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12 Articles in Volume 12, Issue #3
Alternative Medicine in Chronic Migraine: What Clinicians Need to Know
Classic Central Pain Syndromes: Review of Neurologic Causes of Pain
Effective Treatments for Neuropathic Pain
Electric Current and Local Anesthetic Combination Successfully Treats Pain Associated With Diabetic Neuropathy
HCG and Diabetic Neuropathy
Migraine Treatment From A to Z
Opioid-induced Constipation: Causes and Treatments
Pain Management of Diabetic Neuropathy
Partnering With Parents
PPM Editorial Board Discusses Mental Deterioration in Pain Patients
The Critical Necessity to Diagnose Pain That Is Centralized
Unique Use of Near-Infrared Light Source to Treat Pain

Classic Central Pain Syndromes: Review of Neurologic Causes of Pain

Treatment of these very difficult cases involves more than just a medication: a full biopsychosocial intervention is most helpful.

Editor’s Note: Practical Pain Management has invited Dr. Jay, a leader in the pain management movement, to write an article on the classic central pain syndromes. Why? We feel that physicians would benefit from review of the classic neurologic diseases that gave rise to the term “central pain syndrome.” It is now 100 years after Dr. George M. Gould published An Illustrated Dictionary of Medicine, which was the definitive word on medicine at the time. He defined and described pain simply as, “bodily or mental suffering, distressing or agonizing sensation. It is usually due to irritation of a sensory nerve, although there are said to be pains of central origin.” About 50 years later, the term “central pain syndrome” started to be used to describe the pain after a stroke or concomitantly with a central neurologic disease, such as multiple sclerosis or Parkinson’s disease. Today, we now recognize that any peripheral pain, such as a degenerative spine, arthritic foot, or amputated leg, can transform into central pain. Some diseases like fibromyalgia can begin centrally or peripherally and end up becoming mostly central. The proper diagnosis going forward is simply “central pain.” It is incumbent on every practitioner to know that central pain has been suspected for 100 years, and pain accompanying brain disease has been known for at least 50 years. It is clear that a high percentage of pain treated in practice is “central” regardless of where it originates.

Neuropathic pain has a number of forms or diagnoses, but possibly the most difficult to understand and treat is central neuropathic pain (CNP). The various definitions of neuropathic pain indicate that there is pain caused by a lesion or disease of the somatosensory nervous system. The most common neuropathies, peripheral neuropathies, are often secondary to peripheral, small nerve fiber damage typically in the distal upper and lower extremities. This is in counter-distinction to the origins of CNP. Since there are a number of etiologies of CNP (see Table 1), this article will focus on neurologic diseases that cause central pain.

Table 1. The Classic Pain Syndromes

  • Multiple sclerosis
  • Parkinson’s disease
  • Spinal cord injury
  • Phantom limb pain
  • Post-stroke chronic pain

Multiple Sclerosis
Pain in multiple sclerosis (MS) is very common, with prevalence in patients ranging from 43% to 54%,1 to 86%.2 These patients have different types of pain (in addition to central pain), including dysesthesias in the extremities, complex regional pain, L’Hermitte’s sign, trigeminal neuralgia, painful tonic spasms, and pain secondary to painful tonic spasms.

CNP in MS is thought to be secondary to damage to myelinated nerves in the central nervous system and propagated by two main mechanisms: the generation of ectopic impulses at demyelinated lesions in response to neural damage,3or the removal of modulation of afferent A-δ and C-fiber pain pathways by interruption of inhibitory impulses from the brain.4

The pharmacological treatment of CNP can be broken into several treatment management groups. First-line management includes the use of tricyclic antidepressants (TCAs), gabapentin, or topical lidocaine; second-line management involves combination therapy using opioid analgesics or tramadol along with the first-line medications; and third-line management uses other antiepileptics and antidepressants.5

Parkinson’s Disease
The Parkinson’s disease (PD) patient may experience CNP via stabbing, burning, scalding, or lancinating pain, which is unprovoked in unusual locations such as the face, mouth, genitalia, pelvis, anus, or abdomen.6

A neurophysiological study of CNP in PD patients was done by Schestatsky et al7 who found that while conduction along the peripheral and central pain pathways was normal, with or without primary central pain, there were signs of hyperalgesia, and their patients exhibited a lack of habituation of sympathetic sudomotor responses to repetitive pain stimuli, which suggested an abnormal control of pain on the autonomic centers. These abnormalities were diminished by treatment with levodopa (L-dopa), which suggested that the dysfunction might occur in dopaminergic centers regulating the autonomic functions and inhibitory modulation of pain inputs.

