Summary of Key Points
Back pain is a common complaint seen at least once during the life span in more than two thirds of general population.
Failed back surgery syndrome is a common cause of chronic low back pain in which conservative measures should be considered before invasive surgical procedures.
Randomized controlled trials have shown spinal cord stimulation to be superior to conventional medical management or repeat surgery in failed back surgery syndrome.
Severe complex regional pain syndrome carries a poor prognosis with approximately one fourth of affected individuals able to return to normal functioning. Spinal cord stimulation and physical therapy are effective in the management of complex regional pain syndrome.
Intrathecal drug delivery system can be an effective treatment option for patients with cancer pain and select patients with pain of spinal origin.
Morphine and ziconotide are the intrathecal medications currently approved by the U.S. Food and Drug Administration.
Chronic axial or limb pain is common in patients with degenerative or malignant spine disease and may persist after surgical treatment.
Back pain is one of the most common complaints in the general population; more than two thirds of the population have back pain at least once during life. Low back problems are reported to be the second leading complaint in outpatient consultations and the third complaint in hospital admissions. Annual back pain prevalence has been estimated at 15% to 45%. Back pain is the most common cause of activity limitation in younger individuals, and it is the third most common cause of surgical procedures in the United States, in particular, fusion surgery. Although back pain is very common, 60% to 70% of patients with acute back pain are likely to recover in less than 3 months without functional loss. The prognosis worsens significantly when pain becomes persistent for more than 6 months, with less than 50% complete recovery. The recurrence rate is also higher in patients with persistent back pain. Many variables influence recovery, recurrence rates, and the probability of returning to work. Factors related to increased disability include gender (male), age, unemployment, stressful work environment, and compensation related to disability. Psychological factors also influence prognosis.
Although less common than low back pain, neck pain is also a frequent reason for seeking health care. The most common causes of neck pain include musculoskeletal disorders and degenerative disease of the cervical spine. The lifetime prevalence of chronic neck pain ranges from 35% to 50%, and the cross-sectional prevalence is 10% to 35%.
The direct and indirect costs of chronic back pain have been estimated to be greater than $50 billion in the United States, and chronic disability secondary to chronic back pain affects more than 5 million Americans ( Fig. 177-1 ). This chapter focuses on chronic pain associated with spine disease, with emphasis on failed back surgery syndrome (FBSS) and neuromodulatory treatment options. Because of the high prevalence and differential diagnosis with FBSS, we also briefly cover complex regional pain syndrome (CRPS) and treatment options.
The transition from acute to chronic pain can be defined according to time course or healing process. The first criterion is more commonly used, although different cutoff time points have been arbitrarily chosen, ranging from 1 to 6 months. Chronic pain can also be defined as pain persisting beyond the expected time of healing for the given injury. This criterion avoids the need for an arbitrary cutoff but may not be as practical clinically. In this context, chronic pain is understood as pain that is not associated with tissue injury or illness of equivalent severity. Chronic pain is not a purely somatosensory disorder. Cognitive and behavioral factors are equally important in pain chronification and treatment refractoriness.
Nociceptive pain is associated with tissue injury or inflammation, without compromise of the nervous system itself. It is of two types: somatic and visceral. The somatic type is mostly described as sharp, throbbing, well-defined pain that is localized over the injured area, whereas the visceral type is dull vague and ill defined. Examples of conditions producing nociceptive pain are mechanical low back pain and vertebral compression fractures from osteoporosis.
Neuropathic pain may develop from persistent nociceptive pain secondary to continuous sensitization of the nervous system but can also occur as a result of injury directly to the peripheral or central nervous system. It usually consists of a less defined sensation, often described as burning, aching, or electrical shocks, or a ripping or tearing sensation, and it is generally associated with altered stimulus perception, such as allodynia or hyperalgesia. Examples of neuropathic pain are pain associated with FBSS, arachnoiditis, CRPS, radiculopathies, and peripheral neuropathies associated with diabetes mellitus, metabolic disorders, infections, postherpetic neuralgia, multiple sclerosis, stroke, and postamputation.
Mixed Nociceptive and Neuropathic Pain
This type of pain is complex and has characteristics of both neuropathic and nociceptive pain. Examples include FBSS and some forms of cancer pain.
Cancer pain has nociceptive, neuropathic, and ischemic elements and can be a result of direct tissue invasion, inflammation, obstruction (viscera, cerebrospinal fluid), or cancer treatment (surgery, radiotherapy, and chemotherapy).
