Fosaprepitant for the Management of Refractory Pain in a Patient with Cancer-Related Dermatomyositis

Abstract

Objective:

Optimal pain management often requires multiple pharmacological interventions with the goal of disrupting the pain-signaling pathway and targeting the underlying pathophysiology. Off label use of nonpain medications may have a role in treating refractory pain syndromes.

Background:

We report a case of a 60-year-old female with refractory nociceptive and neuropathic pain. Conventional therapies were either ineffective or fraught with side effects. Given the underlying inflammatory nature of her pain syndrome, and the role of substance P (SP) in pain transmission and modulation, we decided to use fosaprepitant, an SP and neurokinin-1 (NK1) receptor antagonist. The patient tolerated fosaprepitant and experienced acceptable analgesia without compromising her mental functioning.

Design:

Study and analysis of a case of a patient with refractory mixed, nociceptive, and neuropathic pain syndrome treated with fosaprepitant.

Results and Discussion:

Fosaprepitant is a potentially novel adjuvant therapy for the treatment of refractory inflammatory pain syndromes in palliative care.

Introduction

While opioids are the mainstay of treatment for severe pain in patients with a serious illness, adjuvant therapies may reduce opioid requirements or augment the patient's response by targeting alternative aspects of the pain signaling pathways, including the role of inflammatory mediators. Substance P (SP) is a well-studied inflammatory mediator that plays a role in both pain and inflammation¹ through its binding to the tachykinin neurokinin-1 (NK1) receptor, often referred to simply as the NK1 receptor (Fig. 1).

FIG. 1.

The role of substance P (SP) in the neurotransmission of pain in the dorsal horn and its modulation by opioid receptors. Both SP (NK1) and glutamate are involved as excitatory neurotransmitters in the neurotransmission of pain in the dorsal column. Opioids can exert both presynaptic and postsynaptic effects to block neurotransmission of pain signals by actions mediated by delta, kappa, and mu receptors. There is evidence that opioids can exert analgesic effects by additional peripheral and central mechanisms as well.¹⁰ Fosaprepitant selectively antagonizes NK1 receptors, thereby blocking SP activation of pain pathways with synergistic augmentation of opioid blockade. NK1, neurokinin-1. Adapted from Schumacher et al.¹⁰

Fosaprepitant selectively antagonizes NK1 receptors. The drug has been extensively studied in and approved for chemotherapy-induced nausea and vomiting. Its use is often restricted to oncology services given FDA indications for use in combination with its expense: a 150 mg injection of fosaprepitant costs ∼$350; the oral suspension form is similar in cost.

There is evidence demonstrating reversal of heat, cold, and mechanical hypersensitivity with NK1 antagonists.² Murine studies³ and research in the sickle cell disease population suggest a role for fosaprepitant in treating nociceptive and neuropathic pain, as well as anticipatory pain.^4,5 In the case that follows, we describe the use of fosaprepitant for pain management in a patient with dermatomyositis with escalating opioid requirements and adverse effects associated with typically used pain management strategies.

Case

FG was a 60-year-old female with extensive dermatomyositis secondary to ovarian cancer: her proximal muscle weakness confined her to bed. She was admitted from clinic with increasing weakness and left-upper extremity swelling. She noted a more severe rash on her chest and arms over the prior two months as well as a three-week history of new, painful sores draining “pus” in her axilla, elbows, legs, and buttocks. Her chronic, nonhealing, open abdominal wall wound from her hysterectomy was stable. Her wounds and skin desquamation necessitated frequent wound care. The patient was unable to tolerate wound care or restorative therapies because of pain. Given FG's presentation and clinical picture, she was admitted to the medicine service for presumed myositis flare: extensive work-up and therapy to include rheumatological and wound-care consults were initiated. She received prednisone, intravenous (IV) immune globulin, methotrexate, and azathioprine.

One month after admission, palliative care was consulted to assist with symptom management. Over the course of her admission, her rash and weakness worsened, she developed more open lesions on her thighs and arms and her pain escalated. She wished to pursue aggressive life-sustaining therapies, yet her pain prohibited interventions. At the time of the initial palliative care evaluation, she was taking 300 oral morphine equivalents (OME) a day in the form of oxycodone immediate and extended release formulations and IV hydromorphone without relief. With parenteral opioids and higher dose oral opioids, she became delirious and agitated. FG's pain prevented wound care, physical therapy, and occupational therapy. As a further complication, she developed oropharyngeal weakness and odynophagia requiring a nasogastric tube for nutrition and medication, thereby limiting use of oral long-acting opioids, including methadone as her QTc was prolonged at 476 ms. Given her symptom burden and adverse reaction to past interventions, FG was apprehensive of new therapies and medications.

