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Pain in Spinal Cord Injury (SCI) and Traumatic Brain Injury (TBI) HOWARD T KATZ, MD GULF STATES PHYSICAL MEDICINE AND REHABILITATION PAIN Pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” The International Association for the Study of PAin Why do we feel pain? •Pain warns organisms of injuries or the potential for injury, alerting the organism to withdraw from the painful stimulus. •In higher species (such as humans) pain also stimulates the areas of the brain responsible for anxiety and anger. •Pain is an important concern in Spinal Cord Injury and Traumatic Brain Injury. ALL PAIN IS NOCICEPTIVE Nociceptors •Pain results from the activation of nociceptors, which are peripheral neurons that respond to the stimuli we perceive as painful. •There are 2 types of nociceptors: C and Aδ (“Adelta”) •Both carry signals to the dorsal root ganglion of the spinal cord. They are also referred to as First Order Pain Neurons. “C” nociceptors •Most common type of nociceptor in humans (around 70%) •Small, unmyelinated nerve cells bundled together and surrounded by Schwann cells •Conduct signal at 0.4 to 1.4 m/s •Respond to thermal, mechanical, or chemical noxious stimuli Aδ (A-delta) nociceptors •Myelinated neurons •Conduct signals at 5-30 m/s (much faster than the C type) •Respond primarily to heat and mechanical stimuli and helps localize the pain Interaction with Central Nervous System All nociceptors terminate in the dorsal root ganglion of the spinal cord. There, they activate one of four types of nocineurons: •High threshold mechanical neurons excited by noxious cutaneous or visceral stimuli. They release glutamate and other neuropeptides that activate dorsal horn neurons •Chemical nociceptors neurons are excited by chemical or thermal stimulation •Thermal nociceptor neurons are also excited by chemical or thermal stimulation •Polymodal nociceptors are exited by both noxious and non-noxious stimuli of various types, and they respond incrementally as the intensity of the stimulation increases Neurospinothalmic Tract After reaching the spinal cord, pain ascends to the brain using on of four pathways. The neurospinothalamic tract is the major and fastest pathway . In this tract, signals cross over the spinal cord, so an injury on the left will travel up the spinal cord on the right, and vice-versa. Trigeminothalmic tract Trigeminal fibers respond to noxious stimuli to the head, fact, and intraoral cavity. These fibers entire the pons, descend to the medulla and make synaptic connections in the spinal trigeminal nucleus. The trigeminothalmic tract provides immediate awareness of pain and its location. Paleopsinothalamic Pathway This third pathway evolved earlier than the other two. The pathway starts at multi-receptive C nociceptors and signal is conveyed up both sides of the spinal cord to the hypothalamus, basal ganglia, insular cortex, and the sensory cortex. Also, this pathway stimulates cells in the brain stem which activate the descending pain suppression pathway. Archispinothalamic Pathway This is the oldest of the four pathways. Signals begin at C fibers and ascend up the spinal cord on both sides, activating the hypothalamus and limbic system. Comparison of the four pathways •Neurospinothalamic and Trigeminal are the fastest and cross the midline, traveling on the opposite side of the stimuli •Paleopsinothalamic and archispinothalamic pathways evolved earlier than the others. They transmit pain signals more slowly and move up both sides of the spinal canal •All pathways end in the thalamus/hypothalamus •The are also referred to as Second Order Pain Neurons After pain signals reach the brain •The thalamus sorts pain signals. •Fast signals from the neospinothalmic tract are rerouted to the primary somatosenory cortex, the secondary somatosensory cortext, the insula cortex, or the anterior cingulate cortex Primary somatosensory cortex •Receives signals from both C and A-delta fibers •Since A-delta fibers transmit signals much faster than C fibers, they are the first to react to a painful stimulus and localize it •The ratio of A-delta fibers to slower C fibers provides information on the intensity of the pain •If painful stimulus is prolonged, then more C fibers are activated, which provokes diffuse, aching pain Secondary somatosensory cortex •Activates only when a certain threshold of stimulation is reached •Above level of pain identification in the primary somatosensory cortex and exhibits no dose response •Though to be involved in learning, memory, and future pain avoidance Insula Cortex •The relationship of the insula cortex to pain is still being explored •Study by Starr et al. suggests it is involved in defining and regulating pain thresholds •It also is believed to be involved in pain memory and psychological reactions to pain Anterior Cingulate Cortex •Involved with the affective and emotional pain •Pain is a subjective experience, and different people can have very different pain reactions to the same stimulus •Pain threshold can be decreased by anxiety and depression •The anterior cingulate cortex is integral to our subjective experience of pain and treatment for pain Amygdala •The amygdala receives secondary activation signals the insula cortex •The amygdala influences our behavioral and emotional responses to pain •Recent research indicates neuroplasticity in the amygdala, which may lead to development of new pain management techniques Prefrontal Cortex •The prefrontal cortex receives secondary activation signals from the anterior cingulate cortex •The prefrontal cortex is central to controlled pain modulation or an individual’s personal pain inhibition mechanism Basal Ganglia •Sensory, motor, autonomic, cognitive, and emotional components of pain are processed in the basil ganglia •Signals arrive from the prefrontal, oribitofrontal, dorsolateral, motor, premotor, sensorimotor and parietal corticies and directly from the thalamus •The basil ganglia also send back signals to the thalamus •In studies, deep brain stimulation of the globus pallidus of the basil ganglia resulted in 70% decrease in reported chronic pain. After signals reach the brain, con’t •Signals traveling along the trigeminal and paleospinothalmic pathways also reach the thalamus •Signals can be routed from the thalamus to the basil ganglia, prefrontal cortex, anterior cingulate cortex, and the primary motor cortex •Responsible for arousal and withdrawal, as well as autonomic and affective responses to pain Types of chronic pain •Inflammatory pain results from direct insult to tissue (whether through trauma, infection, or degenerative processes). •Neuropathic pain results from insult to the nervous system itself (and may be either central or peripheral). •A third type, nerve dysfunction pain, does not fit in either category. Examples are migraines, fibromyalgia, and irritable bowel syndrome. •Both chronic inflammatory and chronic neuropathic pain are common in TBI/SCI survivors. Neuropathic Pain (con’t) Neuropathic Pain is “a complex, chronic pain state that usually is accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional or injured. These damaged nerve fibers send incorrect signals to other pain centers”. The American Chronic Pain Association Neuropathic Pain (con’t) •Neuropathic hyperalgesia can be both primary and secondary •Primary hyperalgesia occurs directly at the site of injury •Secondary hyperalgesia involves undamaged nociceptive fibers near the injury site and is thought to involve central nervous system sensitization •Secondary hyperalgesia responds only to mechanical stimuli, not temperature stimuli Neuropathic pain (con’t) •In the 1990s, two studies provided strong evidence that the central nervous system was involved in secondary hyperalgesia. •Both studies used capsaicin, which is responsible for the burning sensation from chili peppers. Neuropathic Pain (con’t) •In a study by LeMotte et al., one arm was injected with capsaicin. This caused intense burning pain and the formation of three areas of hyperalgesia around the infection site. Tender to gentle stroking Hyperalgesic to normally painful mechanic stimulation (55 sq.cm) (38 sq. cm.) Hyperalgesic to heat (2 sq. cm) Neuropathic Pain (con’t) •In a study by Torebjörk et al, capsaicin was injected into the top of the foot. The researchers directly electrically stimulated the nearby superficial peroneal nerve, producing a painful response at levels of stimulation that would ordinarily be non-painful. Because the peroneal nerve was stimulated directly, the study demonstrated that neuropathic pain was a central nervous phenomenon. Neuropathic Pain (con’t) •Centralized hypersensitivity to mechnostimulation •Both damaged and undamaged nociceptive neurons demonstrate abnormal signal generation Neuropathic Pain (con’t) In SCI: •Changes in Na+ channel receptors reducing their stimulation threshold •Dormant astrocytes and microglial cells are activated in the dorsal ganglia of the spinal cord •Reorganization and remodeling of neural pathways near the brain Pain in SCI •Chronic pain is extremely common in spinal cord injury (SCI) survivors, affecting between 66% and 80% of survivors. •Pain in SCI can be extremely disabling and leads to poor physical and mental health outcomes. Musculoskeletal Pain in SCI •Generally manifests as