Abstract
Interventional pain management procedures for complex regional pain syndrome (CRPS) are often utilized when conservative treatment options fail to provide adequate pain relief and restoration of function. Such procedures include sympathetic nerve blocks, chemical and surgical sympathectomy, intravenous regional anesthesia, intravenous infusion, spinal cord stimulation, intrathecal medication and amputation. The literature support for each procedure is reviewed herein.
Keywords
Intravenous infusion, Spinal cord stimulation, Sympathetic block
Interventional pain management procedures for complex regional pain syndrome (CRPS) are often considered when conservative treatment options such as physical therapy (PT), occupational therapy (OT), and/or medications fail to provide adequate pain relief. The literature supports the concurrent use of certain procedures along with medications, modalities, and psychologic treatment to help maximize pain relief and functional restoration.
Sympathetic Nerve Blocks
The sympathetic nervous system has been implicated in the pathophysiology of CRPS in certain presentations of the syndrome. Thus it may be a useful target for injection therapy. Sympathetic nerve blocks (SNBs) have been used for both diagnostic and therapeutic purposes for many years. Historically, some clinicians diagnosed CRPS only if SNB relieved pain. However, it was found that for some patients, there is a lack of response to SNB, which led to the concept of CRPS variants that are not sympathetically mediated (sympathetically independent pain, SIP) and rethinking of the mechanism behind the disorder. Overall, there is a lack of universally accepted guidelines in selecting patients for SNB and a lack of high-quality studies to provide significant evidence to support or refute the use of SNB for CRPS. Based on the available literature, along with clinical experiences of many experts, it is believed that patients with CRPS with signs of mechanical allodynia and temperature and color changes of the affected limb are more likely to have a positive response from SNB. In general, the procedure is often recommended for those patients who have pain that limits participation in PT or OT despite adequate oral medications.
The primary targets for SNB involve the stellate ganglion (SGB) for upper extremity CRPS and the lumbar sympathetic chain (LSB) for lower extremity CRPS. The stellate ganglion is composed of the inferior cervical ganglion and the first thoracic ganglion. It is typically located anteriorly to the first rib. SGB was traditionally performed “blindly” via palpation of anatomic landmarks, but now it is done via guidance with fluoroscopy, ultrasonography, or computerized tomography. The typical target of the needle is the junction of the vertebral body and uncinate process of C6 (Chassaignac tubercle). An example of the procedure being performed under fluoroscopic guidance is shown in Figs. 9.1–9.4 . Both the C6 and C7 vertebrae have been used as targets for injection, but injection at the C6 level has become a more common practice to lessen potential complications such as pneumothorax and vertebral artery puncture. For LSB, the lumbar sympathetic chain ganglia are located along the anterolateral aspect of the first through fourth lumbar vertebral bodies. The target of injection is usually at the inferior portion of the L2 or superior portion of the L3 vertebral body ( Figs. 9.5 and 9.6 ). An example of the procedure being performed under fluoroscopic guidance is shown in figures 9.5 and 9.6 . After the needle reaches the target site, a small volume of contrast dye is injected to confirm localized spread and rule out vascular uptake. Then 5–10 mL of local anesthetic is injected, usually lidocaine or bupivacaine, with or without corticosteroid.
Success of the SGB is defined by Malmqvist et al. as: (1) Horner’ syndrome, which consists of ptosis (drooping of upper eyelid), anhidrosis (decreased sweating on the affected side of the face), and miosis (constricted pupil); (2) Gutman sign, which is increased skin and upper limb temperature >34°C (or by 1–3 degrees compared with before the procedure) within 5 min of the block; (3) increased blood flow by more than 50% by laser Doppler flowmetry; (4) abolition of radial and ulnar skin resistance response; (5) increase in the skin resistance level by 13% or more. However, even in the study by Malmqvist, complete sympathetic blockade of the stellate ganglion meeting all five criteria was met only in 6 of the 54 blocks and only 15 of 54 cases met four of the criteria. This indicates that there is a high rate of incomplete or partial sympathetic blockade in SGB. Another study by Schurmann et al. demonstrated there is difficulty in correlating increased limb temperature, Horner syndrome, and complete sympathetic blockade. In addition, even in patients with complete sympathetic block, the amount of pain relief following the SGB was just slightly more than 50%, further supporting the concept of nonsympathetically mediated CRPS, or SIP. Temperature testing is perhaps the most widely used measurement of sympathetic blockade. Subjective successful responses to a block include patient’s report of decreased pain and/or allodynia of the affected limb.
