Essentials of Assessment
Rehabilitation Management and Treatments
Available or current treatment guidelines
Awareness of complex regional pain syndrome (CRPS) by general practicing physicians is poor, which often leads to delays in treatment. Aggressive treatment should not be delayed as progressive worsening of symptoms is associated with poor prognosis.1 Rehabilitative therapies coupled with pharmacotherapy are the mainstays of early treatment. Interventional treatments are considered if conservative strategies fail.2 There are no well-accepted treatment guidelines for pharmacotherapy.2 Best evidence supports a multidisciplinary approach.
1. Physical therapy and occupational therapy
Physical therapy (PT) and occupational therapy (OT) can improve outcomes in CRPS, when started early (symptoms for less than 1 year).3 Objectives of PT and OT in CRPS are to improve range of motion, desensitization, minimize swelling, promote normal positioning, decrease muscle guarding, and increase functional use of the extremity.4
2. Mirror box therapy
Mirror box therapy may improve affected limb range of motion (ROM) by cortical
reorganization of pain and motor neural networks.5 It is an adjuvant treatment of post-stroke upper limb CRPS. Besides optimizing pain control and function, it is also associated with shorter hospital stays.20
3. Graded motor imagery
Graded motor imagery (GMI) treatment is focused on training the brain to re-connect to the body part affected by pain. When you have CRPS in one part of your body, your brain recognizes the extremity affected as a painful threat. There are 4 steps to GMI, and these include laterality, imagery, sensory discrimination, and mirror therapy. GMI has been shown to improve altered central processing in CRPS, which may improve symptoms.6 Trials have demonstrated improvement in pain and functional disability at 6 months in patients with CRPS I.1
4. Tactile (or sensory) discrimination training
Tactile (or sensory) discrimination training has been shown to help pain and function in CRPS.7 By teaching the body part and the associated area of the brain how to differentiate between various sensations, it helps clear the picture in the brain.
5. Transcutaneous nerve stimulation (TENS)
Results in decreased pain and edema and provides minimal functional benefits in combination with PT.20
6. Cognitive Behavioral Therapies
Regardless of the duration of the condition, all CRPS patients and their families should receive education about the negative effects of disuse, the pathophysiology of the syndrome, and possible interactions with psychological/behavioral factors. All patients with chronic CRPS should receive a thorough psychological evaluation, followed by cognitive-behavioral pain management treatment, including relaxation training with biofeedback, reframing, hypnosis, and behavioral modifications.8
1. Complementary therapies
Isolated case studies show a potential role for acupressure and acupuncture. Herbal medicines, anti-inflammatory type diets, and natural supplementation have also found roles in treatment for CRPS.5
2. Hyperbaric oxygen
Hyperbaric oxygen therapy has been shown to induce analgesic effects in nociceptive, inflammatory and neuropathic pain in animal models. In patients with post-traumatic CRPS of the wrist, it may lead to potential improvement in range of motion, pain control, and edema management.5 It is not clear these results are generalizable to other populations.21
3. Electroconvulsive therapy
There are case reports of secondary improvement in CRPS symptoms when electroconvulsive therapy is used for depression.5
1. Nonsteroidal anti-inflammatory agents
Clinical trials have shown mixed results, questioning their benefit in CRPS.7
2. Antiepileptic drugs
Gabapentin has moderate evidence in improving pain symptoms such as hyperesthesia and allodynia.22
Gabapentin and amitriptyline were compared in the pediatric population and showed both drugs were effective in reducing pain intensity and improving sleep, but no difference between them. Other options include pregabalin and topiramate. Also, carbamazepine was studied in a small trial with 600mg per day for 8 days and showed pain reduction. 1,7
Bisphosphonates may be beneficial through several different mechanisms. They can reduce osteoclastic activity and modify inflammatory cytokines, although the exact mechanism remains unclear.5
Studies show consistent statistically significant effects in pain relief, functional improvement and overall improvement, but these are low quality studies. 22
Analgesic properties in the central nervous system through release of β-endorphins and bone resorption inhibition.22
Conflicting evidence, though treatment is relatively simple, safe and better on early CRPS. 22
Frequently used in clinical practice despite relatively weak evidence for effectiveness.22
Appears to be more useful in chronic post stroke patients compared to post-traumatic injuries.22
