Hydromorphone


Article Author:
Karl Abi-Aad


Article Editor:
Armen Derian


Editors In Chief:
Rudolf Bickel
Abdolreza Saadabadi
Cornel Stanciu


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Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/23/2019 8:28:45 AM

Indications

Hydromorphone is a pure opioid indicated for moderate to severe acute pain, and severe chronic pain. It is only prescribed when other first-line of treatments have failed, due to its high potency, abuse potential, and overdose risk. Moreover, it can be prescribed off-label for refractory cough suppression.

Mechanism of Action

Hydromorphone is an opioid agonist that binds to several opioid receptors. Its analgesic effect is through its effect on the mu-opioid receptors. It also acts centrally at the level medulla, depressing the respiratory drive and suppressing cough.

Administration

Administration and dosing

Hydromorphone can be administered through intramuscular, intravenous, subcutaneous or oral routes.

Intramuscular, intravenous, or subcutaneous: injected at a concentration up to 10 mg/ml.

Oral: It can be taken with or without food in the immediate or extended-release form. The latter cannot be crushed, chewed, or dissolved, because it will void immediate release of the formulation [1].

Pharmacology

Immediate-release oral formulations have an onset of action at 15 to 30 minutes, peak at 30 to 60 minutes, and last 3 to 4 hours. Half-life is 2 to 3 hours.

Extended-release formulations have an onset of action at 6 hours, peak at 9 hours, and lasts 13 hours. Half-life is approximately 11 hours but varies between 8 to 15 hours.

The volume of distribution is 4 L/kg, where 8% to 19% of the drug is protein bound. Metabolism occurs in the liver through glucuronidation where most of it is converted to hydromorphone-3-glucuronide.

Excretion is mainly through urine in the glucuronidated form. The residual unchanged form is excreted in the urine (7%) and in the feces (1%).

The equivalence of hydromorphone to other opioid is presented below.

Availabilities

As seen above, oral tablets can be in the immediate release form (Dilaudid) and the extended-release form (Exalgo).

  • Dilaudid oral solutions have a dosage of 1 mg/1 ml, while oral tablets can be either 2 mg, 4 mg, or 8 mg.
  • The dosage of Exalgo oral tablets is either 8 mg, 12 mg, 16 mg, or 32  mg. This latter does not have an oral solution form.
  • Injection solutions can be found in the following concentrations: 1 mg/ml, 2 mg/ml, 4 mg/ml, and 10 mg/ml.
  • Intravenous solutions are available in the following formulations: 2 mg/1 ml, 2500 mg/250 ml, 10 mg/1 ml, 500 mg/50 ml.

Adverse Effects

Hydromorphone has potential adverse effects on several organ systems: the integumentary, gastrointestinal, neurologic, cardiovascular, endocrine and respiratory systems [2].

  • Common adverse effects include flushing, pruritus, sweating, dry mouth, nausea/vomiting, constipation, asthenia, dizziness, headache, and somnolence.
  • Serious adverse effects include hypotension, syncope, adrenal insufficiency, coma, raised intracranial pressure, seizure, suicidal thoughtsapnea, respiratory depression or respiratory arrestdrug dependence or drug withdrawal, and drug withdrawal syndrome in newborns [3].

Contraindications

Hydromorphone is contraindicated in patients reporting allergies to the drug itself, sulfites, or any other component of the formulation used.

It is not to be administered to patients with bronchial asthma, or any other form of a respiratory disease with clinical respiratory compromise. This can induce respiratory arrest. In terminal cancer patients, opioids are not to be restrained even when signs of respiratory depression are evident. [4]

Hydromorphone is to be avoided in any gastrointestinal obstruction or hypomotility, including ileus. Postoperative ileum should prompt careful administration of hydromorphone, to avoid prolonged ileus.

It is also to be avoided in genitourinary obstructions, central nervous system (CNS) depression, hypotension, and hypovolemia. It is to be carefully administered in cases of concomitant psychiatric illness.

United States Black Box Warning

Addiction, abuse, and misuse are all potential risks affecting hydromorphone users. Chronic users are to be regularly monitored with a clear plan for the duration of treatment. Patients who no longer require a chronic treatment should be weaned off the medication gradually, to avoid withdrawal symptoms.

Overdose and life-threatening respiratory depression can happen in cases of accidental ingestion or intended abuse. Concerning signs include confusion, dizziness, bluish lips and fingernails, cold skin, constricted pupils and weak blood pressure. In cases of overdoses suspicion, Naloxone (Narcan) is to given immediately in the intravenous, intramuscular, or subcutaneous form. The required dose is 0.4 mg to 2 mg every 2 to 3 minutes when needed, and not to exceed 0.001 mg/kg or 10 mg.

Neonatal withdrawal syndrome occurs in the neonates of women with chronic hydromorphone usage. For this purpose, prolonged treatment of hydromorphone is to be avoided during pregnancy. Whenever neonatal withdrawal syndrome is expected, adequate management should be available, which includes proper administration of Morphine to the neonate.

The risk of medication error is another potential harm, where the medical staff (doctor or nurse) provides the patient with a wrong formulation or the wrong dose. Proper medication check with institutional regulations is mandatory prior to opioid administration.

Monitoring

Drug interactions

Naltrexone and nalmefene are opioid receptor antagonists that can precipitate withdrawal symptoms when used along with hydromorphone, decreasing its analgesic effect.

The use of hydromorphone in patients taking safinamide (MAO inhibitor) can precipitate serotonin syndrome and is to be administered cautiously. It should also be administered carefully to patients taking selective serotonin inhibitors (SSRI) or tricyclic antidepressants (TCA) for this same reason.

Concurrent use of hydromorphone with other CNS depressants, including benzodiazepine and barbiturates can induce severe respiratory and/or CNS depression. For this purpose, the use of alternative analgesic agents is required.

