Posts Tagged "headache treatment"

Last updated on September 17th, 2021 at 06:39 am

MEDICAL MARIJUANA (CANNABIS) FOR MIGRAINE, HEADACHE AND PAIN. A CRASH COURSE OF EVERYTHING YOU NEED TO KNOW.

@Neuralgroover

BACKGROUND

Medical marijuana (medical cannabis) for treatment of migraine, headache, pain, and chronic pain has become an increasingly hot topic of interest. As states continue to legalize the use of medical marijuana, there are increasing discussions and questions about its medical uses. What are the best medical marijuana strains for migraine, headache, and pain? Is medical marijuana helpful for migraine, chronic migraine, headache, pain, and chronic pain? How is medical marijuana used and dosed? Is medical marijuana legal to use? What are the side effects of medical marijuana? How do you get medical marijuana? How does marijuana differ from CBD (cannabidiol)? What is the best CBD dose for pain? What is the best CBD dose for migraine? What is the best THC dose. How do you increase CBD dosing, THC dosing, or cannabis dosing?

 

Patients ask about these treatments all the time, so this blog is to provide a comprehensive overview to answer all of these questions and much more. Reading the whole blog will give you a comprehensive, yet condensed detailed education of its history and everything you need to know about cannabis, CBD, and THC for medical use, with an additional focus in the treatment of migraine and pain. Alternatively, you can skip down to find the specific topic that you are looking for information on. For example, specific suggestions for how to begin CBD or THC dosing, and a schedule of how to titrate upwards can be found below. If you would like to skip to a specific topic, here is the sequence of the topics discussed:

 

-HISTORY CRASH COURSE OF MARIJUANA (CANNABIS) IN THE TREATMENT OF MIGRAINE, PAIN, PROHIBITION, AND RETURN TO LEGAL STATUS.

-STATES WHERE MEDICAL AND RECREATIONAL (ADULT-USE) MARIJUANA (CANNABIS) ARE LEGAL.

-MEDICAL MARIJUANA (CANNABIS) USE FOR PAIN AND MIGRAINE.

-WHAT TYPES OF MARIJUANA (CANNABIS) ARE THERE AND HOW DO YOU KNOW WHICH ONE TO USE?

-WHAT IS THE EVIDENCE FOR MARIJUANA (CANNABIS) USE FOR MIGRAINE?

-GENERAL SUGGESTIONS OF HOW TO USE MEDICAL MARIJUANA (CANNABIS).

-HOW DO YOU ESTIMATE THC CONTENT, WHAT IS THE BEST THC DOSE, AND HOW DO YOU USE THC?

-WHAT IS THE BEST CBD DOSE AND HOW DO YOU USE CBD?

-SIDE EFFECTS AND ADVERSE REACTIONS OF MEDICAL MARIJUANA (CANNABIS).

-WHAT IS CANNABIS HYPEREMESIS SYNDROME AND HOW DO YOU TREAT IT?

-CANNABIS (MARIJUANA) ADDICTION AND ABUSE

 

When many people hear the term “medical marijuana”, they think of a street drug with no true medicinal qualities, used only for recreation and abuse. Their mind immediately activates the visual hippie imagery of the 1967 Summer of Love and 1969 Woodstock festival. However, this is an outdated view in the scientific research community. The term “marijuana” (sometimes spelled marihuana) is a loaded term with many negative connotations including old political and racial associations, and is associated with the plant being used recreationally as a drug of abuse. Cannabis is the scientific name of the plant and is the preferred terminology.

 

It is best to think of cannabis, as a broad class of medication. Within this medication class there are many types of cultivars (strains, breeds), or more accurately, chemovars (chemotypes). “Cultivar” is short for “cultivated variety”, while “chemovar” refers to “chemical variety”. The older cultivar classification system (Sativa, Indica, Ruderalis) has evolved to the more current, scientific, and simplified chemovar classification system. These systems are discussed in more detail further down under the treatment section.

 

Each chemovar has standardized reproducible compositions of cannabinoids and terpenes, which are the phytochemicals in cannabis that make up most of the medicinal qualities. The CBD and THC (tetrahydrocannabinol) cannabinoids and terpenes are discussed further down, and are also discussed in great detail here. Similar to a medication, there will be some variation in benefits, responses, effectiveness, and side effects between patients for each chemovar. Also similar to a medication, there are common characteristics attributed to each chemovar that the majority of users will experience.

 

For comparison of this concept, antidepressants are a broad class of medication. Within this medication class there are many types of drugs. Each drug has standardized reproducible compositions of neurotransmitter targets. Similarly, there will be some variation in benefits, responses, effectiveness, and side effects between patients for each drug, and a set of common characteristics attributed to each drug that the majority of users will experience.

 

HISTORY CRASH COURSE OF MARIJUANA (CANNABIS) IN THE TREATMENT OF MIGRAINE, PROHIBITION, AND RETURN TO LEGAL STATUS.

To understand the current legal status of cannabis, it is important to know the history of cannabis, detailed here. The use of cannabis for medicinal purposes dates back to ancient times, with a Western/Central Asian botanical origin. Medicinal uses have been documented to 4000 BC or more. Chinese physicians were using it for joint pains and analgesia in childbirth 5000 years ago. Fast forward to 1839 when Dr. William Brooke O’Shaughnessy introduced the Western world to the medicinal uses of Cannabis indica, or “Indian hemp”, after he spent a professorship in Calcutta, India and learned of its uses while there. He advocated for its use in analgesia and muscle relaxation.

 

Throughout the 1800s into the 1900s, it was being recommended by many prominent physicians of those times for numerous diseases, particularly pain, headache, chronic daily headache, migraine, and chronic migraine, and was being used both acutely and preventatively.

 

In 1890, Sir John Reynolds, President of the British Medical Association, and Physician to the Royal household, wrote a paper in Lancet on his 30 years of experience prescribing cannabis for variety of ailments, particularly migraine and neuralgia.

 

In 1915, the “Father of modern medicine”, Sir William Osler, was recommending cannabis for migraine treatment in his historic medical textbook of those times, The Principles and Practice of Medicine. He went on to suggest that when treating migraine, “Cannabis indica is probably the most satisfactory remedy. Seguin recommends a prolonged course.” Dr. E.C. Seguin whom he referenced was a well-known neurologist and was the President of the NY Neurological Society. He was a vocal proponent of cannabis for migraine.

 

Cannabis-based preparations had been listed in the US Dispensatory in 1845. In North America, some pharmaceutical companies including Bristol-Meyers Squib, Parke-Davis, and Eli Lilly were producing cannabis-based preparations, as was Burroughs-Wellcome & Co. in England.

 

In the 1930s, Harry Anslinger was leading the Federal Bureau of Narcotics, which was essentially the early DEA. He began a campaign against cannabis, attempting to associate psychosis, mental deterioration, addiction, and violent crimes to cannabis use. He claimed cannabis was a drug of abuse used by minority and low-income communities. Instead of using the term cannabis when he was pushing his prohibition bill in front of congress in 1937, he purposely would use the term “marijuana,” subtly trying to convey a racial connection since it was commonly associated with recreational use among poor Mexican immigrants who would bring it from Mexico to the USA at that time. He reportedly chose his terminology wisely to fit this agenda and distance the plant from the more scientific term cannabis along with its growing uses for medicinal and industrial purposes. Furthermore, marijuana has a general connotation of being used as an intoxicant and recreationally, whereas cannabis has more of a scientific association. For all of these reasons, cannabis should really be the preferred terminology over marijuana.

 

The Marihuana Tax Act of 1937 was passed, attributing large fines and prison time to anyone involved with cannabis. Some historians also discuss influence on this law from prominent businessmen such as Andrew Mellon and the DuPont family since the hemp industry was gaining traction in industrial uses, posing a threat to synthetic and other more common competitor products, but that is a whole different discussion. The AMA (American Medical Association) strongly opposed this law.

 

In 1938, Dr. Robert Walton argued against the new Marihuana Tax Act and published a comprehensive review of cannabis, referencing 12 experts on its effectiveness for migraine.

 

In 1941 cannabis preparations were taken off the US Pharmacopoeia and National Formulary.

 

In 1942, Dr. Fishbein, the Editor of JAMA (Journal of the American Medical Association), published his recommendations for oral preparations of cannabis over ergotamine for menstrual migraine. Other physicians also published supporting evidence for cannabis in migraine treatment.

 

Then the 1960s hit, where there was a resurgence of recreational marijuana use. This left a lasting and ongoing negative stigma of cannabis. Again, cue the visual hippie imagery of the 1967 Summer of Love and 1969 Woodstock festival. Unfortunately, many people who are not aware of cannabis history have been stuck in this mindset since…

 

The final nail in the coffin for legal cannabis use came with the Controlled Substances Act of 1970. This is what changed cannabis to its schedule 1 drug illegal status, of which it has remained since that time. The Assistant Secretary of Health, Dr. Roger O. Egeberg, stated his reason as follows, “Since there is still a considerable void in our knowledge of the plant and effects of the active drug contained in it, our recommendation is that marijuana be retained within schedule 1 at least until the completion of certain studies now underway to resolve the issue.”

 

Well, we are well past those studies Dr. Egeberg mentioned, and extensively more have been completed since then, yet cannabis remains federally illegal, despite all the evidence and vast amount of knowledge that we have gained from research. Thus, it is only a matter of time until the tide finally turns completely, and cannabis is rescheduled from Schedule 1 in my opinion.

 

So, cannabis has been a schedule 1 drug since 1970. Schedule 1 drugs also include heroin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (Ecstasy). According to the United States Drug Enforcement Agency (DEA), Schedule I drugs have a high potential for abuse, and have no accepted medical treatment use. If you are saying to yourself, that cannabis doesn’t seem like it fits into this category, you are certainly part of the majority opinion, which has shifted over the years. The DEA has continued to claim that cannabis has “no accepted medicinal use”, a statement which has no evidence to support it, but rather more evidence exists that disprove that claim.

 

Interestingly, despite this claim of no medicinal benefit, the US Government’s Department of Health and Human Services was awarded a patent (US Patent #6,630,507) for “cannabinoids as antioxidants and neuroprotectants” in 2003. Furthermore, the FDA has approved 3 synthetic versions of cannabinoids for medicinal purposes. Two are synthetic forms of THC (Dronabinol (Marinol), Nabilone (Cesamet)), and one is a purified form of CBD (Epidiolex). So, these statements and facts are clear contradictions to one another…

 

The schedule 1 classification has been a huge barrier preventing US federal funding for research and the legal ability to even proceed with research, although this has loosened up in recent years. This has historically been the primary hurdle in conducting medical research needed to obtain the evidence-based medicine in support of cannabis in the US. Meanwhile, many other countries such as Israel and Canada have been researching for years and have federal cannabis programs. For example, the Canadian equivalent to the US FDA is Health Canada. They have maintained a successful federal cannabis program for years. Despite this schedule 1 hurdle in the US, there has been accumulating evidence for various therapeutic benefits of cannabis, especially in the treatment of pain disorders.

 

In 1976, the FDA began an Investigational New Drug Program, after a glaucoma patient sued the government on grounds that cannabis was helping him, and won. This program closed in 1992, and 13 patients in the program at the time of closure were allowed to continue. Most recently, there were still 2 remaining who still receive monthly government supplied cannabis; one for multiple hereditary exostoses (painful bone tumor disorder), and the other for glaucoma. Access to this government supplied cannabis has since been controlled by the National Institute on Drug Abuse (NIDA), and the only federally approved cannabis source for decades has been from a farm at the University of Mississippi, who has had an ongoing contract with the federal government since 1968.

 

Through the 1990s-2000s, there was growing commentary from leading physicians and journals supporting cannabis for medicinal purposes. This has been accompanied by a growing push by medical organizations to reschedule cannabis to allow research and for patients who need it when they have failed all conventional treatments. Some of these organizations include American Academy of Neurology (AAN), American Medical Association (AMA), Epilepsy Foundation, American Journal of Public Health, and American Academy of Pediatrics (AAP).

 

In 2013, Dr. Sanjay Gupta MD, CNN Chief Medical Correspondent, issued a public apology article retracting his previous anti-marijuana stance which can be read here. He noted that “of more than 20,000 papers published in recent times, only 6% of the studies look at potential benefits of cannabis, while all the rest investigate potential harm, leading to an inherent bias and a profoundly distorted view.” He went on to further say:

“Well, I am here to apologize. I apologize because I didn’t look hard enough, until now. I didn’t look far enough. I didn’t review papers from smaller labs in other countries doing some remarkable research, and I was too dismissive of the loud chorus of legitimate patients whose symptoms improved on cannabis. Instead, I lumped them with the high-visibility malingerers, just looking to get high. I mistakenly believed the DEA listed marijuana as a Schedule 1 substance because of sound scientific proof. Surely, they must have quality reasoning as to why marijuana is in the category of the most dangerous drugs that have “no accepted medicinal use and a high potential for abuse.” They didn’t have the science to support that claim, and I now know that when it comes to marijuana neither of those things are true. It doesn’t have a high potential for abuse, and there are very legitimate medical applications. In fact, sometimes marijuana is the only thing that works. We have been terribly and systematically misled for nearly 70 years in the United States, and I apologize for my own role in that.”

 

Dr, Gupta has done a series of documentaries on CNN about the medicinal benefits of cannabis and are very enlightening to watch. This change in Dr. Gupta’s public opinion was also occurring along with spreading anecdotal cases of children with refractory pediatric epilepsy who were improving dramatically with CBD extracts from cannabis. One of these children, Charlotte Figi, became the poster child for this movement. In fact, the cannabis strain bred and extracted for high CBD for these purposes (Charlotte’s Web), was named after her. Unfortunately, she died 4/7/20 at the age of 13, and was remembered here.

 

STATES WHERE MEDICAL AND RECREATIONAL (ADULT-USE) MARIJUANA (CANNABIS) ARE LEGAL.

The legal use of medicinal cannabis continues to increase globally, including the United States. In 1996, CA became the 1st state to pass the Compassionate Use Act, allowing the legal use of cannabis for medicinal purposes. Since that time, legalized cannabis has continued to grow. As of 11/4/20, medical use of cannabis is legal in 35 states (AK, AR, AZ, CA, CO, CT, DE, FL, HI, IL, LA, ME, MD, MA, MI, MN, MO, MS, MT, ND, NH, NJ, NM, NY, NV, OH, OK, OR, PA, RI, SD, UT, VT, WA, WV) + Washington DC. Recreational marijuana use (“adult use”) is approved in 15 states (AK, AZ, CA, CO, IL, MA, ME, MI, MT, NJ, NV, OR, SD, VT, WA) + Washington DC. Despite a number of states legalizing cannabis use at the local level, it is still illegal federally in all states.

 

States which have medical cannabis programs have a list of qualifying conditions, which vary by state. The State Medical Board certifies doctors to “recommend” medical cannabis (Certificate to Recommend; CTR). The physician then confirms the qualifying condition and signs a “recommendation” form for potential benefit from medical cannabis. The patient then takes the recommendation to the local dispensary (which are also highly regulated by the state) and the patient discusses the best options there. However, it is important to remember that under the CSA (Controlled Substances Act), cannabis remains a schedule I drug, so doctors can’t “prescribe” cannabis. They can only “recommend” it. Also, interstate travel with any amount of cannabis or plant extract (including CBD products with THC content >0.3%) violates federal law and could potentially result in federal drug trafficking charges with stiff penalties of prison time and fines.

 

In 2009, the Justice Department sent a memorandum to federal prosecutors stating that patients and their providers should not face federal prosecution if they are following state law. In 2013 the Cole Memorandum was sent to US Attorney Generals, reinforcing that the Justice Department would not enforce federal prosecution in legal states who are following their state laws. In 2018, the Cole Memorandum was rescinded by Attorney General Jeff Sessions, which sent shockwaves through the industry. However, President Trump has continued to reinforce his support in protecting states that have legalized cannabis from federal prosecution. There have been discussions of re-evaluating the rescheduling of cannabis to remove the federal schedule 1 illegality, and it is suspected to be only a matter of time until this eventually happens.

