Selmar Q.

Maribojo, Jr Morphine
Chapter 31 Opioid Analgesics & Antagonists  Full agonist at the  opioid receptor
 Simple substitution of an allyl group on the nitrogen
INTRODUCTION Codeine
What are analgesics?  Partial (or "weak")  receptor agonist.
 Substances employed for their ability to reduce the perception of Naloxone
pain impulses by the CNS  Strong antagonist at  receptor
 Simple substitution of an allyl group on the nitrogen plus addition
Terminology: of a single OH group
Opioid Nalbuphine
 All compounds related to opium  Capable of producing an agonist (or partial agonist) effect at one
Opiates opioid receptor subtype and an antagonist effect at another
 Drugs derived from opium
Narcotic III Endogenous Opioid Peptides
 “Stupor”, substance with abuse or addictive potentials  Naturally occuring ligands for opioid receptors
Three families of endogenous opioid peptides with their precursor proteins
Opioid analgesics have been described in detail:
 Natural and semisynthetic alkaloid derivatives from opium  Endorphins
 Synthetic surrogates o Prepro-opiomelanocortin (POMC)
 Opiod like drugs whose actions are blocked by naloxone  Enkephalins
 Endogenous peptides that interact with opioid receptors o Preproenkephalin (proenkephalin A)
 methionine-enkephalin (met-enkephalin)
Morphine  leucine-enkephalin (leu-enkephalin)
 Prototypical opioid agonist  Dynorphins
 Standard against which all drugs with strong analgesic action are o Preprodynorphin (proenkephalin B)
compared
 Relieve severe pain with remarkable efficacy POMC
 Pure alkaloid, naming it after Morpheus, the Greek god of dreams  Contains the met-enkephalin sequence, β-endorphin, and several
nonopioid peptides, including adrenocorticotropic hormone
Opium poppy (ACTH), β-lipotropin, and melanocyte-stimulating hormone
 Source of crude opium from which isolated morphine
Preproenkephalin
Naloxone  Contains six copies of met-enkephalin and one copy of leu-
 Nonselective antagonist enkephalin
 Blocked the action opioid analgesic and other opioid-like drugs  Leu- and met-enkephalin have slightly higher affinity for the 
(delta) than for the  opioid receptor
BASIC PHARMACOLOGY OF THE OPIOID ANALGESICS
I Source of Morphine Preprodynorphin
 Opium is obtained from the poppy  Yields several active opioid peptides that contain the leu-
o Papaver somniferum and P album enkephalin sequence:
 Crude opium o Dynorphin A
o After incision, the poppy seed pod exudes a white o Dynorphin B
substance that turns into a brown gum o α and β neoendorphins
 Opium contains many alkaloids, the principle one being
morphine, which is present in a 10 % concentration Additional family: Endomorphin-1 and endomorphin-2
 Codeine is synthesized commercially from morphine  Unknown mechanism
 Possess many of the properties of opioid peptides, notably
II Classification & Chemistry analgesia and high-affinity binding to the  receptor.
A. Spectrum of clinical use  Selectively activate central and peripheral -opioid receptors
o Analgesics
o Antitussives “Both the endogenous opioid precursor molecules and the endomorphins
o Antidiarrheal are present at CNS sites that have been implicated in pain modulation. “
B. Strength of analgesia  Suggests that they can be released during stressful conditions
o Strong such as pain or the anticipation of pain and diminish the sensation
o Moderate of noxious stimuli
o Weak
C. Ratio of agonist to antagonist Dynorphin A
o Agonists  An analgesic action through its binding to (kappa) opioid receptors
o Antagonist “controversial”
o Mixed agonist-antagonis  Found in the dorsal horn of the spinal cord
o Role in the sensitization of nociceptive
neurotransmission.
Opiod drugs
o Increased levels can be found in the dorsal horn after
tissue injury and inflammation
Agonist Partial agonist Antagonist  Proposed to increase pain and induce a
(Morphine) (Codeine) (Naloxone) state of long-lasting hyperalgesia.
 Appears to be independent of the opioid receptor system but
 Certain opioid analgesics are modified in the liver, resulting in dependent on the activation of the bradykinin receptor
compounds with greater analgesic action  Can bind and activate the N -methyl-D-aspartate (NMDA) receptor
 Opioids derived from opium are phenanthrene derivatives and complex
include four or more fused ring
 Most of the synthetic opioids are simpler molecules
 Receptores types Opioid motif – Tyr-Gly-Glu-Phe-(Met or Leu)
I Classic Receptor Selected Endogenous Opioid Peptides
