NORD gratefully acknowledges Prof. Sergio Canavero, MD, Turin Advanced Neuromodulation Group, Torino, Italy, for assistance in the preparation of this report.
Central pain syndrome is a neurological disorder caused by damage to the sensory pathways of the central nervous system (CNS). Common symptoms include pain (but also pruritus) and loss of sensation, usually in the face, arms and/or legs. Pain is often constant (but can be intermittent) and can be mild, moderate, or severe in intensity. Affected individuals may become hypersensitive to painful stimuli. The specific type of pain experience can vary from one individual to another based, in part, upon the underlying cause of the disorder and the area of the central nervous system affected. Central pain syndrome can potentially disrupt an individual’s daily routine. In severe cases, the pain can be agonizing and unrelenting and dramatically affect a person’s quality of life. Central pain syndrome can develop following a variety of conditions including stroke, multiple sclerosis, spinal cord injury, brain tumors, or iatrogenic damage to the central nervous system.Introduction
Central pain was first described in 1891 by German neurologist L. Edinger. For years, it was believed that the majority of cases of central pain syndrome were due to damage of the thalamus most often caused by a stroke. Later on, the disorder came to be labelled Dejerine-Roussy syndrome after the two French neurologists who described the so-called thalamic syndrome (1906), which included a pain component. Thereafter, and up until recently, central pain became synonymous with thalamic pain syndrome. However, researchers now know that damage to the pain-conducting pathways anywhere along the neural axis, from the spinal cord to the sensory cortex, can cause central pain syndrome, including cases following injury or a stroke. Consequently, the current name for this group of disorders is central pain syndrome to acknowledge that damage to various areas of the CNS (and not predominantly the thalamus) can cause central pain and that a stroke is not necessarily the primary cause. Central pain syndrome can be broken down into central pain of brain or brainstem origin or central pain of spinal cord origin. The term for the specific subtype of central pain syndrome caused by CNS damage due to a stroke is central post-stroke pain. Pains described as central pain in such conditions as Parkinson’s disease are not truly central pain and have a different pathophysiology and treatment: these are termed central-pain allied conditions.
The onset of central pain syndrome can vary from days to weeks to months or more than a year after injury to the central nervous system. However, the disorder can also appear immediately after an injury or within a day. In most cases, central pain syndrome remains a lifelong condition.
Central pain syndrome can be limited to a specific area of the body such as the hands or feet or may be widespread over a large portion of the body. Some areas of the body may be more intensely affected than other areas. Pain can fluctuate during the day and can be affected by several factors including touch, emotions such as stress, certain movements or overall level of activity, and temperature changes, especially cold temperatures. Rest and distraction may lessen symptoms.
Central pain syndrome can vary greatly from one individual to another, in part, based upon the underlying cause of the condition. In some cases, symptoms of central pain syndrome can be vague and difficult to characterize. Many different pain sensations including burning, stabbing, lacerating, pressing, aching, prickling or tingling (a feeling of being on “pins and needles”) may occur. A constant burning sensation is in several cases the most prominent symptom. Pain can be constant and unrelenting or it may come and go (intermittent). In most cases, pain is constant and usually moderate or severe in intensity. In some cases, pain has been described as agonizing. Some affected individuals may experience short bursts of sharp, excruciating pain, which has been compared to the pain that occurs when a dental probe strikes an exposed nerve. In some cases, the constant pain associated with central pain syndrome can be debilitating and affect an individual’s ability to perform daily tasks and significantly impair quality of life.
Pain sensations associated with central pain syndrome are generally spontaneous, which means they occur despite no apparent cause or trigger. People with this disorder may be extra-sensitive or have a heightened response to acute painful stimuli (hyperalgesia, hyperpathia), which means that pain that would normally be small or minimal is felt to a far greater degree. In addition, individuals may feel pain from stimuli that would normally not be painful (allodynia). For example, affected individuals may experience pain when touched, even when lightly touched. In severe cases, this can include pain caused by a strong breeze, the weight of a blanket, or even the clothes a person is wearing.
