DESCRIPTION OF THE ANALYTIC PROCESS
ANALYSIS OF EVIDENCE
Question 1: Are there effective nonpharmacologic treatments for muscle cramps?
Question 2: Is quinine effective in the treatment of muscle cramps?
Class I studies.
Class II studies.
Adverse effects of quinine and its derivatives.
Question 3: Are there any other pharmacologic treatments effective for the treatment of muscle cramps? Class I studies.
Class II studies.
RECOMMENDATIONS FOR FUTURE RESEARCH
CONFLICT OF INTEREST
- amyotrophic lateral sclerosis
- confidence interval
- Food and Drug Administration.
We thank Drs. Mauskop, Rison, Mahajan, and Engel for their comments.
The term "symptomatic" in our assessment refers to the symptom of muscle cramps rather than implying an underlying cause for cramps such as magnesium deficiency. As stated in the methods,  we purposefully excluded articles dealing with treatment of muscle cramps during pregnancy and due to medical conditions such as cirrhosis and hemodialysis, which likely have distinct mechanisms of action from idiopathic muscle cramps. Full coverage of these diverse conditions was outside the scope of our assessment. A Cochrane review of the treatment of muscle cramps during pregnancy does support the use of magnesium lactate or citrate in this particular clinical circumstance.  We would not recommend extending this practice to all patients experiencing muscle cramps simply because magnesium is an inexpensive or benign drug, particularly when 2 Class II studies refute its efficacy. [12,13]
We thank Drs. Rison, Mahajan, and Engel for sharing their experience with primrose oil, baker's yeast, and clonazepam. In our review, we did not encounter any human trials using primrose or baker's yeast, and none of the studies quoted by Dr. Rison appear to monitor muscle cramps. There is a surprising lack of published evidence for GABAergic agents and antiepileptic drugs in our review, which are drugs frequently used by clinicians—including ourselves—for the treatment of cramps.
As stated in the Recommendations for Future Research, well-designed studies on the pharmacological and non-pharmacological treatments of cramps are needed, and these should include alternative medicines. We hope that the recognition of the gap in published evidence will stimulate much-needed research in the treatment of this common condition.
11. Young GL, Jewell D. Interventions for leg cramps in pregnancy. Cochrane Database Syst Rev. 2002;(1):CD000121.
12. Roffe C, Sills S, Crome P, Jones P. Randomised, crossover, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit 2002;8:CR326 –CR330.
13. Frusso R, Zarate M, Augustovski F, Rubinstein A. Magnesium for the treatment of nocturnal leg cramps: a crossover randomized trial. J Fam Pract 1999;48:868–871.
Disclosures: See original article for full disclosure list.
Painful muscle cramps (PMC's) are usually due to aberrant repetitive discharges of lower motor neurons, causing intermittent, or nearly constant, painful contractions of larger or smaller groups of muscle fibers. Initial management is a) prohibiting all caffeine and other stimulants, and b) trying to substitute for â-agonists and other adrenergics. Based on multiple N-of-1 repeated on-off studies of >100 PMC patients over 10 years, we find clonazepam (Klonopin) much superior in benefit:side-effects ratio compared to the 2 FDA-approved medications, diltiazem and vitamin B complex, which were rated as "possibly effective" in the new AAN Guidelines for treating PMC's. The guideline does not even mention clonazepam .
Controlled trials are helpful but do not provide all the information useful for clinical management. Absence of a Guidelines benefit is not absence of relevant benefit. Numerous "N-of-1" experiences with carefully-monitored individual patients are also pertinent.
Very-low-dose clonazepam, a benzodiazepine, is our choice for treating PMC's (e.g. in peripheral neuropathy or ALS), which are generated by a disturbance anywhere in the lower motor neuron: soma, axon-schwann cell complex, or distal axonal twigs . PMC's are often worse at the end of an especially active day or during that night. They can cause "painful insomnia" (difficulty achieving sleep and awakening during sleep). Evening or bedtime clonazepam can decrease intensity and frequency of cramps, and be mildly soporific. With very-low doses, patients typically have more restful nights and no sluggishness the next morning. Clonazepam 0.25, 0.5 or1.0 mg h.s. has, without significant side-effects, benefited >80% of patients, referred to our tertiary center, who were previously unresponsive to one or more relaxing agents, e.g. pregabalin, duloxetine or gabapentin, and hypnotics. Complex trials are not required to demonstrate clonazepam's effectiveness. No drug build-up is needed. At a given dose, it either provides relief the first night -- e.g., "the first good night's sleep I've had in months" -- or it doesn't. Some patients with troublesome daytime muscle cramps, or fasciculations, benefit from 0.25-0.5mg during the morning without engendering sleepiness.
Pharmacologically, clonazepam acts especially on benzodiazepine receptors, integrated in pentameric GABA-gated chloride channels (the GABAA receptor), to facilitate GABA-mediated chloride conductance, causing hyperpolarization (inhibition of excitability) -- and conceptually, perhaps it also acts on peripheral-type benzodiazepine receptors. The locus of clonazepam's benefit for cramps is uncertain: possibly on motor axons prejunctionally or junctionally, or on myofiber T-tubule dihydropyridine-receptor excitation-contraction coupling mechanisms , or perhaps on spinal neurons,
Although clonazepam is not "FDA-approved" for PMC's, it can be effective and safe. In our experience, it has benefited patients, who are grateful for less pain and better sleep.
