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Promethazine Drug Information

Migraine associated with moderate to severe disability afflicts more than 8.7 million women and 2.6 million men in the United States.[1] Direct and indirect costs are estimated to be $5.6 to $17.2 billion in time lost from work and loss of productivity.[2, 3] As one of the top 10 causes for outpatient physician visits in the United States, headache requires optimal therapy.[4] Compared with patients without migraine, patients with migraine have greater morbidity in general and greater costs in health care resources.[5]

Part 1 of this article discusses abortive treatment of migraine headache and management of rebound headache. Part 2, to be published in a later issue, will include an in-depth examination of preventive (prophylatic) medications used for migraine.

Pathophysiology of Pain

Release of vasoactive substances (e.g., substance P, calcitonin-gene related peptides and neurokinin A) from trigeminal nerve fibers induces a sterile inflammatory reaction around the blood vessels at the base of the brain and in the blood vessels of the aura and pie. This "neurogenic inflammation" may be accompanied by vasodilation and is triggered by nerve impulses originating in the caudal trigeminal nucleus. Specific abortive agents for migraine such as sumatriptan (Imitrex), dihydroergotamine (D.H.E. 45) and ergotamine can reverse this neurogenic inflammation. This effect is probably mediated by interaction with specific serotonin receptors (5-[HT.sub.ID].[6] Stimulation of inhibitory (5-[HT.sub.1]) serotonin receptors is thought to turn off neurogenic inflammation, whereas activation of the excitatory (5-[HT.sub.2]) serotonin receptors can lead to migraine. Many medications used for migraine prophylaxis work by blocking 5-[HT.sub.2] receptors.

Acute Therapy for Migraine

The pharmacologic treatment of migraine is divided into acute (abortive, symptomatic) treatment and preventive (prophylactic) treatment. Most patients with migraine need only abortive treatment for their headaches.[7] Table 1[8] lists the major antimigraine abortive agents. Use of abortive agents should be limited when possible to two days a week, since frequent use of analgesics, ergotamine and, possibly, sumatriptan can lead to so-called "rebound" headache and make preventive medications less effective. Simple analgesics such as aspirin and acetaminophen or nonsteroidal anti-inflammatory drugs may be effective for mild to moderate attacks that are not associated with severe nausea or vomiting.

[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII]

Even if the patient is not vomiting, however, oral agents may be ineffective for severe migraine attacks because of decreased gastric motility. Effervescent analgesic preparations are more rapidly absorbed and may be more effective.[9] Concurrent use of metoclopramide (Reglan) at 10 mg or cisapride (Propulsid) at 20 mg can improve gastric motility and increase the efficacy of oral agents.[10] Unlike metoclopramide, cisapride has no serious extrapyramidal effects. While metoclopramide has antiemetic properties, cisapride is ineffective in the treatment of the nausea and vomiting that often accompany migraine headache. Parenteral metoclopramide can rapidly reverse gastroparesis. Oral metoclopramide, absorbed in the intestine, does not provide immediate relief of gastroparesis.

Migraine attacks that peak in one hour or less and attacks associated with severe nausea and vomiting may not respond to oral agents. Rectal, nasal or intramuscular/subcutaneous routes should be used to treat these attacks. However, before prescribing drugs designed to be taken other than orally, it is helpful to explore the patient's acceptance of alternative routes of drug administration.

Ergotamine suppositories can provide relief if taken at the onset of a migraine attack. Patients who have not used ergotamine before should be instructed to use one third of the 2-mg suppository initially and repeat the dose in 30 to 60 minutes. Refrigerating the suppository allows it to harden and facilitates slicing it.[8]

The most effective dose of ergotamine is a subnauseating dose. Higher doses that precipitate severe nausea or vomiting may be less effective. Rectal suppositories of ergotamine provide much more reliable absorption than oral or sublingual forms. It is advisable to limit ergotamine use to no more than two days a week to avoid resultant rebound headache. An exception can be made in the case of menstrual migraine, where more frequent perimenstrual administration is acceptable provided that ergotamine use is then restricted for the rest of the month.

Exceeding the recommended dose or frequency can lead to vasospastic side effects. Use of ergotamine is contraindicated in patients with known coronary, cerebral or peripheral vascular disease. Other contraindications include uncontrollable hypertension, hepatic or renal insufficiency, and pregnancy.

Recurrent nausea and vomiting caused by migraine can be more disabling and demoralizing than the pain. Subcutaneous sumatriptan can reduce gastrointestinal symptoms, but antiemetic medications are often needed as adjunctive therapy. Antihistaminic antiemetics such as dimenhydrinate (Dramamine) and hydroxyzine (Atarax) may be adequate for nausea, but patients with severe nausea and vomiting should use a potent phenothiazine antiemetic such as chlorpromazine (Thorazine), prochlorperazine (Compazine) or promethazine (Phenergan). These agents can provide sedation. Intravenous prochlorperazine or chlorpromazine can be used to abort prolonged attacks of severe migraine but only in selective cases and are usually given in a hospital setting because of possible hypotensive and extrapyramidal side effects.

