US Pharm. 2007;32(5):HS-20-HS-31.

Central pain is defined as pain associated with lesions of the central nervous system that lead to damage of somatosensory pathways.1 It is considered to be one of the most distressing forms of chronic pain and can be intractable in many patients. Central pain can be nociceptive and/or neuropathic in nature and can be precipitated by trauma, stroke, multiple sclerosis, or compression of cranial nerves. Patient history is the most effective means for diagnosing central pain, and each syndrome is associated with its own array of cardinal symptoms. Central pain syndromes are difficult to manage, and complete pain relief is often unattainable. Reducing pain to a level that is acceptable for the patient should be the primary goal of  therapy. This article will focus on pharmacologic therapies that have been evaluated in spinal cord–related pain, brain-related pain, multiple sclerosis–related pain, and trigeminal neuralgia.

Spinal Cord–Related Pain
Trauma is the most common cause of spinal cord–related pain, with an incidence rate ranging from 6.4% to 94% according to published estimates.1 Pain after spinal cord injury can occur immediately or can be delayed for up to five years. When the onset of pain is delayed beyond one year, more than half of such patients may suffer from a pathologic lesion in the spinal cord that expands and damages the center of the cord, a condition known as syringomyelia.2 Although the quality of pain described can vary between patients, there are three common components: spontaneous steady, spontaneous neuralgic, and evoked pain. Spontaneous steady pain may occur as a result of deafferentation of sensory nerves in the central nervous system, resulting in pain that is expected yet unpredictable. Spontaneous neuralgic pain may be derived from neural damage and is most commonly described as a burning sensation. Evoked pain consists of allodynia and/or hyperpathia, conditions where nonnoxious stimuli such as light touch provoke pain. In any case, classifying pain related to spinal cord injury can be challenging due to poor localization and drastic temporal variations. In 2000, an International Association for the Study of Pain (IASP) task force developed a classification system for patients with spinal cord–related pain that identifies the pain type, system involved, and structures or pathology.2

Brain-Related Pain
The majority of cases of brain-related central pain are caused by strokes. Brain-related central pain is rare and occurs in only 1% to 2% of all stroke patients, with 90% arising from vascular etiology.1 Central poststroke pain (CPSP) has been referred to as "thalamic pain," but this term has fallen out of favor in light of evidence showing that pain can arise from numerous sites within the brain. Furthermore, it has been suggested that CPSP can arise from a chemical imbalance between glutamate and gamma-aminobutyric acid (GABA). By correcting this imbalance, pain relief is possible.1,2 Onset of CPSP can occur within one to two months after a cerebrovascular accident, but may be delayed for as long as one to six years after injury. The predominant characteristics are steady and evoked pain, although neuralgic pain is still present. Similar to spinal cord–related pain, there is vast interpatient variability in CPSP. Common symp­ ­ ­ toms include: muscle pain, dysesthesias, hyperpathia, allodynia, intermittent shooting/lancinating pain, circulatory pain, and peristaltic/visceral pain.2

Management of Spinal Cord–Related and Brain-Related Pain
Nonopioid (i.e., NSAIDs) and opioid analgesics are virtually ineffective for the management of spinal cord–related or brain-related central pain. Other therapeutic classes that have been investigated include anticonvulsants, antidepressants, N -methyl-d-aspartate (NMDA) receptor antagonists, and GABA agonists. Based on evidence from small, double-blind, placebo-controlled trials, intravenous lidocaine, ketamine, or propofol may be beneficial for short-term pain control (up to 45 minutes, 30 minutes, and 3 hours, respectively).3-5 Unfortunately, the chronicity of central pain warrants the use of agents that provide long-term relief. Amitriptyline or lamotrigine can be considered as first-line therapy (TABLE 1).6 Amitriptyline use was associated with a reduction in pain and improvement in patient global rating when used in doses of 75 mg po daily over four weeks in a small, double-blind, placebo-controlled trial of 15 patients with CPSP.7 Vestergaard et al8 identified that the titration of lamotrigine up to 200 mg po daily over eight weeks was associated with a reduction in pain scores when compared to placebo in a small group of patients with CPSP. When evaluated in patients with spinal cord–related pain, lamotrigine use resulted in a reduction in brush-evoked allodynia (pain evoked by an innocuous brush) and wind-up-like pain (pain caused by repeated prickling of the skin).9 Second-line therapies include mexiletine, fluvoxamine and gabapentin; the data supporting the use of these agents, however, are based on poor-quality studies and/or anecdotal experience.3,10





