Patients with chronic pain, including those with migraines, have been shown to benefit from psychological interventions. There is a wide variety of such treatments – biofeedback, meditation, acceptance-commitment, dialectical behavioral, and other types of therapy. These treatments improve the frequency and the severity of migraine attacks, as well as other types of pain which in turn leads to improved mood, sleep, and physical function. What we don’t know is which treatment is the most effective.

In a study just published in Pain, the journal of the International Association for the Study of Pain, researchers compared cognitive therapy (CT), mindfulness-based stress reduction, and behavioral therapy (BT) with treatment as usual (TAU).

This was a randomized controlled study of 521 patients with chronic low back pain. Each person underwent eight weekly individual treatment sessions. The primary outcome measure was pain interference, which assessed interference with general functioning due to pain. Secondary outcome measures were pain intensity, depressive symptoms, physical function, and sleep disturbance.

All three interventions produced similar improvement on all five outcome measures. And on all five measures, all three interventions produced better results than TAU. The difference with TAU was noted after the 6th treatment session and this improvement was still present six months later.

These findings are not surprising. The authors mentioned that three recent comparative outcome studies with fairly large samples also found similar efficacy of different psychosocial approaches. One study compared cognitive-behavioral therapy (CBT) with MBSR with usual care. Another compared CBT with pain education with usual care, And the third one compared CBT with emotional awareness and expression therapy with pain education.

The authors discussed the possibility that all psychological interventions produce similar results. However, it is more likely that the individual psychosocial characteristics of each patient is what determines the response. So it is possible that different patients may respond to different treatments and some will not respond to any. The researchers are planning to look at various patient characteristics that they’ve collected to see if any were predictive of a positive response to various treatments.

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Cluster headaches are considered to cause the worst pain imaginable. We have a variety of medications – both acute and preventive – that help relieve the pain of cluster headaches. For some, none of these treatments work and we do need additional medications. Ketamine could be one such drug.

Ketamine has been in use for over 50 years. Its main indication is intravenous anesthesia. Recently, the FDA approved ketamine nasal spray for depression. It is also being widely used intravenously and by mouth for depression, chronic pain, and migraine headaches. A group of researchers at the Danish Headache Center in Glostrup, Denmark tested the efficacy of ketamine nasal spray for the acute treatment of cluster headaches.

Anja Petersen and her colleagues selected 20 cluster patients whose attacks did not respond sufficiently well to sumatriptan or oxygen – the two most effective acute therapies for cluster headaches. Patients treated a single cluster attack with 15 mg of intranasal ketamine. They could repeat this dose every 6 minutes, for up to 5 times. Four patients took another medication after 15 minutes. Of the 16 remaining ones, 11 had a drop in pain severity by an average of four points, to four or lower on a one to 10 scale. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No patient had any serious side effects from ketamine during the trial.

Ketamine nasal spray that is approved for depression is a more potent version of ketamine called esketamine (Spravato). It is a patented and branded product and it is very expensive. Ketamine itself, however, is a cheap drug. A compounding pharmacy can prepare a nasal spray for as little as $60 for a month supply. Most insurers do not cover compounded drugs, so you’d have to pay for it.

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I’ve been prescribing medical marijuana (MM) since 2016 when it became legal in New York. We still lack controlled clinical trials of MM for the treatment of migraines. Most of my patients who find MM useful report that it relieves nausea or anxiety, helps them go to sleep and sometimes relieves pain. Others find that taking it daily prevents migraines. CBD alone can be also helpful, but most patients need a combination of CBD and THC as well in order to obtain a therapeutic effect.

Like any other drug, MM can have side effects. One of them is cognitive impairment. A study just published in the New England Journal of Medicine describes the effect of recreational marijuana legalization in Canada on injuries to car drivers. The researchers studied drivers treated after a motor vehicle collision in four British Columbia trauma centers from 2013 through 2022. They discovered that after legalization, the number of moderately injured drivers with a THC level above the legal limit doubled. The largest increase was seen in older and male drivers.

