Hydromorphone - Drug Monograph

Introduction

Hydromorphone hydrochloride is a potent semi-synthetic opioid analgesic derived from morphine. First synthesized in the 1920s, it is approximately 5-7 times more potent than morphine and is classified as a Schedule II controlled substance in the United States due to its high abuse potential. Hydromorphone is widely used in clinical practice for the management of moderate to severe acute and chronic pain.

Mechanism of Action

Hydromorphone exerts its analgesic effects primarily through agonist activity at mu-opioid receptors in the central nervous system. Like other opioid agonists, it binds to specific opioid receptors in the brain, spinal cord, and peripheral tissues, resulting in:

• Inhibition of nociceptive neurotransmission
• Alteration of pain perception
• Increased pain threshold
• Modulation of emotional responses to pain

The drug also produces effects on kappa and delta opioid receptors, though with lower affinity compared to mu receptors.

Indications

FDA-approved indications include:

• Management of acute pain severe enough to require an opioid analgesic
• Management of chronic pain severe enough to require a daily, around-the-clock opioid analgesic
• Alternative to morphine for patients who cannot tolerate morphine's side effects

Off-label uses may include:

• Patient-controlled analgesia (PCA) in postoperative settings
• Cancer-related pain management
• Palliative care and hospice pain management

Dosage and Administration

• Initial adult dose: 2-4 mg orally every 4-6 hours as needed
• Opioid-naïve patients: Start with lower end of dosing range

• For opioid-tolerant patients only
• Dosing individualized based on prior opioid exposure

• IV: 0.2-0.6 mg every 2-3 hours as needed
• IM/SubQ: 0.8-1 mg every 3-4 hours as needed

• Renal impairment: Reduce dose by 25-50% for CrCl <60 mL/min
• Hepatic impairment: Use caution and consider dose reduction
• Elderly: Start with lower doses due to increased sensitivity
• Pediatric: Safety and efficacy not established for children

Pharmacokinetics

• Oral bioavailability: 25-50%
• Tmax: 1-1.5 hours (immediate-release)
• Food does not significantly affect absorption

• Volume of distribution: 2-3 L/kg
• Protein binding: 8-19%
• Crosses placenta and blood-brain barrier

• Primarily hepatic via glucuronidation to hydromorphone-3-glucuronide (inactive)
• Minor pathways include reduction to dihydromorphine
• CYP450 system plays minimal role

• Half-life: 2-3 hours
• Excretion: Primarily renal (75%), with fecal elimination accounting for remainder
• Dialysis: Not effectively removed

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma
• Known or suspected gastrointestinal obstruction
• Hypersensitivity to hydromorphone or other morphine analogs
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapy

Warnings and Precautions

• Risk of respiratory depression, especially with initiation and dose increases
• Risk of life-threatening respiratory depression in children with obstructive sleep apnea
• Potential for abuse, addiction, and diversion
• Neonatal opioid withdrawal syndrome with prolonged use during pregnancy

• Increased risk of overdose in opioid-naïve patients
• Risk of adrenal insufficiency with long-term use
• Potential for severe hypotension in volume-depleted patients
• Risk of seizures in patients with seizure disorders
• Caution in patients with head injury or increased intracranial pressure
• Risk of serotonin syndrome when used with other serotonergic drugs

Drug Interactions

• CNS depressants (benzodiazepines, alcohol, barbiturates): Additive CNS depression
• MAOIs: Risk of serotonin syndrome and exaggerated opioid effects
• Mixed agonist/antagonist opioids (pentazocine, nalbuphine): May reduce analgesic effect
• Anticholinergic drugs: Increased risk of urinary retention and constipation

• Serotonergic drugs: Increased risk of serotonin syndrome
• Diuretics: Reduced efficacy due to release of antidiuretic hormone
• CYP3A4 inhibitors/inducers: Minimal effect due to non-CYP metabolism

Adverse Effects

• Nausea and vomiting
• Constipation
• Sedation/drowsiness
• Pruritus
• Sweating

• Dizziness
• Dry mouth
• Headache
• Flushing
• Urinary retention

• Respiratory depression
• Hypotension
• Bradycardia
• Anaphylaxis
• Adrenal insufficiency
• Serotonin syndrome
• Seizures

Monitoring Parameters

• Pain assessment using validated scale
• Respiratory rate and pattern
• Blood pressure and heart rate
• Renal and hepatic function
• Risk assessment for substance use disorder

• Pain control efficacy (regular assessment)
• Respiratory status (especially during initiation and titration)
• Sedation level
• Bowel function (constipation management)
• Signs of misuse, abuse, or addiction
• Psychological and physical dependence assessment
• Adrenal function with long-term use

• Complete blood count
• Comprehensive metabolic panel
• Opioid treatment agreement compliance
• Safe storage and disposal practices

Patient Education

• Proper dosing and administration instructions
• Never exceed prescribed dose or frequency
• Risk of respiratory depression, especially with other CNS depressants
• Importance of not sharing medication with others
• Safe storage away from children and others
• Proper disposal of unused medication

• Constipation prevention strategies (increased fluids, fiber, stool softeners)
• How to manage nausea (may decrease with continued use)
• Avoiding alcohol and other sedating substances
• Not driving or operating machinery until effects are known

• Difficulty breathing or shallow breathing
• Extreme drowsiness or confusion
• Chest pain or palpitations
• Severe constipation or abdominal pain
• Signs of allergic reaction
• Thoughts of self-harm or suicide

• Pregnancy and breastfeeding considerations
• Elderly patients: Increased sensitivity to effects
• Importance of informing all healthcare providers about opioid use

References

1. American Pain Society. (2016). Guidelines on the Management of Postoperative Pain. 2. FDA Prescribing Information: Dilaudid (hydromorphone hydrochloride). (2022). 3. Trescot AM, Datta S, Lee M, Hansen H. (2008). Opioid pharmacology. Pain Physician. 4. Benyamin R, Trescot AM, Datta S, et al. (2008). Opioid complications and side effects. Pain Physician. 5. Dowling J. (2018). Pharmacogenetics of opioids. Clinical Pharmacology & Therapeutics. 6. National Comprehensive Cancer Network. (2023). Adult Cancer Pain Guidelines. 7. Webster LR, Fine PG. (2012). Review and critique of opioid rotation practices and associated risks of toxicity. Pain Medicine. 8. Chou R, Fanciullo GJ, Fine PG, et al. (2009). Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. The Journal of Pain.