Intravenous Therapies for Complex Regional Pain Syndrome: A Systematic Review

Xu, Jijun MD, PhD; Yang, Jing MD; Lin, Peirong MD, PhD; Rosenquist, Ellen MD; Cheng, Jianguo MD, PhD

doi: 10.1213/ANE.0000000000000999
Pain Medicine: Review Article

Complex regional pain syndrome (CRPS) remains a challenging clinical pain condition. Multidisciplinary approaches have been advocated for managing CRPS. Compared with spinal cord stimulation and intrathecal targeted therapy, IV treatments are less invasive and less costly. We aimed to systemically review the literature on IV therapies and determine the level of evidence to guide the management of CRPS. We searched PubMed, Embase, Scopus, and the Cochrane databases for articles published on IV therapies of CRPS up through February 2015. The search yielded 299 articles, of which 101 were deemed relevant by reading the titles and 63 by reading abstracts. All these 63 articles were retrieved for analysis and discussion. We evaluated the relevant studies and provided recommendations according to the level of evidence. We conclude that there is evidence to support the use of IV bisphosphonates, immunoglobulin, ketamine, or lidocaine as valuable interventions in selected patients with CRPS. However, high-quality studies are required to further evaluate the safety, efficacy, and cost-effectiveness of IV therapies for CRPS.

From the Departments of *Pain Management and Pediatric Anesthesiology, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio.

Jing Yang, MD, is currently affiliated with Chinese People Liberation Army (PLA), Department of Anesthesiology General Hospital, Beijing, China.

Peirong Lin, MD, PhD, is currently affiliated with Department of Anesthesiology, Beijing Anzhen Hospital, Beijing Capital Medical University, Beijing, China.

Accepted for publication July 20, 2015.

Funding: This work is partially funded by a Research Fellowship Grant from the Foundation for Anesthesia Research and Education (FAER).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Jijun Xu, MD, PhD, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195. Address e-mail to xuj3@ccf.org.

Article Outline

Complex regional pain syndrome (CRPS), formerly known as “reflex sympathetic dystrophy” (RSD) or “causalgia,” is one of the most challenging clinical pain syndromes, with an uncertain pathophysiology and an unpredictable clinical course, despite decades of basic and clinical research.1,2 Multiple pathophysiologic mechanisms3 underlying the development and maintenance of CRPS may include vasoconstriction-mediated hypoxia, over-reactive inflammation, sympathetic dysfunction, N-methyl-D-aspartate (NMDA) receptor activation, and psychological derangement. Treatment of CRPS remains a clinical challenge to health providers.4–7 An interdisciplinary approach,1,6 including pharmacologic management (antiinflammatory therapy such as nonsteroidal antiinflammatory drugs [NSAIDs], analgesics, vasodilatory and anticonvulsant therapies), physical rehabilitation, and psychological support, remains the mainstay of therapy for CRPS. Interventional pain management techniques (IV regional block, sympathetic block, and neurostimulation) are options for reducing pain and improving function. Compared with spinal cord stimulation and intrathecal targeted therapy, IV treatments are less invasive and less costly. However, there are few clinical guidelines for using IV therapies in treating CRPS. Therefore, we conducted an updated systematic review of the literature focusing specifically on IV therapies for CRPS and reviewed the levels of evidence for various agents used in IV therapy. Such information can be useful in the clinical decision-making process.

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METHODS

We systematically searched the literature from PubMed, Medline, Embase, Scopus, and the Cochrane library for all reports published in English on CRPS IV treatment from inception up through February of 2015. Search terms included the following: “complex regional pain syndrome,” “CRPS,” “reflex sympathetic dystrophy,” “RSD,” “causalgia,” “treatment,” and “intravenous.” The following is an example of the query that was performed for the PubMed/Medline database: (“CRPS”[MeSH Terms] OR “complex regional pain syndrome”[All Fields] OR “RSD”[MeSH Terms]) OR (“reflex sympathetic dystrophy”[All Fields] OR “causalgia”[MeSH Terms]) AND “treatment”[All Fields] AND “intravenous”[All Fields] OR “Regional block” [All Fields]). Records from the query were further filtered to extract evidence-based publications in the format of systematic reviews, meta-analyses, clinical trials, case series, anecdotal reports, and clinical experience. A further manual search was undertaken to exclude irrelevant articles by screening the title and the abstract. The abstracts were subsequently reviewed, and full-text publications were retrieved whenever necessary. Levels of evidence and implications for recommendations of all studies were graded based on “grading strength of recommendations and quality of evidence in clinical guidelines” described by Guyatt et al.,8 adapted by van Kleef et al.9 and by our group10 (Table 1). This method of classification considers the type of the study (systematic review with/without meta-analysis, randomized controlled trials [RCTs] or observational study), the quality of the study (methodological design such as sample size and power analysis), and the quantity of studies included in meta-analyses and systematic reviews. Levels of evidence of systematic reviews or meta-analyses were graded according to the same scale by the quality of studies incorporated into a particular meta-analysis or systematic review. Three of the authors independently performed the search and extracted data from articles. The extraction of publications thought to be of interest for pain physicians was also performed. Disagreements were resolved by discussion.

