Multiple sclerosis (MS) is a chronic disease involving the central nervous system, which is based on inflammation, demyelination, and neurodegeneration processes. It affects around 2.2 million people worldwide, mostly young adults [1]. In most cases, the disease initially develops in attacks with variable severity and duration, with typical remission after a few weeks. Along with the evolution of the disease, the degree of disability increases, and the symptomatology is no longer intermittent.

In addition to motor and sensory deficits, this disease can also be associated with painful manifestations such as headaches, temporomandibular joint pain, Lhermitte’s sign, several types of neuralgia (occipital neuralgia, trigeminal neuralgia), muscle spasms, and restless legs syndrome, all this leading to a supplementary decrease in the patient′s quality of life [2].

Considering the increased incidence of headaches in MS, the physician must be aware of the diagnosis and management of common headache types. These patients frequently have primary headache disorders, with migraines taking the lead, followed by tension-type headaches and then cluster headaches. Depending on the case, secondary causes should be investigated and excluded. Even if disease-modifying drugs (DMTs) are the focus of MS treatment, they can lead to the worsening of pre-existing headaches or their appearance as a side effect. Therefore, proper knowledge of the therapeutic agents and their effects can help to treat headaches and improve compliance.

2. Types of Headaches in Multiple Sclerosis Patients

The main types of headache (tension-type headaches, migraines, and cluster headaches) are also present in the case of multiple sclerosis patients, but with some percentage differences, depending on the studied population. Migraines and MS share some common background factors, including gender (with a female predominance), hormonal status (with premenstrual or postmenopausal variations), and psychological feature periods accompanied by anxiety, depression, stress, the diagnosis itself leading in many cases to this type of manifestation) [3]. It was also observed that both migraine frequency and MS activity were reduced during pregnancy. Neuroinflammation is the process that seems to play a key role in the physiopathogenesis of both diseases, with at least one common downstream pathway. Female sex is a relevant risk factor for migraines, not for tension-type headaches. No link was found between age and one of the types of primary headaches, but it seems that the elderly associate migraines with aura more often [4]. Previous studies have shown a different onset time depending on the type of primary headache; in a significant number of cases the migraine attacks started before the MS diagnosis, while tension-type headaches seemed to begin after MS onset [4]. In terms of the clinical presentation of demyelinating diseases, research has indicated a higher occurrence of migraines in individuals diagnosed with relapsing–remitting forms of multiple sclerosis, whereas the tension-type headache had a higher frequency in patients with chronic progressive MS ^[5][6][5,6]. When considering the types of headaches experienced by individuals with multiple sclerosis, it is notable that migraines rank as the most prevalent, with a prevalence of 31% [7], followed by tension-type headaches. Cluster-type headaches have been reported in a few cases. There have been rare instances of cluster-type headaches reported among these patients. The infrequency of cluster-type headaches in this context could be attributed to their low prevalence in the general population ^[8][9][8,9]. Migraines associated with multiple sclerosis represent the subject of many studies. Initially, they were regarded as an exclusion criterion for MS [10] and continue to be considered a red flag in clinical assessments. The similarity in clinical presentation can frequently lead to difficulties in distinguishing between a multiple sclerosis relapse and a migraine aura. In 1952, Compston made the first assumption about a potential connection between migraine and multiple sclerosis. It remains uncertain whether these two diseases are causally linked or if they are only comorbid conditions. It has been shown that brain stem and upper cervical demyelinating lesions (situated in the C2 dorsal horn) are associated with headaches in MS ^[11][12][11,12]. On the other hand, patients reported the occurrence or exacerbation of the cephalalgic syndrome after the initiation of therapy for multiple sclerosis (disease-modifying drugs). Elderly patients, with longer disease evolution and a lower SDMT score, complain more often of migraines with aura [13]. MS patients who associate migraine headaches seem to have typical migraine characteristics but with a more important severity regarding the intensity of pain and a high frequency of headache attacks [13]. The most frequent headache triggers described in the studies were fatigue and stress [8]. It has also been shown that stress precipitates MS exacerbations. Other migraine triggers in the MS population were weather change and sleepless nights [14]. All of these can be improved through a balanced lifestyle and an individualized work schedule. Several hypotheses regarding the association between multiple sclerosis and migraine have been proposed: disrupting the pathways which are involved in the pathogenesis of migraines by the inflammatory demyelinating MS lesions can induce headache episodes [15]; there is a connection between headache exacerbation and malfunction of the serotoninergic system caused by demyelinating lesions [16]; demyelination with cortical localization has been shown to speed up cortical spreading depression, this being a key mechanism involved in migraine pathophysiology [17].