 

MEDICAL MARIJUANA (CANNABIS) USE FOR PAIN AND MIGRAINE.

In medical cannabis registries, the most commonly reported reason for cannabis use is chronic pain of various types. Because of the increasing evidence of cannabis in the treatment of pain, the Canadian Pain Society revised their consensus statement in 2014 to recommend cannabinoids as a third-level therapy for chronic neuropathic (nerve) pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3 (the number of patients needed to treat for 1 of them to receive benefit). In 2017, The U.S. National Academies of Sciences, Engineering, and Medicine published a statement that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults. In February 2019, the World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category.

 

Cannabis works through our endocannabinoid system. The endocannabinoid system is a normal and important biological system within everyone which helps to maintain homeostasis. It plays a role in many regulatory physiological processes across all organ systems, and is widely distributed throughout the central nervous system (brain and spinal cord) and peripheral nervous system (nerves outside of the spinal canal). This system is involved in the “runner’s high” as well. Notably, it plays a very strong role in pain pathways. This system works by the interaction of our own natural endocannabinoids turning on or turning off various endocannabinoid receptors throughout our body.

 

Over 540 phytochemicals have been described in cannabis, 18 different chemical classes, and more than 100 different phytocannabinoids. THC and CBD have been the most researched and are considered the major cannabinoids. There are many additional cannabinoids referred to as minor cannabinoids. The quantities of major and minor cannabinoids are widely variable between different types of cannabis chemovars. There is evidence for analgesic and anti-inflammatory effects in many of the cannabinoids. Cannabinoids are unique to the cannabis plant, and can be thought of as the “plant equivalents” of our own endocannabinoids. So, they interact with the same endocannabinoid receptors in our body as our own endocannabinoids do. The existing literature and research on the treatment of pain have primarily studied cannabis itself with its variable and often undefined combinations of THC, CBD, other cannabinoids, terpenes, and other constituents. These compounds, especially cannabinoids and terpenes, play significant roles in influencing one another and working together. The synergy and interactions between these compounds are referred to as the “cannabis entourage effects”. Thus, the medicinal benefits of cannabis are suspected to be from the “entourage effects”, more so than any of the individual components alone.

 

THC is a major cannabinoid and the most researched in cannabis. THC causes the psychoactive qualities (“high”) of cannabis. THC has been shown to be 20 times more anti-inflammatory than aspirin and 2 times as anti-inflammatory as hydrocortisone. It is also a potent anti-emetic (anti-nausea), which is why there are two FDA-approved synthetic THC medications for chemotherapy related nausea and vomiting (Dronabinol, Nabilone). THC is the cannabinoid which is tested for in drug tests. It is important to know that most CBD products contain trace amounts of THC, although there are some varieties that do not. It is typically a negligible amount unlikely to show up on a drug test, but it is not completely risk free. You can read about the different types of CBD products here. THC can be detected by a variety of ways, although most commonly it is tested in the urine. Here are the general timeframes that it will show positive:

  • Blood:
    • Few hours to 1-2 days after a single use
    • In heavy users (multiple times a day), possibly up to a week
  • Saliva:
    • Appears in saliva an hour after use, detectable for up to 1-2 days
  • Urine:
    • 5-12 days after one-time use
    • 11-18 days when used 2-4 days/week
    • 33-48 days when used 5-6 days/week
    • Around 50-65 days if used daily (stored in adipose tissue)
  • Hair:
    • Generally 90 days, but some hair follicle tests can go back years

CBD is the other major cannabinoid and has gained a lot of attention as a therapeutic agent over the past several years given a wide range of reported anecdotal benefits. It is discussed in much greater detail here. In contrast to THC, CBD is non-intoxicating (no “high”). Furthermore, it helps to neutralize some of the negative THC side effects. CBD has been shown to be several hundred more times anti-inflammatory than aspirin. Greater than 65 molecular receptor targets and greater than 80 mechanisms of action have been identified. There have been scientific, animal models, and very limited human clinical trials documenting its anti-inflammatory and analgesic (pain-relieving) properties. However, there are no high-quality research studies to date evaluating isolated pure CBD in any pain, migraine, or other headache disorders. So, it is unclear how much benefit CBD in isolation provides outside of the presumed entourage effects that it contributes to.

 

In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related problems associated with its use. In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes. In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD. The Farm Bill also removed hemp from the Controlled Substances Act, making it no longer an illegal substance under federal law. Up until the Farm Bill was passed, any form of cannabis or cannabis derivatives (including CBD) have been federally illegal since the Controlled Substance Act of 1970. Therefore, it is important to remember that cannabis chemovars and CBD oils with greater than 0.3% THC are still illegal federally, require a medical cannabis card for use, and are illegal to cross state lines with. In May 2019, TSA began to allow travel with CBD products containing 0.3% or less of THC.

 

The terpenes account for many of the pharmacological properties of cannabis, as well as many medicinal herbs, plants and essential oils. They are the source of flavors, aromas, and other characteristics that help differentiate cannabis cultivars. Terpenes are often used in many household products such as limonene (citrus), pinene (pine, conifer), and linalool (lavender) to name just a few. Similar to the cannabinoids, many have anti-inflammatory and analgesic properties.

 

WHAT TYPES OF MARIJUANA (CANNABIS) ARE THERE AND HOW DO YOU KNOW WHICH ONE TO USE?

As discussed at the beginning of the blog above, there are many types of cannabis chemovars that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and chemovar characteristics. Different chemovars have different ratios of these compounds, and thus have different characteristics.

 

The older cultivar (strain, breed) classification system was based on strain appearance, smell, and clinical effects. Cannabis Sativa strains were generally described by patients as uplifting, energetic, creative, euphoria, spacey, cerebrally-focused effects, and better for day use, while cannabis Indica strains were typically described as calming, relaxing, sedative, full body effects such as “body buzz”, and better for night use. Cannabis ruderalis (hemp) strains were considered predominantly or purely high CBD without any real clinical use effects.

 

However, biochemical studies of specific strain names often do not accurately distinguish CBD and THC content, which was the predominant basis for strain classification. Strain characteristics and clinical effects are dependent on varying ratios of major and minor cannabinoids and terpenes, not only from CBD:THC ratios, as there are no significant differences in CBD:THC ratios between many Sativa and Indica strains when studied chemically. Most strains used today are hybrid strains genetically cross-bred for standardized CBD, THC, terpenes, and minor cannabinoid content.

 

The older cultivar classification system has evolved to the newer and more scientific chemovar (chemotype) classification system, and is divided into type I-III chemovars. This system allows medical users to find a chemical profile better matching their pharmacological needs.

 

Type I chemovars are THC predominant. They are high THC (>0.3%, but generally >10-20%), and low CBD (<0.5%, but generally <2%). They are very intoxicating, and associated with recreational more than medical use. They are moderately-heavily psychedelic with changes in perception and sensory awareness and have the potential for significant physiological changes in heart rate and blood pressure. They can intensify relief from symptoms like nausea or pain, so terminal cancer patients may be one of the few true medical uses for these chemovars.

 

Type II chemovars are more balanced THC and CBD. They are high THC (>0.3%, but generally 3%-10%), and high CBD (>0.5%, but generally 1%- 14%). They are intoxicating to a lesser degree than Type I chemovars. They can be mildly-moderately psychedelic with milder cerebral and cognitive changes in perception and sensory awareness possible. In general, they can be more effective at treating symptoms with less negative side effects.

 

Type III chemovars are CBD predominant. They are low THC (<0.3%, but generally 0%-1%), and high CBD (>0.5%, but generally 5%-20% or more). They have low to no intoxication side effects. There is little to no cognitive impairment for most, but there can be possible mild effects in sensitive users, depending on the THC content.

 

WHAT IS THE EVIDENCE FOR MARIJUANA (CANNABIS) USE FOR MIGRAINE?

The benefits of cannabis/cannabinoids in various chronic pain disorders has been well established. These benefits are suspected to likely extrapolate to headache disorders including migraine given overlapping neurobiological pathways of pain. There are some notable interactions and synergies between the cannabinoid receptors and pathways of migraine involving the trigeminovascular system (including the same receptors that the triptans work on) and serotonergic system. A more detailed discussion of this physiology can be read here and here. The medical literature regarding treatment of headache, migraine, and facial pain disorders shows limited supporting evidence for cannabis/cannabinoids in the treatment of chronic headaches, migraine including chronic migraine, medication overuse headache, cluster headache, idiopathic intracranial hypertension, and multiple sclerosis (MS) associated trigeminal neuralgia. However, the majority of this limited supporting evidence consists primarily of case series, case studies, case reports, surveys, clinical/anecdotal reports, and one retrospective analysis. There have been no placebo-controlled studies of cannabis for headache disorders or migraine thus far. There are only two prospective trials containing a control group evaluating the use of cannabinoids in the treatment of headache disorders, both of which showed benefit. The details and references of these studies and all of the smaller case studies mentioned can be read here and here.

 

Part of the difficulty in these types of trials, besides the federal illegality and the schedule 1 status of cannabis, is that there are so many variations of chemovars. It is unknown what chemovars and varieties of cannabis might be most helpful for migraine treatment. Most likely, it is not a one size fits all. Similar to how patients have a wide variety of therapeutic responses to abortive and preventive migraine treatments (what works for one person often does not work for another, etc.), responses to chemovars is probably similar. One person may respond very well to a specific chemovar, while another may respond better to a different one. Everyone is different, so like the trial and error process of trying different medications to see which may work best, cannabis chemovars most likely have a similar process.

 

With that said, there have been a couple studies evaluating a large medical cannabis registry, in an attempt to determine what chemovars patients with migraine and headache prefer to use. In one study, which can be read here, chemovars with high THC and low CBD were most preferred. “OG Shark” was the most preferred chemovar and consisted of high THC/THCA (tetrahydrocannabinolic acid) and low CBD/CBDA (cannabidiolic acid), with predominant terpenes β-caryophyllene and β-myrcene. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Notably in that study, many headache patients replaced pharmaceuticals with cannabis, most commonly opiates/opioids (43.4% in headache patients, and up to 73% in chronic pain patients), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anticonvulsants (7.7%), muscle relaxers (7%), and ergots (0.4%).

 

In a follow up study (publication pending) 6 of the top 8 preferred chemovars were again high THC/low CBD, with “Headband” (22-24% THC, <1% CBD), “Warlock CBD” (8-11% THC, 8-11% CBD), and “Master Kush” (24-26% THC, <1% CBD) all tied for the top preferred cannabis chemovar. All three of these chemovars again had β-caryophyllene as one of their top 3 predominant terpenes, along with a mix of linalool, limonene, β-myrcene, bisabolol, and humulene as one of the top 3 predominant terpenes between them. There were 2 preferred chemovars which had high CBD and lower THC. They were “Warlock CBD” (8-11% THC, 8-11% CBD) which was in a 3-way tie for top preferred chemovar as mentioned above, and “Cannatonic” (3-7% THC, 6-10% CBD).

 

GENERAL SUGGESTIONS OF HOW TO USE MEDICAL MARIJUANA (CANNABIS).

Cannabis can be used by smoked, vaporized, oral, oral-mucosal, topical, or rectal routes of administration. Oral routes cause a slower onset of action and a prolonged duration of action. Smoking and vaporizing cause the fastest onset of action and the shortest duration of action. Smoking is not recommended due to the production of unhealthy respiratory irritants and toxins. Vaporizing is a newer technique with a goal of suppressing irritating respiratory toxins by heating cannabis to a temperature where active cannabinoid vapors form, but below the point of combustion where smoke and associated respiratory toxins are produced.

 

Start low on the dose, go slow, and stay on as low of a dose as possible. This promotes tolerance to the THC psychoactive effects. Use the lowest dose THC possible, and use CBD and THC together because CBD helps to neutralize some of the negative THC side effects. Approximately 15-20% CBD with less than 1% THC is a good starting point to consider. CBD predominant preparations are better for working and daytime use, while THC predominant preparations are better for after work and at bedtime. Long acting oral formulations are better for chronic conditions and symptoms. Vaporization can be an as needed (prn) for episodic symptom exacerbations. Driving should be avoided for at least 4 hours after inhaled cannabis, 6 hours after ingested cannabis, and 8 hours if euphoria is experienced.

 

Common dosing quantities and terminology include one cannabis cigarette (“joint”) = 0.3-0.5 grams, one eighth = 3.5 grams, one quarter = 7 grams, and one ounce = 28 grams. Based on peer-reviewed literature, the majority of patients using smoked or orally ingested cannabis for medical purposes have been observed to use between approximately 10-20 grams of cannabis per week, 1-3 grams per day, and a frequency of 3-4 times daily. With that said, specific dosing recommendations are not available, and this is one area of much needed research in order to determine the best dosing for various disorders.

 

The matching of the proper chemovar to the proper patient will be widely variable based on the targeted symptoms and the patient’s experience with cannabis. The anti-pain effects of THC may need a Type I or Type II chemovar, although the side effect profile will be higher (highest with Type I). The anti-anxiety or anti-inflammatory effects of CBD may require a Type II or Type III chemovar. Type III chemovars will have the least risk of side effects. Patients new to cannabis should be started with a Type II or Type III chemovar and it can be adjusted as needed and as tolerated.

 

HOW DO YOU ESTIMATE THC CONTENT, WHAT IS THE BEST THC DOSE, AND HOW DO YOU USE THC?

For THC dosing, 1-2.5 mg is a good starting dose. For example, starting at bedtime and increase 1-2.5 mg every few days at bedtime or daytime (depending on treatment goals) until benefits or side effects are reached. At 5 mg THC, many will experience benefit without excess side-effects. At 10 mg, most will have side effects. At 15 mg or more it may cause psychiatric side effects. The total daily THC dose should be less than 20-30 mg to limit adverse effects and tolerance. In addition, THC should preferably be used with CBD as mentioned above because it helps to neutralized out some of the negative THC side effects. Use of high dose THC chemovars more than 5 grams per day of flower suggests possible tolerance or misuse, and is usually unjustified medically unless perhaps an end stage cancer patient.

The best way to estimate the mg of THC in flower to get the goal THC dose is as follows. Say that you have 1 gram (1000 mg) of flower (typical cannabis cigarette quantity) from a chemovar with 10% THC. That means 1 gram flower contains 100 mg THC (1000 mg x 10%)!! With that formula in mind, you can easily figure out the THC content by switching out those numbers of weight and THC percentage in the flower or product being used. Taking this example a step further, 30 mg would be just more than 1/3rd (30 mg THC goal / 100 mg THC), 20 mg THC would be 1/5th of the 1 gram flower quantity (20 mg THC goal / 100 mg THC), 10 mg THC would be 1/10th of the 1 gram flower quantity (10 mg THC goal / 100 mg THC), 5 mg THC would be 1/20th of the 1 gram flower quantity (5 mg THC goal / 100 mg THC), and so on. So the easiest way to fine tune your THC dose from your flower would be to divide 1 gram of flower into a specific fraction as outlined (depending on dosing goals), so you can know exactly how much to use and exactly how much THC you are ingesting.

 

WHAT IS THE BEST CBD DOSE AND HOW DO YOU USE CBD?

For CBD dosing, a good general guideline of how to begin CBD dosing with a gentle titration is as follows:

-Week 1: 5-10 mg at bedtime

-Week 2: 5-10 mg twice daily

-Weeks 3-4: 5-10 mg three times daily

-Weeks 5 onwards: 20 mg three times daily

It is suspected that high doses are likely needed for pain and inflammation disorders, but this needs to be clarified with research. There are no established dosing guidelines or max doses established. For reference, doses of 400-600 mg/day showed benefit in anxiety, doses of 600-800 mg/day showed benefit in psychosis, and doses up to 2500 mg/day (25-50 mg/kg) have been used in epilepsy studies.

 

SIDE EFFECTS AND ADVERSE REACTIONS OF MEDICAL MARIJUANA (CANNABIS).

