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Severe CRPS type 1 after calcaneus fracture treated with palmitoylethanolamide, vitamine D3 and keta

Chronic regional pain syndrome (CRPS) can be intractable to treat and patients sometimes suffer for many years. Therefore, new treatment strategies are needed to alleviate symptoms in CRPS patients. This case report describes a patient suffering from intractable CRPS type 1 for 9 months after a fracture of the os calcaneus at the right side.

The etiology and pathogenesis of chronic regional pain syndrome (CRPS) is poorly understood and the syndrome is often misdiagnosed and undertreated. There is usually a delay of many months between the onset of symptoms and the clinical diagnosis of CRPS.

To date, there is no consensus on how to treat CRPS type 1 and type 2. Many patients suffering from these disorders remain in pain and have to live with a functional handicap. Most patients who do not respond to initial interventions are treated with a multitude of analgesics, such as pregabaline, gabapentine, tramadol, and/or amitriptyline. However, proof from well-powered, double-blind, placebo- controlled clinical trials for the efficacy of these analgesics in CRPS is lacking. Most clinical trials in this field are small and have short follow-up periods.

While analgesics may occasionally decrease pain, very often increasing dosages are not well tolerated and patients refrain from treatment. Bisphosphonates and radical scavengers, such as topical dimethyl sulfoxide (DMSO) 50% cream, might also bring relief. However, there is clearly an urgent need for new innovative approaches that are not only effective, but also have a favorable profile in terms of side effects and drug interactions. In particular, multimodal treatment strategies for complex pain syndromes, such as neuropathic pain and CRPS, are needed to effectively alleviate symptoms.4 At the 14th World Congress on Pain 2012, the importance of multimodal therapy was again outlined, and, specifically related to our topic, the authors pointed out that “a further approach to treating neuropathic pain is to harness endogenous regulatory mechanisms that suppress excessive inflammation.

Palmitoylethanolamide (PEA) harnesses the endogenous regulatory mechanisms suppressing chronic neurogenic inflammation, and can be well combined with topical compounded analgesic creams. In the case described below, PEA is combined with ketamine 10% cream, which has a documented antiallodynic action. We will present a case of severe chronic intractable CRPS type 1 that responded well to this treatment regime.

A 48-year-old woman with intractable CRPS type 1 severe pain for nearly one year. The syndrome developed after she fell on the stairs and broke the ankle bone, the calcaneus dextra. An X-ray did  show this fracture. Since the fracture severe, intractable pain developed, and the patient was unable to stand or walk, and had to use a wheelchair. A clear Sudeck picture develoed, with discolored skin, hair abnormalities and swelling. Painscores were around 8. Bone scans after some months showed pathologies of bone density.

Acetylcysteine 600 mg/day and calcitonin inhections did not result in reduction of pain and related symptoms. When she visited the clinic she could only lay in bed; walking was nearly impossible due to pain. She scored her quality of life 4.

Tramadol had no effect at all, apart from side effects and several sympathetic blocks resulted in transient analgesia only for some days.

We saw the patient in March 2013, and had her 25-OH-vitamine D assessed. It was 24,9 ng/ml. We started therapy suppleting the vitamine D3 deficientcy wirh 7000 IE/day.

We started treating with our combined treatment strategy for CRPS: ketamine 10% cream was applied locally three times daily and PEA, as PeaPure® 400 mg capsules (JP Russell Sciences Ltd, Nicosia, Cyprus), was taken orally three times daily. The instruction for PEA administration was to open the capsules and pour the contents under the tongue for the first 10 days, and then PEA was to be taken orally. This administration was suggested in order to avoid the first pass effect and thus heighten the bioavailability of the substance, which might lead to a more robust and faster effect.

We als prescribed a compounded 10% ketamine cream. The rationale for prescribing topical ketamine is based on its affinity for the N-methyl-D-aspartate receptors, which are present both in the central nervous system and also peripherally. Also, allodynia seems particularly responsive to ketamine cream.

Our advice for the ketamine 10% cream is to apply 1–2 gram on the painful area, maximally three to four times daily. To date, systemic side effects have not been reported in our institute. We then recommend that a lesser amount of cream be applied.

Two months later, the vitamine D3 level was 41,5 ng/ml, and there were no signs of Sudeck anymore; pain was 7. Again 3 months later, the painscores were around 3, with rare peaks of 7. She did not use the wheelchair anymore, and walked with a cane. The week before, for the first time she walked 2 km! Againa month later the vitamine D3 levels was 55,9 ng/ml.

This CRPS case is comparable to one described below in literature, in the positive reaction on the combination of PEA and topical ketamine cream.


Authors: Keppel Hesselink JM, Kopsky DJ Treatment of chronic regional pain syndrome type 1 with palmitoylethanolamide and topical ketamine cream: modulation of nonneuronal cells Journal of Pain Research 2013.