Background   Common opioid side effects (constipation, nausea, pruritus, and urinary retention) are well-recognized by clinical teams.  Less well appreciated are the neuroexcitatory effects, commonly seen among patients on chronic opioids.  Among these, myoclonus is the typical herald symptom.  This Fast Fact will discuss risk factors and patient assessment of the neuroexcitatory opioid side effects, particularly myoclonus. Fast Fact #58 will discuss treatment options. 

Physiology and risk factors    Myoclonus can occur in patients on chronic therapy with most opioids including morphine, hydromorphone, fentanyl, meperidine, and sufentanil.  Higher doses more frequently result in myoclonus, but the dose relationship is variable.  Myoclonus can occur with all routes of administration.  Current research implicates the 3-glucuronide opioid metabolites as one likely cause of neuroexcitatory side effects. The symptoms may not develop until a neurotoxic threshold is surpassed, although current understanding is limited.  Co-morbid factors for neurotoxicity include renal failure, electrolyte disturbances, and dehydration. 

Clinical scenarios    Myoclonus – the uncontrollable twitching and jerking of muscles or muscle groups – usually occurs in the extremities, starting with occasional random jerking movement.  A patient’s family member may be the first to recognize this symptom. With continued opioid administration, the jerking may increase in frequency. At the extreme, there is constant jerking of random muscle groups in all extremities. As myoclonus worsens, patients may develop other neuroexcitatory signs: hyperalgesia (increased sensitivity to noxious stimuli), delirium with hallucinations, and eventually grand mal seizures.  Well-meaning clinicians may misinterpret the hyperalgesia as increasing pain, leading to a vicious cycle of increasing dose, increasing hyperalgesia, increasing dose, worsening delirium, and finally seizures. After identifying a patient with possible opioid toxicity, the clinician should complete a chart review and physical examination. 

Chart review and history 

• Review recent laboratory studies if available.  Check renal and liver function, magnesium levels, glucose, and/or sodium. 
• Review the recently documented opioid analgesic history.  What is the current drug and dose?  How has the dose changed over the past few days and weeks? 
• Review the medication list for potentially exacerbating drugs with a clinical pharmacist. For example, CYP3A4 inducers/inhibitors may alter opioid bioavailability.   
• Evaluate onset and evolution of the neurotoxic symptom burden. 

Physical Examination 

• Assess frequency of myoclonic jerks.  Stand at the bedside and observe a patient for 30-60 seconds.  Watch for and count the number of uncontrolled jerking movements. 

• Determine if there is evidence of a new or worsening delirium.  Complete a bedside mini-mental assessment. 
• Assess hydration status. 
• Estimate prognosis: hours, days, weeks, months or years?  A longer prognosis demands a more definitive change in treatment. 

For other applications of the role of neurotoxicity in serious illness care, see Fast Fact #161, Fast Fact #188, and Fast Fact #392.   

References: 

1. Cherny N, Ripamonti C, Pereira J, et al.   Strategies to manage the adverse effects of oral morphine:  an evidence based report.  J Clin Oncol.  2001; 19:2542-2554. 
2. Mercadante S.  Pathophysiology and treatment of opioid-related myoclonus in cancer patients.  Pain. 1998; 74:5-9. 
3. Smith M.  Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.  Clinical and Experimental Pharmacology and Physiology. 2000; 27:524-528. 
4. Paramanandam G, Prommer E, Schwenke DC. Adverse Effects in Hospice Patients with Chronic Kidney Disease Receiving Hydromorphone Journal of Palliative Medicine. September 2011, 14(9): 1029-1033. 
5. Wright A, Mather L, Smith M.  Hydromorphone-3-glucuronide, a more potent neuro-excitant than its structural analogue morphine-3-glucuronide.  Life Sciences. 2001; 69:409-420. 
6. Godwin B, Frank C, Molnar F, et al. Identification and management of opioid-induced neurotoxicity in older adults. Can Fam Physician. 2022 Apr;68(4):269-270. 

Version History: originally edited by David E Weissman MD.    2nd Edition published July 2006; 3rd Edition May 2015; 4th Edition February 2024 after being reviewed and revised by Ryan Jozwiak MD. 
Conflicts of Interest: None to report