Oral phenoxybenzamine is an alpha-1 antagonist that has shown benefit in CRPS. The dose is slowly increased up to a maximum daily dose in the range of 40 to 120 mg, with treatment duration of 6 to 8 weeks. Orthostatic hypotension and ejaculatory problems can be expected at the higher dose range.5
Limited data may indicate that the calcium channel blocker, nifedipine, may be helpful at daily doses of up to 60 mg.5
There is a lack of evidence to support long term (>6 months) opioids in CRPS. While tramadol may be of benefit in neuropathic pain, there is, again, little scientific support in CRPS.7
Similarly, there is insufficient evidence to support or refute fentanyl use for any neuropathic pain condition. 22
NMDA receptor and hyperpolarization activated cyclic nucleotide gated potassium channel 1 receptor antagonist that also has dopaminergic effects which may produce improvement in pain and can decrease opioid requirements. The largest study randomized subjects to a 4 day infusion of IV ketamine (1.2-7.2μg∙kg〖^(-1)〗∙min〖^(-1)〗) vs normal saline titrated according to pain relief and side effects. However, the initial improvements in pain lasted until week 11th of the study. 23, 20
Offers temporary relief from severe, debilitating pain and does not improve affected limb functionality.20 Nevertheless, studies available are too heterogenous and additional higher quality studies are needed.
While commonly used in neuropathic and chronic pain conditions, there is little specific evidence of their benefits in CRPS.7
11. Disease modifying antirheumatic drugs
TNF-α signaling has been reported to contribute to the development of nociceptive sensitization in CRPS and tissue necrosis factor-alpha inhibitors has shown effectiveness in case studies. However, a randomized-controlled trial failed to demonstrate the benefit of this medication in CRPS.
12. Free radical scavengers
There is moderate evidence for topical 50% dimethyl sulfoxide (DMSO) and oral N-acetylcysteine in early and chronic CRPS effectiveness respectively.22
13. Topical agents
Long-term topical capsaicin application can reduce epidermal C fiber density with resultant decreased substance P production. There are clinical strengths ranging from 0.025% to 0.15%, but this has been poorly tolerated in CRPS because of inherent burning sensation when applied despite concentrations administered.5
- Transdermal lidocaine
Compared with capsaicin, transdermal lidocaine may be better tolerated. Few cases in the literature demonstrate long term improvement of pain.7
- Isosorbide dinitrate
Vasodilator, for which there has been only a small study in the CRPS1 population, but not CRPS2. 24 patients with ‘‘cold’’ CRPS of the hand were randomized for topical ointments applied 4 times daily for 10 weeks vs placebo. No difference was observed in skin temperature, pain, activity level or levels of NO and endothelin 1. 20 Another study showed some improvement in mean skin temperature in “cold” CRPS1.5
- Topical clonidine
Clonidine is an alpha-2 adrenergic agonist, and topical administration may help local CRPS induced allodynia and hyperalgesia.5
- Topical diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug, and it may serve as an effective treatment option for patients with neuropathic pain from CRPS.11
14. Intravenous immunoglobulin (IVIG)
IVIG can interfere with proinflammatory markers and cytokines. Small studies of low dose IVIG have shown some benefit in chronic pain syndromes and CRPS.12
However, the LIPS trial, a randomized placebo-controlled study, concluded that IVIG therapy is not an effective analgesic regimen for long-standing CRPS.24
15. Therapeutic Plasma Exchange
Considering the evidence of immune system involvement in CRPS, plasma exchange showed to be effective in a subset of patients with long standing CRPS. Plasma exchange is hypothesized to reduce a number of factors that contribute to neuropathic pain such as inflammatory cytokines and fibrinogen, and it can also increase serum anti-inflammatory cytokines.13
1. Sympathetic block
Considering autonomic dysregulation and exaggerated response to catecholamines is thought to contribute to the pathophysiology of CRPS, sympathetic blocks have been used for both diagnostic and therapeutic purposes in CRPS. Sympathetic block is generally considered the first choice when interventional treatments are considered. Stellate ganglion blocks are indicated for upper-extremity CRPS, and lumbar sympathetic blocks are indicated for lower-extremity CRPS. Sympathetic blocks are generally more likely to help if skin discoloration and temperature changes are present. A series of injections is usually prescribed; however, there is no convincing evidence to conclude that a series of sympathetic blocks is indicated unless there is progressive improvement of symptoms with each injection.5
