Category Archives: News

President’s Message: When Was That Taught?

Harry J. Gould, III MD, PhD

It has been more years than I care to admit since I graduated from medical school. As most of us have realized, with time, advances are made, with experience, skills are refined and as practitioners, we adapt to change and challenge and improve in our ability to care for patients. An unfortunate corollary to the essential fine-tuning of the evolving practitioner, especially in specialty and sub-specialty practices, is that many components of our general training are infrequently called to bear in daily practice, are less well remembered, and suffer from lack of reinforcement. I have recently been more aware of this disappointing realization both in my own practice when confronted with patients suffering with problems involving infectious disease, endocrinology, hematology, pulmonology, cardiology, and gynecology and from a different perspective, in observing the practices of colleagues who consult me for recommendations to help care for their patients in pain.  Some problems require complex solutions, but surprisingly, most can be addressed simply by returning to the basic principles learned in those early courses when we received so much “irrelevant material”.

My reason for addressing this topic is that I have noticed, more recently, probably over the last 2-3 years, that well over half of the consults directed to our in-patient consultation service for pain management have inquired as to what else can we recommend to control pain and/or whether an additional opioid medication should be added to the analgesic regimen to improve pain control for a patient. Virtually all of the presenting analgesic regimens in these cases, regardless the type of pain or pain history, include gabapentin < 300 mg daily, a muscle relaxant, and not atypically, orders for multiple formulations of mu-opioid analgesics, e.g., hydrocodone PO as needed for pain between 3-6/10 in intensity, oxycodone PO as needed for pain > 7/10 and hydromorphone IV scheduled every 3-4 hours.  The total daily morphine milligram equivalents (MME) ordered is, not infrequently, less than that in the patient’s routine outpatient regimen for chronic pain. It is possible that the initial ineffective treatment regimens have been designed in an attempt to comply with published guidelines designed to minimize opioid use, but it seems more likely that the failed attempts reflect a prevailing assumption that complex problems require complex solutions.  Obvious to a specialist, but not so to the physician with medical school a distant image in the rearview mirror of life, is that simple solutions within recommended guidelines are more often likely to produce favorable outcomes because they are less likely to introduce complications that lead to confounding results.

More efficient use of the dynamic interaction between referring physician and consultant may be the best way improve patient care because the best learning opportunities seem to occur when therapeutic approaches are introduced or reviewed in the context of administering in real-time to an interesting patient or a problem situation (“When I was a resident, I had a patient that…”) and take less time out of a busy practitioner’s day than a formal course for review.  A referral for consultation provides a platform for the specialist to offer a focused review of basics from their specialty that reinforce optimum therapeutic approaches for managing a given problem and a platform for the referring team to provide feedback to the specialist as to the rationale for either accepting or declining to implement a given recommendation.

In the offered example, a good place to start might be to determine and establish an analgesic treatment base before embarking on diagnostic tests or therapeutic treatments that are likely to produce additional pain. The process of determination would be comprised of an assessment of the type of pain that is being experienced, a determination of co-morbid problems and whether the patient has had or is currently receiving medications, especially opioids, for a previous acute or a chronic problem, for which medications had been used and if current, what dose is being taken. It also would seem reasonable to take advantage of prior history and to start with a medication that has been shown to be effective for the particular patient and to anticipate that any new pain may require MME dosing equal or greater than the premorbid regimen to achieve adequate pain control and to prevent the onset of withdrawal symptoms. The pharmacologic principles that simple, monotherapy regimens are easier to administer, have higher rates of compliance and are more effective are generally good principles to follow when designing a treatment regimen.  Mu-opioid agonists due to chemical configuration and available routes of administration have different benefit potential and different side effect profiles that provide the basis of therapeutic selection.  Unfortunately, analgesic benefits of mu-agonists are achieved through a single mechanism of action, regardless the formulation precluding a hoped for reduction of daily MME by providing treatment with multiple mu-opioid agonist at low doses. Furthermore, the simultaneous initiation of treatment with multiple formulations complicates the recognition of which agent(s) might be responsible for any benefits or adverse effects observed.  Because of incomplete cross-tolerance between mu-opioid agonists, the concurrent use of multiple formulations, also effectively eliminates or greatly reduces any possibility for drug rotation, if needed. Thus, selecting a single mu-agonist formulation, determining the route of administration and the proper dosing allows for early identification of tolerance and dosing efficacy. Finally, the use and selection of potentially beneficial adjuvant agents based on pain type and benefits that may be realized from their otherwise adverse, side effect profile, e.g., drowsiness in patients with difficulties sleeping, are important components of the analgesic regimen that are likely to produce benefit without undesired adverse effects if they are prescribed in adequate doses. 

In the midst of the exponential growth in technology and continued advances in the era of information explosion that often lead to overwhelming increases in system complexity, it may be comforting to remember that the old, simple, basic principles that we learned as fledgling healthcare providers are still useful and may be our best means for caring for our modern day patients in a rapidly expanding and changing world of pain medicine.

Treatment of Refractory Chronic Migraine With Worm Eggs: A Therapy Rooted in Evolution

Lawrence Robbins, MD and Hanah Alley, MD

(originally published in Medicine Connections, 2021 vol.1, issue 2: a journal of the World Headache Society)

Abstract

Introduction: This was a small open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine (RCM) patients. It is probable that the immune system is involved in migraine.1 Helminth worms have populated the GI tract of primates for millions of years. They downregulate the immune response. When the helminths (and other parasites) are removed, the result may be an increase in autoimmune illness. The immune system and inflammation are involved in migraine pathophysiology.

Study design:  Eleven RCM patients were enrolled. After the run-in period, patients ingested the helminth eggs every 2 weeks for 5 months.  These eggs were from the pig whipworm, T. suris. The primary endpoint involved the number of moderate or severe headache days per month. The first (run-in) month was compared to the last 2 months of active therapy. Secondary endpoints included disability, depression, anxiety, and quality of life.

Results:  5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 of the 5 patients who met the primary endpoint.

4 of 11 patients who completed the study did not meet the primary endpoint. 1 other patient did not supply data, and another discontinued treatment due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not improve.

Conclusion:  This study indicates that there may possibly be a role for helminth therapy in treating refractory chronic migraineurs. 5 of 11 patients did well. This treatment is rooted in evolution. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may possibly help in the treatment of conditions that involve the immune system, such as migraine.

Keywords:  Migraine, Refractory Migraine, Headache, Helminth,  Evolution, Chronic Migraine, long haul Covid worm eggs,

Introduction

The concept of migraine as an autoimmune entity has been discussed for many years.1 Migraine is a common disabling neurological disorder. Despite available therapies, a subset of patients remains unresponsive to preventive treatment. Individuals with Refractory Chronic Migraine (RCM) have failed a number of the available preventatives, and suffer from frequent moderate or severe headaches2,5. Individuals with Chronic Migraine (CM) are those with a headache occurring on 15 or more days/month for more than 3 months.  For at least 8 days/month their headaches are migrainous.4,6  The pathophysiology of migraine is interwoven with the immune system, which is the reason for the current study7,8.

Helminth worms have co-existed in primates for millions of years. Helminths, along with other parasites, downregulate the human immune response. In many human populations, the helminths have largely been eradicated. This resulted in an increase in autoimmune illness. 9,10,11,12,16,17,18.

There is a robust literature, dating back more than 20 years, introducing helminth eggs into the GI tract of those with various autoimmune illnesses. 

Helminth therapy has been extensively evaluated for its safety and efficacy in the context of autoimmune diseases9,10,11,15. These include Inflammatory Bowel Disease (IBD)9,10,12, Type 1 Diabetes Mellitus (T1DM) 16,17 and Systemic Lupus Erythematosus (SLE)12,13,18. Helminths elicit an immune response by promoting production of anti-inflammatory mediators14,15,19,.  The result is to downregulate the host immune response to various antigens9 .

Helminths have lived in the GI tract of primates for millions of years.  Over time, a homeostasis was achieved between the parasites and the host immune system.  The host primate’s immune system has been downregulated in response to the helminths. It is easy and relatively safe to reintroduce helminth eggs into the GI tract.  This study was undertaken in order to assess the effect of introducing helminth eggs into the GI system of patients with refractory chronic migraine.