Anatomy and Physiology of Pain-Related Pathways
Peripheral Nervous System
Noxious stimulation causes the peripheral nervous system to be activated by depolarization of receptors in the distal end of primary afferent axons, which transmit the information processed to the central nervous system (CNS). Only a part of the pain information processed in the periphery is transmitted to the brain because of the interference of modulatory mechanisms. Continuous or repetitive stimulation may lead to peripheral and central sensitization, contributing to the conversion of acute pain into a chronic pain syndrome. This section describes the components of the pain pathways and the mechanisms of acute pain as an introduction to the mechanisms underlying chronic pain.
When excited by a stimulus, the peripheral receptor acts as a transducer, transforming the initial information into chemical signals. Receptor depolarization is mediated by transmembrane potentials, triggered by external stimulation that reaches a specific threshold. Receptors are located on the endings of sensory axons in the skin and other tissues and are composed of free, partially covered or encapsulated nerve endings. Receptors are stimulus specific and generally do not depolarize with other types of stimuli at normal intensities. Three main modality-specific receptor subtypes are associated with spinal pain: (1) nociceptors, which respond to tissue damage; (2) mechanoreceptors; and (3) thermoreceptors.
Peripheral Nerve Fibers
Peripheral nerves are formed by the union of the dorsal root, which carries afferent information, and the ventral root, which contains mainly efferent information. The epineurium is formed not only by collagen and vessels but also by sympathetic fibers and polymodal receptors, forming the nervi nervorum. These are possibly associated with the occurrence of chronic pain after nerve injury, promoted by sympathetic sprouting and sensitization.
Nerve fibers are classified according to their myelinization and conduction velocity: Aβ fibers are the second fastest type, carrying tactile, pressure, and proprioceptive afferents. These fibers are recruited during inflammation or other injury-related phenomena to participate in mechanisms of nociception, hypersensitivity, and sensitization. Aδ fibers carry not only cold information but also nociception when associated with polymodal receptors. B fibers are related to autonomic activity, and C, or unmyelinated, fibers are related to nociception transmission and postganglionic autonomic function.
Painful stimuli are transmitted from the peripheral nerve to the dorsal root ganglion, dorsal root, and dorsal horn. At the level of the dorsal root entry zone, most unmyelinated and small myelinated fibers assume a more lateral position to enter the Lissauer tract ( Fig. 177-2 ). The Lissauer tract comprises a bundle of longitudinal fibers and, as proposed by Ranson, is part of the pain transmission pathway. Unmyelinated fibers make up most of the Lissauer tract, and their central terminations are located mainly in lamina II of Rexed. Aδ fibers have a broader arborization and terminate in laminae I, II, V, and X. The dorsal horn is divided into 10 laminae as defined by Rexed. Lamina I is related specifically to nociceptive and thermal information and is composed mainly of two types of cells: nociceptive-specific neurons, which respond to noxious stimuli, and wide dynamic range (WDR) cells, which respond to both noxious and non-noxious stimuli and are thought to be major contributors in the development of chronic pain. This lamina contributes to the formation of the spinothalamic tract (STT) ( Fig. 177-3 ). Lamina II, also known as the substantia gelatinosa, receives nociceptive, thermoreceptive, and mechanoreceptive input. Cells in this lamina project to laminae I, III, and IV and contain opioid receptors, corroborating the importance of lamina II in modulating nociceptive information. Lamina III receives inputs from Aβ fibers and mechanoreceptive Aδ fibers. The sprouting of the low-threshold terminals present in this layer to the more superficial laminae, which are generally associated with nociception, suggests a role in chronic pain. Lamina V is another important component of nociception because of its inputs from Aδ and C fibers and WDR neurons, contributing to the formation of the STT.
The cell projections of laminae I and V, after crossing the anterior aspect of the central canal, course through the STT in the contralateral ventrolateral column to reach the ventroposterior thalamus. Fibers of laminae I, VII, and IX, related to WDR neurons, project to the nonspecific intralaminar nuclei and to the brain stem reticular formation, periaqueductal gray matter, and hypothalamus, forming the paleospinothalamic tract (see Fig. 177-3 ). Because the WDR neurons have larger receptive fields and respond to different kinds of stimuli when compared to the specific nociceptive neurons, they are involved in poorly localized and nondiscriminative types of pain, in addition to the transformation of acute pain into chronic pain syndrome.
After thalamic processing, pain information is projected to the primary somatosensory cortex and secondary somatosensory cortex. The thalamus also projects to the insula and the anterior cingulate cortex, which are primarily related to the motivational and affective spheres of chronic pain (see Fig. 177-3 ).
