Pain and CNS Disorders

Pain and CNS Disorders Charles E. Argoff, MD, CPE

Disclosure  Consultant/Independent Contractor: Boehringer Ingleheim, Grünenthal Pharmaceuticals, Depomed, Jazz Pharmaceuticals, plc, Insys Pharmaceuticals, Shinogi Pharmaceuticals  Grant/Research Support: Endo Pharmaceuticals, Forest Laboratories, Lilly USA LLC, NeurogesX, Pfizer Inc.  Honoraria: Boehringer Ingleheim, Depomed Endo Pharmaceuticals, Forest Laboratories, Janssen, Jazz, King, Lilly USA LLC, Neurogesx, Nuvo Research, Pfizer Inc. Sanofi-Aventis, US, LLC  Speakers Bureau: Endo Pharmaceuticals, Forest Laboratories, Janssen Pharmaceuticals, Inc. Lilly USA LLC, Pfizer Inc., Neurogesx

Learning Objectives  Describe common pain states associated with CNS Disorders  Describe available medical treatments for common pain states associated with CNS Disorders  List available interventional treatments for common pain states associated with CNS Disorders

Pain and CNS Disorders  Central pain has been defined as pain that results from lesions of the central nervous system. Since central pain is associated with lesions of the central nervous system, it is considered a type of neuropathic pain.  Multiple distinct clinical conditions resulting in pain following central nervous system lesions exist and several of these will be discussed in more detail  Causes of central pain include trauma, vascular, infectious, inflammatory, demyelinating, and hereditary and neoplastic

General Considerations  Central pain results from injury to somatosensory pathways in the central nervous system (spinal cord or brain)  The injury may be massive or minimal; some individuals with central pain have no obvious sensory loss despite the severe pain  The onset of pain following the injury may be delayed  The pain is sometimes reversible

General Considerations (continued)  Three main components of central pain include: pain evoked by stimulation, steady and neuralgic like pain and spontaneous pain  The pathophysiology of central pain is not well understood  Treating central pain successfully can be very challenging

Brain Central Pain  The most common cause of central pain resulting from brain injury is that resulting from stroke  Brain central pain may result from any type of lesion occurring at any level from the foramen magnum to the cerebral cortex  Seemingly paradoxical, the patient with central pain following a brain lesion may not have any clearly detectable sensory loss  Although previously thought to occur only as the result of thalamic lesions, it is now known that this type of pain can occur from any brain lesion affecting sensory processing areas

Brain Central Pain (continued)  Of interest is that traumatic brain injury and craniotomy do not frequently result in central pain  The onset of brain central pain may be immediate and most commonly it will occur within the first year following the injury; however, it may uncommonly have its onset more than one year after the injury  Brain central pain has been reported to be reversed following a stroke, or following the removal of a brain tumor.

Brain Central Pain (continued)  Pain is very commonly experienced in patients with various movement disorders including Parkinson’s Disease  Dystonia, a central condition associated with abnormal motor control of various muscle groups can be quite painful and may be focal, multifocal or generalized. Causes of dystonia include hereditary, post-traumatic, post-infectious and idiopathic.

Brain and Spinal Central Pain  Multiple sclerosis is a central nervous system demyelinating disorder that is frequently associated with pain  Painful conditions associated with multiple sclerosis include: acute transverse myelitis, pain due to spinal cord demyelination (myelopathy related pain), spasticity and trigeminal neuralgia (other secondary types of pain associated with multiple sclerosis, e.g. associated with osteoporosis, wheel-chair positioning, are not included here)

Spinal Cord Central Pain  Lesions of the spinal cord as the result of a diverse group of medical conditions can result in central pain  The most common reported cause of spinal cord injury is trauma with the cervical spinal region most commonly affected  The onset of spinal cord central pain is not infrequently delayed after the event that has caused it- actually in some reported instances for years

Spinal Cord Injury Central Pain (continued)  In one series of spinal cord related central pain, 75% of patients reported pain that was burning, 44% evoked by normal or painful stimulation, 31% shooting and 15% musculo-skeletal like  Patterns of sensory loss in this one series were quite variable with 42% of patients experiencing complete sensory loss, 39% incomplete loss, 16% dissociated loss and 3% did not experience any sensory loss

Spinal Cord Injury Pain (continued)  Central neuropathic pain is the most severe pain that may occur following spinal cord injury and may be more intense at the transition areas from normal to abnormal sensation  When the spinal cord is injured above the mid-thoracic region, the pain may be associated with painful muscle spasms and spasticity

Spinal Cord Injury Pain (continued)  Syringomyelia, refers to the development of a cystic cavitation (syrinx) within the central canal of the spinal cord  Causes of syringomyelia include: congenital (in association with the Arnold-Chiari malformation), post-traumatic, in associated with hematomyelia, post-infections and in association with an intramedullary spinal cord tumor

Spinal Cord Injury Pain (continued)  The pain that may accompany syringomyelia is most often neuropathic with patients experiencing burning, allodynia and hyperalgesia at the same time that they experience numbness in the affected region  Facial pain may occur when the syrinx extends into the upper cervical spinal cord  If the syrinx affects the thoracic region, the patient may complain of abdominal pain or pain around the truncal region and dissociated sensory loss and spasticity may be noted on examination

Diagnostic Evaluation  There are no general laboratory tests for this group of conditions.

For patients with suspected multiple sclerosis, spinal fluid analysis and various electrophysiologic studies such as visual evoked responses may be necessary to make this diagnosis  Neuroimaging studies including MRI and in certain instances CT/Myelography are important diagnostic modalities to use when evaluating and treating a patient with central pain

Treatment  There are no known consistently successful preventative strategies to consider for any type of central pain.

