In Part 2 (below), Dr. Bonakdar picks up the conversation by talking about riboflavin, feverfew, and magnesium as supplements in the management of headache. He discusses the use of supplements, such as CoQ10 and magnesium for children who suffer from headaches. And then he comments on the role of probiotics in pain management and inflammation.

Dr. Rakel: Dr. Bonakdar, everyone is familiar with the nonsteroidal anti-inflammatory drugs (NSAIDs) and the opioids for pain, but many people think that supplements are not strong enough to influence pain. Is that true?

Dr. Bonakdar: Many supplements are good adjuncts to our current approaches to pain management. SAM-e is an example. We need to learn how to combine the use of supplements with our current approach to pain.

SAM-e for osteoarthritis pain, depression

Dr. Rakel: SAM-e has a novel mechanism of action, and the evidence supports its benefit for depression as well as osteoarthritis pain.

Dr. Bonakdar: Yes. Moderate doses of SAM-e, 600 to 800 mg/day, can produce benefits similar to those obtained with anti-inflammatory drugs such as celecoxib.¹ The onset of effect may take a while, however; so, you need to take a balanced approach. A patient may be taking NSAIDs for acute pain, such as for an acute arthritic flare, but SAM-e could be added to that at the time of onset. Then, in a few weeks or a month later, the patient can hopefully taper off the NSAID. This would be important for individuals who might have contraindications to long-term NSAID use. The patient could then be maintained on SAM-e.

For a patient with arthritis and comorbid depression—for which he or she may be taking a selective serotonin reuptake inhibitor (SSRI)—SAM-e may hasten remission of the depression. The dose for depression is generally higher than that for treating arthritis pain, up to 1200 to 1600 mg/day. In a case like this, you would need to analyze the patient’s current therapy and figure out how to use one agent for multiple effects.

Dr. Rakel: The side-effect profile with SAM-e is fairly favorable. One side effect with SAM-e is euphoria, and another is insomnia. How do you manage these effects?

Dr. Bonakdar: SAM-e can have a euphoric effect, and it can cause mild agitation. It should be avoided in those with history of mania or bipolar disorder. I also let people know about initial agitation and sleep disruption so they are aware. And I instruct most of my patients to take it earlier in the day. They might take their full dose of 400 to 800 mg in the morning, with their breakfast, and then not take any later in the day. If they need to divide the dose, they can take their second dose in the early afternoon and not take any at nighttime. I tell my patients to expect having some difficulty falling asleep when they first start SAM-e, and to tell me if it becomes significant. Some people can lower their dose and still receive benefit. You need to work with them to titrate the dose to a level where you find a good balance between efficacy and side effects.

Turmeric for pain, depression, dyspepsia

Dr. Rakel: The COX-2 inhibitor scare with regard to cardiovascular disease caused many people to stop taking these drugs, which left them wondering what they could take for pain. What is your view on turmeric?

Dr. Bonakdar: Turmeric isone of my top choices, along with SAM-e. Similar to SAM-e, turmeric has been used traditionally for arthritis pain, but we now know that it is effective for depression and dyspepsia as well. Results of a recent pilot study showed that turmeric improved depression comparable to an SSRI.²

It is important to understand that we have an evidence-based rationale for using nutritional supplement formulations of turmeric. One of these, called Meriva, at a dosage of 500 mg twice a day, is very helpful in arthritis. We also use another standardized formulation, called BCM-95, for patients with rheumatoid arthritis. In a comparative study with diclofenac in rheumatoid arthritis, BCM-95 effected similar pain reduction.³

We have come a long way in understanding the properties of these substances. The essential message is that they can help the patient with pain plus other comorbidities.

Dr. Rakel: What about turmeric’s effect on dyspepsia?

Dr. Bonakdar: Turmeric’s effect on dyspepsia is a benefit for patients on long-term NSAID therapy, who sometimes develop stomach upset. Adding turmeric to their treatment may help alleviate this side effect.

The effect on dyspepsia is interesting, because we think of both cumin and turmeric as components of curry, which can cause stomach upset. However, using turmeric in pill form has been shown to be helpful in dyspepsia. Not every patient achieves that benefit, but it is definitely something to hope for.