This is relevant to the users of MM as well. From now on, I will caution my patients not to drive after taking any THC-containing products. Just like with alcohol, you don’t need to have a blood level above the legal limit to slow your reflexes.

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Worsening of headaches in children is one of many deleterious effects of the pandemic and measures to control it. A survey of children in a headache clinic at the Children’s National Hospital in Washington DC by Dr. DiSabella and his colleagues showed that 46% of children had worsening of their migraine headaches during the pandemic.

They also reported much higher rates of anxiety, depression, and stress. Two-thirds of children reported that they exercised less. This could be one of the contributing factors since exercise has been shown to reduce the frequency and the severity of headaches.

What this survey did not explore is the effect of family stress and the presence of child abuse. Reports of child abuse have actually declined during the pandemic because most of these reports come from teachers. Chronic migraines and chronic pain are much more common in patients with a history of being physically, emotionally, or physically abused. PTSD from other causes has a similar predisposing effect and many children and adults have been traumatized by the pandemic.

Some children (as well as adults) report improvement of their headaches during the pandemic. My patients tell me that because they do not have to commute, they have more time to exercise, meditate, cook healthy meals, and get more sleep. I see this in a small proportion of patients. A larger group did worse with additional factors being worsening of headaches due to COVID and in a very small number, COVID vaccines.

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There is a new and surprising connection between postoperative nausea and vomiting (PONV) and migraines. It offers a very effective treatment that will relieve the suffering of tens of thousands of patients.

Many migraine patients tell me that they develop a severe migraine following surgery. Possible reasons include the stress of the operation, fasting before surgery, the effect of anesthetic drugs, pain medicines given after surgery, an awkward head position, and caffeine withdrawal. But some patients report severe nausea and vomiting that occurs without a headache.

PONV affects about 30% of all patients undergoing surgery under general anesthesia. Some patients develop intractable vomiting that does not respond to typical nausea medications even though there are more than a dozen such medications. This often requires hospital admission when surgery is done in an ambulatory (outpatient) setting. Admissions for PONV are more common than for surgical or cardiovascular complications. Intractable PONV can cause opening of the sutured wound, aspiration pneumonia, bleeding, and other complications.

It appears that patients who suffer from migraines or have had migraines in the past are more prone to develop intractable PONV. I learned about this last month while participating in a headache conference in Zurich. Dr. Leander Sakellaris, a Swiss anesthesiologist and pain specialist, told me about his Masters degree thesis on this topic. He allowed me to share its full text – MasterThesis-PONV.

His thesis describes ways to reduce the risk of PONV. If possible, ask for surgery to be done under regional and not general anesthesia. Ask if total intravenous anesthesia is an option. Avoid nitrous oxide, etomidate, thiopental and after surgery, opioid drugs. Good hydration during the operation is also helpful. I would also add a request for an intravenous (IV) infusion of magnesium. IV magnesium is a standard procedure after open heart surgery because it prevents irregular heart beats (arrhythmias), but it is not given after other types of surgery. Magnesium is depleted by physical and emotional stress and surgery induces a major stress response.

The most fascinating part of Dr. Sakellaris’ thesis is the description of eight patients he has encountered in his practice. They all developed intractable PONV but did not have a headache. However, they all had a history of migraines or headaches suggestive of migraines. After they failed to respond to the usual nausea medications, Dr. Skellaris gave them either an injection of sumatriptan or intranasal zolmitriptan. They all had a prompt and dramatic relief of their vomiting and were able to go home.

This should not be very surprising because abdominal migraines and cyclic vomiting syndrome, conditions without a headache that are considered to be migraine variants, also respond to triptans.

Dr. Sakellaris made an important discovery that deserves to be widely disseminated. Forty million Americans suffer from migraines, millions of Americans undergo surgery under general anesthesia, of whom 30% suffer from PONV. It is very likely that many thousands of patients with PONV who do not respond to standard therapies could be helped by triptans.

