Treatment Guidelines for Complex Regional Pain Syndrome—Role of Compounded Topical Pain Relief

Treatment Guidelines for Complex Regional Pain Syndrome—Role of Compounded Topical Pain Relief

i-bottleIt may sound contrary, but compounding pharmacists need to think beyond the pain when it comes to understanding complex regional pain syndrome. Profound pain is the primary symptom, but this is true of all pain syndromes. For CRPS you need to envision a person with a normal left hand and a right hand that’s swollen to the size of a baseball, or maybe a normal right foot, with a left foot that’s red with swelling that reaches the knee. And none of the symptoms subside. Treatment may help some patients, but others live with CRPS indefinitely. The treatment guidelines for complex regional pain syndrome offer suggestions, including topical pain relief to facilitate mobility. Compounding pharmacists can make a difference for these patients by reaching out to discuss compounded options.

What Is Complex Regional Pain Syndrome?

Complex regional pain syndrome (CRPS) was once known by several other names, including reflex sympathetic dystrophy (RSD) and causalgia. The name change makes an important point—it’s complex and regional—but it also aptly conveys the sense that little is known about this condition. Four diagnostic guidelines for CRPS currently exist. They’re similar, yet none have been uniformly accepted as the protocol to follow. Its complex pathophysiology isn’t well understood and the paucity of clinical trials often make treatment choices a challenge.

CRPS begins with injury to one of the extremities, typically from sprains, strains, surgical wounds, fractures, and crush injuries. Then the swelling and pain become chronic and disproportionate to the initiating event. A key feature of CRPS is that the pain is not limited to the territory of a single peripheral nerve. Patients are diagnosed with type 1 CRPS if nerves are not injured. When nerve damage is confirmed, they’re diagnosed with type 2 CRPS. The International Association for the Study of Pain recommends diagnosing CRPS if the following criteria are met and when one sign from at least two categories is present at the time of evaluation:1

1. Continuing pain that is disproportionate to the inciting event

2. At least one symptom reported in at least three of the following categories:

  • Sensory – allodynia and/or hyperesthesia
  • Vasomotor – temperature asymmetry, change in skin color or skin color asymmetry
  • Edema/sudomotor – edema and change in sweating or sweating asymmetry
  • Motor/trophic – decreased range of motion, motor dysfunction (weakness, tremor, dystonia) or trophic changes

3. No other diagnosis explains the degree of pain and dysfunction.

While its pathophysiology has yet to be confirmed, most experts believe that CRPS develops when persistent stimuli from the injured region lead to peripheral and central sensory impairment and pain that spreads beyond the original injury. Experts also hypothesize that CRPS is caused by an aberrant healing response with exaggerated and persistent inflammation.

Pharmaceutical and Physiotherapeutic Treatments

While the degree of pain varies in each patient, it’s often severe enough to be crippling. The treatment goals—relieve pain, restore function and improve psychological state—are achieved using a multimodal approach that includes the appropriate combination of drugs, psychological therapy, invasive procedures such as nerve blocks, and occupational and physical therapies.

Physical therapy: Physical therapy is so essential that one group of experts calls it the cornerstone of treatment. It’s recommended as part of first-line treatment and acknowledged for its ability to improve mobility and reduce pain and edema—in spite of a Cochrane review published in February 2016 that noted the lack of any high-quality clinical trials.2 Physical therapy is generally done in combination with pain control medications.

Pharmaceutical treatments to consider:

  • Anti-inflammatory drugs – Corticosteroids relieve inflammation and edema early in CRPS but they’re less likely to be effective with symptoms that last more than six months. NSAIDs may help relieve mild pain.
  • Anticonvulsants – A few case studies show that gabapentin is effective for relieving pain and sensory symptoms.
  • Antidepressants – Duloxetine and venlafaxine are currently recommended as first-line analgesics, but other drugs to consider include amitriptyline, doxepin, nortriptyline, desipramine and trazodone.
  • Opioids – Use of opioids for CRPS hasn’t been studied, but most experts recommend considering them for second or third line treatment.
  • NMDA receptor antagonists – Patients with severe refractory CRPS may find relief from ketamine in anesthetic doses. In some cases, complete remission was maintained for six months. Amantadine and dextromethorphan may also be effective.
  • Calcitonin – Intranasal calcitonin in doses of 100 to 300 units daily can significantly reduce pain.
  • Bisphosphonates – In one of the few randomized controlled trials, intravenous neridronate provided significant improvement in pain and quality of life. Alendronate, clodronate and pamidronate delivered intravenously also relieve pain and improve mobility.3
  • Other drugs – Nifedipine, propranolol, baclofen, mexiletine and an IV lidocaine infusion have been effective in isolated cases but they haven’t been studied.