The pain relief from an SNB often lasts longer than the duration of effect of the local anesthetics, and in some cases, it may provide long-lasting relief, although the response duration and efficacy is variable. Based on the currently available treatment guidelines, patients should immediately begin aggressive PT and OT. The treatments focus on desensitization, normalizing sensation, restoration of range of motion (ROM), and promoting functional use of the affected limb. A successful response would be expected in patients with sympathetically maintained pain (SMP) as compared with those with SIP. Many researchers have studied the effectiveness of the SGB and LSB in CRPS. However, the majority of these are low-quality studies and lack significant numbers of subjects. Price et al. conducted a double-blind crossover study evaluating the use of anesthetic versus saline in SGB and LSB. Analgesia was achieved within 30 min of using both anesthetic and saline, but the anesthetic group with a mixture of lidocaine and bupivacaine resulted in average of 3 days 18 h of analgesia versus 19 h for the saline group. Cepeda and colleagues conducted a systematic review evaluating SNB with local anesthetics. Among the 30 studies that were evaluated, only a few were prospective, randomized, and placebo controlled. In total, over a 1000 patients were included. Overall, 29% of patients had a full response, 41% had partial response, and 32% had no response to SNB. Another review evaluated the results of two additional small randomized, double-blinded, crossover studies. The combined effect of the two trials (23 subjects) produced a relative risk to achieve at least 50% of pain relief for 30 min to 2 h after the sympathetic blockade of 1.17 (95% confidence interval 0.80–1.72). However, the effect of sympathetic blockade on long-term pain relief was inconclusive. A randomized trial of SGB with 0.5% bupivacaine versus guanethidine intravenous (IV) regional block (which in itself lacks strong evidence of efficacy as discussed later) found significant improvement in both groups and no significant difference between SGB and guanethidine IV regional block.
SNBs may be repeated if there is short-term benefit in those patients who had a clear reduction of pain, improved ROM, and increase tolerance to PT and/or OT. However, there is lack of evidence to support routine extended series of SNB.
The addition of botulinum toxin to LSB has been studied as a potential option to prolong the analgesic duration of the LSB. Carroll et al. conducted a small prospective, randomized, double-blind, controlled crossover study of nine patients with refractory CRPS type I. The botulinum toxin enhanced the analgesic effect of LSB. Each patient received two injections, the first with 10 mL of 0.5% bupivacaine and the second with 10 mL of 0.5% bupivacaine plus 75 units of botulinum toxin A. The median time to analgesic failure in patients who received bupivacaine plus botulinum toxin was 71 days compared with less than 10 days when patients received bupivacaine alone. Choi et al. reported similar findings in a case study consisting of two male patients with CRPS after ankle injuries. Pain relief lasted for 2 months after injection of 5 mL of 0.25% bupivacaine plus 5000 IU of botulinum toxin type B compared with only 5 h after injection with bupivacaine alone. Furthermore, there was no further need for opioid pain medications after LSB using botulinum toxin. Despite these promising findings, additional studies with larger sample sizes are required.
Potential complications of SGB and LSB include needle injury to the nearby visceral organs and neurovascular structures. The SGB can cause pneumothorax, hemothorax, and injury to the brachial plexus, trachea, or esophagus. The local anesthetics can cause laryngeal nerve block, resulting in hoarseness of voice, or phrenic nerve block, which can lead to diaphragmatic paralysis with respiratory depression, and hence bilateral SGB is contraindicated. SNB can cause vasodilation of the extremities, which may lead to orthostatic hypotension; thus blood pressure needs to be monitored. Genitofemoral neuritis is a possible complication specific to LSB. As with any injection, infection can occur.
