Medical Policies - Medicine
Intravenous or Subcutaneous Histamine Therapy
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Intravenous or subcutaneous histamine therapy is considered experimental, investigational and/or unproven for all indications, including but not limited to headache, sudden hearing loss and Ménière disease.
The intravenous or subcutaneous administration of histamine is proposed as a treatment for headaches, particularly cluster headaches, sudden hearing loss, and Ménière disease.
Interest in the therapeutic use of histamine was prompted by the 1937 observation that infusions of intravenous histamine provoked the onset of headaches. This led to the use of chronic intravenous or subcutaneous histamine as a type of desensitization therapy.
This medical policy was originally created in 1990 and has been updated with searches of the MEDLINE database. The most recent literature search was performed through June 2017.
King (1) conducted a retrospective office study of 100 randomly selected patients with headache and/or vertigo. Low-dose histamine appeared to be helpful in 70% of the patients and some value in 10% of patients. The author reported that 20% of the patients did not improve within two months on the treatment and were switched to a different therapy. The author concluded that low-dose histamine therapy for the appropriate patient often significantly reduces morbidity and dependence on other medications.
In 2006, Millan-Guerrero et al. (2) conducted a double-blind, placebo controlled Phase III clinical trial which evaluated the efficacy of Nα-methylhistamine in migraine prophylactic treatment. In this 12-week clinical trial, the efficacy of subcutaneous administration of Nα-methylhistamine 1–3 ng twice a week was studied against placebo, evaluating the outcome of headache intensity, frequency, duration, and analgesic intake. Comparison between the groups treated with placebo (n=30) and Nα-methylhistamine (n=30), on data collected for the 4th, 8th and 12th weeks of treatment, revealed that compared to placebo, Nα-methylhistamine exerted a significant (p< 0.0001) reduction in intensity, frequency, and duration of migraine attacks, as well as the use of analgesics. No significant (p>0.05) adverse experiences or side effects developed in either group. The authors concluded this study provides “evidence of the efficacy of Nα-methylhistamine, given subcutaneously at doses of 1–3 ng twice a week, offering a new therapeutic alternative and laying the clinical and pharmacological groundwork for the use of histaminergic H3-agonists in migraine prophylaxis, which may specifically inhibit the neurogenic edema response involved in migraine pathophysiology.”
In 2004, the National Headache Foundation published a guideline addressing the treatment of cluster headache. (3) The guideline states that “intravenous histamine has been found to be an effective treatment for patients with cluster headache that has become refractive to medical therapy. Patients treated with histamine infusions repetitively over a course of about 10 days appear to have restitution of response to standard medical therapies. Because of the prolonged nature of intravenous therapy, it is not recommended for patients who have other medical options available. Since the course of histamine infusions can be repeated if cluster headaches recur and since this therapy is well tolerated by most patients, it may be considered as an alternative to surgery.” The guideline states that the type of evidence supporting the recommendations is not specifically stated. The 2000 evidence-based guideline for treatment of migraine headache developed by the American Academy of Neurology does not mention histamine desensitization therapy as a treatment for migraine.
Histamine is proposed to treat migraine headache because histamine has a selective affinity for H3 receptors and it may specifically inhibit the neurogenic edema response involved in migraine pathophysiology. In 2008, Millan-Guerrero et al. conducted a study to evaluate the therapeutic potential of subcutaneous administration of histamine in migraine prophylaxis, compared with oral administration of topiramate. Ninety patients with migraine were selected in a 12-week double-blind controlled clinical trial to evaluate the efficacy of subcutaneous administration of histamine (1-10 ng twice a week) compared with oral administration of topiramate (100 mg daily dose). The variables studied were: headache intensity, frequency, duration, analgesic intake and Migraine Disability Assessment. The data collected during the 12 weeks of treatment revealed that headache symptoms improved in both the histamine and topiramate groups, which was evident within the first month after the initiation of treatment, with statistically significant (p < 0.001) reductions in headache frequency (50%), Migraine Disability Assessment score (75%), intensity of pain (51%), duration of migraine attacks (45%), as well as in the use of rescue medication (52%). The authors concluded that there was evidence of the efficacy of subcutaneously applied histamine and orally administered topiramate in migraine prophylaxis, and therefore subcutaneously applied histamine may represent a novel and effective therapeutic alternative in resistant migraine patients. However, further research is needed to validate these results. (4)
Only 5 studies or reports were found on the use of histamine for hearing loss, Ménière's syndrome or other indications; reports that were located were from the 1940-1970 era.
A search of peer reviewed literature through July 2013 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.
A search of peer reviewed literature through February 2015 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.