The role of descending pathways in pain modulation is well established, starting in the periaqueductal gray matter, rostral ventromedial medulla, and dorsolateral pontine tegmentum. The periaqueductal gray matter receives inputs from the dorsal horn, brain stem, diencephalic system, and cortex and sends inhibitory projections to the dorsal horn. It also projects back to the thalamus and orbital frontal cortex, possibly exerting an ascending control of nociception. Another important pathway that plays a significant role in spinal pain modulation is the noradrenergic system, which projects extensively to the dorsal horn ( Fig. 177-4 ). The development of chronic pain is related not only to ascending pain-facilitating mechanisms but also to reduced pain inhibition from descending and ascending modulatory mechanisms.
Physiology of Pain
During inflammation, different events occur that culminate in the generation of prolonged pain. Among these, sensitization and hyperalgesia are significant contributors. However, before continuing this discussion, it is helpful to understand some physiologic conditions involved in these mechanisms.
Each nerve fiber has different physiologic response durations, known as adaptation . Because C fibers are usually slowly adapting, and their responses last longer than the stimuli, the occurrence of temporal and spatial summation of painful stimuli during tissue injury may occur. Properties of other fibers include a well-defined receptive field and spontaneous discharges, generated without exogenous stimuli. Summation, expansion of the receptive field, and increase in spontaneous discharges are significantly enhanced during inflammation, leading to the development of hyperalgesia and sensitization. In addition to this mechanism of primary hyperalgesia, secondary hyperalgesia—increased pain sensitivity and allodynia in the surrounding uninjured area—may also occur, secondary to peripheral and central events, such as increased response to glutamate and central neuronal plasticity ( Fig. 177-5 ).
Each sensory cell has specific thresholds to respond to a given stimulus, which is lowered during inflammation. This condition is defined as sensitization, which is divided into peripheral and central according to the mechanisms involved. Peripheral sensitization is characterized by a decreased threshold and increased response to suprathreshold stimuli, spontaneous nociceptive neural activity, and expansion of the receptive fields after tissue injury ( Fig. 177-6 ).
Central sensitization is mediated by short-term and long-term changes in the dorsal horn of the spinal cord. This mediation is supported by the occurrence of allodynia in association with the recruitment of Aβ fibers and their sprouting from lamina III into lamina II and loss of regulation of nociceptive fibers. Repetitive stimulation of C fibers, triggered by tissue injury, can lead to hyperexcitability and overactivity of these fibers and further perpetuation of nociceptive transmission. This perpetuation of nociceptive transmission can result in magnification of the sensory input and consequent expansion of the receptive fields, a phenomenon known as wind-up.
A key component in the development of chronic pain is antinociception and the failure of its underlying mechanisms. The inhibitory control of pain pathways is exerted in part by the spinal cord via several neurotransmitters, in addition to the descending inhibitory system as discussed previously. Another important inhibitory pathway is the opioid system, with neurotransmitters that bind to three main receptors: mu, the most common opioid receptor in the spinal cord, which has the highest morphine affinity and mediates not only analgesia (µ1) but also respiratory depression (µ2) ; kappa, which binds to dynorphin; and delta, which binds to enkephalins.
Cognitive and Behavioral Considerations in Chronic Pain
The gate control theory by Melzack and Wall in 1965 is a landmark in the understanding of chronic and neuropathic pain. The gate control theory suggested that pain is not merely transmitted by the peripheral nervous system to the CNS and proposed instead endogenous modulatory mechanisms. According to this theory, pain transmission is modulated by a gating mechanism in the dorsal horn composed of large-diameter and small-diameter fibers that close (inhibit) and open (facilitate) the pain gate.
In 1999, Melzack proposed the neuromatrix theory. In the neuromatrix model, pain modulation occurs not only at the spinal level; cerebral mechanisms of pain processing and transmission are also taken into consideration, and cognitive and affective inputs are recognized to influence the final pain experience as much as sensory mechanisms ( Fig. 177-7 ). Several studies have corroborated further the role of cognitive and limbic systems in central pain processing. A patient’s beliefs and understanding about his or her pain syndrome, pain sensitivity, fear, anger, depression, anxiety, and catastrophic thinking influence the final pain experience. Patients who are able to develop techniques to cope with pain and reduce the impact of psychological comorbidities generally have a better prognosis. Work disability also plays a key role in the perpetuation of chronic pain, and its impact on long-term prognosis cannot be underestimated. Although the American Medical Association defines disability as “an alteration of an individual’s capacity to meet personal, social, or occupational demands…because of an impairment,” work disability agencies use more restricted definitions to guide benefit eligibility or ability to work.
