Chemotherapy Withdrawal Migraine

Introduction

Cancer-related headache or facial pain can result from tumor involvement of the brain or surrounding structures or from anti-cancer therapy [1]. Differentiating cancer progression from the neurotoxic effects of cancer therapy can be helpful in guiding treatment. Various chemotherapeutic agents have been directly implicated in their ability to cause central neurotoxic effects such as headache, despite the protective role of the blood–brain barrier [2]. The following case details the clinical course of a patient with multiple myeloma treated with immunomodulatory chemotherapy. To our knowledge, this is the first report of chemotherapy-withdrawal migraine in an adult.

Case Presentation

We present a case of a 75-year-old male with a 16-year history of multiple myeloma being managed at the time of the initial presentation with pomalidomide (a thalidomide derivative) and dexamethasone, with 2 weeks of treatment followed by 2 weeks off. The patient also had a history of episodic migraine, with attacks occurring one to two times per month without aura or prodrome. These attacks previously had been successfully treated with an oral triptan (sumatriptan).

Since the initiation of pomalidomide, the quality and pattern of his attacks had changed, with an attack beginning 2–3 days after the cessation of every cycle. These attacks would begin with a prodrome of neck stiffness for 2 days before developing into severe (10 of 10 Numeric pain rating scale), throbbing, unilateral pain. The pain was worsened by movement and light and accompanied by nausea. No red flag signs or symptoms were present. Each attack lasted 48–72 hours, and previously effective oral triptans were only partially effective, with limited pain relief. Given the patient’s history, we were concerned about new central nervous system (CNS) involvement. However, magnetic resonance imaging of the brain performed just a few weeks prior (and after the worsening attacks) showed no evidence of CNS myelomatous involvement.

We initially considered that the migraine attacks might have been triggered by the withdrawal of steroids (a known phenomenon). However, the patient had tried remaining on dexamethasone between treatments, with no change. We next considered the possibility that the known adverse effects of pomalidomide (muscle spasm, back pain) [3] were causing neck muscle stiffness, leading to increased nociceptive input to the trigeminocervical complex (TCC). To test this hypothesis, we performed greater occipital nerve (GON) blocks with local anesthetic at C2 under ultrasound guidance, a well-described approach described elsewhere [4]. We timed this block approximately 24 hours after the cessation of chemotherapy.

One week after the block, the patient reported that his neck pain/tightness had not occurred, nor had he experienced a migraine attack. However, with the next cycle of chemotherapy (3 weeks later) his symptoms recurred. While discussing the option of monthly preventive GON blocks or botulinum toxin injections to the same region, the patient revealed that he was actually getting complete relief from his previous triptan, but the relief was lasting only 2–4 hours. Thus, we sought to trial a long-acting triptan (frovatriptan) to cover the duration of his post-chemotherapy attack. This approach was completely successful, with the patient taking a single dose at the onset of neck stiffness. The patient’s symptoms remain well controlled on this regimen 2 years later.

Discussion

It is challenging to distinguish between secondary headaches due to intracranial neoplasm and those due to side effects of cancer therapeutics. The International Classification of Headache Disorders (ICHD)-3, notes that the characteristic secondary headache attributed to intracranial neoplasm is a headache that is usually progressive, worse in the morning or during daytime napping, and aggravated by Valsalva maneuvers [5]. It is crucial to maintain a high index of suspicion and to obtain neuroimaging if there are red flag symptoms, features different from a patient’s primary headache, or an abnormal neurological examination (Table 1) [6].

Table 1

Red Flags for Secondary Headache (SSNOOP Mnemonic)

S	Systemic symptoms (fever, chills, myalgia, weight loss)
S	Secondary risk factors (systemic disease, history of neoplasm, HIV/immunocompromise)
N	Neurological deficit or dysfunction (including decreased consciousness)
O	Onset of headache is sudden or abrupt
O	Older (age >50 years)
P	Previous headache history: first time or change in pattern Papilledema Precipitated by Valsalva maneuvers Postural aggravation Pregnancy or puerperium

