Methadone-Induced Neurotoxicity in Advanced Cancer: A Case Report

Introduction

Methadone is a potent synthetic analgesic that works as a mu opioid agonist and N-methyl-d-aspartate (NMDA) receptor antagonist. ¹ NMDA receptor antagonist activity is felt to be responsible for decreasing opioid tolerance and attenuating neuropathic pain.^2,3 The frequency of methadone use is increasing in hospice and palliative care as a second-line agent in the management of severe cancer-related pain. ⁴ It has a number of qualities that make its use favorable, including lack of known active metabolites, low cost, minimal accumulation in renal failure, long administration intervals, and availability, in the United States, by the oral, sublingual, rectal, and parenteral routes.^2,3,5

Methadone is highly lipophilic and protein bound to alpha-1-acid glycoprotein. Methadone has a high volume of distribution with ∼1% of the drug in free form in the blood. ⁶ It has an extensive reservoir as it accumulates in the tissues with repeat dosing. Both the volume of distribution and the strong affinity for alpha-1-acid glycoprotein contribute to the long plasma half-life with accumulation of the drug as a potential problem ⁶ leading to toxicity. It is metabolized by the liver to several inactive metabolites and excreted mainly through the fecal route.^2–4

Opioid-induced neurotoxicity (OIN) is a syndrome characterized by the neuroexcitatory effects of opioids, including hyperalgesia, agitated delirium, myoclonus, and/or seizures.^7,8 OIN has often been attributed to accumulation of renally excreted opioid glucuronides. Since methadone has no known active metabolites, it is not thought to be a typical cause of OIN. Methadone is often used in opioid rotation in patients who have exhibited signs of neurotoxicity from other opioid medications. There are a limited number of published reports in the literature on neurotoxicity associated with methadone.^2,4,9,10 In this article, the authors present a case in which a patient undergoing treatment of severe cancer-related pain with oral methadone developed OIN. In-depth details of the clinical situation and medication profile are presented.

Case Description

A 57-year-old male with bladder cancer metastatic to the lungs, bone, and soft tissue of the right pelvis was prescribed extended-release morphine and immediate-release oxycodone for his severe cancer-related pain. Due to poor pain control, his doses were adjusted until he was taking morphine extended release (ER) 150 mg PO Q8H and oxycodone 10 mg PO Q4H PRN for breakthrough pain. At this point, his morphine ER and oxycodone IR were discontinued due to loss of clinical benefit despite ongoing titration, and he was prescribed transdermal fentanyl 150 mcg/hour, hydromorphone 2–4 mg PO Q2H PRN, and gabapentin 300 mg PO TID. After one week, his transdermal fentanyl would not adhere properly; so it was discontinued and methadone 10 mg PO TID was prescribed. His hydromorphone was increased to 6 mg PO Q2H PRN for breakthrough pain.

Over the next month, his opioids were uptitrated frequently in an attempt to achieve adequate pain control. His methadone dose was escalated to 40 mg PO TID and hydromorphone was increased to 6–8 mg Q2H PRN for breakthrough pain. He reported little perceived benefit from the hydromorphone and use was inconsistent. At a clinic visit, five weeks after the initiation of methadone, he was noted to have mild myoclonus, but stated that he was not bothered by the symptom. Secondary to his inconsistent use of oral hydromorphone, the treating clinician considered the possibility that the myoclonus was due to methadone. This was discussed with the patient, but he did not want to change his long-acting opioid due to its analgesic effectiveness. A review of his medication profile was conducted and the patient was not found to be taking any confounding medications. One week later, the mild myoclonus continued and due to its inconsistent use and lack of benefit, the oral hydromorphone was discontinued.

Four weeks after the myoclonus was first noted, the patient sustained a fall at home with an exacerbation of his right hip pain. He was admitted to the hospital for pain control and evaluation of his fall. On admission, he was noted to have continued mild myoclonus. Laboratory studies at the time of admission were largely unremarkable with no metabolic disturbances demonstrated as a potential cause of the myoclonus. Kidney function was within normal limits. Given that his oral hydromorphone had been discontinued previously and he continued to have myoclonus, the physician felt that the methadone was the probable cause. The physician discussed this concern with the patient, but he did not want to make any changes to his methadone due to its helpfulness in his pain control. His methadone was continued at 40 mg PO TID and IV hydromorphone 0.5 mg IV Q2H was added to try to improve his pain.

After an inpatient palliative care consult, the patient shifted his goals of care to include a comfort-focused/hospice approach. Following this consultation and one week after his initial admission, he was transferred to an inpatient hospice and palliative care unit for further care. On day 1 of his admission to the unit, his methadone was increased from 40 to 50 mg PO TID for uncontrolled pain. His IV hydromorphone was also increased to 1 mg Q2H PRN for breakthrough pain and he was utilizing ∼8 mg of IV hydromorphone in a 24-hour period. He denied discomfort related to the myoclonus and was satisfied with his pain regimen. The physician counseled the patient on the concern of methadone-induced myoclonus and toxicity, but he did not want to change the regimen as he continued to have perceived benefit from the medication.

