Some Migraine Drugs Linked to Cognitive Impairment, Dementia in Older Adults

This post was updated at 12:40 p.m. PDT on April 19, 2016.

What kind of long-term impact will taking migraine drugs have on my body? Am I trading a better present for more problems in the future?

These and similar questions have flitted through my mind for years. I usually push them aside—I need these drugs to function, so I don’t feel like I have much choice. Besides, an abstract future worry is so vague that it doesn’t seem to require much attention. Thanks to new research, that worry no longer seems abstract or vague.

Cognitive impairment and dementia in older adults have been linked to anticholinergic drugs, which block the neurotransmitter acetylcholine, in an increasing number of studies over the last decade. Some popular antihistamines, antidepressants, and anti-nausea meds used as migraine drugs have anticholinergic effects.

The research may not be cause for alarm, which I’ll explain in a moment. The first question you want answered is likely: Which drugs put me at risk?

Migraine Drugs With Anticholinergic Effects

This list contains drugs I’m aware of people using for migraine, but it is not an exhaustive list of anticholinergics. Indiana University has a more complete list of anticholinergic drugs (PDF). A JAMA article on the topic also includes Vivactil (protriptyline) and Compazine (prochlorperazine). ACB score refers to “anticholinergic cognitive burden,” which determines if a drug has mild or moderate anticholinergic effects.

Mild Anticholinergic Effect (ACB Score 1)

• Actiq (fentanyl)
• Duragesic (fentanyl)
• Effexor (venlafaxine)
• Flexeril (vyclobenzaprine)
• Immodium (loperamide)
• Valium (diazepam)
• Wellbutrin (bupropion)
• Xanax (alprazolam)

Moderate Anticholinergic Effect (ACB Scores 2 & 3)

• Advil PM (diphenhydramine)
• Atarax (hydroxyzine)
• Benadryl (diphenhydramine)
• Dramamine (dimenhydrinate)
• Elavil (amitriptyline)
• Flexeril (cyclobenzaprine)
• Gravol (dimenhydrinate)
• Norflex (orphenadrine)
• Norpramin (desipramine)
• Pamelor (nortriptyline)
• Periactin (cyproheptadine)
• Phenergan (promethazine)
• Sinequan (doxepin)
• Tegretol (carbamazepine)
• Tylenol PM (diphenhydramine)
• Vistaril (hydroxyzine)

Anticholinergic Burden Unknown

(have an anticholinergic effect, but do not have an ACB score)

• Compazine (prochlorperazine)
• Vivactil (protriptyline)

Anticholinergic Drugs, Cognitive Impairment, and Dementia: The Research

Keep in mind that:

1. These studies do not provethat anticholinergic drugs cause cognitive impairment or dementia. They have found that a link exists between taking the drugs and cognitive impairment or dementia.
2. All published studies have focused on older adults, most with an average participant age in the early 70s. It is speculated that increased age makes the body more susceptible to these effects, possibly because these drugs permeate the blood-brain barrier more readily in older people.

Risk depends on strength of cholinergic effect

Drugs with a mild cholinergic effect (an ACB of 1) can cause cognitive impairment in older adults within 90 days of continuous use. Those with a strong cholinergic effect (ACB of 2 or 3) can cause cognitive impairment in 60 days of continuous use. Non-continuous use can also have an impact, though the exact length of time varies. Cognitive effects were increased with the number of anticholinergic drugs a patient took. (See Just 2 Months’ Exposure to Anticholinergics Affects Cognition)

Dose matters (somewhat)

The higher the drug’s dose, the greater the risk, according to a study published in 2015. However, even at the minimum effective dose, taking the drugs for prolonged periods were linked to a greater likelihood of cognitive impairment or dementia than for those not taking anticholinergic drugs. “This is not excessive use,” said the lead author Shelly Gray, PharmD, from the University of Washington. “Many of these agents are used chronically, and chronic use—even at low doses—would put you in the highest risk category.” (See ‘Strongest Evidence Yet’ Links Anticholinergic Drugs, Dementia)

Changes in the brain

Brain imaging found lower brain metabolism and reduced brain sizes among participants taking anticholinergics, as reported in a study published this week. Participants taking the drugs also scored lower on cognitive tests than those not taking the drugs. This is the first study looking at the underlying biology of the link identified by earlier research. (See IU Scientists: Brain Scans Link Physical Changes to Cognitive Risks of Widely Used Class of Drugs)

Age of participants

The published studies I found are focused on older adults. Researchers believe that a person’s central nervous system becomes more sensitive to anticholinergic medications with age. It could be that younger patients don’t have the same risks, but that’s uncertain. This warning from Dr. Gray haunts me: ‘There is no data on how these drugs may affect younger people, but I personally will avoid taking anticholinergic agents.”