The ICHD-3 also notes a separately classified subform of secondary headache attributed to exposure to or withdrawal from a pharmacologically active substance. This type of secondary headache can occur soon after exposure or cessation in a patient with a history of a primary headache disorder [5]. Cancer treatment–induced headaches have been shown to occur more frequently in patients with a history of headache and with agents that penetrate the blood–brain barrier [7]. In this case, our patient had preexisting migraine that changed in character and severity in close temporal relation to the end of his chemotherapy cycles with pomalidomide. Pomalidomide is an immunomodulatory drug used in the treatment of multiple myeloma and has broad anti-inflammatory effects owing to its anti–tumor necrosis factor (TNF)-α activity [8]. It is noted to have the highest potency comparatively within the class of thalidomide analogs, has been shown to cross the blood–brain barrier with excellent CNS penetration, and has been implicated in clinically significant CNS neurotoxicity [9]. We speculate that the potent anti-inflammatory effect during treatment resulted in increased sensitivity to TNF-α and other cytokines. Withdrawal of the drug may have disrupted homeostatic balance and resulted in a lower threshold for migraine attacks.

Headache patterns related to chemotherapy may depend on the patient’s vulnerability, the type of agent used, and the route of delivery. Other chemotherapeutic agents, such as methotrexate, all-trans-retinoic acid, temozolomide, fluorouracil, trastuzumab, and intrathecal administration, have also been implicated in the development of chemotherapy-related headache [7]. In a retrospective chart review of 109 consecutive patients receiving intrathecal chemotherapy, headache was the most frequent treatment-related side effect (15%) [10].

Migraine is a recurrent, disabling primary headache disorder with an underlying state of increased responsiveness of cortical and subcortical networks that amplify the perception and modulation of sensory stimuli [11]. Prophylactic and abortive treatment is commonly used as a combination therapy in migraineurs. However, for a small proportion of patients with refractory migraine, additional therapeutic options are needed.

Peripheral nerve blocks have long been used to reduce the frequency and severity of migraine attacks, and GON blocks have been reported to have potential for treatment of refractory migraine disorders. The GON is the most common nerve targeted, either alone or in combination with other peripheral nerves, such as the lesser occipital nerve and branches of the trigeminal nerve [4]. The convergence of afferent information from the craniofacial structures forms a TCC for processing sensory information. Reducing input into the TCC with peripheral nerve blocks may diminish central sensitization [12].

The serotonin (5-hydroxytryptamine [5-HT]) receptor subtype 1B/1D agonists, called triptans, are commonly used as abortive therapy to stop an attack from progressing further. They have at least three mechanisms of action: 1) intracranial vasoconstriction of pain-sensitive vascular smooth muscle, 2) inhibition of the release of vasoactive neuropeptides from trigeminal afferents on the dural vasculature, and 3) inhibition of nociceptive transmission within the TCC [13]. The choice of triptan can be guided by patient’s preference, treatment response, and headache profile. Frovatriptan has the longest half-life by a large margin (∼25 hours) and can be a good choice for long-duration attacks or attacks that recur after treatment [12]. One disadvantage is its slow onset; however, this was mitigated in this patient by the prodromal symptoms, which allowed for preemptive dosing.

Conclusion

Recognition of cancer progression and cancer treatment–induced neurotoxicity is crucial to prevent delays in diagnosis and treatment. It is important to consider that patients with a history of primary headache disorder may have progression of their symptoms while undergoing cancer treatment. Review of a patient’s headache profile and timing of symptoms may be helpful in individualizing a patient’s treatment regimen. Chemotherapy-related migraine attacks may benefit from a multimodal approach involving traditional migraine medications and interventional peripheral nerve blocks.

Questions

1. Which common feature of headaches in the setting of malignancy should raise suspicion of intracranial involvement?

• A. Worsening with Valsalva

• B. Worsening when transitioning from supine to standing

• C. Unilateral pain

• D. Headache associated with peripheral neuropathy

• E. Headache after chemotherapy infusion

Answer: A. In a patient with a known malignancy, head pain that is worse after sleep and worse with Valsalva should be investigated, as they may be indicators of intracranial involvement.

2. Which medication from the triptan family has the longest duration of action and may be appropriate for patients with prolonged migraine attacks?

• A. Rizatriptan

• B. Frovatriptan

• C. Sumatriptan

• D. Zolmitriptan

• E. Eletriptan

Answer: B. The initial choice of abortive therapy should take into account the temporal pattern of the patient’s migraine attack (e.g., rapid ramp-up, prolonged symptoms). Frovatriptan has the longest half-life and may be a good choice for patients with extended attacks.

Funding sources: None.

Conflicts of interest: None.