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Chapter 28
Opioid (Narcotic) Analgesics, Opioid
Antagonists, and Nonopioid Centrally
Acting Analgesics
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Analgesics and Opioids


Analgesics are drugs that relieve pain without
causing loss of consciousness.
Opioids are the most effective pain relievers
available.
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Opioid Analgesics, Opioid Antagonists,
and Nonopioid Centrally Acting Analgesics





Introduction to the opioids
Basic pharmacology of the opioids
Clinical use of opioids
Opioid antagonists
Nonopioid centrally acting analgesics
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Introduction to the Opioids




Terminology
Endogenous opioid peptides
Opioid receptors
Classification of drugs that act as opioid
receptors
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Terminology

Opioid


A general term defined as any drug, natural or
synthetic, that has actions similar to those of
morphine
Opiate

Applies only to compounds present in opium
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Endogenous Opioid Peptides

Three families of peptides



Enkephalins
Endorphins
Dynorphins
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Opioid Receptors

Three main classes of opioid receptors



Mu receptors
Kappa receptors
Delta receptors
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Classification of Drugs That Act as
Opioid Receptors
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Basic Pharmacology of the Opioids

Strong opioid agonists




Morphine
Other strong opioid agonists
Moderate to strong opioid agonists
Agonist-antagonist opioids
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Morphine

Source


Seedpod of the poppy plant
Overview of pharmacologic actions






Receptors involved
Pain relief
Drowsiness
Mental clouding
Anxiety reduction
Sense of well-being
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Morphine

Therapeutic use: relief of pain




Mechanism of analgesic action
Moderate to severe pain
Constant dull pain vs. sharp intermittent pain
Preoperative treatment of anxiety
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Morphine

Adverse effects

Respiratory depression
• Infants and the elderly are especially sensitive
• Onset:


IV 7 min; IM 30 min; subQ up to 90 min, may persist 4–5 hr
Spinal injection—response may be delayed by hours
• Tolerance to respiratory depression can develop
• Increased depression with concurrent use of other drugs
that have CNS depressant actions (eg, alcohol,
barbiturates, benzodiazepines)
• Can compromise patients with impaired pulmonary
function

Asthma, emphysema, kyphoscoliosis, chronic cor
pulmonale, bariatric
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Morphine

Adverse effects (cont’d)








Constipation
Orthostatic hypotension
Cough suppression
Biliary colic
Emesis
Urinary retention
Euphoria/dysphoria
Sedation
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Morphine

Adverse effects (cont’d)





Miosis
Neurotoxicity
Intracranial pressure (ICP)
Birth defects
Adverse effects from prolonged use
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Morphine

Pharmacokinetics




Administered by several routes: PO, IM, IV, subQ,
epidural, and intrathecal
Not very lipid-soluble
Does not cross blood-brain barrier easily
Only small fraction of each dose reaches site of
analgesic action
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Morphine

Tolerance and physical dependence

Tolerance
• Increased doses needed to obtain same response
• Develops with analgesia, euphoria, sedation, respiratory
depression
• Cross-tolerance to other opioid agonists
• No tolerance to miosis or constipation develops
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Morphine

Tolerance and physical dependence

Physical dependence
• Abstinence syndrome with abrupt discontinuation
• About 10 hours after last dose:

Initial reaction (yawning, rhinorrhea, sweating)

Violent sneezing, weakness, nausea, vomiting, diarrhea,
abdominal cramps, bone and muscle pain, muscle spasm,
kicking movements
• Progresses to:
• Lasts 7–10 days if untreated
• Withdrawal unpleasant but not lethal, as is possible with
CNS depressants
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Morphine


Abuse liability
Precautions





Decreased respiratory reserve
Pregnancy
Labor and delivery
Head injury
Other precautions
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Morphine

Drug interactions







CNS depressants
Anticholinergic drugs
Hypotensive drugs
Monoamine oxidase inhibitors
Agonist-antagonist opioids
Opioid antagonists
Other interactions
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Morphine