Unfortunately, the patient's pain continued to worsen over a period of four days with a substantial increase in the amount of PRN IV hydromorphone utilized. On day 5, he was started on a hydromorphone subcutaneous drip with a basal rate of 1.5 mg/hour with 2–4 mg IV Q30min nursing-administered boluses for uncontrolled breakthrough pain. His myoclonus was also noted to be increased and he subsequently developed delirium and hallucinations. Family was reluctant to change the methadone as they supported the patient's previous statements of perceived benefit. He was given one dose of diazepam 10 mg PO for moderate myoclonus with perceived benefit from the family. Haloperidol PRN was also initiated to treat the delirium and hallucinations. His hydromorphone SQ drip was increased over several days to a basal rate of 4.5 mg/hour. Secondary to increasing symptoms of OIN, the physician spoke with the family regarding the initial concern of methadone-induced neurotoxicity and recommended that the methadone dose be decreased in an attempt to control his symptoms of myoclonus and delirium/hallucinations. On day 13, his family agreed to decrease the methadone dose from 50 mg PO TID to 30 mg PO TID. The hydromorphone was increased to 6 mg/hour. On day 14 and within 24 hours after the methadone dose reduction, the myoclonus had reduced significantly and his hallucinations resolved. Hydromorphone dosing remained the same at 6 mg/hour with 2–4 mg IV Q30min nursing-administered boluses available utilizing ∼150 mg/24 hours.

The patient's global condition continued to deteriorate as he approached death. On day 18, the patient developed difficulty swallowing, which lead to all of his oral medications being discontinued, including the methadone. On day 21 and within 72 hours of the discontinuation of methadone, the patient's tremor and myoclonus resolved. He remained comfortable-appearing without overt signs of neurotoxicity despite continued use of high-dose hydromorphone (∼150 mg of IV hydromorphone daily) until his death.

Comment

While thought to be rare, the exact incidence of OIN is unknown. There are no clearly established clinical or research criteria to define this condition. Our observation is that clinicians use it to describe clinical scenarios in which patients exhibit a constellation of signs and symptoms attributed to the neuroexcitatory effects of opioids, including hyperalgesia, myoclonus, tremors, hyperactive delirium, and/or seizures. The mechanism of OIN is poorly understood, but widely hypothesized in the published literature to be due to the toxic accumulation of active glucuronide metabolites in patients on chronic morphine or hydromorphone therapy.^11–13 However, despite this hypothesis, myoclonus and OIN can occur with opioids such as methadone and fentanyl,^2,9,14 which do not have known active metabolites. This suggests that the metabolite hypothesis is incomplete or incorrect for opioids such as methadone and fentanyl.

Hypotheses for the mechanism of methadone-induced myoclonus include the activation of NMDA neuroexcitatory receptors and delta receptors.^15,16 One hypothesis is that the NMDA receptor antagonistic effects of methadone are overcome by its neuroexcitatory effects leading to myoclonus. ² This hypothesis has been developed by research demonstrating that morphine-3-glucoronide postsynaptically amplify the NMDA receptor-mediated glutamate responses. ¹⁷ Literature demonstrates that opioid-induced excitatory effects are attenuated by NMDA receptor antagonists. ¹⁸ Another hypothesis is that myoclonus may be mediated through the delta opioid receptor secondary to methadone's strong agonist affinity for the delta receptor. ² Research has shown delta receptor agonists cause myoclonus. ¹⁶ However, we note that several opioid analgesics with low affinity to the delta receptor are known to cause myoclonus. Higher doses of opioids may stimulate rather than inhibit the central nervous system. ¹⁹ This underlies another hypothesis that the neuroexcitatory effects of methadone may be dose related, leading to NMDA receptor-activated initiation of intracellular processes that cause neuronal plastic changes that ultimately result in hyperalgesia and possibly myoclonus. ² We observe that our patient developed myoclonus on relatively high methadone doses. In short, mechanisms of opioid-induced myoclonus are plural, and incompletely understood.

OIN can be mistaken for increasing restlessness from uncontrolled pain, delirium from other causes, or extrapyramidal phenomena. Therefore, a complete history, physical exam, and chart review are necessary to confirm it or rule it out. ²⁰ Often, the diagnosis of OIN is merely suspected and only becomes clear after a patient improves with opioid rotation or discontinuation. This case highlights the importance of a complete history to obtain the historical elements of opioid use. It is prudent to know the current opioids prescribed and how the patient is taking them as well as the dose, how has this dose been changed over the past few days/weeks, have other opioids been tried in the past, and to review the medication list to see if there are any potentially exacerbating drugs such as haloperidol or chlorpromazine.

While OIN can occur in any patient on chronic opioid therapy, in opioids with active metabolites, renal failure, dehydration, and electrolyte abnormalities are risk factors for it. Regardless the cause, early identification is important to developing effective treatment strategies aimed at treating the myoclonus and reducing the offending opioid. ²¹ Several treatment strategies, including hydration, for reducing the neurotoxic effects of opioids exist. First, if the myoclonus is mild, and the patient is not bothered by the symptom, it is reasonable to observe the patient.^8,21 Second, it may be reasonable to reduce the opioid dose to see if the symptoms resolve over the course of a few hours to days. ²¹ Nonopioids, such as corticosteroids, may allow for opioid dose reduction with preservation of analgesia. Third, opioid rotation to a lower dose of a structurally dissimilar opioid may be done with resolution over a course of hours to days. ²¹ Benzodiazepines may also be utilized to reduce myoclonus and antipsychotics to assist with delirium management.

It is important to remember that despite its lack of known active metabolites, methadone must remain on the differential diagnosis for a patient experiencing myoclonus. Several case reports have demonstrated this phenomenon, which will likely become increasingly more common as the use of methadone increases. Further research on methadone-induced neurotoxicity is needed.