CRPS and Non-Conventional Pharmacological Therapies

Complex regional pain syndrome (CRPS) is a chronic neuro-inflammatory disorder that affects one or more extremities, usually following surgery, injury, or trauma, but also occurs spontaneously. The pathophysiology of CRPS is complex and poorly understood; therefore, well-defined criteria for diagnosis are limited.

Clinical features include allodynia, hyperalgesia, sudomotor and vasomotor abnormalities, and various trophic changes (eg, skin or tissue wasting, thinning of the bones, thickening or brittle hair/nails). This condition can be divided into two categories:

1. CRPS type 1, also known as reflex sympathetic dystrophy (RSD) syndrome, which lacks documented nerve injury
2. CRPS type 2, formerly known as Sudeck’s atrophy or causalgia, is diagnosed following nerve injury.¹

Prevalence

Most cases in the US involve CRPS type 1 at an incidence rate of 5.46 per 100,000 person years as compared to 0.82 per 100,000 person years in CRPS type 2.²

FDA Approved Medications for CRPS

There are no FDA approved medications for the treatment of CRPS. Guidelines therefore recommend multimodal approaches such as physical therapy, sympathetic nerve blocks in conjunction with local anesthetics, or simple approaches such as NSAIDS for pain and inflammation.¹

Other effective treatments include low-dose intravenous (IV) ketamine and corticosteroids.¹˒³˒⁴ In addition to these therapies, the remaining evidence exists for CRPS type 1, which includes gabapentin, calcitonin, botulinum toxin A, and topical treatments containing free radical scavengers such as dimethyl sulfoxide (DMSO).¹

Non-Conventional Treatments for CRPS: What the Data Reveal

Gabapentin

Gabapentin is an anti-epileptic drug used for chronic pain management, specifically neuropathic pain. While the mechanism of action in relation to neuropathic pain remains unclear, this is a prominent feature in CRPS.⁸

Previous studies have shown possible benefits in neuropathic pain with the use of gabapentin, including an RCT assessing the effects of gabapentin in adults with CRPS type 1, and a pediatric study, with remaining data observed in low-quality designs (case report, non-controlled, retrospective cohort studies).⁹⁻¹²

Few published studies have assessed the efficacy of gabapentin in CRPS. One randomized placebo-controlled crossover study observed 58 adults with chronic CRPS type 1 who experienced pain in upper or lower extremities. Group 1 received gabapentin followed by placebo treatment for three weeks, while group 2 received placebo followed by gabapentin treatment for three weeks. Both groups had a 2-week washout period in between treatments. Titration of gabapentin started with 600 mg daily on days 1 to 2, increased to 600 mg twice daily on days 3 to 4, and ended with a max of 600 mg three times daily on days 5 to 21. The titration schedule of placebo was identical.⁸

Remaining evidence evaluating use of gabapentin is limited by design.⁹⁻¹¹

Practical Takeaway: Overall, data to support the use of gabapentin in CRPS is sparse, making it difficult to include its place in therapy.

Bisphosphonates are antineoplastic agents used to treat osteoporosis, Paget’s disease, and bone malignancies. It has been proposed that accelerated bone resorption might play a role in the development of CRPS. Based on the inhibition of bone resorption and neuropeptide release, bisphosphonates may have the mechanistic ability to reduce pain in patients with CRPS type 1.¹³ The evidence available is primarily with second-generation drugs, alendronate and pamidronate, in patients with CRPS type 1 affecting the upper or lower extremities.¹⁴

One review included all randomized placebo-controlled trials that evaluated the use of bisphosphonates in CRPS type 1. The agents utilized were alendronate (IV and oral), pamidronate, and others that are unavailable in the US. The interventions were oral alendronate 40 mg daily for eight weeks, IV alendronate 7.5 mg daily for three days, and IV pamidronate 60 mg as a one-time infusion.

For efficacy, the pooled analysis showed reduced short-term pain (within 30 to 40 days of treatment onset) compared to placebo that was statistically and clinically significant (SMD = -2.6, 95% CI [-1.8 to –3.4] along with reduced medium-term pain (within second to third month after treatment onset) in favor of bisphosphonate therapy (SMD = -2.5, 95% CI [-1.4 to –3.6]). Regarding safety, adverse events occurred at a higher rate compared to placebo (35.5% vs. 16.4%, RR = 2.10, 95% CI [1.27 to 3.47]), with no serious events noted. Adverse events included mild fever, GI intolerance, infusion site reactions, hypocalcemia with no clinical symptoms, and arthralgia.¹⁴

Calcitonin

Calcitonin is a polypeptide hormone released by the thyroid gland to maintain calcium levels in the body. Based on the evidence of analgesic effects with calcitonin, it is typically used off-label in patients with CRPS type 1 and is FDA-approved for postmenopausal osteoporosis.¹⁷ The mechanism behind analgesia is unclear, but many theories exist. Previously, it was proposed that analgesic effects resulted from bone resorption inhibition, but recent explanations include prostaglandin and cytokine inhibition, as well as stimulation of beta-endorphins resulting in pain relief.¹⁸

Participants in the treatment group received daily active and passive physical therapy in addition to 100 units of intranasal salmon calcitonin three times daily for 3 weeks. The control group received the same physical therapy and a placebo of the same color, taste, and odor as calcitonin.

