Nocturnal leg cramps in diabetes type 2 treated with palmitoylethanolamide

Sir,

Secondary leg cramps that are related to various disorders and primary idiopathic leg cramps are fairly common. More then half of all adults report that they have had nocturnal leg cramps. [1] Although benign, nocturnal cramps can disrupt sleep and have a substantial negative impact on quality of life.  Muscle cramps may be a symptom of many different conditions, including  peripheral vascular disease, radiculopathies and lumbar canal stenosis, diabetes mellitus, liver disorders and cirrhosis , metabolic myopathies and neuropathies. Muscle cramps can also be a side effect of drugs, such as potassium-sparing diuretics, or thiazidelike diuretics. [2] If no clear cause exist we speak of primary idiopathic leg cramps. To attribute a common symptom such as muscle cramps to an etiological cause  (disorder or side effect) is clearly quite complicated, of not impossible.

Quinine is traditionally prescribed in leg cramps of unknown origin,  but as  there are a number of reported severe or fatal thrombocytopenia after taking quinine to prevent leg cramps, this therapy cannot be recommended anymore for the treatment of a benign but irritating symptom such as leg cramps. [3] Evidence for the efficacy of other pharmacological interventions, such as magnesium, calcium channel blockers, carisoprodol, or vitamin B12 is limited or absent. Other non-drug treatments for lower limb muscle cramps have limited value. [4] Forced gastrocnemius stretching has long been recommended to prevent leg cramps. [5]

We present a 84 year old male patient, still very vital and able to walk many kilometers, with complaints of muscular cramps, mostly of nocturnal nature, since 2005. Diabetes type 2 diagnosed in 2000, treatment to date rosuvastatin calcium 2.5 mg/day, diltiazem 200 mg/day,hydrochlorothiazide 12.5 mg/day, losartan 50mg/day, aspirine 100 mg/day and metformin 1000 mg twice daily. Some signs of retinopathy were detected by the ophtalmologist, and angina pectoris since 2000. He started suffering from neuropathic pains in both feet since 2005, and increasingly painful nocturnal cramps. The meanscore of these cramps during one week on the numeric rating scale was 5. Patient did not wish analgesic therapy, because he was fit enough to cope with some pain, according to his sayings.

Patient visited our clinic for neuropathic pain, and his main wish was to reduce the painful nocturnal pains. He did not wanted to try drugs such as pregabalin and amitriptyline, so we started treatment with palmitoylethanolamide (PeaPure), 400 mg twice daily. Within one weeks his cramps were noticeably reduced, and after 2 weeks the pain-crampscore was down to 1. Actually he stated that the last month of treatment no cramps occurred anymore.

Palmitoylethanolamide (PEA) is a nutraceutical available under the brand names PeaPure (and Normast in Italy and Spain) since 2008. It is naturally occurring fatty acid amide, belonging to the class of the nuclear factor peroxisome proliferator- activated receptor (PPAR)-agonists. In addition to its affinity for the PPAR, it has high affinity for the GPR55 receptor and a number of other targets. PEA has been evaluated in a number of placebo controlled randomized clinical trials and has been found to be effective in various neuropathic pain states and inflammation.[6][7][8] PEA is produced in the body on demand and accumulates locally during several inflammatory and pain disorders, eg, intestinal inflammation,neuropathic pain, cerebral ischemia, and multiple sclerosis.[9] PEA is an compound which can be synthesized in muscle tissue, and such synthesis seems disturbed in fibromyalgia. [10] It has been documented as valuable in the treatment of neuropathic pain in chronic idiopathic axonal neuropathy.[11] ALthough the pathophysiology of muscular cramps remains poorly understood, the endogenous pleiotropic lipid messenger palmitoylethanolamide might play a role in stabilizing overactive muscles giving rise to cramping during the night. [12]

Its side effect profile is very benign, tolerability is good and dose limiting side effects up to several grams/day have not been reported. [13] Drug-drug interactions have also not been reported so far. Due to the positive balance between efficacy and safety the nutraceutical palmitoylethanolamide is a new compound in our armaentariumn for the treatment of neuropathic pains, and perhaps nocturnal painful muscular cramps.

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