I found one study presented at a conference that looked at the ACB of younger patients with chronic pain. Participants with chronic pain had significantly higher ACB scores than healthy participants and their cognitive function appeared to be affected. The burden was greatest in patients aged 30 to 39. (See Pain Patients at Cognitive Risk From Anticholinergic Burden?)

Cognitive Impairment vs. Dementia

Cognitive impairment and dementia are very different things. Several studies show that cognitive impairment due to the drugs could be reversible. The drugs could magnify symptoms of an already present mild dementia or bring symptoms on earlier than would have happened otherwise. However, brain atrophy, as found in the study published this week, doesn’t sound reversible.

What’s the Actual Risk?

No one knows for sure. The research is concerning, but is far from conclusive. Many questions still remain. Talk to your doctors and pharmacists for advice that’s best suited to you—it will depend on your age, the medications you take and why you take them, how effective the medications are for you, what alternative medications might help you, and other health problems you may have. Please don’t stop taking your medications without first talking to your health care providers—doing so could put you at risk of other problems.

I plan to ask all my doctors and pharmacists for input. My gynecologist and endocrinologist haven’t prescribed anticholinergics, but I trust them both and want them to weigh in on this, too.

Why I’m Sharing This Research

I freaked out when I first learned about this research last year. I started to write about it, then set it aside. I decided the research was too inconclusive to scare people by reporting it. When I saw the study published this week, I changed my mind. The research is still very preliminary and I don’t want people to panic. Nonetheless, patients should be aware that this research exists so they can make an informed decision about which medications are best for them. Your doctor will probably tell you that it’s not cause for concern, but it’s better to be able to ask them about it than remain completely in the dark.

Kerrie’s Uneasy Truce

The two medications I take daily, cyproheptadine and Wellbutrin, are on the list. My paternal grandmother had Alzheimer’s and I have been afraid of the disease for as long as I can remember. I doubt I would have started the drugs if I’d known about this research. I’m not sure that’s a good thing. These medications allow me to get out of bed. The past four years have been relatively manageable thanks to them. They have improved my quality of life enough that I’ve been able to aggressively pursue other treatments.

I was terrified when I started writing this post, but I have calmed down considerably the more I have learned. This is preliminary research. Cause and effect hasn’t been established. I’m 28 years younger than the average patient in the studies. I’m actively trying to find alternative treatments to these medications. Migraine research is making tremendous strides in preventive treatment. Of course I’m still a little worried that I’m trading the present for the future. I’d be worried about that even without these drugs.

REFERENCES

American Academy of Pain Medicine (AAPM) 29th Annual Meeting. Poster 221. Presented April 12, 2013.

Anderson, P. (2013, May 22). Just 2 Months’ Exposure to Anticholinergics Affects Cognition. Medscape. Retrieved 4/18/16 from http://www.medscape.com/viewarticle/804558.

Anderson, P. (2013, Apr 15). Pain Patients at Cognitive Risk From Anticholinergic Burden? Medscape. Retrieved 4/18/16 from http://www.medscape.com/viewarticle/782520.

Cai, X., Campbell, N., Khan, B., Callahan, C., & Boustani, M. (2013). Long-term anticholinergic use and the aging brain. Alzheimer’s & Dementia, 9(4), 377-385.

Hughes, S. (2015, Jan 27). ‘Strongest Evidence Yet’ Links Anticholinergic Drugs, Dementia. Medscape. Retrieved 4/18/16 from http://www.medscape.com/viewarticle/838788.

Gray, S. L., Anderson, M. L., Dublin, S., Hanlon, J. T., Hubbard, R., Walker, R., … & Larson, E. B. (2015). Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA internal medicine,175(3), 401-407.

Indiana University (2016, Apr 18). IU scientists: Brain scans link physical changes to cognitive risks of widely used class of drugs [Press release]. Retrieved 4/18/16 from http://news.medicine.iu.edu/releases/2016/04/anticholinergics-brain-effects.shtml.

Risacher, S. L., McDonald, B. C., Tallman, E. F., West, J. D., Farlow, M. R., Unverzagt, F. W., … & Saykin, A. J. (2016). Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults. JAMA Neurology, April 2016 DOI:10.1001/jamaneurol.2016.0580

Salahudeen, M. S. and Nishtala, P. S. (2016) Examination and Estimation of Anticholinergic Burden: Current Trends and Implications for Future Research. Drugs & Aging, April 2016 DOI: 10.1007/s40266-016-0362-5