If you suffer from migraines or have had them in the past and are having an operation, you may want to bring with you an injection of sumatriptan. Outpatient surgery clinics may not have it while hospitals may take a long time to get it to you. I would discuss this with your surgeon and the anesthesiologist before surgery.

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Magnetic stimulation with a single pulse has been shown to be effective in aborting a migraine attack with the eNeura Spring TMS device.
Repetitive magnetic stimulation (rTMS) of the brain has been shown to relieve depression. A pilot study just published in the journal Brain Stimulation examined the effectiveness of repetitive magnetic brain stimulation for the prevention of migraine attacks.

German and Moldovan researchers conducted a double-blind, randomized controlled study in patients with episodic migraine. They compared real and sham stimulation in 60 patients. Participants received six treatment sessions over two weeks. The primary outcome measure was the number of patients whose migraine days dropped by 50% or more. The frequency and intensity of migraine attacks over a 12-week period were also assessed.

Real rTMS produced at least a 50% reduction in migraine days in 42%. This number was 26% in the sham group. The mean migraine days per month decreased from 7.6 to 4.3 days in the real rTMS group and from 6.2 to 4.3 days in the sham rTMS group. The reduction in migraine attack frequency was also higher in the real rTMS compared to the sham group. No serious adverse events were observed.

There are a couple of practical issues with this treatment approach. The rTMS equipment is already being used for depression, which in theory should make it easy to adapt for migraines. However, this treatment is time-consuming and expensive and is not likely to be covered by insurance. Another problem, which we also encountered in our study of transcranial direct current stimulation, is that there are many variables to consider. Placement of electrodes, the strength of stimulation, frequency, and duration of treatments are some of these variables.

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Ketamine was approved by the FDA in 1970 and was originally used for the induction of anesthesia. It has been shown to relieve depression and is also widely used to treat pain. For depression, it is approved by the FDA in a nasal spray form. For severe pain, it is often given intravenously. Oral ketamine is probably the least effective.

In a recent study, Australian researchers compared the pain-relieving effect of oral and sublingual ketamine in 16 patients. The study was double-blind. Sublingual administration of ketamine resulted in a faster onset of pain relief – 7 minutes with sublingual and 13 with oral. Side effects were also more common with the sublingual route. In all other measures, sublingual and oral administration produced similar pain-relieving effects.

Oral and sublingual ketamine are not available at regular pharmacies. It is, however, easily made up by compounding pharmacies. The sublingual ketamine is available as a lozenge which is also called troche. I usually prescribe ketamine infusions or troches only after a wide variety of other treatments do not provide relief.

Ketamine is a controlled drug with a potential for misuse. It can also cause psychiatric side effects such as hallucinations, disinhibition, delusional thinking, and depression.

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With Swiss colleagues Drs. Caterina Podella, Livia Granata, and Reto Agosti at the headache conference held on November 4, 2021, in Zürich.
Dr. Podella presented a very comprehensive approach to the treatment of migraine headaches. Dr. Granata expertly covered the topic of cluster headaches. I spoke about the challenges of treating refractory migraine headaches and Dr. Agosti provided a lively and insightful discussion of all these topics.

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The influence of estrogen on migraines in women is well established – women often experience migraines before or during menstruation and ovulation and their migraines usually subside during pregnancy and menopause.

According to a new study published this month by Dutch researchers, men who suffer from migraines often have a deficiency of male hormones.

Gisela Terwindt and her collaborators evaluated a possible deficiency of androgens or male hormones in 534 men with migraine and 437 men with cluster headaches. These men were compared to 152 healthy controls. Two validated questionnaires were used to measure androgen deficiency scores. The researchers controlled for age, weight (BMI), smoking, and lifetime depression. They also measured four sexual symptoms (beard growth, morning erections, libido, and sexual potency). These four symptoms have been shown to differentiate between hormonal deficiency from anxiety and depression. They did not perform blood tests to measure hormone levels.

Patients reported more severe symptoms of clinical androgen deficiency compared with controls. Both patient groups were more likely to suffer from any of the specific sexual symptoms compared to controls (18% migraine, 21% cluster headache, 7% controls).