Failed Back Surgery Syndrome (Postlaminectomy Syndrome)
Although approximately 90% of low back pain cases are nonsurgical, the proportion of patients undergoing spine surgery has progressively increased, and success rates remain variable (23% to 83%). Patient selection is known to be a key factor for successful outcomes, and less strict selection is likely associated with a higher frequency of FBSS.
FBSS, is characterized by persistent, recurrent, and chronic axial low back pain with or without radiation to the lower extremities after previous anatomically successful spine surgery. The syndrome comprises different clinical etiologies and can occur after any surgical procedure, with or without fusion or instrumentation. FBSS can be associated with numerous etiologies, including recurrent or residual disc herniations, ruptured discs and fragments, which are found in approximately 15% to 35% of cases ; degenerative changes in levels adjacent to instrumentation ; extensive fusion associated with flat back syndrome ; pseudarthrosis ; instability caused by facet joint failure after decompression, foraminal stenosis, either residual or worsened by instability, and central or lateral canal stenosis However, FBSS is also frequently associated with persistent radicular and back pain symptoms not caused by mechanical compression or instability. Peripheral and central sensitization may push the transition from the acute to chronic state of neuropathic pain, which can then be perpetuated without anatomic compression. Furthermore, permanent injury to neural elements associated with the underlying disorder or secondary to surgical complications can in some cases explain the lack of pain relief after surgery.
Furthermore, neuropathic pain caused by prolonged dorsal root ganglion or nerve injury may lead to severe and refractory chronic pain. Arachnoiditis related to surgical manipulation or to the underlying disorder can also lead to persistent pain.
The treatment of FBSS is challenging, and a multidisciplinary approach has been recommended that includes physical therapy, rehabilitation, pain management, and possibly surgical intervention including neuromodulatory options.
Medical Management of Failed Back Surgery Syndrome
Back pain can be associated with modifications in neuromuscular activity, altering abdominal and back muscle function and contributing to the maintenance of the pain state. Patients are strongly recommended to reduce weight and participate in physical rehabilitation aimed at reducing biomechanical deficits and restoring strength and range of motion.
The most common medications used for treatment of low back pain are nonsteroidal anti-inflammatory drugs, muscle relaxants, opioids, benzodiazepines, antidepressants, and antiepileptic drugs. Nonsteroidal anti-inflammatory drugs can be effective for acute and chronic pain, although long-term use of these agents is generally limited by side effects.
Muscle relaxants and benzodiazepines act predominantly on pain states perpetuated by muscle spasms. Additional care has to be taken with benzodiazepines because of the risk of aggravating depression further and exacerbating the baseline condition.
The use of opioids in the treatment of chronic nonmalignant pain is controversial and variable. Long-term use of narcotics has been linked to tolerance, addiction, and cognitive decline, which emphasizes the need for cautious use of these medications as a long-term option. Neuropathic pain and allodynia may not respond well to opioids. Major long-term complications of opioid use include physical dependence, tolerance, addiction, opioid hyperalgesia, and cognitive dysfunction.
Antidepressants are commonly prescribed and can provide significant pain relief in various chronic pain states. Studies in chronic low back pain indicate variable efficacy. Tricyclic antidepressants such as amitriptyline and imipramine that block the reuptake of norepinephrine and 5-hydroxytryptamine in addition to H 1 , adrenergic, and cholinergic receptors tend to be the most efficacious but are not always well tolerated.
Anticonvulsants such as carbamazepine, topiramate, gabapentin, and pregabalin are also frequently tried in the medical management of neuropathic pain. Improvements in pain scores were seen with the use of these medications, mainly when radiculopathy was present, although patients with axial symptoms may also have some benefit. Anticonvulsants work primarily via suppression of abnormal discharge at nerve injury sites by Na + channel block.
Surgical Management of Failed Back Surgery Syndrome
Patients with FBSS and low back pain caused by ruptured discs or facet joint instability may undergo provocative discography or medial branch block, although the diagnostic usefulness of these methods remains operator dependent and controversial. Minimally invasive techniques can also be considered alternatives for the management of chronic pain related to FBSS. Procedures such as intradiscal electrothermal therapy and medial branch lesioning may provide functional improvement. Patients with predominantly leg pain may benefit from nerve root blocks as a guide for subsequent treatments. Pulsed radiofrequency lesioning of dorsal root ganglion has shown promising results in the treatment of radiculopathy associated with low back pain. Epidural injections, performed alone or in association with spinal endoscopy, have variable long-term efficacy in this population.