Treatment (continued)  Non-pharmacologic approaches must be considered and these, depending upon the associated neurological impairment of the patient, may include urologic care, pulmonary care, wound care, optimizing wheelchair/general seating and positioning, treatment of spasticity and muscle spasms (which may be painful as well), proper nutrition, physical and occupational therapy

Treatment (continued)  When medical therapies are considered for the management of central pain, one should keep in mind that although many treatments have been attempted, very few have been consistently helpful  Recently the FDA has approved pregabalin for the treatment of spinal cord injury pain  Gabapentin, a medication with a similar mechanism of action as pregabalin, may be considered as well  Different forms of gabapentin are now available

Treatment (continued)  Other medications that may provide some benefit to patients with spinal cord injury pain include amitriptyline, desipramine, carbamazepine, lamotrigine, non-steroidal anti-inflammatory agents, clonazepam, oral baclofen and tizanidine  Both baclofen and tizanidine are used to control spasticity but each may have analgesic qualities as well

Treatment (continued)  Medications that have not been shown to be helpful for spinal cord related central pain include: trazodone, valproic acid and mexiletine  The same medications may be considered for brain injury related central pain and in addition, studies have suggested that naloxone, or propofol may be helpful as well  For both spinal cord related central pain and brain injury related central pain, there are inconsistent results with the use of opioids for treating the chronic pain associated with these conditions

Treatment (continued)  Interventional therapies for central pain have also been utilized again with mixed and too often disappointing results  Peripheral nerve blocks may offer patients with spinal cord injury pain, temporary but not sustained pain relief  Intravenous lidocaine infusions may also result in temporary pain relief and some patients have experienced prolonged benefit with repeated infusions. These should only be completed in a monitored environment supervised by an experienced practitioner.

Treatment (continued)  The use of botulinum toxin injection should be considered when painful spasticity and/or painful muscle spasms associated with the central pain are present  For some patients with more generalized spasticity, the use of intrathecal baclofen via an implanted pump may be more appropriate than the use of botulinum toxin injections due to the widespread involvement in that setting

Implantable Intrathecal Pump

Treatment (continued)  Many patients with severe and widespread painful spasticity due to brain or spinal cord injury may actually benefit from both of these modalities. In this instance, the use of intraspinal baclofen would be helpful in reducing the more generalized spasticity and the use of botulinum toxin would be targeted in a more localized manner to address those areas that may be more resistant to treatment with intrathecal baclofen.

Treatment (continued)  These treatments combined or used singly certainly need to be individualized in a patient centered manner to address the specific needs of specific patients. Other intraspinal treatment approaches for central pain include the use of intraspinal morphine, clonidine or ziconotide

Treatment (continued)  The intraspinal treatments are highly specialized and should only be offered by those practitioners with sufficient training and experience to do so.  Particularly with respect to the use of these intraspinal therapies, monitoring and ongoing care is not only vital to the success of the treatment but is necessary and imperative from a patient safety perspective.  In order for these modalities to be used properly, it must be clear that the patient will and can be followed as closely as required by a properly trained and experienced practitioner for all aspects of intraspinal pump/medication management, including but not restricted to dose adjustment, pump refills, and all aspects of pump troubleshooting

Treatment (continued)  Additional surgical treatments for central pain due to spinal cord injury include percutaneous radiofrequency rhizotomy in which radiofrequency lesioning is directed towards specific nerve roots in an attempt to relieve especially allodynia and pain in the distribution of a particular nerve root  Cordectomy involves the transection of the spinal cord above the level of the area responsible for the pain. This is often not an acceptable approach not only because it is not always successful but because cord transection would prevent any chance of restoration of spinal cord function

Treatment (continued)  The Dorsal Root Entry Zone procedure (DREZ lesion) involves making a lesion into the pain fibers as they enter the dorsal horn of the spinal cord and is not without its risks of injury as well  Spinal cord stimulation, which can be successful for the treatment of post-laminectomy pain, as well as various other types of neuropathic pain has NOT been shown to be consistently effective for central pain associated with spinal cord injury

Treatment (continued)  Neurosurgical procedures such as deep brain stimulation while not helpful generally for patients with spinal cord injury related central pain, this modality has been used with varying degrees of success (0-80%) for patients with central post stroke pain

Follow-up  There are no general recommendations regarding follow up for patients with central pain. If a patient is being managed with intraspinal medications via an implanted pump or if a patient is being treated with botulinum toxin, those patients will require careful regular follow up consistent with the modality (no less frequently than every 6 months- often less for patients with pumps and generally every 12 weeks for patients receiving botulinum toxin injections). If a patient is being treated medically, periodic follow up is certainly recommended

Prognosis  Central pain remains an extremely challenging group of pain conditions from diverse causes to treat effectively on a long-term basis. Prognosis in general is therefore guarded.

Selected References  Hansen AP, Marcussen NS, Klit H, et al. Pain following stroke: A prospective study.

Eur J Pain. 2012 Mar 9.  Kim JS, Bashford G, Murphy TK, et al. Safety and efficacy of pregabalin in patients with central post-stroke pain. Pain. 2011 May;152(5):1018-23.  Klit H, Finnerup NB, Jensen TS Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol. 2009 Sep;8(9):857-68.  Finnerup NB, Baastrup C. Spinal cord injury pain: mechanisms and management.

Curr Pain Headache Rep. 2012 Jun;16(3):207-16.  Hadjimichael O, Kerns RD, Rizzo M, et al. Persistent pain and uncomfortable sensations in persons with multiple sclerosis. Pain. 2007 Jan;127(1-2):35-41.  Tasker, RR. Central Pain States. In: Warfield C and Bajwa Z. Principles and Practice of Pain Medicine, 2nd ed. Chapter 38. McGraw-Hill, 2004.