8. Katzberg HD, Khan AH, So YT. Assessment: Symptomatic treatment for muscle cramps (an evidence-based review). Neurology 2010;74:691-6.
9. Engel WK. Multi-Microcramps (MMC) Syndrome: a new pathogenic concept of subtle lower motor-neuron (LMN) lability causing very disturbing, continuous muscle pains, sometimes gratifyingly treatable – but often misinterpreted as mysterious "fibromyalgia" or "psychogenic". Neurology 2010; 74(Suppl 2): A465.
10. Chiou LC, Chang CC. Pharmacological relevance of peripheral type benzodiazepine receptors on motor nerve and skeletal muscle. Br J Pharmacol 1994;112: 257-261.
Disclosure; the authors report no disclosures.
I read with interest the recent evidence-based review by Katzberg et al. regarding the treatment of muscle cramps.  I was surprised to read that the dietary supplements primrose oil (Efamol) and brewer's yeast (EpiCor) were not mentioned.
Primrose oil is a rich source of omega-6 fatty acids used for certain neurologic conditions including chronic fatigue syndrome (myalgic encephalomyelitis) on the biochemical basis that it ultimately promotes production of membrane-stabilizing fatty acids (lipophilic pentacyclic triterpenes) with anti-oxidant and free-radical scavenging properties. 
Furthermore, primrose oil has also been used in diabetic peripheral neuropathy  and shown to improve nerve conduction velocities in animal models.  In addition, it has improved vasa nervorum perfusion secondary to increased endoneurial capillary density from angiogenesis. 
Similarly, brewer's yeast has been shown to improve myalgias and other symptoms associated with seasonal influenza vaccine.  On the basis of this data, I have used both primrose oil and brewer's yeast in treating muscle cramps from various neuropathic conditions including amyotrophic lateral sclerosis and diabetic peripheral neuropathy with reasonable success.
Although unpublished, I suspect that these complementary alternative medicinal agents— with excellent side effect profiles— are used for the treatment of symptomatic muscle cramps.
4. Puri BK. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). J Clin Pathol 2007;60:122-124.
5. Halat KM, Dennehy CE. Botanicals and dietary supplements in diabetic peripheral neuropathy. Am Board Fam Pract 2003;16:47-57.
6. Cameron NE, Cotter MA, Robertson S. Essential fatty acid diet supplementation. Effects on peripheral nerve and skeletal muscle function and capillarization in streptozocin-induced diabetic rats. Diabetes 1991;40:532-539.
7. Ford I, Cotter MA, Cameron NE, Greaves M. The effects of treatment with alpha-lipoic acid or evening primrose oil on vascular hemostatic and lipid risk factors, blood flow, and peripheral nerve conduction in the streptozotocin- diabetic rat. Metabolism 2001;50:868-875.
8. Moyad MA. Brewer's/baker's yeast (Saccharomyces cerevisiae) and preventive medicine: Part II. Urol Nurs. 2008;28:73-75.
Disclosure: Dr. Rison is an Associate Editor for Journal of Medical Case Reports, Case Reports in Neurology and was previously an Associate Editor for Cases Journal.
Katzberg et al. analyzed two negative papers regarding the use of magnesium citrate for the treatment of muscle cramps. 
They omitted a positive double-blind trial where proprietary "primarily magnesium lactate, magnesium citrate" product was used.  However, "symptomatic" in the paper by Katzenberg et al. implies that no underlying cause has been detected, while muscle cramps are a typical symptom of magnesium deficiency  and it would be more appropriate to consider hypomagnesimia as a specific, correctable cause.
Due to the benign nature and low cost of magnesium, empiric therapy with magnesium in all patients may be worthwhile. However, oral magnesium is often poorly absorbed and lack of a response to treatment does not rule out the presence of magnesium deficiency. Serum levels are not useful because only 1% of magnesium in the body is extracellular and there is poor correlation between serum and the more accurate RBC or ionized magnesium levels.
Since ionized levels are not commercially available and RBC magnesium levels are fairly expensive (about $80 US), an empirical trial with magnesium oxide, magnesium citrate, or a chelated form of magnesium is warranted. However, in severe cases, measuring RBC magnesium levels and administration of IV magnesium sulfate can be considered.
1. Katzberg HD, Khan AH, So YT. Assessment: Symptomatic treatment for muscle cramps (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010;74:691-696.
2. Dahle L, Berg G, Hammar M, Hurtig M, Larsson L. The effect of oral magnesium substitution on pregnancy-induced leg cramps. American Journal of Obstetrics and Gynecology 1995:173;175-180.
3. Coghlan HC, Natello G. Erythrocyte magnesium in symptomatic patients with primary mitral valve prolapse: relationship to symptoms, mitral leaflet thickness, joint hypermobility and autonomic regulation. Magnes Trace Elem. 1991-1992;10:205-214.
Disclosure: Dr. Mauskop owns patents for Migralex and is part owner of Migralex, Inc.
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