Table 2 compares dihydroergotamine and sumatriptan in the treatment of severe migraine attacks. These agents can treat the entire migraine complex, including the associated nausea, vomiting, photophobia and phonophobia. They are also effective in the treatment of prolonged attacks, although ideally they should be taken at an early stage.

TABLE 2
Comparison of Sumatriptan (Imitrex) and Dihydroergotamine
(D.H.E. 45) for Severe Migraine Attacks

Feature                 Sumatriptan            Dihydroergotamine

Efficacy in relief      ++++                   ++++
 of pain
Efficacy in relief      ++                     --
 of nausea, vomiting
 and photophobia
Efficacy in relief      --                      +++
 of aura symptoms
Efficacy in relief      ++                     ++++
 of status migrainosus
 (disabling headaches
 lasting [is greater
 than or equal to]
 72 hours)
Recurrence of pain      Common (40             Uncommon
                         percent)
Cost                    ++++                   ++
Convenience             ++++                   +
Oral form               Yes                    No
Intravenous use         Contraindicated        Approved
Precautions             Ischemic heart         Peripheral vascular
                         disease or coronary    disease
                         vasospasm             Coronary artery
                        Uncontrolled            disease
                         hypertension          Uncontrolled
                        Concurrent use of       hypertension
                         ergotamin             Impaired hepatic
                         dihydroergotamine,     or renal function
                         methysergide or       Pregnancy
                         combination drug      Previous
                         (Midrin), in prior     hypersensitivity
                         24 hours
                        Hemiplegic or basilar
                         migraine
                        Pregnancy
                        Previous
                         hypersensitivity
Rebound headache        Rare                   Not reported
with frequent or
 daily use

TABLE 3
Sumatriptan (Imitrex) Prescribing Guidelines

Never use sumatriptan to establish a diagnosis of migraine.
Try simpler, less expensive medications first to determine
  if efficacious.
Do not administer to patient with basilar or hemiplegic migraine.
Advise patients not to use sumatriptan if their headache is
  atypical.
Patients with cardiovascular or cerebrovascular disease are more
  susceptible to sumatriptan-induced coronary vasospasm and
  hypertension.
Consider cardiovascular assessment in patients with possible
  occult coronary disease (men older than 40, postmenopausal
  women, patients with coronary artery disease risk factors such
  as hypertension, hypercholesterolemia, obesity, diabetes and
  strong family history); consider giving first dose in the
  office following a satisfactory cardiovascular assessment.
If patients experience chest tightness or pain, consider
  baseline electrocardiogram.
Treatment is contraindicated in patients with suspected or
  confirmed ischemic heart disease (angina pectoris), history
  of myocardial infarction; documented silent ischemia);
  Prinzmetal's angina, vascular disease; uncontrolled
  hypertension; concomitant use of MAO inhibitors or use within
  2 weeks of discontinuing MAO inhibitors; concomitant use with
  ergotamine-based or ergot-like drugs (within 24 hours).
Use with caution in patients taking dexfenfluramine (Redux).
Use with caution in patients with seizure disorders, as treatment
  has occasionally been associated with convulsions.
Use with caution in patients with severely impaired hepatic
  function.
Use with caution in pregnant or lactating women.

Patient education is essential whether withdrawal is done on an outpatient or inpatient basis. Physicians should avoid blaming patients or using terms like "drug abuse." It is our practice to discuss the studies on analgesic rebound and ergotamine dependency without specific reference to the patient's overuse of abortive agents. Patients are given a copy of Table 6,[20] which summarizes a study showing that continued use of analgesics decreases the success rate in treatment of chronic daily headache. Before withdrawal, patients should be given the following information: (1) after cessation of abortive agents, headache may worsen within 24 to 48 hours, and severe headache may last 72 hours or longer; (2) measures will be taken to minimize the severity of the rebound headache; (3) hospitalization is an option if the rebound headache is prolonged, severe or associated with nausea or vomiting; (4) it may take eight to 12 weeks for patients to regain normal responsiveness to appropriate therapy (the analgesic wash-out period), and a positive response to preventive agents may also be delayed.[21]

TABLE 6
Effect of Continued Analgesic Use in 100
Patients with Chronic Daily Headache

                                        Mean
Treatment group                        improvement (%)

Amitriptyline (Elavil) plus
   no analgesics                            72
Placebo plus no analgesics                  43
Amitriptyline plus as-needed
   analgesics                               30
Placebo plus as-needed
   analgesics                               18

Dr. Noble has served as a co-investigator for Merck Research Laboratories and Abbott Laboratories.

The authors thank Catina Brandon, Pharm.D., and Frances Newman for help in manuscript preparation, and William Replogle, Ph.D.,for manuscript review.

REFERENCES

[1.] Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA 1992;267:64-9.

[2.] de Lissovoy G, Lazarus SS. The economic cost of migraine. Present state of knowledge. Neurology 1994;44(6 Suppl 4): S56-62.

