This document addresses the use of intravenous or subcutaneous administration of dihydroergotamine (Dihydroergotamine mesylate injection USP, Bedford Laboratories™, Bedford, OH) for the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes in adults.

Medically Necessary:

Intravenous or subcutaneous dihydroergotamine therapy is considered medically necessary for the acute treatment of migraine attacks with aura in adults meeting the following International Headache Society consensus criteria (Cephalalgia, 2005):

1. At least two attacks fulfilling criteria B.-D.
2. Aura consisting of one of the following but no motor weakness:
   1. Fully reversible visual symptoms including positive features (e.g., flickering lights, spots or lines) and/or negative features (i.e., loss of vision); or
   2. Fully reversible symptoms including positive features (i.e., pins and needles) and/or negative features  (i.e., numbness); or
   3. Fully reversible dysphasic speech disturbance.
3. At least two of the following:
   1. Homonymous visual symptoms and/or unilateral sensory symptoms.
   2. At least one aura symptom develops gradually over greater than or equal to five minutes and/or different aura symptoms occur in succession over greater than or equal to five minutes.
   3. Each symptom lasts greater than or equal to five minutes and less than or equal to 60 minutes.
4. Headache fulfilling criteria B.-D. for migraine without aura begins during the aura or follows aura within 60 minutes.          
5. Not attributed to another disorder.

Intravenous or subcutaneous dihydroergotamine therapy is considered medically necessary for the acute treatment of migraine attacks without aura in adults meeting the following International Headache Society consensus criteria (Cephalalgia, 2005):

1. At least five headache attacks fulfilling criteria B.-D.
2. Headaches lasting 4-72 hours (untreated or unsuccessfully treated).
3. Headache has at least two of the following characteristics:
   1. Unilateral location
   2. Pulsating quality
   3. Moderate or severe pain intensity
   4. Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs).
4. During headache at least one of the following:
   1. Nausea, vomiting or both; or
   2. Photophobia or phonophobia.
5. Not attributed to another disorder.

Intravenous or subcutaneous dihydroergotamine therapy is considered medically necessary for the acute treatment of cluster headache episodes in adults meeting the following International Headache Society consensus criteria (Cephalalgia, 2005):

1. At least five attacks fulfilling criteria B.-D.
2. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15 to 180 minutes if untreated.
3. Headache is accompanied by at least one of the following:
   1. Ipsilateral conjunctival injection and/or lacrimation; or
   2. Ipsilateral nasal congestion and/or rhinorrhoea; or
   3. Ipsilateral eyelid edema; or
   4. Ipsilateral forehead and facial sweating; or
   5. Ipsilateral miosis and ptosis; or
   6. A sense of restlessness or agitation.
4. Attacks have a frequency from one every other day to eight per day.
5. Not attributed to another disorder.

Intravenous or subcutaneous dihydroergotamine therapy is considered medically necessary in adults for any of the following conditions:

• Status migrainosis or rebound withdrawal type of headaches; or
• Individual has only received narcotics for severe migraine or cluster headaches; or
• Individual is unresponsive to prior use of triptans for severe migraine or cluster headache.

Not Medically Necessary:

Intravenous or subcutaneous dihydroergotamine therapy is considered not medically necessary when the criteria listed above are not met.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

The International Headache Society acknowledged in a 2004 Cephalalgia report that a migraine is a common disabling primary headache disorder ranked by the World Health Organization (WHO) as number 19 among all diseases worldwide causing disability.

Migraine can be divided into two major sub-types:

1. Migraine without aura is a clinical syndrome characterized by headaches with specific features and associated symptoms.
2. Migraine with aura is primarily characterized by focal neurological symptoms that usually precede or sometimes accompany the headache.  Some individuals also experience a premonitory phase, occurring hours or days before the headache, and a headache resolution phase.  Premonitory and resolution symptoms include hyperactivity, hypoactivity, depression, craving for particular food and repetitive yawning (International Headache Society, 2004).