Side effects are influenced by dose, method of administration, patient tolerance, chemovar of cannabis, ratios of THC to CBD, cannabinoids, terpenes, production quality control (toxins, fungus, bacteria, heavy metals, etc.) to name a few. Many studies have been inconclusive or contradictory in terms of association with stroke, heart attack. This publication provides the most comprehensive review of cannabis and its recognized side effects. The most common side effects (which vary depending on the chemovar) include dizziness, dry mouth, increased appetite, disturbances in concentration, and sedation/drowsiness. Less common side effects can include incoordination, euphoria, anxiety, and paranoid thinking. In the majority of trials, side effects have been well tolerated, mild to moderate, transient, and not bothersome enough that many patients withdrew from studies. Overdose can occur and is typically from high THC content and oral dosing. Signs may include tachycardia, arrhythmia, confusion, panic attack, extreme paranoia, and hallucinations.

 

From existing research, there is concern for possible long-term cognitive side effects of cannabis use during adolescent years when the brain is still rewiring, pruning, and organizing itself. Studies suggest a decline in IQ/neurocognitive function when used frequently under age 18. In adults, a larger study suggested problems in verbal memory recall after chronic cumulative use (after 5 years of cumulative frequent/chronic use, 1 in 2 people may recall 1 word less from a list of 15 words). Current users had both decreased verbal memory and processing speed.

 

According to “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research”, published by the National Academies of Sciences, Engineering, and Medicine in January 2017, the following are conclusions regarding cannabis side effects based on existing literature reviews.

 

For cardiovascular risk, there is limited evidence of cannabis triggering an acute MI (heart attack), ischemic stroke, or subarachnoid hemorrhage. There is no evidence to support or refute chronic cannabis use and increased risk of acute heart attack.

 

For cancer risk, there is moderate evidence of no association between the incidence of lung cancer (cannabis smoking), or the incidence of head and neck cancers. There is no or insufficient evidence to support associations with other cancers.

 

For respiratory disease risk, there is substantial evidence for worse respiratory symptoms and more frequent chronic bronchitis episodes (long-term cannabis smoking).

 

For neurocognitive risk, there is moderate evidence of impairment in the cognitive domains of learning, memory, and attention with acute cannabis use, but limited evidence for persistent impairments in cognitive domains of learning, memory, and attention after sustained cannabis abstinence.

 

For mental health risk, there is substantial evidence for development of schizophrenia or other psychoses in those at risk genetically, with the highest risk among the most frequent users. There is moderate evidence for increased symptoms of mania and hypomania in bipolar disorder. There is a small increased risk of depressive disorders and an increased incidence of social anxiety disorder. There is an increased incidence of suicidal ideation and suicide attempts with higher incidence in heavier users, and an increased incidence of suicide completion.

 

For prenatal, perinatal, and neonatal exposure, there is substantial evidence between maternal cannabis smoking and lower birth weight. During lactation, the amount reaching the infant is very low, although the effects of this are unknown. Therefore, it is recommended to not use cannabis in either pregnancy or breastfeeding.

 

There is substantial evidence for an increased risk of motor vehicle crashes. There is moderate evidence for increased risk of overdose, especially among pediatric populations. There is no or insufficient evidence for all-cause mortality, and there has been no documented death exclusively attributed to cannabis overdose or use. Cannabis has been shown in toxicology studies to be 114 times less lethal than alcohol. In fact, the deadliest substances in one toxicology study in order were alcohol, heroin, cocaine, tobacco, ecstasy, methamphetamine, and lastly, cannabis.

 

WHAT IS CANNABIS HYPEREMESIS SYNDROME AND HOW DO YOU TREAT IT?

Cannabis hyperemesis syndrome (CHS) has become increasingly seen as states legalize cannabis. It presents with clinical symptoms of cyclical nausea/vomiting, diffuse abdominal pain, and the need to take frequent hot showers (this is a pathognomonic sign).

 

Episodes of these symptoms last 24-48 hours, may last 7-10 days, and often recur with re-exposure of cannabis. CHS tends to be associated with high-dose, high-THC regular cannabis use. It can be confused with CVS (cyclical vomiting syndrome), and is differentiated by a history of chronic cannabis use and frequent hot bathing which produces temporary relief. The etiology (cause) of CHS is not fully understood. It has been theorized that there is a dysregulation of the endogenous cannabinoid system by downregulation of CB1 (cannabinoid 1) receptors, and in the GI (gastrointestinal) tract this may slow gastric motility, causing hyperemesis. Genetic differences in the cytochrome P450 system (enzymes in the liver which metabolize drugs) has also been proposed. The TRPV1 receptor in our bodies interacts with the endocannabinoid system. More specifically, anandamide (our main natural endocannabinoid) works at this receptor (one of many). Interestingly, this receptor is also the capsaicin receptor, and is activated by heat such as in hot peppers (which contain capsaicin). Therefore, it has also been proposed that perhaps the fact that these patients take frequent hot showers/baths for relief is because they are indirectly activating their endocannabinoid system.

 

Treatment of CHS revolves around cannabis cessation. There is no way around it. Supportive therapy can assist with fluid resuscitation. Capsaicin 0.075% topically to areas of the abdomen, back of arms, and areas that hot water gives symptom relief have shown some benefit (not using on private areas or mucosal surfaces). Antipsychotics such as Haloperidol and Olanzapine showed some temporary benefit. Conventional antiemetics, antihistamines, serotonin antagonists, benzodiazepines have shown limited evidence for effectiveness, and opiates should be avoided.

 

CANNABIS (MARIJUANA) ADDICTION AND ABUSE

Comparative addiction rates between substances have included tobacco 32%, heroin 23%, cocaine 17%, alcohol 15%, and lastly cannabis 9% (but 17% when used in adolescence, and 25-50% in adolescents who are using daily). Tolerance develops much faster with high potency high THC chemovars.

The DSM-5 recognizes 5 cannabis-associated disorders:

-Cannabis Use Disorder

-Cannabis Intoxication

-Cannabis Withdrawal

-Other Cannabis-Induced Disorders (Cannabis Intoxication Delirium, Cannabis Induced Psychotic Disorder, Cannabis Induced Anxiety Disorder, Cannabis Induced Sleep Disorder

-Unspecified Cannabis-Related Disorder

 

An estimated 3-4% of users meet criteria for Cannabis Use Disorder. The prevalence decreases with age, with the highest ages 18-29 years old (4.4%), and lowest ages 65 and older (0.01%). Cannabis Use Disorder is divided into mild (2-3 criteria), moderate (4-6 criteria), and severe (7 or more criteria). These criteria include any of the following:

  • Cravings and urges to use cannabis
  • Failure to fulfill major role obligations (work, school or home)
  • Unsuccessful attempts to quit/cut down
  • Spends excessive time in acquisition, using or recovering from use
  • Using Cannabis in larger amounts or for longer than you meant to (tolerance)
  • Continued use despite consistent social or interpersonal problems
  • Recurrent use in hazardous situations
  • Important social, occupational, or recreational activities are given up or reduced because of cannabis use
  • Needing more cannabis to get the effect you want (Tolerance)
  • Uses despite negative effects (physical or psychological)
  • Development of withdrawal symptoms, which can be relieved by taking more of the substance

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

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Last updated on October 1st, 2021 at 01:32 pm

NATURAL MIGRAINE TREATMENT FOR PREVENTION WITH VITAMINS AND SUPPLEMENTS. WHICH ARE BEST?

@Neuralgroover

Worldwide, migraine affects more than 10-12% of the population, with approximately 1 billion migraineurs estimated worldwide.1 It is estimated that there are 39 million migraineurs in the US, accounting for 12% of the US population. Migraine affects 18% of women and 6% of men2,3. Nearly 25% of U.S. households include someone with migraine.




In 2016, migraine was determined to be the 2nd leading cause of all global disability, and the 2nd leading cause of all neurological disease burden4. Migraine accounts for 50% of all neurologic disability. Furthermore, chronic pain in general is the largest contributor to years lived with disability globally5, and is associated with tremendous negative impacts on social, economic, and personal function.

 

In addition to the attack-related disability, many sufferers live in fear because their migraines disrupt their ability to work, go to school, partake in social activities, or care for their families, and this significantly limits their overall quality of life. More than 90% of migraine sufferers are unable to work or function normally during their attacks. American employers lose more than $20 billion each year as a result of 113 million lost workdays due to migraine.6

 

Migraine treatment is divided into acute (as needed) and preventive (prophylactic) therapy. Most existing preventive therapies are adopted from anti-epileptic, antidepressant, and antihypertensive medications. However, many of these medications are not well tolerated, resulting in poor compliance. Adherence to oral migraine preventative medication is around 26% at 6 months and declines to 17% at one year.7 This is often due to intolerable side effects. Many patients, due to lack of efficacy of preventative treatments, often resort to overuse of acute medications. This results in additional decline in quality of life and economic burden.8 Onabotulinumtoxin-A (Botox) is currently the only FDA-approved treatment available for chronic migraine. However, most patients must fail at least three preventative treatments prior to receiving Onabotulinumtoxin-A. As such, Onabotulinumtoxin-A is typically a fourth line option for the prevention of chronic migraine. In addition, it is not approved for patients who have episodic migraine. There are 4 calcitonin gene related peptide (CGRP) monoclonal antibody antagonists that have been approved for the prevention of migraine.  There also exists a limited number of neuromodulatory devices. Lack of insurance coverage of these devices precludes their routine use in clinical practice.  This confers a large unmet need for additional preventive migraine treatments and additional therapeutic targets.

 

Migraine prevention is a key aspect to maintaining a good quality of life.  Abnormal neuronal membrane ion channels, low ionized magnesium levels, increased excitatory glutamatergic activity, and mitochondrial dysfunction with abnormal energy metabolism are associated with migraine. The goal of nutraceuticals is to target these factors in order to improve energy metabolism and reduce neuronal hyperexcitability in the brain. Patients often seek natural migraine treatment with complementary and alternative medicine (CAM) after finding standard prescription treatments intolerable due to side effects, or just ineffective. Many patients feel that “natural” substances are less toxic than prescription medications. Thus, the nutraceutical and herbal supplement industry is a multibillion-dollar industry. CAMs include, but are not limited to, nutraceuticals (vitamins and supplements such as magnesium, coenzyme Q10 (CoQ10), vitamin B2 (riboflavin), alpha lipoic acid, vitamin D, 5-HTP, fish oil, melatonin), and herbal preparations (butterbur, feverfew, ginger, and cannabidiol). Other natural treatments such as yoga and meditation for migraine treatment can also be very helpful.

 

The use of CAMs has been significantly rising in the US and Europe9–12, and is becoming more evident especially in patients with migraine and other headache disorders. In a recent questionnaire-based survey in Germany and Austria, 81.7% of patients seen in tertiary outpatient headache clinics reported use of CAM13.  There are a multitude of different migraine related supplements on the market with variable combinations or sold separately as the individual components. Below, we discuss the most commonly used and studied supplements for migraine prevention.

 

VITAMINS and SUPPLEMENTS FOR MIGRAINE PREVENTION:

  1. Magnesium

Magnesium has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 It is also rated highly and recommended by the Canadian Headache Society.15 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. More than 325 enzymes are magnesium dependent, many of which are brain enzymes. Magnesium is involved in all reactions that involve the formation and utilization of adenosine-5′-triphosphate (ATP) in energy metabolism16–19. Proper magnesium levels are known to help normalize blood pressure, have anticoagulant, anti-platelet aggregating effects, regulate cell proliferation, protein synthesis, cellular energy and cell membrane stability, as well as blood sugar levels19–21. Studies have shown low levels of brain magnesium22,23 may be a contributor to migraine pathophysiology. Magnesium influences multiple steps in the current understanding of migraine pathophysiology including cortical spreading depression, serotonin receptor activity, neurotransmitter release, interference with inflammatory mediators, nitric oxide production, platelet aggregation, vascular tone, NMDA receptor interaction, CGRP release, production and release of substance P which activates pain fibers24–31. Magnesium is a mineral that functions as a coenzyme for various neurologic functions and other physiologic mechanisms.    According to two double-blind studies, high-dose oral magnesium supplementation appears to be effective in migraine prophylaxis. Trials have shown that magnesium supplementation is very effective in migraine treatment, with migraine attack reductions of up to 42%.32–37 Other studies have also shown benefit in migraine prevention when combined with coenzyme Q10 and feverfew as well.38 Magnesium (250 mg twice a day or 500 mg at bed) has a relaxant effect on smooth muscles such as blood vessels. We often give intravenous magnesium to patients who come into the emergency department for migraine because it helps to break the migraine. Three trials found 40-90% average headache reduction when used as a preventative. Magnesium also demonstrated the benefit in menstrually related migraine. Magnesium is part of the messenger system in the serotonin cascade and it is a good muscle relaxant. Some forms can be useful for constipation which can be a side effect of other medications used to treat migraine. Good sources include nuts, whole grains, and tomatoes.

 

There are different forms of magnesium, and we’ll discuss the most common types. Magnesium types can be tailored to patient characteristics as follows.39 Magnesium glycinate is a good choice for those with a sensitive stomach who have gastrointestinal side effects such as diarrhea with other forms of magnesium. It is anecdotally also helpful with anxiety and sleep. Magnesium threonate also has low risk of gastrointestinal side effects and anecdotally helpful with cognitive function and brain fog symptoms. Magnesium malate has low gastrointestinal side effects and is reportedly more energizing and anecdotally often helpful in fibromyalgia and chronic fatigue syndrome. Magnesium citrate is one of the most studied, popular, and well-absorbed forms of magnesium. It can also be mixed easily with liquids if you can’t take pills. However, it comes with a higher risk of diarrhea and gastrointestinal side effects, although this could be helpful for those with constipation. Magnesium oxide is also well studied, cheap, and often used for heartburn and indigestion. However, it is not well absorbed and can have some laxative side effects as well, so can also be helpful for constipation.

 

Dosing should generally be somewhere between 400-800 mg daily. It should preferably contain 24 mmol (600 mg) of elemental magnesium daily as magnesium citrate​ based on trials that showed benefit with this specific one more than others, and this is the recommendation of the Canadian Headache Society.15 If this type is not tolerated, other forms of magnesium as discussed above are certainly acceptable.

 

  1. Vitamin D3 (Cholecalciferol)

Vitamin D deficiency is a worldwide problem. Vitamin D is not actually a vitamin, but a hormone that the body makes from a type of cholesterol in the skin when it is exposed to UVB radiation from the sun. Small amounts also come from diet. It has anti-inflammatory activities, analgesic effects, may reduce nitric oxide and assists in magnesium and calcium absorption. Deficiency is suspected to play a role in mechanisms responsible for migraine and other pain syndromes, and vitamin D levels have been shown to be low in chronic migraineurs40. The best form is vitamin D3 (cholecalciferol) anywhere from 1,000 to 4,000 IU daily.

 

  1. 5-HTP (5-Hydroxytryptophan)

This is an amino acid that is made by the body from tryptophan (amino acid you get from your diet), and is involved in mood, sleep, and pain regulation. 5-HTP is typically produced from the seeds of the Griffonia simplicifolia plant. 5-HTP is converted into serotonin (5-hydroxytryptamine), an important brain neurotransmitter involved in migraine pathways and other neurologic pathways. 5-HTP is also converted into melatonin which aids in sleep, as well as dopamine, another important neurotransmitter. The effects of 5-HTP are felt to be similar to the antidepressants that are thought to increase the amount of serotonin available to the brain, and thus a mood enhancing chemical. Some studies have suggested that 5-HTP was as effective as some prescription migraine medications such as propranolol and methysergide (75% improvement in methysergide vs. 71% improvement in 5-HTP) in reducing the frequency and severity of migraines41–45. Side effects can include nausea, diarrhea, and stomach pain, and it should be used cautiously with medications which increase serotonin levels (such as most antidepressants) due to potential risk of serotonin syndrome. Typical doses are around 100–200 mg, 2–3 times per day with meals.

