Case Based for January

Teaching Case: An Escalating Agitation Syndrome with Misleading Clues

An 82-year-old woman with a history of chronic pain due to metastatic diffuse large B-cell lymphoma s/p radical neck and mouth dissection and G-tube placement presented to the ED with severe oral pain, nausea, worsening anxiety, and a profound sensation of “feeling toxic.” She lived alone and managed her medications independently. She reported taking multiple doses of hydrocodone/acetaminophen and diazepam over the preceding 24 hours. She was also maintained on a PRN Valium, hydrocodone and 125 mcg/hr fentanyl patch Q3 days, but instead of applying a new patch that morning, she had removed the old patch and moved it to a new location—a practice she used because she believed relocation to a location with more body fat was equivalent to replacement. She was a very low-body-weight patient, approximately 82 lbs, which heightened her sensitivity to rapid changes in opioid exposure.

On arrival, her blood pressure was 179/67, with otherwise stable vitals. She remained alert and oriented but was increasingly restless and unable to remain still. Her laboratory studies—including CBC, CMP, magnesium, phosphorus, EKG CK, troponin, and TSH—were all within normal limits, and urinalysis was unremarkable. Her urine drug screen was negative for opiates and benzodiazepines, despite her reported intake of Valium and Hydrocodone. This tox panel did not test for fentanyl.

Based on her symptoms and the interpretation that she may not have adequately taken her home medications, the initial working diagnosis was acute anxiety with poorly controlled pain. At 01:26 she received lorazepam 1 mg IV and morphine 2 mg IV. Shortly thereafter, she experienced a marked and abrupt deterioration: she became intensely agitated, thrashing in bed, gripping the rails, unable to sit still, and repeatedly describing the sensation of “jumping out of my skin.” Because this escalation occurred immediately after lorazepam, we grew concerned about a paradoxical benzodiazepine reaction, especially in the setting of a seemingly inconsistent medication history and a negative drug screen.

In response, we administered treatment appropriate for suspected paradoxical agitation. At approximately 02:00, she received diphenhydramine 25 mg IV. Between roughly 02:15 and 03:00, she received haloperidol 0.5 mg IV, then another 0.5 mg, and later 1 mg—a total of 2 mg—with no meaningful improvement. Around 03:30, after consultation with the pharmacist, she received olanzapine 10 mg, followed later by midazolam 1 mg IV ×2. Discussions again held with the pharmacist, reviewing potential interactions and toxicologic patterns, and we agreed the presentation was still most consistent with a paradoxical benzodiazepine response or medication-related delirium. Still, her complete lack of improvement was highly atypical.

During this period, we made repeated attempts to transfer her to a higher level of care, but no medical beds were available. I also consulted neurology, who felt her preserved orientation, normal imaging, and clinical trajectory were not consistent with seizure or stroke.

By early morning, the failure of multiple benzodiazepines, antipsychotics, antihistamines, and sedatives prompted us to reassess the foundational assumption that she was adequately opioid-covered at home. A closer review revealed that although she had taken hydrocodone and diazepam, she had not applied a new fentanyl patch—she had only relocated the old one. Given her low body weight and dependence on high-dose transdermal fentanyl, this meant she had likely been without meaningful long-acting opioid delivery for nearly 24 hours. At 07:29, we administered fentanyl 50 mcg IV.

Her response was immediate and striking: agitation subsided, thrashing resolved, and she became calm and able to rest. Mild myoclonus persisted, consistent with opioid-induced neurotoxicity, but the extreme restlessness and subjective distress abated within minutes. This confirmed the final diagnosis: severe opioid withdrawal with superimposed opioid-induced neurotoxicity, precipitated by inadequate fentanyl delivery and worsened by insufficient opioid replacement in the ED.

Discussion:
This case highlights how difficult it can be to interpret inconsistent toxicology, especially in older adults who self-manage multiple medications. The negative urine drug screen probably reflected limitations of the test—it did not include fentanyl, and standard immunoassays occasionally fail to detect hydrocodone and diazepam metabolites. However, alternative explanations must be considered. The patient lived alone and may have inadvertently taken something other than her prescribed hydrocodone or diazepam, believing it was the correct medication. Additionally, she was prescribed furosemide, which could have produced a dilute urine sample, reducing the detectability of substances even if she had taken them. This was felt to be unlikely as her urine specific gravity was 1.015.  Thus, the tox screen could have been falsely negative either because of technical limitations, dilution, or true non-ingestion.

The case also underscores the importance of recognizing that moving a fentanyl patch does not replace it, particularly in patients with minimal body fat and high opioid requirements. In this context, even a single missed replacement can precipitate profound withdrawal. When agitation fails to respond to usual sedatives—and especially when it worsens after benzodiazepines—clinicians must step back and reconsider the patient’s baseline opioid physiology. In this instance, the correct treatment was not escalating sedation but restoring adequate opioid levels.

Written by Babak Imanoel, D.O.

ERx Clinical Partners Physician at Dorminy Medical Center, Fitzgerald, GA

This is for informational purposes only. For medical advice or diagnosis, consult a physician