In part 1 of this post, pain and psychiatric issues often travel together. Chronic headache pain can lead to long-lasting psychological distress, and depression and anxiety increase the perception of both acute and chronic pain. They are intimately connected. This post will continue the discussion about psychiatric co-morbidities and headache, focusing on psychopharmacology.
What is the mechanism of action? Serotonin (5-hydroxytryptophan (5-HT)) is a neurotransmitter that plays a major role in both nociception (pain perception or sensation) and mood regulation. It can both decrease and increase the magnitude of pain following noxious stimulation. Selective serotonin reuptake inhibitors (SSRI) medications work by inhibiting the reuptake of serotonin into the presynaptic neuron after it has been released, affecting the duration and intensity of the serotonin communication, pain perception and mood. Serotonin-norepinephrine reuptake inhibitor (SNRI) medications work to balance serotonin, norepinephrine, and other neurotransmitters to inhibit descending pain pathways and effect central pain processing. The goal is to manage pain and to balance the noradrenergic system activity. So both SSRIs and SNRIs are useful for both mood regulation and pain reduction, though it seems that SNRIs are more effective with regard to overall pain reduction.
Typical psychopharmacologic agents used in patients with headache/migraine:
Tricyclic Antidepressants (TCAs) are commonly used as preventive medications for migraine. This group of medications is one of the original antidepressants, though the therapeutic mood effects are seen at doses much higher than are used for headache prevention. Pediatric dosing of amitriptyline are typically no more than 50mg daily, while generally higher dosing is used for mood (100-150mg/day). This group of medications is not the first choice for an antidepressant in pediatrics related to the potent anticholinergic and anti-arrhythmogenic effects, plus the side effects of sedation and mental clouding.
Selective Serotonin Reuptake Inhibitors (SSRIs) can be the most beneficial medications for the treatment of psychiatric co-morbidities, but have minimal direct pharmacological benefit on pain. There are a number of appropriate and well-tolerated medications in this group, with FDA approval for pediatrics. Fluoxetine (ages 7 and up) has a long half life and can be quite useful for those who have trouble taking a daily medication, and is approved for depression. Sertraline (ages 6 and up) is approved and quite useful for obsessive compulsive disorder (OCD) and social and generalized anxiety. Escitalopram (ages 12 and up) is approved for OCD and depression. Citalopram can be used for older teens for depression. Paroxetine has many side effects, difficult withdrawal effects, contraindicated during pregnancy and not generally recommended. Vortioxetine is a newer SSRI, effective for anxiety and depression, but also may produce positive cognitive effects, often a benefit for those with chronic headache pain.
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are a group of medications used for major depressive disorder, generalized anxiety, panic disorder and social anxiety, and for chronic pain conditions, such as fibromyalgia. Duloxetine is approved for ages 7 and up for generalized anxiety, but can be difficult with drug interactions in the setting of polypharmacy. Venlafaxine is approved for teens for depression and anxiety, and for chronic pain. Patients need to have excellent compliance, and abrupt discontinuation or even missing doses can lead to withdrawal symptoms. Venlafaxine and duloxetine are effective for mood at the same dosages that are useful for treating pain.
Atypical Antidepressants are other psychopharmaceuticals used for mood, headache and commonly insomnia. Mirtazapine (Remeron) is a tetracyclic antidepressant, an alpha-2 antagonist. It improves gut motility, abdominal pain and nausea, reduces anxiety and may benefit chronic pain. Common side effects are weight gain and sedation, often given for sleep issues. Trazodone, a serotonin antagonist reuptake inhibitor (SARI) is a weak antidepressant often used for the treatment of insomnia due to its sedative effect. It is non-addictive and has few drug interaction considerations.
A few tips about psychopharmacology
It is not uncommon for patients and families to be wary about starting a medication for mood. A way to explain it to patients and families is to state that the neural pathways for pain and headache and those for depression and anxiety exist right next to each other in the nervous system. If you are able to treat one type of pathway effectively, it is likely that the other will also improve. If you reduce anxiety, chronic daily headache may improve; if migraine frequency reduces, depressed mood may lighten.
It is also not uncommon for the patient to report not feeling any better after 1-2 months on a medication. However, observational input from the family is invaluable in assessing effect. Often the parents report the teen is “much easier to live with” since starting the medication. The emphasis can be more on behavioral changes rather than mood changes. Do they call their friends more? Eating in the cafeteria at school vs the guidance office? Are there less headache complaints?
Cardinal rule for dosing is to start low and go slow, to allow time for the medication to take effect and to avoid side effects. The goal dose is the lowest dose to give adequate therapeutic effect with minimal side effects.
You also want to have an adequate clinical trial of a medication before switching to another one. That means staying on a medication, slowing increasing the dose, until it either achieves the desired benefit or side effects are unacceptable. Only then can you say there was an adequate clinical trial and can try another medication. Not surprisingly, there may be some pushback from families, hoping for quick results, but resist if possible for best practice.
Side effects on starting an SSRI/SNRI: it is frequent for patients to experience nausea/GI distress and/or activation (increased anxiety), for several weeks after starting the medication, which should resolve on its own. A black-box warning regarding an increase in suicidal thoughts is attached to all antidepressants, and needs to be discussed together with parent and child. This brings the concern into the open, lets all concerned know what side effects need to be reported and what to watch out for. Despite the BBW, epidemiologic studies consistently show a decrease in completed suicides for individuals who take antidepressants versus those who have depression and are unmedicated and untreated.
Strongly encourage psychotherapy or counseling in addition to a psychotropic medication. It can be a precondition to starting a medication, and the combination gives the best results.
You may need to refer to a child psychiatrist/MHNP if the family or you are uncomfortable prescribing these medications, or if you have tried 1-2 medications and have not had success. They can be safely prescribed but the patients do need close follow up and check-ins.
Be aware of drug interactions, since combining SSRI and SNRI medications with other serotonergic and noradrenergic medications may be unsafe. This is an active concern and a number of different headache and migraine medications do interact.
Serotonin syndrome: This most often occurs when two or more medications that raise the level of serotonin are combined. Several classes of medications can cause high levels of serotonin to accumulate. It is important to recognize this risk and combine medications cautiously. Usually low dosing of medications is protective but combining can be risky.
Signs and symptoms of serotonin syndrome include anxiety, agitation, high fever, sweating, confusion, tremors, restlessness, a lack of coordination, blood pressure instability, tachycardia, and seizures. Patients need to seek immediate medical attention if they have any of these signs or symptoms.
Suspect medications used in the headache/migraine world include: amitriptyline or any TCA, SSRIs, SNRIs, triptans for aborting migraine, MAOIs, buspirone, trazodone, opioids (fentanyl, tramadol, meperidine), metoclopramide, prochlorperazine, and ondansetron.
Other medications and products include dextromethorphan (cough medicine), St John’s Wort and ginseng supplements, LSD or cocaine.
Example: A typical patient with migraine might be on a low dose of amitriptyline 10-20mg daily for migraine prevention, low dose sertraline 50mg daily for anxiety. Once per week they might use sumatriptan 100mg + naproxen + ondansetron 4mg for a migraine episode. This may very well be a safe combination, but not so safe if that patient has an uptick in migraine and is taking her rescue meds several times/week, or needs to go to the ED and receives metoclopramide and prochlorperizine IV. It is an infrequent occurrence but certainly clinically significant.
So care needs to be taken in prescribing medications for mood in patients with headache and migraine. However, judicious use of these medications can have a positive effect on both anxiety and depressive symptoms and frequency of migraine.