Butterbur for migraine headache

Dr. Bonakdar: Butterbur has recently been recognized by the American Academy of Neurology as an effective preventative for migraines.⁴

Traditionally, mostly in Germany, butterbur has been used as an allergy medication. There is some evidence that it produces mast cell stabilization, a mechanism relevant to control of allergy. Crossover between an allergic response and the onset of migraine is well-established. In this process, the trigeminal nerve becomes irritated, which triggers the production of various chemicals and histamines, leading to migraine.

The use of butterbur for migraine is an innovative approach, as it draws upon its relevant mechanism in allergy. I have used it in patients whose headaches or migraines seem to involve environmental sensitivity. However, even for classic migraine, butterbur at 150 mg/day can be quite effective as a preventative. It is also safe in children, for whom the dose is 100 mg/day.

Dr. Rakel: Do you usethe whole herb, or just the Petasites extracts?

Dr. Bonakdar: Petadolex, which is the German extract of the raw herb, excludes specific alkaloids that have been shown to be toxic to the liver if used in wild form, just as certain mushrooms are. When I discuss use of an herb, I try to mention a specific, standardized formulation, if it exists. That helps to bypass some of the questions about safety and efficacy. Petadolex is available in the United States.

• References

  1. Najm WI, ReinschS, Hoehler F, et al. S-adenosyl methionine (SAM-e) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. BMC Musculoskelet Disord. 2004;5:6.
  2. Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial [published online ahead of print July 6, 2013]. Phytother Res. doi: 10.1002/ptr.5025.
  3. Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26(11):1719-1725.
  4. Holland S, Silberstein SB, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353.

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  Part 2

  Full Story

  Other supplements for headache
  

  Dr. Rakel: Riboflavin (vitamin B2), as well as feverfew and magnesium, have also been touted for headaches. What are your thoughts on those?

  Dr. Bonakdar: Feverfew formulations are typically not very well-standardized in the United States. In addition, the evidence base is inconclusive. The analyses that have been done have been based on four or five different trials that used various formulations, most of which are not available in this country. Overall, we are not quite sure if feverfew works for headaches. Some formulations seem to work, but others do not. There is an interesting sublingual formulation of feverfew and ginger known as LipiGesic, which has been studied in some small trials with positive results for aborting acute migraine.^1,2 I think in some patients that this might be worth trying to see if helps them find another route for decreasing burden of acute headache. Lastly, there is some concern regarding feverfew’s safety in women’s health, particularly in pregnancy; so, it is important to mention this to patients in this group.

  The efficacy of some of the other supplements, such as magnesium, CoQ10, and riboflavin, relates to the ability to shift the mitochondrial energy complex. Some emerging reports in the literature have begun describing migraines in terms of mitochondrial dysfunction.³

  Several small- to medium-sized trials on CoQ10 have shown that 50 to 200 mg/day may be helpful for migraine,⁴including in the pediatric population. Riboflavin may be used at 400 mg/day.

  Magnesium is used in various doses because there are so many formulations. I usually start with simple, cheap, readily available magnesium oxide. One trial in pediatric patients used a magnesium dose of 9 mg per kg.⁵ Magnesium reduced scores on the PedMIDAS and improved quality of life in children with migraines.

  A study done in Canada found that more than 30% of children and adolescents with migraine (average age, 13 years) were already deficient in CoQ10.⁶ Thus, there appears to be some characteristic of migraine that depletes these essential mitochondrial nutrients. Alternatively, there may be a genetic deficiency. Either way, it makes sense to use these supplements, as they are quite benign, and there is evidence that the mitochondrial theory is plausible.

  Supplements for headaches in children
  

  Dr. Rakel: The side-effect profile of supplements is very good, which is especially important in children. What supplements would you recommend for a 10-year-old patient with headaches?

  Dr. Bonakdar: Most patients whom I see are looking for a quick fix for their headaches, especially if stress is involved. They have the same expectation if they are taking a pharmaceutical agent; they want it to act quickly. My quick solution is magnesium. I usually start with magnesium because it tends to be the most cost-effective. For the child you mentioned, I might start with 250 mg of magnesium oxide—9 mg per kg, with a child weight of 40 to 50 kg—quickly increasing the dosage to two tablets at night, or 500 mg. Taking it at night helps to eliminate some of the stomach irritation that can occur.
  

