Background    Fast Fact #57 reviewed the pharmacology and patient assessment aspects of opioid induced neurotoxicity, notably myoclonus. This Fast Fact discusses treatment. 

General Approach    Decisions about the most appropriate treatment approach need to consider features of the physical examination (the frequency and intensity of symptoms, hydration status, and estimated prognosis) and information from the medical record (temporal pattern of opioid use and dose escalation, other medications, the presence of electrolyte abnormalities and major organ dysfunction). Whenever medically appropriate, easily treatable causes or exacerbating factors should be corrected (e.g., correct hypomagnesemia).   

Treatment Strategies    The treatment of opioid-induced neurotoxicity can be challenging, as the patient undergoing this side effect is likely continuing to experience disease-specific pain. As such, the management of pain and direct opioid neurotoxic effects is divided into strategies to treat the myoclonus and strategies to reduce the offending opioid. 

1. Observation.   Mild myoclonus may trouble family members more than the patient.  If the patient is satisfied with current therapy, explaining the cause/progression of symptoms may be all that is necessary. This may be a preferred approach for patients who are imminently dying (e.g., prognosis of hours to short days) wherein changes to medications may risk unnecessary symptom distress immediately prior to death. 
2. Hydration. If dehydration is a potential precipitating factor of neurotoxicity, a trial of parenteral hydration (either IV or via subcutaneous infusion) may help shorten the duration and reduce the severity of symptoms. 
3. Opioid dose reduction.   Seeing that some observational studies suggest that neuroexcitatory symptoms from opioids may not develop until a certain neuroexcitatory threshold of 3-glucoronide metabolites is surpassed, myoclonus may resolve over a few days with a decrease in opioid dose.  However, make sure you are not reducing the opioid dose solely to control myoclonus at the expense of good pain control.   
4. Rotate to a dissimilar opioid.   Rotating to a lower dosage of a structurally dissimilar opioid will often reduce myoclonus and other neuroexcitatory effects within 24 hours, while achieving comparable pain control (Fast Fact #175 discusses opioid structural classes.)  Rotation is especially important in patients with opioid-induced hyperalgesia.   As a rule, decrease the morphine equianalgesic dose by at least 50% when switching to a new medication (see Fast Fact # 36).  For patients on very high doses, rotate to a new opioid at 25% of the morphine equianalgesic dose.  Historically, methadone and fentanyl have been better opioids to rotate to as they have no active metabolites (which are implicated in the neuroexcitatory effects of other opioids).  This observation is empiric, and has not been evaluated in clinical trials; clinicians should be cautious of using methadone without familiarity with its pharmacology (see Fast Fact #75 and Fast Fact #86).    
5. Adjuvant and other analgesic therapy.   Adjuvant analgesics (e.g. ketamine, anticonvulsants, antidepressants, corticosteroids) or non-drug therapies (e.g. acupuncture, TENS, heat, cold) may allow for opioid reduction, with preservation of analgesia. 
6. Benzodiazepines and other drugs to reduce myoclonus.   The addition of a benzodiazepine can reduce myoclonus without alteration of the opioid dose, although increasing sedation may be an unwanted side effect.  Start with clonazepam 0.5-1 mg at night or 0.5 mg 2-3 times a day.  Alternative agents include lorazepam orally or sublingually, starting at 1-2 mg q8 hours.  A continuous infusion of midazolam is an expensive but effective option.  Alternatives to benzodiazepines include baclofen, gabapentin, and nifedipine.  Start baclofen at 5 mg 3 times a day and increase as needed/tolerated to 20 mg 3 times a day.  Start gabapentin at 100 mg 3 times a day and increase as needed to 900-3600 mg total a day.  Nifedipine (10 mg 3 times a day) can also be used. 
7. Haloperidol to palliative delirium and hallucinations. For patients experiencing agitated delirium, haloperidol can be considered at doses of 1-2 mg oral/IV/subcutaneous every 4 hours as needed. 

Bottom-line:  Keep in mind that there may not be a “best” treatment method in the setting of opioid-induced neurotoxicity. Treatments may require an escalation of care, rotation away from common palliative medications, and/or invasive work-ups/treatments. Therefore, it is paramount to continue active goal of care discussions to ensure that an individualized care plan is achieved that remains in line with the patient’s wishes.  

References 

1. Abrahm J.  Advances in pain management for older adult patients.  Clinics in Geriatric Medicine. 2000; 16:269-311. 
2. 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. 
3. Ferris D.  Controlling myoclonus after high-dosage morphine infusions. American Journal of Health-System Pharmacy. 1999; 56:1009-1010. 
4. Hagen N, Swanson R.  Strychinine-like multifocal myoclonus and seizures in extremely high-dose opioid administration:  treatment strategies. J Pain Symptom Manage. 1997; 14:51-57. 
5. Mercadante S.  Pathophysiology and treatment of opioid-related myoclonus in cancer patients.  Pain. 1998; 74:5-9. 
6. 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.
7. Mercadante S.  Gabapentin for opioid-related myoclonus in cancer patients. Support Care Cancer. 2001; 9:205-206. 
8. Watanabe S.  Methadone: the renaissance.  J Pall Care. 2001; 17:117-120. 
9. Mercadante, Sebastiano. “Opioid-induced Neurotoxicity in patients with cancer pain.” Current Treatment Options in Oncology 2023; 24.10:1367-1377. 

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