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

BACKGROUND

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 syndromes^1–4, and it has been a historical treatment for headache and migraine for centuries.^2,3,5–7 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.

 

SAFETY AND SIDE EFFECTS

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.

 

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HOW TO BREAK FREE FROM THE VICIOUS CYCLE OF REBOUND HEADACHE (MEDICATION OVERUSE HEADACHE).

 

 

Chronic daily headache being endlessly fueled and driven by rebound headache (medication overuse headache; 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 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.

 

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”).

 

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 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.
Week 7: Use no more than 1 day 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!

NOT ALL TRIPTANS ARE CREATED EQUAL. HOW TO FINE-TUNE WHICH WILL BE MOST EFFECTIVE FOR YOU.

 

Since 1992, 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 (gepants, ditans) have become available (will be detailed in a separate blog).

 

The first triptan developed was sumatriptan in 1991 and since that time there have been a total of 8 triptan options to choose from. 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, which limits those symptoms.

 

Triptans are all similar in mechanism of action. However, there are many differences 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.

 

TRIPTAN OPTIONS:
-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 25% 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) which have become available in 2020 and will be detailed in a separate blog.