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14 Articles in Volume 15, Issue #6
Antihistamine for G-CSF–Induced Bone Pain
Book Review: Advanced Headache Therapy
Brain Drain: Lymphatic Drainage System Discovered in the Brain
Case History of Chronic Migraine: Update 2015 Part 2
Disturbed Sleep: Causes and Treatments
Is Topical Ketamine Ready For Prime Time?
Letters to the Editor: Central Sensitization, Microglia Modulators, Supplements
New App Helps Interpret Urine Drug Test Results
Osteoarthritis Update: 2015
Pain Catastrophizing: What Clinicians Need to Know
PPM Editorial Board: Tips for Treating Osteoarthritis
Practical Overview of Osteoarthritis
Status Report on Role of Stimulants in Chronic Pain Management
Treatment of Osteoarthritis

Case History of Chronic Migraine: Update 2015 Part 2

A step-by-step guide to the diagnosis and treatment of patient with refractory complex headache.

This is the second part of our series titled “Case History of Chronic Migraine.” Our previous article followed the diagnosis of a complex patient with the pseudonym “Heather,” who was initially seen when she was 24 years of age.1 To recap, Heather had moderate chronic daily headache, with migraine 6 times per month. She also suffered from anxiety and depression (the mild end of the bipolar spectrum), had irritable bowel syndrome (IBS; primarily diarrhea), and neck pain.

History: Heather was prescribed topiramate (Topamax, others) as a preventive (starting dose, 25 mg at night, increasing to 50 mg) as well as the following abortive medications: sumatriptan (Imitrex, others), naproxen (Naprosyn, Aleve, others), ondansentron (Zofran, others) (for nausea), and occasional hydrocodone-acetaminophen (Vicodin, Norco, others). Heather reported that the topiramate helped her headaches but possibly exacerbated her depression and caused mild memory disturbances—50 mg of topiramate was the most she could tolerate because she experienced memory disturbances at a higher dose. Sumatriptan was only mildly helpful, but over-the-counter naproxen was useful and ondansetron relieved her nausea. She was exercising 20 minutes daily. We added quetiapine (Seroquel, others), slowly increasing to 50 mg at night, and substituted rizatriptan (Maxalt, others) for sumatriptan. Quetiapine helped her moods, but she could not tolerate more than 25 mg qhs. Rizatriptan was not very helpful, so we prescribed zolmitriptan (Zomig) nasal spray. We also encouraged Heather to see a psychotherapist.

Six Months Later

Heather returned 6 months later at age 25. At this point, her menstrual migraines were severe, but zolmitriptan nasal spray (with naproxen) helped at least most of the time. Heather was cycling in and out of depression, alternating with hypomania. She was chronically irritable and somewhat angry, which was interfering with relationships. Heather had had a rough go of it. She had a deadbeat boyfriend, Eric, who somehow neglected to inform her of his wife and two kids. She also had to deal with an alcoholic, abusive mother, although her 2 sisters were fairly supportive. Heather was not ruminating about suicide but occasionally wished she were dead. She had no active suicidal plans. Heather loved her job as a hairdresser, finding solace in the salon, but she bickered with Alan, a new stylist who had been stealing some clients. So, along with headaches and neck pain, Heather was angry and depressed. She found herself looking at every young, married woman with envy.

Q: What Treatment Options Should Be Considered?

Of course, I had a long talk with Heather about psychotherapy. She was reluctant to go, due to money, time, and stigma. I suggested a “sliding scale” therapist or a publicly-funded therapy organization and tried to “de-stigmatize” going to therapy. I often say, ”If it was up to me, everybody in our country would see a therapist.” I have found that it may take many years of pushing and suggesting to convince reluctant patients to seek therapy.

Heather’s headaches were somewhat controlled on topiramate (50 mg qhs) and quetiapine (25 mg), with the following abortives: zolmitriptan nasal spray, naproxen, ondansetron, and occasional hydrocodone. Her moods were more of an issue at this point. Thus, I searched for medication options that could help Heather’s (mild) bipolar moods as well as her headaches.

Possibilities included: lamotrigine (Lamictal, others), oxcarbazepine (Trileptal, Oxtellar XR, others), valproate sodium (Depokene, others), another atypical antipsychotic (such as aripiprazole [Abilify, others]), or lithium (Lithobid, others). I wanted to avoid antidepressants, although some patients with bipolar disorder who are on an adequate mood stabilizer may tolerate antidepressants.

Lamotrigine has minimal side effects (rarely does lamotrigine cause tiredness or weight gain). Oxcarbazepine is a mild (and often overlooked) mood stabilizer that is available in a long-acting form (Oxtellar XR). Although related to carbamazepine (Tegretol, others), oxcarbazepine has markedly fewer adverse effects. Valproate sodium can help stabilize moods as well as headaches, but it tends to cause weight gain and fatigue and has greatly increased risks if the patient becomes pregnant. Adding aripiprazole is an option because it does not tend to cause the weight gain and fatigue that quetiapine may produce. Lithium, in low doses, often is very effective. Lithium is probably underused in the “mild” bipolar population. However, with lithium, particularly in higher doses, weight gain, fatigue, and hypothyroidism somewhat limit its use.