 

  1. Fish oil (Eicosapentaenoic acid (EPA) + Docosahexaenoic acid (DHA))

Fish oils are found in the tissues of fish. They contain a certain type of fat called omega-3. Potential mechanisms for anti-inflammatory effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and synthesis of lipid suppressors of inflammation (resolvins)46. Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) give rise to these resolvins which are anti-inflammatory and inflammation resolving47. These compounds may relieve joint pain and stiffness in a similar way as non-steroidal anti-inflammatory drugs (NSAIDs)46,48. One study reported dramatic decreases in headache frequency (15 per month down to 2 per month) and decreases in headache severity (reduction from 5 to 3 on a 7-point scale)49. Fish oils have also been studied and found to be useful in other inflammatory conditions such as rheumatoid arthritis46,48,50–53. Large trials have showed a significant beneficial effect on pain, morning stiffness, number of painful and/or tender joints and NSAID consumption50. Recommended dosing consists of 30% EPA and DHA with a ratio of EPA to DHA of 1.5. Research suggests the minimum dose needed to reduce the joint inflammation associated with arthritis is 2.7 grams of omega-3 (EPA + DHA) daily, which could also be divided such as 900 mg EPA and 450 mg DHA twice daily.

 

  1. Melatonin:

Increasing evidence shows correlation between melatonin secretion and headache conditions. Melatonin supplementation has shown decreased headache intensity and duration. It is widely used as a sleep aid. Sleep is nature’s way of dealing with migraine. A dose of 3 mg is recommended to start for headaches including cluster headache. Higher doses up to 15 mg has been reviewed for use in cluster headache and have been used, if not making too groggy in the morning. The rationale behind using melatonin for cluster is that many theories regarding the cause of cluster headache center around the disruption of the normal circadian rhythm in the brain. This helps restore the normal circadian rhythm. It should be taken at least 2 hours before bedtime.




MITOCHONDRIAL SUPPLEMENTS FOR MIGRAINE PREVENTION:

Mitochondria are the powerhouses within all cells of the body. These crucial metabolic organelles use oxygen to produce ATP, which is the primary energy source for the cell, and thus, for your body. Mitochondrial dysfunction leads to impaired oxygen metabolism and is suspected to play a role in migraine pathophysiology. Some migraineurs have been shown to have reduced mitochondrial activity which may lead to altered neuronal processing, and therefore a lower threshold for migraine attacks54–58. Riboflavin (vitamin B2), CoQ10 (ubiquinone; CoQ10), and alpha lipoic acid (thioctic acid) all play key roles in mitochondrial activity, and therefore have been implicated in migraine treatment by optimizing mitochondrial functioning.

 

  1. Riboflavin (Vitamin B2)

Riboflavin assists nerve cells in the production of ATP, a principal energy storing molecule. Riboflavin is an essential precursor to coenzymes involved in electron transport in oxidation reduction reactions within the Krebs cycle. This metabolic cycle is critical in production of ATP and generation of energy in the mitochondria, oxidative metabolism, maintaining membrane stability, and for all energy-related cellular functions59,60. It is necessary for many chemical reactions in the body. Brain riboflavin metabolism is suspected to affect migraine pathophysiology via several mechanisms, providing migraine preventive benefit.36,37

 

Riboflavin has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The Canadian Headache Society Guidelines strongly recommend B2 for migraine prevention as well.15 There have been at least 3 clinical trials of riboflavin using 400 mg per day all of which suggested that migraine frequency can be decreased. All 3 trials showed significant improvement in over half of migraine sufferers. Trials of riboflavin have suggested significant improvements in migraine by up to 59%61. Riboflavin (Vitamin B2): 200 mg twice a day (or 400 mg daily). The supplement is found in bread, cereal, milk, meat, and poultry. Most Americans get more riboflavin than the recommended daily allowance, however riboflavin deficiency is not necessary for the supplements to help prevent headache. One side effect to be aware of is that it can turn your urine bright neon yellow, although this is not harmful. Recommended dosing is 200 mg twice daily (or 400 mg once daily).

 

  1. Coenzyme Q10 (Ubiquinone; Ubiquinol; CoQ10)

CoQ10 is present in every membrane of all cells in the body62. Similar to riboflavin, CoQ10 plays a crucial role in electron transport and energy metabolism given its heavy involvement in mitochondrial function. CoQ10 is incorporated into the mitochondria, where it facilitates the transformation of fats and sugars into energy, thus it is often marketed to be an “energy enhancer”. Studies have shown that a nutritional supplement of CoQ10 can reduce the frequency of migraine attacks by improving the energy production of cells as with riboflavin. It also functions as an antioxidant by protecting against toxic oxidative reactions in the body, and CoQ10 tissue levels are known to decrease with age19,63. In one study, CoQ10 was found to be low in about 1/3rd of patients studied, and when replaced, headache frequency improved64. Migraine frequency was shown to improve significantly in more than 61% of patients in one study65, and 50% of patients in another study,66 supporting use for migraine prevention.36 Other studies have also shown benefit in migraine prevention when combined with magnesium and feverfew as well.38 The Canadian Headache Society guidelines strongly recommend use of CoQ10.15 Suggested dosing is around 150 mg-200 mg twice a day.

 

  1. Alpha Lipoic Acid (Thioctic Acid)

Alpha lipoic acid enhances the metabolism of oxygen and energy production by mitochondria67, and has shown reduction of migraine frequency68 when studied. Doses are typically around 300 mg twice daily.

 

HERBAL SUPPLEMENTS FOR MIGRAINE PREVENTION:

  1. Feverfew (Tanacetum parthenium)

Feverfew is a common garden herb native to Europe and popular in Great Britain as a treatment for disorders typically controlled by aspirin. The mechanism of action is unknown but is believed to be related to a chemical called parthenolide which helps the body use serotonin more effectively. Serotonin helps prevent migraine and assists with resolution when it occurs. Parthenolide also inhibits the release of histamine which is linked to pain and inflammation. Consistency of active ingredients in different products can be a problem. Some formulations don’t have the active ingredient (parthenolide) that prevents migraine. A parthenolide content of 0.2% is generally recommended.

 

Feverfew has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The anti-migraine action36–38,69–75 of Feverfew is felt to be related to the parthenolides within the leaves. Studies have shown that the parthenolides provide anti-inflammatory and analgesic effects through several mechanisms involved in the migraine process that normally lead to pain. These include inhibition of phospholipase A, prostaglandin biosynthesis and platelet aggregation, and actions on serotonin including release of serotonin from platelets and white blood cells, as well as interaction at various serotonin receptor subtypes19,76–89. Study results have been variable based on wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations used. However, a new, more stable feverfew extract (MIG-99) was created and showed a significant improvement in patients with high-frequency migraine90,91. The recommended dosing is generally around 50 mg twice daily (standardized to a high parthenolide content of 0.7% and stability measures of parthenolide), or, preferably MIG-99 6.25 mg three times daily if it can be found.

 

  1. Butterbur Extract (Petasites hybridus)

Butterbur is an extract derived from the petisides hybridus root, which has been used for medicinal purposes since ancient times. Butterbur is a well-researched and proven herbal supplements for migraine prevention36,69,70,92. For many years, it was the only supplement with a Level A (highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society,14 with a higher evidence recommendation than many of the prescription medications we use for migraine prevention. However, this recommendation was withdrawn a few years ago given a small handful of cases of liver failure reported in Germany. Although it is classified as an herbal supplement in the US, it is a licensed pharmaceutical medicine in Germany (Petadolex). Its two active compounds, petasin and isopetasin, help reduce cerebral blood vessel spasm and stop the inflammatory cascade which occurs in migraine93–95. Butterbur is thought to act through anti-inflammatory inhibition of leukotriene biosynthesis for its analgesic effects but also has calcium channel regulatory properties, both of which play a role in migraine19.

 

Studies have also shown anti-inflammatory effects mediated through inhibiting the additional inflammatory enzymes cyclooxygenase and prostaglandin production96. Notably, this is also what gives aspirin its anti-inflammatory effect. Trials have shown very positive results with significant decreases in migraine frequency of up to 58-77%, with 91% reporting overall improvement97–100. Side effects can include burping/belching. Raw butterbur root contains toxic chemicals that must be filtered out during the manufacturing process. To be sure you are choosing a safe product, look for a formulation that does not contain pyrrolizidine alkaloids since these are toxic to the liver. Recommended dosing is typically around 75 mg twice daily (free of Pyrrolizidine Alkaloids (PAs), standardized to contain a minimum of 7.5 mg of petasin and isopetasin).

 

  1. Ginger (Zingiber Officinale)

Ginger has anti-histamine and anti-inflammatory properties such as blocking pain-producing prostaglandins101,102, and helps with circulation and potentially headache. It is also widely used to treat nausea and vomiting, which accompany migraine103, and this is what it is primarily useful for. Recommended dosing ranges from 100-200 mg three times per day to 150 mg twice daily (standardized to contain 20% of gingerol and shogaol (dosage).

 

  1. CBD (Cannabidiol)

There have been a multitude of studies documenting the analgesic and anti-inflammatory benefits of medicinal cannabis (marijuana) across many chronic pain syndromes104–106, and it has been a historical treatment for headache and migraine for centuries.105–109 A detailed overview of medical cannabis for the treatment of migraine and chronic pain is discussed here. The vast majority of supporting evidence of cannabis and cannabinoids involves various chronic pain syndromes. These benefits are hypothesized to extend to headache disorders such as migraine given overlapping neurobiological pathways of pain. Some data suggests that cannabinoids appear to work uniquely within the inherent anatomical pathways of migraine (including serotonergic triptan pathways) and pain.104,105,107–139 Unfortunately, the majority of data supporting the use of cannabis and cannabinoids in migraine and headache disorders is based on case series, case reports, surveys and anecdotal evidence.105,107,145–154,108,155–161,134,135,140–144 There has been one retrospective study of cannabis use in the treatment of migraine which reported strong statistically significant findings of benefit.162 There have been only two limited prospective trials of cannabinoids containing a control group in headache disorders. One reported significant benefit in chronic daily headache associated with medication overuse headache,163 and the other reported significant benefit in both the acute and preventive treatment of chronic migraine.164

 

Given the growing evidence of cannabis and cannabinoids in the treatment of chronic pain and other medical conditions, in February 2019 The World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category. In January 2017, the National Academies of Sciences, Engineering, and Medicine concluded that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults.165 In 2014, the Canadian Pain Society revised their consensus statement to recommend cannabinoids as a third-level therapy for chronic neuropathic pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3.166

 

Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two predominant cannabinoids found in cannabis and are discussed in more detail here. CBD is several hundred more times anti-inflammatory than aspirin.104 There have been scientific, animal models, and limited human clinical trials documenting its anti-inflammatory and analgesic properties.167–176 In contrast to THC, CBD is non-intoxicating (no “high”).167 In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related concerns associated with its use.177 In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes.178

 

In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law in the United States. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD, as well as removed hemp and its extracts (including CBD) from the Controlled Substances Act, making it no longer an illegal substance under federal law.

 

Thus, the use of CBD products has been exploding and is a new industry projected to exponentially increase into a multi-billion dollar industry179,180. Many patients are using these products for a variety of reasons181,182, most commonly in pain, including migraine prevention, given their easy access and availability. However, there are no studies evaluating CBD alone in treatment of migraine or any other headache disorders, so this is purely anecdotal. CBD products can readily be purchased online from a multitude of companies, in local health food and drug stores, and common retail pharmacies.183 CBD and suggested dosing (which are not currently clearly known) are discussed in much greater detail here. Medical marijuana (cannabis) for the treatment of migraine is also discussed in much greater here.




IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

REFERENCES

  1. Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30(2):107-119. doi:10.1055/s-0030-1249220 [doi]
  2. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349. doi:10.1212/01.wnl.0000252808.97649.21
  3. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-657.
  4. Steiner TJ, Birbeck GL, Jensen RH, Katsarava Z, Stovner LJ, Martelletti P. Headache disorders are third cause of disability worldwide. J Headache Pain. 2015;16:58. doi:10.1186/s10194-015-0544-2 [doi]
  5. Holland S, Silberstein SD, 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. doi:10.1212/WNL.0b013e3182535d0c [doi]
  6. Evers S, Afra J, Frese A, et al. EFNS guideline on the drug treatment of migraine–revised report of an EFNS task force. Eur J Neurol. 2009;16(9):968-981. doi:10.1111/j.1468-1331.2009.02748.x [doi]
  7. Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-488. doi:10.1177/0333102414547138
  8. Lanteri-Minet M, Duru G, Mudge M, Cottrell S. Quality of life impairment, disability and economic burden associated with chronic daily headache, focusing on chronic migraine with or without medication overuse: a systematic review. Cephalalgia. 2011;31(7):837-850. doi:10.1177/0333102411398400
  9. Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in use of complementary and alternative medicine by US adults: 1997-2002. Altern Ther Health Med. 2005;11(1):42-49.
  10. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of afollow-up national survey. JAMA. 1998;280(18):1569-1575.
  11. Kessler RC, Davis RB, Foster DF, et al. Long-term trends in the use of complementary and alternative medical therapies in the United States. Ann Intern Med. 2001;135(4):262-268.
  12. Haussermann D. Increased confidence in natural therapies. Deutsch Arztebl. 1997;94:1857-1858.
  13. Gaul C, Eismann R, Schmidt T, et al. Use of complementary and alternative medicine in patients suffering from primaryheadache disorders. Cephalalgia. 2009;29(10):1069-1078. doi:10.1111/j.1468-2982.2009.01841.x
  14. Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache. 2012;52(6):930-945. doi:10.1111/j.1526-4610.2012.02185.x
  15. Pringsheim T, Davenport WJ, Mackie G, et al. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci. 2012;39(2 Suppl 2):S1-59.
  16. Eby GA 3rd, Eby KL. Magnesium for treatment-resistant depression: a review and hypothesis. Med Hypotheses. 2010;74(4):649-660. doi:10.1016/j.mehy.2009.10.051
  17. Eby GA, Eby KL, Murk H. Magnesium and major depression. In: Vink R, Nechifor M, eds. Magnesium in the Central Nervous System [Internet]. Adelaide (AU); 2011.
  18. Connolly E, Worthley LI. Intravenous magnesium. Crit Care Resusc. 1999;1(2):162-172.
  19. Taylor FR. Nutraceuticals and headache: the biological basis. Headache. 2011;51(3):484-501. doi:10.1111/j.1526-4610.2011.01847.x
  20. Romani AMP. Magnesium homeostasis and alcohol consumption. Magnes Res. 2008;21(4):197-204.
  21. Wolf FI, Trapani V, Cittadini A. Magnesium and the control of cell proliferation: looking for a needle in a haystack. Magnes Res. 2008;21(2):83-91.
  22. Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KM. Low brain magnesium in migraine. Headache. 1989;29(9):590-593.
  23. Jain AC, Sethi NC, Babbar PK. A clinical electroencephalographic and trace element study with special reference to zinc, copper, and magnesium in serum and cerebrospinal fluid (CSF) in cases of migraine. J Neurol. 1985;(Suppl)(232):161.
  24. Mody I, Lambert JD, Heinemann U. Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J Neurophysiol. 1987;57(3):869-888. doi:10.1152/jn.1987.57.3.869
  25. Coan EJ, Collingridge GL. Magnesium ions block an N-methyl-D-aspartate receptor-mediated component of synaptic transmission in rat hippocampus. Neurosci Lett. 1985;53(1):21-26.
  26. Baudouin-Legros M, Dard B, Guicheney P. Hyperreactivity of platelets from spontaneously hypertensive rats. Role of external magnesium. Hypertens (Dallas, Tex 1979). 1986;8(8):694-699.
  27. Altura BM, Altura BT. Cardiovascular risk factors and magnesium: relationships to atherosclerosis, ischemic heart disease and hypertension. Magnes Trace Elem. 10(2-4):182-192.
  28. Altura BM, Altura BT. New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. I. Clinical aspects. Magnesium. 1985;4(5-6):226-244.
  29. Altura BT, Altura BM. The role of magnesium in etiology of strokes and cerebrovasospasm. Magnesium. 1982;1:277-291.
  30. Turlapaty PD, Altura BM. Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science. 1980;208(4440):198-200.
  31. Altura BM, Altura BT, Carella A, Gebrewold A, Murakawa T, Nishio A. Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus organic calcium channel blockers on myogenic tone and agonist-induced responsiveness of blood vessels. Can J Physiol Pharmacol. 1987;65(4):729-745.
  32. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991;31(5):298-301.
  33. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257-263. doi:10.1046/j.1468-2982.1996.1604257.x
  34. Koseoglu E, Talaslioglu A, Gonul AS, Kula M. The effects of magnesium prophylaxis in migraine without aura. Magnes Res. 2008;21(2):101-108.
  35. Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in the prophylaxis of migraine–a double-blind placebo-controlled study. Cephalalgia. 1996;16(6):436-440. doi:10.1046/j.1468-2982.1996.1606436.x
  36. Rajapakse T, Pringsheim T. Nutraceuticals in Migraine: A Summary of Existing Guidelines for Use. Headache. 2016;56(4):808-816. doi:10.1111/head.12789
  37. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: arandomized trial. Headache. 2004;44(9):885-890. doi:10.1111/j.1526-4610.2004.04170.x
  38. Guilbot A, Bangratz M, Ait Abdellah S, Lucas C. A combination of coenzyme Q10, feverfew and magnesium for migraine prophylaxis: a prospective observational study. BMC Complement Altern Med. 2017;17(1):433. doi:10.1186/s12906-017-1933-7
  39. The Dizzy Cook. The Best Magnesium Supplements for Migraine. https://thedizzycook.com/magnesium-supplements-explained-which-one-is-best-for-vestibular-migraine/. Accessed December 6, 2020.
  40. Wheeler S. Vitamin D deficiency common in patients with chronic migraine. In: American Headache Society 50th Annual Scientific Meeting: Abstract S33.
  41. Titus F, Davalos A, Alom J, Codina A. 5-Hydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial. Eur Neurol. 1986;25(5):327-329. doi:10.1159/000116030
  42. Bono G, Criscuoli M, Martignoni E, Salmon S, Nappi G. Serotonin precursors in migraine prophylaxis. Adv Neurol. 1982;33:357-363.
  43. Yoon M-S, Savidou I, Diener H-C, Limmroth V. Evidence-based medicine in migraine prevention. Expert Rev Neurother. 2005;5(3):333-341. doi:10.1586/14737175.5.3.333
  44. Maissen CP, Ludin HP. [Comparison of the effect of 5-hydroxytryptophan and propranolol in the intervaltreatment of migraine]. Schweiz Med Wochenschr. 1991;121(43):1585-1590.
  45. Ribeiro CA. L-5-Hydroxytryptophan in the prophylaxis of chronic tension-type headache: a double-blind, randomized, placebo-controlled study. For the Portuguese Head Society. Headache. 2000;40(6):451-456.
  46. James M, Proudman S, Cleland L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc. 2010;69(3):316-323. doi:10.1017/S0029665110001564
  47. Calder PC. Fatty acids and inflammation: the cutting edge between food and pharma. Eur J Pharmacol. 2011;668 Suppl:S50-8. doi:10.1016/j.ejphar.2011.05.085
  48. Proudman SM, James MJ, Spargo LD, et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis. 2015;74(1):89-95. doi:10.1136/annrheumdis-2013-204145
  49. Harel Z, Gascon G, Riggs S, Vaz R, Brown W, Exil G. Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents. J Adolesc Health. 2002;31(2):154-161.
  50. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007;129(1-2):210-223. doi:10.1016/j.pain.2007.01.020
  51. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68(5):280-289. doi:10.1111/j.1753-4887.2010.00287.x
  52. Rosenbaum CC, O’Mathuna DP, Chavez M, Shields K. Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis. Altern Ther Health Med. 2010;16(2):32-40.
  53. Hurst S, Zainal Z, Caterson B, Hughes CE, Harwood JL. Dietary fatty acids and arthritis. Prostaglandins Leukot Essent Fatty Acids. 2010;82(4-6):315-318. doi:10.1016/j.plefa.2010.02.008
  54. Koo B, Becker LE, Chuang S, et al. Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations. Ann Neurol. 1993;34(1):25-32. doi:10.1002/ana.410340107
  55. Lanteri-Minet M, Desnuelle C. [Migraine and mitochondrial dysfunction]. Rev Neurol (Paris). 1996;152(4):234-238.
  56. Montagna P, Cortelli P, Monari L, et al. 31P-magnetic resonance spectroscopy in migraine without aura. Neurology. 1994;44(4):666-669. doi:10.1212/wnl.44.4.666
  57. Bresolin N, Martinelli P, Barbiroli B, et al. Muscle mitochondrial DNA deletion and 31P-NMR spectroscopy alterations in a migraine patient. J Neurol Sci. 1991;104(2):182-189.
  58. Sparaco M, Feleppa M, Lipton RB, Rapoport AM, Bigal ME. Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia. 2006;26(4):361-372. doi:10.1111/j.1468-2982.2005.01059.x
  59. Evans RW, Taylor FR. “Natural” or alternative medications for migraine prevention. Headache. 2006;46(6):1012-1018. doi:10.1111/j.1526-4610.2006.00473.x
  60. O’Brien HL, Hershey AD. Vitamins and paediatric migraine: Riboflavin as a preventative medication. Cephalalgia. 2010;30(12):1417-1418. doi:10.1177/0333102410378358
  61. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology. 1998;50(2):466-470. doi:10.1212/wnl.50.2.466
  62. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660(1-2):171-199.
  63. Beyer RE, Burnett BA, Cartwright KJ, et al. Tissue coenzyme Q (ubiquinone) and protein concentrations over the life span of the laboratory rat. Mech Ageing Dev. 1985;32(2-3):267-281.
  64. Hershey AD, Powers SW, Vockell A-LB, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. 2007;47(1):73-80. doi:10.1111/j.1526-4610.2007.00652.x
  65. Rozen TD, Oshinsky ML, Gebeline CA, et al. Open label trial of coenzyme Q10 as a migraine preventive. Cephalalgia. 2002;22(2):137-141. doi:10.1046/j.1468-2982.2002.00335.x
  66. Sandor PS, Di Clemente L, Coppola G, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology. 2005;64(4):713-715. doi:10.1212/01.WNL.0000151975.03598.ED
  67. Matalon R, Stumpf DA, Michals K, Hart RD, Parks JK, Goodman SI. Lipoamide dehydrogenase deficiency with primary lactic acidosis: favorable response to treatment with oral lipoic acid. J Pediatr. 1984;104(1):65-69.
  68. Magis D, Ambrosini A, Sandor P, Jacquy J, Laloux P, Schoenen J. A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. 2007;47(1):52-57. doi:10.1111/j.1526-4610.2006.00626.x
  69. Silberstein SD. Preventive Migraine Treatment. Continuum (Minneap Minn). 2015;21(4 Headache):973-989. doi:10.1212/CON.0000000000000199
  70. D’Onofrio F, Raimo S, Spitaleri D, Casucci G, Bussone G. Usefulness of nutraceuticals in migraine prophylaxis. Neurol Sci Off J Ital Neurol Soc  Ital Soc Clin Neurophysiol. 2017;38(Suppl 1):117-120. doi:10.1007/s10072-017-2901-1
  71. Wider B, Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane database Syst Rev. 2015;4:CD002286. doi:10.1002/14651858.CD002286.pub3
  72. Saranitzky E, White CM, Baker EL, Baker WL, Coleman CI. Feverfew for migraine prophylaxis: a systematic review. J Diet Suppl. 2009;6(2):91-103. doi:10.1080/19390210902861809
  73. Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane database Syst Rev. 2004;(1):CD002286. doi:10.1002/14651858.CD002286.pub2
  74. Ernst E, Pittler MH. The efficacy and safety of feverfew (Tanacetum parthenium L.): an update of a systematic review. Public Health Nutr. 2000;3(4A):509-514. doi:10.1017/s1368980000000598
  75. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia. 1998;18(10):704-708. doi:10.1046/j.1468-2982.1998.1810704.x
  76. Heptinstall S, White A, Williamson L, Mitchell JR. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet (London, England). 1985;1(8437):1071-1074.
  77. Barsby RW, Salan U, Knight DW, Hoult JR. Feverfew and vascular smooth muscle: extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. Planta Med. 1993;59(1):20-25. doi:10.1055/s-2006-959596
  78. Bejar E. Parthenolide inhibits the contractile responses of rat stomach fundus to fenfluramine and dextroamphetamine but not serotonin. J Ethnopharmacol. 1996;50(1):1-12.
  79. Weber JT, O’Connor MF, Hayataka K, et al. Activity of Parthenolide at 5HT2A receptors. J Nat Prod. 1997;60(6):651-653. doi:10.1021/np960644d
  80. Mittra S, Datta A, Singh SK, Singh A. 5-Hydroxytryptamine-inhibiting property of Feverfew: role of parthenolide content. Acta Pharmacol Sin. 2000;21(12):1106-1114.
  81. Shrivastava R, Pechadre JC, John GW. Tanacetum parthenium and Salix alba (Mig-RL) combination in migraine prophylaxis: a prospective, open-label study. Clin Drug Investig. 2006;26(5):287-296. doi:10.2165/00044011-200626050-00006
  82. Heptinstall S, Groenewegen WA, Spangenberg P, Losche W. Inhibition of platelet behaviour by feverfew: a mechanism of action involving sulphydryl groups. Folia Haematol Int Mag Klin Morphol Blutforsch. 1988;115(4):447-449.
  83. Heptinstall S, Groenewegen WA, Spangenberg P, Loesche W. Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups. J Pharm Pharmacol. 1987;39(6):459-465.
  84. Loesche W, Groenewegen WA, Krause S, Spangenberg P, Heptinstall S. Effects of an extract of feverfew (Tanacetum parthenium) on arachidonic acid metabolism in human blood platelets. Biomed Biochim Acta. 1988;47(10-11):S241-3.
  85. Pugh WJ, Sambo K. Prostaglandin synthetase inhibitors in feverfew. J Pharm Pharmacol. 1988;40(10):743-745.
  86. Makheja AN, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium). Prostaglandins Leukot Med. 1982;8(6):653-660.
  87. Collier HO, Butt NM, McDonald-Gibson WJ, Saeed SA. Extract of feverfew inhibits prostaglandin biosynthesis. Lancet (London, England). 1980;2(8200):922-923.
  88. Thakkar JK, Sperelakis N, Pang D, Franson RC. Characterization of phospholipase A2 activity in rat aorta smooth muscle cells. Biochim Biophys Acta. 1983;750(1):134-140.
  89. Marles RJ, Kaminski J, Arnason JT, et al. A bioassay for inhibition of serotonin release from bovine platelets. J Nat Prod. 1992;55(8):1044-1056.
  90. Diener HC, Pfaffenrath V, Schnitker J, Friede M, Henneicke-von Zepelin H-H. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention–a randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia. 2005;25(11):1031-1041. doi:10.1111/j.1468-2982.2005.00950.x
  91. Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke-von Zepelin HH. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis–a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia. 2002;22(7):523-532. doi:10.1046/j.1468-2982.2002.00396.x
  92. Benemei S, De Logu F, Li Puma S, et al. The anti-migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel. Br J Pharmacol. 2017;174(17):2897-2911. doi:10.1111/bph.13917
  93. Eaton J. Butterbur, herbal help for migraine. Nat Pharm. 1998;2:23-24.
  94. Pearlman EM, Fisher S. Preventive treatment for childhood and adolescent headache: Role of once-daily montelukast sodium. (Abstract). Cephalalgia. 2001;21:461.
  95. Sheftell F, Rapoport A, Weeks R, Walker B, Gammerman I, Baskin S. Montelukast in the prophylaxis of migraine: a potential role for leukotriene modifiers. Headache. 2000;40(2):158-163.
  96. Fiebich BL, Grozdeva M, Hess S, et al. Petasites hybridus extracts in vitro inhibit COX-2 and PGE2 release by direct interaction with the enzyme and by preventing p42/44 MAP kinase activation in rat primary microglial cells. Planta Med. 2005;71(1):12-19. doi:10.1055/s-2005-837744
  97. Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with aspecial butterbur root extract. Headache. 2005;45(3):196-203. doi:10.1111/j.1526-4610.2005.05044.x
  98. Grossman M, Schmidrams H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Int J Clin Pharmacol Ther. 2000;38:430-435.
  99. Diener H, Rahlfs V, Danesch U. The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: Reanalysis of efficacy criteria. Eur Neurol. 2004;51(2):89-97. doi:10.1159/000076535
  100. Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;63(12):2240-2244. doi:10.1212/01.wnl.0000147290.68260.11
  101. Srivastava KC, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Med Hypotheses. 1989;29(1):25-28.
  102. Srivastava KC, Mustafa T. Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypotheses. 1992;39(4):342-348.
  103. Mustafa T, Srivastava KC. Ginger (Zingiber officinale) in migraine headache. J Ethnopharmacol. 1990;29(3):267-273.
  104. Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache J Head Face Pain. 2018;58(7):1139-1186. doi:10.1111/head.13345
  105. Baron EP. Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache J Head Face Pain. 2015;55(6):885-916. doi:10.1111/head.12570
  106. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245-259.
  107. Russo E. Hemp for headache: an in-depth historical and scientific review of cannabis in migraine treatment. J Cannabis Ther. 2001;1:21-92.
  108. Russo E. Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain. 1998;76(1-2):3-8.
  109. Lochte BC, Beletsky A, Samuel NK, Grant I. The Use of Cannabis for Headache Disorders. Cannabis cannabinoid Res. 2017;2(1):61-71. doi:10.1089/can.2016.0033 [doi]
  110. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev. 2011;12(10):570-584. doi:10.1038/nrn3057 [doi]
  111. Greco R, Gasperi V, Sandrini G, et al. Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat. Cephalalgia. 2010;30(3):296-302. doi:10.1111/j.1468-2982.2009.01924.x [doi]
  112. Haj-Dahmane S, Shen RY. Endocannabinoids suppress excitatory synaptic transmission to dorsal raphe serotonin neurons through the activation of presynaptic CB1 receptors. J Pharmacol Exp Ther. 2009;331(1):186-196. doi:10.1124/jpet.109.153858 [doi]
  113. Palazzo E, de Novellis V, Petrosino S, et al. Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system. Eur J Neurosci. 2006;24(7):2011-2020. doi:EJN5086 [pii]
  114. Voth EA, Schwartz RH. Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med. 1997;126(10):791-798.
  115. Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther. 2004;309(1):56-63. doi:10.1124/jpet.103.059808 [doi]
  116. Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther. 2007;320(1):64-71. doi:jpet.106.106971 [pii]
  117. Kelly S, Chapman V. Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo. J Neurophysiol. 2001;86(6):3061-3064.
  118. Meng ID, Johansen JP. Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience. 2004;124(3):685-693. doi:10.1016/j.neuroscience.2003.10.001 [doi]
  119. Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia circuit activated by cannabinoids. Nature. 1998;395(6700):381-383. doi:10.1038/26481 [doi]
  120. Palazzo E, Marabese I, de Novellis V, et al. Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacology. 2001;40(3):319-326. doi:S002839080000160X [pii]
  121. Finn DP, Jhaveri MD, Beckett SR, et al. Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology. 2003;45(5):594-604. doi:S0028390803002351 [pii]
  122. Maione S, Bisogno T, de Novellis V, et al. Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 re. J Pharmacol Exp Ther. 2006;316(3):969-982. doi:jpet.105.093286 [pii]
  123. de Novellis V, Mariani L, Palazzo E, et al. Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat. Neuroscience. 2005;134(1):269-281. doi:S0306-4522(05)00334-9 [pii]
  124. Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: implications in migraine. J Neurosci. 2013;33(37):14869-14877. doi:10.1523/JNEUROSCI.0943-13.2013 [doi]
  125. Knight YE, Goadsby PJ. The periaqueductal grey matter modulates trigeminovascular input: a role in migraine? Neuroscience. 2001;106(4):793-800. doi:S0306452201003037 [pii]
  126. Knight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci. 2002;22(5):RC213-8P_$Fhttp://www.ncbi.nlm.nih. doi:20026167 [pii]
  127. Knight YE, Bartsch T, Goadsby PJ. Trigeminal antinociception induced by bicuculline in the periaqueductal gray (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neurosci Lett. 2003;336(2):113-116. doi:S0304394002012508 [pii]
  128. Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor 1 gene predispose to migraine. Neurosci Lett. 2009;461(2):116-120. doi:10.1016/j.neulet.2009.06.021 [doi]
  129. Nyholt DR, Morley KI, Ferreira MA, et al. Genomewide significant linkage to migrainous headache on chromosome 5q21. Am J Hum Genet. 2005;77(3):500-512. doi:S0002-9297(07)63030-4 [pii]
  130. Bartsch T, Knight YE, Goadsby PJ. Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann Neurol. 2004;56(3):371-381. doi:10.1002/ana.20193 [doi]
  131. Vaughan CW, McGregor IS, Christie MJ. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol. 1999;127(4):935-940. doi:10.1038/sj.bjp.0702636 [doi]
  132. Vaughan CW, Connor M, Bagley EE, Christie MJ. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol. 2000;57(2):288-295.
  133. Greco R, Mangione AS, Sandrini G, Nappi G, Tassorelli C. Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model. J Headache Pain. 2014;15:14. doi:10.1186/1129-2377-15-14 [doi]
  134. Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int J Clin Pharmacol Res. 1985;5(4):243-246.
  135. Greco R, Gasperi V, Maccarrone M, Tassorelli C. The endocannabinoid system and migraine. Exp Neurol. 2010;224(1):85-91. doi:10.1016/j.expneurol.2010.03.029 [doi]
  136. Mailleux P, Vanderhaeghen JJ. Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons. Neurosci Lett. 1992;148(1-2):173-176.
  137. Moldrich G, Wenger T. Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides. 2000;21(11):1735-1742. doi:S0196-9781(00)00324-7 [pii]
  138. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2008;29(2):192-200. doi:NEL290208R02 [pii]
  139. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2004;25(1-2):31-39. doi:NEL251204R02 [pii]
  140. Noyes Jr R, Baram DA. Cannabis analgesia. Compr Psychiatry. 1974;15(6):531-535.
  141. Schnelle M, Grotenhermen F, Reif M, Gorter RW. Results of a standardized survey on the medical use of cannabis products in the German-speaking area. Forsch Komplementarmed. 1999;6 Suppl 3:28-36. doi:57154 [pii]
  142. el-Mallakh RS. Marijuana and migraine. Headache. 1987;27(8):442-443.
  143. Grinspoon L, Bakalar JB. Marihuana: The Forbidden Medicine. New Haven, CT: Yale University; 1993.
  144. el-Mallakh RS. Migraine headaches and drug abuse. South Med J. 1989;82(6):805.
  145. Gorji A. Pharmacological treatment of headache using traditional Persian medicine. Trends Pharmacol Sci. 2003;24(7):331-334. doi:S0165-6147(03)00164-0 [pii]
  146. Robbins MS, Tarshish S, Solomon S, Grosberg BM. Cluster attacks responsive to recreational cannabis and dronabinol. Headache. 2009;49(6):914-916. doi:10.1111/j.1526-4610.2009.01344.x [doi]
  147. Donnet A, Lanteri-Minet M, Guegan-Massardier E, et al. Chronic cluster headache: a French clinical descriptive study. J Neurol Neurosurg Psychiatry. 2007;78(12):1354-1358. doi:jnnp.2006.112037 [pii]
  148. Leroux E, Taifas I, Valade D, Donnet A, Chagnon M, Ducros A. Use of cannabis among 139 cluster headache sufferers. Cephalalgia. 2013;33(3):208-213. doi:10.1177/0333102412468669 [doi]
  149. Evans RW, Ramadan NM. Are cannabis-based chemicals helpful in headache? Headache. 2004;44(7):726-727. doi:10.1111/j.1526-4610.2004.04133C.x [doi]
  150. Consroe P, Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol. 1997;38(1):44-48.
  151. Mackenzie S. Remarks on the value of Indian hemp in the treatment of a certain type of headache. Br Med J. 1887;1:97-98.
  152. Nunberg H, Kilmer B, Pacula RL, Burgdorf J. An Analysis of Applicants Presenting to a Medical Marijuana Specialty Practice in California. J Drug Policy Anal. 2011;4(1)://www.ncbi.nlm.nih. doi:1 [pii]
  153. Donovan M. On the physical and medicinal qualities of Indian hemp (Cannabis indica); with observations on the best mode of administration, and cases illustrative of its powers. Dublin J Med Sci. 1845;26:368-461.
  154. Reynolds JR. On some of the therapeutical uses of Indian hemp. Arch Med. 1868;2:154-160.
  155. Waring EJ. Practical Therapeutics. Philadelphia: Lindsay & Blakiston; 1874.
  156. Ringer S. A Handbook of Therapeutics. London: H.K. Lewis; 1886.
  157. Hare HA. Clinical and physiological notes on the action of Cannabis indica. There Gaz. 1887;11:225-228.
  158. Suckling CW. On the therapeutic value of Indian hemp. Br Med J. 1891;2:11-12.
  159. Mikuriya TH. Chronic Migraine Headache: Five Cases Successfully Treated with Marinol and/or Illicit Cannabis. Berkeley, CA: Schaffer Library of Drug Policy; 1991.
  160. Lucas P, Baron EP, Jikomes N. Medical cannabis patterns of use and substitution for opioids &amp; other pharmaceutical drugs, alcohol, tobacco, and illicit substances; results from a cross-sectional survey of authorized patients. Harm Reduct J. 2019;16(1):9. doi:10.1186/s12954-019-0278-6
  161. Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):1-28. doi:10.1186/s10194-018-0862-2
  162. Rhyne DN, Anderson SL, Gedde M, Borgelt LM. Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population. Pharmacotherapy. 2016;36(5):505-510. doi:10.1002/phar.1673 [doi]
  163. Pini LA, Guerzoni S, Cainazzo MM, et al. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain. 2012;13(8):677-684. doi:10.1007/s10194-012-0490-1 [doi]
  164. Nicolodi M, Sandoval V, Terrine A. Therapeutic use of cannabinoids – Dose Finding, Effects, and Pilot Data of Effects in Chronic Migraine and Cluster Headache. Abstract presentation at 3rd Congress of the European Academy of Neurology (EAN), Amsterdam, 6/24/17. In: 3rd Congress of the European Academy of Neurology (EAN), Amsterdam 6/24/17. Amsterdam.
  165. Committee of the Health Effects of Marijuana: An Evidence Review and Research. The Health Effects of Cannabis and Cannabinoids. The Current State of Evidence and Recommendations For Research.Washington, DC: The National Academies Press.; 2017.
  166. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-335.
  167. Russo EB. Cannabidiol Claims and Misconceptions. Trends Pharmacol Sci. 2017;38(3):198-201. doi:10.1016/j.tips.2016.12.004
  168. Pisanti S, Malfitano AM, Ciaglia E, et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol Ther. 2017;175:133-150. doi:S0163-7258(17)30065-7 [pii]
  169. White CM. A Review of Human Studies Assessing Cannabidiol’s (CBD) Therapeutic Actions and Potential. J Clin Pharmacol. 2019;59(7):923-934. doi:10.1002/jcph.1387
  170. Palmieri B, Laurino C, Vadala M. Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination. Isr Med Assoc J. 2017;19(2):79-84.
  171. Cunetti L, Manzo L, Peyraube R, Arnaiz J, Curi L, Orihuela S. Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant Proc. 2018;50(2):461-464. doi:10.1016/j.transproceed.2017.12.042
  172. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17(1):21-29.
  173. Philpott HT, O’Brien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017;158(12):2442-2451. doi:10.1097/j.pain.0000000000001052
  174. Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain. 2016;20(6):936-948. doi:10.1002/ejp.818
  175. Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000;97(17):9561-9566. doi:10.1073/pnas.160105897 [doi]
  176. Costa B, Colleoni M, Conti S, et al. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol. 2004;369(3):294-299. doi:10.1007/s00210-004-0871-3 [doi]
  177. World Health, Organization: Expert Committee on Drug Dependence. Cannabidiol (CBD) Pre-Review Report. http://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf.
  178. (WADA) WA-DA. “Prohibited List: January 2018”. The World Anti-Doping Code International Standard. https://www.wada-ama.org/sites/default/files/prohibited_list_2018_en.pdf.
  179. Garber-Paul E. Exclusive: New Report Predicts CBD Market Will Hit $22 Billion by 2022. Roll Stone. September 2018.
  180. Kovacevich N. With CBD, Cannabis Wellness Market Goes Big. Forbes. March 2019. https://www.forbes.com/sites/nickkovacevich/2019/03/06/with-cbd-cannabis-wellness-market-goes-big/#1591fba63fcb.
  181. Velasquez-Manoff M. Can CBD Really Do All That? How one molecule from the cannabis plant came to be seen as a therapeutic cure-all. New York Times. https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html. Published May 14, 2019.
  182. Williams A. Why is CBD Everywhere? New York Times. https://www.nytimes.com/2018/10/27/style/cbd-benefits.html. Published October 27, 2018.
  183. Schiller M. CVS and Walgreens Plan to Carry CBD Products: What’s Next for the Rapidly Growing Market? Cannabis Bus Times. April 2019. https://www.cannabisbusinesstimes.com/article/cvs-walgreens-carry-cbd-products-whats-next-for-market/.
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Last updated on September 17th, 2021 at 06:37 am

