Histamine Desensitization Therapy for Intractable Headaches

Number: 0647

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses histamine desensitization therapy for intractable Headaches .

  1. Experimental and Investigational

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

  2. Related Policies


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

There is no specific code for histamine desensitization therapy:

Other CPT codes related to the CPB:

96365 - 96379 Therapeutic, prophylactic, and diagnostic injections and infusions

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

G43.001 - G43.919 Migraine
G44.001 - G44.029 Cluster headaches
G44.1 Vascular headache, not elsewhere classified
G44.201 - G44.229 Tension-type headache
R51 Headache


Histamine is a physiologically active amine found in plant and animal tissue and released from mast cells as part of an allergic reaction in humans. It stimulates gastric secretion and causes dilation of capillaries, constriction of bronchial smooth muscle and decreased blood pressure.

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.


The above policy is based on the following references:

  1. 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.
  2. 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.
  3. Diamond S, Freitag FG, Prager J, et al. Treatment of intractable cluster. Headache. 1986;26(1):42-46.
  4. 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.
  5. Ekbom K, Hardebo JE. Cluster headache: Aetiology, diagnosis and management. Drugs. 2002;62(1):61-69.
  6. Freitag FG. Cluster headache. Prim Care. 2004;31(2):313-329, vi.
  7. 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.
  8. Horton BT. Histaminic cephalgia: Differential diagnosis and treatment. Mayo Clin Proc. 1956;31:325-333.
  9. Jackson CM. Effective headache management. Strategies to help patients gain control over pain. Postgrad Med. 1998;104(5):133-147.
  10. King WP. The use of low-dose histamine therapy in otolaryngology. Ear Nose Throat J. 1999;78(5):366-370.
  11. Krabbe AA, Olesen J. Headache provocation by continuous intravenous infusion of histamine. Clinical results and receptor mechanisms. Pain. 1980;8(2):253-259.
  12. 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.
  13. Sargeant L, Blanda M. Cluster headache. In: eMedicine Emergency Medicine Topic 229. Omaha, NE: eMedicine.com; updated March 10, 2005.
  14. Schmetterer L, Wolzt M, Graselli U, et al. Nitric oxide synthase inhibition in the histamine headache model. Cephalalgia. 1997;17(3):175-182.
  15. 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.
  16. Ward TN. Providing relief from headache pain. Current options for acute and prophylactic therapy. Postgrad Med. 2000;108(3):121-128.