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Headaches induced by medication overuse and by other trigger substances
This is a group of secondary headache disorders related to ingested or inhaled substances, both therapeutic and toxic. The types of headache attributable to medication and other ingested or inhaled substances (or their withdrawal) include:
- Headaches caused by acute substance use or exposure (including toxins, drugs and food substances).
- Medication-overuse headache (MOH) - previously called rebound headache, drug-induced headache or medication-misuse headache.
- Headaches as an adverse effect of chronic medication - eg, combined oral contraception, hormone replacement therapy.
- Headaches caused by substance withdrawal - including therapeutic (non-analgesic) substances, opioids and caffeine.
Headache induced by acute substance use or exposure
These are acute headaches triggered by ingested chemicals including therapeutic substances, environmental toxins and food. Vasodilatation is often but not always thought to be the final common path to head pain. Examples include:
- 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. Alcohol can be a potent vasodilator in some people.
- Headache induced by food components and additives. Examples include phenylethylamine, tyramine and aspartame and monosodium glutamate.
- Immediate nitric oxide donor-induced headache: all nitric oxide donors (eg, amyl nitrate, erythrityl tetranitrate, glyceryl trinitrate (GTN), isosorbide mononitrate or dinitrate, sodium nitroprusside, mannitol hexanitrate, pentaerythrityl tetranitrate) can cause headache, especially in people who experience migraine.
- Illicit substance misuse: cocaine, amfetamine, cannabis.
- Calcitonin gene-related peptide (CGRP)-induced headache (this substance is a vasodilator produced by the body and implicated in the pathophysiology of migraine.
- Therapeutic non-analgesic medications: headache has been reported after use of a number of drugs. Most often incriminated are: atropine, digitalis, disulfiram, hydralazine, imipramine, nicotine, nifedipine, nimodipine.
- Headache has been reported after exposure to a number of organic and inorganic substances. Commonly incriminated substances include:
- Inorganic compounds: arsenic, borate, bromate, chlorate, copper, iodine, lead, lithium, mercury, tolazoline hydrochloride.
- Organic compounds: alcohols (long-chain), aniline, balsam, benzene (found in aerosols), camphor, carbon disulfide, carbon tetrachloride, chlordecone, ethylenediaminetetraacetic acid (EDTA), heptachlor, hydrogen sulfide, kerosene, methyl alcohol, methyl bromide, methyl chloride, methyl iodine, naphthalene, organophosphate compounds (parathion, pyrethrum).
- Treatment of these headaches involves avoidance of exposure to the cause.
MOHs are the most common type of headache after tension-type headache and migraine.
MOH should therefore be considered when headache is present for 15 days or more per month and has developed or worsened while taking regular symptomatic medication.
MOH is defined as:
- Headache present on at least 15 days per month.
- Headache which has developed or markedly worsened during medication overuse.
- Headache which resolves or reverts to its previous pattern within two months of discontinuing overused medication.
- Regular overuse for three months or more of one of the following drugs for headache:
- Has taken triptans, opioids, ergots or combination preparations on at least 10 days per month.
- Has taken paracetamol, aspirin (or other non-steroidal anti-inflammatory drugs (NSAIDs)) or combinations of these on at least 15 days per month.
For definite diagnosis the headache must resolve (or revert to its previous pattern) within two months of cessation of overuse if the diagnosis is to be definite. Prior to this happening the diagnosis is 'probable MOH'.
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.
Cause of MOH
The headache mechanism is thought to be an increase in headache pain receptors. MOH is particularly associated with taking medication for treatment of headache. If the medication is being used for something else, the same effect is not seen, except in some headache-prone individuals. This is thought to relate to heightened receptor sensitivity in these individuals, who have an increased tendency to upgrade the headache receptors. All simple analgesics and triptans are implicated.[6, 7, 8]
- Opiate-containing medications cause problems most frequently. Codeine, both alone and in co-codamol, is probably the most common cause.
- Triptans are common culprits.
- NSAIDs are less likely to cause MOH but can do so.
- For this reason ten days a month or more of triptan or opiate use is considered to be overuse, whereas fifteen days or more a month of paracetamol or NSAID use is considered as overuse.
- It is a combination of frequency AND regularity of medication use which seems to trigger the problem.