 All are members of the G protein-coupled family of receptors and Leu-enkephalin Tyr-Gly-Glu-Phe-Leu
show significant amino acid sequence homologies. Met-enkephalin Tyr-Gly-Glu-Phe-Met
Dynorphin A Tyr-Gly-Glu-Phe-Leu-Arg-Arg-Ile….
Mu receptors Dynorphin B Tyr-Gly-Glu-Phe-Leu-Arg-Arg-Gln….
 Mediate supraspinal and spinal analgesia, sedation, respiratory α neoendorphins Tyr-Gly-Glu-Phe-Leu-Arg-Lys-Try-
depression and physical dependence, miosis, and reduced GI Pro-Lys
motility, modulation of hormone and neurotransmitter release β neoendorphins Tyr-Gly-Glu-Phe-Leu-Arg-Lys-Try-Pro
 Subtypes μ 1 , μ 2 β3 endorphin Tyr-Gly-Glu-Phe-Met-Thr…..
o μ 1 – supraspinal and spinal analgesia Novel Endogenous Opioid related Peptides
o μ 2 – mediate respirator depression Orphanin FQ/Nociceptin Phe-Gly-Gly-Phe-Thr…..
 Enkephalins and endorphins are endogenous ligands
 Morphine is an exogenous ligand PHARMACOKINETICS
 Endorphins > Enkephalins > Dynorphins Absorption
 Most opioid are well absorbed when given by subcutaneous,
Delta receptors intramuscular, and oral routes
 Mediate supraspinal and spinal analgesia, dysphoria, o Considerable interpatient variability in the first pass
psychotomimetic effects (eg hallucination), respirator and effect
vasomotor stimulation caused by drugs with antagonist activity  Unable to predict effective oral dose
 Subtypes δ 1 , δ 2  Oral dose of the opioid (eg, morphine) may need to be much
 Enkephalins are endogenous ligands higher than the parenteral dose to elicit a therapeutic effect due
 Morphine is an exogenous ligand to first pass effect.
 Enkephalins>> Endorphins & Dynorphins  Morphine, hydromorphone, oxymorphone undergo extensive first
pass effect
Kappa receptors  Certain analgesics such as codeine and oxycodone are effective
 Mediate supraspinal and spinal analgesia, psychotomimetic orally because they have reduced first-pass metabolism
effects (eg hallucination), slowed GI transits  Nasal insufflation of certain opioids can result in rapid therapeutic
 Subtypes κ 1 , κ 2 , and κ 3 blood levels by avoiding first-pass metabolism.
o κ 1 – mediates spinal analgesia  Other routes of opioid administration include oral mucosa via
o κ 2 - unknown lozenges, and transdermal via transdermal patches
o κ 3- mediates supraspinal analgesia
 Dynorphins are endogenous ligands Distribution
 Morphine is an exogenous ligands  All opioids bind to plasma proteins with varying affinity
 Dynorphins >> Endorphins and Enkephalins o Rapidly leave the blood compartment and localize in
 Propsed to mediate a sedation analgesia with reduced addiction highest concentrations in tissues that highly perfused
liability and respiratory depression  Brain, lungs, liver, kidneys, and spleen
o Respiratory depression and miosis may be less severe  Drug concentrations in skeletal muscle may be much lower
with κ agonists o Serves as the main reservoir because of its greater
bulk.
Summary Tables  Blood flow to fatty tissue is much lower than to the highly
Receptor Functions Endogenous Opioid Peptide perfused tissues
Subtype Affinity o very important of accumulation after frequent high-
 (Mu) Sedation Endorphins > enkephalins > dynorphins dose administration or continuous infusion of highly
Inhibition of respiration lipophilic opioids that are slowly metabolized, eg,
Modulation of hormone fentanyl
Neurotransmitter release  Cross the placental barrier
 (Delta) Modulation of hormone Enkephalins > endorphins and dynorphins
Neurotransmitter release Metabolism
 (Kappa) Psychotomimetic effects Dynorphins > > endorphins and enkephalins  The opioids are converted in large part to polar metabolites
All Receptor subtypes functions as supraspinal and spinal analgesia (mostly glucuronides), which are then readily excreted by the
Mu & Kappa subtypes also functions as slowed gastrointestinal transit kidneys
A. Conjugation in the liver by UDP-glucuranosyltransfereases
II Non Classic Receptors B. Hydrolysis by common tissue esterases
C. Hepatic oxidative metabolis by CYP3A4, CYP2D6
 ORL1 (orphanin opiod like subtype 1), also known as NOP
Conjugation in the liver by UDP-glucuranosyltransfereases
Orphanin FQ/Nociceptin
 Novel receptor-ligand system homologous to the opioid peptides
o Receptors: G protein-coupled orphanin opioid-receptor-
like subtype 1 (ORL1)
o Ligand: Nociceptin/Orphanin FQ
 Widely expressed in the CNS and Periphery
 Implicated in both pro- and anti-nociceptive activity as well as in
the modulation of drug reward, learning, mood, anxiety, cough,
and of parkisonism

