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Clinical Policy Bulletin:
Histamine Desensitization Therapy for Intractable Headaches
Number: 0647


Policy

Aetna considers histamine desensitization therapy (e.g., intravenous histamine infusion or subcutaneous injection of histamine) for the treatment of intractable headaches (e.g., chronic cluster headaches and migraines) or other indications experimental and investigational because its effectiveness has not been established by randomized controlled studies.

See also the following headache-related CPBs: CPB 0011 - Electrical Stimulation for Pain (regarding electroceutical therapy); CPB 0113 - Botulinum ToxinCPB 0132 - Biofeedback; CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)CPB 0388 - Complementary and Alternative Medicine (regarding craniosacral therapy); and CPB 0462 - Migraine and Cluster Headache: Nonsurgical Management.



Background

Histamine has been used experimentally to induce headache attacks in healthy subjects, as well as in patients with vascular headaches such as migraines and cluster headaches.  Histamine desensitization therapy (e.g., intravenous administration of low dose of histamine) has been used as a treatment of last resort for refractory cases of vascular headaches.  This therapy usually entails a prolonged hospital stay of 1 week with repeated intravenous infusions of histamine.

Although it has been asserted that histamine desensitization therapy is of benefit patients with intractable migraine and cluster headaches (e.g., Freitag, 2004; Biondi and Mendes, 2004), it is unclear whether desensitization plays a role in any improvement in headaches.  There are no well-designed studies (prospective, randomized, controlled trials) demonstrating the clinical effectiveness of histamine desensitization therapy.

Sargeant and Blanda (2005) explained that histamine desensitization was introduced by Dr. B. Horton at the Mayo Clinic, and was popular in the 1940s and 1950s (Horton et al, 1939; Horton, 1956).  This treatment was based on the contention that metabolic derangement of histamine played an important role in producing cluster headaches.  Sargeant and Blanda (2005) noted that results of histamine desensitization were inconsistent and that “minimal hard data exist on recurrence rates and follow-up duration.”  Sargent and Blanda (2005) explained that because the episodic nature of cluster headaches was not recognized fully at that time, spontaneous improvements were attributed to treatment.

Dodick and Campbell (2001) stated that histamine desensitization for the treatment of patients with intractable cluster headaches is not widely used at this time.  Reviews on effective methods of pain relief from headaches (Jackson, 1998; Ward, 2000) did not mention histamine desensitization therapy.  Moreover, the American Academy of Neurology's evidence-based guidelines for migraine headache (2000) did not include histamine desensitization therapy as a management tool.

In a 12-week, double-blind controlled clinical trial (n = 90), Millan-Guerrero et al (2008) evaluated the effectiveness of subcutaneous administration of histamine (1 to10 ng twice-weekly) compared with oral administration of topiramate (100 mg daily).  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 the present study provided evidence of the effectiveness of subcutaneously applied histamine and orally administered topiramate in migraine prophylaxis.  Subcutaneously applied histamine may represent a novel and effective therapeutic alternative in resistant migraine patients.  These findings need to be validated by future studies.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
There is no specific code for histamine desensitization therapy:
Other CPT codes related to the CPB:
96365 - 96379
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
307.81 Tension headache
339.00 - 339.02 Cluster headaches
346.00 - 346.93 Migraine
784.0 Headache


The above policy is based on the following references:
  1. Horton BT. Histaminic cephalgia: Differential diagnosis and treatment. Mayo Clin Proc. 1956;31:325-333.
  2. Horton B, MacLean A, Craig W. A new syndrome of vascular headache: Results of treatment with histamine - preliminary report. Mayo Clinic Proc. 1939;14:257-260.
  3. Krabbe AA, Olesen J. Headache provocation by continuous intravenous infusion of histamine. Clinical results and receptor mechanisms. Pain. 1980;8(2):253-259.
  4. Diamond S, Freitag FG, Prager J, et al. Treatment of intractable cluster. Headache. 1986;26(1):42-46.
  5. Anselmi B, Tarquini R, Panconesi A, et al. Serum beta-endorphin increase after intravenous histamine treatment of chronic daily headache. Recenti Prog Med. 1997;88(7-8):321-324.
  6. Schmetterer L, Wolzt M, Graselli U, et al. Nitric oxide synthase inhibition in the histamine headache model. Cephalalgia. 1997;17(3):175-182.
  7. Jackson CM. Effective headache management. Strategies to help patients gain control over pain. Postgrad Med. 1998;104(5):133-147.
  8. King WP. The use of low-dose histamine therapy in otolaryngology. Ear Nose Throat J. 1999;78(5):366-370.
  9. Ward TN. Providing relief from headache pain. Current options for acute and prophylactic therapy. Postgrad Med. 2000;108(3):121-128.
  10. Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):754-762.
  11. Dodick DW, Campbell JK. Cluster headache: Diagnosis, management, and treatment. In: Wolff's Headache and Other Head Pain. 7th ed. SD Silberstein et al., eds. New York, NY: Oxford University Press, Inc.; 2001; Ch. 12: 283-309.
  12. Ekbom K, Hardebo JE. Cluster headache: Aetiology, diagnosis and management. Drugs. 2002;62(1):61-69.
  13. Freitag FG. Cluster headache. Prim Care. 2004;31(2):313-329, vi.
  14. Biondi D, Mendes P. Treatment of primary headache: Cluster headache. In: Standards of Care for Headache Diagnosis and Treatment. Chicago, IL: National Headache Foundation; 2004.
  15. Sargeant L, Blanda M. Cluster headache. In: eMedicine Emergency Medicine Topic 229. Omaha, NE: eMedicine.com; updated March 10, 2005. Available at: http://www.emedicine.com/EMERG/topic229.htm. Accessed September 30, 2005.
  16. Millan-Guerrero RO, Isais-Millán R, Barreto-Vizcaíno S, et al. Subcutaneous histamine versus topiramate in migraine prophylaxis: A double-blind study. Eur Neurol. 2008;59(5):237-242.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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