The findings in men with cluster headaches are not surprising. Prior reports have documented low testosterone levels in this population. A small study by Dr. Mark Stillman suggested that those cluster patients who have low testosterone levels could benefit from hormone replacement therapy.

There are also reports of low testosterone levels in men with chronic migraines but the connection is less established.

This study may prompt me to pay more attention to sexual dysfunction in men with chronic migraines. I may also start checking testosterone levels in such patients.

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The placebo effect is a bane of clinical trials. It is, however, a great tool in clinical practice. It is unethical to prescribe an actual placebo but there is no reason not to try to enhance the placebo effect when prescribing any treatment, pharmacological or non-drug.

A new and unique study that was just published in Pain, a journal of the International Association for the Study of Pain, suggests that looking at others who respond to treatment makes people more likely to respond to that treatment as well.

German researchers decided to study what is called social observational learning (SoL). This was a double-blinded randomized controlled clinical trial in 44 patients with chronic low-back pain (CLBP). They compared the effects of observing positive treatment outcomes in a sham or pretend patient versus hearing the same sham patient report neutral effects. In the SoL group, the sham patient told study patients about his improved pain due to amitriptyline and he also demonstrated his improved mobility by bending forwards and sideways. The same sham patient told the control group only that he was taking amitriptyline. The researchers collected data before and after the intervention and two weeks later. After the intervention, pain decreased in both groups with no difference between groups. The SoL group, however, showed a significantly larger decrease in perceived disability.

The authors concluded that “The CLBP patients’ direct observation of positive treatment outcomes in the sham patient appears to have enhanced the treatment effects, while indirect verbal reports of reduced pain did not.”

These findings are not surprising. I often have patients ask for a particular treatment because their friend or relative had a very good response to it. If it is a reasonable treatment for a particular patient, I usually oblige, hoping for an enhanced placebo effect.

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I am honored to participate in a symposium on headache management,
“THE CHALLENGE OF MIGRAINE AND CLUSTER HEADACHES”. The title of my presentation is The challenge of migraine: new perspectives in refractory cases

This interactive neurological conference will be held in-person on Thursday, November 4, 2021 at the Zurich Marriott Hotel, Zurich, Switzerland

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To gain FDA approval a drug has to be shown to be better than a placebo. The placebo effect is a well-established psychological contributor to the efficacy of most treatments.

A group of Italian researchers just published an interesting study looking at other psychological factors that might influence the response to treatment.

They evaluated chronic migraine patients who were treated with erenumab (Aimovig). Erenumab is a monoclonal antibody that targets CGRP, a neurotransmitter involved in the development of migraine attacks.

Monthly erenumab injections were given for one year to 75 patients with chronic migraine who had already failed at least three other oral preventive drugs. A full psychological evaluation assessed personality disturbances, mood and anxiety disorders, as well as childhood traumas, and ongoing stressors.

After 12 months of treatment, 53 patients had at least a 50% drop in the number of headache days per month. The other 22 did not. When compared to responders, non-responders were more likely to have personality disorders with anxious-fearful, avoidant, dependent, and obsessive-compulsive features. Non-responders were also more likely to suffer anxiety disorders and had a higher number of current major stressors.

A very practical application of these findings is that doctors need to address anxiety when treating migraine and chronic pain patients. I’ve seen a number of patients whose migraines improved with an SSRI antidepressant such as fluoxetine (Prozac) or escitalopram (Lexapro). SSRIs do not possess pain-reliving properties. However, they are good at relieving anxiety and so can indirectly improve migraines. Most of the time, I prescribe SNRIs such as duloxetine (Cymbalta) or a tricyclic antidepressant such as nortriptyline (Pamelor) because they relieve anxiety and can have a direct pain-relieving effect.

The old dogma in psychology was that you cannot change your personality. We now know that such change is possible. Different types of cognitive-behavioral therapy (CBT) can be very helpful. Swedish researchers showed that even a brief internet-based CBT can produce long-term changes in personality traits.

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