Multiple Sclerosis–Related Pain
Patients suffering from multiple sclerosis (MS) endure a multitude of symptoms, including pain as a common complaint. Studies from the past 20 years have indicated a pain prevalence of 29% to 79% accompanying those afflicted with MS.11 Pain related to MS exists through two possible mechanisms, central (neuropathic) and musculoskeletal, and may present acutely and/or chronically. 12 Neuropathic pain stems from direct neurologic damage caused by demyelinating lesions, while musculoskeletal pain generally arises from reduced mobility.13 Osterberg et al14 identified that central pain occurs in approximately 28% of patients and that it typically presents in the early stages of the disease; in some cases, it is the initial clinical manifestation. Pain will likely increase as the patient's age and the duration of the disease increase, and may be the only indication of relapse. Central pain related to MS will predominantly affect the lower extremities, mainly the legs and feet, but can affect other areas as well.14 Patients with MS who suffer from central pain can have exacerbations precipitated by light touch, changes in temperature (specifically cold), physical activity, and emotional stress.15 In 2003, Svendsen et al found that patients with MS, when compared to reference subjects, described pain presenting most often as tiring/exhausting (48.6%), shooting (36.3%), hot/burning (22.9%), cramping (20%), heavy (24.7%), and aching (19.9%).16 Patients receiving interferon therapy to help slow the progression of MS may also experience muscle aches and headaches.17 In 2004, the National Collaborating Centre for Chronic Disease, based in London, released guidelines outlining treatment strategies for the management of MS.13

The initial treatment of central neuropathic pain related to MS should be with anticonvulsants, typically carbamazepine (Tegretol) or gabapentin (Neurontin). Tricyclic antidepressants (TCAs), initiated at low dosages, are useful for dysesthetic extremity pain. Lidocaine 5% transdermal patches (administered 12 hours on, 12 hours off) can also be considered as first-line therapy. Combinations of more than one initial treatment may be instituted to provide additional benefit. NSAIDs are the drugs of choice for patients suffering from musculoskeletal pain, and methocarbamol (Robaxin), a muscle relaxant, may also be considered. 17,18 Second-line treatments, such as lamotrigine (Lamictal), are beneficial if a patient is not responding to titrated dosages of carbamazepine or gabapentin. Lamotrigine should be titrated slowly due to the risk serious adverse effects. If patients are not responding to TCAs, other antidepressants such as bupropion (Wellbutrin), citalopram (Celexa), and venlafaxine (Effexor) may be initiated. Opioid therapy is likely to be effective in patients suffering from neuropathic pain that is refractory to first-line therapies. Patients should be initiated on short-acting opioids and titrated up based on symptom severity. Long-acting opioids should be reserved for chronic refractory conditions and patients who cannot be adequately controlled on short-acting medications.17

Other possible treatments for pain related to MS include capsaicin (Zostrix), which can decrease burning and tingling of the extremities by interfering with pain transmission; methylprednisolone for optic neuritis; clonidine; dextromethorphan; mexiletine; and ketamine.17-19 The use of cannabis has been investigated in patients with MS. Chong et al demonstrated that almost one third of surveyed patients were using cannabis illegally in an attempt to alleviate symptoms. There has been a significant correlation between use and disability.20 Cannabis has been shown in several studies to help decrease neuropathic pain as well as spasticity, an increase in muscle tone that occurs due to demyelination of certain central nervous system pathways, although controversy surrounding its use remains. Many believe its benefits in MS are comparable to short-acting opioid therapy, and most governments have rejected its approval as a viable therapeutic option. The Canada government recently approved a cannabis extract formulated as an oromusocal spray (Sativex) for neuropathic pain.21

Spasticity occurs in roughly 75% of patients with MS. Pain can present as exaggerated contractions or as muscle stiffness. Baclofen (Lioresal), a centrally acting skeletal muscle relaxant, and tizanidine (Zanaflex), an alpha2-adrenergic receptor agonist, are the most effective medications prescribed. Baclofen may be administered as an implantable, intrathecal pump, allowing drug to be delivered directly to the cerebrospinal fluid. This requires surgery, and both infection and withdrawal are possible complications. Botulinum toxin (Botox) injections may be used if a patient is suffering from localized, focal spasticity. Injections are repeated every three to four months and are very expensive.17,22 Diazepam (Valium) and dantrolene (Dantrium) should only be considered in patients nonresponsive to other therapies.

Trigeminal Neuralgia (tic douloureux)

Trigeminal neuralgia (TN), or tic douloureux, is defined as sudden, severe, and recurrent unilateral facial pain. It is considered to be a disease of the elderly, with a peak incidence between the ages of 50 and 70.23,24 Sixty percent of patients diagnosed with TN are female, and no racial or ethnic predisposition has been identified.23 Classic TN, formerly known as idiopathic TN, accounts for 80% to 90% of cases and may be attributed to compression of the trigeminal nerve by an anomalous loop of artery or vein that results in nerve demyelination.24 The superior cerebellar artery is the compressing vessel in almost 75% of cases.25 Benign tumors, such as meningiomas, or MS is identified in less than 10% of patients presenting with symptomatic TN. It is unclear how nerve demyelination or compression lesions cause the symptoms characteristic of TN. Neuronal hyperactivity, altered peripheral nerve sensitivity, and increased sensitivity to chemical and mechanical stimuli may explain the spontaneity of pain onset and cessation. 23-25 Furthermore, neuronal hypersensitivity can mimic focal epilepsy, thus possibly explaining the role of anticonvulsants in the pharmacologic management of TN.