  I start the dosing below 500 mg to make sure the patient can tolerate the magnesium. You don’t want to start too high since it may cause gastrointestinal upset. I increase the dose to approximately 500 mg, since that represents the typical capsule out on the market. A lot of children with magnesium issues are constipated, so magnesium oxide or sulfate works well. If they are sensitive to the gastrointestinal effects, then I would try magnesium glycinate, which is buffered; the glycinate portion may also have a relaxation component to it, so it is suitable for use at bedtime.

  After the magnesium, I would add CoQ10, usually at 50 to 100 mg/day for a typical child or adolescent. I would reevaluate this regimen over the next 1 or 2 months.

  Dr. Rakel: What else would you add?

  Dr. Bonakdar: Depending on the severity of the problem, I might start butterbur sooner rather than later, and I might add other supplements, such as riboflavin. Some multivitamins are “headache friendly,” having higher amounts of magnesium, high amounts of riboflavin, and even CoQ10. A few multivitamins can be combined with butterbur. Obviously, in younger patients, the pill burden can become an issue. If they are not used to taking pills, you can start with a magnesium powder.

  Dr. Rakel: How do you use the powder? Do you mix it in water?

  Dr. Bonakdar: Magnesium citrate powders come in a flavor, such as a berry flavor. You can put it in water or juice, mix it up, and the child can drink it at bedtime. The powder can be easily dosed upward to get to the therapeutic level. You can track the effect on the headaches and also the gut function.

  I often find that muscle function also improves. Magnesium appears to have a mild effect on muscle relaxation. It can also help with mood, because magnesium deficiency seems to be related to a decrease in mood. All of those conditions are probably interconnected. If you are alleviating the headaches, you are going to affect those other things as well, but those are beneficial side effects.

  Probiotics
  

  Dr. Rakel: What other pearls can you offer us with regard to nutritional supplements and pain?

  Dr. Bonakdar: Probiotics have been generating a lot of interesting research in the area of pain management. We think of probiotics in connection with gut function, because the gut is where toxins and inflammatory substances can enter our system. However, some probiotics seem to have an ability to reduce pain. There is at least one trial in rheumatoid arthritis indicating benefits from probiotics,⁷ but this is not seen with all types of probiotics; so, formulation is key to derive potential benefit. In addition, some acidophilus strains of probiotics seem to help patients with obesity-related pain, caused by obesity-related cytokines.⁸ In those cases, probiotics may help with both inflammation and weight reduction.

  Dr. Rakel: What do you think is the mechanism for the effect of probiotics on pain and inflammation?

  Dr. Bonakdar: Modulation of the immune system, which is one of the main effects of probiotics, may itself temper these conditions. Secondarily, probiotics may stimulate an internal signal that shuts down some of the pathways involved, such as in joint inflammation. We see this in autoimmune conditions.

  The first tactic is to not let substances into the body that are going to stimulate the immune system to overreact. Then, once the immune system balances out, you can obtain the secondary benefit. The mechanisms for the effects of probiotics have not yet been delineated. We’re just at the tip of the iceberg in our understanding.

  • References

    1. Cady RK, Goldstein J, Nett R, et al. A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic™ M) in the treatment of migraine. Headache. 2011;51(7):1078-1086.
    2. Cady RK, Schreiber CP, Beach ME, Hart CC. Gelstat Migraine (sublingually administered feverfew and ginger compound) for acute treatment of migraine when administered during the mild pain phase. Med Sci Monit. 2005;11(9):PI65-69.
    3. Stuart S, Griffiths LR. A possible role for mitochondrial dysfunction in migraine. Mol Genet Genomics. 2012;287(11-12):837-844.
    4. Rozen TD, Oshinsky ML, Gebeline CA, et al. Open label trial of coenzyme Q10 as a migraine preventive. Cephalalgia. 2002(2);22:137-141.
    5. Wang F, Van Den Eeden SK, Ackerson LM, et al. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial. Headache. 2003;43(6):601-610.
    6. Hershey AD, Powers SW, Vockell AL, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. 2007;47(1):73-80.
    7. Mandel DR, Eichas K, Holmes J. Bacillus coagulans: a viable adjunct therapy for relieving symptoms of rheumatoid arthritis according to a randomized, controlled trial. BMC Complement Altern Med. 2010;10:1.