- The level of medication use which can lead to MOH is variable, but it is more likely to occur with use for more than three consecutive days per week for several weeks.
- Lifetime population prevalence is estimated at 1-2%.
- About 20% of patients with chronic headaches and most with daily headaches have analgesic rebound headaches.[10, 11]
- 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.
- Patients are most commonly those who experience migraine or tension-type headache in the 30- to 40-year age group.
- Rebound headaches after analgesic use are common. Patients with frequent headaches (eg, tension-type headaches or migraine) self-medicate to pre-empt or cure headache and a vicious cycle occurs, of analgesia, rebound headache and more analgesia.
- MOH 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.
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 MOH use large quantities of drug and multiple analgesic agents. Use of the medications occurs both frequently and regularly, ie on at least several days each week.
- Bunching of treatment days with long periods without medication intake is much less likely to cause MOH.
- 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 MOH should include consideration of psychiatric comorbidity and dependence behaviour.
Management of MOHs
Patients usually have a long history by the time they consult a physician for care. Treatment is based on education, support, withdrawal treatment (detoxification), and prophylactic treatment. It also includes management of withdrawal headache.
If there is another underlying headache process then after the withdrawal period headaches are reduced/returned to their previous pattern. After this a programme of preventative medication for the original, baseline headache management may be instituted.
If medication overuse is the only cause of the headache then headaches should cease completely after the withdrawal headache period and prophylaxis will not be required.
Five stages of management of MOH
- Management is dependent on gaining the patient's understanding and acceptance of the cause of their condition. It is no easy task to withdraw from medication for MOH and to withstand the rebound headaches that may follow this. The most important part of treatment is therefore for the patient to recognise and understand the cause of the headaches. A good diet, maintaining hydration, regular exercise and simple relaxation techniques should also be advised.
- Explain to the patient WHY they have developed MOH and WHAT to expect during and after withdrawal.
- A full headache history including details of the original headache pattern prior to the development of MOH (if there was one) will aid in this.
- Advise the patient to stop taking all overused acute headache medication. This should be stopped for at least one month. Withdrawal of ergots, triptans and non-opioid analgesics should be abrupt but it may be necessary to taper opioids and benzodiazepines in view of the risk of more serious withdrawal effects.
- With the agreement of the patient, plan a day to stop the medication altogether - a more effective approach than trying to cut down gradually.
- Medication will need to be discontinued for at least one month, but may need to be discontinued for as long as two months.
- Patients will need to be advised that rebound worsening of the headaches is likely to occur. Considerable willpower is needed to get through this period.
- For some patients, discontinuation and management of withdrawal will mean an inpatient stay.
- A three-week course of ibuprofen can be helpful to break the cycle of MOH. However, if this is not successful on the first attempt it should not be repeated. This is only an option if an anti-inflammatory painkiller is not the cause of the medication headache.
- Patients are likely to experience withdrawal symptoms - particularly an initial worsening of headache, but also some or all of:
- Poor sleep
- Gastrointestinal upset
- These withdrawal symptoms are more likely when withdrawing from opiates. Nausea may be managed with antiemetics.
- Once the MOH has ceased then regular, preventative treatment for headache may be commenced.
- There is some evidence that early introduction of prophylaxis may be more effective than the established method of withdrawing the overused medication until headaches cease.
- The choice of prophylactic medication will depend on the underlying primary headache disorder.
- Prophylactic agents which may be effective for frequent headaches persisting 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.
- A tapered dose of prednisolone has been successfully used to cover the first days of analgesia withdrawal, to counteract withdrawal headaches.
- The European Federation of Neurological Societies (EFNS) recommends inpatient withdrawal therapy for patients overusing opioids, benzodiazepine, or barbiturates.
- EFNS recommends commencing prophylactic drug treatment at the first day of withdrawal therapy or even before.
- The only drug with moderate evidence for prophylactic treatment in chronic migraine and medication overuse is topiramate up to 200 mg.
- Corticosteroids (at least 60 mg prednisone or prednisolone) and amitriptyline (up to 50 mg) are possibly effective in the treatment of withdrawal symptoms.
- Naproxen has been shown to reduce withdrawal symptoms in ergotamine-induced headache.