Nociceptin
 Structurally similar to dynorphin except for the absence of an N-
terminal tyrosine
 Acts only at the ORL1 receptor, now known as NOP
Metabolism of morphine Excretion
 Urinary tract/Enterohepatic circulation
 Polar metabolites, including glucuronide conjugates of opioid
Conjugation of analgesics, are excreted mainly in the urine
Morphine
 Small amounts of unchanged drug may also be found in the urine
 Glucuronide conjugates are found in the bile, but enterohepatic
circulation represents only a small portion of the excretory
~10%: morphine-
process.
Morphine-3-
6-glucuronide
glucuronide (M3G)
(M6G)
Common opioid analgesics
Generic name Brand Approx O:P Duration Intrinsic
equiv. Potency of activity
Active metabolite Act as dose ratio analgesia
Limited ability to Produce
with analgesic
cross the blood- unexpected
neuroexcitatory to (mg) (hr)
potency four to six GABA/glycinergic
times
brain barrier adverse effects
system
Morphine -- 10 Low 4-5 High
Hydromorphone Dilaudid 1.5 Low 4-5 High
Oxymorphone Numorphan 1.5 Low 3-4 High
 CNS uptake of M3G and, to a lesser extent, M6G can be enhanced Methadone Dolophine 10 High 4-6 High
by coadministration with probenecid or with drugs that inhibit Meperidine Demerol 60-100 Med 2-4 High
the P-glycoprotein drug transporter. Fentanyl Sublimaze 0.1 Low 1-1.5 high
Sufentanil Sufenta 0.02 IV only 1-1.5 High
Metabolism of Hydromorphone
Alfentanil Alfenta Titrated IV only 0.25- High
0.75
Hydromorphone-3-
Hydromorphone Conjugation
glucuronide (H3G)
CNS excitatory Levorphanol Levodromoran 2-3 High 4-5 High
Codeine -- 30-60 High 3-4 Low
Hydrocodone -- 5-10 Med 4-6 Med
Oxycodone Percodon 4-5 Med 3-4 Med
 However, hydromorphone has not been shown to form significant
Propoxyphene Darvon 60-120 Oral only 4-5 Very
amounts of a 6-glucuronide metabolite
low
 The effects of the active metabolites should be considered in
Pentazocine Talwin 30-50 Medium 3-4 Med
patients with renal impairment before the administration
especially when given at high doses. Nalbuphine Nubain 10 IV only 3-6 High
Buprenorphine Buprenex 0.3 Low 4-8 High
Metabolism of Heroin and Remifentanil “Esters” undergo hydrolysis by Butorphanol Stradol 2 IV only 3-4 High
common tissue esterases
Heroin Hydrolysis PHARMADYNAMICS
A Mechanism of Action
 Opioid agonists produce analgesia by binding to specific G protein-
Monoacetylmorphine
coupled receptors that are located in brain and spinal cord regions
involved in the transmission and modulation of pain.
Morphine
 Some effects may be mediated by opioid receptors on peripheral
sensory nerve endings.
Conjugation of morphine "Glucoronidation:

Glucuronic acid: M3G & M6G

Metabolism of Phenylpiperidine opiods

 Meperidine
 Fentanyl “no active metabolites”
 Alfentanil
 Sufentanil
o Hepatic oxidative metabolism is the primary route of
degradation
o Leaves only small quantities of the parent compound
unchanged for excretion.

Normeperidine
 Accumulation of a demethylated metabolite of meperidine
o May occur in patients with decreased renal function
and in those receiving multiple high doses of the drug.
 In high concentrations, may cause seizures.

