Drug-Induced Headache: Causes

Pathogenesis (disease development)

In principle, any drug used to treat headache can also induce headache. Neurobiological processes of pain processing and psychological factors seem to play a role. A genetic predisposition seems to be a prerequisite for the development of drug-induced headache. The identified genes are involved in different processes such as development of dependence, serotonergic and dopaminergic transmission, oxidative stress, and CGRP-dependent processes (Calcitonin Gene-Related Peptide).

Etiology (Causes)

Biographic Causes

• Genetic burden (to date, 33 genes have been identified that increase the risk for drug-induced headache)
• Socioeconomic factors – low social status.

Behavioral causes

• Drug use
  • Heroin
• Overweight (BMI ≥ 25, obesity).

Disease-related causes

Mouth, esophagus (food pipe), stomach, and intestines (K00-K67; K90-K93).

• Chronic gastrointestinal symptoms, unspecified.

Musculoskeletal system and connective tissue (M00-M99).

• Chronic musculoskeletal complaints, unspecified.

Psyche – nervous system (F00-F99; G00-G99).

• Depression

Other causes

• HADS score (Hospital Anxiety and Depression Scale; used to screen for mental impairment) > 10.

Medication

• Acetylcholinesterase inhibitors (donezepil, galantamine, rivastigmine).
• Alpha-adrenoreceptor antagonists or alpha-blockers (alfuzosin, tamsulosin).
• Analgesics [analgesic-induced MOH is preceded by an average duration of use of 4.8 years]
  • Non-opioid analgesics (flupirtine).
  • Nonacid analgesics (NSAIDs) (acetylsalicylic acid (ASA), coxibe, diclofenac, ibuprofen, indometacin, meloxicam, naproxen, acetaminophen/paracetamol)
  • Opioids (alfentanil, buprenorphine, dextropoxyphene, diamorphine (heroin) fentanyl, hydromorphone, levomethadone, meptazinol, morphine, nalbuphine, oxycodone, pentazocine, pethidine, piritramide, remifentanil, sufentanil, tilidine, tramadol).
  • Other analgesics
• Antiarrhythmics
  • Adenosine, Ia antiarrhythmics (ajmaline).
  • Ic antiarrhythmics (flecainide, propafenone).
  • Class II antiarrhythmics (esmolol, metoprolol).
  • Class IV antiarrhythmic drugs (diltiazem, verapamil).
• Anthelmintics (albendazole, diethylcarbamazine).
• Antibiotics
  • Aminoglycoside antibiotic (paromomycin).
  • Quinolones (ciprofloxacin)
  • Derivative of rifamycin (rifaximin).
  • Epoxide antibiotics (fosfomycin trometamol).
  • Macrolides (azithromycin, clarithromycin, erythromycin).
  • Nitroimidazoles (metronidazole).
  • Oxazolidinones (linezolid)
  • Rifampicin
  • Sulfone (dapsone)
• Anticholinergics (ipratropium bromide).
• Antidepressants
  • Serotonin antagonists (dolasetron, granisetron, ondansetron, tropisetron).
  • Selective dopamine and norepinephrine reuptake inhibitor (NDRI) – bupropion.
  • Selective serotonin reuptake inhibitors (SSRI = Selective Serotonin Reuptake Inhibitor) – citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine, sertraline.
• Antiepileptic drugs
  • Carboxamide derivatives (eslicarbazepine acetate).
  • Functionalized amino acids (lacosamide).
  • Classical antiepileptic drugs (gabapentin, topiramate).
• Antihistamines (cetirizine, clemastine, dimetindene, ketotifen).
• Antimalarials (artemether, atovaquone, quinine, chloroquine, dihydroartemisinin, lumefantrine, primaquine, proguanil).
• Antimony preparations (pentavalent antimony).
• Antifungals, systemic
  • Azoles (griseofulvin)
  • Triazole derivatives (ketoconazole)
• Antipsychotics (neuroleptics) – melperone, risperidone.
• Antirheumatic drugs, non-steroidal – acetylsalicylic acid (ASA), diclofenac, ibuprofen.
• Antisympathotonic (clonidine, urapidil).
• Antitussive
  • Non-opioid antitussives (levodropropizine, noscapine, pentoxyverine).
• Antivertiginosa (betahistine).
• Anxiolytics (hydroxyzine)
• Α2-agonists (apraclonidine, brimonidine, clonidine).
• Barbiturates (pentobarbital, phenobarbital, primidone, thiopental).
• Benzodiazepine-like substances (buspirone).
• Beta-blockers
  • Nonselective beta-blockers (e.g., carvedilol, pindolol, propranolol, soltalol).
  • Selective beta blockers (e.g., atenolol, acebutolol, betaxolol, bisoprolol, celiprolol, nebivolol, metoprolol).
• Beta-blockers, eye drops – betaxolol, timolol.
• Betamimetics (synonyms: β2-sympathomimetics, also β2-adrenoceptor agonists) – fenoterol, formoterol, hexoprenaline, indaceterol, olodaterol, ritodrine, salbutamol, salmeterol, terbutaline.
• Biologicals (secukinumab).
• Calcium antagonists (amlodipine, diltiazem, felodipine, fendiline, gallopamil, lacidipine, lercanidipine, nitrendipine, nifedipine, nimodipine, nicardipine, isradipine, nisoldipine, nilvadipine, manidipine, verapamil)
• Calcium channel blockers
  • Benzothiazepines (diltiazem)
  • Dihydropyridines (amlodipine, felodipine, isradipine, lercandipine, nicardipine, nilvadipine, nisoldipine, nitrendipine)
  • Phenylalkylamine (verapamil)