Chemical and Surgical Sympathectomy
For longer term relief, chemical or surgical sympathectomy has been performed for SMP from CRPS in those patients who receive transient relief from SGB or LSB. Chemical sympathectomy involves using alcohol or phenol injection to denature the proteins of the sympathetic chain ganglion. Outcomes for chemical sympathectomy are variable with uncertain efficacy. Surgical treatment can be performed by open removal or electrocoagulation of the sympathetic chain ganglion or by minimally invasive techniques using stereotactic thermal or laser ablation. The effect of analgesia may last for up to 1 year with radiofrequency ablation. Nerve regeneration is common following both surgical and chemical ablation, and recurrence of symptoms and development of postsympathectomy neuralgia is common. Manjunath et al. randomized 20 patients with lower limb CRPS to either radiofrequency or phenol lumbar sympathectomy and found a statistically significant reduction from baseline in all pain scores for both treatment groups at 4 months’ follow-up. Complications of sympathectomy include postsympathectomy neuralgia in up to 50% of patients, as well as hyperhidrosis and persistent Horner syndrome (for SGB). Owing to the poor evidence for long-term effectiveness coupled with the risk of complications, sympathectomy should be used with great caution and reserved only for patients who have failed other treatments options but responded to SNB.
Intravenous Regional Anesthesia
Intravenous regional anesthesia (IVRA) involves peripheral injection of medication, including sympatholytics, anesthetics, or nonsteroidal antiinflammatory drugs into the affected extremity. IVRA has been used for many years to empirically treat CRPS with a wide variety of substances, including guanethidine, lidocaine, bretylium, clonidine, droperidol, ketanserin, or reserpine. IVRA with guanethidine to treat CRPS was first described by Hannington-Kiff, and the procedure consists of intravenous injection of guanethidine, followed by elevation of the injected arm and then inflation of a tourniquet above the patient’s systolic pressure. The tourniquet is then maintained for 15–30 min while the medication bathes the area, then the tourniquet is slowing released. The theory is that this causes displacement of noradrenaline from presynaptic vesicles and prevents the reuptake causing increased blood flow. Numerous IVRA trials using guanethidine have been conducted and have been proved to be largely ineffective. Perez et al. conducted a meta-analysis of nine IVRA studies, and six of those included guanethidine. The analysis showed a lack of proven effect of IVRA overall and guanethidine in particular. Other studies have also reported generally negative outcomes. Ramamurthy et al. conducted a double-blind, multicenter randomized control trial comparing IVRA with guanethidine with control of lidocaine in 60 patients with CRPS and found no difference in long-term outcomes. Another study compared low-dose guanethidine with saline and did not find significant differences between the groups. The study had to be terminated because of complications from high-dose guanethidine.
Many other IVRA trials have been done using atropine, guanethidine, lidocaine, bretylium, clonidine, droperidol, ketanserin, and reserpine. Of these agents, only bretylium and ketanserin IVRA have shown some modest efficacy. One retrospective study that evaluated IVRA using lidocaine and ketorolac showed ketorolac had pain-relieving effects. However, a randomized, double-blind crossover study found that lidocaine with ketorolac reduced pain significantly for only 1 day. All other outcome measures found no difference between treatment with lidocaine alone and lidocaine with ketorolac. In summary, based on the available literature, the efficacy of IVRA in treating CRPS is poor.
Intravenous Infusion
Various agents have been used for intravenous infusion attempting to treat CRPS. Ketamine has been the most widely utilized and studied. Ketamine, an N -methyl- d -aspartate (NMDA) receptor antagonist, has been used in the treatment of acute and chronic pain, targeting the central sensitization of pain. Central sensitization is a phenomenon whereby persistent activation of the nociceptor results in an increased excitatory transmission along the afferent fibers. Over time the continuous and repetitive activation results in modulation of the dorsal root ganglion (DRG) and dorsal horn wide dynamic range (WDR) neurons, which accentuate the responsiveness of the nociceptive pathways. NMDA receptor activation plays a significant role in the accentuated response to repeated noxious stimulation.