In 2009, Millan-Guerrero et al. evaluated the efficacy and tolerability of the subcutaneous administration of histamine and botulinum toxin type A (BoNTA) in migraine prophylaxis. (12) In a 12-week double-blind controlled clinical trial, 100 patients with migraines were selected to evaluate the efficacy of subcutaneous administration of histamine (1-10 ng twice a week) (n = 50), compared with administration of 50 U of BoNTA (one injection cycle) (n = 50). The results reported by the authors included the data collected during the 4th week of treatment which revealed a significant decrease in all parameters studied, in histamine and BoNTA (P < 0.001). Conclusions noted in the randomized study revealed that both histamine and BoNTA are similarly effective and well tolerated in reducing or eliminating headache in migraine prophylaxis. Low doses of histamine applied subcutaneously may represent a novel and effective therapeutic alternative in migraine patients and lay the clinical and pharmacological groundwork for the use of H3 agonist in migraine prophylaxis.
A search of peer reviewed literature through June 2017 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.
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The following codes may be applicable to this Medical policy and may not be all inclusive.
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The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.
A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. King, W.P. The use of low dose histamine therapy in otolaryngology. Ear, Nose, and Throat Journal (1999 May) 78(5):366-70. PMID 10355198
2. Millan-Guerrero, R.O., Osaos-Millan, R., et al. Nalpha-methyl histamine safety and efficacy in migraine prophylaxix: phase III study. Canadian Journal of Neurological Science (2006 May) 33(2):195-9. PMID 16736729
3. National Headache Foundation. Biondi, D., and P. Mendes. Treatment of Primary Headache. In: Standards of care for Headache Diagnosis and Treatment (2004) Available at <https://www.guideline.gov> (accessed – 2008 January 17).
4. Millán-Guerrero RO, Isais-Millán R, et al. Subcutaneous histamine versus topiramate in migraine prophylaxis: a double-blind study. Eur Neurol. 2008;59(5):237-42. doi: 10.1159/000115637. PMID 18264012
5. Silberstein, S.D. Practice parameter: evidence-based guidelines for migraine headache (as evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology (2000 September 26) 55(6):754-62. PMID 10993991
6. Lewis, D., Ashwal, S., et al. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology (2004 December 28) 63(12):2215-24. PMID 15623677
7. Intravenous or Subcutaneous Histamine Therapy (Archived). Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual 2.01.15. (4:2005).
8. Pietrini, U., De luca, M. et al. Prophylactic activity of increasing doses of intravenous histamine in refractory migraine: Retrospective observations of a series of patients with migraine without aura. Curr Ther Res Clin Exp 2004 Jan; 65(1): 70-8. PMID 24936105
9. National institute of Neurological Disorders and Stroke (NINDS) Headache information page condensed from Headache: Hope through Research. Available at <https://www.ninds.nih.gov> (accessed–2017 June 21).
10. Standards of Care for Headache Diagnosis and Treatment. An overview of the National Headache Foundation's (NHF) Standards of Care for Headache Diagnosis and Treatment which include the U.S. Headache Consortium's recommendations for the proper diagnosis of and treatment options for migraine. (2007) Available at < http://www.headaches.org> (accessed-2017 June 21).
11. CMS - National Coverage Determination (NCD) for Intravenous Histamine Therapy (30.6) Centers for Medicare and Medicaid Services. Available at <http://www.cms.gov> (accessed 2017 June 21).
12. Millán-Guerrero R, Isais-Millán S, Barreto-Vizcaíno S, et al. Subcutaneous histamine versus botulinum toxin type A in migraine prophylaxis: a randomized, double-blind study. Eur J Neurol. 2009 Jan; 16(1):88-94. PMID 19087155
|7/15/2018||Reviewed. No changes.|
|9/1/2017||Document updated with literature review. Coverage unchanged.|
|11/1/2016||Reviewed. No changes.|
|4/15/2015||Document updated with literature review. Coverage unchanged.|
|10/15/2013||Document updated with literature review. Coverage unchanged.|
|3/1/2008||Revised/updated entire document.|
|3/1/2006||Revised/updated entire document|
|12/1/2003||Revised/updated entire document|
|11/1/1999||Revised/updated entire document|
|5/1/1996||Revised/updated entire document|
|12/1/1993||Revised/updated entire document|
|5/1/1990||New medical document|
|Title:||Effective Date:||End Date:|
|Intravenous or Subcutaneous Histamine Therapy||09-01-2017||07-14-2018|
|Intravenous or Subcutaneous Histamine Therapy||11-01-2016||08-31-2017|
|Intravenous or Subcutaneous Histamine Therapy||04-15-2015||10-31-2016|
|Intravenous or Subcutaneous Histamine Therapy||10-15-2013||04-14-2015|
|Intravenous or Subcutaneous Histamine Therapy||03-01-2008||10-14-2013|
|Intravenous or Subcutaneous Histamine Therapy||03-01-2006||02-29-2008|
|Intravenous or Subcutaneous Histamine Therapy||12-01-2003||02-28-2006|