Headache due to Substance or its Withdrawal

Headaches caused by a substance or its withdrawal are common and require very careful assessment and management in order to ensure a correct diagnosis and exclude any other cause of headache, and to provide effective treatment and support for the patient. Migraine headaches may be provoked or activated in susceptible individuals by a variety of substances, including alcohol, food and food additives, and chemical and drug ingestion and withdrawal.

A diagnosis of headache due to a substance usually becomes definite only when the headache resolves or greatly improves after withdrawing the substance. Headaches attributable to a substance or its withdrawal include:¹

• Headaches caused by acute substance use or exposure, e.g. nitrates, calcium channel blockers, phosphodiesterase inhibitors, carbon monoxide, alcohol, food components or additives (e.g. monosodium glutamate), cannabis, histamine.
• Medication-overuse headaches (previously called rebound headache, drug-induced headache or medication-misuse headache), e.g. ergotamine, triptans, analgesics.
• Headaches as an adverse effect of chronic medication, e.g. combined oral contraception, hormone replacement therapy.
• Headaches caused by substance withdrawal, e.g. caffeine, opioids, oestrogens, corticosteroids, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and non-steroidal anti-inflammatory drugs (NSAIDs).

May be caused by an unwanted effect of a toxic substance, or by an unwanted effect of a substance in normal therapeutic use.

• Immediate nitric oxide donor-induced headache: all nitric oxide donors (e.g. amyl nitrate, erythrityl tetranitrate, glyceryl trinitrate (GTN), isosorbide mono- or dinitrate, sodium nitroprusside, mannitol hexanitrate, pentaerythrityl tetranitrate) can cause headache, especially in people with migraine.
• Carbon monoxide poisoning:
  • Typically mild headache without gastrointestinal or neurological symptoms with carboxyhaemoglobin levels in the range 10-20%.
  • Moderate pulsating headache and irritability with levels of 20-30%.
  • Severe headache with nausea, vomiting and blurred vision with levels of 30-40%.
  • With higher carboxyhaemoglobin levels (>40%) headache is not usually a complaint because of changes in consciousness.
• Immediate alcohol-induced headache
• Headache induced by food components and additives: phenylethylamine, tyramine and aspartame have been incriminated; monosodium glutamate-induced headache.
• Cocaine, cannabis
• Histamine
• Calcitonin gene-related peptide (CGRP)-induced headache
• Medications: headache has been reported after use of a number of drugs. The following are the most often incriminated: atropine, digitalis, disulfiram, hydralazine, imipramine, nicotine, nifedipine, nimodipine.
• Headache has been reported after exposure to a number of organic and inorganic substances. The following are the most commonly incriminated substances:
  • Inorganic compounds: arsenic, borate, bromate, chlorate, copper, iodine, lead, lithium, mercury, tolazoline hydrochloride.
  • Organic compounds: alcohols (long-chain), aniline, balsam, camphor, carbon disulfide, carbon tetrachloride, clordecone, EDTA, heptachlor, hydrogen sulfide, kerosene, methyl alcohol, methyl bromide, methyl chloride, methyl iodine, naphthalene, organophosphorous compounds (parathion, pyrethrum).

• Medication overuse headache is described as headache which is present for 15 days or more per month and which has developed or worsened while taking regular symptomatic medication.²
• Rebound headaches after analgesics are common. Patients with frequent headaches (e.g. tension headaches or migraine) self medicate to pre-empt or cure headache and a vicious cycle occurs, of analgesia, rebound headache and more analgesia.³
• All simple analgesics, especially those with narcotic content, and NSAIDs, ergotamine, caffeine and triptans are implicated.⁴
• Rebound headaches may occur after only a few days of analgesic dosing per week.⁵
• Medication overuse headache must be excluded in all patients with chronic daily headache (headache for 15 days or more each month for longer than three months).²
• A period of two months after cessation of overuse is stipulated in which improvement must occur if the diagnosis is to be definite.
• When exposure to a substance ceases but headache does not resolve or markedly improve after three months, a diagnosis of chronic post-substance exposure headache is considered if all other causes of headache can be excluded.

Epidemiology

• About 20% of patients with chronic headaches and most with daily headaches have analgesic rebound headaches.^6,7
• Low doses daily carry greater risk than larger doses taken weekly.
• Patients with migraine, frequent headaches, and those using opioid-containing medications or overusing triptans are at most risk.²
• Patients are most commonly migraine or tension headache sufferers in the 30-40 year age group.
• Medication overuse headache affects more women than men (5:1).
• Compound analgesics are more likely to induce analgesic rebound headaches than the use of just single medications.
• Analgesic rebound headaches may be a common cause of post-traumatic headaches.⁸

Presentation

Diagnosis is made from the history and having a high level of suspicion.