In a randomized controlled trial by Sigtermans, patients receiving 100 h continuous IV infusion of subanesthetic ketamine had a significantly lower pain score for the first 11 weeks of the study compared with those receiving placebo. However, by week 12 of the study, there was no significant improvement in pain relief. Also, there was no significant improvement in function. Schwartzmann conducted a double-blind placebo-controlled study of 19 patients with CRPS and found that IV infusion of normal saline with ketamine for 4 h daily for 10 days resulted in a significant reduction in weekly pain measures for the duration of the study (12 weeks) and nonsignificant improvements in quantitative sensory testing. Kiefer et al. conducted a nonrandomized, open label, Phase II trial of continuous IV infusion of ketamine at an anesthetic dose for 5 days in 20 patients with refractory CRPS. All patients were sedated during the treatment period. The study showed a significant pain reduction in the Numeric Rating Scale from baseline in all patients at 1 week and at 6 months (8.0 vs. 2, P < .001) post infusion. They also found complete remission from CRPS in all patients at 1 month, in 17 of 20 patients at 3 months, and in 16 of 20 patients at 6 months. The study demonstrated efficacy using an anesthetic dose of ketamine, but investigators highlighted safety as a main concern.
Adverse effects of ketamine have been found to include possible liver toxicity, psychotropic side effects, nightmares, insomnia, and hallucinogenic and other psychomimetric effects. Although ketamine is generally safe, there is only low- to moderate-quality evidence showing the efficacy of IV ketamine infusion in treating CRPS.
Spinal Cord Stimulation
Mechanism of Action
Spinal cord stimulation (SCS) is a reversible and nondestructive method of controlling chronic, severe, and intractable pain. SCS involves delivering an electrical field directly over the dorsal columns of the spinal cord to modulate pain generation and processing. It is approved by the US Food and Drug Administration for failed back surgery syndrome (FBSS) and CRPS when there has been a failure or inadequate response to more conservative medical management.
The development of the Gate Control Theory of pain by Wall and Melzack in 1965 led to the first case report of SCS in a human for chronic intractable pain. In 1967 Shealy performed a thoracic laminectomy and sutured an electrode to the dura of a patient with intractable chest and abdominal wall pain from inoperable metastatic lung cancer. The patient had significant pain relief and was quickly off opioid medications. Unfortunately, the patient died shortly thereafter from medical issues unrelated to the procedure. The technology and understanding of its mechanism of action has evolved over time.
The current understanding of the mechanism of pain relief of SCS has been found to be complex and incompletely understood. The Gate Control Theory still serves as a core mechanism of action, but the details are controversial and there are other factors and distinct mechanisms of action. Wall and Melzack theorized that cells of the substantia gelatinosa in the dorsal horn of the spinal cord act as a gate control system, modulating transmission of nerve impulses from the peripheral to central nervous system via inhibitory interneurons. Stimulation of large myelinated afferent αβ fibers effectively “closes the gate” to pain-transmitting small unmyelinated C fibers and small myelinated αδ fibers.
Modulation of neural activity with SCS has been found to occur at several levels of the nervous system, including ascending and descending pathways via peripheral nerves, suppression of dorsal horn WDR neuronal hyperexcitability, supraspinal inhibition, and the sympathetic nervous system. In addition, alterations of local neurochemistry have been identified. Cerebrospinal fluid analysis in the area of SCS in animal models has demonstrated an increased release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Furthermore, pain relief from SCS can be blocked with a GABA antagonist. Increased glycine, serotonin, and adenosine have also been found, as well as decreased excitatory neurotransmitters of glutamate and aspartate. Contributions from endogenous opioid release have not been found to exist, and the pain relief of SCS is not reversed or blocked by naloxone.
Procedure Technique
Placement in the epidural space over the dorsal columns is typically performed in a two-stage process. Initially, a temporary trial is undertaken, whereby a cylindrical lead with multiple electrodes at its tip is placed percutaneously via an introducer needle under fluoroscopic guidance. The target spinal level of placement is guided by the sensory mapping work of Barolat, where the goal is to overlap pleasant paresthesia sensations in the area of the patients’ pain. Sedation is diminished so that patients can clearly confirm that paresthesia coverage is present over their appropriate individual painful sites. Intraoperative adjustments of electrode location can be made via repositioning the lead(s). Once the location is optimal, the needle is removed and the electrode is secured to the skin and left in place for the 3- to 7-day trial period (see Figs. 9.7–9.9 ). An example of the procedure being performed under fluoroscopic guidance is shown in figures 9.7–9.9 . The external portion is connected to a controller that allows programming with variations in frequency, pulse width, and amplitude to optimize pain control.