TN is characterized by shock-like stabbing pain that is unilateral and abrupt in onset and termination, and is precipitated by nonnoxious stimuli. It is rarely accompanied by sensory loss.26 Pain is brief, lasting only a few seconds, and paroxysmal, with absence of pain in between episodes. Pain is provoked by the nonnoxious stimulation of trigger zones that can arise from cutaneous areas innervated by the trigeminal nerve or from teeth or oral mucosa.23 Cutaneous triggers include gently touching the face or shaving and mostly arise from the anterior regions of the face. Brushing the teeth, chewing, swallowing, or talking can also trigger paroxysms that arise from the oral region. Brief spasms of the facial muscles may accompany any episode. Other symptoms such as lacrimation or rhinorrhea rarely occur.25 Considered an intermittent disease, months to years can pass in between painful episodes of TN. When the patient experiences a recurrence, it is almost always in the same facial region, which can expand over time.23-25 In patients experiencing facial pain, other more common causes that are distinguishable from TN should be investigated. These include dental pain, temporomandibular joint pain, cluster headaches, migraines, and persistent idiopathic facial pain.24 In the absence of clinically useful diagnostic studies, patient history and dental examination are used to establish the presence of TN. Magnetic resonance imaging can visualize a vascular compression lesion or tumor, but this test is reserved for patients considering surgical treatment options.24

Anticonvulsants are considered the mainstay of therapy for TN. Carbamazepine is FDA approved for the treatment of TN in adults and is considered the drug of choice. Although its mechanism of action is not fully understood, carbamazepine is thought to reduce neuronal hypersensitivity by blocking voltage-sensitive sodium channels. 27 A systematic review of four placebo-controlled trials found that carbamazepine improved pain scores and reduced pain intensity in patients with TN.28 When compared to active control, carbamazepine was found to be superior to tizanidine and less effective than pimozide.28 Small sample sizes, variation in dosing between trials (400–2400 mg/day), and lack of standardized measures are just a few limitations that demonstrate the need for high-quality studies in this population. However, the rarity and spontaneity of TN may preclude this.

The recommended initial dose of carbamazepine is 100 mg orally twice daily and can be increased by 50 to 100 mg every three to four days, with a maximum recommended daily dose of 1,200 mg. Due to its ability to act as an autoinducer of cytochrome P-450 3A4, a dose adjustment may be warranted after the first three to five weeks of therapy, the time at which autoinduction is complete in patients managed on a fixed-dose regimen.27 The normal therapeutic range for the treatment of neuralgias is 2 to 7 mcg/mL, and concentrations measured during the first few weeks of therapy should be evaluated cautiously due to enzyme autoinduction. Carbamazepine is associated with several adverse effects including drowsiness, ataxia, photosensitivity, and blurred vision. More serious adverse effects include bone marrow suppression, hepatitis, and hyponatremia, and complete blood counts, liver function tests, and serum sodium levels should be evaluated prior to therapy and periodically thereafter. Oxcarbazepine may be considered as an alternative to carbamazepine due to its similar mechanism of action and more favorable adverse effect profile24; however, efficacy data in this population are derived from uncontrolled studies, and further evaluation is needed.

In patients who fail or cannot tolerate carbamazepine therapy, choice of therapy becomes less clear. Several other agents have been evaluated, but evidence supporting their use is weak and may be limited due to intolerable adverse effects. Anticonvulsants that can be considered as second-line therapy include gabapentin, lamotrigine, and phenytoin.29,30 Baclofen may be useful in patients with TN associated with MS.31 When pharmacologic interventions have been exhausted, surgical options should be explored. Available procedures with high initial response rates include microvascular decompression of the trigeminal nerve and nerve ablation.24 Microvascular decompression is associated with long-term pain relief and a low risk of sensory loss.

Discussion

Historically, there has been limited information regarding treatment options for central pain syndromes. As the pathophysiology becomes increasingly understood, new therapeutic options have emerged and the role of existing pharmacotherapeutic agents has expanded. Due to varying mechanisms of pain, medication selection and dosage are both issues. Certain medications will, in fact, have differing dosages based on the syndrome being treated. Pharmacists can play an integral role in drug selection based on the type of central pain that is being treated. In addition, therapeutic monitoring for several pharmacologic agents is essential for adequate and sustained patient care. This includes pain assessment, compliance issues, adverse drug reactions, and, in some instances, monitoring therapeutic levels. Through close patient interaction and attention to specific symptoms, pharmacists can make sound interventions to help patients avoid potential complications and achieve appropriate analgesia.

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