Introduction

Migraine is one of the most prevalent and incapacitating neurological disorders. Chronic migraine (CM) is a condition that is defined by the recurrence of severe headache episodes accompanied by a cluster of symptoms that can have a significant impact on the quality of life of the patients. CM can progress to resistant migraine (RCM), which is still treatable with certain medications, and refractory migraine, which is not well controlled with any treatment.

The precise pathophysiology of CM is yet to be fully elucidated. Treatment options for CM are divided into preventive and abortive. The efficacy of pharmacological treatment may be unsatisfactory and can be poorly tolerated (1). A variety of pharmacological agents are commonly used for the prophylactic treatment of migraine. These include antidepressants, anticonvulsants, antihypertensives, gepants, and calcitonin gene-related peptide (receptor) monoclonal antibodies. There are newer drugs that have been proven to be effective and well tolerated, but they are mostly available at a significantly higher cost, which restricts access to their use (2).

Ziconotide is a 25-amino-acid polybasic peptide derived from the venom of the marine snail Conus magus. It is a non-opioid analgesic utilized for intrathecal therapy, exhibiting selective binding affinity for N-type voltage-sensitive calcium channels. Subsequently, calcium influx is disrupted, preventing the release of neurotransmitters and neuropeptides that are involved in pain transmission. Blocking calcium channels on primary nociceptive afferent nerves in the dorsal horn of the spinal cord is an effective treatment for many forms of chronic pain, including both cancer- and noncancer-related pain of neuropathic or nociceptive etiology (3). The side effects of ziconotide include psychiatric symptoms such as confusion, memory impairment, speech disorder, hallucinations, paranoid reactions, hostility, delirium, psychosis, suicidality, and manic reactions (3,4).

The authors present a case in which intrathecal ziconotide therapy was successful in the treatment of RCM, which contributes to the growing body of evidence that ziconotide may be a valuable therapeutic option for the management of severe RCM.

Case presentation

Clinical feature

A 46-year-old male with a history of resistant migraine and complex regional pain syndrome type II and sympathetically independent pain in the right lower leg, which started after fibula surgery. The skin of the affected leg was shiny and slightly edematous. The patient reported that over-the-counter analgesics, including acetaminophen, meloxicam, and ibuprofen, as well as selective norepinephrine reuptake inhibitors (duloxetine 60 mg daily), pregabalin (150 mg q12 h), opioids (fentanyl 50 µg q72 h, oxycodone 10 mg q6 h), vitamin B1, multiple nerve and sympathetic blocks, lidocaine patches, and physical therapy, did not provide the desired therapeutic benefit. No efficacy of spinal cord stimulation. The patient indicated that he was experiencing severe headaches, which were localized primarily to the right frontal and temporal regions. The headaches were abrupt in onset, persisting for approximately four to 48 hours, and were often accompanied by photophobia, phonophobia, and nausea. The average pain score reported by the patient was 7/10, the Migraine Disability Assessment (MIDAS) score was 32, and the Headache Impact Test-6 (HIT-6) score was 62. He was often forced to seek a quiet and dark room because of the intensity of the pain. Magnetic resonance imaging and angiography confirmed no structural abnormalities. He was discharged on verapamil and levetiracetam for migraine prevention, as well as butalbital/acetaminophen/caffeine for acute treatment of migraine attacks. No efficacy of therapy with botulinum toxin A (Figure 1), using 5 unit of botulinum toxin in each puncture point. Informed consent for publication of this case report was obtained from the patient, and authorization was obtained from Ethics Committee of The Hospital Virgen de las Nieves of Granada (Spain) to publish the case.

Treatment

The patient exhibited increasing anxiety and depressive symptoms following the failure of multiple therapeutic interventions for CM and leg pain. Following a comprehensive review of the medical history, intrathecal ziconotide therapy was recommended as a treatment option for the refractory complex regional pain syndrome. The patient underwent placement of SynchroMed II (Medtronic) intrathecal pump in the left abdomen. The intrathecal catheter tip was placed at T12. The intrathecal pump was set to deliver 0.5 µg of ziconotide per day. In the subsequent visits, the intrathecal dose of ziconotide was increased from 0.5 µg/day.

Outcomes

The patient reported a complete resolution of his migraine with ziconotide 2.0 µg/day and 3.5 µg/day for right lower leg pain. After 18 months of treatment with ziconotide administered via an intrathecal pump, the patient’s clinical condition continued to improve, with a notable reduction in migraine frequency and intensity. The average pain score in global was reduced to 1-2 of 10. Additionally, the patient exhibited a significant improvement in disability levels, from severe to minimal, as evidenced by validated instruments (MIDAS, HIT-6, and IBS Patient Global Impression of Change). No side effects were experienced by the patient associated with either the ziconotide trial or the subsequent placement of the intrathecal pump.