Note: Aura is early symptoms of an attack of migraine with aura, being the manifestation of focal cerebral dysfunction. Aura typically lasts 20-30 minutes and precedes the headache.

Acute Migraine Treatment

Despite recent advances in the science and treatment of migraine over the past decade, many clinicians have not significantly changed their approach to managing migraine. Nearly 60% of migraine sufferers continue to use over-the-counter (OTC) remedies exclusively to manage their headaches, despite a rise in the number of physician-diagnosed migraines (Bahra, 2002). Many of these diagnosed individuals still report significant suffering, highlighting the need for appropriate treatment in the management of migraine headache.

Effective migraine treatment begins with an accurate diagnosis and a thorough understanding of the impact a primary headache has on the individual's daily life. Clinicians should be aware of the use and the effectiveness of previous and current treatments, bearing in mind that both prescription and over-the-counter (OTC) products have the potential for exacerbating underlying headache patterns. Once a diagnosis is established, it is essential to explain the condition to the individual. Reassuring an individual that their headaches are not caused by something life-threatening, such as a brain tumor or an aneurysm, is an important part of the treatment process. 

Cluster Headache Treatment

The International Headache Society (2004) has published criteria for diagnosing cluster headache. Criteria for diagnosis specify an individual must have had at least five attacks occurring from one every other day to eight per day, attributable to no other disorder. In addition, headaches must cause severe or very severe unilateral orbital, supraorbital, or temporal pain lasting 15 to 180 minutes if untreated and be accompanied by one or more of the following: ipsilateral conjunctival injection or lacrimation, ipsilateral nasal congestion or rhinorrhea, ipsilateral eyelid edema, ipsilateral forehead and facial sweating, ipsilateral miosis or ptosis, or a sense of restlessness or agitation.

Episodic cluster headache is defined as at least two cluster periods lasting seven to 365 days and separated by pain-free remission periods of one month or longer. Chronic attacks recur over more than one year without remission or with remission lasting less than one month.

The absence of aura, nausea, or vomiting has helped distinguish cluster from migraine headaches, but studies indicate that 14% of individuals with cluster headache experience aura, 51% have a personal or family history of migraine, 56% report photophobia, 43% report phonophobia, and 23% report osmophobia (Van Vliet, 2003). Therefore, the presence of aura, nausea, vomiting, or photophobia should not rule out a diagnosis of cluster headache. A characteristic feature of cluster headache, noted by 93% of individuals in one study, is restlessness, with behaviors such as pacing and rocking the head and trunk with head in hands (Bahra, 2002). Most of these headaches last 15 minutes to three hours and recur at the same time of day, often at night. Many attacks begin during the first rapid-eye-movement sleep phase. Individuals may report a seasonal pattern of cluster headache with spring and autumn peaks.

U.S. Headache Consortium

The U.S. Headache Consortium (Matchar, 2003) identified the following goals for successful treatment of acute attacks of migraine:

• Treat attacks rapidly and consistently and prevent recurrence
• Restore the patient's ability to function
• Minimize the use of backup and rescue medications
• Optimize self-care and reduce subsequent use of resources
• Be cost-effective in overall management
• Have minimal or no adverse events

Medical Management Information

• DHE injection is administered in the outpatient setting or inpatient if moderate to severe intractable migraine or cluster headache fails to respond to appropriate and aggressive outpatient or emergency department measures and requires repetitive sustained parenteral DHE treatment.
• Cases of drug abuse and psychological dependency in individuals on other forms of ergot therapy have been reported. Due to the chronicity of vascular headaches, individuals should be advised not to exceed recommended dosages.
• DHE is not recommended for use in individuals in whom unrecognized coronary artery disease (CAD) is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoking, obesity, diabetes, strong family history of CAD, females who are surgically or physiologically postmenopausal, or males who are over forty years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the individual is reasonably free of coronary artery, ischemic myocardial disease, or other significant cardiovascular disease.
• The safety and effectiveness of DHE have not been established in pediatric-age individuals (Dihydroergotamine mesylate injection USP, Product Insert Information, 2008; DrugPoints™, 2010).