Toxicity

Clinical manifestations
• Classic triad





Coma
Respiratory depression
Pinpoint pupils
Treatment
• Ventilatory support
• Antagonist: naloxone (Narcan)
General guidelines
• Monitor full vitals before giving
• Give on a fixed schedule
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Morphine

Preparations, dosage, and administration

General guidelines on dosage and administration
• Preparations
• Morphine/Naltrexone (Embeda): designed to discourage
morphine abuse
• Dosage and routes of administration





Oral
Intramuscular and subcutaneous
Intravenous
Epidural and intrathecal
Extended-release liposomal formulation (DepoDur)
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Fig. 28–1. Structural similarity between morphine and met-enkephalin.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Other Strong Opioid Agonists

Fentanyl (Sublimaze, Duragesic, Abstral,
Actiq, Fentora, Onsolis)


100 times the potency of morphine
Five formulations in three routes
• Parenteral (Sublimaze)

Surgical anesthesia

Patch—heat acceleration
Iontophoretic system—needle-free
• Transdermal (Duragesic)

• Transmucosal




Lozenge on a stick (Actiq)
Buccal film (Onsolis)
Buccal tablets (Fentora)
Sublingual tablets (Abstral)
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Other Strong Opioid Agonists



Alfentanil and sufentanil
Remifentanil
Meperidine




Short half-life
Interacts adversely with several other drugs
Toxic metabolite accumulation
Methadone

Treatment for pain and opioid addicts
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Other Strong Opioid Agonists

Heroin





Used legally in Europe to relieve pain
High abuse liability
Not more effective than other opioids
See Figure 28-2
Hydromorphone, oxymorphone, and
levorphanol


Basic pharmacology
Preparations, dosage, and administration
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Fig. 28–2. Biotransformation of heroin into morphine.
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Moderate to Strong Opioid Agonists

Similar to morphine in most respects


Produce analgesia, sedation, euphoria
Can cause:
• Respiratory depression, constipation, urinary retention,
cough suppression, and miosis


Can be reversed with naloxone
Different from morphine

Produce less analgesia and respiratory
depression than morphine
 Somewhat lower potential for abuse
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Moderate to Strong Opioid Agonists

Codeine


Actions and uses
• 10% converts to morphine in liver
• Pain and cough suppression
Preparations, dosage, and administration
• Usually oral (formulated alone or with aspirin or
acetaminophen)
• 30 mg produces same effect as 325 mg acetaminophen
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Moderate to Strong Opioid Agonists

Oxycodone


Analgesic actions equivalent to those of codeine
Long-acting analgesic
• Immediate-release
• Controlled-release (OxyContin)


Abuse: crushes and snorts or injects medication
2010 OP formulation much harder to crush and does not
dissolve into an injectable solution to decrease risk of
abuse
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Moderate to Strong Opioid Agonists

Hydrocodone



Tapentadol



Most widely prescribed drug in the United States
Combined with aspirin, acetaminophen, or ibuprofen
Analgesic effects equivalent to oxycodone
Causes less constipation than traditional medications
Propoxyphene



Analgesic effect equal to that of aspirin
Combined with aspirin or acetaminophen
Propoxyphene products, such as Darvon and
Darvocet, have been withdrawn owing to limited
efficacy and the risk of potentially fatal dysrhythmias
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Agonist-Antagonist Opioids

Pentazocine





Actions and uses
Preparations, dosage, and administration
Nalbuphine
Butorphanol
Buprenorphine


7-day patch: Butrans
Sublingual film: Suboxone
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Clinical Use of Opioids

Pain assessment



Essential component of management
Based on patient’s description
Evaluate:
• Pain location, characteristics, and duration; things that
improve/worsen pain
• Status before drug and 1 hour after
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Dosing Guidelines

Assessment of pain


Dosage determination


Opioid analgesics must be adjusted to
accommodate individual variation
Dosing schedule


