two main components of pain

1. physical (acute/chronic, nociceptive/neuropathic, somatic/visceral)

2. psychological (memory, fear, anticipation, depression)

two classes of pharmacologic analgesics

1. Narcotics (opioids)

2.Non-Narcotic analgesics (NSAIDs etc.)

Opioid effects on both main aspects of pain

physiological threshold for pain percpetion raised

affective response (psychological reaction) altered (often producing euphoria or disphoria)

Sites of Opioid Action

Thalamus

Limbic System(amygdala, hippocampus, fornix, etc.)

Brain Stem

Spinal Cord--spinothalamic tracts especially, respond to endogenous and exogenous opioids, targeted by intrathecal or epidural opioids to cause analgesia--pre-synaptic opioid receptors inhibit neurotransmitter release while post-synaptic opioid receptors inhibit AP propagation

Endogenous Opioids

enkephalins (from proenkephalins)

endorphins (from pro-opiomelanocortin POMC)

dynorphins (from prodynorphin)

peptide neurotransmitters, same properties as exogenous opioids (analgesic effects, blocked by naloxone, act on opioid receptors in CNS)

basis for pain releif using acupuncture

Opioid Receptors

7 transmembrane domain G protein coupled receptors (GPCRs)

distributions of subtypes vary throughout CNS

mu (most important for analgesia)

kappa (prevalent in spinal cord)

delta

sigma (not a true opioid receptor though some opioids cross react with sigma receptors)

mu opioid receptor

most important for pain control

binds morphine

GPCR which when stimulated may produce analgesia, euphoria, sedation, physical and psychological dependence, respiratory depression (hypoxia)

kappa opioid receptor

widely distributed in spinal cord

GPCR which when stimulated may produce dysphoria (opposite of euphoria), analgesia, and sedation

Morphine

prototypic exogenous opioid derived from poppies or synthesized in labs

full mu receptor agonist--binds domains of receptor embedded in plasma membrane in addition to the N terminal binding site for endogenous opioids

maximum analgesic effect

euphoria, nausea/vomiting, mental clouding, antitussive, bronchoconstriction, respiratory depression, miosis, urinary retention, gonadotropin release inhibition, vascular dilation (orthostatic hypotension), constipative/antidiarrheal

low oral bioavailability

active metabolite (analgesic and possibly nephrotoxic action)=morphine-6-glucuronide, excreted in urine (primary method of elimination)

induces tolerance (cross tolerance w/other opioids) and physical dependance, high abuse potential

withdrawl/abstinence syndrome possible

low lipid solubiliby (hard to cross BBB)

Tolerance

progressively higher doses required to achieve same effect

most opioid have complete or incomplete cross-tolerance with other opioids

tolerance to opioids is always pharmacodynamic (receptors downregulated or endocytosed in presence of drug) NOT metabolic (induction of liver CYPs etc.)

Physical Dependence

patient undergoes withdrawl/abstinence syndrome when opioid is removed from system or blocked (naloxone induces withdrawl in an opioid dependent person)

develops during long-term opioid use

not equivalent to addiction

Adverse effects of Opioids

respiratory depression (especially in opioid niaive pts!)

constipation (decreased peristalsis)

nausea & vomiting (stimulation of chemorecptor trigger zone)

abuse potential (euphoria, dependence, tolerance)

confusion/lethargy/apathy/sedation

bronchoconstriction (directly and indirectly via histamine release, especially morphine)

miosis

urinary retention (increased ADH release & direct action on bladder destrusor muscle)

hormonal disturbances (inhibits gonadotropin release)

orthostatic hypotension (histamine release, depressed adrenergic and vasomotor tone)

Clinical uses for opioids

Analgesia--typically for moderate or severe pain levels

Antitussive (rare use these days)

Antidiarrheal

Opioid overdose triad

1.miosis

2.respiratory depression

3.coma

treat immediately with Naloxone=Narcan (opioid receptor antagonist) until triad of symptoms reverses

Antidiarrheal Opioids

 Loperamide

Diphenoxylate

Antitussive Opioids

Codeine

Dextromethorphan

Opioids and Mood Changes

Euphoria (most common change)

Dysphoria also possible (especially kappa agonists)