We decide to proceed with lamotrigine—starting at 25 mg and, after 10 days, increasing to 50 mg (Table 1). The risk with lamotrigine is the development of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS is an immunologically based form of erythema multiforme—SJS and TEN are probably manifestations of the same disease process, with SJS being milder and TEN more severe. SJS usually involves the mucous membranes and skin. With SJS, the male-to-female ratio is 2:1 in patients with a genetic predisposition. Infectious SJS begins with nonspecific upper respiratory infection symptoms, with a sudden onset of skin lesions. Drug causes are varied—from oxicam-containing NSAIDs to sulfa drugs to anticonvulsants. The more severe TEN implies more skin area involvement than is seen with SJS.

These serious systemic and skin reactions only are observed in approximately 1 in 2,500 to 3,000 patients taking lamotrigine. However, a “regular” drug rash often is seen (at least 10% of patients). TEN carries a mortality rate of 30% to 50%, whereas SJS has a mortality rate of 1% to 5%. With any rash, I stop lamotrigine (or any drug new to the patient).

Lamotrigine Follow-up

Three weeks after we initiated the lamotrigine, Heather called and reported no rash but also no improvement in moods. We increased the lamotrigine to 75 mg for 10 days, then 100 mg per day. I instructed her to discontinue lamotrigine at the first sign of a rash. Six weeks later, Heather came for a visit, and stated that her mood is significantly improved. She had been working out her differences with Alan at work. She had been less irritated and depressed, and her feeling of “mind racing” had lessened. Mind racing may be a result of several conditions, particularly anxiety vs. mania (or hypomania). It is important to inquire as to the “quality” of the rumination and racing. If it is constant worry, anxiety is the likely cause. With hypomania, it may simply be random thoughts racing through the brain and not necessarily connected to worry or anxiety.

Heather’s headaches were more severe with the lamotrigine. She was taking 50 mg of topiramate as a headache preventive, 25 mg of quetiapine for moods, sleep, headache, and 100 mg of lamotrigine for moods (although lamotrigine also may alleviate headaches in some patients). It is possible that the lamotrigine had exacerbated Heather’s headaches. This is a common situation with comorbid conditions for which we are juggling various medications: a drug may help one condition but worsen another. In this case, Heather’s moods were better on lamotrigine but her headaches were more severe.

Q: What Medication Changes Should Be Considered?

We could have considered adding another medication for Heather’s headaches or decreasing the dose of lamotrigine. I usually choose to decrease the dosage of medication that is causing significant side effects rather than add more medication.

There are exceptions to this as, for instance, when a patient finally finds a drug that “is the only one that has ever been helpful.” With Heather, we chose to reduce the dose of lamotrigine from 100 mg to 75 mg per day. At that point, we considered that if the lowered dose did not help her headaches, further dose reductions could be necessary. However, because lamotrigine had been very helpful for Heather’s moods, we wanted to try to work with the drug.

When Heather was 26 years old, her regimen consisted of lamotrigine (75 mg), topiramate (50 mg), and quetiapine (25 mg). Due to side effects, she could not tolerate high doses of any of these medications. Her moods and irritability had improved on lamotrigine, but her headaches still were not well controlled. To address that, Heather received onabotulinumtoxinA (Botox) injections, which are FDA-approved for the treatment of chronic migraine.

In clinical trials, onabotulinumtoxinA had a 55% to 65% chance of producing reasonable improvement in headaches for 2 to 3 months. The official FDA-indicated dose is 155 units, via 31 injections; however, some patients require 100 to 200 units. Repeated injections over time (every 3 months for 1 year) may have a beneficial, cumulative effect. Onabotulinumtoxin A probably works at the neuronal level via anti-inflammatory mechanisms. Botulinum may be an effective inhibitor of the inflammatory compound calcitonin gene-related peptide, which is crucial in the propogation of chronic migraine pain.

Heather received 16 units in the right and left temple and forehead (totaling 48 units; this is considered a low dose). For 3 months after onabotulinumtoxinA injections, Heather’s headaches were 40% improved. We gave her a second series of injections at the low dose (48 units), which helped her for an additional 2.5 months. Her moods were improved and her medication regimen remained the same.

Heather had started seeing a psychotherapist to deal with many issues. She had stopped seeing her boyfriend and was learning to set limits with her difficult, alcoholic mom. Heather was doing yoga and exercising and was much more positive about her future. Massage had not been very helpful. She tried acupuncture, which can be beneficial, but her results were short-lived. We planned to consider food sensitivity testing due to her migraines and IBS.