Relatively weak evidence exists supporting effectiveness, mostly used in chronic lower limb CRPS. 22
2. Radiofrequency sympathectomy
Considered when sympathetic blocks provide short-term relief.5 In a randomized double blind study, comparing radiofrequency lumbar sympathectomy versus lumbar sympathectomy with phenol seem about equally efficacious. However, there is poor quality and very limited evidence.28 Limited data suggests sympathectomy is not effective for reducing pain. 23
3. Intravenous regional blocks
Administration of Intravenous (IV) medication after exsanguination of a limb followed by tourniquet placement. Guanethidine, reserpine, droperidol, and atropine have not been shown to be effective. However, regional blockades with bretylium or ketanserine can result in significant pain reduction.7
Relatively weak evidence for effectiveness and if used , confined to patients that respond to phentolamine tests. No significant differences on pain relief, and functional improvement. 22
4. Spinal cord stimulation
Spinal cord stimulation directly stimulates the dorsal columns to modulate neuropathic pain. Good evidence to support spinal cord stimulation durability for long term pain, satisfaction and quality of life improvement. Limited evidence supporting functional improvement.14
There is moderate evidence for reduction of pain symptoms, but no effect on function. Risks associated with invasiveness of procedure must be balanced against potential benefit.
Recommended by the National Institute for Clinical Effectiveness (NICE) in the UK. 22
5. Dorsal Root Ganglion stimulation
The dorsal root ganglion (DRG) is considered an important target for neuropathic pain management since it transmits input from peripheral to central nervous system. Has the potential of achieving pain relief in focal neuropathic pain syndromes, including those difficult to maintain or target with spinal cord stimulation (SCS). DRGS demonstrated greater improvement in quality of life and psychological disposition with less postural interference from stimulation or unwanted paresthesia compared to SCS in refractory lower limb CRPS. Also, it was preferred over dorsal column stimulation in another study evaluating patients with knee CRPS. DRGS is a promising method since it results in significantly improved analgesia, function and mood at one year compared to SCS with high evidence levels. 26
6. Implantable intrathecal continuous infusion pump
- Opioid Infusion:
Studies specific to CRPS are lacking with implantable continuous infusion pumps with opioid therapy and use is generally not recommended in CRPS. It has been considered; however, only in specific patients with very poor pain control, hypersensitivity, and markedly decreased range of motion. In rare cases, it should be combined with aggressive physical therapy to improve mobilization.5
- Clonidine and Adenosine Infusion:
Preclinical data suggest that intrathecal clonidine and adenosine reduce hypersensitivity. The prevalence of sensory gain and loss on testing in patients with neuropathic pain varies as a function of presumed etiology, with hyperalgesia being most common in CRPS. Both intrathecal clonidine and adenosine acutely inhibit experimentally induced and clinical hypersensitivity in patients with chronic regional pain syndrome.14
7. Intrathecal baclofen therapy
A few studies have shown that intrathecal baclofen therapy may be of benefit in CRPS1 patients, particularly those with dystonia.7
Also, a combination of intrathecal baclofen with spinal cord stimulation may decrease pain and improve dystonia in patients with CRPS refractory to conservative treatment.23
Considered in “end-stage” CRPS and may be appropriate for pain relief and improving quality of life in therapy resistant disease, intractable, debilitating pain, totally dysfunctional limb, severe recurrent infections and chronic trophic ulcers. 22
Several retrospective studies of CRPS1 (but not CRPS2) patients indicate that approximately half had pain improvement after amputation. In patients with intractable CRPS, when compared to nonamputees, those who undergo amputation exhibit better pain scores, less disability, improved quality of life, and less depression. However, there is the risk of CRPS recurrence stump or phantom limb pain.22, 7
2. Surgical sympathectomy
If there is excellent but temporary improvement from sympathetic blockade on repeated occasions, then surgical sympathectomy may be of benefit. Its chance of success is best if performed within the first 3 months after the initial trauma. Relief of pain may decline with time.5
3. Motor cortex stimulation
Recent case reports illustrate the use of motor cortex stimulation in CRPS. A craniotomy is performed and placement of an extradural grid is optimized using somatic evoked responses to cover the areas of pain. The mechanism of action probably involves spinal cord structures including spinal sympathetic nucleus and ventral roots.