3. Other Pain Syndromes in Multiple Sclerosis Patients

Pain is a disabling medical condition with a significant adverse effect on the individual’s quality of life. Neuropathic pain is a symptom that is frequently reported by patients with multiple sclerosis, with a fairly variable prevalence between 25% and 90%, and it is a chronic pain, associated with depression and significant MS-related disability ^[18][38]. Patients usually complain of this type of pain from the early stages of the disease. The most common types of cranial neuralgias, including occipital neuralgia, trigeminal, and glossopharyngeal neuralgias, can appear in the case of MS patients. The pathophysiological mechanisms underlying trigeminal neuralgia encompass several intricate factors. One significant aspect involves the compression exerted on the trigeminal nerve root. Additionally, conditions characterized by primary demyelination play a contributory role in the development of trigeminal neuralgia. Furthermore, the sensitization and dysfunction of central circuits associated with pain processing contribute to the complexity of this neurological disorder. These multifaceted elements collectively contribute to the manifestation and progression of trigeminal neuralgia ^[19][39]. Neuralgia secondary to MS has common characteristics with the classic one, it more often affects women and the right side of the face, but in a percentage of 18% of MS patients, the neuralgia is located bilaterally ^[20][40]. Also, it seems to appear at a younger age. To diagnose secondary trigeminal neuralgia, it is necessary to observe the presence of a structural abnormality that involves the path of the trigeminal nerve other than vascular compression. These may include abnormalities or tumors located at the level of the skull base and demyelinated plaques which are multiple-sclerosis-related, with a preponderance of the latter. MS patients have a significantly higher risk of developing trigeminal neuralgia ^[21][41]. MRI is the preferred diagnostic method to show evidence of trigeminal pathway damage, generally, with plaques located in the ventrolateral pons. Neurophysiological investigations can also be performed to support the diagnosis: trigeminal reflex testing having a high sensitivity and specificity ^[22][42]. In patients experiencing neuralgia secondary to multiple sclerosis, a substantial 89% exhibited abnormal results in the trigeminal reflex test. In contrast, individuals with idiopathic neuralgia displayed abnormal test results in only 3% of cases ^[23][43]. Trigeminal neuralgia in most MS patients has an intermittent evolution, with periods of remission. Hypotheses have been issued according to which the cause of this type of neuralgia is represented by a reduction in neuronal excitability and partial remyelination, without evidence to support them ^[19][39]. In several cases, imaging investigations followed by surgical treatment suggest a double-crash mechanism (neurovascular compression in concern with pontine plaque) ^[24][44]. Although classical trigeminal neuralgia and trigeminal neuralgia secondary to MS present similar characteristics, MS patients more frequently reported bilateral pain, with an estimated percentage of 18% ^[25][26][45,46]. A study conducted by the MS Treatment and Research Center of Minneapolis which included a small batch of patients (71 persons) suggests that fampridine can cause a reactivation of neuropathic pain due to trigeminal neuralgia ^[27][47]. Occipital neuralgia is characterized by paroxysmal intense pain that feels like a sharp, jabbing, electric shock in the distribution of one of the three major occipital nerves. It can also be associated with a decreased sensation or dysesthesia. Occipital neuralgia is in most cases idiopathic. The other etiologies include neurosyphilis, C1-C2 arthrosis, corticomedullary dural arteriovenous fistula, vascular compressions, upper cervical cavernous angioma, and MS ^[28][48]. A recent study concluded that occipital neuralgia may be a symptom of MS relapse or the initial symptom of MS ^[29][49]. Considering that it is not a common pathology (incidence and prevalence are unknown), suspicion of MS in cases with occipital neuralgia could reduce the delay in diagnosis of demyelinating disease and decrease disability by enabling early treatment. In some cases, occipital pain with intense and paroxysmal onset can signal a relapse of MS, and these patients need a cervical MRI with gadolinium for high diagnostic accuracy ^[30][50]. SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a part of the group of trigeminal autonomic cephalalgias and is a relatively new nosological entity ^[31][51]. It represents a rare condition which is characterized by brief, unilateral, and painful attacks typically located in the orbital or temporal area and associated ipsilateral autonomic manifestations ^[32][52]. Although many cases reveal no apparent structural causes in imaging studies, SUNCT has been reported secondary to structural lesions in the posterior fossa. Short-lasting unilateral headache with cranial autonomic symptoms (SUNA) has a similar definition to SUNCT; this could involve any of the autonomic symptoms. In the existing literature, secondary conditions associated with these abnormalities encompass a limited number of cases involving multiple sclerosis patients ^[33][53]. Additionally, other examples documented in the literature include cortical dysplasia and patients with vertebral artery dissection. In patients with multiple sclerosis who present lesions of the posterior fossa, these two entities must also be taken into account. Another paroxysmal pain syndrome in MS patients is Lhermitte’s sign, described as a painful, electric-current-like sensation in the spine when the patient flexes the neck. In 95% of the patients presenting this sign, cervical demyelinating lesions were detected during MRI examination ^[34][54]. Chronic pain, both nociceptive and neuropathic, is a common symptom that patients with multiple sclerosis often complain about ^[20][40]. It can appear at some time during disease, in a percentage of 50–75% of MS patients ^[18][38]. Neuropathic pain is most often chronic (duration over 12 weeks), present from the early stages of the disease, and in many cases it requires treatment. The main types of chronic neuropathic pain conditions have been described above. It was noted that patients with the primary progressive form of the disease complain more often of dysesthesia ^[25][45].