A lidocaine infusion was initiated to address both FG's nociceptive and neuropathic pain.⁶ Topical cocaine was trialed on her groin ulcers.⁷ She initially experienced relief with increased care tolerance and improved pain control. Five days after starting the lidocaine infusion, she became nonresponsive with concern for seizure activity; she was transferred to intensive care unit (ICU). The prolonged duration and high dose of her lidocaine infusion raised concern that it may have lowered her seizure threshold, thus it was discontinued. Electroencephalography was consistent with diffuse encephalopathy.

Upon return to the floor, she received scheduled immediate release oxycodone and PRN IV hydromorphone (Table 1). She initially allowed wound care and participated with physical therapy. Despite increased opiate dosing, her pain rebounded: she could not tolerate touch or intervention. Patient experienced some relief when hydromorphone patient controlled analgesia (PCA) was started with demand only delivery of medication (i.e., no basal dose); however, she became increasingly agitated, paranoid, and confused, experiencing auditory and visual hallucinations. The opioid dose was decreased to alleviate side effects, and although this effort did lead to abatement of delirium, her pain escalated.

Table 1.

Patient Course from Palliative Care Consult: Pharmacotherapy Use Including Opioid Selection and Daily Oral Morphine Equivalents for Pain Control, Adjuvant Drugs, Patient Response, and Significant Events

		Pharmacotherapy
		Opioid
Day ^a	Pain score ^b	Basal	PRN	OME ^c	Adjuvant ^d	Notes ^e
0	10	Oxycontin	Hydromorphone	300		Initial palliative care consult
3	10	Oxycontin	Hydromorphone	300	Lidocaine
4	10	Oxycontin	IV hydromorphone	150	Lidocaine, topical cocaine
8	8	Oxycontin	IV hydromorphone	150	Lidocaine, topical cocaine	Seizure, patient unresponsive, lidocaine discontinued, patient moved to ICU
9	8	Fetantyl gtt		96		ICU/intubated: team hesitant for opioids given AMS extubated
14	9	Fetantyl gtt		96		Transferred to floor; unable to swallow, Dobhoff tube continued; patient tolerated physical therapy
15	9	Oxycodone	IV hydromorphone	200		Patient unwilling to participate with physical or occupational therapy or speech; declined wound care
16	9	Oxycodone	Hydromorophone demand only pca; IV rescue	240		Patient unwilling to participate with physical or occupational therapy or speech; declined wound care
17	10	Oxycodone	Hydromorophone demand only pca; IV rescue	240	Fosaprepitant	Patient hesitant to participate/allow interventions; paranoia and anticipatory anxiety noted
18	6	Oxycodone	Hydromorophone demand only pca; IV rescue	300	Fosaprepitant	Patient clearer and less paranoid; allowed wound care
19	7	Oxycodone	Hydromorophone demand only pca; IV rescue	96	Fosaprepitant	Participated with PT/OT; allowed wound care
21	2	Hydromorphone pca basal	Hydromorophone demand only pca; IV rescue	144	Fosaprepitant	Delirium/paranoia escalated, now interfering with therapies; quetiapine 50 mg qHS started
22	2	Hydromorphone pca basal	Hydromorophone demand only pca; IV rescue	144	Fosaprepitant
23	6	Hydromorphone pca basal	Hydromorophone demand only pca; IV rescue	180	Fosaprepitant	Increasing and refractory delirium/paranoia
24	5	Fetantyl gtt		150	Fosaprepitant	Transferred to ICU for delirium, airway protection, pending respiratory distress
27	3	Fetantyl gtt		200	Fosaprepitant
28	3	Fetantyl gtt		300	Fosaprepitant, dexmedetomidine	Cleared sensorium
29	2	Fetantyl gtt		400	Fosaprepitant, dexmedetomidine
30	0	Fetantyl gtt		400		Fosaprepitant discontinued
31	10	Fetantyl gtt		1440		Pain crisis; opioid rotation
32	5	Hydromorphone gtt		100	Fosaprepitant	fosaprepitant restarted
33	3	Hydromorphone gtt		1100	Fosaprepitant	Transitioned to full comfort care
35	2	Hydromorphone gtt		1920	Fosaprepitant	Death

Day from initial palliative care consult.

Median daily pain score on a scale from 0 (no pain) to 10 (worst pain) as recorded in electronic medical record.

Daily OME in mg/day.

In addition to the listed agents, patient had scheduled gabapentin 400 mg q8h as well as PRN acetaminophen. Lidocaine infusion was started at 0.5 mg/kg/h and titrated to 2 mg/kg/h. Four percent topical cocaine applied q6h. One hundred fifty milligrams of fosaprepitant was administered intravenously, daily dexmedetomidine infusion administered at 0.2 μg/kg/h.

Notes include major events, adverse reactions, transitions of care, and notable medications changes.

ICU, intensive care unit; IV, intravenous; OME, oral morphine equivalents; AMS, altered mental status; PCA, patient controlled analgesia; PT/OT, physical therapy/occupational therapy.