Contraindications

Intravenous or subcutaneous dihydroergotamine therapy is contraindicated for use in individuals in any of the following situations (Dihydroergotamine mesylate injection USP, Product Insert Information, 2008):

• Black box warning: Serious or life-threatening peripheral ischemia has been associated with the coadministration of DHE with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. The risk of vasospasm is increased leading to cerebral ischemia or ischemia of the extremities;
• Coronary artery vasospasm including Prinzmetal variant angina;
• DHE given within 24 hours of administration of other ergot/5-HT derivatives including triptans (e.g., sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, eletriptan);
• Hemiplegic or basilar-type migraine;
• Hypersensitivity to ergot alkaloid products;
• Individuals experiencing chest pain or severe anxiety following the first dose of DHE (e.g. do not repeat);
• Ischemic heart disease (angina pectoris, history of myocardial infarction, or documented silent ischemia) due to the potential for adverse cardiac events including acute myocardial infarction, life threatening disturbances of cardiac rhythm, and death;
• Peripheral arterial disease, sepsis, following vascular surgery and severely impaired hepatic or renal function;
• Peripheral vascular disease, severe;
• Pregnancy and lactation (as DHE possesses oxytocic properties);
• Uncontrolled hypertension.

Peer Reviewed Publications:

1. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology. 2002; 58(3):354-361.
2. Beck E, Sieber W, Trejo R. Management of cluster headache. Am Fam Physician. 2005; 71(4):717-724, 728.
3. Silberstein SD, McCrory DC. Ergotamine & dihydroergotamine: history, pharmacology, & efficacy. Headache. 2003; 43(2):144-166.
4. Silberstein SD, Young WB, Hopkins MM, et al. Dihydroergotamine for early and late treatment of migraine with cutaneous allodynia: an open-label pilot trial. Headache. 2007; 47(6):878-885.
5. Van Vliet JA, Eekers PJ, Haan J, Ferrari MD. Features involved in the diagnostic delay of cluster headache. J Neurol Neurosurg Psychiatry. 2003; 74(8):1123-1125.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2010^®. Bethesda, MD: American Society of Health-System Pharmacists^®, 2010.
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: 59-72.
3. Colman I, Brown MD, Innes GD, et al. Parenteral dihydroergotamine (DHE) for acute migraine. Cochrane Database Syst Rev. 2003; (1):CD003970.
4. Dihydroergotamine. In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. November 5, 2010. Available at: http://www.thomsonhc.com. Accessed on November 15, 2010.
5. Dihydroergotamine mesylate injection USP [Product Information], Bedford, OH. Bedford LaboratoriesÔ; August 2008. Available at: http://www.bedfordlabs.com/BedfordLabsWeb/products/inserts/DHE-P03.pdf. Accessed on November 5, 2010.
6. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: 2^nd edition. Cephalalgia. 2004; 24(Suppl 1):1-160.
7. Institute for Clinical Systems Improvement. Health care guideline: Diagnosis and treatment of headache. March 2009, 9^th Edition; 1-77.
8. Landy S, Smith T. National Headache Foundation. Standards of care for headache diagnosis and treatment. Treatment of primary headache: acute migraine treatment. 2004; 27-39.
9. Matchar DB, Young W, Rosenberg J, et al. U.S. Headache Consortium. American Academy of Neurology. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. Neurology. 2003; 60(7) Suppl 2:S21-S23.
10. Snow V, Weiss K, Wall E, Mottur-Pilson C. Commission on Clinical Policies and Research of the American Academy of Family Physicians (AAFP) and the American College of Physicians-American Society of Internal Medicine (ACP-ASIM). Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002; 137(10):840-852.

Cluster Headaches
Dihydroergotamine Mesylate (DHE)
Headaches
Migraine
Migraine Headaches

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