• Daily or almost daily headache, with daily use of analgesic medication.
• Many patients with medication overuse headache use large quantities of drug and multiple analgesic agents. Use of the medications occurs both frequently and regularly, i.e. on at least several days each week.
• Bunching of treatment days with long periods without medication intake is much less likely to cause medication-overuse headache.
• The headaches are usually intermittent tension-type headaches. Chronic tension-type headache is less often associated with medication overuse but episodic tension-type headaches often become a chronic headache through overuse of analgesics.
• The headache associated with medication overuse often has a peculiar pattern, shifting (even within the same day) from having migraine-like characteristics to having those of tension-type headache.
• The headaches are often worst on waking in the morning and often increased after physical exertion.
• There is often a history of superimposed vascular or migraine-type headaches in addition to the baseline daily headache. The history may begin with episodic headache months or years earlier.
• Depression and sleep disturbances frequently co-exist.
• The assessment of patients with medication overuse headache should include consideration of psychiatric comorbidity and dependence behaviour.²

Management of medication overuse headaches²

Patient education, withdrawal of the offending drug and psychological support are the cornerstone of treatment. A good diet, maintaining hydration, regular exercise and simple relaxation techniques should also be advised. Use of a diary to record symptoms and medication use during withdrawal is strongly recommended.⁹

Most people can withdraw successfully with the right support and encouragement.¹⁰ Most respond fairly rapidly to the withdrawal of the offending agent. The rate of success is about 60% at five years.⁷ However the rate of recovery can occasionally be a slow process taking more than six months of analgesia withdrawal and support before six consecutive headache-free days.¹¹

• Patients with medication overuse headache caused by simple analgesics or triptans should be advised to withdraw the overused medication abruptly.
• Withdrawal symptoms are likely to occur. Symptoms usually settle within seven days but may take up to three weeks to resolve fully. Withdrawal symptoms include worsening headache, nausea, agitation and sleep disturbances.¹⁰
• Medication overuse headache caused by opioids and opioid-containing analgesics should be managed by gradual withdrawal of the overused medication.
• Prophylactic agents may be effective if frequent headaches persist after the overused medication has been withdrawn:
  • Prednisolone, naratriptan, amitriptyline, sodium valproate, gabapentin, topiramate and propranolol have been shown to be effective in patients abruptly withdrawing symptomatic medication, in terms of fewer withdrawal symptoms, using fewer symptomatic medications and using symptomatic medication for a shorter period.
  • Tapering dose of prednisolone has been successfully used to cover the first days of analgesia withdrawal to counteract withdrawal headaches.¹²
  • Naproxen has been shown to reduce withdrawal symptoms in ergotamine-induced headache.
• Patients who have psychiatric comorbidity or dependence behaviour may require referral to a psychiatrist or psychologist.²

Complications

• Analgesic rebound headaches are frequent, very disabling and lead to a large number of days missed from work.⁴
• Prolonged use of analgesics may cause a variety of side-effects, e.g. on the kidneys and liver and, with use of NSAIDs, on the upper gastrointestinal tract.

Prognosis

• Early intervention is important because the long-term prognosis depends on the duration of medication overuse.
• The headache usually starts to improve within two weeks and the improvement then continues for weeks or even months.
• The patient may revert to their original headache type.

• Usually follows daily intake of a substance for longer than three months, which is then interrupted
• The headache develops in close temporal relation to withdrawal of the substance
• The headache resolves within three months after withdrawal
• Common examples of substances causing withdrawal headaches include:
  • Opioid-withdrawal headache
  • Oestrogen-withdrawal headache
  • Caffeine
  • Headache attributed to withdrawal from chronic use of other substances; it has been suggested, but without sufficient evidence, that withdrawal of the following substances may cause headache: corticosteroids, tricyclic antidepressants, SSRIs, and NSAIDs.

1. International Headache Society; The International Classification of Headache Disorders.
2. Diagnosis and management of headache in adults, SIGN (November 2008)
3. Tonore TB, King DS, Noble SL; Do over-the-counter medications for migraine hinder the physician? Curr Pain Headache Rep. 2002 Apr;6(2):162-7. [abstract]
4. Taimi C, Navez M, Perrin AM, et al; Headaches caused by abuse of symptomatic anti-migraine and analgesic treatment. Rev Neurol (Paris). 2001 Oct;157(10):1221-34. [abstract]
5. Maizels M; The patient with daily headaches. Am Fam Physician. 2004 Dec 15;70(12):2299-306. [abstract]
6. Warner JS; The majority of chronic daily headaches of prolonged duration are rebound headaches: a new look at old data. Headache. 2002 Sep;42(8):835-7.
7. Prusinski A; Drug rebound headaches. Neurol Neurochir Pol. 1999;32 Suppl 6:31-7. [abstract]
8. Lane JC, Arciniegas DB; Post-traumatic Headache. Curr Treat Options Neurol. 2002 Jan;4(1):89-104. [abstract]
9. Guidelines for All Healthcare Professionals in the Diagnosis and Management of Migraine, Tension-Type, Cluster and Medication-Overuse Headache, BASH (2007)
10. Headache - medication overuse, Clinical Knowledge Summaries (August 2009)
11. Warner JS; Prolonged recovery from rebound headaches. Headache. 2001 Sep;41(8):817-22. [abstract]
12. Krymchantowski AV, Barbosa JS; Prednisone as initial treatment of analgesic-induced daily headache. Cephalalgia. 2000 Mar;20(2):107-13. [abstract]

• Headache - assessment, Clinical Knowledge Summaries (August 2009)