• Calcium sensitizer (levosimendan).
• Chelating agents (deferoxamine, deferasirox, deferiprone).
• Chloride channel activator (lubiprostone).
• Cholinergics (carbachol, physostigmine, pilocarpine).
• Direct factor Xa inhibitor – rivaroxaban.
• Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors; gliptins) – saxagliptin, sitagliptin, vildagliptin
• Dopamine agonists (cabergoline, bromocriptine).
• Endothelin receptor antagonists (endothelin receptor antagonists) – ambrisentan, bosentan.
• Ergotamine (ergot alkaloids).
• Glutamate modulator (acamprosate)
• Cardiac glycosides (digoxin, digitoxin, ß-acetyldigoxin, ß-methyldigoxin).
• Hormones
  • ADH analogues – desmopressin
  • Anti-androgens (cyproterone acetate, flutamide).
  • Aromatase inhibitors (anastrozole, testolactone).
  • Progestins (dyhrogesterone)
  • Gonadotropins (FSH. LH)
  • GnRH analogues (buserelin, buderelin acetate, goserelin, goserelin acetate, leuprorelin, leuporelin acetate, nafarelin acetate, triptorelin, triptorelin acetate).
  • GnRH antagonists (abarelix, cetrorelix, degarelix).
  • Contraceptives (estrogen-progestin combination).
  • LHRH agonists (goserelin)
  • LHRH analogues
  • Estrogens
  • Parathyroid hormone analogue (teriparatide)
  • Progesterone receptor antagonist (mifepristone).
  • Prolactin inhibitors (bromocriptine, cabergoline, lisuride, metergoline, quinagolide).
  • Prostaglandin analogues (alprostadil/prostaglandin E).
  • Prostanoids (prostacyclins) – epoprostenol, iloprost, treprostinil.
  • Somatotropic hormone (STH) – growth hormones (somatotropin; growth hormone (GH)).
• Immunosuppressants (azathioprine, ciclosporin (cyclosporin A), methotrexate (MTX))
• Immunotherapeutics (fingolimod, mitoxantrone, natalizumab).
• Intestinal anti-inflammatory (sulfasalcin).
• Local carbonic anhydrase inhibitors (brinzolamide, dorzolamide).
• Lipid-lowering agents
  • Cholesterol absorption inhibitor – ezetimibe
  • HMG-CoA reductase inhibitors (statins) – atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
• MAO inhibitors (tranylcypromine).
• Monoclonal antibodies – pertuzumab, trastuzumab.
• MTOR inhibitors (everolimus, temsirolimus).
• Multi-tyrosine kinase inhibitor (vandetanib).
• Mucolytics (acetylcysteine (ACC), N-acetylcysteine (NAC); N-acetyl-L-cysteine).
• Muscle relaxants (baclofen, tizanidine).
• Ergot alkaloids (ergotamines)
• Neurokinin antagonists (aprepitant, fosaprepitant).
• Nicotinic antagonist (varenicline).
• N-methyl-D-aspartate recptor antagonist (Memantine).
• Nitrates (glycerol nitrate, glycerol trinitrate, isosorbide dinitrate (ISDN), isosorbide 5-mononitrate, molsidomine, nitroglycerin, nitroprusside sodium).
• Opioid antagonists (loperamide, nalmefene, naltrexone).
• Parasympathomimetics
  • Indirect parasympathomimetics (cholinesterase inhibitors): alkylphosphates, distigmine, donepezil, galantamine, neostigmine, physostigmine, pyridostigmine, rivastigmine, tacrine
• Phosphodiesterase-4 inhibitor/PDE4 inhibitor (apremilast).
• Phosphodiesterase-5 inhibitors/PDE5 inhibitors (sildenafil, tadalafil, vardenafil).
• Proton pump inhibitors (proton pump inhibitors, PPI; acid blockers) – esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.
• Psychotropic substances such as modafinil.
• Retinoids (acitretin, alitretinoin)
• Rheologics (pentoxifylline)
• Selective α1-adrenoceptor antagonists (selective alpha-1-adrenoceptor antagonists; α1-blockers) – alfuzosin, doxazosin, tamsulosin, terazosin.
• Sinus node inhibitor (ivabradine).
• Spasmolytics (tolterodine, trospium chloride).
• Stronitum salt (strontium ranelate).
• Sympathomimetics
  • Α-sympathomimetics (oxymetazoline, xylometazoline).
• Tranquilizers
  • Benzodiazepines (diazepam, lorazepam, midazolam, temazepam).
• Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) [triptan-related MOH is preceded by an average duration of use of 1.7 years].
• Tyrosine kinase inhibitors (vandetanib).
• Uricosurics (benzbromarone, probenecid).
• Vasoactive substances – alprostadil (prostaglandin E), dihydralazine, vasopressin, diazoxide.
• Antivirals
  • Nucleos(t)idic polymerase (NS5B) inhibitors (sofosbuvir).
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) – didanosine, efavirenz, nevirapine, rilpivirine.
  • NS5A inhibitors (daclatasvir, ledipasvir,
  • Nucleoside analogues (abacavir, aciclovir, brivudine, famciclovir, foscarnet, ganciclovir, ribavirin, telbivudine, valaciclovir.
  • Nucleotide analogues (adefovir, tenofovir).
  • Nucleoside reverse transcriptase inhibitors (NRTI) – entecavir, lamivudine, stavudine, zidovudine.
  • Protease inhibitors (PI; protease inhibitors) – atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir.
• Bismuth (bismuth nitrate, bismuth subcitrate, bismuth subsalicylate).
• Cytokines (glatiramer acetate, interferon ß-1a, interferon ß-1b).
• Cytoreductive drugs (anagrelide).
• Cytostatic drugs (methotrexate (MTX))