Reoperation for Failed Back Surgery Syndrome
Reoperation for FBSS in the absence of a clearly defined anatomic cause is a controversial option and may not provide significant improvement of the baseline condition. Success rates of reoperations in patients with FBSS may vary from 22% to 80%. Usual indications to consider additional back surgery include reasonable evidence of a surgically treatable condition like instability as well as compression of neural elements that fail to improve with adequate conservative treatment. Back pain not associated with radicular symptoms, poor outcome after the first procedure, pseudarthrosis, epidural fibrosis, and psychological comorbidities all are factors associated with a worse prognosis.
A significant proportion of patients with FBSS can fail to achieve pain relief with the previously discussed treatment options. The use of long-term intrathecal infusion of pharmacologic agents and spinal cord stimulation (SCS) (discussed later in this chapter) can be considered an alternative in these cases.
Spinal Cord Stimulation for Failed Back Surgery Syndrome
Randomized controlled trials have shown SCS to be superior to both conventional medical management and repeat surgery in patients with FBSS. The prospective multicenter trial (PROCESS trial) compared patients with FBSS who had SCS plus conventional medical management with those who had only conventional medical management. The study found significant pain relief and health care–related quality of life in their study population at 6 months. Studies with longer follow-up showed SCS to be cost effective compared to other treatment options like conventional medical management or repeat surgery.
Intrathecal Drug Delivery for Failed Back Surgery Syndrome
Intrathecal drug delivery (ITDD) is another treatment option for patients with FBSS. Prospective studies with a long-term mean follow-up of 46.7 months have shown that ITDD with opioids can improve pain and quality of life in patients with FBSS. For patients refractory to opioid, the addition of bupivacaine to opioid has been shown to significantly reduce pain with improved patient satisfaction. However, ITDD is now used less frequently in the management of noncancer pain, mainly due to concerns for adverse effects related to long-term use, particularly in younger patients.
Complex Regional Pain Syndrome
This disease, formerly called reflex sympathetic dystrophy and causalgia, is a complex painful condition that develops within 4 to 6 weeks following trauma to an extremity. Severe and medically refractory forms of CRPS carry poor prognosis with only about 25% of patients being able to return to a normal level of functioning. The diagnosis of this disorder is based on clinical criteria, even though its specificity is limited. The clinical picture comprises a triad of symptoms that include autonomic (disturbances of skin temperature, color, sweating abnormalities), sensory (pain and hyperalgesia), and motor (paresis, tremor, and dystonia) disturbances. These symptoms are not limited to the distribution of a single peripheral nerve and are disproportionate to the inciting event. CRPS is subdivided into CRPS I, when there is no obvious nerve injury, and CRPS II, when there is associated nerve injury. Lower limb involvement is more common than that of upper limbs. Even though the symptoms of CRPS can subside with physical therapy and pharmacologic therapy, a large proportion of patients continue to have chronic pain and remain treatment-refractory.
Chronic CRPS is believed to be related to central neuroplasticity and is associated with significant morbidity. SCS has shown to be effective in the treatment chronic CRPS in patients for whom other treatment modalities have failed. Cervical SCS is considered in patients with upper limb CRPS and thoracic SCS is performed for lower limb CRPS.
In the Cochrane review on the treatment of patients with CRPS, the authors observed lack of high-quality evidence for the effectiveness of most therapies for this disorder. Kemler and coworkers published a series of articles addressing the effect of SCS in patients with CRPS with follow-up ranging from 6 months to 5 years. The authors observed statistically significant improvement in pain and quality of life up to 3 years. In our own experience, 70% of patients with CRPS who received SCS implants with a paddle lead remain satisfied with their outcome in the long term. Cost analysis of patients treated for chronic CRPS has shown SCS to have substantial long-term economic benefits compared to conventional treatment protocols.
Invasive Neurosurgical Procedures for Pain
There are numerous neurosurgical procedures other than spine surgery for treatment of FBSS. The surgical procedures chosen for a patient should be tailored to meet the needs of the patient and the skill and comfort of the surgeon with the procedure. These procedures can be broadly classified into neuromodulative procedures and ablative procedures. The neuromodulative procedures include motor cortex stimulation, thalamic deep brain stimulation, SCS, peripheral nerve stimulation, and neuraxial drug infusion (epidural or intrathecal). Ablative procedures include cingulotomy, thalamotomy, hypophysectomy, neurectomy, sympathectomy, ganglionectomy, rhizotomy, spinal dorsal root entry zone lesioning, cordotomy, and myelotomy. However, central nervous system ablation is seldom performed for FBSS and carries a greater morbidity for long-term neurologic deficits. In this chapter, we will be discussing the ITDD and SCS procedures.