- Patients who have psychiatric comorbidity or drug dependence may benefit from referral to a psychiatrist or psychologist.
- Patients after withdrawal therapy should be followed up regularly to support their continued headache management and prevent relapse of medication overuse.
- Review patients 4-8 weeks after medication has been withdrawn, to confirm diagnosis and assess progress.
- Confirm the diagnosis of MOH.
- Reinforce use of headache diary.
- Overused medications may be cautiously reintroduced, with clear restrictions on use.
- Reconsideration of prophylaxis for primary headache disorder.
Most patients respond to this therapy with the right support and encouragement. Most respond fairly rapidly to the withdrawal of the offending agent. The rate of success is about 60% at five years. 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.
- Analgesic rebound headaches are frequent, very disabling and lead to a large number of days missed from work.
- Prolonged use of analgesics may cause a variety of side-effects - eg, on the kidneys and liver and, with use of NSAIDs, on the upper gastrointestinal tract.
- 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.
MOH is associated with considerable long-term morbidity and disability.
Headache attributed to substance withdrawal
- This type of headache 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 of withdrawal.
- Common examples of substances causing withdrawal headaches include:
- Opioid-withdrawal headache (this overlaps with MOH, above, but is included here as it also occurs if the opiate is being taken for another use - eg, drug dependency management - rather than for headache).
- Oestrogen-withdrawal headache (includes the combined oral contraceptive pill).
- Management is as for MOH, avoiding acute headache relievers for the withdrawal headache (risking development of MOH) and instead considering prophylaxis where needed.
Further reading and references
Headache assessment; NICE CKS, May 2013 (UK access only)
The International Classification of Headache Disorders; International Headache Society
Gillespie JG., Vasodilatory Properties of Alcohol: Br Med J. Apr 29, 1967; 2(5547): 274–277.
Hagen K, Linde M, Steiner TJ, et al; Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trondelag Health Studies. Pain. 2012 Jan153(1):56-61. doi: 10.1016/j.pain.2011.08.018. Epub 2011 Oct 22.
Headaches in over 12s: diagnosis and management; NICE Clinical Guideline (September 2012)
Smith TR, Stoneman J; Medication overuse headache from antimigraine therapy: clinical features, pathogenesis and management. Drugs. 200464(22):2503-14.
Bongsebandhu-phubhakdi S, Srikiatkhachorn A; Pathophysiology of medication-overuse headache: implications from animal studies. Curr Pain Headache Rep. 2012 Feb16(1):110-5. doi: 10.1007/s11916-011-0234-y.
Taimi C, Navez M, Perrin AM, et al; Headaches caused by abuse of symptomatic anti-migraine and analgesic treatment. Rev Neurol (Paris). 2001 Oct157(10):1221-34.
Evers S, Jensen R; Treatment of medication overuse headache--guideline of the EFNS headache panel. Eur J Neurol. 2011 Sep18(9):1115-21. doi: 10.1111/j.1468-1331.2011.03497.x.
Warner JS; The majority of chronic daily headaches of prolonged duration are rebound headaches: a new look at old data. Headache. 2002 Sep42(8):835-7.
Prusinski A; Drug rebound headaches. Neurol Neurochir Pol. 199932 Suppl 6:31-7.
Lane JC, Arciniegas DB; Post-traumatic Headache. Curr Treat Options Neurol. 2002 Jan4(1):89-104.
Headache - medication-overuse; NICE CKS, November 2012 (UK access only)
Tepper SJ, Tepper DE; Breaking the cycle of medication overuse headache. Cleve Clin J Med. 2010 Apr77(4):236-42. doi: 10.3949/ccjm.77a.09147.
Diagnosis and Management of Migraine, Tension-Type, Cluster and Medication-Overuse Headache; British Association for the Study of Headache (BASH) Guidelines, (2010 - reviewed 2014)
Hagen K, Albretsen C, Vilming ST, et al; Management of medication overuse headache: 1-year randomized multicentre open-label trial. Cephalalgia. 2009 Feb29(2):221-32. doi: 10.1111/j.1468-2982.2008.01711.x. Epub 2008 Sep 24.
Warner JS; Prolonged recovery from rebound headaches. Headache. 2001 Sep41(8):817-22.
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