Fentanyl
 Hepatic oxidative metabolism by the P450 isozyme CYP3A4
metabolizes by N-dealkylation in the liver.
o CYP3A4 is also present in the mucosa of the small
intestine and contributes to the first-pass metabolism
when it is taken orally.
Metabolism of Codeine, oxycodone, and hydrocodone
 Undergo metabolism in the liver by P450 isozyme CYP2D6,
resulting in the production of metabolites of greater potency.
Potential receptor mechanisms of analgesic drugs. The primary afferent neuron (cell body not shown)
originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it
synapses via glutamate and neuropeptide transmitters with the secondary neuron. Pain stimuli can be
attenuated in the periphery (under inflammatory conditions) by opioids acting at μ-opioid receptors
(MOR) or blocked in the afferent axon by local anesthetics (not shown). Action potentials reaching the
dorsal horn can be attenuated at the presynaptic ending by opioids and by calcium blockers
(ziconotide), α 2 agonists, and possibly, by drugs that increase synaptic concentrations of
norepinephrine by blocking reuptake (tapentadol). Opioids also inhibit the postsynaptic neuron, as do
certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.
I Receptor types
Brainstem local circuitry underlying
 All are members of the G protein-coupled family of receptors and
the modulatin effect of μ-opioid
show significant amino acid sequence homologies. receptor (MOR)–mediated
 Multiple receptor subtypes have been proposed based on analgesia on descending pathways.
pharmacologic criteria The pain-inhibitory neuron is
o μ1,μ2 indirectly activated by opioids
o δ1,δ2 (exogenous or endogenous), which
o κ 1 , κ 2 , and κ 3 inhibit an inhibitory (GABAergic)
interneuron. This results in
enhanced inhibition of nociceptive
II Cellular actions processing in the dorsal horn of the
 The opioids have two well-established direct G protein-coupled spinal cord
actions on neurons:
o Close voltage-gated Ca 2+ channels on presynaptic
nerve terminals
 Reduce transmitter release
o Hyperpolarize and thus inhibit postsynaptic neurons by
opening K + channels. Opioid analgesic action on the
descending inhibitory pathway.
III Relation of physiologic effects to receptor type Sites of action of opioids on pain-
modulating neurons in the midbrain
 The majority of currently available opioid analgesics act primarily
and medulla including the midbrain
at the μ-opioid receptor periaqueductal gray area (A), rostral
 Analgesia and the euphoriant, respiratory depressant, and ventral medulla (B), and the locus
physical dependence properties of morphine result principally caeruleus indirectly control pain
from actions at μ receptors. transmission pathways by
 Opioid analgesic effects are complex and include interaction with enhancing descending inhibition to
the dorsal horn (C).
δ and κ receptors.
 Morphine does also act at κ and δ receptor sites
 κ opioid receptors have been developed for reduced incidence of
respiratory depression or propensity for addiction and
dependence
 Butorphanol and nalbuphine have shown some clinical success as
analgesics
o Can cause dysphoric reactions and have limited
Organ System Effects
potency
CNS:
 Butorphanol has also been shown to cause significantly greater
 Analgesia (Sensory & Affective)
analgesia in women than in men.
 Euphoria; Drowsiness; Apathy; Mental confusion; alteration in
Mood
IV Receptor Distribution and Neural Mechanisms of Analgesia
 Sedation – little or no amnesia
 All three major receptors are present in high concentrations in the
 Dysphoria (restlessness & Malaise
dorsal horn of the spinal cord.
 Respiratory depression secondary to inhibition of brainstem
 Receptors are present both on spinal cord pain transmission
respiratory mechanism; dose related; decreased response to CO2
neurons and on the primary afferents that relay the pain message
challenge
to them (Figure below, sites A and B).
 Cough suppression
 Opioid agonists inhibit the release of excitatory transmitters and
they directly inhibit the dorsal horn pain transmission neuron.  Miosis
o Thus, opioids exert a powerful analgesic effect directly  Truncal rigidity
on the spinal cord  Nausea and vomiting – caused by direct stimulation of the emetic
chemoreceptors located in the medulla; ? vestibular component
Site of Actions of opiod analgesics
A Ascending Pain Sensory Pathway Peripheral Effects
 Nociceptive nerve endings Cardiovascular
 Spinal Cord  Most have no significant direct effect on the heart and cardiac
 Thalamus rhythm except bradycardia
B Descending Pain Modulation Pathway  Medperidine  tachycardia secondary to its antimuscarinic
 Midbrain effects
GIT
 Medulla
 Stomach
“Part of the pain relieving action of exogenous pepides involves the release of o Motility is decreased
endogenous peptides” o Tone is increased
o Decreased HCL secretion
Putative sites of action of opioid  Small intestines
analgesics. Sites of action on the o Increased resting tone with periodic spasm
afferent pain transmission pathway o Decreased amplitude in nonpropulsoive contraction
from the periphery to the higher  Large intestines
centers are shown. o Decreased propulsive peristalsis
o Increase tone
A: Direct action of opioids on
inflamed or damaged peripheral  Biliary tract
tissues o Contract biliary smooth muscles
B: Inhibition also occurs in the Renal function
spinal cord  Depressed secondary to decrease renal plasma flow
C: Possible sites of action in the  Mu opioids have antidiuretic effects
thalamus.
 Enhance renal tubular Na reabsorption
 Increas4e ureteral/bladder tone
  Increase sphincter tone Benzomorphone
Uterus – prolong labor  Pentazocine – a kappa agonist with weak mu anagonist or partial
Neuroendocrine – stimulate the release of ADH, prolactin, somatotropin; agonist properties
inhibit the release of LH  Dezocine – highest affinity for mu receptors and less interaction
Pruritus with kappa receptors