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RESULTS

The search strategy yielded 299 articles, of which 101 articles were deemed relevant by reading the titles and 63 by reading abstracts. All these 63 articles were retrieved for analysis and discussion (Fig. 1).

It is noteworthy that most of the studies were conducted before the Budapest criteria were established.11–13 The diagnosis of CRPS may thus have been less specific.14 Every effort should be made to adhere to the Budapest diagnostic criteria of CRPS in future clinical studies (Table 2).

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IV Bisphosphonate

IV Pamidronate

In an open prospective study16 of 11 patients experiencing RSD refractory to calcitonin and physical therapy, more than half of the patients showed significant or excellent improvement in pain after 30 mg IV pamidronate in 500 mL of saline infused over 4 hours daily for 3 consecutive days. (The use of calcitonin in the management of CRPS is reviewed elsewhere55 and was excluded in this review because it was administered either intranasally or IM.) Other case studies reported on the effectiveness and safety of IV pamidronate in recalcitrant RSD patients,56,57 including a lactating mother58 and an adolescent.59 Pain was significantly improved, and adverse events included transient fever, venous inflammation, transient symptomless hypocalcemia, nausea, lymphopenia, and transient hypertension.56 A single infusion of 60 mg pamidronate had no effect on phosphate excretion.60 Urinary phosphate excretion parameters were identical in pamidronate cases and in controls.

A randomized, placebo-controlled study reported that overall improvements in pain score, patient’s global assessment of disease severity score, and physical function score were noted with a single 60 mg IV pamidronate other than IV normal saline15 in 27 patients with CRPS type 1. Although treatment response of pamidronate was variable among individuals, most patients improved.

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IV Alendronate

In a randomized trial,17 20 patients with RSD were randomly treated with either 7.5 mg IV alendronate in 250 mL saline solution or placebo saline infusions daily for 3 days. Two weeks later, all patients received open alendronate 7.5 mg/d for 3 days. In the patients treated with blind alendronate, a diminution in spontaneous pain, tenderness, and swelling (circumference of the affected limb) and improvement in motion were significantly different from baseline (P < 0.001), from those observed within the first 2 weeks in the control group (P< 0.01), and from week 2 to week 4 (P < 0.01). In patients given blind placebo infusions, no relevant symptomatic changes were observed after the first 2 weeks of follow-up, but these patients responded to the open alendronate therapy given afterward. Alendronate, at a daily oral dose of 40 mg, provided better pain control and range of motion than placebo in a subsequent RCT in treating 39 posttraumatic CRPS patients.61

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IV Clodronate

A short course of IV clodronate62 was reported to be effective in treating RSD caused by an acute attack of gout. IV clodronate, 300 mg daily for 10 consecutive days, was compared with placebo18 in a randomized trial in 32 patients with RSD. Forty days later, the placebo-treated patients received the clodronate treatment. At 40-day follow-up, the 15 patients randomly assigned to clodronate treatment showed significant decreases in visual analog scale (VAS) and clinical global assessment (CGA) (P = 0.002, P = 0.001, respectively). All 32 patients had a significant overall percentage decrease of VAS at 180-day follow-up, with 30 patients significantly improved or asymptomatic.

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IV Ibandronate

An open-label trial (n = 10)19 of 6 mg ibandronate infusions showed significant improvements in average and worst pain ratings during a 4-week follow-up period. Patients experienced characteristic transitory but tolerable flu-like symptoms with bisphosphonate treatments. Participants with hand CRPS improved significantly more than those with foot CRPS in average and worst pain.

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IV Neridronate

A recent multicenter double-blind, placebo-controlled RCT (82 patients, all patients fulfilled the Budapest criteria) showed that IV infusion of 100 mg neridronate20 given 4 times over 10 days (total dose 400 mg) to patients with a disease duration of <4 months resulted in significant decrease in VAS scores and improvement in other pain indices and quality of life for 40 days, whereas placebo only had some effect for 20 days. After 50 days, the placebo group received open-label neridronate and showed a significant decrease in VAS score. Smaller doses (200 and 300 mg) of IV neridronate did not provide significant remission, and symptoms partially relapsed within 1 to 3 months.