Materials/Methods:   

Study patients:  Eleven patients (10 women, 1 man) with the diagnosis of refractory chronic migraine were enrolled in the study. Refractory chronic migraine was defined according to the European federation consensus.2 They were patients well known to the treating physician.  Ages ranged from 25 to 67. Patients’ names and information were de-identified.

Study Design: This was an open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine patients. The study included a one-month run-in prior to the actual treatment phase.  Patients then were to receive the helminth eggs every 2 weeks for 5 months.  There were 11 total doses of the eggs.  Patients kept daily track of the headache severity. They used a simple paper calendar.  A visual analog scale, 1 to 10, was utilized. A headache day was considered moderate to severe if the severity was rated 5 or greater. Mild days were listed but did not count for the purpose of this study. IRB approval was obtained. The IRB was through Advarra: PRO ID# 00051859, CR 00316902.  Possible risks were explained, and written consent was obtained.

The patients were allowed to remain on stable preventive medication/approaches. They were asked not to add new preventive medication or approaches. To our knowledge, none of the patient received new preventive medication during the study.

Safety of the Eggs: The eggs are from the whipworm, Trichuris suis. Safety of these eggs has been evaluated for 20+ years. There have been various studies, primarily regarding autoimmune illnesses.  Patients have also been able to order the eggs from the Tanawisa Company. Over 36,000 patients have ingested the eggs. There is a helminth therapy Facebook group.  The eggs have not produced adverse effects, except for occasional mild diarrhea14. There was one instance of eggs maturing into actual worms (which are benign). The company stated that it was unclear whether the eggs actually contributed to that one case.  We had multiple conversations with the Tanawisa Company regarding safety. The eggs are contained in a solution with 98% viable eggs. These attach to the mucosa surrounding the caecum. The eggs release molecules that induce regulatory T-cells by the human host. In theory, with a severely compromised GI mucosa, the eggs could attach and hatch, although this has not happened in the studies involving GI illness. We did not allow patients with GI mucosal illnesses to participate. The eggs “modulate” the immune system, but have not resulted in infections or immune deficiency issues. The eggs were donated by Tanawisa, the company that produces them. The company has extensive safety and efficacy information on Tanawisa.com.  The results of the studies, and extensive information on safety and risks, were given to all patients as part of the informed consent.  A number of these studies are listed in the reference section below. There has been no evidence that the egg exposure actually compromises the immune system, or leads to infection or immune based problems.

Patient visits and lab tests:  Patients were seen in person prior to the run-in month, after 1 month, after the 3rd month, and after the 6th month. Patients were given the egg solutions to ingest every 2 weeks, and the solutions were stored in their refrigerators. In addition, phone visits were done after the 2nd, 4th, and 5th months. A physical exam was performed on the first visit, at the 3rd visit, and after the final visit. An ECG was performed prior to the study. Blood tests (cbc, cmp, TSH, T4, sedimentation rate, ANA, and Hemoglobin A1c) were drawn 2 times: prior to month 1, and after month 3. All visits and blood tests were at no cost to the patient.  

Screening tests: These were done prior to the study, and after the last visit. The screens included the Beck Depression Inventory, the Beck Anxiety Inventory, Migraine Disability Assessment Test (MIDAS), and the Health Related Quality of Life Measure (number of unhealthy days per month).

Beck Depression Inventory:  1 to 10=none, 11 to 16=mild mood disturbance, 17 to 20= borderline clinical depression, 21-30=moderate depression, 31 to 40= severe depression, 40 or more=extreme depression.

Beck Anxiety Inventory:  0 to 7=none or minimal, 8 to 15=mild, 16 to 25= moderate, 26 to 63=severe.

MIDAS:  0 to 5=little or no disability, 6 to 10= mild, 11 to 20=moderate, 21 or more=severe.

HRQOL:  # of unhealthy days per month: maximum number= 30 days per month

Refractory Chronic Migraine Severity Scale: This scale was developed by Lawrence Robbins, and separates patients into mild, moderate, and refractory chronic migraine. Ten criteria are used in the scale. (5)

Inclusion Criteria: Patients known to the Robbins Headache Clinic, 18 to 70 years old.  Each patient had a well-established diagnosis of chronic migraine, according to ICHD-3 criteria (4). Every patient had the diagnosis of refractory chronic migraine (RCM)(2). The patients were graded as to the severity of the RCM (5).

Exclusion Criteria:  1. Patients with IBS-D or other gastrointestinal conditions that would result in diarrhea. Patients with a compromised GI mucosa due to a GI illness were excluded, 2. Severe psychiatric or medical illness which, in the judgment of the PI, might endanger the patient, 3. Use of probiotics during the course of the trial, 4. Inability to adequately track the headaches and side effects, Any other condition that would interfere with the ability of the patient to successfully complete the study, and 6. Pregnancy: See pregnancy section below.

Medication Use: Patients were allowed to continue on their usual medications. If possible, patients were encouraged not to change the dosage of their preventive medications. They were also asked not to start new preventive medications. If necessary, medications changes were allowed. If patients needed to take an antibiotic that opposed the action of the egg solution, they would be discontinued from the study.

No patients changed preventives during the trial. The doses of their pre-existing preventives were kept steady throughout the trial.

Pregnancy:  There is not enough evidence to state that the eggs are safe for use during pregnancy. If pregnancy was being considered, the patient was excluded from entering the study. For those women where pregnancy was not being considered, but was possible, adequate birth control methods were to be employed. To our knowledge no patient became pregnant during the trial.

Safety Monitoring and Adverse Events/Adverse Effects:  Dr. Robbins or the study coordinator conducted monthly discussions with each patient about adverse events and adverse effects.  Patients were encouraged to report any new effects, particularly GI adverse effects.

Primary endpoint: The number of moderate or severe headache days during months 5 and 6 (average of the 2 months), as compared to the number of moderate or severe headache days during the run-in period (first 30days).   Success is a decrease in monthly moderate or severe headache days by 3 or more days per month. Moderate or severe was a 5 or greater on the 1 to 10 severity scale.   

Secondary endpoints: 1. Disability assessment before and after the study (MIDAS), 2. Evaluation of depression before and after the study (Beck Depression Inventory),  3. Comparison of anxiety after the study versus during the run-in phase (Beck Anxiety Inventory) and 4. Evaluation of a quality of life assessment before and after the study (Health-Related Quality of Life Scale, as measured by the number of unhealthy days per month).

Results

Patient #1: 42 y.o. F with moderate refractory chronic migraine (RCM).

Pre-study month (run-in) # of moderate or severe headache days: 30

Month #1 (active study): 30 moderate to severe days

Month #2: 24 days

Month #3: 24 days

Month #4: 22 days

Month #5: 22 days

Midas (disability): pre-study=51, post-study=30

Beck Depression: pre-study=0, post-study=1

Beck Anxiety: pre-study=6, post-study=3

QOL: pre-study # of unhealthy days per month=30, post-study (the last month)=26

Summary: The # of moderate or severe headache days did decrease from 30 to 22 (average of the last 2 months). Disability remained high but improved. Depression was low (pre and post) and anxiety, which was mild pre-study, did lessen.

Patient #2: 39 y.o. F with mild RCM.

Pre-study month (run-in): 20 moderate or severe headache days(and 6 mild days)

1st  (active) month: moderate to severe days: 13

2nd month: 15

3rd month: 12

4th month: 8

5th month: 6

Midas: pre-study= 18, post-study=9

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=5, post-study=3

QOL: pre-study= 0, unhealthy days, post-study= 0

Summary: The # of moderate or severe headache days decreased from 20 pre-study to 7 (average of the last 2 months). Midas disability improved. Depression was low and anxiety, which was low, did improve.

Patient #3  36 y.o. F with moderate RCM.