Intrathecal Drug Delivery
ITDD can be useful in the management of patients with cancer pain and select patients with noncancer pain who either cannot achieve adequate analgesia or develop severe side effects from oral and transdermal pain medications. The advantage of ITDD is the proximity of the drug delivery to the receptors as it diffuses passively in the dorsal horn, bypassing the blood-brain barrier allowing for lower effective doses and consequently a reduced rate of side effects.
A review of available evidence for the use of ITDD for chronic pain showed that its effectiveness for cancer-related pain was better than that for noncancer pain (level II-2 versus level II-3, based on U.S. Preventive Services Task Force criteria).
Drugs Used for Intrathecal Drug Delivery
Intrathecal medications that are currently approved by U.S. Food and Drug Administration (U.S. FDA) and considered first-line treatment for pain are morphine and ziconotide. In patients who fail therapy with morphine due to either intolerable side effects or the development of tolerance, the options include replacement with another opioid or adding another agent to the opioid. Recommendations to improve patient safety and efficacy while using these drugs intrathecally either alone or in combination are put forward by the Polyanalgesic Consensus Conference in 2012.
Complications of Intrathecal Drug Delivery
In addition to device-related complications, the major complications related to ITDD devices include infections involving the implanted hardware, postural headaches, cerebrospinal fluid leak, pseudomeningoceles, and seromas associated with the pump reservoir. Catheter-related complications are commonly the cause of premature failure of the implanted system. Spinal cord injury associated with implantation of the catheter has been reported, but its frequency, although thought to be low, has not been established.
A complication specific to ITDD is the development of a catheter tip inflammatory mass. Although administration of different pharmacologic agents have been related to this complication, it seems to be more common with higher concentrations and doses. Screening of patients with intrathecal pump systems has been suggested to enable early detection of inflammatory masses. Clinicians managing these patients are recommended to maintain a high index of suspicion and a low threshold for requesting imaging examination when a patient presents with a subjective change in neurologic function or a loss of efficacy of the administered drug. Treatment options for catheter tip inflammatory masses include replacing the solution for saline and careful neurologic examination. Patients with new onset neurologic deficits may need surgical intervention aimed at decompression of the spinal cord and removal of the hardware.
Patient Selection for Opioid Intrathecal Drug Delivery
Appropriate patient selection is an essential step for satisfactory results and includes symptoms that are refractory to less invasive therapies, response to oral doses of opioids, significant response to intrathecal opioid trial, absence of addiction history, and favorable psychosocial evaluation. The option for intrathecal opioids may be more logical in elderly patients, for whom the goal is to achieve some degree of pain alleviation in the final years of life. Long-term management is more complicated in young patients, who are likely to increase the opioid dosage gradually over decades of use.
Opioid Intrathecal Drug Delivery Trial
Even though ITDD trial with opioids is generally recommended before its permanent implantation, trialing is debatable especially in patients with cancer pain. The intrathecal trial can be performed with sequential injections of bolus dosing with progressively increasing doses or continuous opioid infusion with an externalized catheter. After a trial, permanent implantation of a pump and catheter system can be considered when a significant improvement is achieved (generally ≥ 50% reduction in pain) with tolerable side effects.
Side Effects of Opioid Intrathecal Drug Delivery
The most common side effects described with intrathecal opioids include nausea, sedation, confusion, pruritus, urinary retention, myoclonus, reduced libido, and respiratory depression, which are greater with intrathecal hydrophilic drugs. Peripheral edema, usually unresponsive to diuretics, is another side effect of morphine and can be managed by changing to a lipophilic agent.
Although long-term intrathecal infusion of opioids is a well-established treatment for cancer pain, its usefulness for noncancer pain is controversial. Randomized controlled trials have shown the efficacy of intrathecal morphine therapy in reducing cancer pain with reduced drug toxicities and improved survival with control of pain in as high as 91% patients at a follow-up of 4 months. Some studies have shown efficacy of morphine ITDD in alleviating noncancer pain with favorable results varying from 50% to 73% of the patient population. Systemic reviews have failed to find high-quality evidence for the recommendation of morphine ITDD for nonmalignant pain. The efficacy of morphine ITDD in controlling nonmalignant pain was found to last up to 3 years after the initiation of treatment; however, studies with long-term follow-up often describe a decrease in responsiveness over time, without success in recapturing the same extent of early benefits. It is important to note that long-term use of intrathecal opioids in younger patients with FBSS carries a greater risk of failure and complications. SCS is usually attempted before ITDD is considered for the management of patients with FBSS with predominant leg pain.