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IV Immunoglobulin

IV immunoglobulin (IVIG) was anecdotally administered to a patient with primary hypogammaglobulinemia and unexplainable pain that was not caused by CRPS. Pain relief was unexpected and reproducible when IVIG treatment was repeated. In a prospective, multiple-dose, open-label cohort study,22 IVIG was administered to patients between 18 and 65 years of age who experienced chronic (>3 months) non-cancer pain, including CRPS, and who had insufficient pain relief with all appropriate established treatments, such as NSAIDs, opioids, anticonvulsants, antidepressants, and transcutaneous electrical nerve stimulation. An initial total dose of 9 to 18 g of IVIG divided into 3 applications was given over 1 week. If pain relief was suboptimal after 28 days, IVIG at a higher dose of 10 g was given 3 times over 1 week. In the CRPS group, 18.2% of 11 patients reported 25% to 70% pain relief and 27.3% patients reported >70% pain relief over a 36-month study period after IVIG therapy. IVIG should not be used in patients with selective IgA.

In another randomized, double-blind, placebo-controlled crossover trial,21 13 CRPS patients with a pain score >4 on a scale of 0 to 10, and who had had pain syndrome for 6 to 30 months that was refractory to standard treatment were administered either IVIG 0.5 g/kg or normal saline divided by a washout period of at least 28 days. Twelve patients completed the trial. The average pain intensity was 1.55 lower in the IVIG group than in the saline group. No serious adverse reactions were observed. In a recent literature review based on Medline database and International Trial Registry databases, Goebel63 indicated that IVIG has emerged as a novel treatment modality for refractory pain cases of CRPS. A multicenter, double-blind, randomized parallel-group, placebo-controlled trial designed to evaluate the efficacy, safety, and tolerability of IVIG treatment for CRPS is currently underway in the United Kingdom.64

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IV NMDA Receptor Antagonist

IV Ketamine

Complete pain relief has been reported in severe refractory CRPS using an IV anesthetic dose of ketamine65 but not with subanesthetic dose of S(+)-ketamine (gradually titrated, 50–500 mg/d over a 10-day period).66 A retrospective review67 analyzed 33 patients with CRPS who had undergone ketamine treatment at least once. There was complete pain relief in 25 (76%) and partial relief in 6 (18%) patients after the initial course of therapy. All 12 patients who received second courses of treatment experienced complete relief of their CRPS pain. The most frequent side effect observed was a feeling of inebriation and hallucinations. Less frequent side effects included complaints of lightheadedness, dizziness, and nausea. A 4-hour ketamine infusion, escalated from 40 to 80 mg over a 10-day period, resulted in a significant reduction of pain in an open-labeled, prospective study.25 Analgesia persisting beyond the ketamine infusion period was reported in an observational study26 and a placebo-controlled trial.27 A comparison in brain structures between pain state CRPS and pain-free state CRPS (pain relief after IV ketamine) using functional MRI68 showed significant changes throughout the cerebral cortex (frontal, parietal, temporal, cingulate, and hippocampus), in subcortical regions such as caudate nucleus, and in the cerebellum.

A randomized double-blind placebo-controlled trial23 showed that IV ketamine (0.35 mg/kg/h, not to exceed 25 mg/h over a 4-hour period daily for 10 days, diagnosis met revised International Association for the Study of Pain [IASP] criteria) but not normal saline resulted in statistically significant (P < 0.05) reductions in many pain parameters. Subjects in both the ketamine and the placebo groups were administered clonidine and midazolam. A pharmacokinetic-pharmacodynamic modeling study27 showed that 100-hour infusion of S(+)-ketamine treatment is more effective in pain relief than placebo in CRPS type 1 patients with analgesia outlasting the treatment period by 50 days. A 4.2-day IV infusion of low-dose ketamine resulted in significant pain relief, but not functional improvement, in a double-blind randomized placebo-controlled parallel-group trial.24

In an attempt to minimize the possible adverse effects of IV ketamine infusion, dexmedetomidine was used in combination with ketamine to provide additional analgesia in CRPS. Nama et al.69 reported treatment of acute pain symptoms from CRPS type 1 with subanesthetic IV infusion of ketamine and adjunct dexmedetomidine in a 47-year-old female patient with severe pain, burning, and allodynia from CRPS type 1 refractory to conventional therapy. The patient received a subanesthetic IV infusion of ketamine at a rate of 100 μg/kg/h. Pain subsided at approximately 1 hour after the start of the infusion. A 1-time dose of 8 μg of dexmedetomidine in 2 mL was bloused at 6 hours after starting the ketamine infusion, which further improved her pain. The patient reported complete resolution of pain (0/10 pain rating) at 19 hours after the infusion was started. The synergistic effect of the ketamine and dexmedetomidine together provided excellent symptom relief while decreasing the total ketamine administered.

A 5-year retrospective analysis showed that subanesthetic ketamine infusions significantly decreased the VAS pain score in CRPS patients.70 However, in a recent meta-analysis, no significant pain relief could be established for ketamine IV in treating CRPS (−0.65 [95% confidence interval, −1.47, 0.16], P = 0.11).71 The authors indicated that additional RCTs are needed to explore the therapeutic potential of NMDA receptor antagonists in CRPS.