Pain status should be evaluated before opioid
administration and about 1 hour after
As a rule, opioids should be administered on a
fixed schedule
Avoiding withdrawal
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Clinical Use of Opioids

Physical dependence


Abuse


State in which an abstinence syndrome will occur
if the dependence-producing drug is abruptly
withdrawn; it is NOT equated with addiction
Drug use that is inconsistent with medical or social
norms
Addiction

Behavior pattern characterized by continued use
of a psychoactive substance despite physical,
psychologic, or social harm
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Clinical Use of Opioids


Balance the need to provide pain relief with
the desire to minimize abuse
Minimize fears about:


Physical dependence
Addiction
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Clinical Use of Opioids

Patient-controlled analgesia




PCA devices
Drug selection and dosage regulations
Comparison of PCA with traditional intramuscular
therapy
Patient education
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Clinical Use of Opioids

Using opioids in specific settings






Postoperative pain
Obstetric analgesia
Myocardial infarction
Head injury
Cancer-related pain
Chronic noncancer pain
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Fig. 28–3. Fluctuation in opioid blood levels seen with three dosing procedures.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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REMS



Risk evaluation and mitigation strategy
(REMS)
Developed by the FDA
Designed to reduce opioid-related injuries
and deaths
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Opioid Antagonists


Drugs that block the effects of opioid agonists
Principal uses:



Treatment of opioid overdose, relief of opioidinduced constipation
Reversal of postoperative opioid effects
Management of opioid addiction
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Pure Opioid Antagonists


Naloxone (Narcan)
Other pure opioid antagonists



Methylnaltrexone (Relistor)
Alvimopan (Entereg)
Naltrexone (ReVia, Vivitrol)
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Naloxone

Mechanism of action



Competitive antagonist
Pharmacologic effects
Pharmacokinetics
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Naloxone

Therapeutic uses


Reversal of opioid overdose
• Drug of choice with pure opioid agonist overdose
• Titrated cautiously with physical dependence
Reversal of postoperative opioid effects
• Titrated to achieve adequate ventilation and to maintain
pain relief

Reversal of neonatal respiratory depression
• Opioids given during labor and delivery may cause
respiratory depression in neonate
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Naloxone

Preparations, dosage, and administration




Preparations and routes
Opioid overdose
Postoperative opioid effects
Neonatal respiratory depression
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Other Opioid Antagonists

Methylnaltrexone


Selective opioid antagonist
Treatment of opioid-induced constipation in latestage disease for patients on constant opioids
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Nonopioid Centrally Acting
Analgesics



Relieve pain by mechanisms largely or
completely unrelated to opioid receptors
Do not cause respiratory depression, physical
dependence, or abuse
Not regulated under the Controlled
Substances Act
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Nonopioid Centrally Acting
Analgesics

Tramadol (Ultram])




Suicide risk
Clonidine (Duraclon)
Ziconotide (Prialt)
Dexmedetomidine (Precedex)
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47
Tramadol

Mechanism of action





Therapeutic use
Pharmacokinetics
Adverse effects and interactions
Drug interactions



Combination of opioid and nonopioid mechanisms
CNS depressants
Abuse liability
Preparations, dosage, and administration

Immediate-release and extended-release
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Clonidine

Mechanism of pain relief


Analgesic use




Used in combination with opioid analgesic
Pharmacokinetics
Adverse effects


Alpha2-adrenergic agonist
Cardiovascular: severe hypotension, rebound
hypertension, bradycardia
Contraindications
Preparations, dosage, and administration
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49
Ziconotide

Mechanism of action



Selective antagonist at N-type voltage-sensitive
calcium channels on neurons
Blocks calcium channels on primary nociceptive
afferent neurons in dorsal horn of the spinal cord
Clinical trials

Three randomized clinical trials
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50
Ziconotide

Pharmacokinetics


Adverse effects


CNS and muscle injury
Drug interactions


Distributed through cerebral spinal fluid (CSF) and
then transported to systemic circulation
Formal studies not done
Preparations, dosage, and administration

Intrathecal administration
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