Pre-study month (run-in): 9 moderate to severe headache days(and 11 mild days)

1st month (active): 7 moderate to severe days

2nd month: 3

3rd month: 2

4th month: 2

5th month: 2

Midas: pre-study=15, post-study=8

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=3, post-study=0

QOL: pre-study=7 unhealthy days, post-study= 0

Summary: The # of moderate to severe headache days decreased from 9 pre-study to 2 (average of the last 2 months).  Midas disability improved. There was no depression, and anxiety, which was low, did improve. The # of unhealthy days dropped significantly.

Patient #4   68 y.o. F with moderate RCM.

Pre-study month (run-in): 15 moderate to severe headache days(and 7 mild days)

1st month (active): 11 moderate to severe days

2nd month: 5

3rd month: 5

4th month: 5

5th month: 2

Midas: pre-study=42, post-study=30

Beck depression: pre-study=7, post-study=8

Beck anxiety: pre-study=12, post-study=8

QOL: pre-study=4 unhealthy days, post-study=4

Summary: The # of moderate to severe headache days decreased from 15 pre-study to 3.5 (average of the last 2 months).  Midas disability improved. Depression did not change, and anxiety improved.  The # of unhealthy days remained the same.

Patient #5 65 y.o F with severe RCM.

Pre-study (run-in): 8 moderate to severe headache days(and 12 mild days)

1st month (active): 9 moderate to severe days

2nd month: 4

3rd month: 5

4th month: 5

5th month: not recorded

Midas: pre-study= 131, post=100

Beck depression: pre-study=4, post=6

Beck anxiety: pre-study=23, post=5

QOL: pre-study=30 unhealthy days, post=30

Summary: The # of moderate to severe headache days decreased from 8 pre-study to 5 (4th month). Midas disability improved. Depression was slightly worse from pre-study to month 4. Anxiety improved significantly. The # of unhealthy days remained the same.

Patient #6  55 y.o. with moderate RCM.

Pre-study (run-in): 30 moderate to severe headache days

1st month (active): 28 moderate to severe days

2nd month: 30

3rd month: 30

4th month: 26

5th month: 29

Midas: pre-study=25, post=12

Beck depression: pre-study=3, post=3

Beck anxiety: pre-study=10, post=10

QOL: pre-study=10 unhealthy days, post=6

Summary: the # of moderate to severe headache days decreased from 30 pre-study to 27.5 (average of 4th and 5th month). Midas disability improved.  Depression was low, and did not change. Anxiety remained unchanged. The # of unhealthy days improved.

Patient #7  24 y.o. M with severe RCM

Pre-study (run-in): 30 moderate to severe days

1st month (active) and months 2 thru 5: 30 moderate to severe days each month

Midas: pre-study=210  (post-study not done)

Beck depression: pre-study= 27  (post-study not done)

Beck anxiety pre-study= 22   (post-study not done)

QOL: pre-study=27 unhealthy days  (post-study not done)

Summary: the # of moderate to severe headache days did not change (30 days per month). This patient did not complete post-study surveys. Pre-study his Midas revealed high disability. Depression and anxiety were significant.

Patient #8: 64 y.o. F with severe RCM.

Pre-study (run-in): 19 moderate to severe headache days(and 6 mild days)

1st month (active study): 22 moderate to severe days

2nd month: 20 moderate to severe days

3rd month: 17

4th month: 22

5th month: 20

Midas disability: pre-study=23, post=26  (post-study not done)

Beck depression: pre-study=26  (post not done)

Beck anxiety: pre-study=21  (post not done)

QO: pre-study=30 unhealthy days  (post not done)

Summary: The # of moderate to severe headache days increased slightly by the 5th month. Disability, depression, and anxiety levels were high (post-study surveys were not done). Pre-study every day of the month was an unhealthy day.

Patient #9:  34 y.o. F with severe RCM

Pre-study (run-in): 21 moderate to severe headache days(and 9 mild days)

1st month (active study): 21 moderate to severe days

2nd month: 19

3rd month: 22

4th month: 23

5th month: 23

Midas disability: pre-study=42, post-study=30

Beck depression: pre-study= 0, post=0

Beck anxiety: pre-study=3, post=2

QOL: pre-study=24 unhealthy days, post=23

Summary: the # of moderate to severe headache days were slightly increased by the 5th month. Disability improved somewhat. There was no depression, and mild anxiety was unchanged.  The # of unhealthy days was essentially unchanged.

Patient #10:  62 y.o F  Severe RCM.

Pre-study:  moderate or severe headache days: 30

This patient did ingest the eggs but no headache data was captured.

Patient #11: 39 y.o. F  Moderate RCM.

Pre-study: moderate to severe headache days: 30. This patient ingested only one dose of the eggs. She subsequently had GI upset and mild diarrhea. She discontinued the therapy. Over the ensuing 4 months, the GI upset and diarrhea improved but did not resolve. GI work-up was pending. The headaches remained unchanged.

Lab tests/ECG:  blood tests were drawn prior to the study, and after the 3rd month. There were no abnormal tests that resulted from the treatment. ECGs did not reveal significant abnormalities.

Summary of Results

5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 patients and remained the same in 3 patients.

4 of 11 patients did not meet the primary endpoint. 1 patient did not supply data, and another discontinued due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not have a successful trial.

Discussion

Eleven patients with refractory chronic migraine were enrolled. Five patients met the primary endpoint.  The 5 patients experienced a decrease in moderate to severe headache days per month of 14 days, 10 days, 8 days, 7 days, and 3 days. Four of the remaining patients finished the study but did not incur any benefit.  One patient did not provide data, and another discontinued the eggs due to diarrhea.  That was the only adverse effect observed in the trial.

The 5 patients who experienced a decrease in the number of moderate to severe headaches also observed a significant lessening of disability. All of these 5 patients had low baseline depression scores.

This was a small open label study that included patients with refractory chronic migraine. They ingested helminth eggs for 5 months. The purpose of the eggs was to downregulate the immune response. Helminths may modulate the immune system via release of excretory/secretory proteins. The cell mediated inflammation may be modulated by the helminth eggs. While the helminth eggs modulate immune activity, there has been no evidence for harm. Tdhe concept of migraine as an autoimmune illness, or at least involving the immune system, has been debated and discussed for decades.1 This study is rooted in evolution. For millions of years the GI tract of primates (and other animals) has been colonized by various worms or other parasites.  It has only been recently, in the past hundred years, that helminths and other parasites have been eradicated from human GI tracts.  This has been accomplished through improved sanitation as well as the introduction of clean water and food.

The role of helminth therapy has been discussed in the introduction section (above).  The studies have involved introducing helminth eggs into patients suffering from various autoimmune illnesses.  

There have been 12 helminth therapy studies conducted for various autoimmune diseases9,10,11,15.  The use of helminthes for various autoimmune disorders has met with reasonable success, with minimal adverse effects. The study on Inflammatory Bowel Disease (IBD)9,10,12 revealed that this may be a viable therapy, and that the eggs appear to be safe.  A study on Type 1 Diabetes Mellitus (T1DM) 16,17 also indicated that the eggs are safe for human consumption. This was also confirmed in a study involving the eggs and Systemic Lupus Erythematosus (SLE)12,13,18.  

Conclusion: This small study indicates that there may be a role for helminth therapy in the treatment of refractory chronic migraineurs. This approach is rooted in evolution. We ignore evolution at our peril. For millions of years helminths and other parasites have populated the GI tract of animals. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may aid in the treatment of migraine headache.  A randomized, placebo-controlled trial would be welcome.

Acknowledgments

Diana Delatre was the study coordinator. The Tanawisa Company donated the eggs for the study. Other than donating the eggs, the company did not play a role in the study.  