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IV Magnesium

IV magnesium administration was evaluated in acute stage CRPS type 1 patients in an RCT.28 Eight patients received 70 mg/kg magnesium sulfate infusions in 4 hours for 5 days, and 2 patients received an equal amount of normal saline solution. Interventions were accompanied by standardized physical therapy. Assessments of pain were performed at baseline and 1, 3, 6, and 12 weeks after intervention. Mild systemic side effects were experienced. Pain was significantly reduced at all follow-up compared with baseline (T1: P = 0.01, T3: P = 0.04, T6: P = 0.02, T12: P = 0.02). Impairment level (P = 0.03) and quality of life (EuroQol P = 0.04, SF-36 physical P = 0.01) were significantly improved at T12. No improvement was found for skin sensitivity and functional limitations. The same group consequently conducted a double-blinded placebo-controlled RCT to evaluate the effect of the magnesium regimen on 56 chronic CRPS type 1 patients.29 They found no significant difference between magnesium and placebo on pain and impairment scores, although the magnesium group did show statistically significant improvement on the impairment and McGill scores compared with baseline. The authors concluded that magnesium provides insufficient benefit over placebo in long-standing CRPS type 1 patients.

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IV Regional Block with Antiinflammatory Medications

IV Regional Block with Glucocorticoids and Local Anesthetics

In a retrospective review of 17 consecutive patients with posttraumatic RSD,36 IV 20 to 40 mL 0.5% lidocaine and 80 mg methylprednisolone were administered using regional block after limb exsanguination. The block was maintained for 20 to 30 minutes under a tourniquet and followed by an average 2-month physical therapy. Most blocks were repeated at 3- to 4-week intervals, and the number of total blocks ranged from 1 to 4 (average 2.4). At the assessment point of 6 months, 11 of 16 patients reported satisfactory pain improvement and most of which occurred in the initial 2 months of the treatment. Furthermore, there was no relapse or worsening of pain in those patients with early improvement at the follow-up time of 28.3 months. These findings were echoed by another study37 where 36 patients with posttraumatic RSD of the upper extremity were treated with regional IV blocks using a solution of 80 mg methylprednisolone, 20 mL 1% lidocaine, and 1000 IU heparin. At 1-year follow-up, 25 patients (69%) had good relief of spontaneous pain, no limitation in finger movement, and 8 (22%) had moderate responses. The authors concluded that regional IV block with methylprednisolone and lidocaine followed by standard physical therapy was an effective treatment for the early stages of posttraumatic RSD. In a 5-year retrospective study, regional block with lidocaine and methylprednisolone provided complete pain relief in 92% of 168 patients with CRPS as a consequence of trauma or surgery to the upper extremity.38

In a randomized, double-blinded, placebo-controlled trial35 of 22 patients with CRPS type 1 in their upper limbs, IV methylprednisolone 40 mg and 2% lidocaine 10 mL were compared with 100 mL saline using a bier block technique in a large cubital vein over 20 minutes. Treatments were applied once a week and repeated for a total 3 sessions. Pain severity, which was assessed using a 0 to 10 numeric scale after each session of block, was improved significantly at 3 assessment time points in both groups. There was no significant difference in improvement of pain scores in either group. These improvements were not observed 1 week or 1.5 months after the block. The authors concluded that IV bier block with methylprednisolone and lidocaine was not superior to placebo. The last study was questioned with respect to the bier block because a large cubital vein was used for drug administration.72 The use of this vein as an access for bier block was questioned on grounds that the injectate should be retained in the periphery to exert the antiinflammatory effect peripherally. The authors replied by indicating that many CRPS patients demonstrate severe peripheral edema and pain, which prevents cannulating a vein at the distal part of the affected extremity.72 In all these studies, IV regional block (IVRB) steroids were given together with lidocaine; it is therefore difficult to evaluate the effect of steroids alone.

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IVRB with NSAIDs

In a randomized, double-blinded, prospective study,32 IV regional block (after limb exsanguination) with 50 mL 0.5% lidocaine plus 0, 30, 60, and 120 mg ketorolac was performed at 1-week interval (total 4 blocks) in 12 adult patients with CRPS of the lower extremity. The block was maintained for 20 minutes. All ketorolac treatment groups showed a reduction in pain score at 1 day after the block. However, no significant long-lasting pain relief was found at 1 week after injection.