Clinical Studies

In a meta-analysis by Bao et al. comparing the effect of hydromorphone to codeine and morphine, the authors analyzed data from 504 oncology patients. There was no significant difference between the three groups, regarding safety profile and effectiveness of the drugs. Likewise, in the EXHEAL trial, Inoue et al. compared the effect of extended-release hydromorphone to extended-release oxycodone in the cancer patient. The efficacy of both drugs was equivalent, with similar adverse event rates.

Moreover, hydromorphone pumps have been studied in intrathecal administration with patient control. Hayek et al. reported their retrospective analysis of 57 patients with the post-laminectomy syndrome, treated with patient-controlled intrathecal hydromorphone and bupivacaine, and presented the data over 24 months [5]. There was a clear decrease in the average pain score with a gradual increase in the hydromorphone dose (up to 487 mcg/day). The complication report was less promising than the decreased pain scores. Fifty-one percent of patients required a pump program, and there was a 5.8% infection rate. Further studies are required to evaluate the efficiency and safety of patient-controlled intrathecal hydromorphone pumps.

Toxicity

Hydromorphone is a rapid-acting potent opioid used in acute and chronic pain. It is interchangeable with other opioids and has a specific conversion scale. Hydromorphone is available in multiple forms including injection and oral forms, immediate release and extended release forms [6]. The risk profile of this drug requires careful prescription and administration, with diligent knowledge of the potential harms and interactions.

Threatening life events are to be managed promptly as the respiratory depression it causes in overdose may lead to death. Finally, hydromorphone is being studied in intrathecal pumps, which has a promising role in refractory pain.

Enhancing Healthcare Team Outcomes

The prescription of hydromorphone requires a multidisciplinary team that consists of the primary physician (e.g. oncologist), a pain specialist, the nurses involved in the care of the patient, and a pharmacist. All parties must agree on the prescription and dosage of the medication as well as recognize the potential harms of this medication. At any moment team members must be able to identify signs of hydromorphone toxicity and administer treatment promptly. In the event of medication dependance event when no longer indicated, a psychologist must be consulted as hydromorphone addiction is serious and may lead to overdoses and potentially death. Hydromorphone overdose will require a toxicologist and nephrologist on board as the need for treatment strategies additional to Naloxone may be needed, depending on serum and urine drug levels as well as symptomatic presentation. The intensive care unit should also be involved as toxicity management also requires to ensure hemodynamic stability and adequate respiratory response. 


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Hydromorphone - Questions

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In which drug class is hydromorphone correctly placed?



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Which of the following drugs can be administered safely with hydromorphone?



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Which of the following is not a contraindication to hydromorphone?



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Which of the following is true regarding long-acting oral hydromorphone?



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A 42-year-old patient complaining of back pain radiating to his left leg, refractory to spinal decompression and NSAIDs presents to the clinic for follow-up. He reports that his pain is constant and 9/10. Which of the following medications would is most appropriate for the long-term management of his pain?



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A 50-year-old female with severe cervical radiculopathy is maintained on low-dose hydromorphone. The patient is known to have diabetes, coronary artery disease, hepatitis B with liver cirrhosis, and a history of a transient ischemic attack. Which of the following is the most appropriate rationale for maintaining the patient on low-dose hydromorphone?



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A patient presented to the emergency department with severe flank pain and was found to have a right kidney stone impacted in the ureter. The patient is on lisinopril, bisoprolol, and omeprazole. The pain specialist recommends against prescribing hydromorphone. Treatment with which of the following medications is a contraindication for opioid prescription?



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A 68-year-old patient is failing extubation after a colectomy procedure for complicated diverticulitis. The patient is maintained on hydromorphone for pain management. Through what mechanism is hydromorphone contributing to the failure of extubation?



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A 62-year-old male arrives at the emergency department with confusion, bluish lips, constricted pupils, and depressed respiratory drive. Upon medical history inquiry, his wife reports that the patient is severely depressed and maintained on hydromorphone for chronic radiculopathy. Which of the following is the next best step in the management of this patient?



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Hydromorphone - References

References

Hydromorphone for cancer pain., Bao YJ,Hou W,Kong XY,Yang L,Xia J,Hua BJ,Knaggs R,, The Cochrane database of systematic reviews, 2016 Oct 11     [PubMed]
A randomized, double-blind study of hydromorphone hydrochloride extended-release tablets versus oxycodone hydrochloride extended-release tablets for cancer pain: efficacy and safety in Japanese cancer patients (EXHEAL: a Phase III study of EXtended-release HydromorphonE for cAncer pain reLief)., Inoue S,Saito Y,Tsuneto S,Aruga E,Ide A,Kakurai Y,, Journal of pain research, 2017     [PubMed]
Intrathecal Hydromorphone and Bupivacaine Combination Therapy for Post-Laminectomy Syndrome Optimized with Patient-Activated Bolus Device., Hayek SM,Veizi E,Hanes M,, Pain medicine (Malden, Mass.), 2016 Mar     [PubMed]
Pharmacodynamics of orally administered sustained- release hydromorphone in humans., Angst MS,Drover DR,Lötsch J,Ramaswamy B,Naidu S,Wada DR,Stanski DR,, Anesthesiology, 2001 Jan     [PubMed]
The effect of opioid therapy on endocrine function., Brennan MJ,, The American journal of medicine, 2013 Mar     [PubMed]
The opioid dependent mother and newborn- an update. The 6th Annual Ivey Symposium., Abrahams R,Chase C,Desmoulin J,Kahan M,Knoppert D,Koren G,Lyons L,Ordean A,Roukema H,Uddin F,, Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharamcologie clinique, 2012     [PubMed]

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