Conflicts of interest: none

NOTE: This therapy could be helpful for long haul Covid symptoms, if studies revealed sufficient efficacy…

References

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  12. Doonan J, Thomas D, Wong MH, et al. Failure of the anti-inflammatory parasitic worm product ES-62 to provide protection in mouse models of Type I Diabetes, Multiple Sclerosis, and Inflammatory Bowel Disease. Molecules. 2018;23(10):2669. Published 2018 Oct 17. doi:10.3390/molecules23102669
  13. Aprahamian TR, Zhong X, Amir S, et al. The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model. Int J Parasitol. 2015;45(4):203-207. doi:10.1016/j.ijpara.2014.12.006
  14. Huang X, Zeng LR, Chen FS, Zhu JP, Zhu MH. Trichuris suis ova therapy in inflammatory bowel disease: A meta-analysis. Medicine (Baltimore). 2018;97(34):e12087. doi:10.1097/MD.0000000000012087
  15. Leroux LP, Nasr M, Valanparambil R, et al. Analysis of the Trichuris suis excretory/secretory proteins as a function of life cycle stage and their immunomodulatory properties. Sci Rep. 2018;8(1):15921. Published 2018 Oct 29. doi:10.1038/s41598-018-34174-4
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The Bipolar Spectrum In Pain Patients: Recognition and Management

Olivia Lee and Lawrence Robbins, MD

Introduction to Bipolar Disorder

The broadening concept of the bipolar spectrum has evolved over the years. We no longer view bipolar primarily as characterized by mania. Bipolar disorder is a chronic psychiatric illness that is broadly categorized in the DSM-V into several subtypes – bipolar I and bipolar II – depending on the presence of depressive, manic, or hypomanic features. It may occur in at least 4.4% of the population, but this number is likely to underestimate the true prevalence.1 There are major issues in identifying the milder bipolar presentations.2 Bipolar disorder often co-occurs with other psychiatric illnesses, creating innumerable patient presentations that may not fit neatly into the boxes of the two subtypes. The word “bipolar” is misleading and creates a stigma of severe mental illness.  There certainly is underdiagnosis for the milder forms. Most patients do not suffer from classic manic symptoms. The milder “hypomanias” are subtle and mild in comparison to true mania. For most patients there is a significant lag time from the onset of milder bipolar symptoms and diagnosis.

The classic mania that defines bipolar I is easily recognized.  Symptoms of mania include euphoric mood, grandiosity, distractibility, flight of ideas, thoughtlessness or risk-taking, and excessive involvement in pleasurable activities (i.e., sex, gambling, spending). Patients in the midst of a manic episode may also take on an excessive number of activities and exhibit pressured speech, excessive speech, irritability, and insomnia.3 These behaviors cause serious impairment to daily functioning and often last for several days or longer. Acutely manic patients are also high risk for harm to themselves or others.4

Milder hypomania is less likely to impair everyday functioning. However, it is also hypomania that is more commonly missed for a variety of reasons.4 Hypomania and the milder end of the bipolar spectrum have various presentations, complicating the diagnosis. These patients may have persistently agitated personalities, with frequent depression or excessive energy but not meeting the classic diagnostic criteria for bipolar I or bipolar II. Brooding, irritable pessimism may be a manifestation of the milder end. They often have a family history of bipolar disorder or depression. Many do not identify or remember a clear hypomanic episode. Diagnosing and treating these patients greatly improves  quality of life and reduces mortality risk from suicide. The clinical stakes for missing bipolarity are enormous.

Speaking with a “significant other” is vital for teasing out mild hypomanic symptoms.4 Most patient simply complain of depression. Signs of mild bipolar disorder may include a history of early onset depression(prior to age 18), severe bouts of depression, rapid onset depression for no apparent reason, poor response to trials of antidepressants (including complaints of being up all night, mind racing, etc.), agitation, anger, high anxiety, hypersomnia or (less likely) insomnia, and irritability. Family history of severe depression, hospitalization, and other bipolar traits is helpful. The “bipolar reaction” to antidepressants may give insight into underlying bipolar disorder.4 Family history of a bipolar reaction to antidepressants may also be a clue. An opposite reaction to other drugs may be present, such as being anxious or wired from benzodiazepines or sleeping pills. Depression is often the primary problem in bipolar II disorder; it is much more pervasive than are the highs of hypomania. Comorbid moderate or severe anxiety may further compound impairment seen in bipolar depression and increase suicidal tendencies by up to 35%.5 Suicide and substance abuse are commonly found among those with untreated bipolar.

Comorbidity of Chronic Pain and Bipolar Disorder

Bipolar disorder patients who also suffer from chronic pain are challenging. Almost 24% of bipolar patients may present with chronic pain.6 The comorbid pain decreases quality of life. Patients with bipolar disorder and chronic pain often respond poorly to treatment and have an increased risk of suicide.6 One study that assessed the relationship between pain and bipolar disorder recommended a pain assessment as part of the routine care for patients suffering from bipolar.6  It requires a multidisciplinary approach to adequately treat these patients. Other than the pain physician/provider, psychotherapists constitute a vital part of the team.

Comorbidity of Migraines and Bipolar Disorder

The comorbidity of migraine with mood disorders has been well documented.  There have been a number of clinic based studies as well as epidemiologic samples from community populations.7 Migraine and depression share some of the same pathophysiology.  Antidepressants or mood stabilizers may alleviate both conditions. In the majority of migraine patients who suffer from depression, anxiety is a complicating factor. The anxiety disorder often precedes the age of onset of migraine, with depression following afterward. Migraine or other pain may exacerbate depression, and depression fuels migraine and pain.  This is in addition to the shared environmental and genetic factors linking migraine and depression.

Emerging data is identifying the relationship between bipolar disorder and migraine. From 25 to 35% of bipolar patients suffer from migraine as well.6  This association may be due to shared pathophysiologic mechanisms.

Treatment Approaches for Bipolar Disorder

It may take some time to find the effective medication, or medications, for a given patient. Mood stabilizers often are the mainstay of treatment, and sometimes help the  headaches. The anticonvulsants, lithium, and the atypicals constitute the 3 classes of mood stabilizers. Lamotrigine is the most commonly used antiepileptic for bipolar, but does not help headaches. Lamotrigine may be beneficial for some with neuropathic pain. Divalproex sodium is effective for mania, hypomania, depression associated with bipolar disorder, and for migraine prevention. Divalproex has been well studied for these conditions and is one of the most commonly used migraine preventives. Carbamazepine and oxcarbazepine are antiepileptics that have utility as mood stabilizers, but not for migraine prophylaxis. They may alleviate neuropathic pain. Oxcarbazepine is somewhat safer than the original carbamazepine. Gabapentin has been effective in high doses for some patients with milder bipolar symptoms. Gabapentin is effective for certain pain syndromes, but not for migraine.

Lithium carbonate is an underutilized mood stabilizer. Low doses of lithium do not usually cause hypothyroidism or irritate the kidneys. With appropriate monitoring these risks can usually be avoided.  Lithium sometimes alleviates cluster headaches.  Lithium has also been evaluated for conditions such as multiple sclerosis and Alzheimer’s.8

Divalproex sodium, carbamazepine, and oxcarbazepine may produce teratogenic effects. Divalproex is more likely than the others to result in birth defects, particularly at doses above 500mg daily. Lamotrigine may be the best choice of an antiepileptic during pregnancy.  Lithium taken during pregnancy is fetal cardiac anomalies, but this is rare.  Lithium may be indicated for bipolar during pregnancy disorder under appropriate circumstances.8–10 For women who were stable on lithium prior to pregnancy, discontinuation during pregnancy may lead to relapse.10

Atypical antipsychotics are also a mainstay for bipolar symptoms.11 These agents include the general categories of “pines”, “dones”, “pips” and “rips”. These include clozapine(the first atypical), olanzapine, quetiapine, risperdone, lurasidone,  brexpiprazole, aripiprazole, and cariprazine.These are efficacious in treating mania and are prescribed as monotherapy or in combination with another mood stabilizer.12 The atypical side effects are many and varied. These include metabolic syndrome (insulin resistance, dyslipidemia, hypertension), weight gain, fatigue, “brain fog”, and extrapyramidal symptoms (akathisia, acute dystonia, dyskinesia/parkinsonism, and tardive dyskinesia).13 Patients on atypical antipsychotics  should receive routine bloodwork.  Signs of EPS may go unnoticed by some patients, rendering it important to ask specific questions. There certainly are concerns about the atypical antipsychotics during pregnancy, but in low doses these have resulted in minimal problems in the newborns.