Another study showed that IVRB with ketorolac (60 mg in 40 mL for upper limbs and in 50 mL for lower limbs) produced significant pain relief in 7 patients with RSD33 whether or not lidocaine was coadministered. The duration of pain relief tended to extend with each subsequent block in most patients. In another case report, 1 or 2 IVRB sessions with ketorolac (0.5 mg/kg) and lidocaine (2 mg/kg) resulted in a complete resolution of the pain in 2 adolescents after conventional pharmacologic therapy and nerve stimulation had failed.34 Frade et al.30 compared systemic (20 mg) versus local (5 mg) effects of IV-specific cyclooxygenase-2 inhibitor, parecoxib, in addition to their routine IV regional block regimen (30 μg clonidine/1 mg/kg lidocaine) in 30 patients with upper-limb CRPS type 1. The time of tourniquet application was 5 minutes, and the limb was not exsanguinated. A small volume (10 mL) was injected. Analgesia was evaluated by the 10-cm VAS. The authors found that, compared with systemic IV parecoxib plus clonidine/lidocaine and control groups (clonidine/lidocaine only), regional IV administration of parecoxib along with clonidine and lidocaine required less daily rescue analgesic (ketoprofen) in the second and third weeks after the block. They concluded that 5 mg parecoxib used in regional bier block is an effective drug in combination with clonidine/lidocaine regional block for CRPS type 1. However, a recent RCT showed that short-term (2-day) treatment of IV parecoxib did not influence pressure pain threshold or edema or pain in CRPS patients.31

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IV Free Radical Scavengers

IV Mannitol

In a retrospective observational study, 1 L of 10% mannitol was administered preferably via a subclavian vein every 24 hours (100 g per 24 hours) in 65 patients after conservative treatments had failed.73 Successful overall improvement was seen in 24% of patients after 1 week and 30% after 1 month. The authors concluded that mannitol did not significantly improve the treatment of CRPS, although warm CRPS and CRPS of the upper extremity appeared to respond better to mannitol treatment than cold and lower extremity CRPS. However, in an earlier retrospective report,74 75 patients with early CRPS type 1 (present for <4 months) received 10% mannitol 2 × 250 mL and 8 mg dexamethasone IV bolus per day for 1 week as inpatients. Significant improvement in pain scores was observed at the initial 1 week and the final 9 (range 8–12) month assessments. The drawback of this study is that there was no control group, and the addition of dexamethasone confounded the effect of mannitol treatment.

In a prospective, randomized, placebo-controlled, double-blinded trial,39 41 patients were randomly infused with either 1 L 10% mannitol (administered over 4 hours via an IV cannula in the unaffected extremity) or 0.9% NaCl (placebo) each day for 5 days. There was no significant improvement with mannitol treatment, except in a subgroup of the Jebsen-Taylor hand function test. No significant differences were found between mannitol and placebo treatment over a 9-week study period. No significant differences were found between both groups in the number of patients requesting rescue pain medication or the amount or strength of pain medication used. The authors concluded that IV 10% mannitol is not more effective than placebo in CRPS type 1 treatment.

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IVRB with Sympatholytics

IVRB with Local Anesthetics

Pain from CRPS type 1 may be relieved by blocking sympathetic efferent-dependent vasoconstriction or by enhancing nitric oxide–dependent vasodilatation in an animal model of postischemic pain.75 IVRB with lidocaine was reported effective in CRPS treatment in case reports,76 and lidocaine may be particularly effective for thermal and mechanical allodynia.42

In a randomized, double-blind, placebo-controlled design in 16 patients with CRPS types 1 and 2 with a prominent allodynia, Wallace et al.40 found that IV lidocaine and diphenhydramine infusion increased the hot pain thresholds in the painful area but had no significant effect on the cool, warm, or cold pain thresholds. Another double-blinded, randomized, placebo-controlled parallel study showed that IV lidocaine 5 mg/kg/h was more effective than saline placebo in relieving spontaneous neuropathic pain in 32 patients (of whom 23 had CRPS).41 Lower doses of lidocaine (1 or 3 mg/kg/h) were no better than placebo in relieving pain.41

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IVRB with Guanethidine and Reserpine

A series of IVRB with guanethidine produced good response in 11 of 20 patients with RSD with minimal side effects.77 Bier blocks composed of lidocaine, methylprednisolone, and reserpine or guanethidine78 improved range of motion in the affected joints (primarily the hand and wrist) from a preblock mean of 46% to 81% of normal following the blocks. Patients also reported an 80% mean improvement in their pain. IVRB with guanethidine provided complete pain relief with 2 injections in a 62-year-old woman experiencing RSD, and the patient remained pain-free for 18 months.79 Complete disappearance of pain and return of the normal movement of the extremity were achieved in 17 patients with CRPS type 1 using a series of IVRB (Bier’s block) sessions with 10 or 15 mg guanethidine and 1 mg lidocaine/kg body weight.80 However, Kaplan et al.81 found that, in 55 RSD patients who received regional IV guanethidine blocks (upper extremities received 20 mg [10 mg/mL] of guanethidine in 30–50 mL of 0.5% lidocaine; lower extremities received 40 mg guanethidine in 40–75 mL of lidocaine), pain resolution improved in only 23.6%, and there was no change in pain in 61.8% of the patients. There were 56 adverse effects in 19 (34.5%) patients (nausea, vomiting, orthostatic hypotension, dizziness, diarrhea, and weakness).