4. Management of Pain in Multiple Sclerosis Patients

Symptomatic treatments are important in helping individuals to fulfil their personal, social, and occupational roles and improve their quality of life, for as long as possible. Unfortunately, any conventional pain medication offers complete pain relief, but even incomplete relief is important in the case of these patients. A temporary relief of pain can be obtained by taking antidepressants and anticonvulsants. Trigeminal neuralgia secondary to MS is treated in first-line therapy with sodium-channel blockers such as carbamazepine or oxcarbazepine ^[24][44]. Other therapeutic options include phenytoin, lamotrigine, and gabapentin ^[35][55]. The residual pains that persist between paroxysms are often resistant to sodium-channel blockers ^[36][56]. Medication-resistant patients can respond to low-dose aripiprazole. In selected cases, baclofen and misoprostol can be used to relieve neuralgia. The last drug can help in nerve stabilization by decreasing the inflammatory activity in the plaques ^[37][57]. Tramadol and opioid analgesics can be used as second-line therapies, for limited periods ^[38][58]. If pharmacological treatment fails, neurosurgical procedures such as rhizotomy, microvascular decompression in the posterior fossa, Gasserian ganglion percutaneous techniques, or gamma knife can be considered. Surgical methods seem less effective than in idiopathic trigeminal neuralgia. Regarding the treatment of migraines, CGRP-specific therapies require additional studies to establish the safety of their association with DMTs. Amitriptyline may be prescribed for patients complaining of chronic dysaesthetic pain. Regarding Lhermitte′s sign, treatment with oxcarbazepin, carbamazepine, and gabapentin can be useful in some patients ^[39][59]. Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents such as baclofen or tizanidine and in patients with phasic spasticity, gabapentin or levetiracetam are administered. In patients with severe spasticity, botulinum toxin injections or intrathecal baclofen merit consideration ^[40][60]. An adjuvant treatment that can be used in MS patients to improve sensory symptoms is transcranial magnetic stimulation (TMS). This method does not seem to interact with DMTs ^[41][61]. In addition to that, TMS can also alleviate spasticity, gait disturbance, and numbness, with patients also noticing positive effects on fatigue ^[42][62]. Another treatment option is transcutaneous electrical nerve stimulation, a therapy used effectively to improve post-stroke spasticity. A study that analyzed its use in the case of multiple sclerosis patients suggested a low effect in terms of spasticity, but it seems to be a good solution for relieving muscle spasms and pain ^[43][63]. Depression is an underdiagnosed and undertreated condition both in the general population but especially in the case of patients with neurological conditions, being associated in many cases with receiving a diagnosis with an important psychosocial impact. Formal screening tools for depression are deemed crucial in studies involving patients with chronic or refractory headaches, with a particular focus on those experiencing migraines ^[44][64]. Some of the most-used tests in studies that include patients with migraines are the Hospital Anxiety and Depression Scale (HADS) and PHQ-9 ^[45][65]. Regarding the association of depression with MS, studies have shown percentages between 20% and 40% ^[46][47][66,67]. Screening for depressive symptoms is crucial for patients with MS and headaches. In terms of psychological counselling, mindfulness interventions and cognitive behavioral therapy are beneficial for these patients, leading to stress reduction and the improvement of depressive symptoms. Improvements were also noted in terms of fatigue, pain, reduction in the intensity of symptoms, anxiety, and tolerating uncertainty. Some lifestyle changes such as limiting alcohol and caffeine, meditation, a regular sleep schedule, a balanced diet, and maintaining an active social life can lead to a reduction in painful symptoms.