It has been shown that the pharmacologic, electric, and surgical manipulation of the substantia nigra and striatum in non-PD patients can affect behavioral and neuronal responses to algetic stimulation; the basal ganglia may be involved in the modulating of nociceptive information (including sensory-discriminative, cognitive, and affective aspects of noxious stimuli). This modulation most likely occurs within the medial thalamus. It is possible that the structures in the basal ganglia provide a gating mechanism for regulation of nociceptive stimuli to higher motor centers.8,9

The use of L-dopa or injections of apomorphine (Apokyn) may transiently help patients with PD experiencing CNP.

Spinal Cord Injury
Pain is a frequent phenomena after spinal cord injury (SCI) and is very difficult to treat. It may involve various aspects of the brain. These patients may experience central pain beginning within weeks or months after injury. It is typically felt at or below the level of SCI in areas where patients have lost some or all of their sensation.

There also may be segmental pain around the border where patients have normal sensation and loss of feeling secondary to the SCI. Segmental pain may be associated with allodynia and hyperalgesia in the painful region. If a patient also has nerve root entrapment and/or syringomyelia (a hollow fluid-filled cavity, or syrinx) in the spinal cord, which commonly expands, more neurological damage may also develop. Some research have demonstrated the development of central sensitization of dorsal horn neurons after spinal cord hemisection. This would provide a logical mechanism for the development of mechanical and thermal allodynia after SCI.10

Recent research takes this hypothesis further. Dendritic spine remodeling occurs on second-order wide dynamic range neurons and accompanies neuropathic pain after SCI, showing the possibility that a synaptic model of long-term memory storage could explain the persistent nature of neuropathic pain, as SCI-induced synaptic potentiation engages a putative spinal memory mechanism.11

However, other research demonstrates that chronic pain after SCI appears to be associated with nociceptive primary afferent neurons, which display persistent hyperexcitability and spontaneous activity in their peripheral branches and somata in dorsal root ganglia (DRG) after SCI, suggesting that SCI-induced alterations of primary nociceptors contribute to central sensitization and chronic pain after SCI.12

Gwak et al indicate the SCI-induced release of glutamate, proinflammatory cytokines, adenosine triphosphate (ATP), reactive oxygen species, and neurotrophic factors trigger activation of postsynaptic neuron and glial cells via their own receptors and channels that contribute to neuronal-neuronal- and neuronal-glial interaction as well as microglia-astrocytic interactions. Post SCI, dysfunctional glia, a condition they call “gliopathy,” is a key contributor to underlying cellular mechanisms contributing to neuropathic pain.13

Finnerup indicates that chronic pain is present in about 70% of patients with SCI and chronic CNP in 30% to 50%.14 She concluded that: 1) evoked types of pain are more common in SCI patients with central pain; 2) lesions in central gray matter are larger in SCI patients with central pain; and 3) spinothalamic tract lesions are equally common in SCI patients with and without central pain.

Phantom Limb Pain
There are many questions behind the pathophysiology of phantom limb pain (PLP). Simply, possibly, one can say it is induced by the elimination or interruption of sensory nerve impulses by destroying or injuring the sensory nerve fibers after amputation or deafferentation. The incidence of PLP after trauma or peripheral vascular diseases is 60% to 80%.15 Stump pain is seen in more than half of the patients with PLP. PLP does not only occur post-limb amputation, but also post-mastectomy (phantom breast syndrome) as well as post-enucleation of the eye.15

PLP may be at least partly explained by considering mixed signals from the brain and to the brain from the spinal cord. After amputation, there is no input from the former limb, and nerve death follows. The brain may remap the part of the body’s sensory circuitry to another part of the body. The information from the expected but now amputated limb is referred elsewhere, from a missing foot to a present nose, for example. In that case, when the nose is touched, it may feel to the patient as if the missing foot is also being touched. However, as this is a tangled sensory web, the result can be pain.