CBD (CANNABIDIOL) FOR MIGRAINE, HEADACHE, AND PAIN. EVERYTHING YOU NEED TO KNOW.

@Neuralgroover

BACKGROUND

CBD (cannabidiol) for migraine, headache, pain, chronic pain, arthritis, and other medical conditions are topics that patients are increasingly asking about. Why? CBD is everywhere! You can buy it at the local grocery store, supplement store, gas station, video rental store, and almost anywhere else nowadays. There are hundreds of brands. Is it right for you? Will it work? How do you take it? How do you know which products are of good quality and are safe? Are there downsides? Are there side effects? Will you test positive on a drug screen? These are a few of the many questions you likely have. Our patients ask about CBD use all the time in regard to migraine and pain. So, I decided to write this blog to provide an overview and answer these burning questions you may have!

 

There have been a multitude of studies documenting the analgesic and anti-inflammatory benefits of medicinal cannabis across many chronic pain syndromes1–4, and it has been a historical treatment for headache and migraine for centuries.2,3,5–7 An extensive discussion of medicinal cannabis, or medicinal marijuana, for chronic pain, headache, and migraine can be read here. The vast majority of supporting evidence of cannabis and cannabinoids involves various chronic pain syndromes. These benefits are hypothesized to extend to headache disorders such as migraine given overlapping neurobiological pathways of pain. Some data suggests that cannabinoids appear to work uniquely within the inherent anatomical pathways of migraine (including serotonergic triptan pathways) and pain.1,2,5–37 Unfortunately, the majority of data supporting the use of cannabis and cannabinoids in migraine and headache disorders is based on case series, case reports, surveys and anecdotal evidence.5,6,32,33,38–57 There has been one retrospective study of cannabis use in the treatment of migraine which reported strong statistically significant findings of benefit.58 There have been only two limited prospective trials of cannabinoids containing a control group in headache disorders. One reported significant benefit in chronic daily headache associated with medication overuse headache,59 and the other reported significant benefit in both the acute and preventive treatment of chronic migraine.60

 

The endocannabinoid system is a normal and important biological system within everyone. It plays a role in many regulatory physiological processes across all organ systems, and is widely distributed throughout the central nervous system (brain and spinal cord) and peripheral nervous system (nerves outside of the spinal canal). Notably, it plays a strong role in pain pathways. This system works by the interaction of our own natural endocannabinoids turning on or turning off various endocannabinoid receptors throughout our body.

 

Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are the two predominant cannabinoids found in cannabis (marijuana). Cannabinoids are unique to the cannabis plant, and can be thought of as the “plant equivalents” of our own endocannabinoids. So, they interact with the same endocannabinoid receptors in our body as our own endocannabinoids do. Given the growing evidence of cannabis and cannabinoids in the treatment of chronic pain and other medical conditions, in February 2019 The World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category. In January 2017, the National Academies of Sciences, Engineering, and Medicine concluded that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults. In 2014, the Canadian Pain Society revised their consensus statement to recommend cannabinoids as a third-level therapy for chronic neuropathic pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3 (the number of patients needed to treat for 1 of them to receive benefit). So naturally, there has been a quickly growing public interest in these potential therapies for a variety of reasons, especially in pain disorders.

 

THC causes the psychoactive qualities (“high”) of cannabis. THC has been shown to be 20 times more anti-inflammatory than aspirin and 2 times as anti-inflammatory as hydrocortisone. It is also a potent anti-emetic (anti-nausea), which is why there are two FDA-approved synthetic THC medications for chemotherapy related nausea and vomiting (Dronabinol, Nabilone). The existing literature and research on the treatment of pain have primarily studied cannabis itself with its variable and often undefined combinations of THC, CBD, other cannabinoids, terpenes, and other constituents. The medicinal benefits of cannabis are suspected to be from the “entourage effects” from synergistic action (working together) between various cannabinoids such as THC and CBD, and terpenes.1,61

 

In contrast to THC, CBD is non-intoxicating (no “high”). CBD has been shown to be several hundred more times anti-inflammatory than aspirin. Greater than 65 molecular receptor targets and greater than 80 mechanisms of action have been identified. There have been scientific, animal models, and very limited human clinical trials documenting its anti-inflammatory and analgesic (pain-relieving) properties. However, there are no high-quality research studies to date evaluating isolated pure CBD in any pain, migraine, or other headache disorders. So, it is unclear how much benefit CBD in isolation provides outside of the presumed entourage effects that it contributes to.

 

In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related problems associated with its use. In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes. In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD. The Farm Bill also removed hemp from the Controlled Substances Act, making it no longer an illegal substance under federal law. To review, up until the Farm Bill was passed, any form of cannabis or cannabis derivatives (including CBD) have been federally illegal since the Controlled Substance Act of 1970, which is when cannabis was changed to a Schedule 1 drug of which it has remained since. Therefore, it is important to remember that cannabis chemovars (strains) and CBD oils with greater than 0.3% THC are still considered marijuana, and thus are illegal federally, require a medical marijuana card for use, and are illegal to cross state lines with. In May 2019, TSA began to allow travel with CBD products containing 0.3% or less of THC.

 

Thus, the use of CBD products has been exponentially increasing for a wide variety of uses, including pain and headache, and anecdotal benefits are commonly reported. Although the various CBD companies provide guidance on dosing, there are no standardized dosing guidelines on optimal dosing, and strengths and frequencies used are widely variable. Some cannabinoid experts feel that most over the counter bought CBD products have too low of milligram content to have true physiological effects based on the high dose needed to enter the central nervous system through the blood-brain barrier. On the other hand, some suggest that “micro-dosing” with the lower CBD doses found in many products is enough to help replace endocannabinoid deficiencies. These dosing uncertainties have yet to be clarified and confirmed scientifically. Pure isolated CBD has never been evaluated prospectively in a randomized controlled trial in the treatment of migraine, headache, or pain to date. So, its use in the treatment of pain disorders including migraine remains primarily anecdotal at this time, but we anticipate future trials will provide more objective scientific data. The FDA is currently gathering and assessing available objective scientific data in anticipation of providing general dosing guidelines and recommendations of use.

 

WHAT IS THE BEST CBD DOSE AND HOW DO I INCREASE THE DOSE?

For CBD dosing, a good general guideline of how to begin CBD dosing with a gentle titration is as follows:

-Week 1: 5-10 mg at bedtime

-Week 2: 5-10 mg twice daily

-Weeks 3-4: 5-10 mg three times daily

-Weeks 5 onwards: 20 mg three times daily

 

SAFETY AND SIDE EFFECTS OF CBD

CBD is generally very well tolerated, and pure CBD is not felt to be sedating. Actually, low to moderate doses are often more alerting.62 Early anecdotal literature involved CBD with sedating components (full spectrum products) including trace THC, other cannabinoids, and terpenes. For example, myrcene is a terpene often attributed to the “couch lock” phenomenon of some cannabis chemovars (strains). So, the sedation was not from the CBD, but actually from these other associated components. More recent studies (up to 600 mg pure CBD) have reported no sedative side effects.