Some individuals with central pain syndrome may initially experience impairment or distortion of sensation, especially of touch (dysesthesia). Dysesthesia is described as vague, unpleasant sensations. Some individuals may experience a painful numbness, especially affecting the feet. Itching (pruritus) has also been reported in individuals with central pain syndrome.
Some individuals with central post-stroke pain may experience painful symptoms on one side of the body (from head to foot); other notable, accompanying symptoms include loss of sensation (hemihypesthesia), partial or complete muscle weakness (hemiparesis, hemiplegia), and , on occasion, abnormal, involuntary, irregular jerky motions and slow, writhing movements (hemichoreoathetosis).
The disorder develops following damage to the central nervous system – the brain, brainstem or spinal cord. Such damage is most often associated with a stroke, multiple sclerosis, spinal cord (but also brain) injury or brain tumors. Central pain syndrome can also develop after neurosurgical procedures involving the brain or spine.
Central pain syndrome results from damage to the pain-transmission pathway from the level of the spinal cord up to the cortex, the grey matter that covers the cerebral hemispheres.
Central pain syndrome is due to a disturbed communication between the sensory thalamus and the sensory cortex. The thalamus is a structure deep in the brain that acts as the key hub in sensory processing, in synchrony with the cortex. When this synchrony is disturbed by neural damage that unbalances the brain’s inhibitory tone, the cortex and some thalamic nuclei are “locked” together in an altered state of activity. CPS is thus due to a dysfunctional corticothalamic loop along the sensory pain-conducting pathways.
This understanding points to new experimental therapeutic strategies (see below).
Central pain syndrome is estimated to affect several million people worldwide. Approximately, 5-10% of individuals who suffer a stroke, 20-40% of spinal cord injury patients, almost 30% of patients suffering multiple sclerosis and an uncertain number with other conditions develop central pain.
A diagnosis of central pain syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Central pain syndrome is suspected in individuals who complain of pain or other abnormal sensations following injury to the central nervous system. Other conditions that cause pain may need to be excluded before a diagnosis of central pain syndrome is made.
Clinical Testing and Workup
Magnetic resonance imaging (MRI) is the technique of choice to visualize tumors, infarcts, cerebral hemorrhage, demyelinating plaques and other causal lesions. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Recent permutations of this technique (such as magnetic resonance spectroscopy or default-state MRI) have only research interest.
Laser evoked potentials are rarely needed to confirm damage to pain conducting pathways and are not available on a routine basis.
Screening tools (in the form of questionnaires) have been developed, but miss 12-45% of cases and as such are not recommended for finalizing a diagnosis.
Treatment for central pain syndrome remains unsatisfactory in that, although most patients find some relief, complete control remains infrequent. Additionally, therapies that have proven beneficial in some individuals may have no benefit in others.
Traditional pain medications (e.g. NSAIDs) generally provide little to no relief for individuals with central pain syndrome. However, drug therapy remains the first-line therapy for most affected individuals. Two drugs, amitriptyline and lamotrigine, have proven beneficial in controlled trials, especially for individuals with central pain of brain origin. Amitriptyline is an antidepressant. Lamotrigine is an anti-seizure drug (anticonvulsant). Antiarrhythmics (mexiletine) and local anesthetics such as lidocaine can be effective.
Gabapentinoids, another type of anti-seizure medication, although FDA approved for central pain, are not indicated as first line therapy for central pain: close, conflict-of-interest-free, scrutiny of the entire database (including unpublished studies) reveals that these drugs are poorly effective in the vast majority of patients, only infrequently affording meaningful benefit. Although FDA approved for chronic pain, unbiased assessment of the entire database shows that use of ziconotide has a very low therapeutic index with lack of consistent benefit in a majority of patients. Opioids such as morphine or levorphanol are not effective in the vast majority of cases and are actually contraindicated for most patients.
In several cases, the effectiveness of drug therapies are limited due to associated side effects.
Recent developments point to alternative/complementary therapies that can be added to drug therapy. Of special interest is virtual-reality-assisted hypnosis. Supportive care, rehabilitation, and psychotherapy are recommended as well.