Opioid stimulated Nausea and Vomiting

Chemoreceptor trigger zone irritation

Respiratory Depression caused by Opioids

opioids decrease brainstem response to CO2 levels (the central drive to breathe)

bronchoconstriction: direct action on smooth muscle cell recpetors

some opioids like morphine also cause histamine release

cough reflex suppression--may be beneficial (antitussive) or harmful (airway obstructing) but typically occurs at doses below analgesic threshold

Opioid Miosis

pinpoint pupil

common sign of overdose

Urinary Retention caused by Opioids

increased ADH release from pituitary-->water reabsorption from colleting ducts in kidneys

direct inhibitory action on detrusor muscle of bladder

Hormonal effects of Opioids

decreased release of LH and FSH

may disrupt fertility in males and females (transient)

menstrual irregularities in females

Cardiovascular effects of Opioids

peripheral vascular dilation-->postural hypotension

caused by histamine release and depressed adrenergic tone

Metabolism and Excretion of Morphine

Metabolism: glucuronide conjugation in liver

Excretion: as glucuronide via the urine

Opioid abstinence or withdrawl sydrome

begins 8-12 hours after last morphine dose and peaks at 36-72 hours (varies with half-life for other opioids)

delayed onset and less severe for long acting opioids

diarrhea, vomiting, chills, fever, lacrimation, rhinorrhea, tremor, kicking/twitching

naloxone to induce (test for heroin addiction or physical depedence to any opioid)

clonidine to treat

Clonidine

centrally active alpha 2 receptor agonist

decreases norepinephrine release in brain

used to treat symptoms of opioid withdrawl

Codeine

orally active opioid analgesic w/approximately 1/10th potency of morphine

used for mild-moderate pain, often in combo. with aspirin, acetaminophen, or NSAIDs

antitussant activity

better lipid solubility vs. morphine--crosses BBB

metabolized by CYP2D6 (pharmacogenetics:poor metabolizers get little effect)

Heroin

opioid drug (diacetylmorphine)

variable oral absorption, parenteral absorption better

high lipid solubility--crosses BBB

IV illicit drug in the U.S.; used medically in some countries

Oxycodone

opioid analgesic with similar potency and efficacy as morphine

but with higher oral availability

used for severe pain

frequently abused--addicts grind this up for a faster high

found in Oxycontin, Percocet (w/acetaminophen), and Percodan (w/aspirin)

Hydromorphone

opioid analgesic with efficacy comparable to morphine but ten times more potent

for severe pain

high oral bioavailability

high abuse potential

(Dilaudid)

Apomorphine

opioid with LITTLE ANALGESIC ACTIVITY

primary use as an EMETOGENIC agent--stimulates vomiting by irritating the CTZ

can still cause respiratory depression like most opioids (titrate carefully and watch patient closely)

Dextromethorphan

opioid with very LITTLE ANALGESIC ACTION

mainly used as an ANTITUSSANT

low addiction potential

less drowsiness and GI upset vs. codeine

a.k.a. Romilar

Meperidine

a.k.a. Demerol

short-acting opioid analgesic

synthetic, orally active, for moderate-severe pain

1/10 the potency of morphine

popular for pain relief for women in labor

according to ICM becoming less popular in hospitals due to side effects (seizures + common opioid adverse effects)

Fentanyl

a.k.a Sublimaze

synthetic opioid analgesic 80X the potency of morphine

short-acting, t1/2 only 20 minutes

highly lipid soluble, crosses BBB, action terminated mainly by resdistribution between body compartments (like thiopental)

oral, sublingual, or IV

for severe pain, anesthetic induction, may be sole anesthetic in cardiac surgery, also used as an antipsychotic (neuroleptic) in combo. w/droperidol=innovar

Alfentanil

short-acting synthetic opioid analgesic/anesthetic similar to fentanyl

causes pain releif and muscle relaxation--good for outpatient surgery

Sufentanil

a.k.a. Sufenta

short-acting synthetic opioid analgesic/anesthetic similar to fentanyl

causes pain releif and muscle relaxation--good for outpatient surgery

Methadone

a.k.a. Dolophine

orally active synthetic opioid analgesic w/action and potency comparable to morphine

long-acting, t1/2 is about 15 hours

used for chronic pain and to treat opioid addiction (methadone maintenance)

causes less euphoria than the commonly abused opioids (heroin, morphine, oxycodone, etc.) but prevents withdrawl in addicts