Effects of Drugs with both agonist and antagonis action Tramadol

Buprenorphine  Central acting analgesic
 Agonist at mu receptor with high binding affinity but low intrinsic  Block serotonin reuptake and inhibit NET function
activity  Weak mu receptor
 Antagonist at delta and kappa receptor  Associated with seizures, nausea and dizziness
 Can antagonize the action of more potent mu agonist  Serotonin syndrome
 Bind to ORL1  May be used as an adjunct with pure opioid agonist in the
Pentazocine treatment of chronic neuropathic pain
 Agonist at kappa, weak antagonist at mu and delta receptors
Nalbuphine Tapentadol
 Similar to pentazocine but a potent antagonist at mu receptors  Has a modest mu opioid receptor affinity and a significant
“Psychotomimetic effects have been reported ff use of drugs mixed agonist- norepinephrine reuptake inhibiting action
antagonist actions  In animal models, its analgesic effects were only moderately
reduced by naloxone but strongly reduced by an alpha 2
Classification Strong agonist Mild to Mixed adrenoreceptor antagonist
Moderate Receptor  Binding to NET > tramadol but binding to SERT < tramadol
agonist actions  As effective as oxycodone in treating mod to severe pain
Phenanthrenes Morphine, all – Codeine, all – Nalbuphine,  Risk for seizure and serotonin syndrome
morphone codone Buprenorphine
Phenylheptylamines Methadone Proxyphene -- Antitussives
Phenylpiperidines Meperidine, Diphenoxylaye, --  Dextromethorphan – stereoisomer of levorphanol; free addictive
Fentanyl, all – Difenoxin, properties, produces less constipation than codeine; enhance the
fentanil Loperamide analgesic action of morphine
Morphinans Levophorphanol -- Butorphanol  Levoprpoxyphene – stereoisomer of dextropropoxyphene, devoid
Benzomorphone -- -- Pentazocine, of opioid effects, sedation as side effect
Dazocine
Opioid Antagonist
Phenanthrenes  Relatively high affinity for mu receptors; lower affinity for other
 Morphine, Hydromorphone, Oxymorphone – strong agonist useful receptors and can reverse agonists at delta and kappa sites
in treating severe pain  Completely reverses opioid effects in 1-3 mins
 Codeine, Oxycodone, Dihydrocodeine, Hydrocodone – Less  No tolerance to antagonistic action
efficacious than morphine; rarely used alone but are combined
with ASA, acetaminophen, etc Naloxone
 Nalbuphine – a strong kappa receptor agonist and a mu receptor  Short duration of action IV
antagonist; respiratory depression is relatively resistant to  Poor efficacy PO
naloxone reversal  Undergoes glucoronide conjugation
 Buprenorphine – potent and long acting partial mu receptor  Treatment of acute opioid overdose, adverse effect assoc with IV
agonist; resistant to naloxone reversal, effective in the and Epidural opioids and opioid induced ileus or constipation
detoxification and maintenance of heroin abusers Naltrexone
 Well absorbed PO
Phenylheptylamines  May undergo rapid 1st pass effect
 Methadone – can be administered PO, IV, SQ, rectal routes;  Maintenance for addicts
potent mu receptor agonist; D and I isomers can block both Nalmefene
NMDA receptor and monoaminergic re uptake; can relieve  Available only IV
difficult to treat pain; use in the treatment of opioid abuse for  Longer half life
detox and maintenance  Treatment of acute opioid overdose
 Propoxyphene – low analgesic activity, low abuse liability but
increase incidence of death association with misuse New Antagonists
 Methylnatrexone and Almivopan
Phenylpiperidines o Do not cross the BBB
 Meperidine – antimuscarinic effects; negative inotropic effect; o Block adverse effects of strong opioids on peripheral