Discussion

The release of neurotransmitters is regulated by the neuronal-type voltage-gated calcium channels (Cav2.2). Ziconotide is a peptide that acts as a selective pore blocker of the Cav2.2 channel, and it has been approved for clinical use as a treatment for patients with of intractable pain. Flunarizine, a long-acting calcium channel blocker, has been shown to be effective in the treatment of hemiplegic migraine in a pediatric study (5). Ziconotide does not cause withdrawal with abrupt discontinuation, does not cause tolerance or dependence, is not associated with catheter tip granuloma, and has not been identified as the agent responsible for any death from an accidental overdose (3,4).

The management of RCM requires optimization of acute and preventive treatment. Additionally, psychological support should be considered. In individuals with RCM, the combination of pharmacological and neuromodulation treatments may be a viable therapeutic option. A review of existing case series and retrospective studies has indicated that dual therapy with botulinum toxin A and CGRP-mAbs may be an effective treatment option for individuals who did not respond to all or the majority of available treatments (3).

The efficacious use of intrathecal ziconotide in the management of CM, chronic trigeminal neuralgia, and persistent idiopathic facial pain, has been documented in various case reports in the scientific literature (6-11) (see Table I). The administration of ziconotide is recommended as a treatment option for patients with neuropathic facial pain subsequent to the implementation of the therapy outlined in the established guidelines (8).

The patient described in this case report exhibited a near-complete resolution of RCM with pump intrathecal monotherapy at exceedingly low doses (2.0 µg/day) of ziconotide (the maximum daily dose of intrathecal ziconotide has been established as 19.2 μg/day). The administration of ziconotide at a dosage of 1-2 micrograms per day has been demonstrated to be an effective treatment for achieving complete resolution in the cases of RCM (6,7). In the case of our patient, the intrathecal catheter tip is situated at the base of the T12 vertebral body. Due to its hydrophilic nature, the ziconotide molecule may be able to diffuse through the cerebrospinal fluid, thereby blocking the transmission of nociceptive signals from higher neurons. The successful treatment of patients with CM and trigeminal neuralgia pain with ziconotide at the T9, T12-L1 and L3-L4 levels indicates that the catheter tip position does not affect the efficacy of the treatment in managing symptoms.

Two novel dosing paradigms have been described in the literature with the aim of improving the safety and efficacy of ziconotide. One of these is the overnight bolus dosing, also known as flex dosing, and the other is the patient-controlled administration (12). The proposed dosing strategies take into account preliminary data indicating a greater distribution of ziconotide in the cerebrospinal fluid when administered via bolus injection rather than with continuous infusion (13). Narain et al. employed bolus/flex doses every four hours (6), whereas Holden et al. started with a continuous dosing regimen. This indicates that the observed symptom relief may be attributable to the overall dosage of ziconotide rather than to the number of dosing intervals (7). In our unit we have used the continuous infusion of ziconotide and recommend that continuous infusion of IT ziconotide is initiated at a dose of 0.5 µg/day and increased in weekly increments of ≤0.5 µg/day depending on analgesia and tolerability.

It has been determined that the occurrence of adverse effects associated with intrathecal ziconotide is independent of the absolute dose administered but dependent on the rate of dose increases (14,15). Staub et al. described two dose increases of ziconotide (at 10 and 18 months) following intrathecal ziconotide pump placement. This may prompt the question of the potential development of tolerance to ziconotide in the patient (10). In the case of the patient described herein, six separate dose increases of ziconotide (0.5 µg/day each time) have been required, and the patient remains free of pain and side effects at the current dose (3.5 µg/day).

Holden and Staub indicated temporary complete resolution of CM and facial pain with a single-injection intrathecal trial of ziconotide.

It is not possible to draw any conclusions from this single, uncontrolled case study. However, our observations and the present case report suggest that intrathecal pump delivery of ziconotide may be a potential therapy for the management of RCM.

Conclusion

Based on our findings, intrathecal pump of ziconotide may represent a promising treatment option for RCM patients. To further investigate the effects of ziconotide in migraine patients and validate these findings, future research is required on a large-scale, with multicenter randomized trials.

Acknowledgements

The staff of the Pain Unit departments of Virgen de las Nieves Hospital (Granada-Spain) are acknowledged for their collaboration in the study. The study results were included in work submitted by Dr. Manuel Alejandro García-Sánchez as part of the requirements of the doctorate program in medicine at the University of Granada, Granada, Spain.

Conflicts of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The case was conducted in the normal course of patient treatment in the Pain Unit. This research received no external funding.

Author contributions

All authors contributed to concept and design, statistical analysis and drafting the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional review board statement

As a single-case report with the patient’s signed consent, no other ethical review was required. However, authorization was obtained from Ethics Committee of The Hospital Virgen de las Nieves of Granada (Spain) to publish the case.

Informed consent statement

The patient gave his consent to publish this paper describing his case.

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