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Chapter 28

Opioid (Narcotic) Analgesics, Opioid Antagonists, and Nonopioid Centrally

Acting Analgesics

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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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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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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

5

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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 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)• Progresses to:

Violent sneezing, weakness, nausea, vomiting, diarrhea, abdominal cramps, bone and muscle pain, muscle spasm, kicking movements

• 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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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

• Transdermal (Duragesic)- useful for patients with chronic, severe pain and high degree of tolerance

Patch—heat acceleration Iontophoretic system—needle-free

• 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

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Fig. 28–2. Biotransformation of heroin into morphine.

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Moderate to Strong Opioid Agonists (hydromorphone, oxymorphone)

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

Most widely prescribed drug in the United States Combined with aspirin, acetaminophen, or ibuprofen

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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

Pain status should be evaluated before opioid administration and about 1 hour after

Dosage determination Opioid analgesics must be adjusted to

accommodate individual variation Dosing schedule

As a rule, opioids should be administered on a fixed schedule

Avoiding withdrawal

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Clinical Use of Opioids Physical dependence

State in which an abstinence syndrome will occur if the dependence-producing drug is abruptly withdrawn; it is NOT equated with addiction

Abuse 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- there are patients who are at higher risk

for abuse, but those taking opioids for severe pain have an extremely low incidence of 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- blood levels stay in the therapeutic range, fewer fluctuations

Patient education- instruct patient to push the “button” as soon as their pain starts to return. Reassure them that they can’t overdose.

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Fig. 28–3. Fluctuation in opioid blood levels seen with three dosing procedures.

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Opioid Antagonists Drugs that block the effects of opioid agonists Principal uses:

Treatment of opioid overdose, relief of opioid-induced 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 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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Other Opioid Antagonists Methylnaltrexone: selective opioid antagonist

Treatment of opioid-induced constipation in late-stage disease for patients on constant opioids

Naloxegol (Movantik) for those using opioids for chronic, non-cancer

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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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Tramadol Mechanism of action

Combination of opioid and nonopioid mechanisms Therapeutic use Pharmacokinetics Adverse effects and interactions Drug interactions

CNS depressants Abuse liability Preparations, dosage, and administration

Immediate-release and extended-release