Ziconotide is a synthetic analogue of venom of conus magnus, a marine snail. This nonopioid drug was approved by U.S. FDA for intrathecal use for chronic pain in 2004. The drug is useful in treating chronic pain of nociceptive and neuropathic types and has proved to be effective in treating cancer pain, noncancer pain, and AIDS-related pain. Ziconotide acts by blocking presynaptic N-type calcium channels. Intrathecal ziconotide can be useful in treating pain that is not responsive to oral or intrathecal opioids, and its safety and efficacy have been supported by three randomized trials.
Typical adverse effects related to opioids like respiratory depression, tolerance, dependence and catheter tip granuloma have not been reported in relation to ziconotide. Compared to morphine, most of the adverse effects of the drug are mild, or moderate but acute psychosis and other behavioral complications can limit the use of this drug. Other adverse effects include dizziness, nausea, nystagmus, gait instability, headache, urinary retention, vomiting, somnolence, postural hypotension, memory impairment, and amblyopia.
Spinal Cord Stimulation
The gate control theory led to the development of novel neuromodulation-based therapies for chronic pain. According to the theory, stimulation of large myelinated fibers could modulate nociceptive input. Encouraging results were seen with peripheral nerve stimulation, taking advantage of the fact that large myelinated fibers can be stimulated at lower thresholds than small unmyelinated fibers. In 1967, Shealy and colleagues were the first to perform spinal cord stimulation (SCS) by stimulation of the dorsal columns via a subarachnoid route to treat refractory lower extremity pain. Initially, the electrodes were implanted in the subdural space, but the occurrence of complications such as fibrosis and cerebrospinal fluid leak limited their use. The technique was later modified to stimulation with epidural electrodes. During the first years of use, SCS was attempted in patients with various pain diagnoses, and results were variable. More consistent results have been seen in subsequent series with better patient selection and technologic advances. In the United States, the most common indications for SCS are back and leg pain, usually associated with FBSS.
SCS has been shown to be effective in alleviating leg pain associated with degenerative spine disease in prospective studies, improving long-term functional capacity and promoting better quality of life. A systematic review of the literature indicated that successful outcomes after SCS (defined as ≥ 50% pain improvement) are seen on average in 59% of cases.
Mechanism of Action of Spinal Cord Stimulation
The exact mechanisms underlying the effects of SCS are still a matter of debate. SCS is believed to alter neuronal inputs and synaptic activity within the dorsal horn of the spinal cord, thereby modulating central transmission of pain. The procedure was initially referred to as “dorsal column stimulation,” but now the preferred terminology is SCS because multiple pathways may be involved in the analgesic effects associated with stimulation ( Figs. 177-8 and 177-9 ). In neuropathic pain, one of the proposed mechanisms is stimulation-induced suppression of central excitability. Peripheral vasodilatation is also believed to be a mechanism for pain relief following SCS. In experimental animals, SCS has been observed to induce alterations in the neurotransmitters in the spinal cord by decreasing the release of excitatory neurotransmitters like glutamate and aspartate while simultaneously increasing the release of gamma aminobutyric acid. This observation indicates that pain is secondary to imbalance between these neurotransmitters and that SCS exerts its effect by maintaining balance between these mediators to reduce pain. This finding is supported by the observation that GABA agonists improves the effect of SCS and that GABA antagonists inhibit SCS.
Spinal Cord Stimulation Leads
The SCS leads can be percutaneous (cylindrical) or paddle (flat) leads ( Fig. 177-10 ). Modern percutaneous leads have 4 to 8 contacts, whereas paddle leads may have up to 32 contacts in up to five rows. The percutaneous leads can be inserted minimally invasively by puncturing the skin and advancing to the epidural space with a Tuohy needle. Percutaneous leads are placed under monitored anesthesia, which permits assessment of the area of paresthesia induced by intraoperative stimulation of the lead while the patient is awake. This helps to assess the location of the lead in relation to the spinal cord and assures that stimulation will provide paresthesia coverage over the affected areas with minimal or tolerable side effects. The disadvantages of cylindrical leads are its potential to radiate current in multiple directions and its greater propensity for migration. The paddle leads are placed via laminectomy or laminotomy. The procedure can be done under conscious sedation but our preference is for implanting paddle leads under general anesthesia, even though that does not allow for intraoperative stimulation testing. The flat configuration and multiple contacts of paddle leads provide better stimulation coverage. Because of the flat design and because paddle leads can be anchored closer to the point of insertion in the spinal canal, paddle leads are less prone to migrate than percutaneous leads. Studies comparing paddle and percutaneous leads have shown superior clinical efficacy and reduced reoperation rates with paddle leads.