As previously mentioned, lamotrigine is a very commonly prescribed mood stabilizer for bipolar disorder. It is one of the only effective medications for bipolar depression.14 Initiating a patient on lamotrigine requires a slow titration due to the rare (1:3,000: according to the German rash registry) but lethal side effects of Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).15 SJS/TEN are variants of the same hypersensitivity reaction, differentiated by the percent of skin surface area that is affected (<10% in SJS, >30% in TEN). This rare rash is characterized by painful blisters, peeling skin, and tissue necrosis. The SJS rash often occurs in unusual areas, such as the palms of the hands, soles of the feet, or mucous membranes. A “regular” drug rash may occur in up to 10% of patients. Signs of SJS/TEN typically occur within 8 weeks of initiation and warrant immediate discontinuation of lamotrigine.15 Many of the anticonvulsants carry the risk of SJS/TEN, such as divalproex, carbamazepine, and oxcarbazepine.

 

Patients with bipolar spend the vast majority of their time in depression rather than in mania. Many of these patients require combination therapy to target depressive symptoms. Lamotrigine and quetiapine are two of the atypicals that may be effective in managing depressive episodes.16 While lithium is a first line therapy for mania, it has also shown efficacy in preventing relapse of depressive episodes and decreasing suicidality.16 Combination therapy of olanzapine and fluoxetine has been approved by the FDA for treating depression associated with bipolar I disorder.16 Lurasidone is an atypical that has shown promise for the depression.4,17 Antidepressants usually result in either no effect, or the typical “bipolar” response (up all night, wired, mind racing). Occasionally they are helpful. Emerging therapies include, among others, ketamine, TMS, and microdosing (primarily psilocybin).16

Conclusion

It is crucial to recognize psychiatric disorders in our pain patients. Patients with unrecognized personality disorders or bipolar disorder often suffer from poor outcomes. Patients with the milder end of the bipolar spectrum frequently are diagnosed and treated as if they suffer from “regular” depression. They generally do not do well on antidepressants.  Patients with psychiatric comorbidities, such as bipolar, require a multidisciplinary approach. The medications that treat psychiatric conditions may also be helpful for the pain conditions as well.

ABOUT THE AUTHORS

Olivia Lee is a fourth year medical student at Des Moines University. Her clinical interests include the interface of psychiatry and neurology. Lawrence Robbins is an associate professor of neurology, Chicago Medical School. He is in private (neurology and headache) practice in Riverwoods, Illinois. Lawrence has contributed to 390 articles/abstracts and written 5 books (on headache). Address correspondence to Lawrence Robbins at lrobb98@icloud.com.

Sources

  1. Harvard Medical School. National Comorbidity Survey (NSC).; 2007.
  2. Kessler RC, Wai TC, Demler O, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627.
  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington D.C: American Psychiatric Press; 2013.
  4. Culpepper L. The diagnosis and treatment of bipolar disorder: Decision-making in primary care. Prim Care Companion J Clin Psychiatry. 2014;16(3). doi:10.4088/PCC.13r01609
  5. Amuk OC, Patel RS. Comorbid Anxiety Increases Suicidal Risk in Bipolar Depression: Analysis of 9720 Adolescent Inpatients. Behav Sci (Basel). 2020;10(7). doi:10.3390/BS10070108
  6. Stubbs B, Eggermont L, Mitchell AJ, et al. The prevalence of pain in bipolar disorder: A systematic review and large-scale meta-analysis. Acta Psychiatr Scand. 2015;131(2):75-88. doi:10.1111/acps.12325
  7. KR M, DE S. Comorbidity of migraine and psychiatric disorders. Neurol Clin. 1997;15(1):115-123. doi:10.1016/S0733-8619(05)70298-X
  8. L L, B C, A N, et al. Lithium Use During Pregnancy in a Patient With Bipolar Disorder and Multiple Sclerosis. Clin Neuropharmacol. 2020;43(5):158-161. doi:10.1097/WNF.0000000000000407
  9. Jones SC, Jones I. Pharmacological Management of Bipolar Disorder in Pregnancy. CNS Drugs. 2017;31(9):737-745. doi:10.1007/s40263-017-0452-x
  10. Yacobi S, Ornoy A. Is lithium a real teratogen? What can we conclude from the prospective versus retrospective studies? A review. Isr J Psychiatry Relat Sci. 2008;45(2):95-106.
  11. JR C, PE K, W M, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351-1360. doi:10.1176/APPI.AJP.162.7.1351
  12. Canadian Agency for Drugs and Technologies in Health. Combination Atypical Antipsychotics in Adolescents or Adults with Bipolar Disorder with Psychotic Features: A Review of Clinical and Cost-Effectiveness and Guidelines.; 2016. https://pubmed.ncbi.nlm.nih.gov/27831672/. Accessed August 15, 2021.
  13. Stroup TS, Gray N. Management of Common Adverse Effects of Antipsychotic Medications. doi:10.1002/wps.20567
  14. Ng F, Hallam K, Lucas N, Berk M. The Role of Lamotrigine in the Management of Bipolar Disorder. Vol 3.; 2007.
  15. Messenheimer J, Mullens EL, Giorgi L, Young F. Safety review of adult clinical trial experience with lamotrigine. Drug Saf. 1998;18(4):281-296. doi:10.2165/00002018-199818040-00004
  16. Yalin N, Young AH. Pharmacological treatment of bipolar depression: What are the current and emerging options? Neuropsychiatr Dis Treat. 2020;16:1459-1472. doi:10.2147/NDT.S245166
  17. Ostacher M, Ng-Mak D, Patel P, Ntais D, Schlueter M, Loebel A. Lurasidone compared to other atypical antipsychotic monotherapies for bipolar depression: A systematic review and network meta-analysis. World J Biol Psychiatry. 2018;19(8):586-601. doi:10.1080/15622975.2017.1285050

President’s Message: Running Headlong into what You Thought Was Behind You

Harry J. Gould, III, MD, PhD

With the FDA’s blessing in mid-December on the administration of vaccines for COVID-19 and subsequent indications of downward trends in the rate of infections, hospitalizations and deaths associated with the virus came a feeling that the worst of the pandemic was past and we were on a return path to recover normalcy. Even with large numbers of individuals that chose not to be vaccinated, the falling numbers reflecting the impact of disease were encouraging and many businesses, organizations, and individuals began to abandon mitigation practices, i.e., social distancing and masking, and began returning to former practices and patterns of behavior. In-person visits in clinical practice began to replace the virtual platforms and we were again able to apply our mitigating strategies for reducing medication misuse, abuse and diversion, thereby lessening some of the provider’s anxiety associated with the impaired ability to identify potential problems related to opioid management.

Indeed, the Southern Pain Society’s (SPS) planning committee for the 2021 Annual Meeting, upon reviewing the trends in societal response to the vaccines, was cautiously optimistic and was looking forward to being able to hold our annual meeting in-person. Despite the committee’s best efforts to plan and deliver an informative and thought-provoking meeting that might also serve as an indicator that we were on the mend, the trend in disease statistics foreshadowed a lack of support for these efforts.  Due to the establishment and spread of variants of COVID-19 in the population, the rate of infections, hospitalizations and deaths shifted and by mid-August had returned to, and in many places surpassed, levels that had been recorded at the peak of the first wave of the pandemic.  By the late August, elective procedures and in-person appointments in clinics were again being replaced by virtual visits.  As a professional organization, the SPS could no longer be reasonably certain about ensuring individual safety for our participants, chose not to put individuals at risk of becoming seriously ill and postponed the 2021 meeting; perhaps a fortuitous decision in light of the additional complications imposed by Hurricane Ida.

The distractions of the last 18 months have emphasized the importance of maintaining and expanding efforts to improve patient safety and reliably delivering appropriate and effective care even in the face of adversity. As the pandemic continues, the SPS is expanding efforts to maintain and offer new opportunities to share ideas and express concerns, challenges, and potential solutions for the challenges facing our patients and practices. In offering opportunities to support scholarly activity and communication, like the recent virtual forum for abstract presentations.  We hope to encourage those with the wisdom and experience accrued through years of experience and those new to the field of pain medicine to come together and share ideas and experiences and hopefully create a forum for inquiry that will foster the pursuit of a better understanding of complex condition we strive to treat; its proper assessment; and optimal treatment options supported by evidence necessary for making the most appropriate management decisions.  I encourage you to follow our newsletter and postings on social media for opportunities as we continue to monitor the pandemic and set our sights on the future when we will be able to meet again with the pandemic behind us, even stronger than before. 