One Year Later

When we say Heather at age 27, her headaches had increased to a daily, moderate migraine. Her moods remained stable with lamotrigine and quetiapine. We increased the topiramate, but 50 mg was the maximum she could tolerate. We were not sure if the topiramate was still helpful. This is commonly seen with preventive medications because they may lose effectiveness over time. The only way to evaluate if the medication is still somewhat effective is to decrease or discontinue it. Many patients can tolerate only 25 or 50 mg of topiramate. Heather could not afford onabotulinumtoxinA injections because her financial situation had taken a turn for the worse with the hair salon closing. Heather also was experiencing widespread pain, with tenderness in many muscle groups. She saw a rheumatologist and was diagnosed with fibromyalgia.

Heather now had 3 commonly linked “central sensitization” syndromes: migraine, IBS, and fibromyalgia. It is common for central sensitization syndromes to be grouped together. The headaches and fibromyalgia pain greatly affected her quality of life. Aside from medication, we encouraged Heather to continue with exercise, yoga, and to take her vitamin D, which may help depression and headaches, among other conditions. She tried acupuncture, but the relief lasted only 2 days.

Q: What Other Medication Options Should Be Considered?

There were a number of medications choices at this point, including:

  • adding a muscle relaxant
  • trying a short course of a low-dose steroid, which could exacerbate her bipolar disorder and would only help for a brief period
  • adding an antidepressant used for pain, such as a tricyclic antidepressant, duloxetine (Cymbalta, others), etc. She was on mood stabilizers, and I thought she might be able to tolerate low doses of an antidepressant without becoming hypomanic
  • trying opioids (not a great choice at her young age—it would be a last resort),

Heather had cycled back into a depression, primarily due to losing her job. She was lonely and under financial stress. I encouraged her to get back into psychotherapy, but Heather was reluctant to do so. Therapy was crucial in Heather’s situation; she had somewhat recreated her childhood abuse by being with an abusive man. Unfortunately, recreating childhood pathology as an adult is all too common.

With the onset of depression, Heather was no longer exercising and was overeating. She was back together with Eric, her lying, abusive boyfriend. Unfortunately, it is common for women to go back to an abusive relationship. Childhood pathological relationships (Heather has a very difficult mother) often are played out and repeated in adulthood, making psychotherapy important. Unfortunately, the reality is that most people with difficult childhoods do not receive the long-term therapy that is necessary to work through the attendant issues.

Because of her chronic pain (fibromyalgia, headache) and depression, we added a low dose (30 mg) of duloxetine. Heather found it too stimulating and, although she was not hypomanic, she could not sleep. We added a low dose (10 mg) of nortriptyline at night. Nortiptyline (Pamelor, others) is a (milder) metabolite of amitriptyline, with less sedation and anticholinergic side effects. Tricyclics such as these may be helpful for sleep, headache, fibromyalgia, and IBS with diarrhea. Heather had all of these conditions.

To minimize medication, we attempted to find drugs that treat several comorbidities simultaneously. Heather tolerated the nortriptyline well, with minimal sedation and dry mouth. We realized that due to her bipolar disorder, Heather might not be able to tolerate more than 25 mg of nortriptyline.

Heather was seen again 6 months later, at age 28. She reported improvements in mood and headache. She was working at a new salon, had left Eric, and was now in group therapy. She was exercising and continued to practice yoga.

Role of Genetic Resilience

Despite her past abuse, Heather had shown some resilience. There is a major genetic component to resilience, the length of the serotonin transporter gene. In the face of childhood abuse (eg, physical, sexual, emotional), it is predictable how an individual will function in adulthood by examining the shape of the serotonin gene. Two long arms to the gene are good, two short arms usually leads to a dysfunctional adult (with severe personality disorder pathology). Nature and nurture also come into play. If a person has two short arms (bad) but a very good, non-abusive childhood, they usually will be ok. If one has two long arms to the gene (good) they usually are fairly functional and do well as adults—even in the face of abuse.

In a prospective monkey study, Bennet et al took two groups of very young monkeys with one group having the short-armed gene, and the other having the long-armed gene.2 They then gave those monkeys an “abusive” childhood by having them raised not by mom but by other adolescent monkeys. Monkeys with the long arms to the gene did fairly well and showed normal functioning as adult monkeys. Those with short arms to the gene were dysfunctional, sitting in the corner, being asocial, biting, etc.

In this case, Heather had significant abuse as a child, but did not have a personality disorder and showed resilience and insight, indicating that she probably has two long arms to the gene. Unfortunately, abuse as a child influences the developing neurotransmitter pathways and often results in moderate or severe psychopathology, as well as chronic pain.

Last updated on: June 12, 2017
Continue Reading:
Alternative Medicine in Chronic Migraine 2014: What Clinicians Need to Know
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