PLP is described as burning, tingling, cramping, shocking, and paresthetic. Pain may vary from an unpleasant itch to a more severe clenching and squeezing sensation.

Aside from pain, after amputation the majority of patients either report the feeling of volitional control over their phantom or a phantom limb that is frozen in a specific position. Anderson-Barnes et al describe “proprioceptive memory” as the memories of the limb’s position prior to amputation that remains embedded within an individual’s subconscious. Pain memories that may be associated with each limb position contribute to PLP as well as to the experience of a fixed or frozen limb.16

Both peripheral and central changes take place post-amputation: sympathetic efferents interacting with sensory afferents modulating afferent activity such as spontaneous pain. Changes in neural processing are found proximally at the DRG and dorsal horn of the spinal cord. Second order neurons, which primarily respond to noxious stimuli, begin to respond to input from low-threshold, mechanosensitive A-β fibers that usually carry non-noxious stimuli, inducing exaggerated pain and allodynia.17,18 This induced central sensitization leads to spontaneous PLP as well as touch-evoked PLP and mechanical residual limb allodynia.19

An additional component to supraspinal changes responsible for phantom phenomena appears to include cortical reorganization. Long-lasting input from the limb and cortical pain memory that enhanced excitability and reorganization of the somatosensory zone correlate to the area of pain.20 This maladaptive plasticity within the sensory-motor cortex needs to be reversed, which newer forms of rehabilitation attempt using mirrors/mirror box therapy as an example.

This is a very difficult disorder to treat adequately. While there are various medications used (including antidepressants, anticonvulsants, mexiletine [Mexitil], opioids, N-methyl-D-aspartate [NMDA] receptor antagonists, clonazepam, etc), non-medical treatment, particularly rehabilitation, is extremely important. In some patients, surgical procedures as treatment options have been attempted including deep brain stimulation.

Central Post-stroke Pain
Central post-stroke pain (CPSP) was originally thought to be “thalamic” pain, as described by Dejerine and Roussy,21 although it was described even earlier in 1883.22 Dejerine and Roussy characterized their eponymous thalamic pain syndrome as including hemiplegia; hemiataxia and hemiastereognosis; difficulties with both superficial and deep sensation; persistent, paroxysmal, typically intolerable pain; and choreoathetoid movements.21 The reported incidence of CPSP varies widely from 2% to 8% in stroke patients and to 25% in patients with lateral medullary infarctions (Wallenberg’s syndrome).23-25

CPSP is broadly defined as CNP, secondary to lesion(s) or dysfunction in the central nervous system. CPSP is most typically associated with a single lesion, related to either a focal gray or white matter lesion; the lesion may be at the spinal, brain stem, or cerebral level, but it is always contralateral to the pain of CPSP. The pain of CPSP may unilaterally involve the contralateral (to the lesion) face, body, and extremities, or it may be focal, involving only a limb, part of a limb, or the face; it is almost always within the region of somatic motor or sensory impairment.26

It is typically characterized by constant or intermittent pain and sensory abnormalities, most commonly of thermal sensation.27 The pain is typically described as burning, scalding, or freezing and burning. Early diagnosis can be difficult, as the patients who develop CPSP may develop the problem long after their cerebrovascular accident (CVA), causing misdiagnosis or significant delay prior to treatment.28-30 Also, as these patients may have cognitive or speech difficulties—as well as depression, anxiety, and sleep problems—diagnosis may be further complicated. They may also develop spontaneous dysesthesias and stimulus-evoked sensory disturbances including hyperalgesia and allodynia.27,28 In 40% to 60% of CPSP patients, the onset of their centrally related pain post-stroke may occur more than one month after the CVA.31 The pain may encompass a large part of the contralateral body, but it may also involve only a small area. Allodynia is found in 55% to 70% of patients.32,33 Hyperalgesia and dysesthesia are also frequently seen.34

Evaluation of the CPSP patient may be more complex than that of the typical pain patient, at least in part for reasons noted above. The pain history must be accompanied by a pain-specific sensory examination; musculoskeletal and myofascial evaluation; and basic psychologic evaluation. Specialized sensory testing may also be needed, something that a neurologist can easily learn but may need specialized tools.35