FG rated her pain 9–10 out of 10 (Table 1). The pain was maximal in her upper extremities and aggravated by movement and touch. She described her pain as superficial, burning, and stinging throughout her body with a deeper pain in her arms and legs. Hydromorphone helped her deeper pain but nothing alleviated her superficial pain. Given her intolerance of and adverse reactions to attempted interventions, fosaprepitant 150 mg IV daily was trialed in hopes of attenuating her pain. Fosaprepitant was selected rather than aprepitant as this patient was not tolerating oral medications and administration of aprepitant through nasogastric and percutaneous gastrostomy tubing is not supported.

The initiation of fosaprepitant coincided with improved subjective rating of her pain, increased tolerance of therapies, decreased opioid use by 250% from 240 to 96 OME (Table 1 and Fig. 2), and decreased allodynia. She was observed to have increased mental clarity with fosaprepitant initiation. FG allowed herself to be touched, her anxiety abated, and she increased interaction with her family and participation with caregivers. Initial benefit was appreciated within 48 hours. Although FG's symptoms persisted, she was content with their management and her trajectory of care.

FIG. 2.

Daily OME and pain score. OME, oral morphine equivalents.

FG did not respond to therapies for her underlying disease process. She ultimately returned to the ICU for delirium and respiratory distress. Her opioid was transitioned to fentanyl and adjuvant therapies continued. Thirteen days after initiation of fosaprepitant, it was discontinued abruptly. A pain crisis ensued: prior doses of fentanyl were incapable of abating her pain. Her opioid regimen was aggressively titrated and fosaprepitant was reinitiated. Unfortunately, we could not attribute further relief to the use of fosaprepitant as her primary condition worsened and she transitioned to a goal focused exclusively on her comfort. With the shift in her goals of care, her opioids were aggressively uptitrated and both lorazepam and haloperidol were added, scheduled, and increased as necessary to control her symptoms during her last hours of life.

Discussion

FG's healthcare goals were to both prolong her life and to preserve her functioning. However, these goals came at the expense of her comfort. As her course progressed, her symptoms became increasingly intolerable and exceedingly difficult to manage.

The patient suffered from a complex pain syndrome that was both nociceptive and neuropathic in nature. In addition, severe anxiety complicated the treatment and severity of her pain. Although she received some relief from opioids and adjuvant therapies such as lidocaine, the adverse effects were untenable. The patient was unable to tolerate these evidence-based analgesic strategies. Given the rationale for an NK1 antagonist, a trial of fosaprepitant was initiated, which she appeared to respond to without evidence of adverse effects despite daily dosing.

The use of fosaprepitant as a novel therapy for refractory pain in this case was predicated on its mechanism of action. SP is an undecapeptide tachykinin, which interacts with NK1 receptors. It is associated with neurogenic inflammation, cell survival, and would healing.¹ NK1—the main receptor for tachykinins—is found in the nervous system and peripheral tissues as well as the immune system.^1,5 SP impacts cellular responses ranging from pain transmission to stress and anxiety.¹ SP is released at a rate proportional to the intensity and frequency of painful stimulus.⁸ SP production is also increased in depression.⁹

Fosaprepitant interferes with the binding of SP to NK1 receptors at postsynaptic neurons. NK1 receptors are expressed by the dorsal horn neurons³: blockade here and in the central nervous system (CNS) limits the reach of SP and impairs central sensitization (Fig. 1). Mu-opioid receptors mediate antinociceptive effects of opioids and are widely expressed in the CNS; in particular they are present in the dorsal horn of the spinal cord in primary sensory afferent pathways, which also contain SP.³ In addition, SP release increases after persistent and intense nociceptive inputs inducing synaptic plasticity³ and promoting central sensitization. Thus, antagonizing NK1 receptors may delay the development of opioid tolerance and act synergistically with opioids to increase the antinociceptive effect.

In addition to its role in mitigating pain and working synergistically with opioids, NK1-receptor antagonist fosaprepitant may have a role in the treatment of depression. Pathophysiological studies have demonstrated that deletion of the SP receptor has an anxiolytic and antidepressant effect.¹ FG had significant depression and anxiety in the context of her progressive disease and symptom burden. These symptoms exacerbated her pain and increased her suffering: her fear of touch and movement was nearly as unmanageable as touch and movement itself. Alleviating the emotional and psychological distress was necessary to treat her pain. It is possible that fosaprepitant may have played a role in reducing FG's anxiety and depression, and thus contributed to her overall improvement in her “total pain.”

It is notable that no adverse events were detected despite daily administration for a prolonged duration. Monitoring for diarrhea, fatigue, and neutropenia is warranted.

Conclusion

Our patient suffered from a complex nociceptive and neuropathic pain syndrome with presumed allodynia complicated by psychological distress. In this patient for whom opioids caused delirium and other adjuvant agents were ineffective or unsafe, initiation of fosaprepitant appeared to provide significant pain relief with decreased allodynia. It is uncertain to what extent fosaprepitant also contributed to alleviating her psychological symptoms as well. Further investigation into the use of fosaprepitant in palliative care as a novel therapy for refractory pain and psychological symptoms is needed.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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