4. Deep brain stimulation
DBS is the most invasive form of neuromodulation. Specifically, it involves targeting a deep structure in the brain. DBS targets CNS structures; if such structures are injured/maladaptive, suboptimal inhibition may be evident. There are no recent studies addressing this treatment option specifically for CRPS, and given the very low quality of evidence, the recommendation is inconclusive, with studies favoring non-invasive strategies research. 27
Prevention of CRPS
Vitamin C has been studied as a prophylactic treatment for CRPS that acts by inhibiting pro-inflammatory pathways mediated through antioxidant mechanisms. There have been mixed results in its effectiveness. However, because it is a low risk intervention physicians may consider it as a prevention strategy.1 Daily supplementation with 500 mg of vitamin C per day for 50 days may be beneficial to decrease risk of developing CRPS-I after distal radial fracture, foot and ankle surgery or trauma.22
Treatment for CRPS can be difficult and frustrating. Each patient will be different, and an individualized approach is essential. Aggressive early treatment should be emphasized through an interdisciplinary approach. Most treatments are not well-documented in the evidence-based literature. Early physical and occupational therapy is important. Sympathetic blockade can be considered as the first interventional technique. Medication management to include corticosteroids and bisphosphonates are best supported in the literature. Other adjuvant medication can be considered, as previously described. Different pharmaceutic interventions can then be attempted to try to improve symptoms.
Prognosis is best with early diagnosis and treatment. Once delayed, CRPS can spread proximally in the affected limb and to other areas of the body. Significant loss of function, atrophy, and contractures can result. Non-organic factors may worsen CRPS. As such, psychological therapy can be an important component and may include cognitive behavioral therapy.
Cutting Edge/ Emerging and Unique Concepts and Practice
An inflammatory immune response can be activated in CRPS. IVIG can affect proinflammatory markers and cytokines and is an encouraging treatment for CRPS. Randomized controlled studies in refractory CRPS have shown benefit.5 Even in a variety of chronic pain syndromes, open label studies using low-dose IVIG have been effective in pain reduction. However, these studies are small, and there are valid concerns about the cost and availability of such treatments.5
In regards to the inflammatory response of CRPS, dexmedetomidine is a selective α2-adrenoceptor agonist, and it might alleviate allodynia through GRK2 upregulation in sympathetic postganglionic neurons.15
Memantine is a drug with the ability to block NMDA receptors in the brain and a potent inhibitor of central and peripheral sensitization. Some studies suggest that it may be a promising option for the treatment of CRPS.16
Microvascular dysfunction and ischemia in muscle play a role in the development of cutaneous tactile allodynia in chronic post-ischemia pain. Pentoxifylline, a vasodilator and hemorheologic agent may be beneficial if used early in treating CRPS related to chronic post-ischemia pain.16
Bisphosphonates, which have a potent inhibitory effect on bone resorption, were proposed for the treatment of CRPS. In fact, several studies indicated that the intravenous or high-dose oral administration of bisphosphonate improved pain and reduced bone turnover in CRPS cases. Administration of low dose of oral risedronate (2.5 mg per day) or alendronate (35 mg per week) markedly decreased pain and regional osteoporotic findings in the foot or ankle.