RCTs failed to support the effectiveness of IVRB guanethidine in CRPS management. In a double-blind crossover study,44 12 patients received 20 mg guanethidine in 50 mL 0.5% lidocaine, 1.25 mg reserpine in 50 mL 0.5% lidocaine, and 50 mL 0.5% lidocaine with a 1-week interval between medications. There were no significant changes in pain intensity for the first 3 days among IVRB guanethidine, reserpine, and control groups. Pain relief from 2 to 14 months was achieved in 2 patients receiving reserpine, 1 receiving guanethidine, and none receiving lidocaine. None of the patients experienced permanent relief. No difference was found between reserpine and guanethidine. A double-blind, randomized study45 compared IVRB sympatholysis using guanethidine, reserpine, and normal saline in 21 patients with RSD. There was significant pain relief in all 3 groups at 30 minutes. There were no significant differences among the 3 groups in the degree of pain relief. A systemic review43 identified 7 RCTs of IV regional sympathetic block in patients with RSD. Four used guanethidine; none showed significant analgesic effect in pain relief. Two reports, one using ketanserin and one bretylium, with 17 patients in total, showed some advantage of IV regional sympathetic block over control. The authors conducted a subsequent randomized, double-blind, crossover study43 in 9 patients to assess the effectiveness of IV regional sympathetic block with guanethidine of high (30 mg for both upper and lower limbs) or low (10 mg for upper and 20 mg for lower limbs) dose and normal saline. The trial was stopped prematurely because of the severity of the adverse effects. No significant difference was found between guanethidine and placebo on any of the outcomes measured. In a double-blind, randomized, multicenter study, 60 RSD/causalgia patients received 4 IV regional blocks at 4-day intervals with either guanethidine or placebo in 0.5% lidocaine.46 Four days after the initial block, the group treated with placebo experienced a greater decrease in pain scores than those treated with IVRB guanethidine, although this difference was not statistically significant. On long-term follow-up, there was no difference in pain scores between groups receiving 1, 2, or 4 guanethidine blocks. Overall, only 35% of patients experienced clinically significant relief on long-term follow-up. In a randomized trial in 57 patients47 with CRPS type 1 of the hand after fracture of the distal radius, the IVRB guanethidine group (15 mg guanethidine in 30 mL of 0.5% prilocaine) experienced more pain in the affected hand (P = 0.025), and at 6 months had more vasomotor instability (P < 0.0001) compared with the control IVRB normal saline group. IVRB guanethidine offered no significant analgesic advantage over the normal saline placebo block in the treatment of early CRPS type 1.

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IVRB with Clonidine or Dexmedetomidine (the α2-Adrenergic Receptor Agonists)

Lidocaine/clonidine IVRB combined with parecoxib was discussed earlier.30 A case study48 reported complete pain relief with 4 to 6 IVRB with a solution containing clonidine 1 μg/kg in a total volume of 50 mL 0.5% lidocaine in 5 of 7 patients with the diagnosis of CRPS of the knee. IVRB clonidine was performed on each patient up to 6 times (maximum of once a week for 6 weeks). No hypotension (mean arterial pressure ≤20% baseline), hypoxemia (SpO2 ≤90%), bradycardia (heart rate ≤60 beats/min), or excessive sedation was found. Another case reported successful treatment of RSD by bier block with 0.5 μg/kg clonidine,82 but the pain relief was obtained using multiple concomitant drugs, including IVRB with 0.5% lidocaine, 0.2 mg/kg labetalol, and 2 mg/kg bretylium. IV dexmedetomidine was used in conjunction with IV ketamine with complete resolution of pain and associated symptoms in a case report as mentioned earlier.69

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IVRB with Phenoxybenzamine

In a case study,49 IVRB with phenoxybenzamine was performed in 5 patients after exsanguination using an Esmarch bandage and a double-cuff tourniquet. Thirty milliliter solution (15 mL of 0.5% lidocaine HCl, 5 mg phenoxybenzamine HCl, 0.05 mL of absolute alcohol, 0.05 mL of propylene glycol, 0.0005 mL of hydrochloric acid, and isotonic saline) was injected into the upper extremity. All patients had significant and prolonged symptom relief (ranging from 7 to 17 months) with a single treatment. Oral phenoxybenzamine was also found effective in treating CRPS in other case studies.83,84

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IVRB with Droperidol

In a double-blind, placebo-controlled, crossover study, IVRB with droperidol (used as an α-adrenergic antagonist here) in 6 RSD patients failed to show any significant analgesic effect over placebo but with adverse effects, including akathisia and dysphoria in 3 patients.50