Locations of the lesions inducing the CPSP have been demonstrated to be referable to the spinothalamocortical tract/pathway, typically associated with abnormal evoked sensations in the peripherally affected area.31,36,37 While at least three thalamic regions, which directly or indirectly receive spinothalamic projections, appear to be involved in the development of CPSP—the ventroposterior thalamus including the posteriorly and inferiorly located nuclei bordering on that region, the reticular nucleus, and the medial intralaminar region—it is the ventroposterior thalamic region that is proposed to be most significantly involved in central pain.38-40 It should also be noted that cerebrovascular lesions located above the diencephalon—that is, in the parietal lobe—may also induce CPSP.32,38,41

While damage to the spinothalamocortical pathway appears to be a necessary condition in CPSP, it is thought that the spontaneous pain linked to CPSP is secondary to hyperexcitability or spontaneous discharges in thalamic or cortical neurons that have lost part of their normal input.42 Studies using magnetic resonance imaging and positron emission tomography (PET) scans have demonstrated anatomical lesions and associated information. One study using functional magnetic resonance imaging and diffusion tensor imaging found that in CPSP, there is an important role of damage of lateral nociceptive thalamoparietal fibers, along with release of activity of anterior cingulate and posterior parietal regions.43 An older study using single-photon emission computerized tomography found a contralateral relative hyperactivity in a central region corresponding with the thalamic region in patients with CNP.44

Using quantitatively evaluated sensory testing, it was found that in CPSP, tactile allodynia occurs in disturbances of thermal/pain pathways that can spare the tactile signaling pathways, and that cold hypoesthesia itself is not necessary or sufficient for cold allodynia.45

A study by Willoch et al using PET scan technology revealed a striking loss of opioid receptor availability widely distributed throughout a great deal of the hemisphere contralateral to the pain (especially in the thalamus, anterior and posterior cingulate cortex, insula, S2, and lateral prefrontal cortex).46 It previously has been pointed out that decreased opioid receptor binding can also indicate the release of endogenous opioids during pain.47 The Willoch group found that the location and distribution of the diminished receptor binding was more extensive and showed little overlap as compared to the older study. It is thought possible that the loss of opioid receptor availability in CPSP may be secondary to a reduction or down-regulation of opioid receptors, resulting in a reduction of effectiveness of endogenous, opioid-mediated, analgesic mechanisms.46

A later study looked at peripheral neuropathic pain versus CNP.48 The authors used PET scans to evaluate patients with peripheral neuropathic pain (n=7) and CPSP (n=8). They found that in CPSP patients, interhemispheric comparison indicated a significant decrease in opioid binding in the posterior midbrain; medial thalamus; and the insular, temporal, and prefrontal cortices contralateral to the painful side. The patients with peripheral neuropathic pain did not show any lateralized decrease in opioid binding. The authors concluded that decreases in opioid binding were much more extensive than anatomical cortical lesions and were not co-localized with the lesions; metabolic depression (diaschisis) and/or degeneration of opioid receptor–bearing neurons secondary to central lesions appear to be a likely mechanism.48

Sympathetic dysfunction also has been felt to play a role in central pain secondary to signs of abnormal sympathetic activity: edema, hypohidrosis, trophic skin changes, changes in skin color, and decreased skin temperature.33,49 It also has been noted that some or many of these changes may be secondary to “movement allodynia,” which makes the patient keep the affected limb motionless.30

Reports of CPSP associated with abnormal “epileptiform” activities in thalamic cells may be involved with central pain.50,51 This would also indicate that some aspects of the problem may be secondary to cortical involvement, as epileptiform discharges are typically associated with that region. Another group also noted that central pain might be a manifestation of partial epileptic seizures.52

Treatment Options
Thalamic changes and many of the noted neuroanatomical and neurophysiological changes may also be involved in the other central pain diagnoses. Treatment of CPSP is difficult and options are limited. It should be noted, however, that the treatments outlined below can be used, to one degree or another, for all forms of CNP.