Efficacy was assessed before treatment, as well as 1, 3, and 8 weeks after treatment. In the calcitonin group, participants experienced significant improvement in pain at rest at weeks 3 and 8 as well as reduction of pain on movement at weeks 1 and 8, and improved range of movement at weeks 1 and 8. The ability to work at 8 weeks post-treatment was only found to be significantly better in the calcitonin group of patients who had CRPS of the wrist. All adverse effects were mild to moderate and did not warrant alterations to treatment. Based on these findings, the use of short-term calcitonin may alleviate pain at rest, but the magnitude of effect is mild. Further, the authors noted that physical therapy alone may be efficient for treatment of CRPS.¹⁹

The primary objectives were to assess analgesic effects (ie, VAS), functional preservation (ie, wrist dorsiflexion and palmar flexion angles), allodynia, hyperalgesia, and trophic changes (eg, elongation of nails, sweating). No outcomes in the study were statistically significant. Since participants were all receiving physical therapy, the researchers concluded that use of calcitonin did not provide additive benefit for these patients.²⁰

Botulinum toxin

Botulinum toxin A (BTA) is an emerging therapy for the management of pain. It is used in different areas to induce analgesia but only FDA approved for chronic migraine.²¹ While the primary mode of action is acetylcholine inhibition resulting in neuromuscular blocking effects, it is proposed that BTA can induce prolonged sympathetic block, therefore resulting in prolonged analgesia.¹˒²² Based on this mechanism, BTA has been studied in patients receiving sympathetic block procedures.

A small pilot randomized controlled crossover study observed the effects of sympathetic block using BTA in patients with refractory CRPS type 1 of the lower extremity who experienced sympathetically maintained pain (SMP). Participants were allocated to receive two lumbar sympathetic injections: one group received 10 mL of 0.5% bupivacaine mixed with 75 units of BTA, while the other group received 10 mL of 0.5% bupivacaine alone. Pain was reported by those who documented pain scores (0 to 10) daily starting 1 week prior to injection and continued until pain returned to baseline or a duration of 1 month, whichever was longer. Crossover injections were received 1 month after pain returned to baseline. The researchers found that use of BTA with local anesthetic bupivacaine during lumbar sympathetic block showed statistical significance in prolonged analgesia with a median of 69 days as compared to a median of less than 8 days using local anesthetic alone.

Similarly, a single-center RCT assessed the effects of BTA (75 units) compared to local anesthetic, 0.5% levobupivacaine, during lumbar sympathetic nerve block on maintaining temperature increase and pain reduction in 48 patients with unilateral lower extremity CRPS types I and II. The researchers found that at 3 months, the pain intensity scores had significant changes in the BTA group compared to local anesthetic alone (-2.0 ± 1.0 vs. -0.6 ± 1.6), as well as statistically significant improvements in cold intolerance based on a decrease in the cold intolerance symptom severity score ranging from 0 to 100 (67.3 ± 13.7 vs. 71.7 ± 19.6, respectively). BTA was well tolerated with no pertinent adverse effects reported. Although the study showed some utility of BTA in patients with CRPS type 1 and symptom management, there were limitations. Along with the small sample size, the study was conducted at a single center and follow-up duration was 3 months, making it difficult to determine the prolonged efficacy and safety of this approach.²³

Practical Takeaway: The level of evidence provided in BTA therapy in patients with CRPS type 1 is low. The results show promising benefits in this approach as an alternative to symptom management, but further research in larger placebo-controlled trials is needed to determine the prolonged effects.

Dimethyl sulfoxide (DMSO) is a topical ingredient that has been studied in patients with CRPS type 1. It is suggested that CRPS symptoms are induced by enhanced inflammatory response to tissue injury, resulting in an abundance of toxic oxygen radical production; therefore, the use of free-radical scavengers can reduce this effect.²⁵ The efficacy of this agent has been evaluated in very few studies, but results indicate a potential benefit.²⁵⁻²⁷

One RCT observed the effects of DMSO compared to N-acetylcysteine (NAC) in 145 participants who had upper or lower extremity CRPS type 1. The study evaluated 2 groups: one group applied DMSO 50% cream five times daily to the affected extremity in combination with three oral placebo effervescent tablets taken once daily, while the other group received NAC 600 mg effervescent tablets in addition to a placebo cream applied to the affected limb five times daily. Assessments took place prior to treatment, at 6 weeks and 17 weeks, with follow-up at 32 and 52 weeks. Participants were allowed to have analgesics based on a strict protocol starting with paracetamol 500 mg, followed by naproxen 200/500 mg and tramadol in gradual doses. In addition, participants also received occupational therapy with upper extremity CRPS type 1 and physical therapy with lower extremity.²⁵

Although the point decrease in ISS scores showed some efficacy in these treatments, there was large variance within the data. The study also did not report the VAS values that were imputed into the ISS scores.

CRPS and Future Treatments

Potential new drug therapies for CRPS are being studied. FDA recently granted the orphan drug status for low-dose naltrexone. Naltrexone is a mu-opioid receptor antagonist indicated for the treatment of alcohol and opioid use disorder. The proposed mechanism of action related to pain involves reduction of pro-inflammatory cytokines, toll-like receptor 4 (TLR4) antagonism, and stimulation of endorphin release.²⁸˒²⁹ While researchers are developing their own formulation in preparation of an investigational new drug application, Soin Neuroscience is seeking FDA approval to launch a large multicenter clinical trial in hopes of helping patients who suffer from CRPS.²⁸

Similarly, Stanford University is starting a clinical trial assessing the use of low-dose naltrexone in this condition.³⁰ With limited existing evidence and research in a debilitating and complex condition, this might be a step in the right direction to expand on the current treatment modalities.

Overall, the pharmacological therapies available for CRPS treatment lack robust evidence. CRPS is a debilitating chronic condition that has a major impact on the patient’s quality of life. With limited data available, it can be concluded that the treatment of CRPS may not be achieved through pharmacological therapies alone and should be approached with multidisciplinary strategies such as physical therapy in addition to pharmacotherapy to provide optimal patient care.