid withdrawal may include:

· Yawning

· Sweating

· Anxiety

· Runny nose

· Watery eyes

· Tremors

· Aching muscles

32

· Hot and cold flashes

· Abdominal cramps

· Diarrhea.

Withdrawal may last a few days. It is selflimited and, while uncomfortable,withdrawal is not life

threatening. To avoid withdrawal from opioids, you should make sure your medicines are

renewed on time by asking for refills before you run out of medicine. If you want to stop taking

opioids, do not stop them suddenly. Instead, contact your doctor about how to slowly reduce the

dose.

Physical dependence is not the same thing as “addiction” and poses no problem as long as you

do not stop the medicine all at once. The opioid can be stopped safely by slowly reducing the

dose, often over two to three weeks.

Psychological addiction or dependence is different. In this case, a person takes a medicine to

obtain mental “numbness” or a “high” instead of pain relief. Unless you have a history of

substance abuse, there is little risk of addiction when opioids are prescribed by a doctor and

taken as directed.

Tolerance is a need for a higher dose to keep the same effect. Tolerance to opioid pain relief

may occur but is fairly rare. On the other hand, patients often develop tolerance to the side

effects (see below) fairly quickly. If you develop a tolerance to pain relief, a modest increase in

the dose may solve the problem. Switching to a different opioid may also help.

CONCLUSION

Opioid receptor heterogeneity opens many new doors in the design and use of analgesics. In

addition to the obvious use of selective agents, the localization of many of these subtypes to

different parts of the neuraxis offer additional opportunities in pain control. The widespread use

of epidural and intrathecal morphine now can be justified scientifically. The presence of other

analgesic systems involving kappa and delta receptors at the level of the spinal cord opens

many additional possibilities. Perhaps kappa drugs such as spiradoline should be administered

at the spinal level to optimize its analgesic actions while minimizing dysphoria and

psychomimetic actions that are elicited supraspinally. Similarly, preliminary studies of DADL in

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patients suggest that delta drugs may have a significant role in spinal analgesia. The availability

of highly selective agents presumably also would lower the incidence of side effects, such as

constipation and respiratory depression, that are commonly seen with mu drugs. The presence

of synergistic regional interactions may also prove helpful. For example, the effectiveness of

epidural opiates may be enhanced enormously by the concurrent administration of low doses of

systemic drugs. Potential interactions between peripheral and complex central opioid systems

also have not been fully explored. While our understanding of opioid analgesia has expanded

remarkably over the past decade, many important questions remain.

REFERENCE

1. Rang and Dale’s Pharmacology, 6th edition,(H.P.Rang, M.M.Dale, J.M.Ritter,

R.J.Flower). Churchill Livingstone publisher, pp 596-605

2. Essential of Medicinal Pharmacology, 6th edition (KD Tripathi) Jaypee publisher, pp 453-

468.

3. http://www.pharmacology2000.com/Central/Opioid/Opioid_obj1.htm

4. http://en.wikipedia.org/wiki/Nociception

34

5. http://www.drug-facts.org/templates/images/Morphine_sulfate2.jpg

6. http://suboxonedetox.org/wp-content/uploads/2008/03/methadone.jpg

7. http://www.rxlist.com/dolophine-drug.htm

8. http://en.wikipedia.org/wiki/Morphine

9. http://www.merck.com/mmpe/lexicomp/meperidine.html

10. http://www.rxlist.com/demerol-drug.htm

11. http://i.ehow.com/images/a04/s4/v6/use-fentanyl-200X200.jpg

12. http://www.bedfordlabs.com/BedfordLabsWeb/products/images/Buprenorphine%20(100-

10).jpg

13. en.wikipedia.org/wiki/Fentanyl

14. http://www.rxlist.com/narcan-drug.htm

15. http://www.rxlist.com/buprenex-drug.htm

16. http://en.wikipedia.org/wiki/Naloxone

17. http://www.atforum.com/images/2007newssumpic-naloxone.jpg

18. http://www.maxpharma.com.au/Naltrexone.jpg

19. en.wikipedia.org/wiki/Naltrexone

20. http://en.wikipedia.org/wiki/Opioid

http://www.uic.edu/classes/pcol/pcol331/dentalpharmhandouts2006/lecture51.pdf