potential for producing seizures secondary to normoperidine mu receptors
 Sulfentanil>>>Fentanyl>Alfentanil o With minimal effect on analgesic action
 Diphenoxylate/Difenoxin – used for diarrhea; used in combination o Without precipitating an abstinence syndrome
with atropine  Methylnatrexone
 Loperamide – limited access to the brain o Tx of constipation in patients with late stage advanced
illness
Morphinans  Almivopan
 Levorphanol – synthetic opioid analgesis resembling morphine o Tx of post operative ileus following bowel resection
 Butorphanol – produce analgesia equivalent to nalbuphine & surgery
Buprenorphin but produce more sedation; predominantly a kappa
agonist but may act as a partial agonist or antagonist at the mu Clinical Use of Opioid analgesic
receptor  Analgesia
 Acute pulmonary edema
 Cough
 Diarrhea
  Shivering Contraindications and Cautions in Therapy
 Premedications and adjuncts in anesthesia  Use of pure agonists with weak partial agonist – risk of
diminishing analgesia or inducing a state of withdrawal
Adverse Effects  Use in patient with head injuries
 Behavioral restlessness, tremuolousness, hyperactivity o Increase CO2 secondary to respiratory depression =
 Respiratory depression cerebral vasodilation
 Nausea and vomiting
 Increased intracranial pressure Opioid Drug Interactions
 Postural hypotension accentuated by hypovolemia Drug Groups Interaction with Opioid
 Constipation Sedative-Hypnotics Increased CNS depression
 Urinary retention Antipyschotic Increased sedation; variable effect on
 Urticaria, Itching around the nose tranquilizers respiratory depression; accentuation of
antimuscarinic and alpha blocking actions
Tolerance and Physical Dependence MAO inhibitors High incidence of Hyperpyrexic coma;
hypertension
Endogenous
ligands
Factors to consider
Endocytosis  Route of administration
Resensitization  Duration of Drug action
Recycling of  Ceiling effect
receptor in the  Duration of therapy
plasma membrane
 Potential for adverse effects
Mu receptor  Patient’s past experience with opioids

Tolerance
 Begins with the first dose, clinically manifests after 2-3 wks of
frequent exposure; develops rapidly with large doses at short
interval
 No tolerance develops to the miotic, convulsant and constipating
actions
 The mechanism of development of tolerance and physical
dependence is poorly understood
o Receptor recycling
 Failure of morphine to induce endocytosis is
an important component of tolerance and
dependence
o Receptor uncoupling
 Tolerance is due to dysfunctional of
structural interactions between the mu
receptor and G proteins, 2nd messenger
systems and their target ion channels
o NMDA receptor complex
 NMDA receptor antagonist can block the
development of tolerance
o Delta opioid receptor function as an independent
component in the maintenance of tolerance

Cross Tolerance
 May develop such as patient tolerant to morphine show
reduction in analgesic response to other agonist opioid but it is
usually partial or incomplete
o Opioid rotation
o Recoupling
o Use of delta antagonist with mu receptor agonist

Physical dependence
 Results in a characteristic withdrawal or abstinence syndrome
 S/Sx – rhinorrhea, lacrimation, yawning, chills, piloerection,
hyperventilation, hyperthermia, mydriasis, muscular aches,
vomiting, diarrhea, anxiety and hostility
 The time of onset, intensity and duration of abstinence syndrome
depend on the drug used and its biologic half life

Psychologic dependence
 Primary reasons for opioid abuse liability
o Euphoria, indifference to stimuli, sedation
o Abdominal effects
o Physical dependence