Implantable Pulse Generators
Implantable pulse generators (IPGs) contain the battery and the programmable elements. IPGs are available in various sizes with different programming technologies. An IPG needs to be replaced when its battery is exhausted. New-generation rechargeable IPGs have an external device with which they can be recharged, allowing the device to be smaller and last several years. The SCS leads are connected to the IPG either directly or with an extension cable.
Targets for Placement of the Leads
The position of the leads can vary from the upper cervical region to the lumbar region depending on the area of the body to be affected. Well-placed leads will provide paresthesia overlap with the area of pain. Percutaneous leads placed for leg pain typically enter the spinal canal at the thoracolumbar transition and are then advanced up to an area between T7 and T12. Cervical leads are usually advanced to a level between C3 and C6.
Indications for Spinal Cord Stimulation and Patient Selection
The primary indication for SCS is neuropathic pain of the extremities that is refractory to conservative management, secondary to etiologies such as peripheral nerve or nerve root damage, CRPS, FBSS, and ischemic pain. A higher probability of success has been seen for patients with radiculopathy, plexopathy, arachnoiditis, peripheral neuropathy, and CRPS. Axial back pain and chronic pain associated with postherpetic neuralgia, prior surgery (i.e., thoracotomy), and incomplete spinal cord injury may not respond as well.
Some prognostic factors to be considered when selecting patients for SCS are (1) extremity pain is more likely to respond to SCS than axial pain, (2) pain related to axial load is less likely to respond to SCS, and (3) patients with complete loss of sensation in the affected areas are less likely to respond than are patients with at least partially preserved sensation. Predictors of good outcome following SCS in patients with FBSS are early treatment (within 3 years) after the first failed back surgery, predominance of neuropathic leg pain, and absence of psychosocial conditions. In current practice, psychological evaluation is routinely performed before implantation of SCS to assess the extent of psychosocial factors on the patient’s pain.
Spinal Cord Stimulation Trial
It is common practice to perform a trial of SCS before permanent implantation of the system. The trial period can help to identify patients who will not respond to SCS or find it uncomfortable. However, a successful trial is not a guarantee of good long-term results. The duration of a trial is usually around 1 week. During the trial, test stimulation should produce paresthesia coverage over the majority of the area of pain. A relief of 50% is regarded as a satisfactory outcome, but some patients may be satisfied with an outcome that offers more modest analgesic effects.
Contraindications for Spinal Cord Stimulation
In addition to usual contraindications for surgery such as untreated medical comorbidities, coagulopathy, immunosuppression, and active infections, SCS may not be feasible in patients with a narrow spinal canal at the desired level of implantation. Placement of the lead in some patients can result in spinal cord injury when the canal is already narrow. In addition, some SCS systems are not compatible with magnetic resonance imaging (MRI) and are not ideal choices for patients with disorders that are known to require follow-up with MRI.
Complications of Spinal Cord Stimulation
Complications can be divided into stimulation-related, device-related, and surgical types. Stimulation-related complications include uncomfortable paresthesias or positional changes, long-term loss of efficacy, and stimulation in areas not affected by the pain. Higher amplitudes may cause stimulation spread to the thoracic roots, leading to uncomfortable muscle contractions. Because SCS is a neuromodulatory technique, adverse effects related to electrical stimulation are usually reversible and can be resolved with reprogramming of the system or turning off the stimulation. Device-related complications have been reported to affect approximately 30% of patients. The most common problem is migration of electrodes (more common with cylindrical leads than with paddle leads) resulting in loss of efficacy. Although reprogramming can be attempted to recapture the lost benefits, a surgical revision may be necessary. The main complication related to the surgical procedure is infection, with a rate of approximately 4.5%. Other complications include dural tear with associated spinal headaches or cerebrospinal fluid leak, postoperative hematoma, spinal cord injury, and other neurologic injuries, which range from 1% to 9%.
Cost Effectiveness of Spinal Cord Stimulation
Although SCS implants are expensive, imposing a considerably high initial cost to the health care system, the overall treatment has been shown to be cost effective in the long term.