Topical and Transdermal Medications Improve Quality of Life

Topical pain relief is included as part of multimodal therapy for CRPS, but it’s seldom discussed in detail or given priority. While that makes sense for physicians challenged to treat systemic vascular- and nerve-related aspects of CRPS, it’s short-sighted from the perspective of encouraging mobility and physical therapy. Compounding pharmacists have the opportunity to reach out to patients and their physicians to talk about topical formulations that can be tailored to each individual. Here’s a roundup of the information currently available on topical treatments:

  • Ketamine, pentoxifylline, clonidine and DMSO combination – Topical formulations used to treat microvascular dysfunction have successfully reduced CRPS-related allodynia in lab rats. Based on the theory that CRPS is a manifestation of microvascular dysfunction, researchers compounded an analgesic cream consisting of ketamine 10 percent, pentoxifylline 6 percent, clonidine 0.2 percent and dimethyl sulfoxide 6 to 10 percent. They treated 13 CRPS patients with the cream and nine of them reported less pain and general symptom relief.4
  • Clonidine transdermal patch – When applied to hyperalgesic skin in CRPS patients, transdermal clonidine substantially reduced hyperalgesia to mechanical and cold stimuli.5
  • Lidocaine – In one case study, 5 percent lidocaine ointment reduced severe allodynia, which enabled the patient to participate in physical therapy and improve range of motion.6
  • Topical ketamine – When researchers applied 10 percent ketamine cream to 20 CRPS patients, the treatment inhibited hyperalgesia and allodynia to light brushing.7 In one patient, a combination of palmitoylethanolamide and ketamine 10 percent cream reduced pain by more than 50 percent after one month of treatment.8
  • Amitriptyline, ketamine and DMSO – Doctors started a CRPS patient on amitriptyline 5 percent cream. A month later they added topical ketamine 10 percent, and then a month after that added DMSO 50 percent to the mix. Over five months, the patient’s pain score dropped from 44 to 12 out of 100 on the Neuropathic Pain Symptom Inventory.9
  • Capsaicin – Topical capsaicin has also effectively relieved pain.

Pharmaceutical Expertise Is Essential for CRPS

As clinicians wait for future CRSP-specific research to provide evidence-based treatment options, pharmacists can offer invaluable expertise to guide the treatment process. This is especially true for compounding pharmacists who can connect with physicians and patients to discuss optimal topical and transdermal treatments that are otherwise overlooked in favor of systemic drugs. Your intervention has the potential to relieve a life of unremitting pain and crippling, and irreversible changes in limb function.

Pharmaceutica North America provides high-quality bulk active pharmaceutical ingredients and emollient delivery bases that meet the analgesic and anti-inflammatory needs of patients with CRPS. Contact us today to talk about how we can support your compounding pharmacy.

Show 9 footnotes

  1. “Complex Regional Pain Syndromes,” December 2015,
  2. “Physiotherapy for Pain and Disability in Adults with Complex Regional Pain Syndrome (CRPS) Types I and II,” February 2016,
  3. “Treatment of Complex Regional Pain Syndrome,” April 2016,
  4. “A Novel Compound Analgesic Cream (Ketamine, Pentoxifylline, Clonidine, DMSO) for Complex Regional Pain Syndrome,” January 2016,
  5. “Understanding the Pharmacologic Therapy for Patients Afflicted with Complex Regional Pain Syndrome,” May 2009,
  6. “Early Adjunct Treatment with Topical Lidocaine Results in Improved Pain and Function in a Patient with Complex Regional Pain Syndrome,” September 2014,
  7. “Reduction of Allodynia in Patients with Complex Regional Pain Syndrome: A Double-Blind Placebo-Controlled Trial of Topical Ketamine,” November 2009,
  8. “Treatment of Chronic Regional Pain Syndrome Type 1 with Palmitoylethanolamide and Topical Ketamine Cream: Modulation of Nonneuronal Cells,” March 2013,
  9. “Multimodal Stepped Care Approach Involving Topical Analgesics for Severe Intractable Neuropathic Pain in CRPS Type 1: A Case Report,” August 2011,

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