Long Haul COVID-19

Olivia Lee and Lawrence Robbins, MD

Introduction

Over 325 million doses of COVID-19 vaccines have been distributed in the United States, and much of the country is looking forward to a return to normalcy. For many, the widespread access to vaccines signaled the pandemic’s defeat, but for millions of COVID-19 survivors, the sequelae following acute infection will trouble them long after the country has returned to its normal state of affairs.

Recent studies have reported that up to 30% of COVID-19 patients experience persistent symptoms in the months following acute illness.1 Lingering myalgias, joint pains, headaches, shortness of breath, fatigue, dizziness, cardiac issues, and brain fog are just some of the reported symptoms.  These often continue long after the virus has been cleared from its host.2 Patients who experience lingering symptoms are collectively termed COVID-19 long-haulers, and diagnostic tests to quantify their disease status are being explored. Long haul COVID-19 has emerged as a growing challenge for physicians, who are working to identify effective treatment strategies for these chronic complications. This paper serves to briefly highlight diagnostic and therapeutic developments in the management of long haul COVID-19.

Demographics of Long Haul Covid Patients

Researchers have begun to establish a general profile of people with long hauling effects of COVID-19.. This may help identify those who are at the greatest risk for developing these chronic COVID-19 complications. Various studies have supported the notion that long haul COVID-19 disproportionately affects patients of older age, higher body mass index, female sex, or those with preexisting asthma.2,3 Female COVID-19 long-haulers are more likely than males to report anxiety, low mood, myalgia, fatigue, insomnia, and memory impairment.4

One study published in 2021 separated the most common symptoms into three “clusters” based on co-occurrence: Cluster A included myalgia and fatigue, Cluster B included low mood, anxiety, and sleep disturbance, and Cluster C included memory impairment, cognitive impairment, and attention deficit.4 Several reports indicate that the likelihood of experiencing these lingering symptoms may be independent from the severity of the acute COVID-19 infection. This suggests that the severity of the acute infection is not a reliable indicator of the risk for developing chronic complications.1,4

Diagnostic Measures

Currently there are no accepted diagnostic tests for long haul COVID-19.  Diagnosing this condition is dependent upon the patient’s history.5 Many COVID-19 long-haul symptoms are nonspecific and could be attributed to other conditions. Long haul COVID-19 is a diagnosis of exclusion. Alternative explanations for a patient’s nonspecific symptoms must first be considered.

Some studies have identified pro-inflammatory markers as being associated with long term COVID-19 illness. Increased levels of pro-inflammatory markers found in long haul patients include CRP, TNF-alpha, IL-1α, IL-1β, IL-6, IL-17A, IL-18, MCP-1, natriuretic peptides, ferritin, troponin, and D-dimer. 2,5,6 These biomarkers are nonspecific and present in other inflammatory conditions. The inflammatory markers have to be interpreted with caution. There are several papers that describe a paucity of pro-inflammatory markers in suspected cases of long haul COVID-19.2 The reasons for these inconsistencies is unknown and warrants further analysis. Despite this conflicting information, it may still be worthwhile to examine pro-inflammatory markers in suspected long haul COVID-19 patients.5 While these markers do not definitively diagnose long haul Covid-19, they provide supporting evidence.

Additionally, the biopsychosocial impact of COVID-19 long haul symptoms is an important consideration. Experiencing brain fog, fatigue, anxiety, depression, and other symptoms will generate more anxiety and depression.  The long haul syndrome sometimes resembles the post-traumatic syndromes observed following the Gulf War and 9/11.4 Thus, a psychological assessment may be indicated in evaluating cases of long haul COVID-19 to determine whether there are neuropsychiatric components that contribute.

Treatments

Several medications are undergoing clinical trials for treating long haul COVID-19: C-C Chemokine Receptor Type 5, (CCR5) antagonists, antiparasitics, and monoclonal antibodies. Physicians at various treatment centers report repurposing medications (including maraviroc, ivermectin, and leronlimab) for treating COVID-19 long-haulers. They provide mixed accounts of the efficacy of these medications. Ivermectin,  an antiparasitic medication, has demonstrated promising results in treating long haul COVID-19.7,8 Its clinical benefits in long-haulers may be attributed to its modulating effects on the immune system. Ivermectin’s suppression of IL-6 may be a key to its benefit.7

Psychotherapy may be helpful in dealing with the devastating consequences of COVID-19. Other avenues such as multi-disciplinary rehabilitation have demonstrated success in subsets of COVID-19 long-haulers. These interventions include stretching, light aerobic activity, breathing exercises, physical therapy, and behavior modification.2 These multi-disciplinary approaches are able to tailor the treatment plan to the individual. There are a growing number of clinics specializing in evaluating and treating long haul patients. 

Vagus nerve stimulation, used for headaches, epilepsy, and depression, has recently been explored as a potential adjunctive therapy for long-haul COVID-19 9. There are reports of improvement in COVID-19 long-haulers undergoing non-invasive vagus nerve stimulation.10,11

Conclusion

Physicians are in the early stages of understanding how to effectively manage long haul COVID-19. Researchers have begun to characterize the profile of long-haulers. Clinical assessment currently depends primarily upon patient histories. Scientists and long haul COVID-19 treatment centers are conducting research into the immune status of long haulers. A vigorous autoimmune response seems to be the likely culprit for the majority of symptoms.  Several pharmaceutical interventions are undergoing clinical trials, but there are no definitive results at this point. Many of the current recommendations are targeted towards symptom management.  Over time recommendations for testing and therapy will emerge.

About the authors: Olivia Lee is a fourth year medical student at Des Moines University. Her clinical interests include the interface of psychiatry and neurology. Lawrence Robbins is an assistant professor of neurology, Chicago Medical School. He is in private (neurology and headache) practice in Riverwoods, Illinois. Lawrence has contributed to 380 articles/abstracts, and written 5 books (on headache). Address correspondence to Lawrence Robbins at lrobb98@icloud.com.

Resources

  1. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months after COVID-19 Infection. JAMA Netw Open. 2021;4(2). doi:10.1001/jamanetworkopen.2021.0830
  2. Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (London, England). 2021:1-18. doi:10.1080/23744235.2021.1924397
  3. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631. doi:10.1038/s41591-021-01292-y
  4. Sykes DL, Holdsworth L, Jawad N, Gunasekera P, Morice AH, Crooks MG. Post-COVID-19 Symptom Burden: What is Long-COVID and How Should We Manage It? Lung. 2021;199(2):113-119. doi:10.1007/s00408-021-00423-z
  5. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ. 2020;370. doi:10.1136/bmj.m3026
  6. Xiao N, Nie M, Pang H, et al. Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications. doi:10.1038/s41467-021-21907-9
  7. Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of Ivermectin against SARS-CoV-2: An evidence-based clinical review article. J Antibiot (Tokyo). June 2021:1-13. doi:10.1038/s41429-021-00430-5
  8. Aguirre-Chang G, Castillo Saavedra E, Yui Cerna M, Trujillo Figueredo A, Cordova Masias J. Post-Acute or Prolonged Covid-19 : Treatment With Ivermectin for Patients With Persistent , or Post-Acute Symptoms. ResearchGate. https://www.researchgate.net/publication/344318845_post_acute_or_prolonged_COVID-19_ivermectin_treatment_for_patients_with_persistent_symptoms_or_post_acute. Published 2020. Accessed June 29, 2021.
  9. Azabou E, Bao G, Bounab R, Heming N, Annane D. Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19. Front Med. 2021;8:625836. doi:10.3389/fmed.2021.625836
  10. Silberstein S. Non-Invasive Vagus Nerve Stimulation May Treat Migraine in Patients with COVID-19, According to Neurologist Stephen D. Silberstein, M.D. | Business Wire. https://www.businesswire.com/news/home/20210216005737/en/. Published February 16, 2021. Accessed June 27, 2021.
  11. Lawson A. MUSC study to address post-COVID neurological and psychiatric symptoms using at-home format | MUSC | Charleston, SC. https://web.musc.edu/about/news-center/2020/11/16/musc-study-to-address-post-covid-neurological-and-psychiatric-symptoms-using-at-home-format. Published November 16, 2020. Accessed June 27, 2021.