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IVRB with Labetalol

IVRB with labetalol (a mixed α- and β-adrenergic antagonist) was reported in a 42-year-old man with CRPS after a right fifth metatarsal fracture. Bier block with bretylium and lidocaine did not improve his pain. An ischemic tourniquet block of the right foot made the pain worse. Bier block with normal saline and lidocaine provided him with only minimal pain relief for a few hours, whereas IVRB with combination of labetalol (20–40 mg) and lidocaine (100–200 mg) relieved his pain for >7 to 10 days.51

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IVRB with Ketanserin

Ketanserin, a selective serotonin receptor antagonist with weak adrenergic receptor blocking properties, was assessed against placebo in a double-blind crossover study of 16 patients with chronic peripheral burning pain. Nine of these patients had signs of RSD. In those patients with RSD, ketanserin, but not placebo, provided significant sustained pain relief as assessed by linear analog scales. No significant relief was seen with placebo or ketanserin in non-RSD pain patients. Side effects were reported at a higher frequency after ketanserin than after placebo, but all were mild and transient.52

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IV Anti-TNF-α Antibodies

Infliximab 3 mg/kg 2 or 3 times during a 3- or 4-week period showed pain improvement in 2 cases of CRPS type 1.53 An RCT using infliximab failed to demonstrate significant change in total pain score impairment level sumscore [ISS]) but yielded a significant decrease in health status (EuroQol VAS) compared with placebo group. The RCT was therefore terminated before the required number of the patients had been reached.54

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DISCUSSION

Different classes of medications have been tried intravenously in treating CRPS. In this review, we discussed the use of IV bisphosphonates, immunoglobulins, NMDA receptor antagonists, antiinflammatory drugs (glucocorticoids and NSAIDs), free radical scavengers (mannitol), sympatholytics, and anti-tumor necrosis factor (TNF)-α antibodies in CRPS. Recommendations are made based on current available level of evidence (Table 1).

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IV Bisphosphonate

Bone demineralization has been found to accompany CRPS. Bisphosphonates have been used in treating CRPS85 by inhibiting bone resorption. A systemic review86 showed that bisphosphonates have the potential to reduce pain associated with bone loss in patients with CRPS type 1. A recent Cochrane review concluded that bisphosphonates may be effective for CRPS when compared with placebo, although the quality of evidence is low.87 On the basis of the level of evidence reviewed, we recommend that IV bisphosphonates can be used to reduce pain associated with bone loss in patients with CRPS (evidence level: 1B+/2C+).

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IV Immunoglobulin

The possible mechanisms underlying IVIG-mediated pain relief are still unclear but may include22 the following: (1) elimination of proinflammatory cytokines (such as interleukin-2, TNF, and interleukin-6); (2) stimulation of macrophages to increase the catabolism of immunoglobulins and potentially noxious autoantibodies present in the serum may thus be eliminated; (3) antiinflammatory action via binding C3b and C4b and reducing the number of activated complement fragments; and (4) downregulation of the production of autoantibodies in B cells or inhibition of cytotoxic T cells. On the basis of the level of evidence reviewed, we recommend that IVIG can be considered for CRPS patients with refractory pain (2B+/2C+).

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IV NMDA Receptor Antagonists

Activation of NMDA receptor signaling has been proposed in induction and maintenance of CRPS. Ketamine and magnesium might be effective in treating refractory CRPS patients by blocking central sensitization of pain transmission neurons through inhibiting NMDA receptors. On the basis of the level of evidence reviewed, we recommend that IV ketamine infusion can be used in selected patients with refractory CRPS (2B+/2C+). Different RCTs yielded contradictory results of IV magnesium in CRPS (2B±).

Patients receiving ketamine often experienced mild to moderate psychotomimetic side effects during drug infusion (76% vs 18%, P < 0.001).26 In a case series of 6 patients who received 2 continuous IV 100-hour ketamine infusions separated by 16 days, liver enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and γ-glutamyl transferase) were reported to be transiently elevated to 3 times the normal upper limits in 3 patients during ketamine infusion.88 The enzyme levels slowly returned to normal range within 2 months once the infusion was promptly discontinued. This observation may suggest that there is an increased risk of ketamine-induced liver injury if the infusion is prolonged and/or repeated within a short period.

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IVRB with Antiinflammatory Medications

The rationale of using antiinflammatory medications in CRPS is that these drugs act against the local neural inflammatory process, which may be involved in the pathophysiology of CRPS. Glucocorticoids and NSAIDs act by inhibiting synthesis of prostaglandins, which may be responsible for tissue inflammation and vasoconstriction. IVRB with methylprednisolone and lidocaine was reported more effective in reducing CRPS pain score/intensity in case series but not superior to placebo in an RCT. IVRB with lidocaine and ketorolac showed short-term pain relief in an RCT. A case series also reported effectiveness of IVRB ketorolac with or without lidocaine. IVRB parecoxib was found to be effective in combination with clonidine or lidocaine in case reports but not in RCT. On the basis of the level of evidence reviewed, we recommend that IVRB with ketorolac (preferable with lidocaine) may be considered for short-term pain reduction in CRPS patients (2B+/2C+), whereas the effectiveness of IVRB with methylprednisolone or parecoxib is not supported by RCTs (2B−/2C+).