 

There is one FDA approved form of CBD called Epidiolex, and these trials are what most of the known CBD safety data comes from. This is a purified cannabis derived form of CBD which was FDA approved in June of 2018 for some forms of refractory pediatric epilepsies.63 Dosing ranges from 5 to 20 milligrams per kilogram body weight total daily dose, which is divided between a morning and evening dose. These does are significantly higher than any form of over the counter non-prescription forms of CBD commonly sold. CBD is metabolized (broken down) in the liver. So, patients with liver disease many need to be more cautious with their dosing. In the Epidiolex studies, there was a slight elevation in liver enzymes in some patients. However, the vast majority of these liver enzyme elevations were in patients using the highest 20 milligram per kilogram daily dose and particularly when CBD was also being used with other anti-seizure medications, especially valproate and clobazam. This risk was much lower in patients outside of these categories. None the less, caution should be used when CBD is used with other medications that are metabolized by the same liver enzyme systems to avoid causing high or low levels of other medications. For example, high doses of CBD (such as those in the Epidiolex trials) may increase levels of certain medications such as warfarin, macrolide antibiotics, calcium channel blocker blood pressure medications, benzodiazepines, cyclosporine immunosuppressants, sildenafil, antihistamines, antidepressants, antipsychotics, antiretrovirals (such as HIV meds), and some antiseizure medications (such as clobazam), to name a few. With that said, the more commonly used doses bought over the counter are nowhere near the high doses of CBD in Epidiolex, so the clinical relevance of CBD use with these liver interactions is unclear at much lower doses. For example, Sativex studies (a whole plant CBD rich sublingual spray) found no interactions with liver enzyme systems with 40 mg CBD. The bottom line is that there are still many uncertainties so it is better to use caution until future studies can help clarify these questions.

 

In the Epidiolex studies, the most common adverse effects in a minority of patients were somnolence, lethargy, drowsiness, fatigue, diarrhea, decreased appetite, and nausea/vomiting. However, these side effects were in patients who were also using other anti-seizure medications (virtually all of which have drowsiness as a universal side effect). In addition, Epidiolex is about 98% pure CBD, but still contains 0.15% or less of THC, traces other cannabinoids and terpenes at a dose of 10 milligrams per kilogram per day. Therefore, these side effects are most likely to be related to these other factors rather than from the CBD content itself.

 

DIFFERENCES IN CBD PRODUCT TYPE, QUALITY, AND SAFETY

CBD has a wide variety of formulations from oral (primarily oils), tinctures, vaporization, and topical creams. Full spectrum or “whole plant” oral CBD products are the most popular. They are most likely to provide the “entourage effects” of cannabis. They contain everything the cannabis plant contains including CBD, trace THC (should be ≤0.3% per Federal law), terpenes, and flavonoids. Broad spectrum CBD products can be thought of as full spectrum without the trace THC. CBD isolate products consist of CBD isolated from all plant contents, without trace THC. It is important to know that use of these products may have a risk of testing positive on a marijuana drug test (which tests for THC). Although this risk is very low and can also be influenced by differing metabolisms between people, it is still a risk to be aware of. The risk of this correlates with the presence of trace THC and this risk would be highest in full spectrum, followed by broad spectrum, followed by CBD isolate products. Lastly, there is a misconception that CBD converts into THC in the human body. This is not true, and there is no evidence of this happening in the human body, and actually more evidence that it does not happen.62 This notion was based on an old lab-based experiment which involved acids and conditions which are not reflective of normal human physiology.

 

CBD products chosen should include independent 3rd party laboratory testing for content and quality. The reason is because there are so many CBD companies and products, and many of them are of low quality. In 2017, there was a study published in the Journal of the American Medical Association (JAMA) which evaluated 84 CBD products analyzed from 31 different companies, including 40 oils, 24 vaporization liquids, and 20 tinctures.64 Only about 30% of the products were labeled accurately with what they claimed to contain, while about 70% of the products were inaccurately labeled based on actual CBD content (43% had higher than advertised CBD, 26% had lower than advertised CBD). In addition, 21.4% had high levels of THC, above legal limits.

 

Another study looked at 13 CBD products tested across Los Angeles and New Jersey.65 Five of them (almost half) had no traceable CBD, and only 1 had an accurately advertised amount of CBD! Two had high THC (3 mg), 1 CBD gel cap product was contaminated with a deadly strain of E. Coli (shiga toxin), and 2 had potentially dangerous levels of ethanol.

 

In 2017, 5 patients in Utah developed seizures, confusion, coma, and hallucinations with a labeled “CBD” product, and 52 patients were harmed through 2018 with this product. This “CBD” product actually contained a synthetic cannabinoid and no CBD at all. The International Cannabis and Cannabinoid Institute in the Czech Republic assessed 29 CBD products and found that 69% exceeded the recommended levels of polycyclic aromatic hydrocarbons. These are known carcinogens and genotoxic mutagens according to International Agency for Research on Cancer. Unregulated CBD products may contain pesticides or heavy metal contamination as well.

 

CONCLUSIONS

In summary, CBD shows analgesic and anti-inflammatory effects in scientific and animal models, but there is limited data involving human studies. However, this should be changing soon now that CBD is federally legal with easier access to research. None the less, there may be a wide variety of tremendous therapeutic potential to be harnessed. Non-FDA approved forms of CBD may have inconsistent levels of CBD, THC, and contamination. Therefore, non-FDA approved forms of CBD should be from companies using independent 3rd-party lab analysis to confirm quality and contents until FDA regulations are available. It is important to know that CBD involves drug interactions with some common liver enzyme metabolism systems, but dosing threshold to interfere with other medications being metabolized in these same pathways is unclear and needs to be further clarified.

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

REFERENCES

 

  1. Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache J Head Face Pain. 2018;58(7):1139-1186. doi:10.1111/head.13345
  2. Baron EP. Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache J Head Face Pain. 2015;55(6):885-916. doi:10.1111/head.12570
  3. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245-259.
  4. Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):1-28. doi:10.1186/s10194-018-0862-2
  5. Russo E. Hemp for headache: an in-depth historical and scientific review of cannabis in migraine treatment. J Cannabis Ther. 2001;1:21-92.
  6. Russo E. Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain. 1998;76(1-2):3-8.
  7. Lochte BC, Beletsky A, Samuel NK, Grant I. The Use of Cannabis for Headache Disorders. Cannabis cannabinoid Res. 2017;2(1):61-71. doi:10.1089/can.2016.0033 [doi]
  8. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev. 2011;12(10):570-584. doi:10.1038/nrn3057 [doi]
  9. Greco R, Gasperi V, Sandrini G, et al. Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat. Cephalalgia. 2010;30(3):296-302. doi:10.1111/j.1468-2982.2009.01924.x [doi]
  10. Haj-Dahmane S, Shen RY. Endocannabinoids suppress excitatory synaptic transmission to dorsal raphe serotonin neurons through the activation of presynaptic CB1 receptors. J Pharmacol Exp Ther. 2009;331(1):186-196. doi:10.1124/jpet.109.153858 [doi]
  11. Palazzo E, de Novellis V, Petrosino S, et al. Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system. Eur J Neurosci. 2006;24(7):2011-2020. doi:EJN5086 [pii]
  12. Voth EA, Schwartz RH. Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med. 1997;126(10):791-798.
  13. Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther. 2004;309(1):56-63. doi:10.1124/jpet.103.059808 [doi]
  14. Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther. 2007;320(1):64-71. doi:jpet.106.106971 [pii]
  15. Kelly S, Chapman V. Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo. J Neurophysiol. 2001;86(6):3061-3064.
  16. Meng ID, Johansen JP. Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience. 2004;124(3):685-693. doi:10.1016/j.neuroscience.2003.10.001 [doi]
  17. Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia circuit activated by cannabinoids. Nature. 1998;395(6700):381-383. doi:10.1038/26481 [doi]
  18. Palazzo E, Marabese I, de Novellis V, et al. Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacology. 2001;40(3):319-326. doi:S002839080000160X [pii]
  19. Finn DP, Jhaveri MD, Beckett SR, et al. Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology. 2003;45(5):594-604. doi:S0028390803002351 [pii]
  20. Maione S, Bisogno T, de Novellis V, et al. Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 re. J Pharmacol Exp Ther. 2006;316(3):969-982. doi:jpet.105.093286 [pii]
  21. de Novellis V, Mariani L, Palazzo E, et al. Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat. Neuroscience. 2005;134(1):269-281. doi:S0306-4522(05)00334-9 [pii]
  22. Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: implications in migraine. J Neurosci. 2013;33(37):14869-14877. doi:10.1523/JNEUROSCI.0943-13.2013 [doi]
  23. Knight YE, Goadsby PJ. The periaqueductal grey matter modulates trigeminovascular input: a role in migraine? Neuroscience. 2001;106(4):793-800. doi:S0306452201003037 [pii]
  24. Knight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci. 2002;22(5):RC213-8P_$Fhttp://www.ncbi.nlm.nih. doi:20026167 [pii]
  25. Knight YE, Bartsch T, Goadsby PJ. Trigeminal antinociception induced by bicuculline in the periaqueductal gray (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neurosci Lett. 2003;336(2):113-116. doi:S0304394002012508 [pii]
  26. Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor 1 gene predispose to migraine. Neurosci Lett. 2009;461(2):116-120. doi:10.1016/j.neulet.2009.06.021 [doi]
  27. Nyholt DR, Morley KI, Ferreira MA, et al. Genomewide significant linkage to migrainous headache on chromosome 5q21. Am J Hum Genet. 2005;77(3):500-512. doi:S0002-9297(07)63030-4 [pii]
  28. Bartsch T, Knight YE, Goadsby PJ. Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann Neurol. 2004;56(3):371-381. doi:10.1002/ana.20193 [doi]
  29. Vaughan CW, McGregor IS, Christie MJ. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol. 1999;127(4):935-940. doi:10.1038/sj.bjp.0702636 [doi]
  30. Vaughan CW, Connor M, Bagley EE, Christie MJ. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol. 2000;57(2):288-295.
  31. Greco R, Mangione AS, Sandrini G, Nappi G, Tassorelli C. Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model. J Headache Pain. 2014;15:14. doi:10.1186/1129-2377-15-14 [doi]
  32. Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int J Clin Pharmacol Res. 1985;5(4):243-246.
  33. Greco R, Gasperi V, Maccarrone M, Tassorelli C. The endocannabinoid system and migraine. Exp Neurol. 2010;224(1):85-91. doi:10.1016/j.expneurol.2010.03.029 [doi]
  34. Mailleux P, Vanderhaeghen JJ. Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons. Neurosci Lett. 1992;148(1-2):173-176.
  35. Moldrich G, Wenger T. Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides. 2000;21(11):1735-1742. doi:S0196-9781(00)00324-7 [pii]
  36. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2008;29(2):192-200. doi:NEL290208R02 [pii]
  37. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2004;25(1-2):31-39. doi:NEL251204R02 [pii]
  38. Robbins MS, Tarshish S, Solomon S, Grosberg BM. Cluster attacks responsive to recreational cannabis and dronabinol. Headache. 2009;49(6):914-916. doi:10.1111/j.1526-4610.2009.01344.x [doi]
  39. Donnet A, Lanteri-Minet M, Guegan-Massardier E, et al. Chronic cluster headache: a French clinical descriptive study. J Neurol Neurosurg Psychiatry. 2007;78(12):1354-1358. doi:jnnp.2006.112037 [pii]
  40. Leroux E, Taifas I, Valade D, Donnet A, Chagnon M, Ducros A. Use of cannabis among 139 cluster headache sufferers. Cephalalgia. 2013;33(3):208-213. doi:10.1177/0333102412468669 [doi]
  41. Evans RW, Ramadan NM. Are cannabis-based chemicals helpful in headache? Headache. 2004;44(7):726-727. doi:10.1111/j.1526-4610.2004.04133C.x [doi]
  42. Consroe P, Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol. 1997;38(1):44-48.
  43. Mackenzie S. Remarks on the value of Indian hemp in the treatment of a certain type of headache. Br Med J. 1887;1:97-98.
  44. Nunberg H, Kilmer B, Pacula RL, Burgdorf J. An Analysis of Applicants Presenting to a Medical Marijuana Specialty Practice in California. J Drug Policy Anal. 2011;4(1)://www.ncbi.nlm.nih. doi:1 [pii]
  45. Donovan M. On the physical and medicinal qualities of Indian hemp (Cannabis indica); with observations on the best mode of administration, and cases illustrative of its powers. Dublin J Med Sci. 1845;26:368-461.
  46. Reynolds JR. On some of the therapeutical uses of Indian hemp. Arch Med. 1868;2:154-160.
  47. Waring EJ. Practical Therapeutics. Philadelphia: Lindsay & Blakiston; 1874.
  48. Ringer S. A Handbook of Therapeutics. London: H.K. Lewis; 1886.
  49. Hare HA. Clinical and physiological notes on the action of Cannabis indica. There Gaz. 1887;11:225-228.
  50. Suckling CW. On the therapeutic value of Indian hemp. Br Med J. 1891;2:11-12.
  51. Mikuriya TH. Chronic Migraine Headache: Five Cases Successfully Treated with Marinol and/or Illicit Cannabis.Berkeley, CA: Schaffer Library of Drug Policy; 1991.
  52. Noyes Jr R, Baram DA. Cannabis analgesia. Compr Psychiatry. 1974;15(6):531-535.
  53. Schnelle M, Grotenhermen F, Reif M, Gorter RW. Results of a standardized survey on the medical use of cannabis products in the German-speaking area. Forsch Komplementarmed. 1999;6 Suppl 3:28-36. doi:57154 [pii]
  54. el-Mallakh RS. Marijuana and migraine. Headache. 1987;27(8):442-443.
  55. Grinspoon L, Bakalar JB. Marihuana: The Forbidden Medicine. New Haven, CT: Yale University; 1993.
  56. el-Mallakh RS. Migraine headaches and drug abuse. South Med J. 1989;82(6):805.
  57. Gorji A. Pharmacological treatment of headache using traditional Persian medicine. Trends Pharmacol Sci. 2003;24(7):331-334. doi:S0165-6147(03)00164-0 [pii]
  58. Rhyne DN, Anderson SL, Gedde M, Borgelt LM. Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population. Pharmacotherapy. 2016;36(5):505-510. doi:10.1002/phar.1673 [doi]
  59. Pini LA, Guerzoni S, Cainazzo MM, et al. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain. 2012;13(8):677-684. doi:10.1007/s10194-012-0490-1 [doi]
  60. Nicolodi M, Sandoval V, Terrine A. Therapeutic use of cannabinoids – Dose Finding, Effects, and Pilot Data of Effects in Chronic Migraine and Cluster Headache. Abstract presentation at 3rd Congress of the European Academy of Neurology (EAN), Amsterdam, 6/24/17. In: 3rd Congress of the European Academy of Neurology (EAN), Amsterdam 6/24/17. Amsterdam.
  61. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364. doi:10.1111/j.1476-5381.2011.01238.x [doi]
  62. Russo EB. Cannabidiol Claims and Misconceptions. Trends Pharmacol Sci. 2017;38(3):198-201. doi:10.1016/j.tips.2016.12.004
  63. Pharma G. Epidiolex (Cannabidiol) Prescribing Information. Carlsbad, CA; 2018.
  64. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. 2017;318(17):1708-1709. doi:10.1001/jama.2017.11909
  65. CBD Craze: FOX 11 and Dr. Oz puts these popular products to the test. https://www.fox5dc.com/news/cbd-craze-fox-11-and-dr-oz-puts-these-popular-products-to-the-test.
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Last updated on November 23rd, 2021 at 08:50 pm

REBOUND HEADACHE (MEDICATION OVERUSE HEADACHE); WHAT IT IS, AND HOW TO BREAK FREE FROM THE VICIOUS CYCLE.

