Opioids

Abstract

Opioids are a group of medications used primarily for management of moderate to severe pain. These agents are available in a number of different doses and are able to be given by multiple routes of administration including oral, buccal, transdermal, intravenous, intramuscular, epidural, intrathecal, and rectal.

Introduction

Opioids are a diverse group of medications derived from opium used for management of pain. They can be divided into categories based on their chemical origin. Natural opioids are derived from the opium poppy and include morphine and codeine. Semi-synthetic opioids have structures that are based on morphine but have been chemically altered. This group includes hydrocodone, hydromorphone, and oxycodone. Synthetic opioids have chemical structures that are different from morphine but have similar activities to morphine on mu opioid receptors. This class includes levorphanol, meperidine, methadone, and the fentanyl derivatives.

The primary mechanism of action of opioids is agonist activity at mu-opioid receptors with effects primarily in the brain and spinal cord but they also exert action on mu-receptors in the periphery. Activation of mu opioid receptors leads to inhibition of pain signals from peripheral nerves, activating inhibitory descending pathways in the spinal cord, and alter central processing of signals.

Adverse reactions are generally shared across this class of medications and include sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, and headache. Sedation, nausea, and itching commonly resolve with after 3–7 days of continued use but the other adverse effects may persist as long as the patient remains on opioid therapy. A more recently described category of adverse effects called opioid-induced neurotoxicity includes myoclonus and hyperalgesia. Myoclonus may occur more often with accumulation of metabolites of opioids while hyperalgesia seems to occur more often with prolonged use of opioids and higher doses [1, 2].

Opioids are all primarily metabolized by the liver. However, consideration of clearance of metabolites should be taken into account in the setting of stage IV or V chronic kidney disease. Fentanyl and methadone have minimal renal clearance and are the safest of the common opioids in this setting. Hydromorphone and oxycodone have some renally cleared metabolites but are generally considered safe. Avoidance of morphine, codeine, and hydrocodone should be considered due to a greater risk of accumulation of renally cleared metabolites and adverse effects [1, 3].

Morphine

• Mechanism of action: Agonist activity at mu opioid receptors.

• Contraindications: allergy to the medication or components, gastrointestinal (GI) obstruction, paralytic ileus, or acute or severe asthma.

• Dosage forms:

• Oral:

  • Immediate-release tablets (MS IR) and solutions in 10 mg/5 ml, 20 mg/5 ml, and 100 mg/5 ml concentrations.

  • Extended-release 12 h tablets (MS Contin, MorphaBond, Arymo) and 24 h capsules (Avinza, Kadian).

• Injectable: multiple concentrations of solutions ranging from 0.5 mg/ml to 25 mg/ml.

• Rectal: immediate-release suppositories in sizes from 5 mg to 30 mg.

• Adverse reactions: sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, hypogonadism, and headache. Itching occurs much more often with epidural administration than systemic administration. Morphine may worsen hypotension in cardiogenic shock by causing peripheral histamine release and vasodilation.

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs.

• Dosage:

• Oral: Immediate-release: 7.5–15 mg every 3 h as needed

  • Extended-release: 10 mg once daily using 24 h capsules or 15 mg every 12 h using 12 h tablets. To be used in opioid tolerant patients.

• IV/IM/SQ: Initial dose is 2.5–5 mg every 3 h as needed.

• Epidural: 30–100 mcg as single dose or a continuous infusion beginning at 200–400 mcg/h.

• Intrathecal: 100–300 mcg as a single dose or a continuous infusion of 200–1000 mcg per 24 h.

• Conversions: Oral to OV ratio of 3:1. IV to epidural conversion is 10:1. Epidural to intrathecal conversion is 10:1 [1, 2].

Hydromorphone

• Mechanism of action: Agonist activity at mu opioid receptors.

• Contraindications: allergy to the medication or components, GI obstruction, paralytic ileus, and acute or severe asthma.

• Dosage forms:

• Oral:

  • Immediate-release tablets (Dilaudid) and solution in a 1 mg/ml concentration

  • Extended-release 24 h capsules (Exalgo)

• Injectable: multiple concentrations of solutions ranging from 1 mg/ml to 10 mg/ml

• Rectal: Immediate-release 3 mg suppository

• Adverse reactions: sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, hypogonadism, and headache.