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IV Free Radical Scavengers

Free radical scavengers, such as mannitol, have been used to attenuate the excess, oxygen-radical–mediated, exaggerated inflammatory responses to tissue injury in CRPS. RCT and retrospective studies failed to demonstrate the effectiveness of IV mannitol in CRPS patients (2B−).

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IVRB with Sympatholytics

Sympathetic activation is found in chronic CRPS.89 There is evidence of heightened expression of α1-adrenoreceptors in the dermal nerves and epidermal cells of CRPS patients.90,91 Sympathetic activation leads to vasoconstriction, cold skin, and tissue hypoxemia.92–94 One RCT reported that IVRB with lidocaine at 5 mg/kg/h but not lower doses (1 or 3 mg/kg/h) was more effective than saline placebo. Another RCT and case reports showed that IV lidocaine was effective to reduce pain—particularly thermal pain—in CRPS patients (2B+/2C+).

Sympathetic blockers, such as guanethidine and reserpine, α1-adrenergic receptor antagonist, and vasodilators, have been historically prescribed in treating CRPS patients based on these concepts. Reserpine depletes storage of norepinephrine, and guanethidine inhibits presynaptic release of norepinephrine in the sympathetic nerve terminal. Both regional IV guanethidine95 and reserpine have been reported in the treatment of RSD. Results from case reports are inconsistent, and RCTs failed to support the effectiveness of IVRB guanethidine, reserpine, or droperidol in CRPS management (2A−/2B−).

The rationale for the use of phenoxybenzamine lies in its noncompetitive, irreversible blockade of α-adrenergic receptors, which might decrease or eliminate the sensitization that characterizes CRPS. Only case studies have shown phenoxybenzamine and labetalol to be effective; no RCT has investigated this medication in CRPS (2C+).

IVRB with ketanserin was reported superior to placebo in pain reduction in an RCT (9 of 16 patients had signs of RSD) (2B+, evidence level is weak because of small number of patients in only one study).

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IV Anti-TNF-α Antibodies

TNF-α signaling has been reported to contribute to the development of nociceptive sensitization in a tibia fracture animal model of CRPS type 1.96 Case studies showed effectiveness of infliximab, the monoclonal antibody against TNF-α, in 2 CRPS patients but RCT failed to demonstrate the benefit of this medication (2B−).

In summary, many IV medications have been used in treating CRPS along with traditional therapies.97 Most of the IV therapies were followed by a standard physical therapy protocol. Several case series have reported effectiveness of several IV medications, but most of these studies lack control groups or placebo for comparison. On the basis of the level of evidence reviewed, we recommend the following strategies:

1. IV bisphosphonates to reduce pain associated with bone loss in patients with CRPS type 1 (evidence level 1B+/2C+); IV immunoglobulin (IVIG) for refractory pain cases of CRPS (2B+/2C+); IV ketamine infusion in some refractory patients (2B+/2C+); IVRB with ketorolac (when used with lidocaine) may be considered for short-term pain reduction in CRPS patients (2B+/2C+); IVRB lidocaine at 5 mg/kg/h may be effective in reducing thermal pain in particular (2B+/2C+).

2. Treatments that lack sufficient evidence or different randomized controlled trials yielded conflicting results: IV magnesium (2B±); IVRB with clonidine, phenoxybenzamine, or labetalol (2C+).

3. Not recommended: IV methylprednisolone and parecoxib (2B−/2C+); IV 10% mannitol (2B−); IV regional block with guanethidine, reserpine, or droperidol (2A−/2B−); IV TNF-α antibodies (2B−).

Because most studies on IV therapies for CRPS are not of high quality,87 further studies on standard RCT quality are required. Whether recommendations can be made regarding the preferred drug based on the acuity or chronicity of CRPS remains debatable. Currently, it is not clear whether bisphosphonates or other drugs are preferable in acute or chronic CRPS.

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DISCLOSURES

Name: Jijun Xu, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, write the manuscript, and is also the archival author.

Attestation: Jijun Xu approved the final manuscript.

Name: Jing Yang, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Jing Yang approved the final manuscript.

Name: Peirong Lin, MD, PhD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Peirong Lin approved the final manuscript.

Name: Ellen Rosenquist, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Ellen Rosenquist approved the final manuscript.

Name: Jianguo Cheng, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Jianguo Cheng approved the final manuscript.

This manuscript was handled by: Spencer S. Liu, MD.

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