@Neuralgroover

Chronic daily headache being endlessly fueled and driven by rebound headache (medication overuse headache or MOH) is one of the most common headache disorders that headache specialists encounter every day in clinic. Chronic daily headache refers to 15-30 days of headache per month on average for 3 or more months. The most common cause of chronic daily headache is typically episodic migraine which has evolved into chronic migraine, in which at least 8 days out of those 15-30 days per month have migrainous characteristics (throbbiness, throbby, pounding, pulsating pain with nausea and/or sensitivity to light (photophobia) and sound (phonophobia)).

Patients that have a prior or current history of headaches such as migraine or tension-type headaches tend to be highly susceptible to developing rebound headache/MOH when certain medications are being used too frequently, but it predominantly occurs in patients with a history of migraine. The overused medications may be actively used for headache (usually the case), but they may also be used for something entirely different such as back pain, nerve pain, arthritis pain, or anything else. The reason these medications are being used doesn’t matter as much as the frequency that they are being used. When certain medications are used too frequently, it will inadvertently cause the patient’s prior migraines to emerge and begin to increase in frequency and severity until it eventually evolves over time into a chronic daily headache with worsening severity. Once someone is stuck in the rut of chronic daily headache from chronic migraine and rebound headache/MOH, it can be very challenging to pull them back out of this cycle, and the rebound/MOH must be eliminated before improvement can occur. In addition, preventative medications (daily medicines used to lessen the frequency and/or severity of headaches) and abortive (“as-needed” at headache onset) pain medications generally become less effective in the setting of rebound/MOH.

 

How Much Medicine Causes Rebound Headache (Medication Overuse Headache)?

Research has shown that medication overuse can transform episodic migraine (0-15 days of headache per month) to chronic migraine (15-30 days of headache per month) if the following medications are used at the following frequencies:

Greater than 10 days per month for 2 or more consecutive months of over the counter (OTC) pain medications (Tylenol, Excedrin, Acetaminophen, Aleve, Naproxen, Motrin, Advil, Ibuprofen, or other non-steroidal anti-inflammatories (NSAIDs)).

Greater than 10 days per month for 2 or more consecutive months of triptans (Sumatriptan, Rizatriptan, Zolmitriptan, Almotriptan, Frovatriptan, Naratriptan, Eletriptan).

Greater than 8 days per month for 2 or more months of any narcotic, opioid, or opiate medication (Vicodin, Norco, Hydrocodone, Oxycodone, Oxycontin, Percocet, Tramadol, Ultram, Ultracet, Morphine, Codeine, Dilaudid, etc.).

Greater than 5 days per month for 2 or more months of any butalbital containing medication (Fioricet, Fiorinal, Esgic); (also known as “the headache specialist’s worst enemy”).

How Do I Get Out of Rebound Headache?

The chronic daily headaches will never improve until a weaning detoxification from the overused medications happens. It can take up to 6-12 weeks for improvement to start to occur beginning after there is a consistent detoxification and minimizing use of the offending medication. This time-frame may vary depending on the medicine used, duration of use, frequency of use, and quantity of use. It is also important to know that as the patient is weaning and detoxing from the overused medications, headaches will commonly get worse (rebound) before they get better. The hardest part of breaking out of this cycle can be getting through that rebound hump. Unfortunately, there is not typically a “quick fix” for this scenario.

 

This process of weaning and detoxification is generally accompanied by starting and adjusting preventative daily headache medications by the patient’s physician. A general slow wean off of overused medications is seen below, and can be adjusted based on quantity and frequency of the overused medication:

Week 1: If using daily, decrease to half of the amount of medication typically used daily (for example, if taking Tylenol 4 times per day, decrease to 2 times per day, etc.).
Week 2: Use no more than 6 days per week.
Week 3: Use no more than 5 days per week.
Week 4: Use no more than 4 days per week.
Week 5: Use no more than 3 days per week.
Week 6: Use no more than 2 days per week or less.

 

Some people prefer to get through this weaning process faster rather than a slow wean such as this. Some choose to stop their overused medications “cold turkey” to expedite the process. This should be discussed with your physician because it can be medically unsafe to abruptly stop some medications such as fioricet, fiorinal, butalbital, opioids and opiates which can result in seizures, irregular heart rhythms, blood pressure changes, or other withdrawal syndromes. A “bridging” medication to help “bridge” out of this cycle is often used, or provided as a rescue to save for use during a slow wean to take if the rebound headache becomes intolerable. These bridging rescue medications may include a course of steroids, NSAIDs, IV infusions, or many other options depending on what medicine is being weaned and other medical conditions present. The bottom line is that it can be a painful, frustrating, and challenging process to pull out of a rebound/MOH cycle. So hang in there and stick with it because once you successfully get out of this rut, you’ll be happy you did!

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

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Last updated on November 23rd, 2021 at 08:46 pm

WHAT ARE THE TRIPTAN DIFFERENCES AND WHICH IS BEST? HOW TO FINE-TUNE WHICH TRIPTAN MAY BE MOST EFFECTIVE FOR YOU.

@Neuralgroover

BACKGROUND:

Imitrex vs. Maxalt, Zomig vs. Maxalt, Amerge vs. Relpax, Frova vs. Imitrex, Maxalt vs. Relpax, Zomig vs. Imitrex, Frova vs. Amerge, Imitrex vs. Treximet. Maxalt vs. Frova. Axert vs. Imitrex. These are the triptans for migraine. There are 8 triptan types within the triptans medication class and include Imitrex (Sumatriptan) vs. Maxalt (Rizatriptan) vs. Relpax (Eletriptan) vs. Zomig (Zolmitriptan) vs. Frova (Frovatriptan) vs. Amerge (Naratriptan) vs. Axert (Almotriptan) vs. Treximet (Sumatriptan/Naproxen).

 

So what are the best triptans to use? Well let’s back up a little first. The ergot based medications such as DHE (dihydroergotamine) and cafergot (ergotamine + caffeine) have been the oldest migraine abortive medications used, which are still used today. However, they often have many side effects for patients and eventually the migraine specific triptans were developed for aborting migraine. Since 1992 (when Sumatriptan first became available), the triptans have been the first and only migraine specific abortive medications available up until 2020 when two new classes of migraine specific abortive medications have FINALLY become available with the gepants (Ubrelvy, Nurtec) and ditans (Reyvow). These new migraine abortive medications can be read about in more detail here.

The first triptan developed was sumatriptan in 1991 and since that time there have been a total of 8 triptan options to choose from. So how do the triptans work? They work by activating (agonist) the serotonin sub-receptor 5-HT1B. The result of activating this receptor is that it helps to constrict (narrow) the dilated inflamed pain-producing meningeal blood vessels which occurs during a migraine attack. The 5-HT1B receptors are also present in the brainstem, and likely play a role in modulating the electrical event of a migraine. Triptans also work by activating (agonist) the serotonin sub-receptor 5-HT1D. The result of activating this receptor is that they stop the trigeminal nerves from releasing a variety of inflammatory proteins around the brain and blood vessels which normally leads to pain during a migraine attack. This also interferes with normal pain processing between the brainstem and the brain (helps to block this electrical transmission), and it helps to block the nausea and vomiting centers in the brainstem. Triptans help to normalize levels of and decrease the release of a very inflammatory protein released during a migraine called CGRP (calcitonin gene related protein). Triptans also inhibit mast cell degranulation in the dural membranes, which also lessens the sterile inflammation which occurs during a migraine.

 

WHAT ARE THE SIDE EFFECTS OF TRIPTANS?

Most patients tolerate triptans very well, however, many patients have side effects and discontinue them. So let’s discuss triptans side effects. Just like any medicine, some patients may have more side effects than others. Furthermore, about 30% of patients with migraine may not respond to triptans (triptan non-responder). If side effects do occur, there is some variability between the different types of triptans. Potential side effects of the triptans include palpitations or racing heart beat, nausea, tingling, numbness or flushing in the face or extremities, drowsiness, fatigue, dizziness, and tightness or pressure in the chest, neck, or jaw. Although the chest pressure is not common, it is usually of a muscular and not a non-cardiac (heart) cause, so it can be scary if you don’t know about this potential side effect. With that said, chest pain could still potentially be a sign of heart attack (myocardial infarction) in patients with vascular risk factors and unknown coronary disease because the triptans do cause some slight vasoconstriction (narrowing) of arteries. So if there is already narrowing in an artery, increasing further narrowing could lead to lack of blood flow to the heart with subsequent heart attack in those at risk.

 

WHEN SHOULD TRIPTANS NOT BE USED?

Triptans can cause a mild degree of artery constriction (narrowing) due to its activity at the 5-HT1B receptor as discussed above. This could theoretically occur in narrowed arteries from cholesterol build up, such as in the heart. Therefore, triptans should not be used in patients who have coronary artery disease, cerebrovascular disease (stroke), peripheral arterial disease, or uncontrolled risk factors for these diseases (high blood pressure, cholesterol, diabetes, smoking, family history of early heart disease) because chest pain for them could truly represent heart attack. If there is concern for the possibility of underlying cardiovascular disease, a cardiac stress test should be performed prior to triptan prescription.

 

Triptans are also considered to be contraindicated in patients with visual snow, persistent migraine aura, and migrainous stroke (infarction) due to theoretical concerns of vasoconstriction potentially causing stroke. This contraindication has historically also included hemiplegic migraine and basilar migraine (now called migraine with brainstem aura). When the triptan studies were done previously, they excluded patients with these forms of migraine due to the ongoing vascular theory of migraine at that time. The vascular theory of migraine assumed that vasoconstriction and lack of blood flow was the cause of aura and neurologic features with migraine. So the thinking was that if you cause further vasoconstriction with a triptan, you may cause stroke. However, we now know that these phenomenon are primarily of an electrical basis and not a vascular basis. Therefore many specialists have gotten more liberal with the use of triptans in patients with hemiplegic or basilar migraine, and there have been a number of case series and case reports of these patients using triptans without any problems. However, larger confirmatory studies would be preferable.

 

Patients that can not use triptans due to side effects, or if they have any of these medical contraindications noted above, should consider one of the newer types of migraine abortive medications available with either the gepants (Ubrelvy, Nurtec), ditans (Reyvow) or neuromodulatory devices. Ubrelvy, Nurtec, and Reyvow are not triptans. These newer options often have a much lower side effect profile, can be taken in the setting of these medical contraindications to triptans mentioned above, and work by an entirely different mechanism of action.

 

It is also important to know that triptans can cause medication overuse headache (rebound headache) if used consistently greater than 10 days per month on average. The result is that the headache continues to worsen in frequency and/or severity. This also happens with NSAIDs, over the counter pain meds, and other types of as-needed pain medications. The phenomenon of rebound headache is discussed in much greater detail here. Notably, the gepants (Ubrelvy, Nurtec) do not cause rebound headache. If triptans, or any migraine abortive medication, is having to be used at this high frequency, a preventive migraine treatment should be used until the migraine and headache frequency is significantly improved consistently for several months. This can be done with a variety of medications which may also include the CGRP monoclonal antibody (mAb) treatments (Aimovig, Ajovy, Emgality, Vyepti), Botox, natural supplements, herbals and vitamins, or neuromodulatory devices.

 

WHAT IS THE BEST TRIPTAN TO USE?

Triptans are all similar in mechanism of action in how they work. So, it is not necessarily that one is better than another and some people may respond better to one versus another. However, there are many differences between the triptans drugs which allow them to be tailored and fine-tuned towards different types of migraine characteristics, as discussed below. This is a very important clinical point that is almost always overlooked by most physicians prescribing these medications if they are not headache specialists. Tailoring triptans to specific migraine characteristics can make a dramatic difference in its effectiveness since triptans are not all one in the same medication. The information below can be discussed with your doctor to hopefully get a better response to your triptan therapy.

 

LIST OF TRIPTANS:

-Sumatriptan: oral, subcutaneous injection, needle-less subcutaneous injection, nasal spray, breath-powered intranasal delivery system
-Zolmitriptan: oral, orally dissolvable tablet, nasal spray
-Rizatriptan: oral, orally dissolvable tablet
-Almotriptan: oral
-Eletriptan: oral
-Sumatriptan/Naproxen: oral
-Frovatriptan: oral
-Naratriptan: oral

GROUP 1 TRIPTANS:

-Faster onset of action, higher potency (thus can have higher side effect potential), tend to have a higher 24-hour migraine recurrence
-Sumatriptan, Sumatriptan/Naproxen, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan

 

GROUP 2 TRIPTANS:

-Slower onset of action, lower potency (thus often have lower side effect potential), lower 24-hour migraine recurrence since the duration of action is longer:
-Frovatriptan, Naratriptan

 

FINE-TUNING YOUR TRIPTAN CHOICE: (Remember the mnemonic CORN, and this will help to narrow down the best triptan to consider):

Contraindications
Onset to peak pain
Recurrence of migraine after treatment
Nausea and vomiting severity

Contraindications: This is not an exhaustive list, but are the most common. Your doctor should be well aware of when triptans should not be used.
-Known vascular disease (coronary artery disease, peripheral vascular disease, history of stroke)
-Vascular risk factors (poorly controlled hypertension, hyperlipidemia, diabetes, smoking, premature family history of coronary artery disease (men less than age 55, women less than age 65), postmenopausal women, etc.
-Kidney or liver failure
-Prinz-Metal angina

 

Onset to migraine peak pain:
-Group 1 triptan (quicker onset) is generally much more useful than a Group 2 triptan (slower onset).
-A subcutaneous injection or nasal spray triptan will typically be most helpful if:
-Patient wakes with migraine already ongoing (waking migraine)
-Migraine hits its peak pain level within 30 minutes or so

 

Return of migraine after treatment:
-If migraine recurrence occurs within 24 hours (for example it goes away with the triptan, but keeps returning later in the day or the next day), or the migraine is usually multiple consecutive days long (such as menstrual migraine):
-Combine the 1st dose of the triptan with an NSAID (such as Naproxen)
-Use a group 2 triptan (Naratriptan vs. Frovatriptan)

 

Nausea and vomiting severity:
-If nausea and vomiting occur early in the attack, or are severe to where it is hard to keep a pill down without vomiting it back up:
-A subcutaneous injection or nasal spray triptan should be used.
-Of note, dissolvable triptan tablets are still absorbed by the gastrointestinal tract, not sublingually. So, vomiting will still make this route ineffective, similar to a regular pill.

 

TRIPTAN PEARLS IN FURTHER FINE-TUNING TRIPTAN CHOICES:

Sumatriptan:
-Highest potency (in subcutaneous form) and quickest onset (subcutaneous > nasal spray) of triptans
-Greatest flexibility is dosing route options

Rizatriptan:
-Fastest onset of oral triptans
-Greatest likelihood of 2h pain-free and sustained pain-free response
-Propranolol increases its serum concentration, so 5mg per dose should be if used together

Zolmitriptan:
-Most likely to treat persistent headache when 1st dose fails

Almotriptan:
-The group 1 triptan with the least side effects

Eletriptan:
-Highest potential for drug interactions. Decrease dosage with CYP3A4 drugs such as macrolides, fungal, HIV, etc.

Naratriptan:
-The “gentle triptan” with the least side effects given its slower onset of action
-Low 24 hour migraine recurrence rate
-Good choice to give shortly prior to an expected and known migraine trigger (menstruation, air travel, etc.)
-Does not have monoamine oxidase metabolism, so it can be given with MAOI (as can Eletriptan and Frovatriptan)

Frovatriptan:
-Low side effect potential given its slower onset of action
-Longest half life
-Low 24 hour migraine recurrence rate
-Good choice to give shortly prior to an expected and known migraine trigger (menstruation, air travel, etc.)

 

CONCLUSIONS:

The triptans were and have been a game changer for millions of migraine patients in aborting migraine attacks. Using the highest available triptan dose is also generally recommended to see the full effect. We see many patients who have “failed triptans”, but on further history they were put on very low doses (such as 25 mg sumatriptan, when 100 mg is the standard dose). Even so, about 30% of migraineurs do not respond to triptans, only 1/3rd are pain-free at 2 hours, and only 17-25% remain pain-free at 24 hours. Therefore, although the majority respond well to triptans, not everyone does. Luckily, there are other medication options including two brand new classes of migraine abortive medications (gepants, ditans), and these are detailed here.

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

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