Hydromorphone

Article Author:
Karl Abi-Aad
Article Editor:
Armen Derian
Updated:
9/10/2019 10:13:55 PM
PubMed Link:
Hydromorphone

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 characteristics are 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 administration can be through intramuscular, intravenous, subcutaneous, or oral routes.

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

Oral: Patients can take it orally 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 converts to hydromorphone-3-glucuronide.

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

The equivalence of hydromorphone to other opioids will follow later.

Availabilities

As seen above, oral tablets can be in the immediate release form and an extended-release form.

  • Immediate-release 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 extended-release 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.

Clinicians should not administer this drug to patients with bronchial asthma, or any other form of respiratory disease with clinical respiratory compromise; this can induce respiratory arrest. In terminal cancer patients, clinicians should not restrain opioid therapy 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 prevent prolonged ileus.

Hydromorphone should also to be avoided in genitourinary obstructions, central nervous system (CNS) depression, hypotension, and hypovolemia. It requires careful administration in cases of concomitant psychiatric illness.

United States Black Box Warning

Addiction, abuse, and misuse are all potential risks affecting hydromorphone users. Chronic users require regular monitoring with a clear plan for the duration of treatment. Patients who no longer need 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 a suspected overdose, naloxone is the immediate therapeutic response 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 a possibility, 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 before 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 necessitates caution in dosing. It also requires careful administration for 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 necessary.

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 the 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 the object of research for 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 distinct 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 necessary 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 thorough 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 a target of research 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 have involvement, as toxicity management is also necessary to ensure hemodynamic stability and adequate respiratory response.

Nursing will have the best opportunity to monitor for adverse effects and toxicity, which with a powerful opioid such as hydromorphone is crucial, and any concerns must be reported to the physician promptly. Pharmacy needs to be involved from start to finish in all aspects of hydromorphone therapy, regardless of the mode of administration, to verify dosing, perform medication reconciliation to prevent drug-drug interactions, and assist the physician with switching to another agent or weaning the patient off. Given the current opioid crisis, pharmacist involvement is more important than ever, working closely with nursing and the physicians. Opioid pain control requires the full collaboriation of the entire interprofessional healthcare team to ensure adequate pain control and patient safety. [Level V]


References

[1] 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 PMID: 11135723]
[2] The effect of opioid therapy on endocrine function., Brennan MJ,, The American journal of medicine, 2013 Mar     [PubMed PMID: 23414717]
[3] 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 PMID: 22408113]
[4] 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 PMID: 27727452]
[5] 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 PMID: 26814257]
[6] 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 PMID: 28860850]