• Drug Interactions: additive central nervous system (CNS) depression with CNS depressants, and increased risk of constipation with anticholinergic drugs.

• Dosage:

• Oral: Immediate-release: 2–4 mg every 3 h as needed

  • Extended-release: 8 mg every 24 h

• IV/IM/SQ: initial dose is 0.2–1 mg every 3 h as needed

• Epidural: 400–1000 mcg as a single dose or a continuous infusion beginning at 30–300 mcg/h

• Conversions: Oral to iv ratio of 5:1. IV to epidural conversion is 10:1 [1, 2].

Hydrocodone

• Mechanism of action: Agonist activity at mu opioid receptors

• Contraindications: allergy to the medication or components, GI obstruction, paralytic ileus, and acute or severe asthma

• Dosage forms:

• Oral:

  • Immediate-release: in combination with acetaminophen as tablets (Norco, Lorcet, Vicodin) or solution (Lortab, Hycet). Also available in combination with ibuprofen as tablets (Vicoprofen, Ibudone, Xylon).

  • Extended-release: Available as plain drug in 12 h capsules (Zohydro) or 24 h tablets (Hysingla)

• Adverse reactions: sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, hypogonadism, and headache.

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs.

• Dosage:

• Oral: Immediate-release: as hydrocodone-acetaminophen or hydrocodone-ibuprofen: 2.5–10 mg of hydrocodone component every 4 h as needed

  • Extended-release: 10 mg every 12 h using the ER capsules or 20 mg every 24 h using the ER tablets [1, 2].

Oxycodone

• Mechanism of action: Agonist activity at mu opioid receptors

• Contraindications: allergy to the medication or components, GI obstruction, paralytic ileus, and acute or severe asthma

• Dosage forms:

• Oral:

  • Immediate-release: capsules, tablets (OxyIR, Roxicodone), and solutions in 5 mg/5 ml and 100 mg/5 ml concentrations.

  • Extended-release: 12 h tablets (Oxycontin, Xtampza)

• Adverse reactions: sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, hypogonadism, and headache.

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs. Oxycodone is also a substrate of Cytochrome P450 3A4 (major). Serum concentrations and clinical effects may be altered when combined with inducers or inhibitors of this enzyme.

• Dosage:

• Oral: Immediate-release: 2.5–5 mg every 4 h as needed

  • Extended-release: 9 mg (Xtampza) or 10 mg (Oxycontin) every 12 h [1, 2].

Methadone

• Mechanism of action: Agonist at mu opioid receptors and antagonist at NMDA receptors.

• Contraindications: allergy to the medication or components, GI obstruction, paralytic ileus, or acute or severe asthma. Methadone is known to cause prolongation of the Q-T interval and it is recommended to avoid use of methadone in patients with a QTc greater than 500 milliseconds.

• Dosage forms:

  • Oral: tablets in 5, 10, (Dolophine) and 40 mg sizes (Methadose) and solutions in 5 mg/5 ml, 10 mg/5 ml (Dolophine), and 10 mg/ml (Methadone Intensol) concentrations

  • Injection: solution in a 10 mg/ml concentration

• Adverse reactions: sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, hypogonadism, headache, and prolonged Q-T interval.

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs. additive QT-prolongation and risk of Torsades de Pointes when combined with other medications that lead to a prolonged Q-T interval. Methadone is metabolized by various Cytochrome P450 isoenzymes including 2B6 (major), 3A4 (major) 2D6 (minor), 2C19 (minor), and 2D9 (minor). It is also a weak inhibitor of 2D6. Use along with various inducers or inhibitors of these enzymes may lead to changes in methadone serum concentrations and clinical effects.

• Dosage:

  • Oral: 2.5–5 mg every 8 h

  • IV/IM: 2.5 mg every 8 h

• Conversions : Oral to IV ratio of 2:1 [1, 2].