aching pain •All bones and joints are at risk of damage in SCI •Upper body pain is thought to result from overuse •Nerve entrapment is also common Visceral Pain in SCI •Visceral pain is poorly localized pain in the abdomen or around the pelvis •Suvivors describe burning, cramping pain that varies in intensity •Visceral pain can occur in the absence of other abdominal pathology Neuropathic Pain in SCI •Frequently described as burning, shooting, stabbing, or tingling •Most commonly occurs at or below the level of cord injury, but also can occur above the level of injury •Neuropathic pain is the most common type of chronic pain in spinal cord injury and is very difficult to treat PAIN in SCI 60+% complain of more than one type of pain • 35% reported 2 types of pain • 20% reported 3 types of pain • 8% reported more than 3 types of pain •70% neuropathic •61% musculoskeletal •35% spastic •30% visceral • 3% syringomyelia NEUROPATHIC PAIN in SCI •52% report pain below the level of injury •38% report pain at the level of injury • 5% report pain above the level of injury •Mean pain intensity ranged between 50 and 60 Pain in SCI (con’t) •There is no one agreed upon standard treatment for pain in SCI •Clinicians often must try many different treatments to find an effective ones for individual patients •When treatment is found, it generally provides only incomplete relief •Depression and anxiety are common comorbidities •Psychiatric treatment such as antidepressants and cognitive behavioral therapy are often important parts of a treatment plan for pain Effectiveness of various pain interventions Effectiveness of various pharmacological treatments for SCI pain as rated by survivors (Huetink et al) Pharmacologic agent Effective to a large extent Somewhat effective Not effective Opioids 54.5% 36.4% 9% Benzodiazepines 52.9% 47.1% 0% NSAIDS 50% 50% 0% Anticonvulsants 46.9% 46.9% 6.3% Antidepressants 38.5% 46.2% 15.4% Cannabis/Alcohol 83.3% 16.7% 0% Other Medications 38.5% 53.8% 7.7% Effectiveness of various pain interventions (con’t) Effectiveness of various non-pharmacological treatments for SCI pain as rated by survivors (Huetink et al) Treatment Effective to a large extent Somewhat effective Not effective Acupuncture 83.3% 16.7% 0% Massage/relaxation 58.7% 38.7% 2.7% Physiotherapy/exercise 68.8% 25% 6.3% Psychological treatment 54.5% 27.3% 18.2% Injections/neurosurgery 40% 30% 30% TENS/Ultrasound 11.1% 55.6% 33.3% Other 61.1% 27.8% 11.1% Musculoskeletal Pain • NSAIDs and physical therapy are first line treatments • Prevent overuse of painful areas • Opioids reasonable if other interventions are ineffective Painful muscle spasm •Baclofen (muscle relaxant) is first line treatment •Phenol or Botox injections may also be tried Visceral pain •Visceral pain has a delayed onset, and the etiology is unclear •The medical literature has little to say on effective treatments for visceral pain Nerve compression pain •Both extremity and central nerves are at risk for entrapment in SCI •Treatment is similar to persons without a spinal cord injury, including injections, massage, physical therapy, and possible decompressive surgery. Post-traumatic syringomyelia •A cyst with cerebral spinal fluid (CSF) can develop in SCI •Causes constant burning pain associated with allodynia •Visible on MRI •Because of severe complications, surgical treatment is indicated Treating neuropathic pain in SCI •Neuropathic pain is clinically the most difficult to treat •Pain is not necessarily severe, but frequently constant and interferes with sleep, rehabilitation, and activities •Even “successful” treatments may only result in 20% to 30% pain relief Treating Neuropathic Pain •GABA agonists •Serotonin and norepinephrine reuptake inhibitors (SNRIs) •Glutamate receptor inhibitors •NMDA receptor inhibitors •Antidepressants/anticonvulsants •All options can have adverse central nervous effects Antidepressants: Amitriptyline •Only tricyclic antidepressant that has been studied for treatment of neuropathic pain following SCI in humans •Adverse effects in 98% of patients (90% adverse effects for plocebo) •Studies conflicting about efficacy in SCI pain, but is reasonable to try due to demonstrated effectiveness in similar conditions •Side effects include dry mouth, constipation, nausea, bladder retention, drowsiness, and fatigue Antidepressants: SNRIs • Venlafaxine and duloxetine, serotonin and norepinephrine reuptake inhibitors (SRNIs), have demonstrated effectiveness in diabetic neuropathy • Venlafaxine can raise blood pressure • Duloxetine is contraindicated if patient has hepatic disease Anticonvulsants: + Ca antagonists •Gabapentin and pregabalin can be effective in