1. Mike, Leigh Ann PharmD

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Q: I recently cared for a patient with severe myoclonus, which improved after we changed his treatment regimen from morphine to hydromorphone. Any information you have regarding causes and treatments of this very disturbing symptom would be greatly appreciated.


A: Opioids are a mainstay in the management of moderate to severe malignant pain.1 In recent years, there has been a change in the pattern of opioid use because of increased availability and better medical education. Opioids are now being used at higher doses and earlier in the course of the disease process, which allows enhanced pain control, and has led to the recognition of neurotoxicity as a major adverse effect of opioids.2


Commonly recognized adverse effects of opioids include sedation, nausea, constipation, respiratory depression, and urinary retention. More recently, a syndrome of neurotoxicity, also called opioid-induced neurotoxicity (OIN), has been described in the literature.2-4 The exact mechanism of OIN has not been fully elucidated. It is postulated that metabolites of opioids (eg, morphine-3-glucuronide, normeperidine) contribute to the development of this syndrome.5


Clinical Presentation of OIN

Patients who develop OIN may present with one or more of the following symptoms: cognitive impairment, severe sedation, hallucinations, delirium, myoclonus, seizures, and hyperalgesia. In some cases, these symptoms may be indistinguishable from disease progression or inadequate analgesic control and often lead to further escalation in opioid dose. This creates a vicious cycle that may further worsen adverse effects.


The occurrence of OIN is dependent on both the dose and duration of opioid therapy. Other precipitating factors include underlying delirium, dehydration, acute renal failure, advanced age, and use of psychoactive medications (eg, benzodiazepines, tricyclic antidepressants).


Management Options for OIN

Before diagnosing a patient with OIN, other potential causes of neurotoxicity, such as brain metastases, infection, dehydration, metabolic abnormalities, and hypoxia should be ruled out. Drugs other than opioids can precipitate symptoms that mimic OIN, and their contribution to a patient's presentation should also be evaluated.2-4


Options for managing acute OIN include dose reduction, opioid rotation, hydration, and the use of adjunctive medications.1


Dose Reduction

Dose reduction has been reported as a strategy for managing OIN and can be a practical solution, for example, in a patient who is experiencing delirium or hallucinations, with adequate pain control. However, because maintaining a balance between adequate analgesia and drug toxicity can be challenging, this management strategy may not be an option for patients with uncontrolled pain. Should this be the case, consider switching to an equivalent dose of another opioid.


Opioid Rotation

It appears that OIN is not a class effect; therefore, switching a patient to an equivalent dose of another opioid may alleviate symptoms.6 For example, if the patient is currently taking morphine, a reasonable alternative is oxycodone or hydromorphone. If OIN persists or develops again, switching to methadone or parenteral fentanyl can be considered.



The active metabolites of morphine are water-soluble and can accumulate in older adults, or patients with acute renal failure or volume depletion.5 Ensuring that patients are adequately hydrated may decrease the severity and duration of OIN. For patients in which hydration is not an option, dose reduction or opioid rotation may be necessary.


Adjunctive Medications

Psychostimulants (eg, methylphenidate, dextroamphetamine) have multiple effects when used as adjuncts for pain management.2-4 They counteract opioid-related sedation and cognitive dysfunction and can potentiate analgesia. Because these drugs may cause hallucinations, delirium, or psychosis, avoid use in patients with these manifestations of OIN.


Antipsychotics (eg, haloperidol, risperidone) may have a role in the symptomatic management of hallucinations and agitated delirium.2-4 However, they should be used only to manage symptoms while other management options (eg, dose reduction, opioid rotation, hydration) are being instituted.



Although opioid analgesics have significant therapeutic value in managing patients in the hospice and palliative setting, their use is associated with severe side effects, including OIN. While the incidence and mechanism of OIN require further investigation, clinicians should closely monitor the patients for the clinical symptoms associated with OIN. Currently, evidence-based management guidelines have yet to be established. Clinicians must exercise good judgment and balance the risks and benefits of each strategy to maximize patient's comfort while minimizing treatment-induced adverse events.


Leigh Ann Mike, PharmD


is a clinical pharmacist at the University of Washington, Harborview Medical Center.




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