LAAM (L-alpha-acetyl-methadol)

a.k.a. Orlaam

long-acting sythetic orally active opioid analgesic (mu agonist)

methadone cogener used for heroin addiction treatment (reduces craving)

Propoxyphene

a.k.a Darvon

orally active synthetic opioid analgesic comparable to codeine in potency and use

for mild-moderate pain

usually combined with aspirin or acetaminophen

Diphenoxylate

combined with atropine to form Lomotil

oral synthetic opioid used as an ANTI-DIARRHEAL

NOT for analgesia

some abuse potential--offset by coformulation with atropine (unpleasant antimuscarinic effects at high doses)

Loperamide

a.k.a. Immodium

OTC oral opioid drug used as an ANTIDIARRHEAL

poorly absorbed from GI tract, acts directly on intestinal musculature to inhibit motility

NOT an analgesic

low penetrantion to CNS--reduced abuse potential compared to diphenoxylate though equally effective in countering diarrhea

Treatment of Opioid Overdose

(CNS depression/coma, repiratory depression, miosis)

1.Restore respiration, estabilish airway if necessary, give supplemental but not pure O2 (CO2 stimulates the stunned central respiratory center)

2.Give Naloxone (antagonist at all opioid receptors) 4-8 mg IV or IM until symptoms reverse

3.Observe patient closely and readminister naloxone as needed (shorter half life vs. most opioid drugs)

Classes of Drugs that interact Additively with Opioids to cause CNS or Respiratory Depression

Sedatives

Sedative-hypnotics

Ethanol

Monoamine Oxidase Inhibitors (MAOIs)

Tricyclic antidepressants

Tranquilizers

Pure Opioid Antagonists

Naloxone and Naltrexone

block all effects of opioids (analgesia, euphoria/dysphoria, respiratory depression, GI upset/constipation, etc.)

used to treat opioid overdose, diagnose physical dependence on opioids esp. in context of addiction, control compulsive use in addiction treatment

Naloxone

a.k.a. Narcan

short-acting pure opioid antagonist, IV or IM

competative antagonism of all opioids (including the endogenous ones) at all opioid receptors (mu, kappa, delta)

t1/2 of 1-4 hours (monitor overdose patients!)

used to treat opioid OD, may trigger withdrawl--use to diagnose dependence

Naltrexone

a.k.a. Trexan

long-acting competative opioid antagonist, t 1/2 is about 24 hours, oral drug

blocks endogenous and exogenous opioid action

used to decrease cravings in programs for heroin and alcohol addiction (reduces compulsive use by eliminating endogenous opioid rush associated with alcohol abuse)

used to diagnose physical dependence on opioids--precipitates withdrawl syndrome

not as good as naloxone for emergency treatment of opioid OD b/c long-acting/slow

Pentazocine

a.k.a. Talwin

mixed opioid agonist/antagonist used for analgesia in mild-moderate pain

kappa agonist--effective spinal analgesia

weak mu ANTagonist--counters morphine analgesia (but not respiratory depression) and induces withdrawl in the morphine-dependent

less severe respiratory depression and withdrawl syndrome vs. morphine

dysphoria and hallucinations at higher doses (from cross-stim. of sigma "not-an-opioid-receptor" receptors)

Nalbuphine

a.k.a. Nubain

kappa opioid receptor agonist

mu opioid receptor ANTagonist--induces morphine withdrawl

analgesic for moderate to severe pain with limited respiratory depression and low risk of mild dependence

low incidence of psychotomimetic effects (dysphoria/hallucinations) b/c does not stim. sigma R's

Butorphanol

a.k.a Stadol

 similar to Nalbuphine

kappa opioid receptor agonist

mu opioid receptor ANTagonist--induces morphine withdrawl

analgesic for moderate to severe pain with limited respiratory depression and low risk of mild dependence

low incidence of psychotomimetic effects (dysphoria/hallucinations) b/c does not stim. sigma R's

Buprenorphine

a.k.a. Buprenex

mixed mu opioid receptor agonist/antagonist

kappa ANTagonist

analgesic for moderate-severe pain

slow onset, long-lasting

lower risk of repiratory depression and withdrawl syndrome vs. morphine (still causes euphoria and miosis though)

induces withdrawl in people severely dependent on morphine

may be alternative to methadone as maintenance drug tx for opioid addicts (reduces craving)