This case suggests that spinothalamic tract injury resulting from SRS for brainstem metastasis in lung cancer is associated with progressive neuropathic pain in this patient. Additionally, methadone has proven to be the most effective treatment in managing the patient’s intractable central neuropathic pain.

Brain metastases are prevalent in lung cancer, with over 10% of patients diagnosed at the initial stage [6] and up to 40–50% during disease progression [6, 7]. Radiation therapy is commonly employed for multiple brain metastases, with SRS recommended for patients with a limited number (up to four) and size (< 3 cm) of metastases, rather than whole-brain radiation therapy (WBRT) [8]. SRS has become a preferred treatment option due to improved accessibility and availability, along with increased concerns about the neurocognitive adverse effects of WBRT. However, SRS for brainstem metastases may damage the density of nuclei and white matter tracts, causing serious complications [4]. Therefore, brainstem metastases are basically treated with WBRT alone, or if ever, with SRS at a lower dose [9]. SRS also carries a higher risk of RN developing in 8–25% of patients treated with SRS [5, 10]. RN is regarded as a late complication of radiotherapy for brain metastases and typically manifests between six months and two years after SRS. Symptoms including headache, seizures, and focal neurologic deficits are present in half of the cases of RN, yet the intractable central neuropathic pain as our patient experienced is infrequent.

In the present case, the pontine lesion is situated in a paramedian to lateral position, affecting the spinothalamic, corticospinal, and abducent tracts. The enlarged necrosis in the pons due to SRS caused damage to the involved cerebral nerves (e.g., trigeminal and abducent nerves) as well as sensory and motor nerve tracts, resulting in ipsilateral face disturbances and contralateral hemiparesis [11]. The injury of nerve fibers and microglial activation in pain transmissions pathways caused central sensitization and disinhibition, leading to thalamic hyperexcitability, which confused the peripheral afferent sensation as central neuropathic pain [2]. When the patient underwent SRS, two additional metastases were discovered in the temporal lobe of the cerebrum. Therefore, WBRT would have been more suitable, as it is less likely to induce radiation necrosis.

Differentiating RN from tumor recurrence on magnetic resonance imaging (MRI) can be challenging, as both may exhibit similar radiologic findings when the treated lesion progresses [5, 10]. Numerous reports have revealed that 11 C-MET-PET exhibits superior detection capability in distinguishing between the two entities [12], although the availability of facilities for this imaging modality is limited due to the short half-life of 11 C-MET [13]. In our case, an accurate diagnosis of RN was made, and sustained CR of lung cancer was confirmed with 11 C-MET-PET, avoiding unnecessary additional treatment. Hence, 11 C-MET-PET should be performed in cases of progression of SRS-treated brain lesions.

The majority of symptomatic cases of RN have been treated with corticosteroids and VEGF inhibitors in an attempt to reduce cerebral edema, while these interventions have presented benefits on a trial basis [5]. However, our patient did not experience any relief with these drugs, and only add-on methadone achieved a beneficial effect on his severe pain. The pharmacological approach for central pain follows the general treatment protocol for neuropathic pain [14]. Antidepressants, such as tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors (SNRIs), are frequently prescribed as first-line therapy. Anticonvulsants, including pregabalin and carbamazepine, are chosen as second-line drugs, although their efficacy has been limited. Opioid analgesics are not recommended primarily due to safety concerns associated with long-term use, including the risk of overdose and addiction. Methadone, the key drug in our case, is a synthetic strong opioid that stimulates mu-opioid and delta-opioid receptors [15]. It inhibits serotonin-norepinephrine reuptake and exerts an inhibitory effect on the upregulated N-methyl-D-aspartate (NMDA) receptor associated with injuries to the spinothalamic tract [16]. It also exhibits a low tendency to develop opioid tolerance [15], contributing to the favorable outcome in the patient suffering from uncontrolled pain. Although methadone is promising for managing intractable neuropathic pain, there are challenges such as the risk of QT prolongation and bioaccumulation due to its long half-life [16, 17]. Furthermore, when considering the transition to methadone, the stop-and-go rotation or the 3-day switch approach is generally employed, but it raises potential risks of increasing pain and overdose, due to the absence of an established conversion ratio from other opioids to methadone [15, 18]. Recently, however, the add-on approach for methadone enables easy introduction and shows superior efficacy for cancer-related intractable pain [19] because the addition of low-dose methadone to ongoing opioids carries fewer risks of worsening pain and reduces the aforementioned adverse effects.

In summary, we present the first case of central neuropathic pain resulting from RN caused by SRS for pontine metastasis in lung cancer. The irreversible RN involving the spinothalamic tract leads to progressive pain, emphasizing the importance of avoiding SRS for this specific tract. Add-on methadone at a low dose is a safe and beneficial treatment for patients suffering from unresolved central pain.