ANA2021 Registration Is Now Open!

ANA2021’s Virtual Annual Meeting is set for October 17-19 with an Opening Symposium on October 16 and registration is now open!

All full registrations include access to the ANA2021 Meeting Recordings package, ensuring you won’t miss out on the latest neurological research even if your schedule should change. Registration also includes complimentary access to the SIG Series featuring virtual presentations related to ANA’s Special Interest Groups. These 18 sessions will be presented on select dates throughout November and December so you can attend as many as you’d like. 

 

ANA2021 is the top meeting for academic neurologists and neuroscientists at every career stage to convene over groundbreaking research and best practices for success in the field. Click here to view the Advance Program. 

 

Don’t miss this opportunity to learn from and connect with the best and brightest in the field – register for ANA2021 today!

Adverse Effects and Clinical Trials: The System is Broken

The CGRP Monoclonal Antibodies for Migraine Are a Prime Example

Lawrence Robbins, M.D.

This letter is in response to an excellent July, 2020 article “Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile” (Boldig and Butala) in the International Journal of Neurology and Neurotherapy. (1) There are a plethora of adverse effects (AEs) from the CGRP monoclonals (mAbs) that were not identified in the Phase 3 trials. Unfortunately we frequently encounter this with new drugs. It often takes several years to identify an accurate picture of the adverse effect profile.

The package insert (PI) for the CGRP mAbs, as with many of the new drugs, identifies few AEs. The reasons for this include:  1. trial investigators did not use a checklist of AEs (a checklist is almost never utilized during drug trials) 2. as with most drug trials, the studies were powered for efficacy but would need many more patients to accurately assess AEs 3. the studies do not extend long enough in order to identify the true adverse effect profile and 4. adverse effects become “disaggregated”.  For instance, one person may say they have malaise while another may state they suffer from fatigue. This adverse effect is disaggregated and subsequently not included in the PI. After the study is completed these effects may be reaggregated, but that method is not accurate.

To accurately assess AEs post-approval, we must examine multiple lines of evidence. The FDA/FAERS website is an important source of information. Unfortunately, the side effects listed are adverse events, not necessarily adverse effects. As of January 2021, (2.5 years post-launch) there were 40,378 adverse events catalogued from the four CGRP mAbs.  On the FDA website, serious adverse events include those that are life threatening, or that resulted in hospitalization. 5,562 serious adverse events were listed. These numbers are staggering, particularly considering that the vast majority of adverse effects, even serious ones, go unreported.  Erenumab resulted in the bulk of the adverse events. This is most likely because erenumab was the first to market and has been the CGRP mAb most widely utilized. Save for constipation, I do not believe that erenumab is necessarily more likely to produce adverse effects than are the other 3 mAbs. 

After the launch of the drug, another line of evidence is the available post-approval studies and case reports.  One of the observational studies concluded that adverse effects resulted in 33% of erenumab discontinuations (2). Another study described 63.3% of patients as having reported an adverse effect, but they concluded that the CGRP monoclonal antibodies were well tolerated. (3)

We published a study of 119 chronic migraine patients who had utilized one of the CGRP monoclonals. (4) We incorporated a checklist of 19 possible adverse effects. The patients were initially asked about adverse effects by posing the question, “Have you experienced any issues, problems, or side effects from the injection?” Subsequently the patients were interviewed regarding each possible adverse effect, utilizing the checklist. A determination was made, between the patient and researcher, as to whether the adverse effect was truly due to the use of the monoclonal. 66% of the patients identified at least one additional adverse effect via the use of a carefully chosen checklist. 18 patients had one additional adverse effect. 56 patients identified 2 to 8 additional adverse effects.

An additional line of evidence is the opinion of high prescribers of the drug. This is gleaned from chat boards of headache providers, private correspondence, and discussions during conferences. Some headache providers feel that the CGRP monoclonals are safe and adverse effects are infrequently encountered. Others believe, as I do, that the mAbs result in a number of deleterious effects.  There is no consensus at this time.

In addition to headache provider comments, the CGRP patient chat boards provide valuable insight into adverse effects. We assessed 2,800 patient comments regarding adverse effects. We judged 490 to be highly believable. The list of common adverse effects, as identified by the highly believable comments, aligns well with our other lines of evidence.

 After assessing the various post-approval lines of evidence, there are signals that the following adverse effects may result from the use of CGRP monoclonals: constipation, anxiety, injection site reactions, weight gain or loss, worsening hypertension, increased headache, insomnia, depression, hair loss, joint pain, fatigue, irritability, muscle pain or cramps, nausea, rash, sexual dysfunction, and tachycardia (or other heart irregularities).  Most likely there are others as well.  In addition, there have been cases of reversible cerebral vasoconstriction syndrome and stroke. Angina and myocardial infarction have also been reported. Thomas Moore, a leading expert in the acquisition of adverse effects of drugs, published a review of the CGRP monoclonals in the online journal QuarterWatch. QuarterWatch utilizes various resources, including FDA reports and published post-approval studies. (5) The report cites the “sheer number of case reports,” and concludes that “…it is likely that adverse effects of this migraine preventive were underestimated in the clinical trials.”

This discussion has revolved around short-term adverse effects. Long-term effects, which are unknown at this time, remain a serious concern. CGRP has been important in various species for 400 million years. We ignore evolution at our peril. There are a multitude of beneficial effects partially mediated by CGRP. These include protecting our cardiac and cerebrovascular systems through vasodilatory effects(particularly during stressful conditions), resisting the onset of hypertension, decreasing oxidative stress in the aorta, improving circulation in the face of heart disease (including heart failure), aiding with wound healing, burns, and tissue repair, minimizing the effects of sepsis, aiding in the healing of GI ulcers, protecting the GI mucosa, affecting GI motility, contributing to flushing and thermoregulation, aiding with cold hypersensitivity, regulating bone metabolism, protecting the kidneys in certain pathologic conditions, playing a role in regulating insulin release, affecting metabolism and body weight, and helping to mediate the adrenal glucocorticoid response to acute stress in the mature fetus. (6) The hypothalamic-pituitary-adrenal axis may be affected by CGRP, and this has not been adequately studied. If these mAbs are to be used in adolescents, we must first study the hormonal effects.

 The package inserts often do not reflect the reality of the AE profile. I believe that the FDA should overhaul the guidelines as to how adverse events are acquired in formal studies. This situation has been harmful to patients. This is not unique to the mAbs. We should work towards improving the early identification of an accurate adverse effect profile. Certain adverse effects, such as sexual adverse effects, or depression, are missed in formal studies.

The CGRP monoclonal antibodies have been beneficial for many migraineurs. The efficacy of these mAbs rivals that of onabotulinumtoxinA. However, CGRP plays a crucial role in many physiological processes. There is evidence for a multitude of deleterious effects that result from blocking CGRP. Long-term effects are completely unknown. We should be cautious and judicious in our use of the CGRP monoclonal antibodies.

Disclosure: L. Robbins is a speaker for Abbott Labs, Teva, and Amgen.