The most common first-line drug is amitriptyline, with other drugs including opioids used as second-line therapy.31 Amitriptyline is thought to be helpful secondary to its reuptake of norepinephrine and serotonin.37 In a controlled trial of amitriptyline and carbamazepine, only patients on amitriptyline reached a statistically significant reduction in pain compared to placebo. Patients on carbamazepine did not, but had “some pain relief” and more side effects.53

Aside from amitriptyline, anticonvulsants including lamotrigine and gabapentin have been reported to provide pain relief with better safety than carbamazepine and phenytoin.54-58 In spite of the articles suggesting lamotrigine provided good relief of CPSP, a Cochrane Review found that lamotrigine had only limited evidence that it would be useful, and it was, in fact, unlikely to be of benefit for the treatment of neuropathic pain.59

The author was introduced to “Sweet’s Cocktail” during training, which had a very narrow therapeutic index—amitriptyline 75 mg at bedtime and trifluoperazine (Stelazine) 1 mg three times per day. While I’ve never been able to find a quotation related to Dr. Sweet, Duthie published on this combination.60 A number of patients who had no pain relief with “typical medications” received relief with this drug combination, although the possible side effects of a phenothiazine must be constantly reviewed. Other antidepressants and anticonvulsants have also been tried in the treatment of CPSP, but none have become a primary or gold standard treatment.61-66

Intravenous lidocaine appeared to be helpful in patients with CPSP.67,68 Intravenous naloxone was not helpful in CPSP,69 while intrathecal baclofen, an agonist of γ-aminobutyric acid (GABA-B) receptors, did provide relief for CPSP patients.70

Stimulation of the primary motor cortex for intractable deafferentation pain, as well as central stroke pain, has been used successfully. The mechanism of pain relief by this form of electrical stimulation of post-central gyrus/M1 is uncertain.71,72 However, motor cortex stimulation is felt to be the treatment of choice in post-stroke pain, thalamic pain, or anesthesia dolorosa of the face.73 One group of researchers looked at the effectiveness of chronic subthreshold stimulation of the contralateral pre-central gyrus in patients with intractable neuropathic pain for more than 15 years. They found that patients with trigeminal neuralgia had a greater positive effect than those with CPSP. They noted that positive effects could last for 10 years in long-term follow-up.74

Repetitive transcranial magnetic stimulation of the primary motor cortex has also been used successfully, as long as the M1 is stimulated.75 Another group found this modality to give good but transient relief.76

Transcutaneous electrical nerve stimulation (TENS), both high and low frequency, was tested on patients with CPSP (n=15). Four patients obtained pain relief, 3 patients continued to use TENS ipsilaterally with good effect at 23 to 30 months, while in one-third of the patients, TENS temporarily increased their pain.77

One undesirable effect of repetitive deep brain stimulation (DBS) is the reduction of the seizure threshold, known as kindling.78-82 An associate of the author (personal communication) described a patient whose pain was only partially reduced with the original stimulus parameters of DBS. In an attempt to improve pain control, that individual used the external controller to increase the amount of stimulation above the amount used by the attending neurosurgeon. After several days of this maneuver, the patient suffered a first-ever focal onset, secondarily generalized seizure. To the author’s knowledge, this patient may represent the first case of self-induced kindling of seizures in a human patient using DBS for pain control.

Other treatments include sympathetic blockade, as well as surgical interventions including cordotomy, dorsal root entry zone lesions, thalamotomy, or cortical and subcortical ablation.83-89

When one looks for evidence-based medicine (EBM) treatment guidelines, an important one was published in 2007 by Dworkin et al.5 Table 2 outlines EBM guidelines for the pharmacological management of neuropathic pain.

Table 2. Guidelines for Treatment of Central Neuropathic Paina

First-line medications

  • Tricyclic antidepressants
  • Selective serotonin and norepinephrine reuptake inhibitors
  • Calcium channel gabapentinoid (α 2-δ) ligands
  • Topical lidocaine

Second-line medications

  • Opioid analgesics
  • Tramadol

Third-line medications

  • Other antiepileptics
  • Other antidepressants
  • Mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicins

a Treatment of very difficult cases may involve more than one medication

Conclusion
Treatment of these very difficult cases involves more than just a medication: a full-out biopsychosocial intervention is most helpful, and was best found in the interdisciplinary pain center, now extremely hard to find. However, while medication choices depend on knowledge, experience, and competence, the use of psychological services (such as cognitive behavioral therapy) as well as true rehabilitation are what will truly help the patient with CNP.90-92

Last updated on: June 11, 2015
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