Individuals with central pain of brain origin who do not respond to drug therapy may be treated with extradural cortical stimulation of the sensory-motor area (MCS/PCS), a procedure that has been used to treat refractory, chronic pain. During this procedure, a stimulating paddle or plate is placed extradurally (or sometimes subdurally) on the primary motor cortex and/or primary sensory cortex to deliver electrical stimulation. Extradurally means that the paddle is placed on the dura mater, the outermost layer of the membranes (meninges) that line the brain and spinal cord. The paddle is inserted through two burr holes or via the temporary removal of a small piece of the skull (craniotomy). According to the medical literature, more than half of individuals have seen a pain reduction of greater than 50% with no significant morbidity. Studies show that this form of stimulation is more effective that placebo stimulation.
Non-invasive forms of cortical stimulation such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) have been employed in the management of CPS, but data show that their efficacy is not on a par with neurosurgical intervention. However, they may help select patients for surgical implantation.
Extensive studies showed that deep brain stimulation is NOT indicated for the treatment of individuals with central pain syndrome, with few exceptions, and only after a trial of CS. During this surgical procedure, an electrode is placed into the thalamus and a thin wire is passed under the skin is connected to a small battery pack (which is also placed underneath the skin). The risk of lethal brain hemorrhage is small, but real.
In resource-constrained contexts, spinal cord stimulation benefited a small percentage of patients with both CCP and BCP, but long-term control is rare.
Some individuals experience pain relief through the direct injection of drugs into the cerebrospinal fluid that surrounds the brain and spinal cord (intrathecal administration). Drugs such as baclofen or midazolam have been used in this manner. A few individuals have experienced pain relief through the insertion of a morphine pump that delivers drugs intrathecally, but as mentioned should be considered as a last-resort. Intrathecal drug delivery is not always effective for the treatment of individuals with central pain syndrome. However, much more research is necessary in this area.
In the past, surgery has been used to treat individuals with central pain syndrome. This includes invasive, drastic surgeries such as the surgical removal or destruction of targeted parts of the brain such as thalamus (thalamotomy) and mesencephalon (mesencephalotomy). However, most of these surgeries were generally associated with low long-term success rates and a high risk of complications and morbidity. Such invasive surgeries are rarely used for individuals with central pain syndrome anymore.
According to the medical literature, a surgical procedure known as subparietal leucotomy/capsulotomy has the potential to eliminate pain associated with central pain syndrome. During this procedure, a small lesion is made in certain areas of the white matter of the brain in order to interrupt the descending arm of the corticothalamic loop. In one case reported in the medical literature, this procedure immediately and completely relieved pain in the affected individual. However, more research is necessary to determine the long-term safety and effectiveness of this procedure as a potential therapy for individuals with central pain syndrome.
Recent advances in the field of spinal cord injury suggest that removal of an injured segment of the spinal cord, wherever feasible, accompanied by vertebrectomy or multiple discectomies might benefit both motor and sensory recovery. This is an experimental avenue that awaits human trials.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials conducted in Europe, contact:
Canavero Sergio, Vincenzo Bonicalzi. Central Pain Syndrome: pathophysiology, diagnosis and management. 3rd Edition, Cham: Springer Verlag (an imprint of SpringerNature), 2018.
Canavero Sergio (editor). Textbook of cortical brain stimulation. 2014, Berlin: DeGruyter Open.
Canavero Sergio (editor). Textbook of therapeutic cortical stimulation. New York: Nova Science, 2009.
Canavero S, Bonicalzi V. Central pain syndrome: elucidation of genesis and treatment. Expert Rev Neurother. 2007;7:1485-1497. http://www.ncbi.nlm.nih.gov/pubmed/17997698
Canavero S, Bonicalzi V. Extradural cortical stimulation for central pain. Acta Neurochir Suppl. 2007;97:27-36. http://www.ncbi.nlm.nih.gov/pubmed/17691286
National Institute of Neurological Disorders and Stoke. Central Pain Syndrome Information Page. May 25, 2017. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Central-Pain-Syndrome-Information-Page Accessed Feb. 6, 2018.
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