Peripheral Receptors

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.

Pain Pathways

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.

Diagram of dorsal root entry zone and distribution of different fibers entering the posterior aspect of the spinal cord before forming the Lissauer tract (LT), which is composed mainly of unmyelinated and small myelinated fibers.

(Copyright Cleveland Clinic Foundation.)

Diagram of the posterior columns in the spinal cord and the medial lemniscus in the brain stem ( A ) and anterior spinothalamic tract ( B ). Diagram of the lateral spinothalamic tract ( C ) and the relays of A, B, and C in the thalamus and their cortical projections ( D ). The posterior columns are responsible for the transmission of discriminative tactile and kinesthetic information, the anterior spinothalamic tract conveys light touch impulses, and the lateral spinothalamic tract conveys pain and temperature impulses. D, 1, dorsomedial nucleus of the thalamus; 2, intralaminar thalamic nuclei; 3, ventral posterolateral thalamic nucleus; 4, parafascicular nucleus of the thalamus; 5, centromedial nucleus of the thalamus; 6, ventral posteromedial thalamic nucleus; 7, hypothalamus.

(Copyright Cleveland Clinic Foundation.)

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.

Diagram of descending inhibitory pain pathways and their respective projections in the dorsal horn. 5HT, serotonin; ALF, anterolateral fasciculus; NE, noradrenaline; SMT, spinomesencephalic tract; SRT, spinoreticular tract; STT, spinothalamic tract.

(Copyright Cleveland Clinic Foundation.)

Percutaneous Procedures

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.

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.

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.

Three-dimensional image of transection of spinal cord showing lamination of the posterior column of the spinal cord, dura, and the position of the epidural paddle lead.

(Copyright Cleveland Clinic Foundation.)

An axial image showing the location of the electrode in relation to the spinal cord, dura, and posterior bony elements of the vertebra.

(Copyright Cleveland Clinic Foundation.)

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.

Different leads used for spinal cord stimulation.

Cylindrical leads ( A ) are generally implanted percutaneously, whereas paddle leads ( B and C ) require a laminectomy for placement. The availability of leads with varied numbers of contacts facilitates not only the initial programming but also posterior adjustments of stimulation.

(Copyright Cleveland Clinic Foundation.)

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.