treating neuropathic pain •Reasonable first line treatments, although caution must be exercised in the presence of renal disease Anticonvulsants: Lamotrigine •Na+ agonist, inhibits glutamate •9 week trail showed significant pain reduction with no significant difference in adverse effects compared to placebo •Due to risk of rare but life-threatening reactions, slow upward titration is warranted Opioids •Demonstrated efficacy in reducing peripheral neuropathic pain, but unclear role in central neuropathic pain •As needed opioid therapy for breakthrough pain is reasonable •Long-term opioid therapy may be considered if other treatment options have been exhausted Cannabinoids •Some evidence of efficacy in central neuropathic pain in multiple sclerosis •Cannot be prescribed in Mississippi Guidelines for pharmacologic treatment of neuropathic pain First line Second line Third line Gabapentin Pregabalin Amitriptyline Nortriptyline Duloxetine Venlafaxine Lamotrigine Tramadol Opioids Chronic pain in traumatic brain injury (TBI) •Difficult to assess pain in moderate to severe traumatic brain injury due to emotional and cognitive deficits •Though generally less severe, emotional and cognitive deficits may impede diagnosis and treatment even in mild traumatic brain injury •Estimates of true prevalence vary widely (11% to 93%) Chronic pain in TBI (con’t) •Higher reported incidence of chronic pain in mild TBI compared to severe TBI •Difference may result from inability of severe TBI survivors to communicate their pain to providers •Most common pain complaint in TBI is headache, with reported incidence between 44% and 64% •TBI survivors with pre-existing headaches experience worsening symptoms Chronic pain in TBI (con’t) •Complex regional pain syndrome (CRPS) is reported in a minority of TBI survivors •Neuropathic pain is believed to result from TBI, but incidence is unknown •Unlikely in SCI, neuropathic pain in TBI is believed to result from direct insult to pain interpreting sections of the brain Chronic pain in TBI (con’t) •Damage to mid-brain, brain stem, or cerebellum can lead to spastic hypertonia •Spasticity is more challenging to treat in TBI than in SCI •Heterotopic ossification (HO), or bone formation within soft tissue, affects 11% to 22% of TBI survivors •HO common in hips, shoulders, and elbows Treatment for headache in TBI There are multiple types of headaches that TBI survivors may suffer from, and treatment depends on the specific diagnosis. Abortive treatments Prophylactic treatments Tension Headache NSAIDs Acetaminophen TCAs (e.g. Amitriptyline) Topiramate Migraine Acetaminophen Aspirin Caffeine Naproxen Ibuprofen Triptrans Antiemetics Dexamethazone DHE Midrin SSRI SNRI Beta blockers Verapamil Amlodipine Anticonvulsants Cluster SubQ or nasal triptans Verapamil Verapamil Prednisone Valproic acid Topiramate Treatment for complex regional pain syndrome (CRPS) in TBI •Difficult to treat •Bisphosphonate compounds (Calcitonin, Clodronate, Alendronate) have shown significant efficacy •Steriod injections and topical analgesics Dimethyl Sulfoxide (DMSO) and lidocaine may improve symptoms Treatment of neuropathic pain and spasticity in TBI •The causes of neuropathic pain and spasticity in different in TBI compared to SCI, but the treatment is similar. Treatment of heterotrophic ossification (HO) • • • • • NSAIDS COX-2 inhibitors Physical therapy Bisphosphonates (prophylaxis) Radiation therapy Opioids in chronic TBI and SCI pain •Opium has been known as an analgesic for thousands of years •Morphine and heroin, isolated in the 19th century, are extremely potent analgesics, but the danger of dependence and adverse effects is extremely high •Other opioids are less potent but still carry significant risks of abuse, dependence, and adverse effects •Due to their efficacy and in spite of their risks, opioids remain a treatment option in acute and chronic pain Action of opioids •Opioids bind to μ-opioid receptors throughout the central nervous system. •They act on components in the brain central to pain processing (amygdala, thalamus, hypothalamus) •Chronic exposure leads to more excitable neurons and therefore can cause hyperalgesia •Due to dopamine sensitivity, the frontal cerebral cortex (the decision making center of the brain) is particularly prone to alteration from opioids Conclusion Chronic pain is a common and complex clinical challenge in both TBI and SCI survivors. Pain receives less attention than motor deficits in SCI or cognitive and emotional deficits in TBI, but the pain can be quite debilitating in its own right. Treatment of pain is very important to the rehabilitation and quality of life of TBI and SCI survivors.