 

References

 

  1. Boldis K, Butala, N (2020) Migraine and CGRP Monoclonal Antibodies: A Review of Cardiovascular Side Effects and Safety Profile. International Journal of Neurology and Neurotherapy 7:101: DOI:10.23937/2378-3001/1410101
  2. Robblee J, Devick K, et al. (2020) Real-World Patient Experience with Erenumab for the Preventive Treatment of Migraine.  Headache 60:9, p. 2014-2025. https://doi.org/10.1111/head.13951
  3. Alex A, Vaugh C., Rayhill M (2020) Safety and Tolerability of 3 CGRP Monoclonal Antibodies in Practice: A Retrospective Cohort Study. Headache 60:10, p. 2454-2462. https://doi.org/10.1111/head13956
  4. Robbins L, Phenicie B, (2020) CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using a Checklist. Practical Pain Management 20:2, p. 48-52.  (online at practicalpainmanagement.com, March/April, 2020)
  5. Moore T. (2019) Aimovig, Ajovy, and Emgality. QuarterWatch Reports 24:16, p. 2-4.
  6. Robbins L (2018) CGRP Antagonists: Physiologic Effects and Serious Side Effects (Letter). Headache 58:9, p. 1469-1471.

Back to the Basics: Managing Pain Months After COVID-19

Harry Gould, MD, PhD

A year ago, the United States was in the midst of understanding and dealing with the complexities of the “Opioid Epidemic”, what until then had been considered the greatest healthcare crisis in U.S. history. Although improvements in some aspects of the crisis were starting to be realized as a result of the development of best evidence-based practice guidelines and the implementation of regulatory mandates for prescribing and monitoring treatment response, we were a long way from achieving our goal; to provide optimum care and improve quality of life for those in pain without causing harm to the patients, the healthcare system or society as a whole.

In many cases, the strides that had been made in mitigating the opioid crisis did not come without their own problems. The change of assessment, prescribing and monitoring standards imposed an unacceptable burden on many well-meaning physicians, who wished to help without harming their patients, but realized that compensation for the time necessary to comply with essential regulatory demands was inadequate. Because compensation issues were accompanied by fear of reprisal for non-compliance, many chose not to provide care for their patients’ pain problems, thus limiting patients’ options for identifying resources for appropriate evaluation and management of ongoing and persistent problems or for complications associated with previous inappropriate misuse, abuse or prescribing of treatments. The resulting uncertainty of care set the stage for frustration, stress, anxiety, anger and depression, each confounding factors in the management of uncontrolled pain.  

If addressing these options weren’t enough of a challenge, a new crisis, “the 2019-nCoV virus (COVID-19) pandemic” emerged in the population. The virulence of the virus, the uncertainty about its course and management, the frustration, stress and depression associated with individual isolation and distancing and the additional limitations on access to proper evaluation, delays in initiating possible condition-limiting treatment, follow up and monitoring of patients requiring controlled medications acutely added to the already present confounding factors that have hindered optimal recovery from the opioid crisis for both patients and practitioners alike.

Unfortunately, the distribution of promising new vaccines and potential control of the current pandemic may not completely eliminate the negative influence that the virus has had on delivering pain care. We are learning that a significant number of individuals, the “long-haulers,” who have survived a COVID-19 infection report experiencing persistent cardiac, pulmonary, renal, psychologic and neurologic problems consistent with direct or indirect multisystem injury as a result of the virus. The distribution and mechanism of injury producing the pain is unknown and likely multifactorial, but presentations are frequently multifocal and possess features of nociceptive and neuropathic pain with a hint of psychogenic quality consistent with organic central and/or peripheral nervous system involvement and the influence of post-traumatic psychosocial stress associated with contracting and fighting the disease. Optimal management of these complex pain problems will likely require a return to the basics promoted by John Bonica and others, that of a comprehensive and multimodal evaluation and the orchestration of pharmacologic, interventional, physical and psychological treatment modalities at all levels of the healthcare system.

As incoming president of the Southern Pain Society, I look forward to–and encourage others to work with me to — learn from healthcare providers and basic and clinical scientists from all specialties to improve and refine assessment skills, to identify viable treatment options and management planning and to provide continued education for clinicians in practice and those new to the field, in the hope of optimizing the quality of life for patients in pain.

Case Sample: Bipolar, Chronic Migraine, Epilepsy, and IBS-D

Lawrence Robbins, MD

Individuals suffering from chronic pain often have psychiatric comorbidities. For instance, among those with chronic migraine approximately 9% fit into the bipolar spectrum. (1) This article discusses a representative case of a patient with chronic migraine and bipolar disorder as well as epilepsy and irritable bowel syndrome.

Caitlin is a 28-year-old female who has experienced frequent depressive states since age 14. Caitlin finally was diagnosed at age 26 to be on the mild end of the bipolar spectrum (DSM-5: Other Specified Bipolar and Related Disorder: 296.89). She presents with her depression in remission. She is on quetiapine 50mg and 100mg of lamotrigine, each once per day.  

The patient has moderate chronic migraine and describes daily mild to moderate daily headache. She has a moderate migraine twice weekly, and a severe migraine attack once a month. She takes 8 OTC aspirin/acetaminophen/caffeine tablets (Excedrin) daily.

Caitlin reports significant occipital and neck pain. She has had tonic-clonic epilepsy since age 12. Her seizures are infrequent, and since being placed on lamotrigine she has had no further seizures. Caitlin also has moderate irritable bowel syndrome, primarily with diarrhea (IBS-D).

Work-up as negative, including MRI of her brain, routine blood tests (including thyroid), and the neurology examination.

What Additional History May be Helpful?

In this case scenario, relevant factors to consider and further investigate include:

  • Frequency and severity of the patient’s headaches
  • the past response to medications and family history of response (family history of medication response brings in the “placebo by proxy” and “nocebo by proxy” responses)
  • Potential sensitivities or side effects to medications
  • Psychiatric comorbidities
  • Medical comorbidities
  • GI issues (in this case, IBS-D)
  • Any complaints related to sleep, fatigue, or insomnia
  • The patient’s job requirements, social support, and any financial/insurance concerns that may impact her treatment
  • Patient preference for medication (eg, they may not wish to take daily medication, or may request to use natural remedies)

In addition, a history of the specifics of this patient’s depression would be helpful. The details of her moods, hypomanic symptoms, triggers, etc. are important if an adjustment to psychiatric medication is appropriate. (2)

Is the Patient Suffering from Medication Overuse Headache?

It is also worth considering whether the patient may have medication overuse headache (MOH) which is often conflated with medication overuse (MO). Medication overuse is arbitrarily viewed as consuming certain abortive medications (eg. combination analgesics, triptans, opioids, butalbital compounds) at least 11 days per month. If patients simply take NSAIDS, MO is defined as consuming the NSAIDS at least 15 days per month.

A determination of MOH is more complex as it tends to be poorly defined and over-diagnosed. (3) To determine if MOH is present, a careful history has to be taken as to the effect the drug had on the person’s headaches. The drug (in this case, Excedrin) must be withdrawn to see if the headaches improve. Caitlin reports taking 8 Excedrin on a daily basis, each of which contains 65 mg of caffeine. It would be helpful to determine how much additional caffeine she consumes.

We should attempt to limit her caffeine intake to 150 or 200 mg daily. While small amounts of caffeine help many patients, other migraineurs cannot tolerate even minimal amounts. 

To read the rest of this article, please click here

https://pro.psycom.net/psychopharmacology/case-bipolar-migraine-epilepsy

In Memory and Appreciation: Dr. John Satterthwaite

Ann Quinlan-Colwell, PhD, APN

It is with deep sadness that we recognize the life and contributions of  John Satterthwaite, MD who transitioned from this earthly world last month.  John’s perspective on the history and devotion to the mission of SPS were priceless. Many have no doubt that the SPS would not exist today it were not for the careful nurturing and stewardship of John during the last 34 years.  During those years, like the captain of a beloved ship he steered and guided SPS as he served as treasurer and  historian. 

As important as his contribution in those roles, John was so much more to many of us in the SPS.  Through his teaching, mentoring, guidance, and voice of reason, he significantly impacted numerous SPS members in ways that can never be repaid.  Not only was John a man of many talents who contributed greatly to the world of pain management but he had paradoxical qualities as well.  Although he was often a wise sage when on the stage, he was equally comfortable and meaningful being the guide on the side.  He was often a man of few words yet a great storyteller with an amazing sense of humor..

John was an expert physician, teacher, patriarch, sage, guide, shepherd, steward, mentor, storyteller,  navigator, voice of reason, friend, and so much more. You will be greatly missed, our dear friend.

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