[3.] Osterhaus J, Gutterman D, Plachetka J. Health care resource and lost labour costs of migraine headache in the United States. Pharmacoeconomics 1992:2:67-76.

[4.] Kroenke K, Mangelsdorff AD. Common symptoms in ambulatory care: incidence, evaluation, therapy, and outcome. Am J Med 1989;86:262-6.

[5.] Clouse JC, Osterhaus JT. Healthcare resource use and costs associated with migraine in a managed healthcare setting. Ann Pharmacother 1994;28:659-64.

[6.] Kumar KL, Mathew NT, Silberstein SD. Migraine: finding the road to relief. Patient Care 1995;29:90-110, 112-15.

[7.] Tfelt-Hansen P, Welch KM. General principles of pharmacological treatment. In: Olesen J, Tfelt-Hansen P, Welch KM, eds. The headaches. New York: Raven, 1993:299-301.

[8.] Capobianco DJ, Cheshire WP, Campbell JK. An overview of the diagnosis and pharmacologic treatment of migraine. Mayo Clin Proc 1996;71:1055-66.

[9.] Welch KM. Drug therapy of migraine. N Engl J Med 1993;329:1476-83.

[10.] Malagelada J, Distrutti E. Management of gastrointestinal motility disorders: a practical guide to drug selection and appropriate ancillary measures. Drugs 1996;52(4):494-506.

[11.] The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. In: Sumatriptan. From molecule to man. An official session at the 8th Migraine Trust International Symposium. London UK, 28 September 1990. Proceedings. Eur Neurol 1991;31:277-344.

[12.] Cutler N, Mushet GR, Davis R, Clements B, Whitcher L. Oral sumatriptan for the acute treatment of migraine: evaluation of three dosage strengths. Neurology 1995;45(8 Suppl 7):S5-9.

[13.] Sargent J, Kirchner JR, Davis R, Kirkhart B. Oral sumatriptan is effective and well tolerated for the acute treatment of migraine: results of a multicenter study Neurology 1995:45(8 Suppl 7):S10-4.

[14.] Package insert. Imitrex. Montvale, N.J.: Glaxo Wellcome, Inc., 1997.

[15.] Winner P, Ricalde O, Le Force B, Saper J, Margul B. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol 1996;53:180-4.

[16.] Klapper JA, Stanton J. Current emergency treatment of severe migraine headaches. Headache 1993;33:560-2.

[17.] Langemark M, Olesen J. Drug abuse in migraine patients. Pain 1984;19:81-6.

[18.] Jaffe J, Martin M. Opioid analgesics and antagonists. In: Gilman AG, et al., eds. Goodman and Gilman's The pharmacological basis of therapeutics. 8th ed. New York: Pergamon, 1990:485-521.

[19.] Mathew NT, Stubits E, Nigam MP. Transformation of episodic migraine into daily headache: analysis of factors. Headache 1982;22:66-8.

[20.] Kudrow L. Paradoxical effects of frequent analgesic use. Adv Neurol 1982;33:335-41.

[21.] Mathew NT. Chronic refractory headache. Neurology 1993;43(6 Suppl 3):S26-33.

[22.] Martignoni E, Solomon S. The complex chronic headache, mixed headache and drug overuse. In: Olesen J, Tfelt-Hansen P, Welch KM, eds. The headaches. New York: Raven, 1993:849-53.

[23.] Mathew NT. Transformed migraine, analgesic rebound, and o[ther chronic daily headaches. Neurol Clin 1997;15(1):167-86.

[24.] Rapoport A, Stang P, Gutterman DL, Cady R, Markley H, Weeks R, et al. Analgesic rebound headache in clinical practice: data from a physician survey. Headache 1996;36:14-9.

[25.] Tepper S. A primary care approach to migraine and chronic headache. Primary Care Reports 1996;2(17): 151-60.

The Authors

KENNETH L. MOORE, M.D. is assistant professor in the Department of Neurology at the University of Mississippi Medical Center, Jackson, Miss. After graduating from the University of Chicago Pritzker School of Medicine, he completed residencies in internal medicine and neurology at Rush-Presbyterian-St. Luke's Medical Center, Chicago. He is on the editorial board for Headache Quarterly, co-editor of the American Council for Headache Education (ACHE) newsletter and head-pain resource for CompuServe Online Service.

SARA L. NOBLE, PHAR M.D. is assistant professor in the Department of Family Medicine at the University of Mississippi Medical Center, where she earned a doctorate in pharmacy. She is also involved with clinical trials of medications used in the management of migraine.

Address correspondence to Kenneth L. Moore, M.D., 971 Lakeland Dr., Suite 654, Jackson, MS 39216. Reprints are not available from the authors.

This is Part I of a two-part artcle on the drug treatment of migraine. Part II "Preventive Theraphy," will appear in the next issue.

Richard W. Sloan, M.D., R.P.H., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvannia State University, Hershey, Pa.

COPYRIGHT 1997 American Academy of Family Physicians
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