Transcranial magnetic stimulation (TMS) is thought to help describe important neurophysiological and pathophysiological aspects of brain involvement in CRPS. In addition, repetitive TMS can modulate cortical excitability and induce long‐lasting neuroplastic changes. Non-invasive procedures based on rTMS are now emerging as an alternative treatment of drug resistant pain. However, well‐designed studies are needed to corroborate initial findings.25 Currently there is a clinical trial running of TMS for CRPS that hypothesizes TMS will improve CRPS-related pain and other symptoms such as cognitive, emotional and physical, when compared to baseline.
Gaps in the Evidence- Based Knowledge
There is controversy over the accepted pathophysiology of the disorder. Initially, CRPS was thought to be predominantly mediated through the sympathetic nervous system; however, autonomic symptoms are often not seen in clinical presentation. Moreover, some CRPS patients do not get relief from sympathetic blockade and plasma catecholamine levels are generally lower in the affected limb.
Other mechanisms thought to be involved include cortical reorganization, exaggerated inflammatory response, and neurogenic inflammation primarily through neuropeptide mediators including bradykinin, calcitonin gene-related peptide, and substance P.5
A major gap in the evidence is the paucity of double-blinded placebo-controlled clinical trials. For a variety of reasons, CRPS patients are commonly excluded from pharmaceutical studies.
There are no absolute specific or generalized guidelines for management of CRPS, nonetheless the treatment must be tailored according to each type of patient based on chronicity and presenting symptomatology. There is not enough evidence to fully support any of the proposed treatment approaches. Some of the factors mentioned include the limitation to find an adequate sample for randomized controlled trials, leaving us with a lack of powerful enough studies to establish standardized management.
- Shim H, Rose J, Halle S, Shekane P. Complex regional pain syndrome: a narrative review for the practising clinician. Br J Anaesth. 2019;123(2):e424-e433. doi:10.1016/j.bja.2019.03.030
- Stanton-Hicks MD, Complex regional pain syndrome: manifestations and the role of neurostimulation in its management. J Pain Symptom Manage. 2006 Apr;31(4 Suppl):S20-4.
- Severens JL, Oerlemans HM, Weegels AJ, van ‘t Hof MA, Oostendorp RA, Goris RJ. Cost-effectiveness analysis of adjuvant physical or occupational therapy for patients with reflex sympathetic dystrophy. Arch Phys Med Rehabil. 1999;80:1038-1043.
- Freedman, Mitchell, Greis, A., Marino L., Sinha, A., and Henstenburg J. Complex regional pain syndrome: diagnosis and treatment.” Phys Med Rehabil Clin N Am. 2014; 25(2):291-303.
- Kishner S, Rothaermel B, Munshi S, Malalis J, Gündüz H. Complex regional pain syndrome. Turk J Phys Med Rehab. 2011;57:156-164.
- Moseley GL. Graded motor imagery for pathologic pain. A randomized controlled trial. 2006;67:2129-2134
- Perez RS, Zollinger RE, Dijkstra PU, et al. Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurol. 2010;10:20.
- Bruehl, Stephen PhD; Chung, Ok Yung MD, MBA. Psychological and Behavioral Aspects of Complex Regional Pain Syndrome Management. Clinical Journal of Pain. 2006; 22(5):430-437.
- Eisenberg E, Sandler I, Treister R, Suzan E, Haddad M. Anti tumor necrosis factor – alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series. Pain Pract. 2013 Nov;13(8):649-56.
- Moseley G, Zalucki N, Wiech K. Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain. 2008;137:600-608.
- Ahmed, Shihab U., Yi Zhang, Lucy Chen, Abigail Cohen, Kristin St. Hillary, Trang Vo, Mary Houghton, and Jianren Mao. Effect of 1.5% topical diclofenac on clinical neuropathic pain. 2015; 123.1: 191-98
- Birklein F. Intravenous immunoglobin to fight complex regional pain syndromes: hopes and doubts. Ann Intern Med. 2010;152:188-189.