Fentanyl

• Mechanism of action: Agonist activity at mu opioid receptors

• Contraindications: allergy to the medication or components, GI obstruction, paralytic ileus, and acute or severe asthma

• Dosage forms:

• Buccal: Film (Onsolis), tablet (Fentora)

• Sublingual: Tablet (Abstral), Spray (Subsys)

• Transmucosal: Lozenge (Actiq)

• Transdermal: Patch (Duragesic, Ionsys)

• Injection: solution in a 50 mcg/ml concentration (Sublimaze)

• Intranasal: spray (Lazanda)

• Adverse reactions: sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, hypogonadism, and headache.

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs. Fentanyl is a substrate of Cytochrome P450 3A4 (major). Serum concentrations and clinical effects may be altered when combined with inducers or inhibitors of this enzyme.

• Dosage:

• IV/IM/SQ: 25–50 mcg every 30 min as needed

• Epidural: single dose of 25–100 mcg or continuous infusion beginning at 25–100 mcg/h

• Intrathecal: single dose of 5–25 mcg. Continuous infusion not recommended in acute pain

• Buccal (lozenge, film, or tablet) and sublingual spray: Initial dose of 100–200 mcg every 4 h as needed, may repeat x1 per episode. Not for use in opioid naïve patients

• Intranasal: Initial 100 mcg every 2 h as needed, may repeat x1 after 30 min per episode. Not for use in opioid naïve patients [1, 2].

Sufentanil

• Mechanism of action: Agonist activity at mu opioid receptors

• Contraindications: same as Fentanyl

• Dosage forms:

• Injection: solution in a 50 mcg/ml concentration (Sufenta)

• Adverse reactions: bradycardia, hypotension, nausea, vomiting, muscle rigidity, respiratory depression

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs. Sufentanil is a substrate of Cytochrome P450 3A4 (major). Serum concentrations and clinical effects may be altered when combined with inducers or inhibitors of this enzyme.

• Dosage:

• IV: Used for surgical anesthesia as incremental doses of 10–50 mcg or as a continuous infusion at a rate of 0.3–1 mcg/kg/h

• Epidural: intermittent doses of 10–15 mcg every 1 h [1, 2].

Remifentanil

• Mechanism of action: Agonist activity at mu opioid receptors

• Contraindications: same as Fentanyl

• Dosage forms:

• Injection: solution in a 1 mg/ml concentration (Ultiva)

• Adverse reactions: headache, hypotension, itching, nausea, vomiting, muscle rigidity, itching, respiratory depression

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs.

• Dosage:

• IV: Intermittent boluses of 0.5–1 mcg/kg every 2–5 min or continuous infusion in a range of 0.025 to 0.2 mcg/kg/min [1, 2].

Alfentanil

• Mechanism of action: Agonist activity at mu opioid receptors

• Contraindications: same as Fentanyl

• Dosage forms:

• Injection: solution in a 500mcg/ml concentration (Alfenta)

• Adverse reactions: headache, hypotension, itching, nausea, vomiting, muscle rigidity, itching, respiratory depression

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs. Alfentanil is a substrate of Cytochrome P450 3A4 (major). Serum concentrations and clinical effects may be altered when combined with inducers or inhibitors of this enzyme.

• Dosage:

• IV: Intermittent boluses of 3–15 mcg/kg every 5–20 min or continuous infusion in a range of 0.5–3 mcg/kg/min [1, 2].

Tapentadol

• Mechanism of action: Agonist activity at mu opioid receptors and also inhibits reuptake of norepinephrine.

• Contraindications: allergy to the medication or components, GI obstruction, paralytic ileus, acute or severe asthma, and use of MAO-inhibitors within the last 14 days

• Dosage forms:

• Oral:

  • Immediate-release: tablets (Nucynta)

  • Extended-release: 12 h tablets (Nucynta ER)

• Adverse reactions: sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, hiperhydrosis, and headache.

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs. There is also an increased risk of serotonin syndrome and seizures when combined with agents that modulate serotonin including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).

• Dosage:

• Oral: Immediate-release: 50–100 mg every 4 h as needed

  • Extended-release: 50 mg every 12 h [1, 2].