- Aradillas, Enrique, Schwartzman RJ, Grothusen, JR, Goebel, A., and Alexander, GM. Plasma exchange therapy in patients with complex regional pain syndrome. Pain Physician. 2015; 18: 383-394.
- Kemler MA, de Vet HC, Barendse GA, et al. Effect of spinal cord stimulation for chronic complex regional pain syndrome Type I: five-year final follow-up of patients in a randomized controlled trial. J Neurosurg 2008;108(2):292–8.
- Rauck, Richard L., James North, and James C. Eisenach. Intrathecal clonidine and adenosine. Pain 2015; 156.1: 88-95.
- Dong, Jing, Li Yang, Jun Tang, and Jijian Zheng. Dexmedetomidine alleviates rat post-ischemia induced allodynia through GRK2 upregulation in superior cervical ganglia. Autonomic Neuroscience. 2015; 187: 76-83.
- Mohammad-Hazem, Ahmad-Sabry, and Gholamreza Shareghi. Effects of memantine on pain in patients with complex regional pain syndrome. Middle East Journal of Anesthesiology. 2015; 23.1: 51-54.
- Ragavendran, J. Vaigunda, A. Laferrière, M. Khorashadi, and T.J. Coderre. Pentoxifylline reduces chronic post-ischaemia pain by alleviating microvascular dysfunction. EJP European Journal of Pain. 2014; 18.3: 406-14.
- Velasco F, Carrillo-Ruiz JD, Castro G, et al. Motor cortex electrical stimulation applied to patients with complex regional pain syndrome. 2009;147:91-98.
- Duong, S. Treatment of complex regional pain syndrome: an updated systematic review and narrative synthesis. Can J Anesth. 2018; 65(6); 658-684
- Sutherland AM, Clarke HA, Katz J, Katznelson R. Hyperbaric Oxygen Therapy: A New Treatment for Chronic Pain?. Pain Pract. 2016;16(5):620-628. doi:10.1111/papr.12312
- Żyluk A, Puchalski P. Effectiveness of complex regional pain syndrome treatment: A systematic review. Neurol Neurochir Pol. 2018;52(3):326-333. doi:10.1016/j.pjnns.2018.03.001
- Urits I, Shen AH, Jones MR, Viswanath O, Kaye AD. Complex Regional Pain Syndrome, Current Concepts and Treatment Options. Curr Pain Headache Rep. 2018;22(2):10. Published 2018 Feb 5. doi:10.1007/s11916-018-0667-7
- Goebel A, Bisla J, Carganillo R, et al. A randomised placebo-controlled Phase III multicentre trial: low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome (LIPS trial). NIHR Journals Library; 2017.
- Nardone, R, Brigo, F, Höller, Y, et al. Transcranial magnetic stimulation studies in complex regional pain syndrome type I: A review. Acta Neurol Scand. 2018; 137: 158– 164.
- Deer TR, Pope JE, Lamer TJ, et al. The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation. Neuromodulation. 2019;22(1):1-35. doi:10.1111/ner.12845
- Cruccu G, Garcia-Larrea L, Hansson P, et al. EAN guidelines on central neurostimulation therapy in chronic pain conditions. Eur J Neurol. 2016;23(10):1489-1499. doi:10.1111/ene.13103
- Straube S, Derry S, Moore RA, Cole P. Cervico-thoracic or lumbar sympathectomy for neuropathic pain and complex regional pain syndrome. Cochrane Database Syst Rev. 2013;2013(9):CD002918. Published 2013 Sep 2. doi:10.1002/14651858.CD002918.pub3
Original Version of the Topic
Stephen Kishner, MD. Complex regional pain syndrome Part 2: Management and Treatment. 7/25/2012.
Previous Revision(s) of the Topic
Stephen Kishner, MD, Brandon L Hicks, MD. Complex regional pain syndrome Part 2: Management and Treatment. 8/22/2016
Fernando Sepúlveda-Irizarry, MD, FAAPMR, CAQSM
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Victor Rosado, MD
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Laura Serrano-Ortiz, MD
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