Tramadol

• Mechanism of action: Agonist activity at mu opioid receptors and also inhibits reuptake of serotonin and norepinephrine.

• Contraindications: allergy to the medication or components, GI obstruction, paralytic ileus, acute or severe asthma, and use of MAO-inhibitors within the last 14 days. May also increase the risk of seizures, especially when combined with other serotonin modulators.

• Dosage forms:

• Oral:

  • Immediate-release: tablets (Ultram)

  • Extended-release: 24 h tablets (Ultram ER) and 24 h capsules (Conzip)

• Adverse reactions: flushing, sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, headache, tremors, and seizures.

• Drug Interactions: additive CNS depression with CNS depressants, and increased risk of constipation with anticholinergic drugs. There is also an increased risk of serotonin syndrome and seizures when combined with agents that modulate serotonin including SSRIs, SNRIs, TCAs, and MAOIs. Tramadol is a substrate of Cytochrome P450 3A4 (major) and 2B6 (minor). Serum concentrations and clinical effects may be altered when combined with inducers or inhibitors of these enzymes.

• Dosage:

• Oral: Immediate-release: 25–100 mg every 4 h as needed

  • Extended-release: 100–150 mg every 24 h [1, 2].

Opioid Characteristics and Their Impact on Spinal Analgesia

The chemical properties of different opioids lead to different activities when given in the epidural and intrathecal spaces. The main property that alters these effects is solubility. Opioids may be divided into groups that are considered hydrophilic or lipophilic. Hydrophilic agents are drawn to fluid compartments while the lipophilic agents are more likely to partition into fatty membranes. The table below lists the relative partition coefficient between octanol and water for commonly used opioids (Table 52.1). Agents with a lower number are hydrophilic while agents with a higher number are lipophilic [4, 5].

Table 52.1 Relative partition coefficient for different opioids

Hydromorphone and morphine which are very hydrophilic drugs have a slower onset and longer duration of action due to more slowly diffusing through the epidural fat. Fentanyl and sufentanil have a more rapid onset and shorter duration of action due to crossing through the epidural fat more easily. The higher concentrations of lipophilic opioids in the epidural fat layer may also lead to more of the drug reaching the plasma and greater risk of systemic adverse effects compared to epidural administration of hydrophilic drugs [4, 5].

The behavior of these agents in the intrathecal space is affected by their solubility as well. Lipophilic drugs have limited rostral spread as they seek out lipid environments and are more quickly eliminated from the CSF. This leads to limited spread of lipophilic agents and activity is seen near the level of the catheter. Hydrophilic opioids such as morphine have a greater spread within the CSF which can lead to a risk of respiratory depression at the time of administration and for up to 24 h following a bolus dose [1, 4, 5].

High Yield Points

• Activation of mu opioid receptors leads to inhibition of pain signals from peripheral nerves, activating inhibitory descending pathways in the spinal cord, and alter central processing of signals.

• Adverse reactions are generally shared across this class of medications and include sedation, dizziness, nausea, delirium, dry mouth, constipation, itching, diaphoresis, and headache.

• Tapentadol and tramadol are agents with unique mechanisms of action including inhibiting reuptake of neurotransmitters.

• Solubility of opioids leads to different activities when administered in the epidural and intrathecal spaces.

Questions

• 1. A patient presents with chronic back pain not relieved by acetaminophen or an NSAID. An opioid appears to be the next step in his therapy. He has comorbid stage IV chronic kidney disease. Which of the following opioids would be the safest choice?

  • A. Morphine

  • B. Hydrocodone-acetaminophen

  • C. Codeine

  • D. Hydromorphone

  • Answer: D

• 2. A patient is taking fluconazole for prevention of fungal infections following a bone marrow transplant. Which of the following opioids would be least likely to interact with this medication?

  • A. Morphine

  • B. Fentanyl

  • C. Oxycodone

  • D. Tramadol

  • Answer: A

• 3. Which of the following adverse effects associated with opioids should resolve with regular use?

  • A. Delirium

  • B. Myoclonus

  • C. Constipation

  • D. Nausea

  • Answer: D